Rheumatology ElMenawy 2021

2021
Basic Rheumatology
Mustafa Elmenawy
Basic Rheumatology Mustafa Elmenawy
CONTENT
Rheumatoid Arthritis 1-42

Juvenile Idiopathic Arthritis 43
Spondyloarthropathy 63
SLE 127
Antiphospholipid antibodies Syndrome 191
Sjogren syndrome 199
Systemic sclerosis 215
Raynaud’s Disease 241
Vasculitis 249
Autoinflammatory Diseases 299
Osteoarthritis 321
GOUT & CPPD 349
Metabolic Bone Diseases 387
Fibromyalgia 439
Mustafa Elmenawy
Basic
Rheumatology
Rheumatoid Arthritis
Rheumatoid Arthritis
Definition: Rheumatoid arthritis (RA) is a chronic systemic autoimmune inflammatory
disease of the synovium that lead to destructive changes in the joints.
Epidemiology:
• Prevalence: The overall prevalence of RA is 1% to 2% of population
• Incidence: 0.5 per 1000 persons per year (in the United States).
• Age of onset: RA can occur at any age, but the typical age of onset in females is
around 40 years (late child bearing years), while occurs in males usually after the
age of 50.
• Sex: Females are affected 3 times more than males.
Clinical Findings
➢ Onset: Insidious (builds up over several weeks to months)
A-General manifestations: Fatigue, possible weight loss &low-grade fevers.
B- Articular Manifestations:
 Distribution of involved joints:

✓ Polyarticular peripheral symmetrical arthritis with centripetal extension.
✓ Start in PIP joints, MCP joints, MTP joints, wrists and ankles joints.
✓ There is proximal spread to large joints (knee & elbow) with sparing of
DIP joints.
 Symptoms :
✓ Pain, swelling & Morning stiffness lasting more than an hour (hallmark symptom of RA).
✓ The PIP, MCP, and MTP joints are the most commonly affected.
✓ Patients with early disease often report:
• Running warm water over their hands to "get them working."
• Pain in the ball of the foot (metatarsalgia) upon arising from bed.
• The rings no longer fit with widening of the forefoot necessitating an
increase in shoe size due to inflammation of the MTP joints.
• Routine activities like brushing teeth and combing hair may be very
difficult early in the morning.
Rheumatoid arthritis 1
Hand examination Foot examination

• Early: • Early:
✓ Hand swelling which is indicative of active ✓ Foot swelling & tenderness indicative of
synovitis. active synovitis which involve:
✓ Fusiform fingers due to swelling of PIP joints • MTP (a widened and puffy forefoot,
(early finding). and frequently splaying of the toes)
• The tibiotalar joint (which mediates
✓ Dorsal wrist swelling.
flexion and extension).
✓ The affected joints appears hot, tender, swollen • The Talonavicular joint (which
with limitation in ROM. mediate inversion and eversion of the
• Then: ankle).
1. Ulnar deviation at MCP joints. • Then:
➢ Cause: Weakening of the extensor carpi ulnaris A. Forefoot:
2. Radial deviation at wrist joints (due to 1. Hallux valgus: lateral deviation big toe
chronic synovitis). at MTP.
3. Swan neck deformity (hyperextension of the 2. Claw toe or hammer toe: This is
PIP joints& flexion of DIP joints). caused by inflammation of the MTP
➢ Cause: Contraction of the flexors (intrinsic joints leading to subluxation of the
muscles) of the MCPs. metatarsal heads ➔ Difficulty fitting his
4. Boutonnière deformity (hyperextension of or her toes into the shoe ➔ Callous or
the DIP joints& flexion of PIP joints). ulcer formation.
➢ Cause: Weakening of the central slip of the B. Midfoot:
extrinsic extensor tendon and a palmar 1. Flat foot: collapse of transverse arch.
displacement of the lateral bands. 2. Metatarsalgia: Pain on the balls of the
5. Z deformity of the thumb (flexion of MCP feet.
joints & hyperextension of the IP joints). 3. Calluses on the inferior surface of the
➢ Cause: : Subluxation of the extensor pollices longus foot: due to displacement of the soft
tendon tissue pad that normally sits
6. Piano sign (prominent tender ulnar styloid underneath the metatarsal heads.
process). C. Hindfoot:
➢ Cause: : Hyperlaxity or rupture of ulnar collateral 1. Valgus deformity of hindfoot: increase
ligament. Talocalcaneal angle due to arthritic
7. Rheumatoid nodules on tendons. involvement of the tarsal joint and
subtalar joint
• Later on 2. Tarsal tunnel syndrome due to synovial
✓ Joint deformity, decreased range of motion, hypertrophy.
Malalignment, or frank dislocation is 3. Tenosynovitis and frank rupture of the
indicative of joint damage. posterior tibialis tendon (inferomedial to the
medial malleolus) >>> resulting in disabling
heel valgus and chronic pain.
 Other joints involvement:

➢ Knee joint: (common in RA)
✓ Large knee effusions may herniate posteriorly, creating popliteal (Baker’s) cyst.
➢ Hip joint: (in 20% of patients).

✓ Synovitis in the hip typically causes groin, thigh, buttock, low back, or referred
ipsilateral knee pain.
✓ Early hip involvement may be asymptomatic.
➢ Temporomandibular joint.: Patients complain of jaw pain or jaw claudication (DD: tooth or
ear problems, giant cell arteritis with polymyalgia rheumatic).
➢ Sternoclavicular joint.
➢ Cricoarytenoid joint: (diarthrodial joints responsible for rotation of the vocal cords as they abduct and adduct)
✓ With cricoarytenoid joint involvement in RA, a patient may complain of new-
onset hoarseness, sore throat, dysphagia, or pain with speech.
✓ In extreme cases, the vocal cords can become immobilized in an adducted
midline position, resulting in inspiratory stridor.
✓ Laryngoscopy and CT scanning are the most sensitive methods to evaluate
for cricoarytenoid arthritis.
✓ In this latter situation, emergent tracheotomy may be lifesaving.
Extra-Articular Manifestations
usually occurs in sero +ve patients
1-Neurological manifestations:
✓ Cervical Spine:
o Early: neck pain & stiffness due to tenosynovitis of the transverse ligament of
C1, which stabilizes the odontoid process of C2.
o Later on: cervical myelopathy due to sublaxation of atlanto-axial joint &
upper cervical joint which results spinal cord and root compression
(myelopathy).
o +ve L,hermittes sign: flexion of the cervical spine ----→ sudden development
of tingling paraesthesia that descend the thoraco-lumbar spine.
o Sublaxation of atlanto-axial joint result from erosion of the odontoid process and/or attrition and rupture of the
transverse ligament.
✓ Entrapment neuropathy: carpal tunnel syndrome and tarsal tunnel syndrome

which result from synovial hypertophy.
✓ Peripheral neuropathy & Mononeutitis multiplex: due to small vessel vasculitis

& presenting as wrist or foot drop.
✓ Depression.
2- Ocular manifestations:(The most common extra-articular manifestation of RA) >>> in 35% of patients:
A- Sjögren’s syndrome: (2ry) Manifested by dry eyes & dry mouth.
B-scleritis& Uveitis.
3- Rheumatoid nodules(subcutaneous nodules) >>> in 25% of patients:

✓ Small firm nodules, Not painful, Not tender, Not adherent to the skin.
✓ Site:
• Over bony prominence & extensor surface, in relation to tendon sheath
(particularly forearms).and also over Achilles tendons, fingers, scalp, and ischial
tuberosities.
• Rarely they develop in viscera (lungs and heart, for example) or in the sclera
of the eye.
✓ Histology: Central fibrinoid necrosis surrounded by lymphocytes and epithelioid
cells in palisade arrangement.
✓ Differential diagnosis: Tophi – Xanthomas – Garrod knuckle pads with
dupuytren contractures – Rheumatic fever - MTX induced accelerated nodulosis.
4- Cardiovascular manifestations:
✓ Pericarditis & Pericardial effusions are the most common.
✓ Constrictive pericarditis.(uncommon & occurs with long standing disease).
✓ Rarely, rheumatoid nodules develop in the conduction system and cause heart
block.
5- Pulmonary manifestations:
➢ Pleurisy& pleural effusions.
➢ Parenchymal diseases:
1. Diffuse interstitial pulmonary fibrosis:
▪ Most common ILD type in RA
▪ Risk factors: Older patient, male, RF +ve, Anti-CCP +ve and Smoking
▪ Symptoms: usually asymptomatic - Patient can have exertional
dyspnea,unproductive cough, clubbing and cyanosis
▪ Signs: Bibasilar late inspiratory crackles (Velcro rales).
2. Pulmonary nodules: Rheumatoid nodules in the lung they are usually solid but
may calcify, cavitate, or become infected).
3. Caplan’s syndrome: RA+ multiple pulmonary nodules+ Pneumoconiosis.
4. Bronchiolitis obliterans: also called constrictive bronchiolitis. Patients have

dyspnea,hyperinflated chest x-ray, and small airway obstruction on PFTs.
5. Bronchiectasis.
6- Cutaneous manifestations:
✓ Fingers ulcers which result from small vessels vasculitis.
✓ Raynauds phenomenon.
✓ Ecchymoses due to:
• Platelet dysfunction(NSAID)
• Capillary fragility (steroid).
✓ Petechiea due to thrombocytopenia (DMRDS).
6- Renal manifestations:
✓ Nephrotic syndrome: caused by amyloidosis OR 2ry to use of gold and
pencillimain.
✓ Interstitial nephritis: 2ry to use of NSAIDs
✓ Chronic renal failure: due to amyloidosis.
7- Others manifestations:
✓ Myopathy & muscle wasting.
✓ Lymphadenopathy.
✓ Hepatosplenomegaly.
✓ Peptic ulcers (complication of NSAID).
NB
Patterns of cervical spine involvement:

A. C1–C2 subluxation:
Types: Anterior – Lateral – Posterior
Anterior subluxation: Anterior atlantoodens interval (AADI): 3 mm Distance between posterior margin of anterior
arch of C1 and anterior margin of dens (odontoid process)
➢ Cause: Synovial proliferation around the articulation of the odontoid process with the anterior arch of C1,
leading to stretching and rupture of the transverse and alar ligaments, which keep the odontoid in contact
with the arch of C1.
➢ Complication: Cervical cord compression.
➢ Examination: Alar ligament stress test.
➢ Investigation: Radiographs should be taken laterally with the neck held in flexion.
➢ Treatment:
- Only a minority of patients require surgical management.
- Non-surgical treatment options include patient education, lifestyle modification and regular radiographic
follow up.
B. C1–C2 impaction:
✓ Destruction between the occipitoatlantal and atlantoaxial joint articulations between C1 and C2, causing a cephalad
movement of the odontoid into the foramen magnum, which may impinge on the brainstem.
✓ Overall, it has the worst prognosis neurologically, especially when the odontoid is ≥5 mm above Ranawat’s line.
C. Subaxial involvement:
✓ Involvement of typically C2–C3 and C3–C4 facets and intervertebral disks. This can lead to “stair-stepping” with
one vertebrae subluxing forward on the lower vertebrae.
 Range of motion of the tibiotalar joint is usually fairly well preserved early on.while diminished inversion and eversion are more
common.
 Patients with nodules but without rheumatoid factor should be carefully evaluated for an alternative diagnosis, such as chronic
tophaceous gout.
 Methotrexate therapy can trigger a syndrome of increased nodulosis
 Renal affection in RA are usually Secondary to medications or inflammation
 Pericardial effusions & pleural effusions are usually asymptomatic.
 Effusion fluid in RA usually have low glucose, high lactate dehydrogenase, and high protein concentration.
Variant of Rheumatoid arthritis

A-Felty syndrome:
 It is the triad of RA, hepatosplenomegaly, and neutropenia.
 Prevalence: 1% of patients with RA (Usually with Long-standing seropositive RA)
 Age: Fifth decade of life, patients having suffered from RA for around 10 years
 Sex: Female preponderance (60-70%)
 HLA association: 95 % of cases associated with HLA DR 4
 Presntation:
✓ Rheumatoid arthritis.
✓ Leg ulcers &skin pigmentation.
✓ Lymphadenopathy (Non-Hodgkin’s lymphoma).
✓ Bone marrow hyperplasia & Pancytopenia.
✓ +ve Rh. Factor.
✓ ANA is positive in more than 90% of patients
 Treatment:
✓ Most patients with Felty syndrome do not require specific therapy; rather,
treatment should be focused on severe RA.
✓ Granulocyte-Colony Stimulating Factor (as Filgrastim) to stimulate production of
granulocytes.
✓ Splenectomy indicated if severe neutropenia exists (< 500 cells/mm3) and is
accompanied by: √ recurrent bacterial infections or
√ chronic nonhealing leg ulcers.
B-Juvenile chronic arthropathy: (Still's disease)

✓ Acute onset of fever , rash , lymphadenopathy & hepatosplenomegaly.
✓ Arthritis appears few weeks.
✓ Rh. Factor usually –ve.
C-Adult Still's disease:

✓ Daily high spiking fever.
✓ Rash.
✓ Arthritis.
✓ Leukocytosis.
D-Caplan’s syndrome: Rheumatoid arthritis+ pulmonary nodules+Pneumoconiosis
F-Palindromic rheumatism:
✓ Sudden attack of intermittent joint pain and mild swelling(mono- or Polyarthritis).
✓ These condition is transient& self-limited ,lasting days to weeks and subsides
without residual signs or symptoms.
✓ Approximately 50%of patients with palindromic rheumatism will go on to develop
(i.e., fulfill criteria for) RA, and only 15% remain symptom-free after 5 years.
LABORATORY FINDINGS
1-CBC:
A-Anemia:
 Normochromic normocytic anemia which may be due to
✓ Anemia of chronic disease is the most common cause (correlates with disease activity; it
improves with successful therapy).
✓ Hemolytic anemia with increased reticulocyte count due to hypersplenism.
 Microcytic hypochromic anemia(iron deficiency anemia) due to GIT Bleeding.
B- Pancytopenia:: (Leukopenia &Thrombocytopenia): which result from:

✓ Hypersplenism associated with felty`s syndrome.
✓ Effect of Medication As MTX (rare).
2-Acute phase reactant: Marked elevation in ESR & CRP.

3-Serological tests:
A- Rheumatoid Factors
1. Rheumatoid factors (RFs) are autoantibodies directed against the Fc portion of IgG
most commonly IgM (but may be IgA or IgG).
2. RFs are also detectable in1% to 4% of healthy individuals, and up to 25% of healthy
individuals over the age of 60 years.
3. RF +Ve in abouts 50%_60% of cases at 1st presentation and additional 25%

becomes +ve within 6th monthes later to diagnosis.
4. RF can be detected by:

A. Latex test (titer greater than 1/80).
B. ELISA (greater than 45 IU/ml).
C. Rose-waller test.
D. Bentonite test.
5. The sensitivity of RF for the diagnosis of RA are roughly 65% and the specificity
70%-90%.
6. Differential of a Positive Rheumatoid Factor:

1-Rheumatic diseases: RA_Sjögren syndrome_SLE.
2- Infections:
√ Viral: Hepatitis C, EBV, parvovirus, influenza.
√ Bacterial: infective Endocarditis, osteomyelitis, others
3- Chronic inflammatory conditions.
4- Liver disease, inflammatory bowel disease.
5- Aging.
B-Anti-Cyclic Citrullinated Peptide Antibodies (anti-CCP).
1. Autoantibodies directed against citrullinated proteins, so-called anticyclic

citrullinated peptide (anti-CCP) antibodies.
2. It is the most specific autoantibodies for RA (95% specificity).
3. Anti-CCP Ab are present in 60–70% of patients with RA at diagnosis(sensitivity).
4. Anti-CCP antibodies are +ve when titer greater than 80 IU/ml(by ELISA)
5. The process of citrullination:

✓ Citrullination is a physiological process, which is believed to be important for
degradation of intracellular proteins during apoptosis.
✓ Citrullination involves conversion of arginine to citrulline by PADIs(peptidyl
arginine deiminase).
✓ In RA, citrullination occurs in the inflamed synovium and the antibodies
produced by resident B cells.
✓ A variety of citrullinated proteins are present in the rheumatoid joint, including
fibrinogen, collagen, and fibronectin.
C-Antinuclear antibody (ANA): +ve in 30% of cases.
NB
 The higher the level of RF & anti-CCP antibody, the higher the correlation with erosive joint disease, functional disability, and
extra-articular disease.
 Anti-CCP and RF have been demonstrated in sera up to 10 years before the onset of articular symptoms in some patients who
later develop RA, and anti-CCP antibodies appear somewhat earlier than RF .This important observation has potential implications
for screening individuals who are at high risk for developing RA, as well as the potential for instituting preventive therapy in the
preclinical stage of disease.
 Just presence of RF, however, is insufficient to initiate arthritis development, as RF are also found in infectious diseases,
autoimmune diseases other than RA and in up to 15% of healthy, mostly elderly individuals.
 MCV: Specific mutations of vimentin have been detected in RA synovial fluid, and serum titres of antibodies targeting these
mutated isoforms (called mutated citrullinated vimentin, MCV) correlate with disease activity.
 35% of patients with a negative RF at presentation will test positively for anti-CCP antibody.
 Anti ccp antibody may also found in psoriatic arthritis_autoimmune Hepatitis_ pulmonary tuberculosis (TB)>>>Rare.
 Rarely, RA patients may exhibit leucopenia or thrombocytopenia,which can be due to Felty’s syndrome or due to medications.
 High ESR and CRP at the onset of disease are predictive of more aggressive disease and potentially worse prognosis.
 Once the diagnosis of RA is established and seropositivity has been determined, testing for RF and anti-CCP to follow
disease activity is not useful.
 Acute phase reactants, such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), are measures
of systemic inflammation.
 The finding of an elevated ESR or serum CRP level is usually indicative of active disease
The Synovial Fluid Analysis:
✓ Synovial fluid in RA is inflammatory:

➢ WBC counts typically range from 5000–50,000 per microliter with predominant
(about 2/3 of cells) neutrophils (PMNLs).
➢ High protein & low glucose concentration
➢ Lymphocytes, macrophages, NK cells, and fibroblasts are also present.
✓ No synovial fluid findings are pathognomonic of RA, but analysis of the synovial fluid is
useful to rule out infectious and crystalline processes.
✓ Synovial biopsy is not routinely recommended unless a chronic infectious process such
as tuberculosis is suspected.
RADIOLOGICAL FINDINGS
Plain X-ray of the joints:
 Early finding:
✓ Soft tissue swelling.
✓ Periarticular osteopenia (earliest changes of RA).
✓ Intraarticular bony erosion (typically appear at the margins of the joints, both medially
and laterally, and on both apposing bones).
 Later on:
✓ Joint space narrowing: due to loss of articular cartilage.
✓ Joint deformity & Sublaxation.
Ultrasonography: Early detection of synovitis, erosion & effusions.
Bone scanning: Findings may help to distinguish inflammatory from noninflammatory

changes in patients with minimal swelling.
NB
 Radiographs of the hands, feet, and wrists are more informative for following disease progression than radiographs of large
joints because of:
√The numerous joints available for assessment
√ The bone is thinner in these joints, erosions are identifed earlier and visualized more easily than in larger joints such as
the knees.
 Joint deformity & Subluxation occurs due to:
√ bone and cartilage destruction. √ laxity or frank rupture of the ligaments & tendons surrounding the joint)
 Most typical changes of RA are juxta-articular bony erosions and symmetrical joint space narrowing.
 Bony changes (erosion & space narrowing) can be evident in the first year of disease and accumulate over time.
 Lateral radiograph taken in flexion and extension are required to diagnose cervical instability.
Classification criteria(2010) for rheumatoid arthritis Score

Target population (Who should be tested?): Patients who
1) have at least 1 joint with definite clinical synovitis (swelling)*
2) with the synovitis not better explained by another disease†
A. Joint involvement
1 large joint. 0
2_10 large joints 1
1_3 small joints (with or without involvement of large joints)# 2
4_10 small joints (with or without involvement of large joints) 3
>10 joints (at least 1 small joint)** 5
B. Serology (at least 1 test result is needed for classification)

Negative RF and negative ACPA 0
Low-positive RF or low-positive ACPA 2
High-positive RF or high-positive ACPA 3
C. Acute-phase reactants (at least 1 test result is needed for classification)

Normal CRP and normal ESR 0
Abnormal CRP or abnormal ESR 1
D. Duration of symptom
< 6 weeks 0
≥ 6 weeks 1
A score of ≥ 6/10 is needed for classification of a patient as having definite RA
NB
 Joint involvement refers to any swollen or tender joint on examination (may be confirmed by imaging evidence of synovitis).
 DIP, first carpometacarpal joints, and first metatarsophalangeal joints are excluded from assessment.
 “Large joints” refers to>>shoulders_elbows_hips_knees_ankles.
 “Small joints” refers to >>the MCP joints_PIP joints_ second through fifth MTP joints,_thumb interphalangeal joints_ wrists.
 Negative refers to IU values that are less than or equal to the upper limit of normal (ULN) for the laboratory and assay.
 Low-positive refers to IU values that are higher than the ULN but ≤ 3 times the ULN for the laboratory and assay
 High-positive refers to IU values that are > 3 times the ULN for the laboratory and assay.
 Where rheumatoid factor (RF) information is only available as positive or negative, a positive result should be scored as low-positive for RF.
 Duration of symptoms refers to patient self-report of the duration of signs or symptoms of synovitis (e.g., pain, swelling,
tenderness) of joints that are clinically involved at the time of assessment, regardless of treatment status.
 Patients with longstanding disease, including those whose disease is inactive (with or without treatment) who, based on
retrospectively available data, have previously fulfilled the 2010 criteria should be classified as having RA.
 Patients with a score of < 6/10 can be reassessed and the criteria might be fulfilled cumulatively over time.
1987 Criteria for Classification of Rheumatoid Arthritis (American Rheumatism

Association)
1. Morning stiffness: Morning stiffness in and around the joints lasting at least 1 hour before maximal
improvement
2. Arthritis of ≥3 joint At least 3 joint areas simultaneously having soft tissue swelling or fluid (not bony
areas overgrowth alone) observed by a physician (the 14 possible joint areas are [right or
left] PIP, MCP, wrist, elbow, knee, ankle, and MTP joints)
3. Arthritis of hand At least 1 joint area swollen as above in wrist, MCP, or PIP joint
joints
4. Symmetric arthritis Simultaneous involvement of the same joint areas (as in criterion 2) on both sides of
the body (bilateral involvement of PIP, MCP, or MTP joints is acceptable without
absolute symmetry)
5. Rheumatoid Subcutaneous nodules over bony prominences or extensor surfaces, or in
nodules juxtaarticular regions, as observed by a physician
6. Serum RF. Demonstration of abnormal amounts of serum RF by any method that has been
positive
7. Radiographic Changes typical of RA on posteroanterior hand and wrist radiographs, which must
changes include erosions or unequivocal bony decalcification localized to or most marked
adjacent to involved joints.
Patient said to have RA if he/she satisfied at least 4 criteria.
Criteria 1-4 must be present for at least 6 weeks, and a physician must observe criteria 2-5.
2016 ACR/EULAR revised criteria for too early diagnosis of RA
A. Entry criteria; No other prominent diagnosis is proposed according to the patient’s

history and physical examination.
B. All peripheral joints are included
C. ACR 66/68 counts for swollen and tender joints is applied (14).
D. In the presence of 6 points or more out of 15 with at least 2 points belonging to domain
I (joints) along with entry criteria the diagnosis of RA can be established.
E. In the presence of pain along with morning stiffness of ≥ 1 hour in a joint if there is not
any clinical synovitis in that, we can apply ultrasonography or MRI for detection of
subclinical synovitis.
F. Past history of heavy smoking or current smoking.
Differential Diagnosis
1. Spondyloarthropathies (Common)
 Non-articular features (heel pain or tenderness and ocular or urethral symptoms).
 Pattern of joint disease:
✓ Asymmetric, oligoarticular.
✓ Lower extremities more than upper extremities.
✓ Large joints more than small joints.
2. Calcium Pyrophosphate Dihydrate Deposition Disease (Common)

3. Gout (Common)
 Large asymmetric erosions with ballooning of the cortex and overhanging edges are
more likely to be caused by gout than by RA.
 RF has been reported in 30% of patients with chronic tophaceous gout who have no
clinical or radiographic signs of RA.
4. Fibromyalgia (Common)
5. Polymyalgia Rheumatica and Giant Cell Arteritis (Common)
6. Osteoarthritis (Common)
✓ Erosive osteoarthritis occurs frequently in middle-aged women.
✓ Characterized by inflammatory changes in PIP joints with destruction and functional
ankylosis of the joints.
✓ The PIP joints can be red and hot.
✓ Joint swelling involves hard, bony tissue, not synovium.
✓ The ESR may be slightly elevated, but RF is not found.
7. Musculoskeletal Pain of Thyroid Disease (Common)

 In hypothyroidism synovial effusions and synovial thickening can simulate RA.
 Knees, wrists, hands, and feet are involved most often.
 The ESR may be elevated because of hypergammaglobulinemia, but C-reactive protein
is normal.
 The joint fluid is noninflammatory and may have increased viscosity.
 The syndrome of thyroid acropachy(periosteal new bone formation associated with a low-grade
synovitis similar to hypertrophic osteoarthropathy) complicates less than 1% of cases of
hyperthyroidism.
8. Viral Infection (Common)

 Fever, sore throat, and cervical adenopathy followed by symmetric polyarthritis are
compatible with infection resulting from:
✓ Hepatitis B& HIV
✓ Rubella ,adenovirus type 7& echovirus type 9.
✓ Mycoplasma pneumonia.
✓ Epstein-Barr virus
✓ Acute rheumatic fever.
✓ Adult-onset Still’s disease.
 Several types of arthropathy have been described in association with HIV infection:
✓ Brief, acute arthralgias concurrent with initial HIV viremia
✓ HIV-associated arthritis, lower extremity noninflammatory oligoarthritis, or a
persistent polyarthritis.
9. Rheumatic Fever (Uncommon)

 The presentation is often that of an additive, symmetric, large joint polyarthritis
(involving lower extremities in 85% of patients), developing within 1 week and associated
with a severe tenosynovitis.
 Dramatic response to salicylates.
 In contrast to Still’s disease in adults, rheumatic fever generally has no remittent or
quotidian fevers and shows evidence of antecedent streptococcal infection.
10. Bacterial Endocarditis (Uncommon)

 Musculoskeletal symptoms of infective endocarditis(30% of patients):
✓ Arthralgias/arthritis.
✓ Back pain & myalgias.
✓ Symptoms typically occur in one or several joints, usually large, proximal ones.
 This synovitis probably is caused by the deposition of circulating immune complexes.

 More than half of patients with endocarditis are seropositive for RF.
 Fever out of proportion to joint findings & leukocytosis should lead to consideration of
infective endocarditis as a diagnostic possibility.
 Peripheral emboli with digital infarctions may be found, simulating palpable purpura when
they occur on the lower legs.
 Blood cultures should be obtained in all patients with polyarthritis and fever.
11. Lyme Disease (Common in Endemic Areas)
12. Relapsing Seronegative Symmetric Synovitis with Pitting Edema (Uncommon)

 RS3PE is an uncommon syndrome marked by:
✓ Edema: Significant pitting edema of the hands and ankles overlying involved distal
joints.
✓ Synovitis: rapid onset of symmetric synovitis & synovial thickening.
✓ Joint tenderness.
 It occurs predominantly in elderly men.
 Symptoms rapidly respond to short courses of corticosteroids and can lead to residual
abnormalities, including flexion contractures of the wrists and fingers.
 Patients are RF negative, and there is increased risk of neoplastic disease.
 A poor response to corticosteroid treatment and the presence of constitutional symptoms
have been observed in patients with an underlying malignancy.
13. SAPHO syndrome:

 Synovitis: sacroiliitis, and peripheral inflammatory Arthritis.
 Acne.
 Pustulosis: palmar and plantar pustules
 Hyperostosis: hyperostotic reactions (particularly in the clavicles and sternum).
 Osteitis.
 SAPHO may resemble psoriatic arthritis and RA.
14. Sarcoidosis (Uncommon)

 Lofgren’s syndrome:
✓ The acute form presented with erythema nodosum ,hilar adenopathy & articular
problems usually are related to periarthritis affecting large joints of the lower
extremities, classically the ankles.
✓ Differential diagnosis may be complicated because many of these patients have RF in
serum.
✓ Joint erosions and proliferative synovitis do not occur in this form of sarcoidosis.
 In chronic granulomatous sarcoidosis:

✓ Cyst-like areas of bone destruction.
✓ Mottled rarefaction of bone and a reticular pattern of bone destruction with a lace-like
appearance on radiographs may simulate destructive RA.
✓ This form of sarcoidosis is often polyarticular.
✓ Biopsy of bone or synovium for diagnosis may be essential because often no
correlation is noted between joint disease and clinical evidence of sarcoid involvement
in other organ systems.
15. Malignancy (Uncommon)

 Direct involvement of the synovium by cancer usually manifests as a monoarthritis.
 Non-Hodgkin’s lymphoma can manifest as seronegative polyarthritis, without
hepatomegaly or lymphadenopathy.
 Lymphoma can manifest as a symmetric polyarthritis.
 In children, acute lymphocytic leukemia can manifest as a polyarticular arthritis.
16. Multicentric Reticulohistiocytosis (Rare)

 MCH causes severe arthritis mutilans with an opera-glass hand (main en lorgnette).
 Other causes of arthritis mutilans include RA, psoriatic arthritis, erosive osteoarthritis
treated with glucocorticoids, and gout (after tophi are resorbed by treatment with
allopurinol).
17. Pigmented Villonodular Synovitis (Rare)

 It is a nonmalignant but proliferative disease of synovial tissue that has many functional
characteristics similar to those of RA but usually involves only one joint.
 The histopathologic appearance is characterized by proliferation of histiocytes,
multinucleate giant cells, and hemosiderin- and lipid-laden macrophages.
 Clinically, this is a painless chronic synovitis (most often of the knee) with joint effusions
and greatly thickened synovium.
complications
1. Joint deformity & Sublaxation.
2. Ankylosis.
3. Muscle wasting.
4. Tendon rupture.
5. Baker`s cyst: which may rupture in calf causing sever pain similar to DVT.
6. Increased risk of Osteoprosis.
Comorbidity
❖ Factors that increase the mortality risk includes:
1. Cardiovascular disease: Increased risk of CVD (cornary artery dse & atherosclerosis) is the
major cause of the excess mortality in RA mostly due to chronic inflammation.
2. Increased risk of infection: due to use of immunosuppressive therapy.
3. RA have an increased risk of lymphomas. Occasionally, B-cell lymphomas may
be associated with immunosuppression and regress after immunosuppression is
discontinued.
4. GIT bleeding.
5. Renal disease.
Prognosis & Outcome:

Prognosis & Outcome of RA depend on:
✓ Early diagnosis.
✓ Use of DMARDs therapy within 1st 3 monthes.
✓ Recognize and treat comorbid conditions.
Prognostic Factors that predict poor outcome

1. Female sex.
2. +ve family history.
3. Low socioeconomic and educational status.
4. Smoking.
5. Sero-positivity( RF & Anticcp ab).
6. High titer of RF & Anti-ccp.
7. HLA-DR4.
8. Early disease activity & High number of swollen tender Joints.
9. Presence of erosive disease at presentation.
10. Rheumatoid nodules & Extra articular feactures.
Epidemiology, Pathology & Pathogenesis
Epidemiology:
• Prevalence: The overall prevalence of RA is 1% to 2% of population
• Incidence: 0.5 per 1000 persons per year (in the United States).
• Age of onset: RA can occur at any age, but the typical age of onset in females is
around 40 years(late child bearing years) , while occurs in males usually after the
age of 50.
RISK FACTORS OF RHEUMATOID ARTHRITIS
Genetic Factors:
✓ There is increased risk of developing the disease in first degree relatives of a
rheumatoid patient by about 2-3 fold higher than the general population.
✓ The most potent genetic risk for RA is conveyed by certain major histocompatibility
complex HLA-DR4
✓ Polymorphisms in several other genes may contribute incremental risk for RA.
Nongenetic Risk Factors:

A- SEX:
✓ Women are two to three times more likely to develop RA than men.
✓ Hormonal factors like estrogen and progesterone may explain some of the
gender effect:
1. Estrogen decrease apoptosis of B cells, potentially permitting the selection of
autoreactive clones.
2. Hormones also have a complex effect on the balance of T-cell subsets with
distinct cytokine profiles.
3. Pregnant women with RA experience spontaneous remission.
4. The disease typically flares within weeks after delivery. These may caused
by Soluble mediators released by the placenta like transforming growth factor
(TGF) beta IL-10, or alpha-fetoprotein.
B-Environmental factors:
 Exposure to various environmental factors increases the risk for RA:
✓ Cigarette smoke is one of the best characterized (inhalation of smoke lead to inflammation
and activation of innate immunity in the airway, which then induces peptide citrullination and developing Anti CCP
Antibody).
✓ Modifying environmental factors such as: Climate_trauma_psychological stress.
C-Infection:
1. EBV, mycobacteria & Parvovirus B19 increase the risk of RA:
✓ Trigger the initial immune response necessary for RA-development in a genetically
susceptible host).
✓ EBV is polyclonal activator of B lymphocytes and increases the production of rheumatoid
factor).
2. HCV also is associated with increased risk of RA.
D- Age at menarche: women with lower age at menarche have a comparatively low risk
for the development of RA.
E- Occupational exposure to mineral oils (e.g. motor oils, hydraulic oils etc.) was found
to be a risk factor for ACPA-positive RA in males.
F- High body-mass index strong association with ACPA-negative RA has been shown
for individuals with high body-mass index.
Pathology &Pathogenesis of RA
 The 1ry target of the disease is the SYNOVIUM
 Pathological changes occurs as following:
1. Synovitis and joint effusion.
2. Proliferation of the Synovial membrane & pannus formation.
3. Cartilage destruction & bone erosion.
4. Fibrosis , Ankylosis ,Deformity &Sublaxation(later on).
SYNOVIAL PATHOLOGY
The Normal Synovium consists of:
1. Intimal lining layer Which is: discontinuous _one to two cell layers thick_ lacks an
underlying basal membrane.
2. Sublining below the intima: contains blood vessels, lymphatics, nerves, and
adipocytes distributed within a less cellular, fibrous matrix.
The intimal lining layer contains two types of cells:

1-Type A synoviocytes (macrophage like synoviocytes ) >>>> phagocytic function.
2-Type B synoviocytes (fibroblast like synoviocytes): responsible for the synthesis of
extrcellular matrix proteins including collagen, fibronectin, hyaluronic acid, and other
molecules that facilitate the lubrication and function of cartilage surfaces.
The Synovium Changes in Rheumatoid Arthritis:
1. Increased cellularity & vascularity.

2. Infiltration with immune inflammatory cells & lymphoid aggregates.
3. Vascular proliferation & Hyperplasia of synovial lining: lead to increase

production of inflammatory cytokines which participates in joint destruction with
activates chondrocytes and osteoclasts.
4. Pannus formation: Villous projections protrude into the joint cavity, invading the
underlying cartilage and bone.
5. The Synovial Fluid changes

 Volume: The volume of synovial fluid increase dramatically in RA due to
increased leakage from the synovial microvasculature.
 Cells:
• Polymorphonuclear (PMNs) leukocytes, are the predominant cell type.
• Lymphocytes, macrophages, NK cells, and fibroblasts are also present..
• PMNs in the synovial fluid are activated by factors such as immune complexes and
cellular debris.
• They degranulate, generate products of oxygen metabolism, metabolize arachidonic acid,
and release proteinases and cytokines.
Cytokine Networks
➢ DEF: Cytokines are hormone-like proteins that enable immune cells to communicate.
➢ Source:
✓ Macrophages, fibroblastlike synovioctyes (Mainly), and T cells are the primary sources
of cytokines in the rheumatoid synovium.
✓ These cells produce proinflammatory cytokines that can activate either or their adjacent cells within
the joint.
✓ They also secrete inhibitory cytokines that only partially suppress the inflammation.
➢ Effect:
 Participating in normal immune responses: Cytokines either can interact with cells
after being released in a soluble form or can be involved with direct cell-cell
communication through membrane-bound factors such as TNF-α.
 IN RA:
✓ The initiation and perpetuation of synovitis.
✓ Stimulate osteoclasts, the main cell type responsible for bone destruction.
RANKL produced by FLS and T activate osteoclasts in the rheumatoid joint.
➢ Types
A. Proinflammatory cytokines:
1. Interleukin-1 Family
 Interleukin 1
 Interleukin-18
2. Tumor Necrosis Factor Superfamily.
5. Interleukin-15
6. Interleukin-32
7. Colony-Stimulating Factors
8. Chemokine Families
9. Platelet-Derived Growth Factor and Fibroblast Growth Factor.
B. Anti-inflammatory cytokines and cytokines antagonists:

1. Interleukin-1 Receptor Antagonist
2. Interleukin-10
3. Transforming Growth Factor-β
4. Soluble Cytokine Receptors and Binding Proteins.
Tumor Necrosis Factor (TNF)

➢ Def: Tumor necrosis factor alpha is a pivotal pro-inflammataory cytokine that is
synthesized as a membrane-bound protein and released after proteolytic cleavage by
TNF convertase (TACE).
➢ Source: In RA, TNF-alpha is mainly produced by synovial macrophages.
➢ Effects:
1. Regulates the production of other proinflammatory cytokines (such as IL-1 and
IL-6) and matrix metalloproteinases by fibroblasts.
2. Decrease the synthesis of proteoglycans by chondrocytes.
3. Activates the endothelium.
4. Stimulates osteoclastogenesis: Promote the differentiation of monocytes to
osteoclasts.
5. Other: TNF-alpha is an important molecule in the host response to certain infectious agents. Opportunistic
infections, including reactivation of latent TB, or defective tumor immune surveillance represent potential
adverse effects of anti–TNF-alpha agents.
Interleukin Family
Interleukin 1(IL-1)
➢ Source: Macrophages are the main source in the rheumatoid synovium.
➢ Effect: interleukin 1 contribute to inflammation in RA through Increased synthesis of IL-

6,chemokines, GM-CSF, prostaglandin and collagenase.
➢ Inflammatory factors induce IL-1 production in RA :

TNF-alpha, GM-CSF, immunoglobulin Fc fragments collagen fragments and, to a
lesser extent, immune complexes.
Interleukin 6(IL-6)
➢ Source: synoviocytes are the major source.
➢ Effect:
✓ Has pleiotropic effects and influences systemic inflammation through its actions
on hematopoiesis and many cell types of the immune system.
✓ Implicated in the activation of the endothelium and contributes to bone erosion
by stimulating the maturation of osteoclasts.
✓ Very high levels of IL-6 are present in the synovial fluid of RA patients and type B IL-6 levels decrease
dramatically after treatment with TNF inhibitors.
Interleukin 1 Receptor Antagonist Protein:
 Interleukin 1 receptor antagonist protein is a natural inhibitor of IL-1 present in the

RA joint, but at concentrations too low to counteract IL-1 activity.
 Administration of exogenous IL-1Ra is very effective in IL-1–dependent diseases

such as systemic onset juvenile idiopathic arthritis, adult Still’s disease.
MECHANISM OF JOINT DESTRUCTION
➢ Angiogenesis and Cell Migration

The generation of new blood vessels is required to provide nutrients to the expanding
synovial membrane and is an early event in the development of synovitis.
➢ Factors that promote angiogenesis & blood vessel growth in the synovium :
✓ Hypoxia of synovial fluid (synovial fluid).
✓ Low pH and high lactate levels.
✓ Vascular endothelial growth factor (VEGF), IL-8, angiopoietin-1.
1. Proinflammatory cytokines induce the expression of specialized receptors on

capillaries and postcapillary venules that regulate the migration of the inflammatory
cells into the synovium.
2. Once leukocytes have migrated into the tissue, they adhere to the matrix through surface
receptors and their survival and proliferation is stimulated by the cytokine milieu.
➢ The Role of Fibroblast like Synoviocytes

➢ Activated type-B synoviocytes are a major source of inflammatory mediators
and metalloproteinases in RA.
➢ Insufficient synoviocyte apoptosis in RA probably contributes to intimal lining
hyperplasia of the synovium due to:
✓ Low expression of anti-apoptotic genes.
✓ Abnormal function of tumor suppressor genes like p53.
Cartilage Destruction
 Major cell types responsible for destruction of the cartilage in RA.:

✓ Aggressive synoviocytes (Synovial fibroblasts) at sites of pannus overgrowth.
✓ cytokine-activated chondrocytes, and PMNs.
 Mechanisem:
➢ Synovial fibroblasts adhere to cartilage via attachment to fibronectin, collagen type
VI and cartilage oligomeric matrix protein (COMP), and display an aggressive
invasive behaviour.
➢ These cells release destructive enzymes in response to IL-1, TNF-alpha, IL-17, an
Immune complexes.
➢ These enzymes degrade extracellular matrix, providing a rich source of potential
neo-antigens for T and B cell polyclonal proliferation.
➢ Large amounts of secreted PGE2 additionally support inflammation.
➢ Reversible loss of proteoglycans occurs early, most likely due to:

• The catabolic effect of cytokines.
• Production of stromelysins and aggrecanases.
➢ Cleavage of native type II collagen by collagenases is an irreversible step that
permanently damages the cartilage.
➢ Enzymes which participate in extracellular matrix degradation of the joint:

• Matrix metalloproteinases (MMPs; collagenases, gelatinases, and stromelysin).
• Serine proteases (trypsin, chymotrypsin).
• Cathepsins.
Bone Destruction
➢ Focal bone erosions are a hallmark of RA that can occur early in the disease and
cause significant morbidity due to subchondral and the cortical bone damage.
➢ Bone erosions are mainly caused by osteoclasts (derived from macrophage

Precursors) which accumulates at the pannus–bone interface and the subchondral
marrow space.
➢ RA is also associated with periarticular bone loss adjacent to inflamed joints and
generalized osteopenia, leading to increased risk of bone fracture.
Schematic diagram of disease mechanisms
➢ Innate immunity could activate fibroblast-like synoviocytes (FLS), dendritric cells (DC),
and macrophages (MΦ) in the earliest phases in individuals with underlying immune
hyper-reactivity as evidenced by the production of autoantibodies.
➢ The genetic makeup of an individual including the presence of certain gene

polymorphisms in genes that regulate immune responses and environmental exposures
are both required.
➢ Chronic inflammation leads to citrullination of proteins in a variety of sites including

mucosal surfaces such as the lungs or the joint.
➢ In a genetically susceptible individual, a breakdown of tolerance can occur with the
formation of anticitrullinated protein antibodies.
➢ DCs can migrate to the central lymphoid organs to present antigen and activate T
cells,which can in turn activate B cells.
➢ These lymphocytes can migrate back to the synovium and enhance adaptive immune
responses in the target organ.
➢ In addition, repeated activation of innate immunity can directly lead to chronic
inflammation and possibly antigen presentation in the synovium.
➢ In the latter phases of disease, many cell types activate osteoclasts (OC) through the
receptor activator of nuclear factor κB (NFκB)/receptor activator of NFκB ligand
(RANK/RANKL) system, although FLS and T cells likely provide the greatest stimulus.
Blank Page for adding special notes
Treatment of RA
Essential to Know:
❖ There is no cure for rheumatoid arthritis (RA), which is a lifelong disease process
requiring lifelong treatment.
❖ The goal of therapy for RA is to:

1. Put the disease in remission (reduce or eliminate pain & swelling) and to
maintain this remission by continuing therapy.
2. Prevent joint damage.
3. Improve physical function.
4. Minimize the disability.
❖ Four broad categories of medical therapies are used for the treatment of RA:
1. Nonsteroidal anti-inflammatory drugs (NSAIDs).
2. Glucocorticoids.
3. Conventional disease-modifying antirheumatic drugs (DMARDs).
4. Biological DMARDs.
❖ Almost all patients require use of more than one type of medication, and all patients
should receive DMARD therapy (with rare exceptions).
❖ The effectiveness of therapy is usually assessed by monitoring of:

1. Symptoms: >>>>>pain and the duration of morning stiffness.
2. Signs: >>>> synovitis(swelling & tenderness).
3. Acute phase reactants (ESR & CRP).
❖ Physiotherapy is advised during chronic stage of the disease , to:

1. Restore & maintain muscle power.
2. Prevent & correct deformity.
MEDICATION
NSAIDs
NSAIDs is important for symptomatic relief the of pain & inflammation but don’t
alternate the underlying disease process.
The most common SE. of NSAIDs is GIT irritation & can be avoided by using PPIs.
Types of NSAIDs used in ttt:

1. Tradional NSAIDs: √Ibuprofen. √Piroxicam. √Indomethacin.
2. Non tradional NSAIDs:
√selective (COX-2) inhibitors: as meloxicam.
√specific (COX-2) inhibitors: as celecoxib.
Glucocorticoids
 Guidelines for the Use of Glucocorticoids in the Treatment of Rheumatoid Arthritis:
1. Start Usually in low dose (prednisone 0.1-0.2mg/kg/day) >>> slowly tapering to the lowest
dose that controls arthritis
2. Use glucocorticoids as a "bridge" to control inflammation while effective DMARD
therapy start to work (Avoid using glucocorticoids without DMARDs).
3. Always consider prophylaxis to minimize osteoporosis.
4. Large dose (0.3-0.5mg/kg/day) may be indicated in:
• Extra-articular manifestations as: Scleritis,Uveitis & pericarditis.
• Active progressive disease.
DMARDs
❖ Definition: DMARDs are drugs which target pathogenic mediators of joint inflammation
and damage so it:
 Can slow the disease progression.
 Have the ability to modify or change the course of RA (produce a disease-modifying effect).
 Prevent irreversible destructive changes if used early.
❖ Types:
➢ Conventional (synthetic) DMARDs: Methotrexate, sulfasalazine, gold,
antimalarials, leflunomide, azathioprine, penicillamine, and minocycline.
➢ Biological DMARDs:
✓ Anti- TNF :Biological agents directed against TNF alph:
• Etanercept >>>>>>>>(Enbrel)
• Infliximab>>>>>>>>>(Remicade)
• Adalimumab>>>>>>>(Humira)
• Golimumab.
• Certolizumab Pegol>>(CIMZIA)
✓ Interleukin-1 inhibitors (anakinra).
✓ Interleukin-6 inhibitors: Tocilizumab>>>>>>>>>>>>>>>>>(Actemra).
✓ Therapies that block T-cell co-stimulation (Abatacept)>>>>(Orencia)
✓ Therapies that target B-cells (Rituximab)>>>>>>>>>>>>>>(Rituxan)
Conventional DMARDs
Drug MTX Leflunomaid SulfaSalaZine HCQ
Mode of • Inhibits dihydrofolate reductase and • It inhibits an enzyme • SSZ suppress • Inhibits chemotaxis of
other folate-dependent enzymes involved in pyrimidine lymphocyte & leukocyte eosinophils.
Action: • inhibits locomotion of
(enzyme needed for DNA synthesis.). synthesis functions.
• SSZ is a drug that neutrophils.
(dihydro-orotate • impairs complement-
linked an antibiotic.
dehydrogenase). sulfapyridine,with an
dependent antigen-antibody
antiinflammatory agent, (5- reactions.
ASA)
Dose • Usual starting dose is 7.5 mg orally • Loading dose: 100 mg/d • Start with a low dose • Hydroxychloroquine: Initial
every week. for 3 days (Because (0.5 g twice daily) and therapy 400 mg/d
• Dose can be increased by increments steady state levels are not increase by 0.5-g at maintenance therapy 200–
reached for 2 months). intervals of a week in 400 mg/d.
of 5 mg every 4–8 weeks until:
✓ There is a therapeutic effect. • Maintenance dose: 20 mg/d order to reduce GIT SE. • Chloroquine: Initial therapy
• Maintenance dose: 1-2 g 500 mg/d; maintenance
✓ The maximal dose is attained twice daily. therapy 500 mg every other
(generally 20–25mg/wk in RA day.
Efficacy • The most effective and widely used. • leflunomide is comparable • The combination of • Slow onset of action (up to 6
• Clinical responses generally occur SSZ, HCQ, & MTX is months)
to sulfasalazine and
after a lag of 4–6 weeks in RA. superior to MTX alone • Less effective than other
moderate doses of
in patients with commonly used DMARDs,
• Its main effect is achieved after 4-6 methotrexate.
such as MTX.
month's. suboptimal responses
• They are typically used to
to MTX.
treat milder forms of RA and
in combination with other
DMARDs.
SE: • GIT disturbances • The most common is GIT • GIT disturbances • Most danger: corneal
• Hepatotoxicity(Elevated Liver enzymes) disturbances (nausea, vomiting, toxicity & retinopathy.
• cytopenias(especially leukopenia). (nausea,vomiting diarrhea diarrhea). especial • Most common: GIT
• pulmonary infiltrates or fibrosis & anorexia). within 1st 2weeks. irritation.
especial within 1st • Allergy & hypersensitivity
2weeks. reactions
CI: • Active liver disease. • Patients with G6PD • Patients with retinopathy
• Active infections (especially TB). deficiency (risk for due to any cause.
hemolytic anemia.)
• Pregnancy& Lactation
Monitori • CBC with platelets counts. • Regular

ng
Therapy • LFTs (ALT, AST ). Ophthalmologic
• Serum creatinine. examination should
be done every 6
months for detection
of retinopathy.
NB
A- Methotrexate (MTX):
✓ Used as monotherapy or as the "anchor drug" in combinations with other conventional DMARDs or with anti–tumor
necrosis factor agents.
Dosing: 2013 EULAR recommendations:
▪ Maximizing treatment efficacy includes reaching an optimal MTX dose within "a few weeks" and maintaining the
maximal dose (25-30 mg/week) for at least 8 weeks.
▪ Given weekly as a single dose (can split dose over 24 hours if gastrointestinal symptoms occur).
▪ Toxicity, particularly liver toxicity, is substantially greater when the same amount of drug is administered on a daily basis rather than
as a weekly pulse.
▪ To improve gastrointestinal tolerability as well as bioavailability, many clinicians switch to parenteral
administration (usually subcutaneous injection) of MTX before discontinuing for lack of efficacy.
B- Leflunomide elimination:
 Why drug elimination is done?
✓ Leflunomide have long half-life (take up to 2 years to be fully eliminated from the blood
normal).
 When?
✓ Serious toxicity (eg, hypersensitivity reactions or liver toxicity).
✓ Women of childbearing age who have stopped taking leflunomide.
 How?
✓ Cholestyramine 8g 3times/d for 11 days.
E- Intramuscular gold:
✓ Intramuscular gold the oldest DMARD, remains an extremely effective therapy for a small percentage of patients.
✓ It is uncommonly used now because of:
▪ Its slow onset of action.
▪ The need for intramuscular administration.
▪ The requirement for frequent monitoring (complete blood cell count and urinalysis).
▪ Frequent toxicities which include: skin rashes, bone marrow suppression, and proteinuria.
✓ There are two parenteral gold formulations ( gold sodium malate and myochrysine) and an oral compound(auranofin).
✓ Dose: test dose of 10mg then 50mg/ week for 3 monthes then 50mg/month.
 The most important and most common adverse events relate to
• Liver and bone marrow toxicity (MTX, SSZ, leflunomide, azathioprine, gold compounds),
• Renal toxicity (cyclosporine A, parenteral gold salts, D-penicillamine),
• Pneumonitis (MTX),
• Allergic skin reactions (gold compounds, SSZ),
• Autoimmunity (D-penicillamine, SSZ, minocycline), and
• Infections (azathioprine, cyclosporine A).
• Antimalarials may cause ocular toxicity.
Biological DMARDs
TUMOR NECROSIS FACTOR (TNF) ANTAGONISTS
General mechanism of action:

 Anti-TNF were engineered to specifically inhibit TNF (Neutrilizing its effect), which is a
critical mediator of joint inflammation: TNF are a pivotal proinflamatory cytokine that:
✓ Regulates the production of other proinflammatory cytokines (such as IL-1 and IL-6)
and matrix metalloproteinases by fibroblasts.
✓ Decrease the synthesis of proteoglycans by chondrocytes.
✓ Activates the endothelium.
✓ Upregulates the expression of adhesion molecules.
✓ Stimulates osteoclastogenesis: Promote the differentiation of monocytes to
osteoclasts.
Onset of action: A rapid onset of action (days to weeks) >>>a significant advantage that these treatments have
over conventional DMARDs.
Efficacy:
✓ All anti-TNF agents have been shown to reduce the signs and symptoms of
synovitis and to diminish radiographic progression of RA(even in patients who have active disease
despite treatment with methotrexate).
✓ Clinical trials indicate that all of these TNF blockers, when added to MTX, produce
incremental ACR20 response rates of approximately 50% to 70%.
Adverse effects:
 Common:
1. Injection site inflammation for etanercept and adalimumab.
2. Infusion-related allergic reactions for infliximab.
3. Upper respiratory infections.
4. Headaches.
 Rare severe adverse effects:

1. Neurologic (demyelinating diseases).
2. An increased risk of serious bacterial and opportunistic infections, especially
reactivation of latent tuberculosis.
3. An increased risk for lymphoproliferative disorders, namely lymphoma (the strength of
this link remains unclear because of the fact that RA itself is associated with an increased risk of lymphoma).
4. Cutaneous vasculitis.
5. Pancytopenia.
6. Development of other autoimmune diseases.
Initiating Therapy:
1. Screen for infections (CHEST X-RAY - HCV Ab &HbsAg - Quantiferon T.B GOLD)
2. Age-appropriate cancer screening.
3. Vaccinations:
✓ Patients should receives:
• Inactivated influenza vaccine (seasonal).
• Age-appropriate pneumococcal, meningococcal, and Haemophilus influenzae B.
• Give herpes zoster vaccine (live) at least 2 to 4 weeks before biologic
✓ Not to receive live vaccinations after initiating or continuing therapy.
4. Patients should be monitored for injection site or infusion reactions while receiving
therapy.
5. Periodic CBC.
Contraindication:
1. Patients with a history of multiple sclerosis of any other demyelinating disease.
2. patients with active acute or chronic infections
NB
✓ To prevent or minimize infliximab allergic reactions, premedication with acetaminophen diphenhydramine, &
hydrocortisone are needed.
✓ Anti-TNF agents should not be used in patients with class III to V heart failure because these drugs may exacerbate
heart failure.
 Anakinra
EFFICACY:
✓ Controlled trial shows the ACR20 response rates using this drug were only 38%.
✓ The clinical benefits of anakinra are less than those of the TNF blockers.
✓ Its onset of action is slower and less dramatic than that of the TNF blockers
✓ For this reason, the use of Anakinra in RA has been limited to selective patients with refractory
disease
SE: include injection-site reactions and pneumonia.
 Abatacept & Rituximab:

✓ Are currently approved for patients with active RA who have had an inadequate response to other DMARDs or
have failed treatment with an anti-TNF agent.
✓ Their onset of action is slower than that of the anti-TNF agents.
✓ To reduce the infusion reactions, intravenous methylprednisolone was given befor the infusion followed by
tapering doses of oral prednisone (PREMEDICATION: solumedrol 100mg i.v+avil amp+2 tab paramol).
Screen for infections (CHEST X-RAY - HCV Ab &HbsAg - Quantiferon T.B GOLD) shoud be done befor
intiating biological therapy.
Dose Mode of action

It is a fully human monoclonal antibody (IgG)
ADALIMUMAB 40 mg Every 2 weeks binds to both soluble and membrane-
HUMIRA S.C bound TNF neutralizing its biologic activities.
ETANERCEPT It is a soluble receptor fusion protein that

ENBREL 50 mg once weekly binds to soluble TNF, neutralizing its
S.C biologic activities.
Loading: 400mg 0-2-4 weeks
followed by It is a fusion protein (Consist of humanized Fab
CERTOLIZUMAB 200mg every 2 weeks S.C sub unit of the antibody) that binds to soluble &
CIMZIA membrane- bound TNF neutralizing its
MAINTAINCE: biologic activities.
Syringe (200 mg) 400mg every 4 weeks S.C
INFLIXIMAB 3-5mg/kg at 0-2-6 weeks It is a chimeric monoclonal (IgG) antibody

REMICADE then binds to both soluble and membrane-
VIALS 100 mg every 8 weeks bound TNF neutralizing its biologic activities.
(I.V infusion in 250 ml saline
over 2 hr)
Golimumab 50mg SC every month. Human monoclonal antibody (IgG) binds to
Simponi Syringe (50 mg) both soluble and membrane-bound TNF
neutralizing its biologic activities.
ABATACEPT • 10mg/kg at 0-2-4 weeks It is a recombinant fusion protein which

ORENCIA Then Inhibites T-cell co-stimulation.
every 4 weeks
VIALS 250mg (I.V infusion in 100 ml saline (binds to CD80 and CD86, blocking their
Syringe125mg over 30 min) interactions with CD28 on T cells prevents
• 125 mg S.C once weekly the second signal of T-cell activation).
RUTIXIMAB 1 gram at 0-2 weeks intervals It is a chimeric anti-CD20 monoclonal

MABTHERA every year antibody.
Rituxan OR Rituximab depletes B cells that have CD20
- 500 mg every 6 months. on their surface.
VIALS 100 & 500
mg (I.V infusion in 500 ml saline (CD20, an antigen found on the surface of
over 6 hr) normal and malignant B lymphocytes).
TOCILIZIMAb 4-8mg/kg monthly Tocilizumab is a recombinant humanized

ACTEMRA monoclonal antibody which inhbites
400 mg,200 mg,80 (I.V infusion in 100 ml saline interleukin-6 (IL-6) receptor
mg VIALS over 1 hr)
150 mg SC every 4 weeks. Human IgG1 monoclonal antibody that
Secukinumab (Approved 2016 for selectively binds to and neutralizes the
(Cosyntex) AS & PsA) proinflammatory cytokine interleukin 17A
(IL-17A).
45 mg SC initially, A human IgG1κ monoclonal antibody that

Ustekinumab followed by 45 mg in 4 binds to the p40 subunit of both IL-12 & IL-
(Sterala) weeks, then 45 mg 23 preventing their binding to their shared
(Approved For As & PsA every12 weeks. cell surface receptor chain, IL-12β.
2015) (If Wt >100 kg: 90 mg SC)
Ixekizumab Loading dose: 160 mg SC Monoclonal antibody that selectively binds
(Talza) (ie, as two 80-mg injections) with interleukin 17A (IL-17A) cytokine
once, and inhibits its interaction with the IL-17
receptor
Maintenance dose: 80 mg
SC every 4 weeks
Targeted DMARDS
✓ Oral small molecule drug.
Tofacitinib: A daily 5mg twice \day taken ✓ It acts to block the body’s production of the
by ORAL rout. enzyme JAKs (Janus Kinase) which play a
Xeljanz (Approved 2017 for AS & PsA) role in joint inflammation in RA.
Apremilast Oral small molecule that inhibits

(Otezla) Dose: 30 mg twice a day phosphodiesterase 4 (PDE4) >>> the
(FDA approval in PsA: 2014) hydrolysis of intracellular (cAMP) is abrogated
which decreases production of TNF-α, IL-12,
IL-23, and others.
• Popular DMARD combination is the triple therapy of MTX combined with HCQ and SSZ.
• The most effective: The combination of MTX and a TNF blocker appears to be the most effective regimen
for preventing radiographic progression of disease.
• In clinical practice, attempting to reduce disease activity as much as possible by
(1) Increasing the dose of medication (eg, MTX),

(2) Switching to other DMARDs in those who do not respond or in those with responses regarded as
insufficient, or
(3) Initiating combination therapy is important.
• Because patients may require 2-3 months to achieve a full response to DMARDs, decisions regarding
changes in medication are often delayed until that time.
EULAR 2019 Guide Lines
Assessment of the disease activity

Disease Activity Indices
Defination: It is the assessment of disease activity in RA through clinical, laboratory, and
radiographic measures.
Measures used to assess disease activity:

o Clinical :
 The number of tender and swollen joints.
 The patient’s overall rating for pain.
 Degree of functional disability.
o LAB: serum levels of acute phase reactants (ESR&CRP).
o Imaging: extent of radiographic progression of the disease.
criteria for Remission of RA

 Five or more of the following for at least 2 consecutive months:
1. Duration of morning stiffness not exceeding 15 minutes

2. No fatigue
3. No joint pain
4. No joint tenderness or pain with motion
5. No soft-tissue swelling in joints or tendon sheaths
6. ESR of less than 30 mm/h in a female or less than 20 mm/h in a male
Disease activity score (DAS28)

 Defination: It is the assessment of disease activity in RA through clinical & laboratory
measures.
 Measures used in DAS28:
✓ The number of tender and swollen joints (28-joint count).
✓ Patient self-assessment of disease activity:
1. Visual analog scale for degree of pain.
2. Visual analog scale for degree of functional disability.
✓ ESR or serum CRP level.
 Importance of DAS28: This formula has been applied in clinical practice to monitor disease
activity and guide treatment decisions.
Value of DAS28 Disease actvity

Less than 2.6 Remission
2.6 - 3.2 Mild activity
3.2- 5.1 Moderate activity
More than 5.1 Sever Activity
28-joint used in DAS28(Bilateral)
PIP>>>>5…….MCP>>>4………Wrist>>>1…..Elbow>>>1……..Shoulder>>>1 Knee>>>1……Ankle>>>1
Functional status of patients with RA

• Class I -Completely able to perform usual activities of daily living
• Class II - Able to perform usual self-care and vocational activities but limited in avocational
activities.
• Class III - Able to perform usual self-care activities but limited in vocational and avocational
activities
• Class IV - Limited in ability to perform usual self-care, vocational, and avocational activities
Treatment of RA Co-morbid conditions

A- Osteoporosis:
 Osteoporosis is a major comorbidity in RA and can result from:
o Persistent inflammation & the immobility
o Prolonged use of corticosteroids.
 Prevention & ttt:
▪ Calcium and vitamin D: Most patients are routinely advised to take calcium
and vitamin D to prevent osteoporosis.
▪ Bone densitometry (DEXA) in patients with risk factors for osteoporosis.
▪ For established cases >>>> Bisphosphonate or a selective estrogen receptor
blocker.
B-Cardiovascular (CV) disease:

➢ Cardiovascular (CV) disease is the number one cause of death in RA patients.
➢ Available data suggest that MTX and anti-TNF treatment reduces the rate of CV events.
➢ Low dose aspirin should be considered in patients over the age of 50 years as primary
prevention for CV disease.
➢ Detection & management of risk factors (Cholesterol levels ,hypertension, diabetes, and obesity)
Recommendations in RA patients with Viral Hepatitis

Hepatitis B Hepatitis C
All Patients with hepatitis B or C who are untreated, should referred for antiviral therapy prior to
immunosuppressive therapy.
RA treatment should be the Disease-modifying drugs such as methotrexate and leflunomide

same as that of unexposed are potentially hepatotoxic and should be used with extreme
patients, as long as the caution.
patient’s viral load is • The Child Pugh score (A to C) is used to assess severity &
monitored regularly prognosis of cirrhosis; Child A patients have the best
prognosis.
• According to the ACR guidelines, in the setting of chronic HCV
infection:
❖ MTX is contraindicated in all patients in CPT class A, B, or
C.
❖ SSZ is contraindicated in patients in CPT class B or C.
❖ HCQ is contraindicated in those in CPT class C.
Rituximab cab be used in the TNF inhibitors therapy can be safely administered in HCV-
treatment of rheumatoid positive patients, if treatment with antiviral therapy is used.
arthritis with hepatitis B
patients.
Management of active RA in Nephritis patient

1- NSAIDs:
✓ NSAIDs are known to have a variety of specific adverse effects on the kidneys
so in Active RA, we should adjust NSAIDs dose.
✓ Selective COX-2 inhibitors would have less renal effects than the traditional
NSAIDS.
2- Corticosteroids:
✓ Prednisone the most commonly used glucocorticoid generally should not be
used in doses higher than 10 mg daily and safe in RA with nephritis and does
not adjust the dose.
3- Conventional DMARDs:
➢ Hydroxychloroquine, leflunomide and sulfasalazine are the most common DMARDs
to treat RA in the setting of renal impairment.
➢ Recommended adjustment (% standard dose) according to British Society For

Rheumatology (BSR) 2018:
➢ Methotrexate and RA with renal impairment:

❖ Dosage adjustments for CrCl:
✓ 61 to 80 mL/min Reduce the dose by 25%
✓ 51 to 60 mL/min Reduce the dose by 30%
✓ 31 to 50 mL/min Reduce the dose by 50-80%
✓ ≤ 30 mL/min Avoid use.
4- Azathioprine:
➢ AZA is most commonly used as a substitute for MTX when contraindications as renal
impairment CrCl ≤ 30 mL/min.
5- Biological DMARDs:
➢ No evidence on the effect of TNF- α inhibitors on renal function or any dose
adjustment required
Notes on Rheumatoid Arthritis

Course of the disease:
1. Intermittent course
o The disease is usually mild
o There is partial to complete remission without need for continuous therapy
o About 15 – 20% of patient with RA enjoy these periods of remission.
2. Long clinical remission

o About 10% of patient may develop a clinical remission for years; nevertheless some signs of disease
activity persist in many through the clinical remission (eg. Elevated ESR).
o Spontaneous remission is uncommon, especially after the first 3-6 months.
3. Progressive disease.
Insidious Onset of RA in Older Individuals

➢ Older individuals (≥65 years old) who develop RA often present with stiffness, limb girdle pain, and diffuse
swelling of the hands, wrists, and forearms.
➢ Clinical onset that mimics polymyalgia rheumatica or remitting seronegative synovitis with pitting edema
(RS3PE) also can occur in the elderly.
➢ Individuals with onset at age 60 years or older are less likely to have subcutaneous nodules or RF at the
onset of disease, despite the high prevalence of RF in the general population in this age group.
➢ Generally, elderly individuals who develop RA tend to have a more benign course than younger people; the
frequency of positive tests for RF is lower, but a strong association with HLA-DR4 has been noted.
➢ Onset is slow, but stiffness is often incapacitating.
The differential diagnosis of rheumatoid nodules:

1. Subcutaneous nodules >>> Rheumatic fever. 6. Granuloma annulare consists of intracutaneous
2. Gottron’s papules >> Dermatomyositis, nodules that are histologically identical to
3. Calcinosis >>>> Scleroderma. rheumatoid nodules.
4. Gouty Tophi 7. Multicentric reticulohistiocytosis: Nodules of
5. Benign nodules: usually found in healthy multicentric reticulohistiocytosis contain large,
children that are nontender and appear on the lipid-filled macrophages.
pretibial regions, feet, and scalp. 8. erythema elevatum diutinum.
9. and leprosy
➢ Histopathology of subcutaneous nodules (rheumatoid nodules): SC nodules that have central area of
fibrinoid necrosis surrounded by a zone palisades elongated histiocyte and peripheral layer of cellular
connective tissues.
Mechanism of some Deformities in RA
➢ Piano sign: The ulnar collateral ligament, stretched by the proliferative synovium of the radioulnar
joint, finally ruptures or is destroyed, and the ulnar head springs up into dorsal prominence, where it
“floats” and is easily depressed by the examiner’s fingers (piano key styloid).
➢ Radial deviation of the wrist: weakening of the extensor carpi ulnaris muscle leads to radial
deviation of the wrist as the carpal bones rotate (the proximal row in an ulnar direction and the distal
ones in a radial direction).
➢ Swan neck deformity is begins with shortening of the interosseous muscles and tendons. Shortening
of the intrinsic muscles exerts tension on the dorsal tendon sheath, leading to hyperextension of the
PIP joint Deep tendon contracture or, rarely, DIP joint involvement with RA leads to the DIP joint
flexion.
➢ Boutonniere deformity: during chronic inflammation of a PIP joint, the extensor hood stretches or is
avulsed, the joint may pop up in flexion, producing a boutonniere deformity The DIP joint remains in
hyperextension.
➢ Inflammation of the carpometacarpal joint leads to volar subluxation during contracture of the
adductor hallucis.
➢ One likely mechanism behind tears is that the rotator cuff tendon insertion into the greater
tuberosity is vulnerable to erosion by the proliferative synovitis that develops there. Marked soft
tissue swelling of the anterolateral aspect of the shoulders in RA may be caused by chronic
subacromial bursitis.
➢ Patients with subluxation of metatarsal heads can develop pressure necrosis of the plantar surfaces.
Alternatively, those who have
➢ Patients with subluxation of MTP joints often develop ulceration over the PIP joints that protrude
dorsally (hammer toes).
➢ The net result is increased pressure on the MTP joints with a sensation described as “walking on
marbles” by many patients.
Mustafa Elmenawy
Basic
Rheumatology
Juvenile idiopathic
arthritis
Juvenile Idiopathic Arthritis

Definition: Juvenile idiopathic arthritis (JIA) refers to the group of disorders characterized
by chronic synovitis in any one joint for more than 6 weeks in a child less than 16
years of age.
Prevalence:
• It is the most common chronic rheumatic disease of childhood.
• Actual estimates of prevalence and incidence vary remarkably in different
geographic regions, ranging from 7 to 400 per 100,000 children, reflecting
variations in disease reporting, classification, and racial/ethnic and environmental
differences in disease expression.
RISK FACTORS OF JIA

✓ Many JIA patients will have a history of upper respiratory infections or vaccinations
preceding the onset of arthritis.
✓ Gene variants in the HLA region of chromosome 6 are associated with JIA, except
for sJIA, similar to other autoimmune diseases.
✓ The HLA-DRB1*0801 gene variant is found to be associated with oligoarthritis &
with polyarticular JIA.
Classification:
➢ JIA are identified and classified based on several factors:
• Age at onset.
• Number of joints involved initially and as the disease progresses.
• Associated clinical features (such as rash, fever, and iritis).
• Lab test results (rheumatoid factor positive or negative).
Essential to Diagnoses:
➢ The criteria for JIA require:
• Onset before the 16th birthday.
• Persistent objective arthritis (swelling, effusion, or the presence of two or more of the
following—limitation of motion, tenderness, pain on motion, or joint warmth, i.e., arthralgia alone is not
sufficient). in one or more joints for at least 6 weeks.
• Exclusion of other causes of childhood arthritis.
Juvenile idiopathic arthritis 43

Classification criteria for JIA

Oligoarticular JIA Polyarthritis Polyarthritis

RF positive RF negative
Incidence: 25- 50% 2- 10% 10- 25%
Age of onset 1-5 years old 8-12 years old 8-12 years old
Sex: 4 Female: 1 male 6-10 Female: 1 male 3 Female: 1 male
Arthritis • Usually asymmetrical Arthritis • Symmetrical Arthritis in • Symmetrical or
affect less than 5 joints. five or more joints at the
asymmetrical Arthritis
• Knees are the most commonly onset of the disease Usually affects large
involved joints. (during the first 6 joints. (Knee Hip,
shoulder, cervical
• Morning stiffness is a prominent months).
spine) and DIP
finding. • Small-joint of the hands
joints.
• The neck at the atlantoaxial (C1– and feet are the most • These children can
C2) joint and the commonly involved have active arthritis
temporomandibular joint are joints for many years
relatively hidden sites where joint without erosive
inflammation can also occur. change on x-ray.
Associated • Iritis: chronic, anterior, non- • Child may have • May be associated
granulomatous uveitis or rheumatoid nodules, with:
iridocyclitis. with aggressive erosive ✓ low-grade fevers,
• Usually: joint disease. fatigue.
✓ Affect very young girls with a ✓ Poor growth and
positive (ANA) test. • Iritis or uveitis is weight loss.
✓ Painless and occurs early in uncommon in this
the course of the illness. subgroup. • Iritis or uveitis is
• (75%) of young girls with uncommon in this
oligoarticular JIA and iritis will subgroup.
have a positive ANA test.
Prognosis • Persistent oJIA has the best • PoJIA RF +ve clinically • The course is
overall articular outcome of all resembles the adult variable, and
JIA categories. form of classic transition to the RF
• Arthritis often resolves by the rheumatoid arthritis positive group can
time they reach school age more than any other JIA occur.
and usually does not lead to subset & their similar
permanent joint damage. HLA-DR4 associations.
Laboratory • In mild cases: usually there is • Elevated ESR & CRP. • Elevated ESR &
Findings: no sign of acute phase response CRP.
in the serum, such as a raised • RF: all patients have
ESR or CRP. immunoglobulin (Ig)M– • ANA: is positive in
• In the more severe cases and anti-IgG RF. about 40% of
in EO patients: • ANA: is positive in patients.
✓ The ESR and CRP are raised. about 55% of patients.
✓ Low titer ANA are frequently • Anticcp Ab: is positive
seen. in 60-70% of patients.
• There are no Rheumatoid factor
or other autoantibodies.

Systemic onset JIA Enthesitis-related Psoriatic Arthritis

JIA/ JSpA JIA
Incidence: 2-17% 2- 10% 2-10%
Age of onset 1-6 years old After the age of 6 years Any age below 16
Sex: Equally affect both sex 7 male: 1 female Equally affect both sex
Arthritis • Usually develops concurrently • At disease onset: • Peripheral, asymmetric.
with the fever and systemic ✓ Peripheral arthritis 80% • Usually involves: knees,
✓ Inflammatory LBP 25%.
features. ankles, and small joints
✓ 1/3 of JSpA children will of the hands and feet.
• But in some patient’s True have the classic finding
arthritis may manifest months of tarsitis, which is • The sacroiliac joint are
after the onset of fever, which inflammation of the affected in about 40%
can make early diagnosis subtalar joint and the of patient.
difficult. surrounding tendon • At onset, about 70% of
sheaths. the pJIA patients have
arthritis in four or more
joints.
Associated • Fever (daily spiking in a "rabbit • Enthesitis: The most • Psoriatic rash: Only
common sites include: about 10% of children
ears" pattern).
the superior curve of the have the onset of the rash
patella, tibial tuberosity and the arthritis at the
AND at least one of the following: attachment of the same time.
• Rash (evanescent, salmon- Achilles tendon and sole • Dactylitis: usually
colored, macular rash on the of the foot at the asymptomatic
trunk and extremities). metatarsal heads
• Generalized LN enlargement. • Asymptomatic chronic
• Hepatomegaly and/or • Acute uveitis: 25% anterior chamber
✓ usually unilateral & uveitis clinically
splenomegaly. intermittet. symmetrical to that
• Serositis. which occurs in oJIA.
(20% of cases)
Prognosis • The long-term prognosis for sJIA ➢ NB: ➢ NB:
is determined by the severity of • LAB: ANA and RF are ✓ The classic psoriatic rash
the arthritis. negative. may not appear for many
Laboratory • Highly elevated ESR &CRP. years after the onset of the
Findings: • Elevated ferritin levels • HLA-B27 is present in arthritis (about 40%–60% of
60% to 80% of patients
• Leukocytosis (mainly neutrophilia with JSpA
the patients).
level) & Thrombocytosis,
• Plain radiographs:
✓ The rash comes first in about
• A hypochromic microcytic anemia. (40%–60%) of the patients.
often do not show the
• RF & ANA: usually negative characteristic changes
• Complement levels are normal or in the SI or lumbosacral
high. spine for many years.
• Immunological abnormalities include
the presence of polyclonal
hypergammaglobulinemia.

NB
Systemic onset JIA
A. Complication: (rare) SJIA patients can develops:
✓ Growth delay & Osteopenia
✓ Macrophage activation syndrome
✓ Pericardial tamponade.
✓ Severe vasculitis with secondary consumptive coagulopathy.
B. Others:
✓ The extra-articular features are usually mild to moderate in severity and almost always self-limited(resolve
when the fevers resolve.)
✓ Raised proinflammatory cytokines, such as IL-1, IL-6, IL-18, and TNF as well as chemokines, such as IL-8
(CXCL8) in the serum or plasma
✓ Positive rheumatoid factor (RF) and uveitis are RARE.
Juvenile Idiopathic Arthritis, Enthesitis-related

➢ In patients with inflammatory bowel disease, the articular involvement may precede the gastrointestinal (GI)
inflammation by months to years.
➢ Clues to the presence of GI involvement include:
✓ Fatigue, weight loss, growth failure.
✓ Nocturnal bowel movement.
✓ Mouth ulcers, erythema nodosum, pyoderma gangrenosum.
✓ Anemia.
➢ Aortic involvement with aortic valve insufficiency has been rarely reported in children with eJIA.
Differential diagnosis of JIA includes:

• Nonrheumatic causes of joint pain and swelling, such as:
✓ Septic arthritis & Reactive arthritis.
✓ Postinfectious arthritides (viral, rheumatic fever, post-streptococcal, Lyme).
✓ Bony fractures, including nonaccidental injury.
✓ Benign or malignant tumors.
✓ Foreign body synovitis & Pigmented villonodular synovitis.
✓ Bleeding disorders (such as hemophilia).
• Rheumatologic diseases such as:

✓ SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteomyelitis), Kawasaki’s disease, and vasculitis.
✓ Both Behçet’s disease and familial Mediterranean fever can have sacroiliitis features and therefore could be
mistaken for JSpA.

Oligoarticular JIA
➢ Subtypes:
▪ oJIA patients are divided into two subcategories:
❖ Persistent oJIA: patients never have a cumulative total of more than four joints with arthritis during the course
of the disease (50% of these patients usually have monoarticular involvement in a knee joint).
❖ Extended oJIA: (more extensive and severe articular involvement):

✓ Patients demonstrate a cumulative total of five or more joints arthritis after the first 6 months of the
disease.
▪ Up to 50% of oJIA cases will evolve to the extended subcategory (30% will do so in the 2 years after disease onset).
▪ Risk factors for developing oJIA extended subcategory (in the first 6 months of disease onset) are:
✓ Arthritis in the wrist, hand or ankle.
✓ Symmetrical arthritis.
✓ Arthritis in more than one joint.
✓ Elevated erythrocyte sedimentation rate (ESR).
✓ Positive antinuclear antibodies (ANA).
➢ Iritis:
▪ One out of five patients with oligoarticular JIA will have asymptomatic iritis.
▪ All children with oligoarticular JIA should have regular slitlamp exams done until they reach 18 years of age, even in the
absence of a red eye or joint symptoms.
▪ Complication: (Serious complications can result from untreated eye disease) such as:
√ Glaucoma. √ Cataracts. √ Band keratopathy.
√ Partial or total visual loss.
➢ Differential diagnosis of oligoarticular JIA includes:

• Other JIA subtypes, especially juvenile spondyloarthritis (JSpA) and juvenile psoriatic arthritis (JPsA);
• Other rheumatic diseases of childhood, or other inflammatory conditions such as inflammatory bowel disease (IBD).
Polyarticular RF Positive JIA

➢ To be considered RF+, the patient must have at least two positive results for RF at least 3 months apart during the first
6 months of disease.( Caution has to be made in the diagnosis of this in children, because RF can be transiently raised
due to infection).
➢ Local growth disturbances occur as a result of inflammation (persistent synovitis) and the accompanying increase in
vascularity (Knee & hip joints are the most frequently affected by growth disturbance).

Macrophage activation syndrome (MAS)

➢ It is a potentially life-threatening complication affect 10% -30of patients with sJIA (as well as sometimes complicating
other rheumatologic conditions, such as juvenile systemic lupus erythematosus).
➢ The mortality rate can be 20% to 30%, accounting for the majority of the mortality een in all patients with JIA.
➢ Pathology:
✓ MAS is a form of secondary or acquired hemophagocytic lymphohistiocytosis (HLH) seen with rheumatic disease.
✓ Result from immune activation of pathogenic T cells and hemophagocytic macrophages.
✓ These macrophages express CD163, a scavenger receptor that recognizes haptoglobin-hemoglobin (HP-Hb) complexes.
Increased uptake of these complexes within the macrophage leads to production of ferritin, explaining the
hyperferritinemia associated with MAS.
✓ Soluble forms of CD25, the alpha chain of the IL-2 receptorexpressed on T cells, and CD163 are useful biomarkers for
MAS in JIA.
➢ Clinical presentation:
✓ High fevers, hepatosplenomegaly, lymphadenopathy.
✓ Petechiae, mucosal bleeding, epistaxis, and hematemesis.
✓ central nervous system (CNS) involvement (seizures/coma),
➢ LAB finding:
✓ Severe cytopenias with decreased leukocyte and platelet counts
✓ liver dysfunction.
✓ Ferritin often exceeds 10,000 ng/mL.
✓ Coagulopathy with elevated prothrombin and partial thrombin times, hypofibrinogenemia
✓ Falling ESR
➢ Risk factor for developing MAS:
✓ Prolonged disease activity.
✓ infectious triggers (Epstein-Barr virus, varicella, coxsackie, parvovirus B19, hepatitis A, Salmonella, and
Pneumocystis),
✓ medication exposures (aspirin, NSAIDs, sulfasalazine [SSZ], methotrexate [MTX], etanercept, anakinra, and gold
salts),
Condition Differentiating Features from Systemic JIA

Infection Positive cultures, PCR, or specific antibodies; continuous or irregular fever, nonquotidian; various
rashes (not typical systemic JIA rash)
Leukemia Nonquotidian fevers; bone pain; systemically unwell constantly
Neuroblastoma Nonquotidian fevers; systemically unwell constantly
CINCA or NOMID Fixed rash; undulating fevers; neurologic complications
Kawasaki disease Fixed rash; mucocutaneous symptoms; coronary artery dilation
Other primary Undulating fevers; fixed, painful rashes or purpura; systemically ill constantly; renal involvement
vasculitis
SLE Constant or nonquotidian fevers; positive ANA and dsDNA antibodies; cytopenias; other organs
involved

• Done as basic evaluation of joint pain in children then serial exams done at 6- to
12-month intervals in selected patients with aggressive disease.
• Damage to cartilage and bone erosion are both seen in JIA.
• There is often uneven local acceleration of growth of epiphyses in the
inflamed area, leading to growth deformities.
Ultrasonography & MRI : Early detection of synovitis, erosion & effusions.
complications
1. Local growth disturbances:

• Mandibular asymmetry - Leg length inequality - Gait abnormalities.
2. Generalized growth retardation & Muscle atrophy.

3. Osteopenia/osteoporosis.
4. Loss of vision, glaucoma, and cataracts.
5. Complications of therapy such as: infection, delayed immunizations,
steroid complications, and dyspepsia from nonsteroidal anti-inflammatory drugs
can occur.
6. Most deaths are in patients with systemic arthritis due to:

• Amyloidosis.
• Macrophage activation syndrome.
Prognostic Factors that predict poor outcome

can help determine patients requiring early aggressive therapy
1. Female sex.
2. +ve family history.
3. Low socioeconomic and educational status.
4. Sero-positivity( RF & Anticcp ab).
5. High titer of RF & Anti-ccp.
6. Early disease activity & High number of swollen tender Joints.
7. Rheumatoid nodules & Extra articular feactures
8. HLA-DR4.

Pathology &Pathogenesis of JIA

 The 1ry target of the disease is the SYNOVIUM
 Pathological changes occur as following:
1. Synovitis and joint effusion.
2. Proliferation of the Synovial membrane & pannus formation.
3. Cartilage destruction & bone erosion.
4. Fibrosis, Ankylosis, Deformity &Subluxation (later on).
The Synovium Changes in JIA:

4. Pannus formation: Villous projections protrude into the joint cavity, invading the
underlying cartilage and bone.
 Cells:
cellular debris.
Summary of Cytokines and Inflammatory Mediators Implicated in JIA

Mediator Cell Pathology
Cytokine mediator Cells Pathology
TNF Monocytes,T, B Activates monocytes and neutrophils
cells,PMNs, mast cells, Damages cartilage
fibroblasts Endothelial cell adhesion molecules
Inhibits regulatory T cells
IL-1β Monocytes,B cells Activates osteoclasts (bone damage)
,fibroblasts Fibroblast cytokine, chemokine release↑Endothelial cell adhesion molecules
IL-17 T cells mast cells-Chemokine Cartilage damage - Activates osteoclasts
(Th17) release (recruit PMNs) Synergizes with TNF and IL-1β
IL-6 Monocytes, fibroblasts,B B cell activation - Inhibits regulatory T cells
cells Growth retardation
Acute phase response and anemia
IFN-γ T cells (CD4+ Activates monocytes
Th1, CD8+,NK cells) ↑Endothelial cell adhesion molecules
MRP 8/14 Monocytes, Activates monocytes
PMNs Promotes pathologic CD8+ T cells
Secretion of IL-1β
↑Endothelial cell adhesion molecules
NB
 IL-18, a macrophage-derived pro-inflammatory cytokine is also grossly elevated in sJIA, with serum levels correlating
with disease activity.
 High IL-18 levels may account for the defective NK cytotoxic function found in sJIA.
 IL-6 is another key player in the pathogenesis of sJIA, secreted by a range of cells, including monocytes.
 IL-6 levels are elevated in the serum and synovial fluid of sJIA patients, levels correlate with disease activity, and
clinical features (including growth failure and osteoporosis) can be explained by high levels of IL-6.
Genetics of Juvenile Idiopathic Arthritis

➢ There is strong evidence for a genetic component to the etiology of JIA.
➢ The strongest genetic associations of JIA are with genes of MHC.
➢ Specific class I MHC alleles are associated with enthesitis related arthritis.
➢ Distinct class II MHC alleles are associated with oligoarthritis and polyarthritis subtypes.
➢ Many genes that alter the threshold of immune cell activation and signaling, or relate to cytokines and their receptors,
are linked with JIA.
➢ The presence of RF and a severe erosive disease course suggests that children in this subgroup represent an early
presentation of adult-onset RA. Indeed, this subtype of JIA shares genetic associations, in particular at the HLA-DRB1
locus, with adult rheumatoid, in particular, the association with the DRB1*0401 allele at this locus.
➢ There is genetic differences between persistent and extended oligoarticular phenotypes include variation in the
class I MHC allele associations25 and IL-10.

Treatment of JIA
Essential to Know:
➢ The goal of therapy for JIA is to:
1. Put the disease in remission (reduce or eliminate pain & swelling) and to
2. Prevent joint damage.
3. Improve physical function.
5. Once joint pain, stiffness, and swelling are reduced, then gait patterns and
patterns of use will return to normal, and muscle atrophy will reverse, making
joint contracture less likely.
➢ Most children in the oligoarticular, polyarticular rheumatoid factor negative, and

enthesitis-related subgroups will not need disease-modifying antirheumatic drugs
to control their arthritis symptoms.
➢ Patients with rheumatoid factor positive polyarticular disease should be treated

aggressively with disease-modifying antirheumatic drugs early to avoid joint erosions
and deformities.
➢ SOJIA patients may require corticosteroids initially to get control of their

symptoms, and biologic therapy or other disease-modifying antirheumatic drugs to
maintain remission.
➢ Most studies in children did not find hydroxychloroquine, oral gold, D-penicillamine,
or azathioprine to be effective in the treatment of JIA.
➢ Life style modification & Physiotherapy:

❖ Physiotherapy is advised during chronic stage of the disease to:
1. Maintain range of motion of the affected joints.
2. Improve muscle strength & prevent deformities.
3. Correct or minimize damage and loss of function.


Treatment for patients with Polyarthritis
NB
❖ Infliximab higher dose 6 mg/kg/ infusion appears to be more effective than the adult dose of 3 mg/ kg/infusion.
❖ Higher doses of infliximab can be given if loss of efficacy with time occurs, possibly from the formation of anti-infliximab
antibodies.
❖ Low-dose MTX given concomitantly may reduce the risk of neutralizing antibody development, as it does in adults.

Treatment for patients with oligoarthritis
NB
❖ Enthesitis-Related Arthritis:
✓ Sulfasalazine may be beneficial, particularly for older males with peripheral arthritis.
✓ Anti-TNF medications are highly effective.
❖ Psoriatic Arthritis:
✓ The presentation of psoriatic arthritis can be as oligo-, poly-, and enthesitis-related arthritis it should be
treated as the parallel JIA subset.

Treatment for patients with Systemic JIA

Corticosteroids
The main indications for systemic use of corticosteroids in JIA are:
➢ Uncontrolled fever.
➢ Serositis.
➢ The macrophage activation syndrome in systemic arthritis.
➢ Use as a bridging medication until other medications become effective.
➢ Periodic intravenous pulses of corticosteroids (30 mg/kg/dose, maximal 1 g) are used instead
of high dose daily oral corticosteroids.
Intraarticular injections of corticosteroids:

➢ There excellent evidence for the efficacy of intraarticular injections of corticosteroids
mainly in patients with oligoarthritis.
➢ The long-acting triamcinolone hexacetonide more effective and had a longer
effect than other forms of injectable corticosteroids
➢ Main Adverse effects associated with these injections is development of
periarticular subcutaneous atrophy. (And can be prevented by injecting small amounts of saline while
withdrawing the needle following the injection and by applying pressure to the injection site).
Methotrexate
➢ The use of methotrexate (MTX) is the cornerstone of the medical management plan
for most patients with JIA and polyarthritis.
➢ The efficacy of MTX differs by the subtype of JIA, with the greatest efficacy seen
in patients with extended oligoarthritis, while less effective in systemic arthritis
Sulfasalazine:
➢ Sulfasalazine is effective in the treatment of oligo- and polyarthritis.

➢ Sulfasalazine seems to be most effective in older males with oligoarthritis
➢ The effect may persist for years after sulfasalazine is discontinued.
➢ Adverse reactions were frequently reported, especially rashes.
Cyclosporine:
➢ Cyclosporine used in patient with systemic arthritis for:

✓ Fever control
✓ Corticosteroid dose reduction
✓ Patients with the macrophage activation syndrome.

Treatment of JIA associated conditions

A- UVEITIS:
➢ Initial treatment consists of:
✓ Topical corticosteroid drops.
✓ Subtenon corticosteroid injections.
➢ Immunosuppresive therapy:
✓ Should be started early in patients with severe uveitis or in those who become
corticosteroid dependent. (MTX is the most common medication used.)
✓ Infliximab: used for patients not responsive to MTX (but not etanercept).
NB:
✓ Uveitis is less likely to persist when arthritis is in remission.
✓ The treatment of uveitis should be directed by ophthalmologists with experience in treating this disorder with the
guidance of pediatric rheumatologists experienced in managing immunosuppressive and biologic-modifying
medications.
B- Osteopenia and Osteoporosis:

➢ Child with JIA is at great risk for failure to achieve adequate postpubertal bone
mass.
➢ Risk factors:
▪ Decreased physical activity & immobility.
▪ Decreased sun exposure.
▪ Decreased dietary intake of calcium and vitamin D.
➢ Management of Osteopenia include:

1. Weight-bearing exercise.
2. Appropriate nutrition.
3. Calcium and vitamin D supplementation.
4. Adequate disease control with suppression of inflammation.

Lifestyle modification & Physiotherapy

A-Physical therapy:
➢ The main purposes of physical therapy are to:
✓ Maintain range of motion of the affected joints.
✓ Improve muscle strength & prevent deformities.
✓ Correct or minimize damage and loss of function.
➢ Methods used include:
▪ Exercises:
✓ Guided and home exercise programs for range of motion.
✓ Muscle strengthening exercises.
▪ Splints.
▪ Orthotics:
1. Shoe lifts: used in the shorter leg patients with leg length discrepancy.
2. Arch support for flat foot in order to:
✓ Decrease pain when walking & improve gait.
✓ Minimize pressure on metatarsal heads thus preventing the
formation of callus or subluxations of the toes.
B- Physical activity:
✓ Physical activity is encouraged but should be tailored by the degree of arthritis and
the joints involved.
✓ Children are encouraged to set their own limits but should not persist in an activity
that causes pain in an arthritic joint.
✓ Activities that are less weight bearing, such as swimming and cycling, are preferred.
C- Occupational therapy: (to maintain and improve the normal life function).
➢ Techniques used include:
o Hand exercises.
o Wrist, hand and finger splints.
o Teaching joint protection techniques.
o Heat pads or bottles, bathing and paraffin baths to decrease morning stiffness.
➢ Common school adjustments which include allowing:
o Elevator use.
o Stretching in class.
o More time to write tests.
o Computer use.
o Gym modifications.
➢ Common School problems for children with arthritis includes: handwriting, opening doors, lateness to class,
physical education participation, carrying books, fatigue, absences, and inadequate understanding by teachers and
peers.
D- Psychological support:
➢ Patients and families should be encouraged to seek support early before a crisis
occurs.
➢ This support is often needed to deal with medication issues such as body image
changes from corticosteroids, nausea from methotrexate, or to increase compliance
with the medication regimen.



Mustafa Elmenawy
Basic
Rheumatology
Spondyloarthropathy
Spondyloarthropathy
➢ Seronegative spondyloarthropathies are a group of autoimmune disorders that involves
chronic inflammation of the sacroiliac joints and spine as well as extraspinal
lesions involving the eye, bowel, and heart.
➢ Seronegative spondyloarthropathies includes:

✓ Reactive arthritis.
✓ Psoriatic arthritis.
✓ Ankylosing spondylitis.
✓ Enteropathic-arthritis: the arthritis associated with inflammatory bowel disease.
➢ Spondyloarthropathy share many clinical features, and it may not be possible to

distinguish among these, particularly in the early phases, leading to a diagnosis of
undifferentiated spondyloarthropathy.
➢ Their shared clinical features include:
1. Arthritis of the axial skeleton (sacroiliac joints and spine).
2. Arthritis of peripheral joints (usually oligoarticular).
3. Enthesitis:
➢ Definition: Inflammation of the sites where fascia, tendons, and ligaments attach to
bone, or enthesitis.
✓ Clinically presented as:
• Swelling & tenderness of the involved tendon or ligament.
• Heel pain is the most common manifestation due to inflammation where the
Achilles tendon inserts onto the calcaneus.
✓ It is usually a prominent feature of reactive arthritis.
4. Dactylitis:
✓ Definition: it is an inflammation of the tendons and the adjacent synovium in a toe
or finger (synovitis and enthesitis).
✓ Clinically presented as:
• Sausage digit: diffuse swelling of the affected digit producing dactylitis.
• Dactylitis involves the toes more commonly than the fingers.
✓ It is usually a prominent feature of reactive arthritis and psoriatic arthritis.
5. Inheritance of human leukocyte antigen (HLA)-B27 increases the relative risk of

developing spondyloarthropathy, particularly when there is involvement of the axial
skeleton.
6. These diseases are not associated with rheumatoid factor and thus are often referred to
as the "seronegative" spondyloarthropathies (Old term).
Ankylosing Spondylitis
Definition:
Chronic inflammatory autoimmune disease affecting mainly young adult male,
characterized by chronic arthritis of the sacroiliac joints and spine with
ankylosis & ossification,and may be associated with a variety of extraspinal
lesions involving the eye, bowel, and heart.
Epidemiology:
• Prevalence: The overall prevalence of AS is 0.1% to 3% of population
• Age of onset: Usually affect young adult male with average age at onset is 26 years
(early adulthood & onset of symptoms after the age of 40 is uncommon).
• Sex: Males are affected 3 times more than females.
• Onset: Insidious (builds up over several months)
Pathogenesis & Pathology
Aetiology
Genetic Risk Factors
 Major Histocompatibility Complex Associations with Ankylosing Spondylitis(HLA-B27)

➢ HLA-B27 is the only known susceptibility gene confers a relative risk for ankylosing
spondylitis
➢ Inheritance of HLA-B27 is strongly associated with ankylosing spondylitis.
➢ Normally: HLA-B27 present in 5% to 15% of the general population (HLA-B27 positive).
➢ Inheritance of HLA-B27 is not sufficient to produce ankylosing spondylitis.
✓ Fewer than 5% of HLA-B27–positive individuals develop SpA.
✓ The great majority of HLA-B27–positive persons (95% in some studies) do not have
ankylosing spondylitis (or any other spondyloarthropathy).
➢ HLA-B27 is present in >90% of patients with AS, as well as 50% to 75% of patients with
other forms of spondyloarthritides.
➢ The shared amino acid sequence between several HLA-B27 genotypic subtypes and K
pneumoniae nitrogenase, especially HLA-B*2705, suggests a link between these enteric
bacteria and the induction of ankylosing spondylitis.
➢ People who are homozygous for HLA-B27 are at a greater risk for ankylosing spondylitis
than those who are heterozygous.
➢ HLA-B27 testing should be ordered when the diagnosis is suggested by the presence of
inflammatory back pain but remains uncertain after appropriate clinical evaluation and
radiographs.
➢ The test results can substantially increase or reduce the probability of disease (but do
not definitively establish or exclude the diagnosis).
➢ The subtypes of HLA-B27, of which there are more than 30, differ in part only by single
amino acids. Only a few HLA-B27 subtypes are associated with AS.
 Non-Major Histocompatibility Complex Associations with Ankylosing Spondylitis:
➢ Interleukin-23 Pathway Genes

✓ The association of IL23R is found in both HLA-B27+ and HLAB27− disease, and thus
the pathway is relevant to both AS subsets.
✓ There are now multiple polymorphisms identified with independent associations at
IL23R that are associated with AS, inflammatory bowel disease (IBD), psoriasis, and
other associated diseases.
✓ Several other IL-23 pathway genes have also now been associated with AS,
including IL12B, TYK2, and JAK2
➢ Lymphocyte Development and Activation Genes

✓ The association of AS with multiple cytokines, cytokine receptors, and transcription
factors involved in controlling lymphocyte development and activation points to the
key involvement of the affected cell types in AS pathogenesis.
✓ Associated genes include EOMES, RUNX3, TBX21, ZMIZ1, IL7, and IL7R
➢ Aminopeptidase Genes and Ankylosing Spondylitis

✓ Three genes in the aminopeptidase pathway are robustly associated with AS: ERAP1
and ERAP2 encoded at chromosome 5q15 and NPEPPS (puromycin-sensitive
aminopeptidase) at chromosome 17q21.
✓ At least two associated haplotypes are present at ERAP1.
✓ Gene-gene interaction between ERAP1 and HLA-B27 is the first example of
replicated, statistically significant interaction in any human disease and indicates that
the mechanism by which HLA-B27 induces AS must involve aberrant peptide
processing.
Environmental Risk Factors

✓ Ankylosing spondylitis does not develop in every person who is HLA-B27 –positive,
indicating that environmental factors are important.
✓ Even first-degree relatives who are HLA-B27 –positive do not uniformly develop the
disease. In fact, only 15-20% of such individuals develop the disease.
✓ Infection may play a major role and that’s suggested by patients with HLA-B27+
ankylosing spondylitis exhibit several differences in their terminal ileal microbial
communities compared with healthy controls, including a higher abundance of
Prevotellaceae and Bacteroidaceae.
Pathogenesis
 HLA-B 27 pathway: The precise role of HLA-B27 in AS remains unclear. There are four
hypothesis for HLA –B27 role:
A. Arthritogenic peptide hypothesis: The arthritogenic response might involve specific

microbial peptides that bind to HLA-B27 and are then presented in a unique manner to
CD8+ (cytotoxic) T cells resulting in disease.
B. Molecular mimicry: The induction of autoreactivity to self-antigens might develop as a

result of “molecular mimicry” between sequences or epitopes on the infecting organism or
antigen and a portion of the HLAB27 molecule or other selfpeptides.
C. Free heavy chain hypothesis: HLA-B27 heavy chains can form stable homodimers
with no associated β-2 microglobulin on the cell surface. These homodimers can trigger
direct activation of natural killer cells through recognition via immunoglobulin receptor (KIR)-
like receptors causing cytokine (IL-17, TNF) release.
D. Unfolded protein hypothesis: HLA-B27 has a propensity to misfold in the endoplasmic

reticulum causing an unfolded protein stress response. This results in the release of
inflammatory cytokines such as IL-23, which can activate proinflammatory T helper 17
(Th17) cells.
 Endoplasmic Reticulum Aminopeptidase (ERAP) pathway:

✓ Outside the HLA locus, ERAP1 is the strongest association with AS susceptibility.
✓ ERAP1 is an aminopeptidase involved in trimming of peptides that have been
processed through the proteasome.
✓ ERAP1 is therefore considered to be a “molecular ruler,” shaping peptides before
loading onto class I MHC molecules.
 IL-23 Signaling Pathway:

✓ IL-23 signals through a cell surface receptor composed of an IL-23–specific subunit
(IL-23R) and a subunit shared with IL-12R (IL-12RB1).
✓ IL-23 signaling is necessary for the development of IL-17– and IL-22–secreting cells.
✓ Polymorphisms in IL23R and, more recently, downstream components of the IL-23
signaling pathway, JAK2 and Tyk2, and the IL-23 subunit IL12B, have been
associated with AS.
Pathological changes
➢ Main pathology: The principal musculoskeletal lesions associated with AS are
✓ Sacroiliitis & spondylitis.
✓ Enthesitis & synovitis.
➢ Sites of inflammation: The most common in AS includes:

➢ Sacroiliac joints.
➢ Vertebral bodies adjacent to intervertebral disks.
➢ Peripheral joints & entheses.
➢ Gastrointestinal tract and the eye.
➢ Cells & Inflammatory mediators:

✓ T cells (CD4+ and CD8+) and macrophages (CD68+) are accompanied by proliferating
fibroblasts and neovascularization.
✓ There is Overexpression of (TNF-alpha) &Transforming growth factor beta (TGF-beta)
mRN .which provided a strong rationale for the use of TNF inhibitors, which are very
efficacious in SpA.
✓ Macrophages appear to play an important role in early disease, but T cells are clearly
involved.
✓ Both innate and adaptive immune responses may have a role in SpA.
➢ Enthesitis:
✓ a hallmark of SpA, is characterized by erosive, inflammatory lesions associated
with an abundance of osteoclasts and infiltration of the bone marrow.
✓ Early: Reactive bone forms a new, more superficial enthesis, which develops into
a radiologically detectable bony overgrowth or spur.
✓ In the spine: enthesitis occurs at capsular and ligamentous attachments and

discovertebral, costovertebral, and costotransverse joints, with involvement also at
bony attachments of interspinous and paravertebral ligaments.
➢ Sacroiliitis
✓ Mainly affect the lower anterior (synovial) portion of the sacroiliac joints and
are associated with juxta-articular osteopenia and osteitis.
✓ Early: This condition leads to radiographic appearances of widening of the
sacroiliac joint.
✓ Later on: Endochondral ossification as a consequence of the osteitis gives the
radiographic appearance of erosion along the lower part of the sacroiliac joints.
✓ Osteitis appears as increased water content of adjacent bone, as seen on
magnetic resonance imaging (MRI).
✓ At last: Destroyed bone is partly replaced, and endochondral ossification results
in bony ankylosis.
➢ Spondylitis: The development of square vertebral bodies is based on a combination of
a destructive osteitis and repair.
Clinical Findings
A- Axial Spine involvement: (Spondylitis& Sacroiliitis)
➢ Inflammatory low back pain:

✓ It is the hallmark symptom of ankylosing spondylitis.
✓ Insidious onset of inflammatory dull-aching pain (pain worsens with rest, improves with
activity), located in the lower lumbar regions& the buttocks.
✓ This pain sometimes radiates down the thighs but never below the knee.
✓ Accompanied by morning stiffness that lasts 30 minutes or longer.
✓ Sacroiliitis is the cause of this pain.
➢ Limited spinal movements:

✓ There is limitation of spinal mobility, particularly of the lumbar spine.
✓ Lumbar flexion is the most commonly affected followed by reductions in lumbar
lateral bending and rotation.
✓ Reductions in mobility can be induced by:
 Pain or muscle spasm (during early stages of the disease).
 Spinal fusion (irreversible).
✓ Range of spinal movements is tested by Schober & modified Schober testes.
➢ With advanced stages of the disease (DEFORMITIES):

✓ A characteristic posture develops due to the spine fusion in flexion leading to:
• Loss of lumbar lordosis.( One of the first clinical signs)
• Exaggeration of thoracic kyphosis.
• Inability to extend the neck.
• Compensatory hip flexion deformities.
B- Peripheral Joint involvement: (affect 1/3 of patients)

✓ Peripheral arthritis, typically monarticular or asymmetric oligoarticular.
✓ The most frequently involved extra-axial joints: Hips, shoulders, knees and
ankles (respectively)
✓ Temporomandibular joints may be affected, leading to reduced mouth opening and
discomfort on chewing.
C- Costovertebral and costochondral joints involvement:

➢ Involvement of these joints leads to:
✓ Impaired chest expansion (<5 cm difference between full inspiration and full expiration when measured
at the fourth intercostal space).
✓ Pain with deep breathing, coughing, or sneezing.
D- Enthesitis:
➢ Clinically presented as:

• Swelling of the involved tendon or ligament with overlying warmth and
tenderness to palpation.
➢ In AS. there is involvement of insertion sites around the pelvis (the ischial
tuberosities, iliac crests, and greater trochanters).
➢ It's appears on radiographs as bony "whiskering" at these sites of attachment.
➢ Achilles tendinitis and enthesitis at the site of the insertion of the plantar fascia onto
the calcaneus can cause unilateral or bilateral heel pain, but not common as in
reactive arthritis.
E- Ocular manifestations: (Acute anterior uveitis).

➢ The most common extra-articular manifestation of ankylosing spondylitis
➢ One-third of patients experience at least 1 episode.
➢ Anterior uveitis is strongly associated with HLA-B27.
➢ Presentation of acute anterior uveitis:
 There is acute or subacute onset of:
✓ unilateral eye pain
✓ Photophobia.
✓ Blurred vision.
✓ Increased lacrimation.
✓ Ciliary flush: an increased conjunctival injection at the rim of the iris (it’s
a characteristic finding).
➢ Slit-lamp examination:
✓ Detect the presence of cells and flare in the anterior uveal chamber which
establishes the diagnosis.
F- Inflammatory bowel disease(IBD):

➢ IBD affect majority of patients with ankylosing spondylitis but usually it is
asymptomatic and diagnosed by histological examination of biopsy specimens
from the small or large bowel.
➢ Only about 10% to 15% of the patients with AS have symptomatic ulcerative
colitis or Crohn’s disease (altered bowel habits with diarrhea and abdominal discomfort, with or without
passage of blood or mucus).
G- Cardiac involvement: (affect 10% of patients & Strongly associated with HLA-B27)
➢ Presented by: Ascending aortitis, aortic regurgitation, conduction abnormalities, and
myocardial disease
➢ The prevalence of aortic regurgitation (which is the most common cardiac problem)
increases with the duration of disease but remains <10% even after 30 years of disease.
H- Uncommon manifestations: Occurs usually in patients with long standing disease.

➢ Apical pulmonary fibro-bullous disease:
✓ It is characterized by slowly progressive fibrosis of the upper lobes of the
lungs.
✓ Presentation: cough, dyspnea, and sometimes hemoptysis
✓ Radiographically resembles reactivation of tuberculosis and that can become
a site for bacterial or fungal infections.
➢ Renal:
✓ Immunoglobulin (Ig)A nephropathy
✓ Microscopic hematuria and proteinuria.
➢ Secondary amyloidosis ---- Retroperitoneal fibrosis.
I- Constitutional manifestationss:
➢ Fatigue: a common symptom may be caused by impaired sleep caused by pain and
stiffness.
➢ Fever and weight loss.
➢ Depression: usually subclinical & accompanied by a loss of libido and reduced
capacity for work.
NB
 Anterior uveitis can precede the onset of ankylosing spondylitis by several years, and a history of anterior uveitis is a helpful
diagnostic clue in a patient with inflammatory back pain or other symptoms of ankylosing spondylitis.
 Restriction in chest wall motion may produces mild restrictive lung function impairment, but rarely leads to ventilation insufficiency
due to the compensation by increased diaphragmatic contribution.
 Characteristic spirometry findings include: a slight reduction of vital and total lung capacity and normal diffusion capacity.
 Most patients are asymptomatic, and clinically significant pulmonary disease is uncommon.
 In contrast to rheumatoid arthritis:
✓ Peripheral joint synovitis usually is oligoarticular, asymmetrical, and episodic rather than persistent.
✓ Upper limb joints (with the exception of the shoulders) are almost never involved in AS, particularly in the absence of
psoriasis.
✓ Ankylosing spondylitis can involve the lumbar, thoracic, and cervical spine unlike rheumatoid arthritis, which only
affects the cervical spine.
 Nerve root pain may arise from the cervical spine, especially when there is marked flexion deformity.
 Nontraumatic causes of neurologic complications caused by compression includes:
✓ Ossification of the posterior longitudinal ligament (which may lead to compressive myelopathy),
✓ Destructive intervertebral disk lesions.
✓ Spinal stenosis.
 Other inflammatory arthropathies which cause enthesitis:

√ Primarily gout. √Disseminated gonococcal infection. √sarcoidosis.
Complications
A-Spinal fracture or subluxation:
➢ Risk factors: The fused, osteopenic spine of ankylosing spondylitis is at great risk
for fracture, which can be precipitated by such minor trauma as insignificant falls,
sneezing, or manual manipulation of the spine.
➢ The most common sites of fracture: C5-C6 or C6-C7 level - the thoracolumbar
and cervicothoracic junctions.
➢ Presentation:
✓ Mostly: new, localized back or neck pain, and in some cases, the
description of recently increased spinal mobility.
✓ Cervical fractures (Atlantoaxial joint subluxation, atlanto-occipital subluxation) may result
immediately in quadriplegia myelopathy or death.
✓ Cauda equina syndrome
B-Osteoporosis:
✓ There is increased risk for OP in due to Spinal immobility and
persistent chronic inflammation.
Physical examinations:
A. Occiput-to-wall test:
➢ Detects loss of cervical range of motion.
➢ Normally with the heels and scapulae touching the wall, the occiput should also touch
the wall.
➢ Any distance from the occiput to the wall represents a forward stoop of the neck
secondary to cervical spine involvement with AS.
B. Chest expansion:
➢ Detects limited chest mobility.
➢ Normal chest expansion is approximately 5 cm. (measured the circumference of the chest at
the fourth intercostal space in men and just below the breasts in women)
➢ Chest expansion less than 2.5 cm is abnormal.
C. Modified Schober test:

➢ Detects limitation of forward flexion of the lumbar spine.
➢ Place a mark at the level of the posterior superior iliac spine (dimples of Venus) and
another 10 cm above in the midline.
➢ With maximal forward spinal flexion with locked knees, the measured distance should
increase from 10 cm to at least 15 cm.
D. Finger to Floor test:

➢ Detects limitation of lateral flexion of the lumbar spine.
➢ Ask the patient to stand upright and lateral flex to the floor, the difference in the
distance of the middle finger between neutral position and lateral flexion is recorded.
E. Patrick’s test: (FABER test)

➢ With the patient’s heel placed on the opposite knee, downward pressure on the flexed
knee with the hip now in flexion, abduction, and external rotation.
➢ Detects contralateral sacroiliac joint tenderness.
F. Gaenslen’s test:
➢ With the patient supine, a leg is allowed to drop over the side of the examination table
while the patient draws the other leg toward the chest.
➢ Detects sacroiliac joint pain on the side of the dropped leg.
G. Pelvic compression:
➢ With the patient lying on one side, compression of the pelvis should elicit sacroiliac joint
pain.
A. Plain X-ray of sacroiliac joint :
➢ View:
✓ Anteroposterior view.
✓ Oblique view.
✓ Ferguson view
➢ Finding:
▪ Early: The 1st radiographic finding is the appearance of iliac erosions
(resembling postage stamp serrations) in the lower one-third of the sacroiliac
joint.
▪ Then, the erosions become more prominent and produce "pseudowidening"
of the sacroiliac joint.
▪ Later on: Progressive inflammation leads to fusion & obliteration of the sacroiliac
joint (Ankylosis) by bone and fibrous tissue.
▪ These changes are bilateral &symmetrical.
Grading of Sacroiliitis: New York Criteria

Grade 0 Normal
Grade 1 Suspicious (blurring of joint margin)
Grade 2 Minimal sacroiliitis (small area of erosion or sclerosis with no alteration in joint width)
Grade 3 Moderate sacroiliitis (erosion, sclerosis, widening or narrowing)
Grade 4 Ankylosis
B- Plain X-ray of Spine :( AP & Lateral view)

➢ Early: appearance of vertebral shiny corners (Romanus lesions): which are a
reaction to inflammation at the site where the annulus fibrosus of the disks inserts
onto the vertebral bodies.
➢ Later on: the lumbar vertebral bodies become "squared off"(Bamboo shaped
spine) in the lateral view due to progressive erosions and formation of new
periosteal bone.
➢ Syndesmophytes:
▪ Bony bridges between vertebral bodies due to (gradual ossification of the edges of the
annulus fibrosus).
▪ Syndesmophytes in AS is characterized by being symmetrical,
delicate&marginal.
▪ It's the most characteristic finding in AS.
➢ Trolley track and dagger signs: Ossification of the supraspinous and

interspinous ligaments produces a characteristic single or double radio-dense sign.
C- Plain X-ray of Peripheral Joints:

✓ Periosteal reaction (whiskering): over bony prominences (site of inflammation),
such as the greater trochanters, calcaneus, and malleoli.
✓ Fluffy periostitis & proliferative erosion.
✓ Hip involvement can produce symmetric narrowing of the joint space.
✓ Radiographic changes in the peripheral joints mainly result from disease of the
synovium or entheses.
D- MRI of sacroiliac joint : (the most sensitive and specific for the diagnosis of sacroiliitis)
➢ Technique:
✓ Fat-saturating techniques, such as short-tau inversion recovery (STIR).
➢ Finding:
▪ Early: (Active inflammation)
✓ Bone marrow edema (Osteitis).
✓ Synovitis & Enthesitis
▪ Later on: (chronic inflammatory lesions)

✓ Subchondral sclerosis – Erosions
✓ Periarticular fat deposition.
✓ Bony bridges / ankylosis
▪ These changes are bilateral &symmetrical.
E- MRI of Spine :
1. Spondylitis & Spondylodisciitis: Spinal inflammation typically seen as bone
marrow edema in the anterior and posterior vertebral corners and the intervertebral
disk.
2. Arthritis of costovertebral (CV) joints & Facet joint.
3. Enthesitis of spinal ligaments
4. Later on: Syndesmophytes & ankylosis
F- Musculoskeletal U/S:
✓ Ultrasound is considered a promising tool for assessing axial and peripheral
arthritis and enthesopathy in AS patients and effectively helps in monitoring of the
treatment response.
G- Bone scanning: Findings may help to distinguish inflammatory from noninflammatory

changes in patients with minimal swelling.
NB
❖ Syndesmophytes DD:
✓ In Ankylosing spondylitis and enteropathic arthritis syndesmophytes are symmetric delicate& marginal
(meaning that they are almost completely vertical in their alignment and arise from the margins of the
vertebral body).
✓ In psoriatic arthritis and reactive arthritis typically have more bulky, asymmetric nonmarginal bony
growths that tend to initially protrude laterally before progressing vertically.
✓ The vertical orientation of syndesmophytes and preservation of the disk space distinguish these from
osteophytes associated with degenerative disease of the spine.
❖ Ferguson view: a superior image to SI joints is achieved through radiograph taken at a 15-degree angle to the prone
pelvis.
❖ MRI to the SI joint can detect sacroiliitis in at least 50% of patients with nonradiographic SpA.
❖ The T1-weighted (T1W) sequence allows detection of erosions and fat metaplasia, which may occur early in the disease
and are associated with resolution of inflammation.
❖ Resolution of inflammation is associated with development of fat metaplasia in these same locations.
❖ Evidence suggests that inflammatory lesions with no signs of concomitant fat metaplasia may resolve completely without
sequelae, provided effective anti-inflammatory therapy is administered.
❖ Inflammatory lesions that already demonstrate fat metaplasia may be at higher risk of developing into new bone formation,
even if the inflammation resolves with treatment.
LABORATORY FINDINGS
1. Acute phase reactant:
✓ Elevated ESR & CRP in only about half of patients and correlate more with
peripheral arthritis than the activity of axial skeleton disease.
✓ A normal ESR or normal CRP level does not exclude active disease.
2. CBC: A mild, normocytic, normochromic anemia, reflective of chronic disease.
3. Serological tests: There is Negative result for RF, Anti CCP & ANA.
4. HLA-B27:
➢ Inheritance of HLA-B27 is strongly associated with ankylosing spondylitis.
➢ Normally: HLA-B27 present in 5% to 15% of the general population (HLA-B27 positive).
➢ Inheritance of HLA-B27 is not sufficient to produce ankylosing spondylitis.
✓ Fewer than 5% of HLA-B27–positive individuals develop SpA.
✓ The great majority of HLA-B27–positive persons (95% in some studies) do not have
ankylosing spondylitis (or any other spondyloarthropathy).
➢ HLA-B27 is present in >90% of patients with AS, as well as 50% to 75% of patients with other forms of
spondyloarthritides.
➢ HLA-B27 testing should be ordered when the diagnosis is suggested by the presence of
inflammatory back pain but remains uncertain after appropriate clinical evaluation and
radiographs.
➢ The test results can substantially increase or reduce the probability of disease (but do not
definitively establish or exclude the diagnosis).
Diagnosis & Classification
2009 ASAS classification criteria for Axial SpA
Sensitivity=82.9% specificity=84.4%
2010 ASAS classification criteria for Peripheral SpA
Sensitivity=77.8% specificity=82.2%
❖ ASAS <<< Assessment of SpondyloArthritis international Society
Modified New York criteria For Ankylosing Spondylitis.

1. Low back pain for at least 3 months’ duration improved by exercise and not relieved
by rest.
2. Limitation of lumbar spine motion in sagittal and frontal planes.
3. Chest expansion decreased relative to normal values for age and sex.
4a. Unilateral sacroiliitis grade 3–4. 4b. Bilateral sacroiliitis grade 2–4.
Definite ankylosing spondylitis if (4a OR 4b) AND any clinic al criteria (1-3)
Criteria for Inflammatory Back Pain (Young to Middle–Aged Adults)

1. Chronic Back Pain.
2. Morning stiffness of at least 30-min.
3. Improvement of back pain with exercise but not with rest.
4. Awakening because of back pain during second half of night only.
5. Alternating buttock pain.
NB
❖ Diagnosis usually delayed (On average, 9 years elapse between the onset of symptoms and the diagnosis of
ankylosing spondylitis) &Several factors contribute to this delay:
✓ The onset of low back symptoms is insidious, and patients may delay seeking medical attention.
✓ Mechanical low back pain is prevalent, and patients with ankylosing spondylitis are often misdiagnosed
as having that disorder.
✓ Radiographic evidence of bilateral sacroiliitis, which is the most definitive finding, usually takes several
years to develop.
✓ There are no diagnostic criteria for the disease.
ASSESSMENT OF DISEASE ACTIVITY.

➢ Assessment of disease activity can be measured by one of the following:
A. Ankylosing Spondylitis Disease Activity Score (ASDAS-CRP)

B. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI):
C. Bath Ankylosing Spondylitis Functional Index (BASFI):
D. Bath Ankylosing Spondylitis Metrology Index (BASMI):
A. Ankylosing Spondylitis Disease Activity Score (ASDAS-CRP)
❖ Aim: Measuring and following disease activity in AS.
❖ Method: Pain on a ten-point scale (1 is none and 10 the worst).
Please indicate your level of ability with each of the following activities during the
past week:
1. Axial pain: How would you describe the overall level of AS neck, back, or hip pain
you have had?
2. Morning stiffness duration: How long does your morning stiffness last form the
time you wake up?
3. Patient global assessment of disease activity How active was your spondylitis, on
average, during the last week?
4. Joint pain or swelling How would you describe the overall level of pain/swelling in
joints other than neck,back or hip you have had?
5. CRP (mg/l or mg/dl)
B. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI):
❖ Aim: Measuring and following disease activity in AS.
❖ Method: Pain on a ten-point scale (1 is none and 10 the worst).
past week:
1. Fatigue: How would you describe the overall level of fatigue/tiredness you have
experienced?
2. Axial pain: How would you describe the overall level of AS neck, back, or hip pain
you have had?
3. Joint pain or swelling How would you describe the overall level of pain/swelling in
joints other than neck,back or hip you have had?
4. Enthesitis: How would you describe the overall level of discomfort you have had
from any areas tender to touch or pressure?
5. Morning stiffness severity: How would you describe the overall level of discomfort
you have had from the time you wake up?
6. Morning stiffness duration: How long does your morning stiffness last form the
time you wake up?
❖ Interpretation:
➢ To give each symptom equal weighting, the average of the two scores relating to
morning stiffness is taken.
➢ The resulting 0 to 50 score is divided by 5 to give a final 0 – 10 BASDAI score.
➢ Scores of 4 or greater suggest suboptimal control of disease
C. Bath Ankylosing Spondylitis Functional Index (BASFI):
❖ Aim: To determine the degree of functional limitation in those with AS.
❖ Method: A visual analogue scale (with 0 being "easy" and 10 "impossible) is used to
answer the questions on the test
past week:
1. Putting on your socks or tights without help or aids (e.g. sock aids)?
2. Bending forward from the waist to pick up a pen from the floor without an aid?
3. Reaching up to a high shelf without help or aids (e.g. helping hand)?
4. Getting up from an armless chair without using your hands or any other help?
5. Getting up off the floor without any help from lying on your back?
6. Standing unsupported for 10 minutes without discomfort?
7. Climbing 12-15 steps without using a handrail or walking aid (one foot on each
step)?
8. Looking over your shoulder without turning your body?
9. Doing physically demanding activities (e.g. physiotherapy exercises, gardening or
sports)?
10. Doing a full day’s activity whether it be at home or work?
❖ Interpretation:
➢ The resulting 0 to 100 score is divided by 10 to give a final 0 – 10 BASFI score.

➢ The higher the BASFI score, the more the patient is limited.
D. Bath Ankylosing Spondylitis Metrology Index (BASMI):

❖ Aim:
✓ To accurately assess axial status of individuals with AS
✓ To define clinically significant changes in spinal mobility.
Method: Five clinical measurements were included in the index:

1. Cervical rotation (degrees of motion)
2. Tragus to wall distance (Cm tape measure)
3. Lumbar side flexion (Cm tape measure)
4. Modified Schober Test (Cm tape measure)
5. Intermalleolar distance (Cm tape measure)
❖ Interpretation:
➢ The resulting 0 to 10 score BASMI score.
➢ The higher the BASMI score, the more the patient movement is limited.
➢ The range of severity 0-10 reflects mild to moderate disease activity and functional
ability in the spinal column.
Assessment of response to treatment and remission:

A. ASAS 20 Response Criteria: B. ASAS 40 Response Criteria:
➢ Improvement of ≥ 20% and an absolute ➢ Improvement of ≥ 40% and an absolute
improvement of ≥ 10 units on a 0-100 scale in ≥ 3 improvement ≥ 20 units on a 0-100 scale in ≥ 3 of
of the following 4 domains: the following 4 domains:
1- Patient global assessment (VAS global). 1- Patient global assessment (VAS global)
2- Pain assessment (VAS total + Nocturnal 2- Pain assessment (VAS total + Nocturnal
pain scores). pain scores).
3- Function (BASFI). 3- Function (BASFI).
4- Inflammation (average last 2 questions of BASDAI). 4- Inflammation (Mean of BASDAI questions 5 and 6).
C. ASAS-5/6 Improvement Criteria: D. ASAS Partial Remission Criteria:
➢ At least 20% improvement in 5 of the 6 following ➢ A value below 20 units on a 0-100 scale in all 4
domains: 1- BASFI domains of the ASAS-20 improvement criteria.
2- Morning stiffness
3- Patient global assessment
4- Pain
5- CRP
6- Spinal mobility (Lateral spinal
flexion)
Treatment
➢ The goal of therapy for AS is to:
1. Put the disease in remission (reduce or eliminate pain & Inflammation) and to
2. Prevent or minimize the disability.
3. Improve function, mobility, and strength.
➢ Lines of the treatment:

A. Rehabilitation
B. Medication
C. Treatment of associated disorders
D. Surgical
A. Rehabilitation:
1. Patient education:
✓ Sleeping on a firm mattressa with thin pillow and lying in a straight position are
preferred.
✓ Lying prone for 15 to 30 minutes daily or sleeping prone at night helps prevent
kyphosis.
✓ Extended periods of immobility, including car and plane travel, should be
minimized and interrupted with breaks to permit frequent stretching.
✓ Cigarette smoking should be avoided as smoking diminishes response to
therapy and accelerates radiographic progression.
2. Exercise
✓ Important for maintenance of function and posture
✓ Deep breathing exercises.
✓ Frequent stretching exercise
3. Physical therapy:
✓ Hydrotherapy (swimming) provides the best environment to maximize the
exercise program.
✓ Heat therapy
B. Pharmacological management:
1. NASIDs:
✓ 1st line of treatment.
✓ Reduce pain and stiffness for most patients.
✓ Continuous treatment with NSAIDs for 2 years significantly reduces radiographic
progression.
✓ Adequate doses of at least two different NSAIDs should be tried for
several weeks before concluding that a patient’s response to NSAIDs has been
suboptimal.
✓ Patients with a significant degree of stiffness and muscle spasm may respond to a
combination of NSAIDs ,analgesics, and muscle relaxants, particularly when
initiating physical therapy.
✓ Examples:
▪ A nonselective NSAID, such as naproxen, is appropriate initial therapy for AS.
▪ Cyclooxygenase-2 (COX-2) inhibitors have similar efficacy to conventional
NSAIDs
▪ A COX-2–selective agent (coxib) may be used in the presence of risk factors for
peptic ulceration.
2. DMARDs:
➢ Disease-modifying antirheumatic drugs have limited use in the treatment of
ankylosing spondylitis.
➢ Modest efficacy in treating the peripheral arthritis of ankylosing spondylitis.
➢ Reduce pain and stiffness.
➢ With continuous treatment it may reduce or slow the rate of radiographic
progression.
➢ It does not appear to be effective for chronic disease of the axial skeleton
➢ Sulfasalazine:
✓ Dose: Start with a low dose (0.5 g/d or 0.5 g twice daily) and increase by
0.5g at intervals of a week in order to reduce gastrointestinal side effects.
Maintenance dose: 1-2 g twice daily.
✓ SE: gastrointestinal disturbances (nausea, vomiting, diarrhea, and
anorexia).especial within 1st 2weeks.
✓ CI : Patients with glucose-6-phosphate dehydrogenase deficiency.
➢ Methotrexate: 12.5mg up to 20mg weekly dose.
3. Glucocorticoids:
✓ Local corticosteroid injections are useful in the treatment of enthesopathies,
peripheral synovitis, and recalcitrant sacroiliitis (short-term symptomatic relief).
✓ Oral corticosteroids have no value in the treatment of the musculoskeletal
aspects of AS can worsen osteopenia.
4. Biological DMARDs
❖ TUMOR NECROSIS FACTOR (TNF) ANTAGONISTS:
➢ Highly effective and produce marked improvements in symptoms (pain &
inflammation) and function (spinal mobility).
➢ Improving quality of life.

 Anti-TNF were engineered to specifically inhibit TNF(Neutrilizing its effect), which is a
critical mediator of joint inflammation:
 Etanercept binds soluble TNF prevents their association with cell-surface receptors, whil both
Both infliximab and adalimumab bind soluble as well as membrane-bound TNF and block cell
signaling through TNF receptor pathways.
Onset of action: A rapid onset of action (days to weeks) >>>a significant advantage that these
treatments have over conventional DMARDs.
Efficacy:
✓ All anti-TNF agents have been shown to reduce the signs and symptoms of AS and
prevent radiographic progression.
✓ In patients with AS all of these agents demonstrated ASAS-20 response rates of 55%
to 60% and ASAS-40 response rates of 45% to 50%.
Initiating Therapy:
3. Vaccinations:
✓ Patients should receive inactivated influenza vaccine (seasonal) and age-appropriate
pneumococcal, meningococcal, and Haemophilus influenzae B (Hib). Give herpes zoster
vaccine (live) at least 2 to 4 weeks before biologic
4. Patients should be monitored for injection site or infusion reactions while receiving therapy.
5. Periodic CBC.
Contraindication:
1. Patients with a history of multiple sclerosis of any other demyelinating disease.
2. patients with active acute or chronic infections
NB
✓ To prevent or minimize infliximab allergic reactions, premedication with acetaminophen diphenhydramine, &
hydrocortisone are needed.
✓ Anti-TNF agents should not be used in patients with class III to V heart failure because these drugs may exacerbate
heart failure.
✓ Etanercept, Infliximab, are the most potent of the currently available therapies for use in ankylosing spondylitis.
✓ Abatacept, tocilizumab, and rituximab are not effective for AS.
✓ Anterior Uveitis 2ry to AS treated with an anti-TNF-I agent (other than etanercept).
5. Pamidronate:
➢ Pamidronate is an intravenously administered bisphosphonate.
➢ Dose: 60-mg intravenous/monthly dose for 6 months.
➢ Effect:
✓ It reduces disease activity.
✓ There was no significant effect on the erythrocyte sedimentation rate or
the level of C-reactive protein.
✓ Acute arthralgia, myalgia, and fever after the first infusion are not
uncommon, but reactions are generally mild and usually decrease with
continued treatment.
C. Surgical Therapy
➢ Total hip arthroplasty should be considered in patients with refractory pain or
disability and radiographic evidence of structural damage. (With risk of postoperative
heterotopic bone formation is increased in those undergoing repeat hip surgery and
those with more spinal ankylosis).
➢ Osteotomy with fixation is performed in patients with severe disabling deformity.
Dose Mode of action

It is a fully human monoclonal antibody (IgG)
ADALIMUMAB 40 mg Every 2 weeks binds to both soluble and membrane-
HUMIRA S.C bound TNF neutralizing its biologic activities.
ETANERCEPT It is a soluble receptor fusion protein that

ENBREL 50 mg once weekly binds to soluble TNF, neutralizing its
S.C biologic activities.
Loading: 400mg 0-2-4 weeks
followed by It is a fusion protein (Consist of humanized Fab
CERTOLIZUMAB 200mg every 2 weeks S.C sub unit of the antibody) that binds to soluble &
CIMZIA membrane- bound TNF neutralizing its
MAINTAINCE: biologic activities.
Syringe (200 mg) 400mg every 4 weeks S.C
INFLIXIMAB 3-5mg/kg at 0-2-6 weeks It is a chimeric monoclonal (IgG) antibody

REMICADE then binds to both soluble and membrane-
VIALS 100 mg every 8 weeks bound TNF neutralizing its biologic activities.
(I.V infusion in 250 ml saline
over 2 hr)
Golimumab 50mg SC every month. Human monoclonal antibody (IgG) binds to
Simponi Syringe (50 mg) both soluble and membrane-bound TNF
neutralizing its biologic activities.
ABATACEPT • 10mg/kg at 0-2-4 weeks It is a recombinant fusion protein which

ORENCIA Then Inhibites T-cell co-stimulation.
every 4 weeks
VIALS 250mg (I.V infusion in 100 ml saline (binds to CD80 and CD86, blocking their
Syringe125mg over 30 min) interactions with CD28 on T cells prevents
• 125 mg S.C once weekly the second signal of T-cell activation).
RUTIXIMAB 1 gram at 0-2 weeks intervals It is a chimeric anti-CD20 monoclonal

MABTHERA every year antibody.
Rituxan OR Rituximab depletes B cells that have CD20
- 500 mg every 6 months. on their surface.
VIALS 100 & 500
mg (I.V infusion in 500 ml saline (CD20, an antigen found on the surface of
over 6 hr) normal and malignant B lymphocytes).
TOCILIZIMAb 4-8mg/kg monthly Tocilizumab is a recombinant humanized

ACTEMRA monoclonal antibody which inhbites
400 mg,200 mg,80 (I.V infusion in 100 ml saline interleukin-6 (IL-6) receptor
mg VIALS over 1 hr)
150 mg SC every 4 weeks. Human IgG1 monoclonal antibody that
Secukinumab (Approved 2016 for selectively binds to and neutralizes the
(Cosyntex) AS & PsA) proinflammatory cytokine interleukin 17A
(IL-17A).
45 mg SC initially, A human IgG1κ monoclonal antibody that

Ustekinumab followed by 45 mg in 4 binds to the p40 subunit of both IL-12 & IL-
(Sterala) weeks, then 45 mg 23 preventing their binding to their shared
(Approved For As & PsA every12 weeks. cell surface receptor chain, IL-12β.
2015) (If Wt >100 kg: 90 mg SC)
Ixekizumab Loading dose: 160 mg SC Monoclonal antibody that selectively binds
(Talza) (ie, as two 80-mg injections) with interleukin 17A (IL-17A) cytokine
once, and inhibits its interaction with the IL-17
receptor
Maintenance dose: 80 mg
SC every 4 weeks
Targeted DMARDS
✓ Oral small molecule drug.
Tofacitinib: A daily 5mg twice \day taken ✓ It acts to block the body’s production of the
by ORAL rout. enzyme JAKs (Janus Kinase) which play a
Xeljanz (Approved 2017 for AS & PsA) role in joint inflammation in RA.
Apremilast Oral small molecule that inhibits

(Otezla) Dose: 30 mg twice a day phosphodiesterase 4 (PDE4) >>> the
(FDA approval in PsA: 2014) hydrolysis of intracellular (cAMP) is abrogated
which decreases production of TNF-α, IL-12,
IL-23, and others.
❖ Guide lines for use of Anti-TNF in AS

✓ Anti-TNF therapy should be given to patients with persistently high disease activity
despite conventional treatments, according to the ASAS recommendations
✓ There is no evidence to support a difference in efficacy of the various TNF inhibitors on
the axial and articular/entheseal disease manifestations.
✓ In adults with active AS and IBD or recurrent iritis, we strongly recommend treatment
with TNF-I monoclonal antibodies over treatment with Etanercept.
✓ There is no evidence to support the use of biologic agents other than TNF inhibitors in AS
2019 ACR Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic
Axial Spondyloarthritis

➢ The course of AS is highly variable, characterized by spontaneous remissions and
exacerbations.
➢ Life expectancy is reduced, particularly after 10 years of disease.
➢ The risk of dying for patients with AS is increased by 50% compared with controls
matched for age and gender.
➢ Causes of death:
✓ Complications of the disease such as amyloidosis and spinal fractures, as
well as cardiovascular, gastrointestinal, and renal disease.
➢ The first 10 years of disease are particularly important as the most of the loss of
function among patients with AS occurs within this period
➢ Radiographic evidence of spinal involvement, especially the presence of
syndesmophytes, appears to be the primary factor that independently predicts
further radiographic progression.
========================================================================
Non-radiographic Axial spondylarthritis (nr AxSpA)

➢ It is a type of axial spondylarthritis which characterized by: low back pain, other
symptoms but with no radiographic sacroiliitis.
➢ It causes joint damage that cannot be seen on X-ray.

➢ The rate of progression to the radiographic stage of Ankylosing spondylitis ranges 10-
20% over 2 years.
➢ The clinical diagnosis should be based on the composite of:

✓ Clinical symptoms and signs of the disease.
✓ HLA B27 status,
✓ MRI of sacroiliitis.
➢ A negative of MRI or HLA B27 does not exclude the diagnosis in patients with a high
clinical suspicion for nrAxSpA.
➢ Treatment:
1- Physical therapy
2- NSAIDs
3- TNF inhibitors.
➢ Difference between radiographic axial SpA and non-radiographic Axial SpA:
1- The proportion of female patients is higher in nr-ax SpA.
2- Shorter mean disease duration in nr-ax SpA group.
3- Less prevalent of uveitis among patients with nr-axSpA.
4- Low CRP in the nr-axSpA group than AS.
5- Less active bony inflammation seen on MRI in patients with nr-axSpA.
NSAIDs & Ankylosing spondylitis

✓ Ankylosing spondylitis patients frequently are treated with nonsteroidal anti-infl ammatory drugs (NSAIDs),
including selective cyclooxygenase (COX)- 2 inhibitors. COX-2 is an inducible enzyme that converts arachidonic
acid to prostaglandin E2, a modulator of bone metabolism.
✓ The inhibition of radiographic progression by continuous intake of NSAIDs may be explained by the inhibition of
prostaglandins by NSAIDs.
✓ Several animal and in vitro studies demonstrated impaired bone healing in the presence of NSAIDs.
✓ The steps involved in bone healing include an inflammatory response, bone resorption, and new bone formation.
✓ Prostaglandins have been shown to elicit and participate in inflammatory responses, enhance osteoclast activity
and subsequent bone resorption, and increase osteoblast activity and new bone formation.
✓ By inhibiting COX and the subsequent production of prostaglandins, NSAIDs act in an anti-infl ammatory mode
and may inhibit new bone formation simultaneously.
Psoriatic arthritis
Definition:
➢ Psoriasis is an inflammatory skin condition that presents with a red scaly rash often
on the extensor surfaces but may also affect the scalp and flexural areas as well as
palms and soles
➢ Psoriatic arthritis is a chronic progressive inflammatory arthritis that occurs in
association with the skin disease psoriasis& developed in 10%-20% of patient with
psoiasis.
Epidemiology:
• Prevalence: The overall prevalence of PsA. is 0.5% to 1% of population

• Age of onset: Average age at onset is 35-50 years old.
• Sex: Males & females are affected equally (increased prevalence of the spondylitic form in males &
the rheumatoid form in females).
• Onset:
✓ Psoriasis precedes arthritis by an average of 8 to 10 years in 67% of patients.
✓ Arthritis precedes psoriasis or occurs simultaneously in 33% of patients,
particularly in childhood and in older patients (> age 50 years).
Aetiology
➢ Genetic factors have a role in susceptibility to psoriatic arthritis (Approximately 40% of patients
with psoriasis or psoriatic arthritis have a family history of these disorders in first-degree relatives).
➢ Twin studies indicate a concordance rate among monozygotic twins of 35-70%,

compared with 12-20% for dizygotic twins.
➢ Psoriatic arthritis is a Polygenic disorder.
✓ A strong association between psoriasis and the HLA-Cw6 which is found in
approximately 60% of psoriasis cohorts.
✓ Additional associations in psoriatic arthritis have been found with HLA-B27,
HLA-B08, HLA-B38, and HLA-B39
✓ HLA-B27 is associated with sacroiliitis and spondylitis.
✓ HLA-B38 and HLA-B39 are associated with psoriatic arthritis
✓ The presence of HLA-DR*04 shared epitope is associated with worse
radiological damage.
✓ HLA-B27 in the presence of HLA-DR7 and HLA-DQw3 in the absence of HLA-
DR7 predict progression, while HLAB22 is protective.
Environmental Risk Factors

A. Trauma:
✓ Koebner phenomenon, described as psoriatic lesions arising at sites of trauma,
occurs in 24% to 52% of psoriasis patients.
✓ Subclinical trauma may also contribute to the distal interphalangeal (DIP) joint
arthritis, dactylitis, and enthesitis.
B. Infection:
✓ Studies suggest involvement of bacterial agents in psoriasis and possibly PsA.
✓ There are high association between guttate psoriasis and preceding streptococcal
pharyngitis and tonsillitis exists in children.
✓ The link between Gram-positive infection and PsA was suggested by high levels of
circulating antibodies to microbial peptidoglycans and elevated levels of group A
streptococcus 16S RNA in the peripheral blood of PsA patients.
✓ Psoriasis or psoriatic arthritis associated with HIV infection is more aggressive.
Pathogenesis &Pathological changes

➢ Main pathology: Synovitis and Enthesitis is the main pathology responsible for
principal musculoskeletal lesions associated with PsA are
➢ The Synovium Changes in PsA:



 Cells:
cellular debris.
➢ Enthesitis:
✓ A hallmark of SpA, is characterized by erosive, inflammatory lesions associated
with an abundance of osteoclasts and infiltration of the bone marrow.
✓ Early: Reactive bone forms a new, more superficial enthesis, which develops into
a radiologically detectable bony overgrowth or spur.
✓ In the spine: enthesitis occurs at capsular and ligamentous attachments and

discovertebral, costovertebral, and costotransverse joints, with involvement also at
bony attachments of interspinous and paravertebral ligaments.
➢ Cellular Activation and Cytokine Pathways in Psoriatic Arthritis
 Recent evidence indicates that cells of the innate immune system ( Dendritic
cells,Fibroblast neutrophils & NK cells) may direct the early events in psoriatic joint
inflammation.
 Type 1 helper T–cell cytokines (eg, TNF-alpha, interleukin [IL]–1 beta, IL-10) are more
prevalent in psoriatic arthritis than in RA, suggesting that these 2 disorders may
result from a different underlying mechanism.
 Dendritic cells:
▪ They have been found in the synovial fluid of patients with
psoriatic arthritis and are reactive in the mixed leukocyte
reaction;
▪ Dendritic cells present an unknown antigen to CD4 + cells within
the joints and skin of patients with psoriatic arthritis, leading to
T-cell activation.
 Fibroblasts: from the skin and synovia of patients with psoriatic arthritis have an
increased proliferative activity and the capability to secrete increased amounts of IL-
1, IL-6, and platelet-derived growth factors.
 Several lines of evidence demonstrate that TNF-alpha is a pivotal cytokine in

psoriatic joint inflammation:
1. There are elevated levels of TNF-alpha in joint fluid and in psoriatic synovial
supernatants.
2. Immuno-histochemical studies demonstrated upregulation of TNF-alpha in the
psoriatic synovial membrane and skin.
3. Histopathologic analysis of synovial specimens from PsA patients treated with
anti-TNF agents revealed decreased vascularity, synovial lining thickness, and
mononuclear cell infiltration following treatment.
4. Anti-TNF agents significantly lessen inflammation in the psoriatic plaque,
entheses, flexor tendons, and the axial skeleton.
PsA pathogenesis model.

➢ The major events in PsA begin in the skin (step 1) and spread to the joint (step 2).
➢ The genetic factors associated with skin or joint disease may not be identical.
➢ In step 1, DC are triggered by trauma, infection, or other signals to activate T cells. Activated T cells
promote entry of monocytes into the dermis and release of TNF and other cytokines that lead to
keratinocyte hyperplasia and PMNs infiltration.
➢ In step 2, activated monocytes and T cells leave the skin and enter the joint that has been subjected to
trauma or infection, after binding to primed ECs. Vascular remodeling is directed by VEGF, MMP-9, and
ang-2. TNF and other cytokines released by these infi ltrating cells drive synovial cell hyperplasia.
➢ The lining cells promote osteoclastogenesis and subsequent bone resorption via RANKL expression
and they release MMPs which mediate cartilage degradation.
➢ Inflammatory events in the subchondral bone foster enthesitis and osteitis.
➢ Activation of BMPs leads to new bone formation.
Abbreviations: EC, endothelial cell; MΦ, monocyte/macrophage; MHC, major histocompatibility complex; MMP:
metalloproteinase; ang-2, angiopoietin 2; VEGF, vascular endothelial growth factor; PMN, neutrophils; BMP, bone
morphogenetic protein; KIR, killer immunoglobulin receptor.
Clinical Findings
Clinical patterns of PsA:
1. Oligoarthritis: Occurs in 70% of the patients.
2. Polyarthritis: Similar to RA, detected in 15% of the patients.
3. A predominantly distal joint disease, Occurs in 5% of the patients.
4. Arthritis mutilans: Occurs in 5%of the patients.
5. Spondyloarthritis, which occurs alone in about 5% of the patients, but may be
associated with one of the other forms in about 40% of the patients.
A. Peripheral Joint involvement: ( Peripheral arthropathy)
➢ Early: an asymmetric oligo- or monarthritis. Usually affect the DIP joints which
become stiff, swollen, and tender.
➢ Later on: In the absence of effective treatment, most patients will progress to
additional joint involvement (polyarticular) with joints destruction and deformities.
➢ With long standing disease: Arthritis mutilans which mean severe

destruction (osteolysis) of involved joint which allows complete subluxation and
telescoping of the involved digit (Opera-glass finger).
➢ Arthritis mutilans describes the end stage of the destructive process
➢ The most frequently involved joints:

▪ Frequent involvement of the distal interphalangeal joints (DIP).
▪ The knees, hips, and sternoclavicular joints.
B. Axial Spine involvement: (Spondylitis& Sacroiliitis)
➢ Inflammatory low back pain: (affect 50% of patients)

➢ Limited spinal movements:

✓ There is limitation of spinal mobility, particularly of the lumbar spine.
✓ Lumbar flexion is the most commonly affected followed by reductions in lumbar
lateral bending and rotation.
✓ Reductions in mobility can be induced by:
 Pain or muscle spasm (during early stages of the disease).
 Spinal fusion (irreversible).
➢ Cervical spine involvement:

✓ A common site of skeletal involvement in psoriatic arthritis is the cervical spine.
✓ Cervical myelopathy: caused by extensive inflammation and erosion that can
lead to atlantoaxial (C1-C2) instability.
C. Enthesitis: (40% of patients)


➢ In PsA.
✓ Mostly presented as heel pain due to Achilles tendinitis.
✓ LBP & buttok pain due to involvement of insertion sites around the pelvis
(the ischial tuberosities, iliac crests, and greater trochanters).
➢ It's appears on radiographs as bony "whiskering" at these sites of attachment.
D. Dactylitis:
➢ Definition: it is an inflammation of the tendons and the adjacent synovium in a toe
or finger (synovitis and enthesitis).
✓ In PsA: Dactylitis is common and affect about 30%-50% of patients.
E. Ocular manifestations: (25% of patients).
➢ Conjunctivitis& Scleritis: Common, particularly early in disease, and is usually mild

and self-limited.
➢ UVEITIS: mostly acute anterior uveitis:

✓ Photophobia.
✓ Blurred vision.
 Slit-lamp examination: Detect the presence of cells and flare in the

anterior uveal chamber which establishes the diagnosis.
F. Skin and Nail Changes:

➢ Type of psoriatic lesions:
✓ Psoriasis vulgaris is the most common type and the most commonly
associated with psoriatic arthritis.
✓ All forms of psoriasis (Inverse-Pustular–Exfoliative) can be associated with
arthritis.
➢ Characteristics: Typical psoriatic lesions are erythematous plaques that
produce scaling with scratching
➢ Site of the lesions:

✓ The extensor surfaces, particularly elbows and knees.
✓ The psoriasis may be subtle. Therefore careful examination of the entire skin
surface must be performed when psoriatic arthritis is suspected, with
particular attention to the hairline, scalp, external auditory canal, periumbilical
area, and gluteal cleft.
➢ Psoriatic nail changes:

✓ Lesion: ridging, pitting, onycholysis, and hyperkeratosis.
✓ May represent the only manifestation of psoriasis before the presence of more
characteristic skin lesions.
✓ Nail changes are seen in 80% of patients with arthritis
➢ There has been no consistent correlation between the degree of psoriasis and the
extent of joint involvement (The most severe form of psoriasis is the erythrodermic type).
G. Mucocutaneous Lesions:
➢ Urethritis & Prostatitis:
➢ Aphthous ulcerations: These lesions are often painless and develop along the oral
or genital mucosa.
NB
 An asymmetric oligoarticular arthritis is the classic description of psoriatic arthritis, but articular manifestations
range from an isolated monarthritis to polyarthritis to widespread destructive arthritis (arthritis mutilans).
 Sacroilitis in psoriatic arthritis is usually unilateral and presents with pain and stiffness in the lower back or
buttock. (thus distinct from the bilateral, symmetric sacroiliitis of ankylosing spondylitis).
 Symptomatic involvement of the sacroiliac joints and axial skeleton is less common than peripheral arthritis.
 Extra-Articular Manifestations: Ocular inflammation (conjunctivitis, iritis, scleritis, and episcleritis), oral
ulcerations, and urethritis occur in psoriatic arthritis, but less frequently than in the other
spondyloarthropathies.
Plain X-ray of Peripheral Joints:
➢ The most common radiographic findings in psoriatic arthritis are joint space
narrowing and erosions involving the DIP & PIP joints (Typically, these
findings are asymmetric).
➢ With long-standing disease: there are severe destructive changes of the joints:
✓ Pencil-in-cup deformity: When a phalanx is involved, it becomes "penciled,

and abuts the base of an adjacent phalanx.
✓ Arthritis mutilans which mean severe destruction (osteolysis) and

disorganization of involved joint which allows complete subluxation and
telescoping of the involved digit (Opera-glass finger).
✓ Acro-osteolysis: Erosions of the terminal tufts.
➢ Periosteal reaction (whiskering): over bony prominences (site of

inflammation), such as the greater trochanters, calcaneus, and malleoli.
➢ Fluffy periostitis & proliferative erosion.
➢ Radiographic changes in the peripheral joints mainly result from disease of the
synovium or entheses.
Plain X-ray of sacroiliac joint :

➢ Only 20-25% of patients with PsA develop radiographic evidence of sacroiliitis.
➢ View:
✓ Oblique view.
✓ Ferguson view
➢ Finding:
❖ Asymmetric changes (only one sacroiliac joint involved and the other being
spared, or with a different degree of involvement)
joint.
▪ Later on: Progressive inflammation leads to fusion & end with complete
obliteration of the sacroiliac joint (Ankylosis) by bone and fibrous tissue.
H- MRI of sacroiliac joint : (the most sensitive and specific for the diagnosis of sacroiliitis)
➢ Technique:
✓ Fat-saturating techniques, such as short-tau inversion recovery (STIR).
➢ Finding:

✓ Bony bridges / ankyloses.
▪ Asymmetric changes (only one sacroiliac joint involved and the other being
spared, or with a different degree of involvement)
I- Musculoskeletal U/S:
➢ Ultrasound is a valid noninvasive tool which is more sensitive than clinical
examination in detecting subclinical synovitis & subclinical enthitis abnormalities in
patient with early disease.
➢ MSUS features at the enthesis includes:
✓ Entheseal thickening, hypoechoic change, increased vascularity as shown on
power Doppler.
✓ Tenosynovitis, and bony erosions or enthesophyte formation
NB
vertebral body).
growths (arise from the midpoint of a vertebral body) that tend to initially protrude laterally before
progressing vertically.
✓ Psoriatic spinal involvement is usually discontinuous, affecting noncontinguous vertebrae or areas (skip
lesions).
✓ The vertical orientation of syndesmophytes and preservation of the disk space distinguish these from
osteophytes associated with degenerative disease of the spine.
❖ Of patients with established psoriatic arthritis, 67% have radiographic abnormalities, 12% and 47% of patients
with recent-onset psoriatic arthritis will have developed erosions within 2 years of disease onset.
LABORATORY FINDINGS
✓ Elevated ESR & CRP in only about half of patients and correlate more with
peripheral arthritis than the activity of axial skeleton disease.
✓ A normal ESR or normal CRP level does not exclude active disease.
3. Serological tests: There is Negative result for RF, Anti CCP & ANA. (Low levels of rheumatoid
factor may be found in patients (5% to 16%) with typical psoriatic arthritis features.)
➢ The diagnosis of psoriatic arthritis may be difficult when the skin manifestations are
subtle or the arthritis antedates the onset of skin lesions.
A. Rheumatoid arthritis:
➢ Clinically:
❖ Rheumatoid Arthritis: Typically affect PIP, MCP and wrist joints in a symmetric
distribution.
❖ PsA: affects all the joints of one digit, in a ray pattern, giving the asymmetric
distribution typical for the disease.
❖ Other clinical finding associated with psoriasis:
✓ Inflammatory low back pain and dactylitis.
✓ The presence of a bluish/purplish discoloration over the inflamed joint is typical
for seronegative disease, including PsA, even in the absence of obvious
psoriasis.
✓ Patients with PsA are not as tender as patients with RA
✓ Many patients present with deformity and joint damage, not having perceived any
pain during the inflammatory phase of their disease.
➢ LAB: The presence of AntiCCP Ab which is highly specific to to rheumatoid arthritis.

➢ Imaging:
A. Periarticular osteopenia is usually absent in psoriatic arthritis.
B. The metacarpophalangeal joints and wrists are usually spared in psoriatic
arthritis while DIP joints usually spared in RA
B. Seronegative spondyloarthropathies (reactive arthritis, ankylosing spondylitis,

and enteropathic arthritis).
C. Osteoarthritis:
D. GOUT:
✓ When acute in onset, the monarticular and oligoarticular forms of psoriatic arthritis
can cause confusion with the crystal arthropathies (gout and pseudogout).
✓ Examination of synovial fluid is usually diagnostic
✓ Dactylitis can be a helpful clue to the presence of a spondyloarthropathy
(particularly reactive arthritis or psoriatic arthritis) but also can be seen in gout and
sarcoidosis.
Diagnosis & Classification
CASPAR Classification Criteria for Psoriatic Arthritis
ASSESSMENT OF DISEASE ACTIVITY.
Disease Activity index for PSoriatic Arthritis 66/68 (DAPSA 66/68)
❖ Aim: Measuring and following Joint disease activity in PsA.
❖ Method:
1. The number of swollen joints (0-66) - hip joints (SJC66)

2. The number of tender joints (0-68) + hip joints (TJC68)
3. Patient global health (PTG) assessment (From 0= best to 10=worst)
4. Pain assessment (PP) on 10 cm VAS (0 is none and 10 the worst).
5. CRP: mg/dL.
❖ Interpretation: To calculate the DAPSA score, the formula is:
DAPSA = SJC + TJC + PtG + PP + CRP [mg/dl].
❖ Improvement: defined as a decrease ≥ 30% in the swollen or tender joint score and a
decrease ≥1 in either of the global assessments
Leeds Enthesitis Index (LEI): Leeds Dactylitis Index (LDI):

❖ Aim: To assess the enthesitis. ❖ Aim: To assess the Dactylitis.
❖ Method: The LEI examines tenderness at six sites:❖ Method: Dactylitis ( a 10% difference in
(the LEI score range is 0-6). the ratio of circumference of the affected
✓ The lateral epicondyles of the humerus. digit to the contralateral digit)
✓ Medial condyles of the femur.
✓ The insertion of the Achilles tendon.
Assessment of response to treatment and remission:

 Minimal disease activity criteria (MDA):
➢ MDA provides an easy method to measure acceptable patient disease activity state.
➢ MDA encompasses both remission and low disease activity as acceptable targets for
therapy.
➢ Patients with psoriatic arthritis are considered to have MDA when they meet 5 out 7 of
the following criteria:
1. Tender joint count ≤1
2. Swollen joint count ≤1
3. PASI ≤ 1, or body surface area (BSA) ≤3
4. Patient pain, visual analogue scale (VAS) ≤15
5. Patient global activity VAS ≤20
6. Health Assessment Questionnaire (HAQ) ≤5
7. Tender entheseal points ≤1
Treatment
➢ The goal of therapy for PsA is to:
✓ Put the disease in remission (reduce or eliminate pain & Inflammation) and to
✓ Prevent or minimize the disability.
✓ Improve function, mobility, and strength.
1. NASIDs:
✓ 1st line of treatment.
✓ Reduce pain and swelling for most patients with peripheral arthritis.
✓ Continuous treatment with NSAIDs for 2 years significantly reduces radiographic
progression.
✓ Examples:
▪ Cyclooxygenase-2 (COX-2) inhibitors have similar efficacy to conventional
NSAIDs
▪ A COX-2–selective agent (coxib) may be used in the presence of risk factors for
peptic ulceration.
2. Glucocorticoids:
✓ Psoriatic plaques are heavily contaminated with bacteria, and considerable care
should be taken to avoid introducing an infection by passing the injecting needle
through a psoriatic plaque into the joint.
✓ Systemic corticosteroids have no value in the treatment of the

musculoskeletal aspects of PsA better be avoided because of the risk that the
glucocorticoid taper can precipitate a severe flare of pustular psoriasis
3. DMARDs:
 Types:
➢ Conventional (synthetic) DMARDs: Methotrexate &sulfasalazine.
➢ It does not appear to be effective for chronic disease of the axial skeleton.
➢ Sulfasalazine:
✓ Dose: Start with a low dose (0.5 g/d or 0.5 g twice daily) and increase by
0.5g at intervals of a week in order to reduce gastrointestinal side effects.
Maintenance dose: 1-2 g twice daily.
✓ SE: gastrointestinal disturbances (nausea, vomiting, diarrhea, and
anorexia).especial within 1st 2weeks.
✓ CI : Patients with glucose-6-phosphate dehydrogenase deficiency.
➢ Methotrexate: 12.5mg up to 20mg weekly dose.
➢
➢ NB: The role of antimalarials (hydroxychloroquine) is controversial. Exacerbation of psoriasis and
erythroderma can occur with antimalarials,and consequently some consider them to be contraindicate.
4. Biological DMARDs: (TNF) ANTAGONISTS (details in AS)

➢ Highly effective and produce marked improvements in symptoms (pain &
inflammation) and function.
➢ Improving quality of life.
 Anti-TNF were engineered to specifically inhibit TNF(Neutrilizing its effect), which is a
critical mediator of joint inflammation:
 Etanercept binds soluble TNF prevents their association with cell-surface receptors , whil both
Both infliximab and adalimumab bind soluble as well as membrane-bound TNF and block cell
signaling through TNF receptor pathways.
Onset of action: A rapid onset of action (days to weeks) >>>a significant advantage that these
treatments have over conventional DMARDs.
Efficacy:
✓ All anti-TNF agents have been shown to reduce the signs and symptoms of PsA
and prevent radiographic progression.
Initiating Therapy:
3. Vaccinations:
✓ Patients should receive inactivated influenza vaccine (seasonal) and age-appropriate
pneumococcal, meningococcal, and Haemophilus influenzae B (Hib). Give herpes zoster
vaccine (live) at least 2 to 4 weeks before biologic
4. Patients should be monitored for injection site or infusion reactions while receiving therapy.
5. Periodic CBC.
Contraindication:
✓ Patients with a history of multiple sclerosis of any other demyelinating disease.
✓ Patients with active acute or chronic infections.
5. Target DMARDs:
 Apremilast (Otezla)
✓ Oral small molecule that inhibits phosphodiesterase 4 (PDE4). By inhibiting PDE4
the hydrolysis of intracellular (cAMP) is abrogated which decreases production of
TNF-α, IL-12, IL-23, and others.
✓ Dose: 30 mg twice a day
✓ FDA approval in PsA: 2014
 Tofacitinib (Xeljanz)
✓ It blocks the body’s production of the enzyme JAKs (Janus Kinase) which play a role
in joint inflammation
✓ Dose: 5 mg twice daily
✓ FDA approval in PsA: 2017
➢ Erosive disease developed in 47% of patients within 2 years.

➢ Markers for Poor progression:
✓ Polyarticular disease.
✓ An elevated ESR – CRP.
✓ Younger age of onset.
✓ Female gender.
➢ Cardiovascular morbidity and mortality:

✓ There is an increased prevalence of cardiovascular disease (myocardial
infarction, ischemic heart disease, and hypertension) in patients with psoriatic
arthritis compared with the general population.
➢ There is an increased prevalence of metabolic syndrome , DM and dyslipidemia
Reactive arthritis
Definition:
➢ Reactive arthritis is a systemic inflammatory condition that is triggered by
bacterial infections of the gastrointestinal or genitourinary tracts ; (a sterile
synovitis following an extraarticular infection).
➢ This form of joint inflammation is called "reactive arthritis" because it is felt to involve
an immune system that is "reacting" to the presence of bacterial infections in the
genital, urinary, or gastrointestinal systems.
Epidemiology:
• Prevalence: The overall prevalence of Reactive A. is 0.5% to 1% of population
• Age of onset: Young adult (20-40 y).
• Sex: Chlamydia-induced disease is more common in men, but men and women are
at equal risk to develop post-enteric disease.
Aetiology

➢ Genetic factors have a role in susceptibility to Reactive arthritis
➢ Human leukocyte antigen (HLA)-B27 is linked to reactive arthritis, but the strength of
the association is not strong as that seen between HLA-B27 and ankylosing
spondylitis.
➢ HLA-B27 present in 5% to 15% of the general population (HLA-B27 positive).
➢ The prevalence of HLA-B27 in series of reactive arthritis ranges from 50-80%,
➢ About 60% to 80% of patients are human leukocyte antigen (HLA)-B27 positive.
➢ The presence of HLA-B27 is associated with more severe arthritis and extra-articular
features and predicts a prolonged disease.
Infection:
➢ Reactive arthritis typically develops 1-4 weeks after attack gastroenteritis
caused by Shigella, Salmonella, Campylobacter, or Yersinia , or after a
genitourinary tract infection with Chlamydia trachomatis.
➢ Sometimes there is no antecedent history of infection, suggesting that reactive

arthritis can follow subclinical infections or that other environmental triggers
are at play
Pathogenesis
➢ The favorite hypothesis involves a cross-reaction between microbial structures and
HLA-B27 or that HLA-B27 its self might be a target of the immune response.
➢ HLA-B27 is not required for the development of reactive arthritis, its presence
contributes to the chronicity of the disease.
➢ The classic reactive arthritis–triggering pathogens are gram-negative obligate or
facultative intracellular aerobic bacteria with a lipopolysaccharide-containing outer
membrane.
➢ They are invasive, and in reactive arthritis, bacterial antigens seem to disseminate from
the mucosa to the joints.
➢ A CD4+ T cell response to the invading microorganism drives the arthritic process, most
likely
Clinical Findings
Peripheral Arthritis: (The dominant manifestation)
➢ An asymmetric oligo-articular.
➢ The affected joints are usually swollen, warm, and tender to palpation with limited
ROM.
➢ The most frequently involved joints:
▪ Lower extremities (eg, knees, ankles, and feet) are more commonly
affected than the joints of the upper extremities.
▪ The sternoclavicular and temporomandibular joints are sometimes involved.
Axial Spine involvement: (Spondylitis& Sacroiliitis)
✓ Sacroilitis often unilateral, and if bilateral, is asymmetric (thus distinct from the bilateral,
symmetric sacroiliitis of ankylosing spondylitis).
Enthesitis: (40% of patients)

➢ In Reactive arthritis.
✓ LBP & buttok pain due to involvement of insertion sites around the pelvis
(the ischial tuberosities, iliac crests, and greater trochanters).
Dactylitis:
➢ Dactylitis is a feature of the spondyloarthropathies, particularly reactive arthritis
and psoriatic arthritis.
Ocular manifestations: (25% of patients).

➢ Conjunctivitis: Common, particularly early in disease, and is usually mild and self-
limited.
➢ UVEITIS: mostly acute anterior uveitis:
✓ Photophobia.
✓ Blurred vision.
 Slit-lamp examination: Detect the presence of cells and flare in the
anterior uveal chamber which establishes the diagnosis.
Mucocutaneous Lesions:
➢ Circinate balanitis:
✓ It is an inflammatory lesion on the glans or shaft of the penis, and it is one
of the characteristic lesions associated with reactive arthritis.
✓ If the male is circumcised, these lesions can appear as multiple, serpiginous,
shallow ulcers with raised borders.
✓ In uncircumcised males, the lesions can appear as dry, hyperkeratotic plaques
that are reminiscent of psoriasis.
➢ Urethritis & Prostatitis:
➢ keratoderma blennorrhagicum:
✓ A skin rash that typically affects the palms and soles.
✓ Start as papular, waxy lesions which can evolve into scaly, hyperkeratotic
lesions resembling psoriasis.
✓ Keratoderma blennorrhagicum cannot be distinguished histologically from pustular psoriasis.
➢ Aphthous ulcerations: These lesions are often painless and develop along the oral or
genital mucosa.
Cardiovascular involvement (rare:)

✓ Inflammation of the interventricular septum can affect the atrioventricular node,
resulting in varying degrees of heart block.
✓ Aortic valve regurgitation due to Inflammation of the aortic root and aortic
valve(Aortitis).
History of recent infection:

➢ Reactive arthritis typically develops 1-4 weeks after attack gastroenteritis or
after a genitourinary tract infection.
➢ Sometimes there is no antecedent history of infection, suggesting that reactive
arthritis can follow subclinical infections or that other environmental triggers
are at play
➢ Preceding symptoms:
✓ In men: Mild dysuria - Mucopurulent discharge - Prostatitis.
✓ In women: Vaginal discharge - dysuria - Cervicitis.
A. Periostitis: (The hallmark radiographic finding)
➢ Periosteal reaction (whiskering): over bony prominences (site of
inflammation), such as the greater trochanters, calcaneus, and malleoli.
➢ Fluffy periostitis & proliferative erosion.
B. Plain X-ray of sacroiliac joint :

➢ Only 20-25% of patients with Reactive A. develop radiographic evidence of sacroiliitis.
➢ View:
✓ Oblique view.
✓ Ferguson view
➢ Finding:
❖ Asymmetric changes (Usually unilateral, and if bilateral, it tend to be
asymmetrical)
joint.
▪ Later on: Progressive inflammation leads to fusion & end with complete
obliteration of the sacroiliac joint (Ankylosis) by bone and fibrous tissue.
C. Plain X-ray of the spine :

➢ Syndesmophytes:
▪ Bony bridges between vertebral bodies due to gradual ossification of the edges
of the annulus fibrosus.
▪ The syndesmophytes of reactive arthritis are bulky, asymmetrical, and
tend to protrude laterally before progressing vertically, whereas the
syndesmophytes of ankylosing spondylitis are symmetric, delicate, and vertical.
NB
vertebral body).
growths (arise from the midpoint of a vertebral body) that tend to initially protrude laterally before
progressing vertically.
❖ Periostitis can be seen along the shafts of the small bones of the hands and feet.
❖ Reactive arthritis can produce articular erosions associated with periosteal reactions ("proliferative erosions").
LABORATORY FINDINGS
✓ Elevated ESR & CRP during attacks.
3. Serological tests: There is Negative result for RF, Anti CCP & ANA.
4. Urine analysis:
• The inciting organism can be detected in approximately 50% of patients with
suspected Chlamydia-induced reactive arthritis.
• Ligase reactions on the first-voided urine are probably the single best test.
5. Arthrocentesis:
• Arthrocentesis reveals inflammatory synovial fluid with cell counts usually in the
range of 2000-50,000 white blood cells per cubic millimeter and a predominance of
neutrophils.
• Cultures: Despite the link with infection, cultures of synovial fluid are sterile
(there is no established role for antibiotics).
➢ The diagnosis of reactive arthritis is based on the clinical presentation and the exclusion
of alternative explanations for an inflammatory oligoarthritis.
➢ With early disease it is critical to exclude infectious causes of arthritis:
1. Disseminated gonococcal infection (DGI):

➢ DGI can be difficult to differentiate from acute-onset reactive arthritis because:
✓ Oligoarthritis, tenosynovitis, and fever can occur in both diseases.
✓ The synovial fluid white blood cell count in DGI is usually within the range seen
in reactive arthritis.
✓ Synovial fluid cultures, moreover, are sterile in >50% of cases of DGI, and
therefore do not distinguish reactive arthritis from DGI.
➢ Swabs: Urethral, pharyngeal, cervical, and rectal swabs for gonococci have a
combined sensitivity of 70-90% in DGI.
➢ Occasionally a therapeutic trial of antibiotics is necessary to make this diagnostic

distinction; a prompt response to appropriate antibiotic therapy points to a diagnosis
of DGI.
2. Nongonococcal septic arthritis:
✓ It can be oligoarticular and occasionally mimics reactive arthritis.
✓ Arthrocentesis: Synovial fluid cultures are usually positive.
3. Post-streptococcal arthritis:
✓ An antecedent sore throat suggests poststreptococcal arthritis, which in adults
usually is additive and is not associated with the extra-articular manifestations
of acute rheumatic fever.
4. Acute viral infections:(such as parvovirus B19)

✓ Usually cause an acute polyarthritis, but occasionally the arthritis involves only a
few joints.
5. Rheumatoid arthritis:
➢ Clinically:
❖ Rheumatoid Arthritis: Typically affect PIP, MCP and wrist joints in a symmetric
distribution – usually polrarticualr.
❖ Reactive A.: Joints of Lower extremities (eg, knees, ankles, and feet) are more
commonly affected than the joints of the upper extremities – usually asymmetric
oligoarticualr.
❖ Other clinical finding associated with Reactive:

✓ Inflammatory low back pain and dactylitis.
➢ LAB: The presence of AntiCCP Ab which is highly specific to to rheumatoid arthritis.
6. GOUT:
✓ When acute in onset, the monarticular and oligoarticular forms of Reactive arthritis
can cause confusion with the crystal arthropathies (gout and pseudogout).
✓ Examination of synovial fluid is usually diagnostic
✓ Dactylitis can be a helpful clue to the presence of a spondyloarthropathy
(particularly reactive arthritis or psoriatic arthritis) but also can be seen in gout and
sarcoidosis.
Treatment
1. NASIDs:
✓ It’s the corner stone for treatment.
✓ Reduce pain and swelling for most patients with peripheral arthritis.
2. Glucocorticoids:
✓ Systemic corticosteroids may be used for short course in moderate dose (prednisone
30-40 mg daily).
3. DMARDs:
➢ Sulfasalazine:
✓ For peripheral arthritis & Persistent synovitis.
4. Antibiotics:
✓ Appropriate antibiotic therapy should be administered if there is active chlamydial
infection (active enteric infection is uncommon).
✓ There is little evidence that the antibiotic itself curbs the symptoms of reactive
arthritis, and the long-term use of antibiotics is probably not of value.
NB
❖ A Minority of patients with sacroiliitis has spondylitis as well; extensive fusion of the spine resembling severe
ankylosing spondylitis can develop but is uncommon.
❖ The prevalence of axial skeleton disease is greater among those with chronic disease and those with HLA-B27 (90% of
patients with radiographic evidence of sacroiliitis are HLA-B27 positive).
❖ All patients with reactive arthritis and uveitis are HLA-B27 positive.
❖ Reactive arthritis can consist of a single attack that runs its course within a matter of months.
❖ Alternatively, patients may experience self-limited attacks, lasting weeks to months, that recur for years after the
onset of initial symptoms.
❖ Dactylitis can be a helpful clue to the presence of a spondyloarthropathy (particularly reactive arthritis or psoriatic
arthritis) but also can be seen in gout and sarcoidosis.
❖ Reactive arthritis should replace the term "Reiter syndrome," which refers to the triad of reactive
arthritis, conjunctivitis, and urethritis.
❖ "Reiter syndrome" is confusing because many patients with reactive arthritis do not have all components
of the triad. Recent revelations concerning Reiter's involvement in war crimes during World War II provide an
additional reason to avoid this eponym
❖ A 3-month, double-blind, randomized, placebo-controlled study found no benefit of ciprofloxacin

treatment in patients with ReA and undifferentiated oligoarthritis.
❖ A 3-month trial of doxycycline for chronic SpA showed this drug to be no

better than placebo for reducing pain or improving functional status, but the causative organism was only
identified in a few patients.
❖ In chlamydia-induced reactive arthritis, studies have suggested that the appropriate

treatment of the acute urogenital infection can prevent reactive arthritis and that treatment of acute reactive arthritis
with a 3-month course of tetracycline reduces the duration of illness.
ENTEROPATHIC
SPONDYLOARTHRITIS
Definition:
➢ It is the arthritis accompanying the inflammatory bowel diseases {Crohn’s disease
(CD) and ulcerative colitis (UC)}.
Epidemiology:
• Prevalence: Crohn’s disease 20-40 cases per 100,000 populations. And in
ulcerative colitis: the prevalence is 70-150 cases per 100,000 population
• Age of onset: Average age at onset is 35-50 years old.
• Sex: The peripheral arthritis of ulcerative colitis or Crohn disease affects Males &
females equally (increased prevalence of the spondylitic form in males).
Aetiology
 Genetic Risk Factors
➢ Genetic factors have a role in susceptibility to IBD
➢ IBD is that polymorphisms involved in a large number of signaling pathways with
relevance for pathogenesis are affected, and that different associations are
found in different populations.
➢ There is a strong association between IBD and HLA & IL-23R
 Infection:
➢ Pathogenic organisms, such as Clostridium difficile, have been linked to
exacerbations of IBD.
Pathogenesis
 The interplay between the intestinal microflora and genetic host factors is disturbed
in IBD.
 Altered cytokine balance & Increased gut permeability are an important factor in
pathogenesis.
 Increased leakage of tissue fluid from the inflamed mucosa allows the egress of
complement-binding IgG, which may contribute to inflammation and further augment
permeability.
 Recent evidence indicates that cells of the innate immune system are involved in
susceptibility to IBD(Type 1 helper T–cell responsible for pathogenesis in Crohn's
disease)
 Increased amounts of proinflammatory cytokines, TNF-α, interleukin (IL)-1β, IL-6,

and IL-8, are released locally in both diseases.
 In Crohn's disease the entire gut wall is involved in a patchy way & in ulcerative
colitis there is diffuse mucosal pathology.
 A chain of events in the pathogenesis of enteropathic arthritis can begin with

gastrointestinal infection with the appropriate microorganism in a genetically
predisposed patient.
 This causes local inflammation in the gut mucosa, formation of secretory IgA,
increased permeability, absorption of foreign material, and triggering of T
lymphocytes.
 Circulating immune complexes and memory T cells localize to joints and cause
synovitis.
Clinical Findings
A. Peripheral Joint involvement: (Peripheral arthritis)
➢ Asymmetric oligo-articular non-erosive arthritis.

➢ Intermittent attacks lasting up to 6 weeks in a migratory pattern or additive
pattern.
➢ The activity of the peripheral arthritis generally correlates well with the degree of
active bowel inflammation, particularly in UC.
➢ The most frequently involved joints: Lower extremity joints (knee, ankle) &
metacarpophalangeal, proximal interphalangeal joints.
➢ Arthritis occurs in 10% to 22% of patients with IBD, with a higher prevalence in CD
than in UC.
B. Axial Spine involvement: (Spondylitis& Sacroiliitis)

✓ Axial disease in IBD does not correlated to the activity of the bowel disease, and
may precede it.
C. Enthesitis: (40% of patients)

➢ In IBD.
✓ LBP & buttok pain due to involvement of insertion sites around the pelvis.
D. Nonarticular Complications of Inflammatory Bowel Disease
✓ Skin lesions can be seen in up to 25% of patients.
➢ Erythema nodosum:Common with Crohn disease
✓ Tends to mirror the activity of the bowel disease and can often parallel the activity of the
peripheral arthritis.
➢ Pyoderma gangrenosum: Common with ulcerative colitis

✓ Painful deep skin ulcerations, it is the most serious skin manifestation but is less
common.
➢ Acute anterior uveitis can be seen in up to 11% of patients and is usually the unilateral.
➢ Intestinal: Abdominal pain, weight loss, diarrhea, and hematochezia.
➢ Aphthous ulcerations.
Work up
Plain X-ray of sacroiliac joint :
▪ Symmetric changes
▪ Early: The 1st radiographic finding is the appearance of iliac erosions (resembling
postage stamp serrations) in the lower one-third of the sacroiliac joint.
▪ Then, the erosions become more prominent and produce "pseudowidening" of
the sacroiliac joint.
▪ Later on: Progressive inflammation leads to fusion & end with complete obliteration
of the sacroiliac joint (Ankylosis) by bone and fibrous tissue.
MRI of sacroiliac joint : (the most sensitive and specific for the diagnosis of sacroiliitis)
✓ Bony bridges / ankyloses.
NB
✓ The spine shows syndesmophytes and apophyseal joint involvement. Bamboo spine is uncommon.
✓ Erosive disease is uncommon in the peripheral joints, but bony spurs at the heel (enthesitis) may be observed.
LABORATORY FINDINGS
A. Acute phase reactant: Elevated ESR & CRP
B. CBC: Iron deficiency anemia, leukocytosis, and thrombocytosis.
C. Serological tests: There is Negative result for RF, Anti CCP & ANA.
D. Fecal calprotectin has emerged as a sensitive screening test for IBD, and it helps to
select cases for endoscopic exploration.
2. Seronegative spondyloarthropathies (reactive arthritis, AS, and Ps arthritis).
3. Behcet Disease
4. Lyme Disease
5. Gonococcal Arthritis
6. Septic Arthritis
7. Sarcoidosis.
8. (SAPHO) syndrome: Synovitis-acne-pustulosis-hyperostosis osteomyelitis
9. GOUT:
Treatment
A. NASIDs:
✓ Better to be avoided as it may exacerbate underlying IBD, particularly UC
B. Glucocorticoids:
✓ Systemic glucocorticoids used as induction treatment for intestinal IBD

C. Sulfasalazine:
✓ Indication: used in the treatment of colonic inflammation in IBD &
peripheral arthritis , but not axial disease.
D. Azathioprine:
✓ Used to treatment & maintain remission in IBD.
✓ Reduce pain and stiffness of the peripheral arthritis.
✓ It should not be combined with 5-aminosalicylic acid, because of a
pharmacokinetic interaction
E. Biological therapy:
➢ Infliximab ( a monoclonal antibody Anti TNF) approved efficacy for treatment in:
✓ Patients with IBD— particularly CD
✓ Effective for both axial and peripheral arthritis associated with CD as it is for
primary AS.
✓ Spondyloarthritis with evidence of sacroilitis in MRI: infliximab should be used.
➢ Vedolizumab is an all human monoclonal antibody against the α4β7 integrin

receptor involved in gut homing of T cells it has been approved for the therapy of
UC and CD. Efficacy in IBD-related spondyloarthritis is not known.
➢ Ustekinumab had an effect in patients with CD in whom treatment with TNF

inhibitors failed
NB: surgical therapy (Colectomy) of UC or CD has no impact on the associated

spondylitis but can be associated with a complete remission of peripheral arthritis.
Mustafa Elmenawy
Basic
Rheumatology
Systemic Lupus Erythematosus

Systemic Lupus
Erythematosus
Definition: Chronic multi-systemic autoimmune disease characterized by autoantibodies
productions and immune complex deposition in multiple target organs.
Epidemiology:
• Prevalence: The overall prevalence of SLE is 20 to 240 per 100,000 persons
• Race: Higher in non-Caucasian individuals (African American, Asian, and Hispanic).
• Age of onset: Mostly affect female in childbearing age (occurs at any age between
15 and 64 years).
• Sex: The female-to-male ratio is 10: 1 in adults, 3: 1 in older-onset SLE, and 8: 1 in
children
Clinical Findings
A-General manifestations: Fatigue, anorexia, possible weight loss &low-grade fevers.
B- Mucocutaneous Manifestations:
(the most common finding & affecte 80% to 90% of Patient)
1. Discoid lupus (15%–30%):
• Incidence:
✓ The most common form of chronic disease.
✓ It can occur as part of the systemic disease or exist in isolation in the absence
of any autoantibodies (2%–10% will develop SLE).
• Description: Discrete erythematous plaques, covered by scale that extends into
dilated hair follicles.
• Site: most typically occur on the face – scalp - in the pinnae behind the ears - neck.
• Progression:
✓ The lesions can progress, with active indurated erythema at the periphery&
Central atrophic scarring is very characteristic.
✓ Irreversible alopecia can result from follicular destruction.
2. Subacute cutaneous lupus erythematosus (SCLE) lesions (7% to 27%):

• Description:
✓ Erythematous small, scaly papules or plaques that can evolve into
papulosquamous (psoriasiform) or annular polycyclic forms.
✓ The lesions are typically symmetric, widespread, superficial non-scarring
• Site: sun-exposed areas (the shoulders, extensor surfaces of the arms, upper chest,
upper back, and neck).
• Progression: May produce large confluent areas with central hypopigmentation
(without scarring).
Systemic Lupus Erythematosus 127

3. Acute Cutaneous Lupus Erythematosus:

➢ Generalized ACLE:
• Photosensitive lupus rash:
✓ Description: widespread macular or maculopapular erythema occurring in
a photosensitive distribution on any area of the body.
✓ Site: The palmar surfaces, dorsa of the hands, and extensor surfaces of
the fingers are commonly involved.
• Bullous lupus erythematosus: a rare cutaneous manifestation characterized by
subepidermal vesiculobullous skin changes (nonscarring bullous eruption).
• Toxic epidermal necrolysis
➢ Localized ACLE (The malar or butterfly rash)(30% to 60%):

• Incidence: It’s the most classic of all the rashes in SLE.
• Description:
✓ Erythematous and edematous rash which simulates the shape of a butterfly
with its body bridging over the base of the nose and wings spreading out over
the malar eminences.
✓ The rash is abrupt in onset and can last for days.
✓ The rash is photosensitive (initiated and/or exacerbated exposure to sunlight).
• Site: butterfly area, forehead and chin & spares the nasolabial folds.
• Progression: Heal without scarring (but temporary post-inflammatory changes suck as Induration,
hyperpigmentation &scaling are common, particularly in patients with pigmented skin).
4. Alopecia:
✓ Diffuse thinning or hair fragility with visible broken hairs.
✓ May be diffuse or patchy.
✓ Usually reversible (Non scarring) but Irreversible or permanently scarring
as a result of discoid lesions in the Scalp.
✓ Lupus frizz: The breakage of hairs at the temples.
5. Mucosal lesions (ulceration):

• Site:
✓ Mouth: on the buccal mucosa & tongue (Sores on the upper palate are being most specific for SLE).
✓ Nose -- Anogenital area.
• Description:
✓ Acute oral lupus lesions present as red macules, palatal erythema or
petechiae, erosions, or ulcerations (usually painless).
✓ Subacute oral lesions (rare): well-demaracted, round, red patches.
✓ Oral discoid lesions present as painful, welldemarcated,round, red lesions
with white radiating hyperkeratotic striae.
6. Cutaneous Vasculitis: (Small blood vessels vasculitis)

✓ It may be manifest as:
• Urticaria-palpable purpura.
• Nailfold or digital ulcerations.
• Erythematous papules of the pulps of the fingers and palms, or splinter
hemorrhages.
✓ Cutaneous leukocytoclastic vasculitis most commonly presents as palpable
purpura on the lower extremities.
7. Lupus panniculitis:
✓ Firm subcutaneous nodules generally without surface changes.
✓ With time, the overlying skin becomes attached to the subcutaneous
nodular lesions and is drawn inward, resulting in deep depressions.
Gilliam Classification of Skin Lesions Associated with Lupus

Lupus erythematosus-specific skin lesions LE-nonspecific skin lesions
1. Acute cutaneous LE (ACLE) 1. Cutaneous vascular disease as
• Localized ACLE • Vasculitis
• Generalized ACLE • Leukocytoclastic vasculitis
2. Subacute cutaneous LE (SCLE) • Livedo reticularis
• Annular SCLE • Raynaud’s phenomenon
• Papulosquamous SCLE
3. Chronic cutaneous LE (CCLE) 2. Nonscarring alopecia “Lupus hair”
• Classic discoid LE (DLE):
• Hypertrophic DLE/verrucous DLE 3. Urticaria
• Lupus panniculitis/profundus 4. Erythema multiforme (Rowell’s
• Mucosal DLE syndrome)
• Chilblain LE 5. Leg ulcers
6.Lichen planus
• Lichenoid DLE (DLE-lichen planus overlap)
NB
 The term “discoid” refers to the sharply demarcated disk shaped appearance of the lesions.
 Chronic cutaneous lupus erythematosus (CCLE) refers to a variety of subtypes of photosensitive lesions that can lead to skin
atrophy and scar and that may persist for several months.
 Antibodies to SSA/Ro ribonucleoproteins are commonly found in patients with SCLE.
 Oral discoid lupus frequently involves the lip and spreads from the vermilion border to the skin of the lip.
 Other forms of lupus-specific skin lesions such as discoid lupus can also occur in the malar distribution.
 DD of the malar rash of SLE:  Other causes of SCLE:
✓ Acne, rosacea (The absence of discrete papules and pustules ✓ Angiotensin-converting enzyme inhibitors,
distinguishes the malar or butterfly rash from acne rosacea). ✓ Terbinafine, hydrochlorothiazide.
✓ Seborrheic dermatitis. ✓ calcium channel blockers.
✓ Perioral dermatitis. ✓ Paraneoplastic syndrome.
✓ Atopic dermatitis & erysipelas.
 DD of photosensitive rash: during evaluation of a photosensitive patient, polymorphous light eruption (PMLE) and phototoxic
medications are important diagnostic considerations.
 Accurate differentiation between PMLE and lupus is essential because PMLE is treated by ultraviolet radiation phototherapy, but
lupus is worsened by it. PMLE can occur concomitantly in patients with known SLE.
 Erythema of ACLE Vs Gottron’s papules of dermatomyositis: the erythema of ACLE spares the metacarpalphalangeal joints
and typically is located between the interphalangeal joints.
 If the diagnosis remains uncertain after an extensive clinical and serologic evaluation, biopsy of the rash can aid in distinguishing
cutaneous lupus from other dermatologic conditions.
 Discoid lupus erythematosus may involve the dorsa of the hands. The lesions spare the proximal interphalangeal joints, a
characteristic feature of lupus-specific rashes.

C - Musculoskeletal system manifestations:

1- Polyarthralgia & Arthritis (75%-100%):
➢ Painful joints are the most common presenting symptom of SLE.
➢ The patient’s complaint of pain may be out of proportion to the degree of synovitis
present on physical examination.
➢ Classical signs of a true arthritis usually absent.
➢ Distribution: Arthritis can affect any joint, but it is most often polyarticular &
symmetrical with involvement of the small joints of the hands (PIP and MCP), wrists
and knees, but sparing the spine.
➢ The arthritis can be evanescent, resolving within 24 hours, or more persistent.

➢ In contrast to RA:
✓ The arthritis in SLE is nonerosive and generally nondeforming.
✓ If patients appear to have deforming features, (such as ulnar deviation,
hyperflexion, and hyperextension) the deformities are generally reducible.
➢ Jaccoud-like arthropathy: hypermobile digits with reducible deformities & occures
secondary to involvement of paraarticular tissues (such as the joint capsule,
ligaments, and tendons.
2- Generalized myalgia:
➢ Generalized myalgia and muscle weakness (frequently involving the deltoids and quadriceps).
➢ It can be accompanying features of disease flares.
➢ Overt myositis with elevations of CPK occurs in about 15% of patients.
➢ Patients with SLE can develop myopathy as a consequence of glucocorticoids
or antimalarials.
3- Osteonecrosis(5-10%)::
➢ Site:
✓ The most common site of involvement the femoral head.
✓ Other sites include the femoral condyles, talus, humeral head, and,
occasionally, the metatarsal heads, radial head, carpal bones, and metacarpal
bones.
➢ Causes:
✓ Use of corticosteroids (the most common).
✓ Raynaud’s, small vessel vasculitis.
✓ Fat emboli.
✓ The presence of antiphospholipid antibodies.
➢ Presentation: patients with osteonecrosis complain of persistent pain localized to a

single joint (usually the hip joint), the pain exacerbated with activity, relieved by
rest.

D- Neuro-psychiatric manifestations:
(affecte about 2/3 of Patient with SLE)
ACR Classification of Neuropsychiatric Syndromes in SLE
Central Nervous System (12) Peripheral Nervous System
1) Acute confusional state 1) Autonomic disorder
2) Aseptic meningitis 2) Cranial neuropathy
3) Anxiety disorder 3) Guillain-Barré syndrome
4) Cerebrovascular disease 4) Mononeuropathy, single/multiplex
5) Cognitive dysfunction 5) Myasthenia gravis
6) Demyelinating syndrome 6) Plexopathy
7) Headache 7) Polyneuropathy
8) Movement disorder
9) Myelopathy
10) Mood disorder
11) Seizure
12) Psychosis
1. Psychiatric disorders: 2. Cognitive impairment

✓ It may present as: mood disorders, depression, anxiety and ✓ The most common form of neurologic involvement occurring
psychosis. in 80% of SLE patients 10 years after diagnosis.
✓ Causes of psychiatric disorders: ✓ Clinically presented as disturbance in Mood, Memory &
1. The stress of having a major chronic illness. Attention.
✓ It is usually progress in patients who are persistently
2. Drugs--Infections -- metabolic disorders.
positive for antiphospholipid antibodies & represents
✓ Psychosis (paranoia or hallucinations) in lupus is rare & should be permanent damage.
differentiated from glucocorticoid psychosis.
3. Encephalopathy (organic brain syndrome or acute confusional state). 4. Headache
✓ Disturbance of consciousness or level of arousal. ✓ Headach is a common complaint in patients with SLE.
✓ Cognitive disturbance and/or changes in mood, behavior. ✓ The lupus headache defined as severe, disabling,
persistent, and not responsive to narcotic analgesics.
5. Seizures: Which may occurs due to: 6. Strokes usually occurs due to:
✓ Represent active lupus. ✓ Comorbid conditions such as hypertension,
✓ Represent an epileptic focus from a past stroke. atherosclerosis.
✓ Secondary to metabolic or toxic factors. ✓ Antiphospholipid syndrome OR Represent active lupus.
7. Neuropathy:
A. Polyneuropathy: may be motor, sensory, mixed motor–sensory
B. Mononeuritis multiplex Due to a vasculitis of the vaso nervorum.
✓ It presents with sensory symptoms followed by motor weakness such as foot drop, mostly in the distal lower extremities.
C. Cranial neuropathies(rare). can result in:
➢ Visual defects, blindness, papilledema -- nystagmus or ptosis--Tinnitus and vertigo-- facial palsy.
8. Other rare neurological manifestations:
A. Lupoid sclerosis: It is complex neurologic deficits similar to those observed in multiple sclerosis.
B. Transverse myelitis (Lower extremity paralysis, Sensory deficits, and Loss of sphincter control).
C. An acute inflammatory demyelinating polyradiculoneuropathy (Guillain–Barre syndrome).
D. Aseptic Meningitis: presenting as headache, often with fever, meningeal signs & sterile CSF.
E. Pseudotumor cerebri: Presenting as headache.
F. Chorea is the most common movement disorder observed in SLE.

E-Pulmonary manifestations:
1. Pleurisy: the most common feature of acute pulmonary involvement in SLE.
2. Pleural effusion
✓ Pleural effusions are most often small and bilateral.
✓ The fluid is usually clear exudative with increased protein, normal glucose.
✓ White blood cell count <10,000, a predominance of neutrophils or lymphocytes.
✓ Decreased levels of complement.
3. Pneumonitis:
 Acute lupus pneumonitis:
✓ Patient with an abrupt febrile pneumonitic process in whom infection has been
ruled out.
✓ C/P:
• Pleuritic chest pain, Cough with hemoptysis, and Dyspnea.
• Rales.
✓ X-ray: Patchy infiltrates or plate like atelectasis (radiography)
 Diffuse alveolar hemorrhage:

✓ Life-threatening pulmonary complication of SLE associated with a 50%
mortality rate.
✓ The characteristic findings are:
• An abrupt onset of dyspnea, coughs, fever, and infiltrates.
• Dramatic fall in hemoglobin.
• Hemoptysis which occurs in 50% of cases only
 Chronic Interstitial pneumonitis (Rare <10%):characterized by:
✓ Progressive dyspnea--Nonproductive cough--Basilar rales.
✓ Diffuse interstitial lung infiltrates.
✓ Should be suspected in patients complaining of progressive shortness of
breath and in whom the chest radiograph is negative and profound hypoxemia
is absent.
Uncommon pulmonary presentations:

4. Pulmonary hypertension:
✓ Presents as dyspnea on exertion, fatigue, chest pain, nonproductive cough
✓ Diagnosis should be confirmed with right heart catheterization
✓ Exclude 2ry causes of pulmonary hypertension, including thromboembolic
disease.
5. Pulmonary hemorrhage.
6. Pulmonary embolism (Unusual presentations).
7. Shrinking lung syndrome:
✓ Unexplained dyspnea.
✓ Small lung volumes with restrictive PFT.
✓ Normal lung field with elevated diagram (radiography).
E-Cardiovascular manifestations:
1. Pericarditis: (the most common 6% to 45%. Of SLE patient):

✓ Substernal or pericardial pain.
✓ Aggravated by motion such as inspiration, coughing, swallowing, twisting, and
bending forward.
✓ Symptoms may either be severe and last for weeks, or mild or last for hours.
✓ A pericardial rub may or may not be present and can be heard in an
asymptomatic patient.
2. Pericardial effusion:
✓ The pericardial fluid is straw-colored to serosanguinous, exudative,and can have a
high white blood cell count with a predominance of neutrophils.
3. Myocarditis.
✓ Myocarditis should be suspected in a patient of SLE which presents with various
combinations of the following clinical features: unexplained heart failure or
cardiomegaly,unexplained tachycardia, and unexplained ECHO abnormalities.
✓ Echocardiography can confirm the presence of systolic or diastolic dysfunction and/
or global hypokinesis.
4. Accelerated atherosclerosis:
✓ Accelerated atherosclerosis is an important cause of morbidity and mortality in SLE.
✓ Factors which contributes to Accelerated atherosclerosis:
√ Hypercholesterolemia__Hypertension__Lupus itself.
√ Glucocorticoid therapy due to the elevation of plasma lipids.
5. Unusual presentations:
➢ Libman–Sacks endocarditis: atypical verrucous endocarditis, the classic cardiac lesion of SLE.
➢ Cardiac tamponade -- Constrictive pericarditis -- Coronary arteritis/aneurysm.
G- Ocular manifestations:
1. Keratoconjunctivitis sicca:
✓ The most common ocular manifestation affecting SLE patient.
✓ It can occur in the presence or absence of secondary Sjögren’s syndrome.
2. Retinal Abnormalities:
➢ SLE retinopathy is believed to be an immune complex–mediated vasculopathy and/or
the result of microthrombotic events.
➢ Retinal hemorrhages & Retinal vasculitis with exudate (cytoid bodies)
➢ Cotton wool spots (not pathognomonic for lupus).
✓ Common ocular lesion affecting SLE patient.
✓ Occur preferentially in the posterior part of the retina and often involve the
optic nerve head and result from focal ischemia.
3. Proptosis may be the presenting feature of SLE.
4. Rare presentations: Uveitis, Episcleritis & retinitis.

H- Gastrointestinal manifestations:
1. Common GI Symptoms: Anorexia ,nausea & vomiting.

2. Esophageal dysmotility –Epigastric pain.
3. Hepatosplenomegaly
4. Elevated liver enzyme which may be due to :
√ During periods of active disease.
√ following the use medications prescribed to treat lupus, such as
(NSAIDs,azathioprine and methotrexate)
5. Melena, diarrhea & malabsorption.
6. Rare presentations:
➢ Mesenteric vasculitis:
✓ Sever postprandial abdominal pain--Rectal bleeding--Bowel perforation.
➢ Protein-losing enteropathy:
✓ Low serum albumin -- Pedal edema -- Absence of proteinuria.
➢ Budd-Chiari syndrome
➢ lupoid hepatitis:
>>It is a subset of chronic active hepatitis.
>>Diagnosed serologically and histologically.
>>It is seen in less than 10% of patients.
NB
 Erosions of SLE may be rarely present and likely result from capsular pressure and an altered mechanical situation
caused by subluxation.
 Erosions of SLE usually nonprogressive.( distinguished from RA).
Neurological manifestations:
 The pathophysiology of this broad clinical category is not well understood,
 Proposed mechanisms include vascular occlusion due to Vasculopathy, Leukoaggregation or Thrombosis, and
antibody-mediated neuronal cell injury or dysfunction.
 Glucocorticoid psychosis is rare if the prednisone dose is less than 20 mg daily.
 Hydroxychloroquine reduces the seizure threshold, and should not be introduced unless seizures are well
controlled.
 Organic brain syndrome often develops over a brief time frame, fluctuates over the day, and covers a wide spectrum
ranging from mild alterations of consciousness to coma.
 DD of the lupus headache includes: Benign intracranial hypertension & Migrain.
 DD of pseudotumor cerebri:
✓ Lupus. √ Glucocorticoids. √ Idiopathic.
 Antiphospholipid antibodies may lead to l a dural sinus thrombosis.

 Because of the difficulty in distinguishing causal SLE associations from certain neurological features of the disease,
only seizure and psychosis are included among the diagnostic criteria.
 Delirium represents a spectrum of fluctuating altered consciousness characteristic of SLE.

 Delirium may be caused by CNS vasculitis, encephalopathy, or the manifestations previously called organic brain
syndrome.
Cardio-pulmonary manifestations:
 Pleurisy with pleuritic chest pain with or without pleural effusions is the most common feature of acute pulmonary
involvement in SLE.
 Pleurisy is a more common feature of serositis than pericarditis.
 The pain of pleuritis can be quite severe and must be distinguished from pulmonary embolus or infection.
 Effusion may be 2ry to process rather than SLE including infection and pulmonary embolism.
 Shortness of breath or dyspnea may be due to many causes.
 Lupus pneumonitis:
• Diagnosis require exclusion of other processes
• Lung biopsy may be required to establish the diagnosis especially in the setting of persistent or progressive finding despite
therapy.
• Abnormal findings in pulmonary function tests are common but patient may have mild or no associated symptoms.
 Pulmonary hypertension without underlying parenchymal lung disease is rarely occurs with symptomatic dyspnea or
right-sided heart failure.
 Hypoxia, tachypnea, crackles, or gross hemoptysis may be signs of pneumonitis or diffuse intrapulmonary
hemorrhage.
 Hemodynamic instability and hypoxia may suggest pulmonary embolism.
 Importantly, when a young woman presents with shortness of breath and pleuritic chest pain, the differential
diagnosis must include SLE, and the patient should be tested for ANA.
 Prophylactic antibiotics for surgical and dental procedures have been recommended for all SLE patients.
 Antimalarials may result in a reduction of plasma cholesterol, low-density lipoprotein (LDL), and very low-density
lipoprotein (VLDL).

Lupus nephritis
 Incidence: One half to two thirds of patients. (50%-75%) with SLE.
 Pathphysiology:
➢ immune complexes deposition:
✓ Autoantibodies form pathogenic immune complexes.
✓ Deposition of these immune deposits in the kidneys initiates an inflammatory
response by activating the complement cascade and recruiting inflammatory
cells.
➢ Thrombosis:
✓ Glomerular thrombosis is another mechanism that may play a role in
pathogenesis of lupus nephritis, mainly in patients with antiphospholipid antibody
syndrome, and is believed to be the result of antibodies directed against
negatively charged phospholipid-protein complexes.
 Presentation:
1. The clinical presentation of lupus nephritis is highly variable, ranging from
asymptomatic hematuria or proteinuria (or both) to frank nephrotic syndrome to
rapidly progressive glomerulonephritis with loss of renal function.
2. Patients usually asymptomatic & diagnosis is based on the presence of:

✓ Proteinuria (dipstick +2, <500 mg/24 hour) or
✓ Elevated serum creatinine.
3. In absence of proteinuria diagnosis is made up by presence of one of the

following:
✓ Persistent hematuria with <5 red blood cells per high power field (in the
absence of other causes such as menstruation).
and/or
✓ Pyuria with <5 white blood cells per high power field (excluding infection).
4. Symptoms related to active nephritis:

✓ Peripheral edema secondary to hypertension or hypoalbuminemia.
✓ Puffy eyes upon waking in the morning.
✓ Frequent urination.
✓ Isolated hypertension outside of the norms for age, race, and gender
should raise suspicion of underlying renal disease.
 Lab. evaluation :
▪ Urine dipstick and microscopic analysis.
▪ A baseline 24-hour urine for measurement of protein and creatinine.
▪ Urinary protein-to-creatinine ratio.
▪ Serum creatinine. Serum albumin.
 Renal ultrasound is another helpful guide to therapy because the chances of successful
treatment become smaller with decreased size and increased echogenicity of the kidneys.
 Renal biopsies
Aim Indications
1) To confirm the diagnosis of LN. 1) Increasing serum creatinine without compelling
alternative causes (e.g., hypovolemia, medication, etc.).
2) Classify the stage of nephritis &evaluate the degree of disease
activity. 2) Confirmed proteinuria of ≥ 1 g/24 hours.
3) To determine an appropriate course of treatment. 3) Proteinuria ≥ 0.5 gram/24 hours plus hematuria.
4) To determine the prognosis of disease. 4) Proteinuria ≥ 0.5 gram/24 hours plus cellular casts.
5) To ruling out other etiologies for the nephropathy such as diabetes,
hypertension, focal segmental glomerulosclerosis or renal thrombosis (which
may complicate antiphospholipid antibody syndrome) for which
immunosuppressive medication would not be appropriate.
WHO CLASSIFICATION OF LUPUS NEPHRITIS
International Society of Nephrology/Renal Pathology Society

Classification of Lupus Nephritis
Class Classification Features
Class I Minimal mesangial Normal light microscopy findings; abnormal electron microscopy findings
Class II Mesangial proliferative Hypercellular on light microscopy
Class III Focal proliferative <50% of glomeruli involved
Class IV Diffuse proliferative >50% of glomeruli involved; classified segmental or global.
Class V Membranous Predominantly nephrotic disease
Class VI Advanced sclerosing Chronic lesions and sclerosis

International Society of Nephrology/Renal Pathology Society

Classification of Lupus Nephritis
Light microscopy findings Normal

Class I Immunofluorescence electron
Minimal mesangial lupus nephritis Mesangial immune deposits
microscopy findings
Clinical manifestations Mild proteinuria
Purely mesangial hypercellularity or mesangial matrix expansion with

Light microscopy findings
mesangial immune deposits
Class II Mesangial proliferative lupus Immunofluorescence electron Mesangial immune deposits; few immune deposits in subepithelial or
nephritis microscopy findings subendothelial deposits possible
Mild renal disease such as asymptomatic hematuria or proteinuria
Clinical manifestations
that usually does not warrant specific therapy
Class III Focal lupus nephritis Active or inactive focal, segmental, or global glomerulonephritis
involving <50% of all glomeruli
Class III (A)
Active lesions – Focal proliferative lupus Immunofluorescence electron
Subendothelial and mesangial immune deposits
nephritis microscopy findings
Class III (A/C)

Active and chronic lesions - Focal
proliferative and sclerosing lupus ✓ Active generalized SLE and mild-to-moderate renal disease with
nephritis Clinical manifestations hematuria and moderate proteinuria in many patients.
Class III (C) ✓ Potentially progressing to class IV lupus nephritis
Chronic inactive lesions - Focal sclerosing
lupus nephritis
Class IV Diffuse lupus nephritis ✓ Active or inactive diffuse, segmental or global

glomerulonephritis involving >50% of all glomeruli.
Class IV-S (A): Active lesions - Diffuse ✓ Subdivided into diffuse segmental (class IV-S) when >50% of
segmental proliferative lupus nephritis Light microscopy findings
involved glomeruli have segmental lesions (involving less than
Class IV-G (A) Active lesions - Diffuse half of glomerular tuft) and diffuse global (class IV-G) when
global proliferative lupus nephritis
>50% of involved glomeruli have global lesions
Class IV-S (A/C) Immunofluorescence electron
Active and chronic lesions - Segmental Subendothelial immune deposits
microscopy findings
proliferative and sclerosing
Class IV-G (A/C)
Active and chronic lesions - Global
proliferative and sclerosing.
Class IV-S (C) ✓ Clinical evidence of renal disease including hypertension,

Chronic inactive lesions with scars - edema, active urinary sediment, worsening renal function.
Diffuse segmental sclerosing lupus Clinical manifestations
✓ Nephrotic range proteinuria in most cases.
nephritis ✓ Active extrarenal SLE in many patients
Class IV-G (C)
Chronic inactive lesions with scars -
Diffuse global sclerosing lupus nephritis

Diffuse thickening of glomerular basement membrane without

inflammatory infiltrate.
Subepithelial and intramembranous immune deposits; subendothelial
Class V Immunofluorescence electron
deposits present only when associated proliferative component is
Membranous lupus nephritis microscopy findings
present
Clinical and laboratory features of nephrotic syndrome, usually
Clinical manifestations
without manifestations of active SLE
✓ Advanced glomerular sclerosis involving >90% of glomeruli,

Light microscopy findings interstitial fibrosis, and tubular atrophy.
Class VI ✓ All morphological manifestations of irreversible renal injury
Advanced sclerosis lupus nephritis ✓ Significant renal insufficiency or end-stage renal disease in
Clinical manifestations most cases.
✓ Unlikely to respond to medical therapy
Active and Chronic Glomerular Lesions
2018 Modified NIH lupus nephritis activity & chronicity scoring system
Modified Activity Index Score (0 to 24): <25% (1), 25%–50% (2), or >50% (3)
1. Endocapillary hypercellularity in of glomeruli score: 0-3
2. Neutrophils and/or karyorrhexis in of glomeruli score: 0-3
3. Fibrinoid necrosis in of glomeruli score 0–3 x 2
4. Wire loop lesions and/or hyaline thrombi in of glomeruli score: 0-3
5. Cellular and/or fibrocellular crescents in glomeruli score 0-3 x 2
6. Interstitial leukocytes in the cortex score: 0-3
Modified Chronicity Index Score (0 to 12): <25% (1), 25%–50% (2), or >50% (3)
1. Total glomerulosclerosis score, global and/or segmental score: 0-3
sclerosis of glomeruli
2. Fibrous crescents of glomeruli score: 0-3
3. Tubular atrophy of the cortical tubules score: 0-3
4. Interstitial fibrosis in the cortex score: 0-3

Severity of Lupus Nephritis
Proliferative Nephritis
Mild:
✓ Class III nephritis without severe histologic features (crescents, fibrinoid necrosis)
✓ Low chronicity index (≤3).
✓ Normal renal function.
✓ Non-nephrotic range proteinuria
Moderately severe
✓ Mild disease as defined above with partial or no response after the initial induction
therapy, or delayed remission (>12 mo),
OR
✓ Focal proliferative nephritis with adverse histologic features or reproducible SCr
increase ≥30%.
OR
✓ Class IV nephritis without adverse histologic features.
Severe
✓ Moderately severe as defined above but not remitting after 6-12 mo of therapy.
OR
✓ Proliferative disease with impaired renal function and fibrinoid necrosis or crescents
in >25% of glomeruli.
OR
✓ Mixed membranous and proliferative nephritis.
OR
✓ Proliferative nephritis with high chronicity alone (chronicity index >4) or in
combination with high activity (chronicity index >3 and activity index >10).
OR
✓ Rapidly progressive glomerulonephritis (doubling of SCr within 2-3 mo)
Membranous Nephropathy
➢ Mild:Non-nephrotic range proteinuria with normal renal function.
➢ Moderate: Nephrotic range proteinuria with normal renal function at presentation.
➢ Severe: Nephrotic range proteinuria with impaired renal function at presentation

(≥30% increase in SCr).

NB
 Urine protein is a critical measurement of ongoing renal lupus activity:

✓ While new proteinuria of 500 mg is significant, patients with membranous nephropathy in particular, can have
continued proteinuria between 500 mg and 2 g and still be considered stable.
✓ In such cases, an exacerbation is best defined as at least a doubling of baseline proteinuria.
 It is essential to monitor blood pressure because hypertension can be a reflection of renal disease activity and, as such,
accelerates functional impairment.
 An elevated creatinine without concomitant proteinuria is unexpected unless advance renal insufficiency is present.
 A low serum albumin is an indicator of persistent proteinuria.
 In the lupus patient with proteinuria or hematuria, it should not be assumed that the underlying pathology is lupus nephritis.
The renal biopsy may identify other lesions, including:
✓ Comorbidity from diabetes mellitus and hypertension.
✓ Interstitial nephritis from drugs.
✓ Renal vasculitis from hepatitis C (cryoglobulinemia).
✓ Microangiopathic changes (often due to antiphospholipid antibodies).
 The most severe form of lupus nephritis is diffuse proliferative nephritis (due to subendothelial immune complex deposits
which can rapidly lead to renal failure) which are associated with a poorer prognosis than membranous or mesangial
disease.
 Focal lupus nephritis (class III) is less severe, but occasional patients do progress to renal failure.
 Membranous lupus nephritis can occur as a pure form, or along with diffuse proliferative glomerulonephritis or focal
lupus nephritis.Its course is more indolent, but there is eventual progression to renal insufficiency and failure.
 Patients with Membranous lupus nephritis usually have nephrotic syndrome (edema, ascites, and pleural and pericardial
effusions without hypertension).
 Nephrotic syndrome is not to be considered benign, because it causes hyperlipidemia and hypercoagulability.
 The mildest form of lupus nephritis is mesangial lupus nephritis (class I).
 Class V/membranous is now purely membranous, and if there is evidence of a proliferative lesion, both classes are
specified, for example, V + III or V + IV.
 The sediment can be bland (consistent with mesangial or membranous) or active containing red blood cell casts
(consistent with proliferative lesions).
 Clinically relevant lupus nephritis is associated with a 30% decrease in creatinine clearance, proteinuria of greater than 1000 mg/d,
and renal biopsy findings indicating active lupus nephritis.
 Spot urine test for creatinine and protein concentration:

✓ Normal creatinine excretion is 1000 mg/24 h/1.75 m2;
✓ Normal protein excretion is 150-200 mg/24 h/1.75 m2.
✓ Normal urinary protein-to-creatinine ratio is <0.2.)
LABORATORY FINDINGS
1-CBC:
A-Anemia: Anemia is very common in SLE & this may be due to
1. Anemia of chronic disease (ACD)
• Most common cause of anemia in SLE
• It is a normochromic, normocytic anemia a relatively low reticulocyte count
characterized by the presence of low serum iron, low transferrin, and normal to
increased serum ferritin.
2. Autoimmune hemolytic anemia (AIHA): occurs in 10% of patients with SLE

• It characterized by an elevated reticulocyte count, low haptoglobin levels, increased
indirect bilirubin concentration, and a positive direct Coombs' test.
3. Renal insufficiency
• An inappropriately low level of erythropoietin (EPO) is a hallmark of anemia due to
renal insufficiency.
4. Other causes:
• Blood loss: Gastrointestinal loss and menorrhagias.
• Pure red cell aplasia.
• Medication-induced myelotoxicity.
• Nutritional deficiency: Iron, folate, B12 deficiencies.
B- Leukopenia:
✓ Common (50%) but usually mild.
✓ Lymphopenia is common and occurs due to:
➢ Side effect of TTT: glucocorticoids & immunosuppressive agents.
➢ Diseas activity ( lymphocytoxic antibodies).
Neutropenia can occur but is rare.
C- Thrombocytopenia:
✓ May be moderate (platelet counts of 50,000–100,000/mm3), chronic and totally
asymptomatic.
✓ May be profound (<20,000/mm3) and acute, with gum bleeding and petechiae.
✓ Thrombocytopenia can be the result of immune mediated platelet destruction similar to
immune thrombocytopenic purpura (ITP). The platelet IIb/IIIa antigen is the primary target.
2-Acute phase reactant:

A- ESR: Is frequently elevated in SLE and is generally not considered a reliable marker
of clinical activity.
B- CRP: A rise in the C-reactive protein may be an indicator of infection, but this has not
proven to be absolute.
C- Complement levels: C3 and C4 levels are often depressed in patients with active
SLE because of consumption by immune complex–induced inflammation.
3-Urine analysis:
➢ Proteinuria alone or proteinuria with an active urine sediment (red blood cells or red
blood cell casts >>> with Lupus nephritis.
➢ 24 hr. urinary protein.

4-Chemistries:
1. The blood urea nitrogen and creatinine may be elevated due to >>renal insufficiency
or failure.
2. Cholesterol: elevated >> secondary to nephrotic syndrome or to high-dose prednisone.
3. Alkaline phosphatase may be elevated >> renal osteodystrophy or 1ry biliary cirrhosis.
4. Creatine kinase may be elevated>> secondary to myositis.
5. Homocysteine, a risk factor for atherosclerosis and thrombosis, is elevated in up to
30%, especially if there is renal insufficiency.
Autoantibodies and Clinical Significance in (SLE)

Autoantibody Prevalence in SLE Clinical Significance
1. ANA < 95% The most sensitive for SLE, but not specific.
2. Anti-dsDNA 30-60% Very specific (95% specificity), but not sensitive.

Fluctuates with disease activity; associated with Nephritis.
3. Anti-Smith 20-30% 99% specificity for SLE
4. Anti-U1RNP 30% Associated with mixed connective tissue disease and lower frequency of
glomerulonephritis
5. Anti-Ro/SSA 30% ✓ Sjِgren’s syndrome, photosensitivity.
✓ SCLE.
6.Anti-La/SSB 20% ✓ Neonatal lupus, Congenital heart block
7.Anti-Ribisomal P 20% Diffuse CNS , Psychosis & Major depression
8. Antihistone 70% Associated with drug-induced lupus
9. Antiphospholipid 30-50% Associated with arterial and venous thrombosis, pregnancy morbidity
✓ Lupus anticoagulant.
✓ Anticardiolipin antibodies.
✓ Anti-B2 glycoprotein-1
Others:
✓ Anti- Factor 8 antibodies: presenting with hemophilia like picture.
✓ False +ve RF in about 15% of cases. --- False +ve test for syphilis.
✓ +Ve Coombs test (with hemolytic anemia denote antibodies on RBCs).
✓ ANA, once documented, its continues measurement is not useful as a gauge of disease activity.
✓ C3 and C4 levels are often depressed in patients with active SLE because of consumption by immune complex–induced inflammation. In
addition, some patients have congenital complement deficiency that predisposes them to SLE.

6-Other tests:
For evaluation of organ affection
Cardiopulmonary involvement:
➢ ECG: For pericardial effusion, pulmonary hypertension, or verrucous Libman-Sacks

endocarditis.
➢ Chest X-ray and chest CT: used to monitor interstitial lung disease and to assess for
pneumonitis, pulmonary emboli, and alveolar hemorrhage.
➢ Respiratory function tests
Musculoskeletal involvement:
 MRI hip for early detection of Osteonecrosis.
 Plain X-ray of the joints:

✓ Provides little evidence of SLE given the absence of erosions, even in the
presence of Jaccoud arthropathy with deformity or subluxations.
✓ The most common radiographic changes in SLE include periarticular
osteopenia and soft-tissue swelling.
Skin Lesions
➢ Skin biopsy: helpful in the diagnosis of SLE cutaneous lesions.

 Lupus-specific skin lesions:
✓ Inflammatory infiltrates at the dermoepidermal junction.
✓ Basal layer vasculopathic degeneration of keratinocytes.
✓ Perivascular and periadnexal inflammation.
✓ Follicular plugging, mucin deposition, and hyperkeratosis.
 The lupus band test: Immunofluorescent stains demonstrate immunoglobulin

(mostly IgG and IgM) and complement deposits at the dermoepidermal basement
membrane.
NB
✓ Thrombocytopenia can be the initial presentation of SLE, antedating the development of other symptoms or signs by years.
✓ Any young woman presenting with “idiopathic” thrombocytopenia should be evaluated for SLE.
✓ The partial thromboplastin time(PTT) may be prolonged due to a lupus anticoagulant.
✓ Leukocytosis in SLE
▪ It is usually due to infection or the use of high doses of glucocorticoids but may occur during acute exacerbations of SLE.
▪ A shift of granulocytes to more immature forms (a "left" shift) suggests infection.
✓ Isolated hematuria is unlikely to be due to lupus nephritis, and would prompt a search for other pathologies, such as menstrual
contamination, trauma, bladder pathology such as hemorrhagic cystitis, polyp or tumor, and renal calculi.

CNS involvement
1.CT & MRI:

✓ Used mainly for exclusion of focal abnormalities such as infarcts, hemorrhage, and
tumors.
✓ Multifocal microinfarcts, cortical atrophy, gross infarcts, hemorrhage, ischemic
demyelination, and patchy multiple-sclerosis–like demyelination are typical findings
in neuropsychiatric lupus.
✓ More than half of patients diagnosed with NPSLE have a normal MRI of the brain.
2. Single photon emission computed tomography (SPECT):

✓ It provides an estimate of regional cerebral blood flow and neuronal integrity and was
thought to be more sensitive than MRI for the evaluation of NPSLE.
3. Electroencephalographic (EEG):
✓ EEG abnormalities are common in patients with neuropsychiatric lupus but are
nonspecific
✓ This is necessary in the evaluation of seizure.
4. CSF examination:
✓ It is useful for exclusion of an infectious origin.
✓ Nonspecific CSF abnormalities such as increased cell count, increased protein, IgG
synthesis rate, oligoclonal bands, antineuronal antibodies, LE cells, or reduced
glucose may be present in about one third of patients.
5. Biomarkers Autoantibodies:
➢ Serum antiphospholipid antibodies associated with focal neurological
manifestations in CNS lupus.
➢ CSF antineuronal antibodies associated with diffuse manifestations of CNS lupus.
➢ Anti-ribosomal P antibodies associated with psychiatric problems (severe

depression and psychosis) in SLE.
➢ N-Methyl-d-aspartate receptor (NMDAR) antibodies are a subset of dsDNA

antibodies that appear to cross-react with the glutamate receptor and are associated
with cognitive dysfunction in SLE.
➢ Anti-aquaporin 4/neuromyelitis optica (NMO) antibodies are associated with

longitudinal transverse myelitis with or without optic neuritis.
NB
 The most common microscopic brain finding in SLE is microvasculopathy, described as “healed vasculitis” consistent with
hyalinization, thickening, and thrombus formation

SLE classification Criteria 2012
CLINICAL CRITERIA
Acute Cutaneous Lupus OR Subacute Chronic Cutaneous Lupus

Cutaneous Lupus ✓ Classic discoid rash localized (above the neck) or
• Acute cutaneous lupus: generalized (above and below the neck).
✓ Lupus malar rash (do not count if malar discoid). ✓ Hypertrophic (verrucous) lupus.
✓ Maculopapular lupus rash. ✓ Lupus panniculitis (profundus).
✓ Photosensitive lupus rash (in the absence of ✓ Mucosal lupus, lupus erythematosus tumidus,
dermatomyositis) chillblains lupus.
✓ Bullous lupus, toxic epidermal necrolysis variant of SLE. ✓ Discoid lupus/lichen planus overlap
• Subacute cutaneous lupus:
✓ Nonindurated psoriaform and/or annular polycyclic Oral Ulcers OR Nasal Ulcers
lesions that resolve without scarring. • Oral: palate, buccal, tongue
• Nasal ulcers
Nonscarring alopecia • In the absence of other causes, such as: vasculitis,
• Diffuse thinning or hair fragility with visible broken hairs.
Behcet’s disease, infection (herpesvirus), inflammatory
• In the absence of other causes such as alopecia areata,
bowel disease, reactive arthritis, and acidic foods.
drugs, iron deficiency, and androgenic alopecia.

Synovitis involving 2 or more joints Renal

• Characterized by swelling or effusion ✓ Urine protein–to-creatinine ratio (or 24-hour urine
• OR tenderness in 2 or more joints and at least 30 protein) representing 500 mg protein/24 hoursOR
minutes of morning stiffness. ✓ Red blood cell casts.
Serositis Hemolytic anemia

• Pleuritis: Typical pleurisy for more than 1 day OR pleural
effusions OR pleural rub. (Leukopenia (<4000/mm3) OR
• Pericarditis: Typical pericardial pain (pain with
Lymphopenia (<1000/mm3)
recumbency improved by sitting forward) for more than 1 ✓ Leucopenia at least once: In the absence of other
day OR pericardial effusion OR pericardial rub OR causes: Felty’s syndrome, drugs & portal
pericarditis by electrocardiography hypertension.
• In the absence of other causes, such as infection, uremia, ✓ Lymphopenia at least once: in the absence of other
and Dressler’s pericarditis. known causes such as corticosteroids, drugs, and
infection
Neurologic
✓ Seizures, psychosis. Thrombocytopenia (<100,000/mm3)
✓ Mononeuritis multiplex (in the absence of other known
causes such as primary vasculitis). ✓ At least once in the absence of other known
✓ Peripheral or cranial neuropathy (in the absence of causes such as drugs, portal hypertension, and
other known causes such as primary vasculitis, infection, and thrombotic thrombocytopenic purpura
diabetes mellitus).
✓ Acute confusional state (in the absence of other causes,
including toxic/metabolic, uremia, drugs).
IMMUNOLOGIC CRITERIA
ANA level above laboratory reference range Antiphospholipid antibody positivity, as

determined by
Anti-dsDNA antibody level above laboratory reference range
(or 2-fold the reference range if tested by ELISA) ✓ Positive test for lupus anticoagulant
✓ False-positive test result for rapid plasma reagin
Anti-Sm: presence of antibody to Sm nuclear antigen ✓ Medium- or high-titer anticardiolipin antibody level (IgA,
IgG, or IgM)
✓ Positive test result for anti–2-glycoprotein I (IgA, IgG, or
Low complement (C3, C4, or CH50)
IgM)
Direct Coombs’ test (in the absence of hemolytic anemia)

2019 ACR/EULAR classification criteria for SLE

ACR 1997 Classification Criteria for SLE

1-Fibromyalgia:
✓ Fatigue or chronic pain.
✓ A positive ANA.
2-Rheumatoid arthritis:
✓ SLE patients may have positive rheumatoid factor.
✓ The usual presentation of lupus arthritis is identical to that of rheumatoid arthritis, but
SLE arthritis is rarely erosive.
3-Dermatomyositis
4-Mixed Connective-Tissue Disease:
5-Undifferentiated Connective-Tissue Disease:
6-Scleroderma:
7-Drug-induced lupus:
8-Malignancy:
✓ A malignancy can cause anemia, elevated erythrocyte sedimentation rate, positive
ANA, vasculitis, and other autoimmune phenomena.
✓ Anemia and an elevated erythrocyte sedimentation rate should also bring to mind
multiple myeloma.
✓ Lymphoma:
9-Viral infections:
✓ Parvovirus can cause a polyarthritis and positive ANA.
✓ HIV can cause thrombocytopenia and positive direct Coombs test.
✓ Hepatitis B can cause vasculitis .
✓ Hepatitis C can cause cryoglobulinemia.
10-Thyroid disorders

Complications & Comorbidity

1- Accelerated atherosclerosis:
✓ The major cause of death in patients with SLE.
✓ Attention to weight, hypertension, hyperlipidemia, smoking, diabetes, and
homocysteinemia is crucial to reduce the risk.
✓ Causes of accelerated coronary artery disease (CAD) in persons with SLE are likely
multifactorial, including:
1. Endothelial dysfunction.
2. Inflammatory mediators.
3. Corticosteroid-induced atherogenesis.
4. Dyslipidemia associated with renal disease.
2- Complication of Lupus Nephritis:

✓ Progressive renal failure leads to: anemia, uremia, and electrolyte and acid-based abnormalities.
✓ Hypertension may lead to an increased risk of coronary artery disease and stroke.
✓ Nephrotic syndrome may lead to edema, ascites, and hyperlipidemia, adding to the risk of
coronary artery disease and the potential for thrombosis.
3- Strokes:
✓ APL syndrome.
✓ HTN.
✓ Atherosclerosis.
✓ Active central nervous system lupus.
4- Opportunistic Infections:
✓ Until proved otherwise, consider infection in a patient with SLE who is febrile.
✓ Glucocorticoid & immunosuppressive are associated with increased risk of infection.
5- Malignancy:
✓ There is an increased risk of malignancy in SLE.
✓ SLE patients who received oral cyclophosphamide had an increase in skin cancer,
and later lymphoproliferative disease.
✓ Women with SLE are more likely to have cervical dysplasia and carcinoma.
6- Associated Autoimmune Diseases:

✓ Hypothyroidism develops in about 10% of SLE patients.
✓ Secondary Sjögren syndrome can occur in SLE patients, with or without the Sjögren
antibodies anti-Ro and anti-La.
7- Complications of Therapy:
➢ Glucocorticoid Complications such as:
✓ Osteoporosis.
✓ Avascular necrosis.
✓ Diabetes mellitus & hypertension.
➢ Cyclophosphamide Complications such as:
✓ Cytopenias.
✓ Hemorrhagic cystitis.
✓ Infertility.
✓ An increased risk of malignancy

SLE Disease Activity Index 2000

Interpretation
➢ The final score ranges between 0 and 105. The higher the score, the more
significant is the degree of disease activity.
➢ A score >20 indicates severely active disease.
➢ A severe flare is defined as an increase in score >12 points (or need to increase
prednisone >0.5 mg/kg/day and/or add an immunosuppressive).
➢ A mild/moderate flare is defined as an increase in score >3 to 4 points (or need

to increase prednisone but <0.5 mg/kg/day and/or add hydroxychloroquine/NSAIDs).
➢ The score is predominantly used in research, usually to determine the changes in

disease activity as consequence of a new therapy.
➢ Computed calculator: https://qxmd.com/calculate/calculator_335/sledai-2k

➢ SLE often waxes and wanes in affected individuals throughout life.
➢ The disease course is milder and survival rate higher among persons with isolated skin
and musculoskeletal involvement than in those with renal and CNS disease.

Treatment of SLE
Essential to Know:
✓ Systemic lupus erythematosus (SLE) is a heterogeneous multisystem disease each
lupus patient manifests her or his disease in a unique way, and treatment should be
adjusted to the type and severity of organ system involvement.
✓ The goal of therapy for SLE is to:

1. Put the disease in remission and to maintain this remission by continuing
therapy.
2. Improvement long-term patient outcomes
3. Prevent target organ damage.
5. Minimize the side effects of therapy.
GENERAL MANAGEMENT
A. Lifestyle modification:
✓ Regular exercise -- Sufficient rest.
✓ Healthful diet & Smoking cessation.
✓ Sun protection:
1. Sun protection forms the cornerstone of the management of cutaneous
lupus.
2. Avoid exposure to sun light & UV rays( especially ultraviolet-B) & fluorescent
lights.
3. Avoid skin trauma: tattoos, skin piercing.
4. Routine sunscreen/sunblock (apply the sunscreen 30–60 minutes prior to
exposure and to reapply the sunscreen every 4–6 hours.)
5. Photo-protective clothing.
B. Prevention of steroid-induced osteoporosis with:

➢ Calcium, vitamin D, and bisphosphonates.
➢ Minimize use of corticosteroids.
C. Minimize the risk of infection by:

➢ Judicious use of corticosteroids and immunosuppressive agents
➢ Appropriate immunization with
✓ Influenza (yearly) and Pneumococcal vaccines (every 5year).
✓ Pneumocystis jiroveci prophylaxis if on CYC and/or glucocorticoids
(prednisone >15–20 mg/day).
D. Early detection and correction of associated co-morbidities:

➢ Good control for accelerated atherosclerosis, Hypertension & DM:
✓ Weight reduction by dietary and exercise modalities.
✓ Good blood pressure control.
✓ Annual monitoring of fasting lipid profiles.

E. Management of Constitutional Symptoms:

✓ Fatigue is prevalent in SLE patients and can be a disabling symptom.
✓ Pain and depression are positive predictors of fatigue in SLE patients.
✓ Treatment depends on the underlying etiology of the fatigue which may be
multifactorial.
✓ Reversible factors which can cause fatigue such as hypothyroidism, anemia, and
diabetes should be managed first.
✓ Antimalarials, modafinil, and DHEA (prasterone 200 mg daily) can help fatigue.
F. Cancer Screening: skin, cervical, anal, breast, colon, bladder, and lymphoma on a yearly
basis.
G. Avoid possible disease triggers:

✓ Sulfa-containing antibiotics
✓ Sun
✓ High-estrogen birth control pills (BCPs)
NB:
✓ Infection common in SLE due to the intrinsic immune dysregulation and chronic immunosuppressive use.
✓ Patients should be advised to seek medical attention for unexplained fevers and not immediately attribute these fevers to
lupus flares.
✓ Patients should not be given live attenuated vaccines (measles, mumps, rubella, polio, Bacillus Calmette–
✓ Guérin, herpes zoster, smallpox, intranasal influenza vaccine, and yellow fever) if on prednisone >20 mg/ day or
immunosuppressive agents.
✓ Patients on low-dose AZA (<3 mg/kg/day) or methotrexate (<0.4 mg/kg/week) can receive live attenuated vaccines.
(Immunizations do not cause flares of SLE.)

EULAR recommendations for the treatment of SLE.

➢ Management for systemic lupus erythematosus (SLE) depends on disease severity.
➢ Mild disease:
✓ Fever, cutaneous manifestations, musculoskeletal manifestations, and serositis
which may wax and wane with disease activity.
✓ Treated with: Low dose steroids + HCQ (NSAIDs may be needed).
➢ More severe disease:

✓ Internal organ affection: CNS involvement and/or renal disease.
✓ Treated with: High dose steroids+ Immunosupressive.
➢ Acute emergencies:
✓ Acute emergencies in SLE includes:
▪ Severe neurologic involvement.
▪ Systemic vasculitis.
▪ Profound thrombocytopenia with a TTP-like syndrome.
▪ Rapidly progressive glomerulonephritis.
▪ Diffuse alveolar hemorrhage.
✓ Treated with: high-dose intravenous steroids and cytotoxic therapy such as

cyclophosphamide.
➢ In rare cases, TTP, diffuse alveolar hemorrhage, or profound steroid-refractory

thrombocytopenia may require plasma exchange or therapy with intravenous
immunoglobulin (IVIG), respectively.

Organ specific therapy

Management of Arthritis, Arthralgia, Serositis & Fever:
1. NSAIDs.
2. Hydroxychloroquine: in patients who have had an incomplete response to
NSAIDs.
3. Short-term use of low doses of glucocorticoids (5–10 mg): to obtain quick control
over an inflammation while waiting for the full effect of hydroxychloroquine.
4. Moderate–dose steroids, as necessary, for acute flares.
5. Methotrexate is frequently used as a steroid-sparing agent.
Management of Cutaneous lesion:

Sun protection: as mentioned before.
➢ First-line treatment: Topical agents (GC and/or CNIs) and antimalarials, with or without
systemic GC (the latter at a starting dose depending on severity of skin involvement)
1. Facial lesions: Low to medium potency nonfluorinated (hydrocortisone, desonide).
2. Trunk and limb lesions: Medium-potency preparations such as triamcinolone

acetonide or betamethasone valerate are used.
3. Severe hypertrophic lesions: high-potency preparations such as(betamethasone

diproprionate, clobetasol) are used.
4. Chronic cutaneous lupus:

✓ Treated with topical Tacrolimus& retinoids, including tretinoin and tazarotene, which
have both anti-inflammatory and immunosuppressive effects.
5. Intralesional injections:
✓ Refractory lesions (such as discoid lupus occurring on the scalp) treated with
Intralesional injections of triamcinolone.
NB:
o Start with hydrocortisone at 1st then fluorinated prepration used for resistant cases.
o The use of fluorinated glucocorticoids is limited to 2 weeks because of the well-recognized side effects of skin
atrophy, striae, depigmentation, and telangiectasias.
➢ Sever & resistant skin lesions: In non-responsive cases or cases requiring high-dose
GC: methotrexate, retinoids, dapsone or mycophenolate can be added.

Management of Neuropsychiatric manifestations :
➢ What Are the Risk Factors for NPSLE?

✓ Generalized (non-CNS) lupus activity or damage.
✓ Previous or other concurrent major NPSLE manifestation(s).
✓ Persistently positive moderate-tohigh titers of aPL antibodies.
➢ When to Suspect NPSLE

✓ Any SLE patient at risk who presents with new-onset neurologic or psychiatric manifestations
without an apparent cause.
✓ In patients with subtle or mild signs or symptoms, a high index of suspicion is required to
exclude underlying overt NPSLE.
➢ Is It NPSLE?
✓ At 1st: it is critical to determine if a particular neuropsychiatric finding is due to active SLE or to
a secondary cause.
✓ Mild manifestations (headache, mood disorders, anxiety, mild cognitive dysfunction,

polyneuropathy without electrophysiologic confirmation) are common (up to 40%) but are not
usually related to lupus.
✓ Non–SLE-related causes (infections, metabolic disturbances, drug adverse effects, diabetes or

hypertension) must be excluded.
✓ Most (40%-50%) lupus-related events occur at onset or during the first 2-4 yr after SLE
diagnosis, common (50%-60%) in the presence of generalized lupus activity.
✓ Attribution to lupus more likely when NPSLE risk factors are present.
➢ What Diagnostic Workup Is Indicated?

✓ MRI to identify: Ischemic/thrombotic, demyelinating, or infectious processes.
✓ Cerebrospinal fluid analysis should be performed when CNS infection is suspected.
✓ Electroencephalogram to diagnose seizure disorder.
✓ Neuropsychologic tests to assess cognitive dysfunction.
✓ Nerve conduction studies for peripheral neuropathy.
 What Is the Treatment?

1. Control aggravating factors (infection, dehydration, metabolic abnormalities, and hypertension).
2. Control symptoms (anticonvulsants, antidepressants, antipsychotics).
3. Seizures & Headach: Usually treated with the same anticonvulsant medications that are used
in non-SLE patients.
4. Glucocorticoids (high-dose or pulse therapy) and/or immunosuppressive therapy in cases of:
✓ Acute confusional state & severe psychosis.
✓ Aseptic meningitis, myelitis, optic neuritis & peripheral neuropathies.
✓ Refractory seizure disorder.
✓ Control generalized (non-CNS) lupus activity.
5. Antithrombotic or antiplatelet therapy:

✓ APL-associated NPSLE (particularly cerebrovascular disease, strock, ischemic optic
neuropathy, chorea).
✓ When antiphospholipid syndrome–associated thrombotic events are present

Management of Hematological manifestations:

Exclude offending drugs or other secondary causes:
1. History of drug exposure, infections, traveling to endemic regions
2. Clinical examination: signs of infection, splenomegaly, lymphadenopathy, skin hemorrhagic lesions.
3. Peripheral blood smear examination (morphology of cells; rule-outs: hematologic,malignancy, myelodysplastic $,
MAHA / TTP.
4. Workup for anemia (ferritin, TIBC, folic acid, vitamin B12, reticulocyte index) and hemolysis (reticulocyte index, LDH,
bilirubin, Coombs IgG, haptoglobulin).
5. Workup for infections (as indicated by history and clinical examination).
 Mild cytopenias require no specific therapy other than regular monitoring

 Indications for immunosuppressive treatment
✓ Autoimmune hemolytic anemia (AIHA) with hemoglobin <10 g/dL.
✓ Leukopenia with white blood cell count <2500/μL or ANC <1000/μL.
✓ All patients with platelet count < 20.000/mm3.
✓ Patients with platelet count < 50.000/mm3 with clinically important bleeding and/or
a history of bleeding.
 How to Manage???
➢ 1ST line TTT:
▪ High dose oral GC (1 mg/kg/day prednisone) OR pulses IV Methyl Prednisolone
(500-1000 mg × 3 days) to allow for lower oral GC (0.5 mg/kg/day).
▪ After improvement in the platelet count (usually within 1 week), the
glucocorticoids are tapered slowly.
▪ Steroids sparing agent: Azathioprine (2 mg/kg/ day) or Cyclosporin.
➢ 2nd line TTT: (refractory/relapsing disease):

a) IV Cyclophosphamide (AIHA, thrombocytopenia)
b) Rituximab (AIHA, Thrombocytopenia, Leucopenia).
c) IVIG (Short-term recovery of platelets).
d) Cyclosporine (Neutropenia, Thrombocytopenia).
➢ 3 line TTT: In sever resistant cases not respond to ttt , Danazol, MMF, plasma
rd
exchange can be used.
➢ Additional or supportive treatment:

✓ Red blood cells transfusion: defer until hemoglobin <7 g/dL
✓ Recombinant erythropoietin: if co-existing chronic kidney disease (stage 4-6)
or anemia of chronic disease.
✓ Prophylaxis or treatment with broad-spectrum antibiotics
✓ Recombinant G-CSF (Neupogen): only if ANC < 500/μL and sepsis; use at
lowest possible doses and until ANC >1000/μL
✓ TPO-receptor agonists (Nplate): safe and efficacious in immune
thrombocytopenia.
✓ Splenectomy: in selected patients with severe refractory AIHA or
thrombocytopenia, when there is no lupus activity in other major organs.

Management of Renal disorders:
 At first concomitant risk factors for the progression to chronic kidney disease should
be detected & treated:
 Control blood pressure:

✓ Angiotensin-converting enzyme inhibitors are used to treat proteinuria and
hypertension.
✓ A combination of antihypertensive agents might be necessary to achieve the
goal blood pressure of <130/80 mm Hg.
 Control hyperlipidemia: Statins are often needed to lower serum low density
lipoprotein cholesterol levels to the goal of <100 mg/dL.
 Renal biopsy is recommended for most patients with suspected lupus nephritis.
 Renal biopsy is used:
✓ To correctly classify the stage of nephritis
✓ In ruling out other etiologies for the nephropathy such as diabetes, hypertension, or
focal segmental glomerulosclerosis, for which immunosuppressive medication would
not be appropriate.
Treatment of Proliferative Lupus Nephritis

A. Cyclophosphamide (CYC) Protocol: B. Mycophenolate mofetil
(MMF) Protocol:
Induction of ✓ CYC: Monthly intravenous infusion pulse CYC ✓ MMF: 2-3g/day for 6 monthes.
remission: (500-1000mg\month) for 6 monthes.
✓ CYC: quarterly pulse intravenous infusion ✓ MMF: 1-1.5g/day for 18 monthes

Maintainence CYC (500-1000mg\ 3month) for 18 monthes + Low dose steroids.
of remission: + Low dose steroids. OR
OR ✓ Aza (1-2mg\kg\day) for 18
✓ Azathioprine (1-2mg\kg\day) for 18 month month + Low dose steroids.
+ Low dose steroids.
Pulse steroids therapy: All induction regimens includes (500-1000mg MPA \ day) for 3 days
followed by High dose glucocorticoids (.5mg-6mg \kg\day) for 4 weeks, then gradual tapering.
Treatment of Membranous Lupus Nephritis

1. Membranous nephritis is often aggressively treated to control the extra-renal aspects of the
disease (morbid cardiovascular effects of the nephritic syndrome).
2. Treatment:
✓ Moderate dose glucocorticoids (.3mg-.4mg \kg\day) prednisone for 1-3 months, followed
by tapering for 1-2 years.
✓ Renoprotective medications: importance for the reduction of proteinuria and/or
✓ Immunosuppressives.
3. The renal prognosis of membranous nephropathy is better than that of proliferative
nephritis.
 Renal response is assessed at 6 months.

 Complete response (CR) is defined as:
✓ Decrease in proteinuria to less than 1 g/ day (or < 0.3
g/day if nephritis was diagnosed in the past 6 months)
with normal serum albumin concentrations.
✓ Inactive urine sediment.
✓ Improved or stable renal function.
 Partial response (PR) is defined as:

✓ Significant change in proteinuria (if nephrotic at baseline
≥ 50% decrease in proteinuria to < 3 g/day; if non-
nephrotic at baseline but not meeting the CR criteria).
✓ Improved or stable renal function.
 All induction regimens include pulse intravenous

methylprednisolone (IV-MP) (1 g/pulse × 3) followed by oral
prednisone (0.5 to 0.6 mg/kg for the first 4 weeks of
induction, then tapered).
Recommended treatment of proliferative lupus nephritis
Prognosis of Lupus Nephritis:

 Excellent prognosis: Minimal mesangial lupus nephritis and mesangial proliferative
lupus nephritis (classes I and II).
 Good prognosis: Focal lupus nephritis (class III), with only a minority of patients
developing progressive renal failure.
 Fair prognosis :
✓ Diffuse lupus nephritis (class IV) with a significant number of patients
developing progressive renal failure.
✓ Membranous lupus nephritis (class V) with a significant number of patients
developing progressive renal deterioration gradually over time.
 Poor prognosis: Advanced sclerosis lupus nephritis (class VI).
Poor prognostic indicators of LN:

1. Delay in treatment of more than 5 months from onset of nephritis
2. Young age at onset of nephritis -- Male sex -- Black racial background
3. Hypertension
4. Nephrotic syndrome
5. Elevated creatinine level (>3 mg/dL) at presentation
6. Persistently elevated anti-dsDNA and low C3 and C4 levels
7. Renal biopsy findings showing diffuse lupus nephritis or high chronicity index

Management of Uncommon Complications:
➢ Acute pneumonitis is treated with high-dose glucocorticoids, and additional

immunosuppressives can be added if necessary.
➢ Diffuse alveolar hemorrhage is typically treated with high-dose glucocorticoids in

conjunction with pulse cyclophosphamide.
➢ Mesenteric vasculitis:
✓ It is life-threatening manifestation of SLE & Bowel perforation is the most feared
complication.
✓ High-dose glucocorticoids and pulse cyclophosphamide are the most commonly used
therapies.
INDICATIONS FOR IMMUNOSUPPRESSIVE THERAPY IN SLE
➢ General Indications:
✓ Involvement of major organs or extensive involvement of nonmajor organs
(skin) refractory to other agents, or both.
✓ Failure to respond to or inability to taper corticosteroids to acceptable doses
for long-term use.
➢ Specific Organ Involvement:

➢ Renal: Proliferative or membranous nephritis (nephritic or nephritic syndrome),
or both.
➢ Hematologic
• Severe thrombocytopenia (platelets <20,000/mm3)
• Thrombotic thrombocytopenic purpura–like syndrome
• Severe hemolytic or aplastic anemia, or immune neutropenia not
responding to glucocorticoids
➢ Pulmonary: Lupus pneumonitis or alveolar hemorrhage, or both.
➢ Cardiac: Myocarditis with depressed left ventricular function, pericarditis with

impending tamponade.
➢ Gastrointestinal: Abdominal vasculitis.

➢ Nervous System:
• Transverse myelitis.
• Cerebritis.
• Optic neuritis, psychosis refractory to corticosteroids.
• Mononeuritis multiplex &severe peripheral neuropathy

MEDICATIONS USED IN TTT OF SLE
NSAID
✓ NSAID are widely used in patients for diverse manifestations including arthritis,
myalgia,serositis, and headaches.
✓ Should be avoided >>>>> In patients with renal impairment from lupus nephritis, >>>>
because the inhibition of cyclooxygenase (COX) by NSAIDs can further impair the renal blood
flow and the maintenance of tubular transport through the reduction of both prostaglandins and
prostacyclins.
CORTICOSTEROIDS
➢ Indications:
A. Mucocutaneous disease>> topical corticosteroids are frequently used.
B. Mild-to-moderate SLE disease (including cutaneous disease, arthritis, and serositis). treated with low dose
Systemic corticosteroids ranging from 0.1- 0.2 mg\ day equivalent dose of prednisone.
C. More severe organ involvement specifically nephritis, pneumonitis, hematologic abnormalities, CNS disease, and
systemic vasculitis, require high dosages of corticosteroids (oral or parental) in equivalent dosages
of prednisone of 0.5 to 1 mg/kg/day.
D. Severe manifestations of SLE (life threatening) treated with IV methylprednisolone (1 g) for

three consecutive days.
E. Systemic corticosteroids can act as bridging therapy for the slower-acting

immunomodulatory agents
✓ Once the disease activity is under control, GC are tapered to none or minimal daily (prednisone
≤5 mg/ day) or alternate-day dosing for maintenance therapy.
✓ The goal of successful tapering of the corticosteroids is to reduce the numerous potential but
common side effects of prolonged corticosteroid therapy while avoiding disease relapse or
exacerbation.
✓ Common side effects of systemic corticosteroids includes:
 Emotional lability.
 Glaucoma & cataracts.
 Peptic ulcer disease.
 Osteoporosis & osteonecrosis.
 Increased infection risk.
 Cushingoid features (central obesity, striae, hypertension, diabetes mellitus, and dyslipidemia).
Antimalarial Drugs (Hydroxychloroquine)

➢ Recommended in all patients with SLE:
➢ Dose: Hydroxychloroquine Initial therapy 400 mg/d; maintenance therapy 200–400 mg/d.
➢ Beneficial effects of HCQ in SLE:
1- Used in cutaneous lupus.
2- Used in joint affections in SLE.
3- Reduces Risk of flares.
4- Reduces Risk of developing end organ damage as Renal or NP affection.
5- Antiplatelet - Antihyperlipidemic - Antihyperglycemic effects.

Methotrexate
➢ Methotrexate in SLE can be used in the treatment of: Active cutaneous lesion And/Or
Articular involvements, allowing corticosteroid tapering.
Mycophenolate Mofetil (MMF; Cellcept)

➢ Mechanism of Action:
• Lymphocytes are dependent on the de novo synthesis pathway of purine nucleotides,
which is catalyzed by inosine monophosphate dehydrogenase.
• MMF reversibly inhibits the type II isoform of inosine monophosphate dehydrogenase,

which is preferentially expressed by activated lymphocytes.
• Inhibits the proliferation of B and T lymphocytes.

• Decreases antibody production.
➢ Indication
✓ Lupus Nephritis:
✓ Systemic Lupus Erythematosus: Treatment with MMF reduced disease activity
(and significantly decreased oral glucocorticoid dose) in patients with manifestations
of SLE refractory to other immunosuppressive agents.
➢ Dosing:
• 1.5–3.0 g/d in divided doses.
• Start with lower doses at first (eg, 500 mg orally at bedtime for several days).
• If the patient and tolerates the low dose without gastrointestinal upset, MMF may be
increased quickly to the target dose.
Cyclophosphamide (CYC; Cytoxan)

 Immunosupression through:
✓ Alkylates various cellular constituents, leading to DNA cross-linking and disruption of
transcription and translation.
✓ Depletes both B and T cells (with perhaps a greater effect on B cells), impacting both
humoral and cellular immunity.
➢ Dose:
➢ Daily use: In the setting of normal renal function, the usual starting dose for CYC is 2
mg/kg/d. Adjustments for both renal dysfunction and advanced age are essential.
➢ Intermittent use( pulse intravenous CYC):
1. Patients with creatinine clearances >30 mL/min may receive 750 mg/m2 body
surface area, with subsequent upward adjustments of the monthly dose if
tolerated to a maximum of 1000 mg/m2.
2. Patients with creatinine clearances <30 mL/min (including dialysis patients)
should receive 500 mg/m2 body surface area.
3. Hemodialysis patients should undergo dialysis 12 hours after CYC.
➢ SE:
1-Infection: most commonly herpes zoster
2-Cytopenias.
3-Malignancy.
4-Premature ovarian failure.
5-Hemorrhagic cystitis: Intravenous infusion of mesna (mercaptoethanesulphonic acid)
&Good hydration can prevent hemorrhagic cystitis and bladder cancer from acrolein, a toxic
metabolite of cyclophosphamide.

Azathioprine (AZA; Imuran)

Immunosupression through:
• Inhibits purine synthesis through its metabolite, 6-mercaptopurine.
• Inhibits the proliferation of B and T lymphocytes.
• Reduces antibody production.
• Decreases interleukin-2 secretion.
➢ Indication:
1- Lupus Nephritis: AZA used for the maintenance of remission in lupus nephritis after ttt
with prednisolone and oral cyclophosphamide for 6 months.
2-Systemic Lupus Erythematosus:
✓ AZA is used as a glucocorticoid-sparing agent for the treatment of other
manifestations of SLE (including arthritis, serositis, anemia, and neuropsychiatric
lupus).
➢ Dosing:
• 1–2.5 mg/kg daily.
• Start AZA at low doses (eg, 50 mg/d orally for several days) to monitor for violent
gastrointestinal intolerance.
➢ Special Precautions:
• AZA is not teratogenic, and when necessary, can be used in pregnant women. Its use
during pregnancy has, however, been associated with premature births and low birth
weight.
Cyclosporine
✓ Cyclosporine impairs production of interleukin-2 and other cytokines, reducing
lymphocyte proliferation.
➢ Indication in SLE:
• Cyclosporine has been reported to improve disease activity; have a glucocorticoidsparing
effect; and improve proteinuria, thrombocytopenia, and leukopenia.
➢ Dose:
• The starting dosage of cyclosporine is 2.5 mg/kg/day, usually administered in divided
doses.
• Clinical response is slow, occurring over 4 to 8 weeks, and may be only maximal after 12
weeks or more of treatment.
• To improve efficacy, the dosage can be increased by 0.5 mg/kg/day at 4- to 8-week

intervals to a maximaldosage of 4 mg/kg/day of the microemulsion formulation.
➢ Complications & Side effects:

1. Hypertension.
2. Nephrotoxicity.
3. Gastrointestinal effects (eg, mild anorexia, nausea, and vomiting): may be reduced by
splitting the dose, reducing the dose, or taking the medication with meals.
4. Malignancy: In transplant recipients, cyclosporine use has been associated with an

increased risk of skin cancer and lymphoma.

Thalidomide
➢ Thalidomide is an immunomodulator with antiangiogenic effects.
➢ Used for treatment of refractory chronic cutaneous lupus. at dosage ranging from 50 to
400 mg/day
➢ Side effects:
1. Well-recognized teratogenicity.
2. There is a high rate (68%) of relapse off the drug.
3. Peripheral neuropathy,(reported in up to 50% of patients).
4. Deep venous thrombosis, which occurs in up to 30% of patients with Malignancy.
IVIG:
 In patients who do not respond to glucocorticoids or who relapse during tapering, IVIG is tried.
 Because IVIG produces a rapid platelet response, it should be used in conjunction with
glucocorticoids.
 Dose of IVIG 2g/kg divided into 2-5 daily dose.
 IVIG is contraindicated in patients with IgA deficiency& in Patients with a hypercoagulable

state, such as antiphospholipid syndrome ( due to the increased risk of
thromboembolism.)
 IVIG provides protection against infections in immunodeficient patients, it is a favorable
treatment alternative in acutely ill patients with SLE when there is a concern for a commitment
infection.
Plasmapheresis
➢ Mechanism: rapidly remove circulating autoantibodies and immune complexes.

➢ Indication In SLE:
✓ Thrombotic thrombocyptopenic purpura (TTP)
✓ Catastrophic antiphospholipid syndrome
✓ Pulmonary hemorrhage.
✓ Cryoglobulinemia,and hyperviscosity syndrome.
✓ Other life-threatening complications of SLE may also be treated with plasmapheresis if
conventional therapy has failed.
➢ Side effect:
✓ Expensive therapy.
✓ Heightened risk of infection and anaphylaxis.

Biologic Therapies for SLE
B Cell–Depleting Therapies: B cells play a key role in lupus pathogenesis by several means.
o First, they produce pathogenic autoantibodies that cause tissue damage by immune complex formation,
complement activation, and direct cytotoxicity.
o They also function as antigen-presenting cells and secrete inflammatory cytokines that activate T cells.
❖ Rituximab:
➢ Mechanism of action:
✓ A chimeric mouse-human monoclonal antibody that targets the cell membrane protein CD20.
✓ Cytotoxicity through complement activation, antibody-dependent cell-mediated cytotoxicity, and
induction of apoptosis.
➢ Dose: 1 g on days 1 and 15 or 375 mg/m2 weekly × 4 doses.
➢ Uses: Autoimmune hemolytic anemia – Thrombocytopenia – Proliferative LN
❖ Ocrelizumab:
✓ The BELONG trial evaluated the efficacy and safety of ocrelizumab (humanized anti-CD20 monoclonal
antibody) versus placebo, both in combination with either MMF (up to 3 g/day) or IV-CYC (Euro-Lupus
protocol) in 378 patients with PLN.
✓ The study was prematurely terminated due to increased rates of serious and opportunistic infections in
ocrelizumab-treated patients, both when combined with MMF and IV-CYC.
B Cell Inhibitors
❖ Belimumab: (Benlysta)
✓ Belimumab is a fully human anti-BLyS monoclonal antibody that inhibits the B lymphocyte stimulator
(BLyS), which modulates B cell growth and survival.
✓ The B lymphocyte stimulator protein (BLyS, also known as B cell activation factor [BAFF]) and the
proliferation-inducing ligand (APRIL) are growth factors important for B cell survival and maturation.
✓ BLyS binds to three different B cell receptors, namely the transmembrane activator and calcium-
modulating cyclophilin ligand interactor (TACI), the B cell maturation antigen (BCMA), and the BAFF
receptor (BAFF-R), whereas APRIL signals through TACI and BCMA.
➢ Dose: 10 mg/kg by IV infusion q 2 weeks for the first 3 doses, followed by 4 week interval.
➢ Indications:
1. Active SLE (SLEDA ≥ 8) in spite of standard-of-care therapy, including GCs, antimalarials, and/or
DMARDs/immunosuppressive drugs
▪ Higher efficacy in patients with SLEDAI ≥10 or with concomitant serologic activity (high anti-dsDNA and/or
low serum C3/C4)
▪ Belimumab is not indicated for the management of active LN or NPSLE.
2. High risk for disease flares young-onset disease (≤25 years old); persistent disease activity, history of renal, CNS
involvement, or skin vasculitis; organ damage (SDI>0); serologic activity, previous SLE flares, no treatment with
anti-malarials.
3. Failure to taper GC to <7.5 mg/day prednisone equivalent.
4. Intolerance to DMARDs/immunosuppressive drugs.
❖ Epratuzumab:
✓ Epratuzumab is a recombinant anti- CD22 monoclonal antibody that modulates lupus B cell function.
✓ CD22 is a membrane co-receptor for the B cell receptor mediating inhibitory signaling through
attenuation of calcium efflux.
❖ Atacicept:
✓ Atacicept (TACI-Ig) is a recombinant fusion protein of the extracellular domain of TACI and the human
IgG1.Fc domain.
✓ TACI mediates signals from both BLyS and APRIL, thus affecting memory B cells, plasma cells, and
immunoglobulin production.

NB NB NB
 Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by a relapsing-remitting

course and a highly variable prognosis.
 Systemic lupus erythematosus (SLE) results from chronic and recurrent activation of the immune system, with
production of antibodies and other protein products contributing to inflammation and tissue damage.
 It is characterized by the production of a broad array of autoantibodies, with antinuclear antibodies having the
greatest sensitivity for the diagnosis and anti–doublestranded DNA and anti-Smith antibodies having the greatest
specificity.
 the products of the immune system including autoantibodies and their immune complexes, cytokines, and
complement components, along with proinflammatory mediators and reactive oxygen products released from
neutrophils and macrophages, remain key mediators of tissue damage.
 Constitutional symptoms, rash, mucosal ulcers, inflammatory polyarthritis, photosensitivity, and serositis are
the most common clinical features of the disease.
 The most common presenting manifestations are constitutional symptoms (fever, fatigue, and/or weight loss),
cutaneous manifestations (e.g., malar rash), and articular manifestations (arthritis and/or arthralgia).
 Each of these manifestations appears to be present in at least 50% of lupus patients at the time of diagnosis.
 Lupus nephritis is the most common of the potentially life-threatening manifestations.
 Atherosclerosis, a complication of long-standing SLE, requires aggressive risk factor modification.
 Use of sulfonamide antibiotics should be avoided, as they can sometimes precipitate lupus flares.
 The presence of 4 of the 11 criteria yields a sensitivity of 85% and a specificity of 95% for SLE.
 Fatigue, can be due to active SLE, medications, lifestyle habits, or concomitant fibromyalgia or affective disorders.
 Reversible factors which can cause fatigue such as hypothyroidism, anemia, and diabetes should be managed
first.
 Pain and depression are positive predictors of fatigue in SLE patients.
 Fever, result from many causes, the most common of which include active SLE, infection.
 Photosensitive lesions include the malar rash, discoid lupus, and subacute cutaneous lupus.
 To avoid SE. of local steroid >> patients can apply the topical corticosteroids on weekdays and none on weekends.

 Other steroid sparing topical agents, such as tacrolimus or pimecrolimus,can be given during “steroid-drug”
holidays.
 It is thought that ointments are generally more effective than creams and that lotions are most useful for hairy
areas such as the scalp.
 If anti-Ro (especially with anti-La) is present, there is a risk of neonatal lupus in the fetus, presenting as
congenital heart block or neonatal lupus rash (the latter being transient).
 Higher anti-dsDNA levels, more thrombocytopenia, and higher steroid requirements in patients with SLE and end-
stage renal disease who are on peritoneal dialysis.
 Infectious complications related to active SLE and immunosuppressive treatment are now the most common cause of death
in early active SLE, and accelerated arteriosclerosis is a key cause of late mortality.
 Periodic follow-up and laboratory testing(At least quarterly visits are recommended in most cases.) including:
✓ Urinalyses.
✓ CBC count with differential.
✓ Creatinine.
➢ These tests are imperative to detect signs and symptoms of new organ-system involvement and to monitor the
response or adverse reactions to therapies.
 The standard of care for SLE with severe, major organ involvement involves the combination of high-dose
glucocorticoids with pulses of intravenous cyclophosphamide CYC (However, this regimen is associated with
significant toxicity including gonadal failure in young women).
 Lupus nephritis:
✓ Lupus nephritis is histologically evident in most patients with SLE, even those without clinical manifestations
of renal disease.
✓ Goal of the therapy: induction of remission with cytotoxic agents given over several months, and then to
maintain the remission by using less toxic medications
✓ Classification system helps to guide the choice of the treatment regimen:
 Patients with proliferative disease and a high activity index usually receive cytotoxic medications and
high-dose glucocorticoids.
 Patients with class I or class II disease can often be treated with angiotensin-converting enzyme
inhibitors and/or angiotensin II receptor blockers.
✓ Class I: Minimal mesangial lupus nephritis require no specific therapy.
✓ Mycophenolate mofetil (MMF) is at least equally effective and has a better toxicity profile than CYC in the
treatment of moderately severe proliferative lupus nephritis
✓ Patients who fail to respond to therapy might require a second biopsy to determine if they still have active
nephritis, or alternatively, if they have developed significant renal scarring that should not be treated with
further immunosuppressives.

✓ In lupus nephritis refractory to standard immunosuppressive therapy, calcineurin inhibitors (cyclosporin A,

tacrolimus) have demonstrated some efficacy exerting significant antiproteinuric effects.
✓ Pregnant patients with lupus nephritis are prone to preeclampsia. Preexisting hypertension and antiphospholipid
antibody syndrome are the two most common factors that predispose to preeclampsia.
 Hemodialysis is preferred over peritoneal dialysis: Hemodialysis has anti-inflammatory effects with decreased T-
helper lymphocyte levels. SLE is generally quiescent in patients on hemodialysis.
 The survival rate among patients on dialysis is fair (ie, 5-y survival rate of 60-70%) and is comparable with
patients on dialysis who do not have SLE.
 SLE pregnancies are considered high risk for maternal and fetal complications, underscoring the importance of
family counseling and planning before pregnancy is sought.
.
 Pediatric-onset SLE is associated with high disease severity and rapid damage accrual. Treatment is guided by
experience obtained in adult patients and involves the combination of glucocorticoids and immunosuppressive
agents for severe manifestations.
 Infections contribute to significant morbidity in SLE: Strategies to decrease their impact include
• Education aimed at both patients and physicians.
• Immunizations similar to those available to the general population.
• Minimization of exposure to glucocorticoids.
• Prompt initiation of antimicrobial therapy in suspected infection.
 Late-onset SLE (>50 years old) is characterized by a more insidious onset with a higher occurrence of serositis
and pulmonary involvement and a lower incidence of malar rash, photosensitivity, alopecia, Raynaud’s
phenomenon, neuropsychiatric disease, and nephritis.

2019 update of the EULAR recommendations for the management of SLE


Approach to the Management of Pregnancy in SLE

➢ Systemic lupus erythematosus (SLE) is one of the most common autoimmune disorders
that affect women during their childbearing years.
➢ Effects of SLE on pregnancy: SLE increases the risk of:

1. Spontaneous abortion(20%).
2. Intrauterine fetal death.
3. Preeclampsia.
4. Intrauterine growth retardation
5. Preterm birth(25%).
Systemic lupus erythematosus Flares with pregnancy

➢ The most common symptoms of these flares include arthritis, rashes, and fatigue.
➢ Time of flare: Flares often occur during the first or second trimester or during the first
few months after delivery.
➢ Risk factor for flare:
✓ Patients with preexisting hypertension or renal disease.
✓ Highly active disease before conception.
➢ Rate of flare: 60% in patients with active disease in the preconception & 10% in those with
quiescent disease.
➢ Pathophysiology of flare
 Increased SLE disease activity is expected during pregnancy because of increased
levels of estrogen, prolactin, and T–helper cell 2 cytokines.
 Causes for flare-ups during the postpartum period:

✓ Decreased levels of anti-inflammatory steroid.
✓ Elevated levels of prolactin (ie, proinflammatory hormone).
✓ Changes in the neuroendocrine axis.
Planning of pregnancy
➢ Ensure that lupus is inactive for at least 6 monthes.
➢ Stop all teratogenic medication: MMF, CYS, MTX, LF.
➢ Educate patients that, because of prolonged half-lives, some medications may need to
be discontinued several months before the planned conception.
➢ At the first visit after or when pregnancy is confirmed, the following assessments are
recommended:
✓ Physical examination, including blood pressure evaluation
✓ CBC count
✓ Serum albumin.
✓ Renal function tests:
1. Serum creatinine(Discourage pregnancy if SCr >2 mg/dL).
2. Glomerular filtration rate.
3. Urinalysis.
4. Urine protein–to–urine creatinine ratio

✓ Serology:
1. Test for anti-Ro/SSA and anti-La/SSB antibodies
2. Lupus anticoagulant and anticardiolipin antibody studies
3. Anti-dsDNA test
✓ Complement (CH50 or C3 and C4) tests.
➢ Evaluations are recommended at the end of each trimester of pregnancy:

✓ Determination of the glomerular filtration rate and measurement of the urine
protein–to–urine creatinine ratio
✓ Anticardiolipin antibody measurement
✓ Complement (CH50 or C3 and C4) test
✓ Anti-dsDNA antibody study
➢ Management of common associated conditions:
✓ Women who have antibodies to Ro/SSA and/or La/SSB are at increased risk of
pregnancies complicated by fetal heart block and need Frequent echocardiographic
monitoring ( especially between 16-24wek).
✓ Frequent monitoring of fetal growth by ultrasonography: For early detection of

intra-uterine growth restriction.
✓ For patients with antiphospholipid syndrome, consider combined heparin and

aspirin to reduce risk for pregnancy loss and thrombosis.
➢ Differentiation of signs and symptoms of normal pregnancy from those of

exacerbations of lupus:
 Differentiate malar rash from chloasma.
 Differentiate thrombocytopenia in pregnancy (ie, hemolysis, elevated liver enzyme
levels, and low platelet counts [HELLP] syndrome) from thrombocytopenia of lupus
exacerbation (ie, thrombocytopenic purpura [TTP] or idiopathic TTP [ITP]).
 Pedal edema and fluid accumulation in joints, especially the knees, can occur in the
late stages of pregnancy and should be differentiated from the arthritis of systemic
lupus erythematosus (SLE).
 Differentiate proteinuria secondary to preeclampsia from proteinuria due to lupus
nephritis.
• Lupus nephritis is often associated with:
▪ Proteinuria.
▪ An active urine sediment (RBCs, WBCs, and cellular casts).
▪ Hypocomplementemia.
▪ Increased titers of anti-DNA antibodies.
• In patients with preeclampsia:

▪ Proteinuria
▪ Thrombocytopenia.
▪ Elevated serum levels of liver enzymes &Uric acid.
▪ Usually occurs in the third trimester of primigravidas.
➢ Safe medication:
▪ Corticosteroids:
✓ Prednisone
✓ Methylprednisone: Metabolized by placenta; thus, lowered concentrations reach
fetus. Therefore, this is the preferred corticosteroid treatment.
✓ If heart block of any degree is found, dexamethasone 4 mg/day is given to the
mother because it crosses the placenta.
▪ Hydroxychloroquine
▪ Azathioprine.
▪ Cyclosporine A.
➢ Contraindicated Medication: Mycophenolate, Cyclophosphamide
➢ Breastfeeding
✓ Contraindicated Medication: immunosuppressive agents are and long-acting NSAIDs.
✓ Safe Medication: antimalarials, low-dose prednisone (<15-20 mg/d), warfarin, and heparin
seem to be safe.
NB: Prednisone can be used safely during breastfeeding because small amounts (5% of the glucocorticoid dose) are secreted in
breast milk. At doses of prednisone higher than 20 mg once or twice daily, breast milk should be pumped and discarded 4 hours after
the dose to minimize drug exposure to the infant.

Neonatal lupus
➢ Definition: It is a passively acquired autoimmune disease of neonates that results
from transplacental passage of maternal anti-SS-A and/or anti-SS-B antibodies
➢ Prevelance: 5% to 20% of offspring of mothers with high circulating levels of these

antibodies.
➢ Presentation:
a) Dermatologic
✓ The skin rash is photosensitive and similar to that of subacute cutaneous lupus
erythematosus.
b) Cardiac:
✓ Congenital heart block (CHB) is the most common cardiac manifestation and
the accompanying myocarditis accounts for the major morbidity and mortality.
✓ CHB is usually irreversible and permanent pacemaker therapy is required in 50%
of cases.
✓ Despite pacemaker placement, 10% of these children develop a subsequent
cardiomyopathy with 20% to 30% mortality before the age of 10 years.
✓ The conduction defect is attributed to maternal IgG anti-Ro (SS-A) and anti-La
(SSB) antibodies that cross the placenta and bind to fetal cardiocytes and heart
conducting cells, eliciting an inflammatory injury during the second trimester of
pregnancy.
c) Less common manifestations include hepatic, hematologic, and neurologic affection.
➢ Management of neonatal lupus:

 During preganancy:
✓ High-dose prednisone and immunosuppressive medications do not lower
maternal autoantibody titers, are ineffective, and should be avoided.
✓ Removal of maternal autoantibodies with plasmapharesis has been reported to

successfully prevent CHB in some patients.
✓ Treatment with fluorinated steroids may offer benefit.

✓ Dexamethasone (4 mg/ day) or betamethasone (4 mg/day) are not metabolized
substantially by the placenta and therefore cross into the fetal circulation.
✓ Studies have shown that neonates with first and second degree heart block can
respond to this therapy and not progress to CHB.
✓ HCQ has been associated with reduced risk for recurrences of cardiac neonatal
lupus.
 Postnatal treatment:
✓ High-dose corticosteroids may prevent progression to complete heart block

DRUG-INDUCED LUPUS ERYTHEMATOSUS

➢ Definition: DILE is a lupus-like illness that occurs in some individuals after exposure to
a causative drug for a few weeks to more than a year.
➢ Epidemiology:
✓ Occurs more commonly in Caucasians and older individuals after age of 50 years
(reflecting the group of patients most likely to take these medications).
✓ It affects both males and females equally.
List of drugs with evidence for causing DILE.

Definite Probable Possible
✓ Procainamide (15-20%). ✓ Anticonvulsants (mephenytoin, phenytoin, carbamazepine), ✓ Statins.
✓ Hydralazine (5-10%). ✓ Antimicrobials (sulfonamides, nitrofurantoin), ✓ Valproate,
✓ Quinidine (2-5%) ✓ Captopril & hydrochlorothiazide. ✓ Gemfibrozil, griseofulvin,
✓ Diltiazem. ✓ Sulfasalazine lamotrigine, others.
✓ Minocycline (5/10000) ✓ Docetaxel, glyburide, amiodarone
✓ Isoniazid, ✓ propylthiouracil (PTU),
✓ Anti-TNFα agents & IFNα (2/1000) ✓ Beta-adrenergic blocking agents,
✓ Methyldopa, chlorpromazine, practolol &, ✓ Rifampin (particularly if they also are receiving clarithromycin or ciprofloxacin)
penicillamine,
Classification & clinical manifestations of DILE

➢ DILE can be classified into three major forms:
1. Systemic DILE:
✓ Patients present with Arthralgia, Myalgia, Serositis, and Constitutional
symptoms.
✓ Usually after taking a drug for at least a month.
✓ Overall symptoms tend to be less severe than idiopathic SLE.
✓ It affects both males and females equally.
✓ Other manifestations of DILE: severe manifestations of SLE, such as cytopenia,
pulmonary infiltrates nephritis, and CNS involvement, are very rare in DILE.
2. SCLE:
✓ Predominant skin involvement similar to idiopathic SCLE, Usually with
photosensitivity, erythematous rash, Malar erythema & other cutaneous lesions
(e.g., vasculitis and bullous lesions).
✓ It usually occurs 1 to 5 months after initiating therapy with the offending
medication.
✓ It affects older females predominantly.
✓ Drug-induced SCLE should be suspected in anyone who develops SCLE after
the age of 50 years.
3. Chronic cutaneous DILE: discoid lupus skin lesions. This is a rare form of DILE
and usually occurs in patients treated with fluorouracil compounds.

Auto-antibodies with DILE
1. ANA: Found nearly in all patients with DILE (mostly homogenous pattern)
2. Anti-histone antibodies: IgG
✓ The most common autoantibodies in DILE. but frequency and specificity vary
between drugs.
✓ Nearly all patients (95%) with symptomatic procainamide- or hydralazine-
induced lupus will test positively for Anti-histone ab.
✓ Not specific to DILE and are present in 50% to 80% patients with idiopathic
SLE (good -ve test for exclusion of DILE).
3. Other autoantibodies: Anti-dsDNA ab. antibodies to Sm, RNP, Ro/SS-A, and
La/SS-B are common in idiopathic SLE but are unusual in DILE (with the exception of DILE due
to anti-TNFα agents or IFNα).
4. Antineutrophil cytoplasmic antibodies (ANCAs)
✓ Positive perinuclear ANCA (pANCA) found in 80%of patients with minocycline-
induced lupus.
✓ Hydralazine can also cause a positive pANCA usually with anti-MPO specificity.
1. Antiphospholipid antibodies:
✓ Can be seen in both systemic DILE and idiopathic SLE, occur most commonly
with three drugs (chlorpromazine, procainamide, and quinidine).
✓ Tend to be IgM, and are rarely associated with thrombosis.
Specific Features for common offending drugs

Procainamide: Over 90% develop a positive Hydralazine: 45% develop a positive ANA Anti-TNFα or IFNα
ANA by 2 years & only 20% develop DILE. after a year of drug therapy only 5-10% ANAs in 13% to 83% of patients.
develop DILE Anti-DNA antibodies in 3% to 32% of
Isoniazid 15% of patients on develop a Minocycline: only 15% have antihistone patients.
positive ANA,but few develop symptoms of antibodies, but 80% have a positive pANCA. Antihistone antibodies 60%
DILE. symptomatic DILE occurs in only 2 /1000
Pathogenesis of DILE
❖ Genetic: slow acetylator status (Metabolism of these drugs involves the hepatic enzyme N-acetyltransferase, which
catalyzes the acetylation of amine or hydrazine groups).
❖ Epigenetic: procainamide and hydralazine can decrease T-cell DNA methylation leading to
overexpression of LFA-1 that induces autoreactivity.
❖ Adaptive immunity: drug-induced changes in T-cell signaling and function.Small molecule
drugs can act as haptens or agonists for drug-specific T cells.
❖ Innate immunity: activated neutrophils & stimulation of autoreactive T and B cells

✓ Procainamide is oxidized by activated neutrophils resulting in production of the toxic
metabolite which can cause direct cytotoxicity.
✓ Several other drugs causing DILE can also undergo biotransformation similar to
procainamide resulting in the generation of toxic metabolites.
✓ Activated neutrophils can release MPO and reactive oxygen species, which can cause
direct cytotoxicity.

Treatment of DILE
➢ Discontinue the offending drug (The first and most important).
➢ NSAIDs: to control symptoms such as arthralgias & myalgia
➢ Corticosteroids (Short course) & HCQ: For patients with more severe signs and symptoms
(pericarditis or pleuritis, rash).
➢ Immunosuppressives: such as azathioprine or cyclophosphamide are almost never
required (may be needed in drug-induced ANCA vasculitis)
NB:
➢ Offending drugs are more likely to cause a positive ANA than symptomatic DILE.
➢ Procainamide may cause pleuritis and/or pericarditis(beside other common systemic symptoms), whereas patients with hydralazine-
induced disease are more likely to have rashes.
➢ Minocycline DILE typically (females > males, ages 14 to 31 years) after an average of 30 months use of the drug for acne in doses of
50 to 200 mg/day.
➢ TNF may cause hematologic abnormalities (leukopenia, thrombocytopenia), antidsDNA antibodies, and hypocomplementemia
➢ IFNα may cause typical lupus manifestations such as oral ulcers, alopecia, and nephritis,
➢ The population at risk for developing systemic DILE is very different compared with that developing idiopathic SLE.
➢ There is no evidence that drugs capable of causing systemic DILE will change or worsen disease activity in a patient with idiopathic
SLE. However, if an alternative drug is available, it may be prudent to use it so that there would not be any confusion if the SLE patient
has a disease flare in the future. This is especially true for
➢ Minocycline should be avoided if possible.
➢ In patients with SCLE who get worsening rash, it is advisable to eliminate medications that can cause drug-induced SCLE if at all
possible.
➢ Overall, the prognosis of DILE is good and symptoms resolve with stopping the offending drug.
➢ The positive ANA may persist for a prolonged time (>1 year) even after symptoms resolve.


Pathology & Pathogenesis

CAUSES OF SLE
➢ The specific cause of SLE is unknown, but there is multiple factors are associated with
the development of the disease, including:
• Immune-system dysregulation (both innate and acquired).
• Immune-complex tissue damage at sites such as the skin and kidneys
• Direct antibody-mediated cytotoxicity that causes thrombocytopenia and
hemolytic anemia are suspected causes.
RISK FACTORS FOR SLE

Genetic Factors
➢ Genetic susceptibility to lupus is inherited as a complex trait.
➢ Evidence for genetic predisposition:
✓ There is increased risk of developing the disease in first degree relatives of a SLE
patient by about 5 fold higher than the general population & 10 times more
frequent in monozygotic than in dizygotic twins.
➢ Genetic variants associated with SLE:

A) Major Histocompatibility Complex (MHC) genes:
✓ HLA-DR2 & HLA-DR3 (increases relative risk twofold to threefold)
✓ Homozygous deficiencies of early complement components (C2, C4A, C4B)
(increase risk 5- to 10-fold)
B) Non-MHC genes:
✓ RF5, IRF7, TNFAIP3, TREX1, STAT4, PTPN22, PCDCD1, BLK, BANK1 and
others.
➢ The most potent genetic risk for SLE is conveyed by certain major histocompatibility
complex of HLA-A1, B8, and DR3.
➢ Polymorphisms in several other genes may contribute incremental risk for SLE.
➢ HLA-DR4 is associated with a lower prevalence of SLE and appears to be protective.
Nongenetic Risk Factors
A- SEX:
✓ Women are 9 to 10 times more likely to develop SLE than men.
✓ Hormonal factors like estrogen and progesterone may explain some of the
gender effect:
• Exogenous oestrogens exacerbating lupus or increasing the risk of
developing this disorder.
• Oral contraceptive use was associated with a slightly increased risk of
developing SLE with a relative risk versus never users of 1.9.

B-Environmental factors: Exposure to various environmental factors increases the risk

for SLE:
Environmental Factors That Might Play a Role in the Pathogenesis of (SLE)
➢ Definite: Ultraviolet B light.

➢ Probable:
✓ Estrogen and prolactin—in humans, female-to-male ratio is 9 : 1 between menarche and
menopause, 3 : 1 in young and old
✓ EBV
✓ Lupus-inducing medications: Hydralazine, Procainamide, Isoniazid, Hydantoins,
Chlorpromazine, Methyldopa, Penicillamine, Minocycline, Tumor necrosis factor inhibitors,
Interferon-α.
➢ Possible
✓ Dietary factors
✓ Alfalfa sprouts and related sprouting foods containing
✓ canavanine
✓ Pristane and other hydrocarbons
✓ Infectious agents other than EBV
✓ Bacterial DNA
✓ Smoking
✓ Human retroviruses or endogenous retroelements
✓ Endotoxins, bacterial lipopolysaccharides
✓ Vitamin D deficiency.

Pathophysiology
➢ SLE is an autoimmune disorder characterized by multisystem microvascular

inflammation with the generation of auto-antibodies (VASCULITIS).
➢ Mechanism for the development of autoantibodies involves the following:

A. Defect in apoptosis:
✓ Causes increased cell death and a disturbance in immune tolerance.
✓ The redistribution of cellular antigens during apoptosis leads to a cell-
surface display of plasma and nuclear antigens in the form of
nucleosomes.
✓ Thus, dysregulated (intolerant) lymphocytes begin targeting normally
protected intracellular antigens.
B. Immune complexes formation & complement activation
✓ Immune complexes form in the microvasculature, leading to
complement activation and inflammation.
✓ Antibody-antigen complexes deposit on the basement membranes
of skin and kidneys.
Pathogenesis
➢ There were Four theoretic stages of systemic lupus erythematosus (SLE) through which
an individual progresses.
1. Predisposition:
✓ An individual in this stage has inherited the susceptibility genes for SLE but is
without any evidence of disease or immunologic abnormalities.
✓ The MHC genes appear to act to influence the shaping of the T-cell repertoire
toward one capable of self recognition through presentation of self peptides that
result in the autoimmune state recognized clinically as SLE.
2. Induction Phase
✓ This precursor state to SLE is characterized by the development of autoreactive T

cells that no longer remain “tolerized” to self.
✓ These initially expand slowly. Limited T-cell help for B cells having surface
immunoglobulin (Ig) specific for autoantigens may be demonstrable.
✓ The individual in this phase of the development of the disease may produce small
amounts of IgM autoantibodies to one or perhaps two members of a linked set of
autoantigens.

✓ The titer and affinity of these antinuclear autoantibodies is likely to be very low.
✓ Effector or memory autoreactive T cells may be present but in numbers too low to
cause damage or be readily detected.
3. Expansion Phase
✓ The expansion phase is another preclinical SLE state and is characterized by

considerable clonal expansion of B and T cells capable of autorecognition.
✓ This phase includes development of considerable T-cell help to shift autoantibody

isotype to IgG, likely occurring through presentation of self peptides to T cells by B
cells reactive to autoantigen.
✓ Antibodies are of higher affinity and titer and include evidence of B-cell somatic
diversification.
✓ By definition, although these patients have an autoimmune state, they are

symptom-free and do not have an autoimmune disease.
4. Injury Phase
✓ In this phase, the disease of clinical SLE develops with the provision of
autoantibodies of the appropriate specificity, IgG class, and maturing affinity as well
as an accessible autoantigen molecule for initiation of immune complex–mediated
injury.
✓ The number of autoreactive T cells is increased and may display a predominance

of either a T-helper 1 (Th1) or a Th2-type cytokine profile.
✓ The nature of the infiltrating T cell is likely to show correlation with the clinical
pattern of disease (e.g., autoreactive Th1 cells having the potential to mediate
direct tissue injury alone or in concert with cells of the monocytic lineage).

 Presentation of unknown antigens by MHC molecules leads to priming of CD4+ T

cells.
 These cells then help B cells in autoreactive germinal centers undergo class
switching, affinity maturation and differentiation into plasma cells that secrete high
levels of soluble autoantibodies of the IgG isotype.
 These autoantibodies form immune complexes by binding autoantigens, and fix
complement or engage Fcγ receptors on several different cell types.
 This can support inflammation and tissue destruction through the recruitment of
inflammatory cells to tissues. Apoptotic cells from damaged tissues can be taken up
by phagocytes, which present novel autoantigens, supporting further priming and
autoreactivity.
 Engagement of TLRs by environmental triggers such as viral infection or DNA
damage by UV rays contribute to the process by inducing the secretion of IFN-I and
other cytokines, supporting lymphocyte autoreactivity as well as tissue destruction.

Major immunologic alterations in SLE
T-Cell abnormalities:
1. T-Cell–Specific Autoimmune Recognition Is at the Center of the Pathogenesis of SLE
✓ Taken together, these phenomena indicate that the autoimmune response of SLE
is an autoantigen-driven process centered on the presentation of autoantigens by B
cells to CD4-positive T cells.
✓ These autoantigens, in turn, provide T-cell help to the B cells, resulting in their
differentiation into cells that produce pathogenic autoantibodies.
2. The T-Cell Compartment in SLE Is Characterized by Extensive and Unexplained

Activation
✓ The number of circulating T cells is decreased in parallel with increases in disease
activity.
✓ In patients with active SLE, there is an increased and prolonged cell surface
expression of CD40L.
✓ CD8-positive T-cell–mediated cytotoxic mechanisms are also decreased.
✓ There is a decrease in interleukin-2 (IL-2) release in most assays of in vitro T-cell

stimulation.
B-Cell Abnormalities:
✓ Despite their role in the production of autoantibodies, the numbers of circulating B
cells in SLE are not increased.
✓ The state of B-cell differentiation is altered, with increased numbers of

plasmacytoid B cells characterized by cytoplasmic Ig and the secretion of IgG
immunoglobulin, particularly in periods of heightened clinical activity.
The role of apoptotic cells (apoptosis):

✓ Autoantigens are released by necrotic as well as apoptotic cells.
✓ Defect in the clearance of apoptotic cells have been described in SLE which may
lead to aberrant uptake by macrophages which then present the previously
intracellular antigens to T and B cells thus driving the autoimmune process.

The role of cytokines:

➢ An elevated level of certain cytokines (mainly IL-6) has been well recognized,
especially during periods of clinical activity.
➢ This may account for some of the characteristic of the SLE illness as:
✓ Fatigue and fever
✓ Certain of the nonlocalized neuropsychiatric alterations in SLE.
✓ Predisposing to immune complex injury in vessels and in the sclerotic response in
glomeruli.
➢ Following activation by antigen, the CD4+ T cell becomes polarized into either of two
main subsets, Th1 or Th2, each defined by its unique cytokine profile.
➢ The Th1 cell, which characteristically secretes:

➢ IL-2, interferon-g (IFN-g), IL-12, and tumor necrosis factor-a (TNF-a), mainly
promotes cellular immune responses via IFN-g action on macrophages, but
is also characterized by IFN-g–mediated antibody class switching to
particular isotypes.
➢ The Th2 cell secretes IL-4, IL-5, IL-6, IL-10, and IL-13, and mainly protects against
extracellular antigens by promoting a humoral immune response.

SUMMARY

Contributors to systemic lupus erythematosus (SLE) pathogenesis.
 Mechanisms that promote development of SLE are related to the underlying genetic profile of the individual.
 Many of the disease-associated genetic variants contribute to:
• Excessive production or impaired clearance of stimulatory nucleic acids.
• Increased generation of products of the innate immune response, particularly type I interferon IFN).
• An altered threshold for activation or efficiency of signaling of cells of the adaptive immune response.
 To establish a state of immune activation multiple genetic risk variants or a mutation of a critical regulator of
immune activation are required to promote development of autoimmunity state that can lead to disease .
 Type I interferon is a product of plasmacytoid dendritic cells (pDCs), and activation of those cells by intracellular
nucleic acids or exogenous triggers such as a virus or debris derived from damaged or dying cells might represent
mechanisms of initiation of disease.
 Once IFN-α is produced, it mediates numerous effects on immune system cells that mimic the response to a viral
infection.
 The antigen-presenting capacity of myeloid dendritic cells can be augmented, promoting activation of self-reactive T
cells and differentiation of B cells toward production of pathogenic antibodies.
 Activated T cells express CD154 (CD40 ligand) and produce interleukin-21 (IL-21), providing effective help for B cells
to generate antibody-producing plasma cells.
 IFN-α also supports the production of B cell activating factor (BAFF), a survival and differentiation factor for B cells.
Once autoantibodies are produced, immune complexes amplify immune activation by accessing endosomal Toll-like
receptors in pDCs and B cells and deposit directly in the vicinity of blood vessels, inducing complement activation,
inflammation, and tissue damage.
 Reactive oxygen species (ROS) and proinflammatory cytokines produced by monocytes and macrophages contribute
to tissue damage, as does IFN-α, which stimulates endothelial cells and is associated with poor vascular repair and
sclerosis.

Mustafa Elmenawy
Basic
Rheumatology
Antiphospholipid
antibodies Syndrome
Antiphospholipid antibodies Syndrome
Definition: An acquired hypercoagulable state presented with arterial or venous

thrombosis, pregnancy loss, or thrombocytopenia due to autoantibodies directed against
phospholipids binding plasma protein.
Epidemiology:
• Age: common in young & middle-aged adult
• Incidence & prevalence:
✓ Antiphospholipid antibodies (aPL) occur in 1% to 6% of the general population
(one of the most common acquired causes of hypercoagulability).
✓ In patients presenting with DVT, up to 30% will have the APS.
✓ In a person under age 50 with a stroke, up to 46% will have APS.
Classification:
➢ Primary APLs: occurs in a patient without SLE or other connective tissue disease, it is
termed primary APS.
➢ Secondary APLs: patients with autoimmune disease (as SLE or RA) who have aPL
and have had thrombosis or pregnancy losses.
➢ SLE & APLs:
✓ 30%- 50% of patient with SLE have APLs (about 30% have anticardiolipin and
about 25% have the lupus anticoagulant).
✓ About 10% of primary APLs patients later develop SLE.
✓ 50% of patients with APLs have SLE
Pathogenesis
✓ In APLs, the homeostatic regulation of blood coagulation is altered.
✓ APL interferes with the activated Protein C complex and also bind to platelets.
✓ The primary target of aPLabs is β2GPI (apolipoprotein H). This is a phospholipid-binding glycoprotein that exists in the blood
in a circular conformation.
✓ It contains five domains (sushi domains) and belongs to the complement control protein superfamily.
✓ It binds through its fifth domain to anionic phospholipid membranes and receptors.
✓ After binding, it undergoes a conformational change to an open “hockey stick” conformation.
✓ With this change, it becomes antigenic by exposing hidden epitopes in the first domain.
✓ The pathogenic anti-β2GPI antibodies bind to an epitope (D8, D9, R39, G40, R43) in the first domain of the β2GPI molecule.
✓ The anti-β2GPI antibodies then bind to the first domain of the uncoiled β2GPI dimers on the cell surface. This binding
results in a proinflammatory and prothrombotic state:
❖ Cell activation: upregulates the expression of prothrombotic endothelial cell adhesion molecules (e.g., Eselectin,
tissue factor), inhibits nitric oxide synthetase production, and activates the mTOR pathway leading to endothelial
cell proliferation. Neutrophil activation with the release of tissue factor and neutrophil extracellular traps.
Monocyte activation with the release of microparticles containing tissue factor. Platelet activation causing
secretion of the platelet factor-4 (procoagulant) and thromboxane A2 (increases platelet aggregation).

❖ Promotion of coagulation: increases expression of glycoprotein IIb/IIIa (fibrinogen receptor) on platelets and
interferes with binding of other phospholipid-binding proteins (e.g., thrombomodulin, annexins, others) with
anticoagulant activity, resulting in the suppression of tissue factor pathway inhibitor activity, decrease in
activated protein C activity, and less fibrinolysis.
❖ Complement activation: anti-β2GPI binding can lead to complement activation with C5a release leading to cellular
recruitment, tissue factor expression, and coagulation cascade activation leading to thrombosis and placental
insufficiency.
❖ Production of antibodies against coagulation factors, including prothrombin, protein C, protein S, and annexins
❖ Activation of platelets to enhance endothelial adherence
❖ Activation of vascular endothelium, which, in turn, facilitates the binding of platelets and monocytes

❖ Diseases & risk factors associated with increased aPL ab production.

❖ Autoimmune or rheumatic diseases: ❖ Infections
✓ SLE - 25-50% ✓ Syphilis
✓ Sjögren syndrome - 42% ✓ Hepatitis C infection
✓ Rheumatoid arthritis - 33% ✓ HIV infection
✓ Autoimmune thrombocytopenic purpura - 30% ✓ Malaria
✓ Autoimmune hemolytic anemia - Unknown ✓ Bacterial septicemia
✓ Psoriatic arthritis - 28%
✓ Systemic sclerosis - 25% ❖ Drugs
✓ Mixed connective-tissue disease - 22% ✓ Cardiac - Procainamide, quinidine, propranolol,
✓ Polymyalgia rheumatica or giant cell arteritis - 20% hydralazine
✓ Behçet syndrome - 20% ✓ Neuroleptic or psychiatric - Phenytoin, chlorpromazine
❖ Genetic predisposition: HLA associations: DRw53, DR7 and DR4
❖ Risk factors for thrombosis with APLs:

High risk groups
➢ Age (>55 yr in men and >65 yr in women). ➢ Abnormal endothelium.
➢ Smoking--Oral contraceptives--Pregnancy. ✓ Active vasculitis/inflammatory disease (SLE).
➢ History of previous thrombosis or fetal loss. ✓ Atherosclerosis and risk factors (diabetes,
hyperlipidemia, high blood pressure).
➢ Antibody characteristics:
✓ Catheterization for arteriography/ (IV) access.
✓ Triple positives (LA, aCL, anti-β2GPI abs).
✓ High titers of aPL antibodies (>40 units).
➢ Hereditary hypercoagulable disorders.
➢ Increased tissue factor release: Infection & Surgery. ✓ Factor V Leiden (activated protein C resistance).
➢ Nephritic syndrome-Malignancy - Homocystinemia. ✓ Protein C or S deficiency.
✓ Antithrombotin III deficiency.
Clinical Findings
▪ Thrombosis: Recurrent arterial & venous thrombosis ▪ Pregnancy Complications:

✓ DVT of the lower extremities. ✓ Pregnancy losses from APS occur in the
✓ Hepatic or splenic infarcts. first trimester or as late fetal deaths.
✓ Budd–Chiari syndrome. ✓ IUGR
✓ Sever pre-eclampsia.
✓ Renal artery thrombosis & Glomerular
✓ HELLP syndrome (hemolysis, elevated liver
capillary thrombi.
enzymes, low platelets).
✓ Myocardial infarction -- Pulmonary emboli.
✓ Libman-Sacks endocarditis & sterile valve ▪ Cutaneous finding:
vegetations. ✓ The most common is livedo reticularis.
✓ Retinal thromboses & Optic neuropathy. ✓ Others: splinter hemorrhages, superficial
✓ Dural sinus thrombosis. thrombophlebitis, digital gangrene, and
✓ Strokes & Transient ischemic attacks. leg ulcers.
▪ Thrombocytopenia: (20% of patients) usually mild in the range of 50 to 140,000/mm3.

Classification Criteria for Antiphospholipid Syndrome

Clinical Criteria
➢ Vascular thrombosis:
✓ One or more clinical episodes of arterial, venous, or small vessel thrombosis in any tissue or organ.
✓ Thrombosis confirmed by imaging or Doppler studies or histopathology, with the exception of superficial
venous thrombosis and
✓ For histopathologic confirmation, thrombosis present without significant evidence of inflammation in the
vessel wall.
➢ Pregnancy morbidity:
✓ IUFD: One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th wk of
gestation, OR
✓ Premature births: One or more premature births of a morphologically normal neonate before the 34th wk
of gestation because of eclampsia, severe preeclampsia, or recognized features of placental insufficiency,
OR
✓ Abortion: Three or more unexplained consecutive spontaneous abortions before the 10th wk of gestation,
with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes
excluded.
Laboratory Criteria:
(On two or more occasions at least 12 wk apart)
1. Lupus anticoagulant activity: detected according to the guidelines of the International Society on Thrombosis and Hemostasis.
2. Anticardiolipin antibody: (Ig)G or IgM , present in medium or high titer (>40 GPL or MPL, or >99th percentile).
3. Anti–β2-glycoprotein I antibody of IgG or IgM isotype in serum or plasma (in titer >99th percentile).
One of the clinical criteria & One of the laboratory criteria makes the diagnosis
❖ Classification of APS should be avoided if less than 12 wk or more than 5 yr separate the positive antiphospholipid antibody test
and the clinical manifestation.
❖ Coexisting inherited or acquired factors for thrombosis are not reasons to exclude patients from APS trials. However, two
subgroups of APS patients should be recognized by the presence and absence of additional risk factors for thrombosis.
❖ LA activity according to following guidelines:
✓ A sensitive screening test must show prolongation of the clotting time. A sensitive activated partial thromboplastin
time (aPTT) or the dilute Russell viper venom time (dRVVT) is recommended for screening. No single screening test
can detect all LAs.
✓ Failure to correct the prolonged coagulation time by a mix of platelet-poor normal plasma.
✓ Shortening or correction of the prolonged coagulation time with excess phospholipid.
✓ Exclusion of other coagulopathies (e.g., factor deficiencies or inhibitors, heparin, direct oral anticoagulants).
❖ Anticardiolipin is actually an antibody directed against negatively charged phospholipids bound to beta 2 glycoprotein I.
❖ Anti–Beta 2 Glycoprotein I: It is unusual for an APS patient to be negative for both LA and aCL. Thus, anti-beta 2 GPI is rarely
necessary to make the diagnosis/classification of APS.
❖ Anticardiolipin & Anti–Beta 2 Glycoprotein I: measured by ELISA

TREATMENT:
❖ Asymptomatic APLs Antibodies Patients with APLs Ab but no history of thrombosis or pregnancy loss
➢ Avoid medications that might contribute to hypercoagulability, including oral
contraceptives and hormone therapy.
➢ Strict control of associated comorbidities as (DM—HTN--Atherosclerosis).
➢ Low dose aspirin (81mg) as a prophylactic therapy especially for high-risk group.
➢ Prophylactic LMW OR low-dose unfractionated heparin in cases of:
✓ After surgical operations, Post-partum & Prolonged immobilization.
✓ Unfractionated heparin starting 1 to2 hours before surgery; or LMWH starting 12 to 24 hours after should be
continued at least 1 week (low risk) to 6 weeks (high risk) postoperative or postpartum.
❖ Pregnancy Loss:
During pregnancy Post-partum
➢ 1st pregnancy without pervious Hx of Low dose aspirin (81mg) as a prophylactic Prophylactic LMW
pregnancy complication or thrombosis: therapy till 28 weeks of gestation heparin.
• Prophylactic subcutaneous Prophylactic SC
➢ Recurrent pregnancy loss with no Hx of [LMWH]+ low-dose aspirin. [LMWH) for 2-6
thrombosis
• Hold therapy at the time of delivery. weeks postpartum
➢ Previous Hx of thrombosis • Therapeutic doses of subcutaneous Oral anticoagulant
[LMWH]+ low-dose aspirin. (Warfarin) for at least 6
• Hold therapy at the time of delivery. months
i. Prophylactic LMWH: 0.5 mg/kg/day (Single SC dose).
ii. Therapeutic LMWH: 1 mg/kg SC twice daily. -- Monitored by antifactor Xa level
iii. Unfractionated heparin (miniheparin): 5000- 10.000 IU SC/12hr — Monitored by PTT, antifactor Xa level.
iv. Warfarin contraindicated during pregnancy but allowed with Breastfeeding.
❖ Thrombosis
➢ Acute cases:
✓ The treatment of an acute thrombotic event (thrombolysis and/or heparin) is not
changed by knowledge that the patient has an APLs.
✓ Intravenous Infusion of unfractionated heparin or therapeutic dose LMWH SC
followed by warfarin therapy.
➢ Prevention of recurrence:
✓ High risk of recurrence of thrombosis in APS & life-long anticoagulation usually
needed (Warfarin+ low dose Aspirin).
✓ Aim of treatment is to keep International Normalized Ratio (INR)in range of (2.0-3.0)
for patients with single thrombotic events & in range (3.0–4.0) for cases with
recurrent thrombosis.
❖ Management of associated Thrombocytopenia
➢ The platelet count should be stable at above 50,000 before chronic anticoagulation is
begun, and the INR goal would be 2.0 in such a patient.
➢ Prednisone and IVIG should be added to keep the platelet count above 50,000.
Criteria for the Classification of Catastrophic Antiphospholipid Syndrome

1. Evidence of involvement of three or more organs, systems, or tissues.
2. Development of manifestations simultaneously or in less than 1 wk.
3. Confirmation by histopathology of small vessel occlusion in at least one organ or tissue.
4. Laboratory confirmation of the presence of antiphospholipid antibody (lupus anticoagulant or
anticardiolipin or anti–β2- glycoprotein I antibodies).
Definite Catastrophic APS: All four criteria
Probable Catastrophic APS: Criteria 2 through 4 and two organs, systems, or tissues involved.
❖ Treatment of Catastrophic Antiphospholipid Syndrome

(Mortality up to 50%)
➢ First-line therapy: IV unfractionated heparin (not LMWH) + Methylprednisolone 1000 mg
daily for 3 to 5 days followed by high-dose oral prednisone.
➢ Second-line therapy: Plasmapheresis daily for 3 days then IVIG 0.4 g/kg/day for 5 days.
➢ Third-line therapy: Cyclophosphamide and/or rituximab, especially if associated with
active SLE.
➢ Anticoagulation should be initiated as soon as possible when considered safe.
Anticoagulation may need to be delayed if the patient is having life-threatening
hemorrhagic complications (pulmonary hemorrhage, intracerebral hemorrhage) as part of
their CAPS presentation.
➢ The combination of plasmapheresis, glucocorticoids, and anticoagulation (“triple therapy”)
has decreased CAPS mortality by 33% compared with any one therapy alone.

NB
❖ Antiphospholipid antibodies (aPLs) are a family of autoantibodies directed against

phospholipid-binding plasma proteins, most commonly β2-glycoprotein I.
❖ The estimated relative risk of venous thromboembolism with anticardiolipin is 2 and with
the lupus anticoagulant is 10.
❖ APS presents in two major ways: thrombosis (venous or arterial) and pregnancy loss.
❖ Stroke is the most common presentation of arterial thrombosis; DVT is the most common
venous manifestation.
❖ Pregnancy losses typically occur after 10 weeks’ gestation, but earlier losses also occur.
❖ Thrombocytopenia does not protect the APS patient from thrombosis.
❖ As platelets play major role in arterial thrombosis, Patient with Hx of arterial thrombosis
should treated by combination antiplatelet agents (ASA [81 mg daily] plus dipyridamole
[200 mg twice a day] OR clopidogrel [75 mg daily]). + Warfarin.
❖ The antithrombotic properties of hydroxychloroquine have long been recognized and may
be considered in the prophylactic treatment of a patient with SLE and a positive aPL antibody
test result.
❖ Catastrophic APS is a rare form of APS that consists of multiple thromboses of medium and
small arteries occurring over days.
❖ The inciting event for CAPS is unknown in 45% of patients. Infections (20%) and surgery
(14%)
❖ When monitoring heparin therapy, note that the aPTT may be unreliable in the presence of
circulating LA with a baseline elevated aPTT. In this case, factor Xa may be helpful.
❖ The risk of thrombosis in a person with aPL abs: The presence of an LA increases the risk of
thrombosis more than aCL/anti-β2GPI abs with the following odds ratios (ORs):
✓ Venous thromboembolism (OR 11) in patients aged <50 years.
✓ Stroke (OR 8.1) in patients aged <50 years.
✓ Fetal loss (OR 7.8) -- Thrombosis in an SLE patient (OR 5.6).
✓ Patients who have all three aPL abs (“triple positives”) including LA, aCL abs, anti-β2GPI
abs have the highest risk for thrombosis (OR 34.4).
❖ Measurement of aCL abs and anti-β2GPI abs are tested by ELISA and not affected by
anticoagulation and can be reliably measured in a patient on heparin or warfarin. However,

coagulation tests to detect LA are affected by heparin, warfarin, and DOACs, and care must
be taken in determining LAs in this situation.
❖ Contraindications of Anticoagulant
Warfarin Heparin
❖ Documented hypersensitivity & active ❖ Documented hypersensitivity & active
bleeding. bleeding.
❖ Malignant hypertension. ❖ Thrombocytopenia.
❖ Severe liver or kidney disease. ❖ Subacute bacterial endocarditis.
❖ Pregnancy ❖ Interactions: Drugs that inhibit platelet
❖ Neurologic, Ophthalmologic, or traumatic activation (eg, aspirin, NSAIDs,
surgery. dipyridamole, sulfinpyrazone, clopidogrel)
may increase risk of bleeding.

Mustafa Elmenawy
Basic
Rheumatology
Sjogren syndrome
Sjogren syndrome
Definition: Sjögren syndrome (SS) is a systemic autoimmune disease that mainly affects
the exocrine glands (salivary and lacrimal glands) and usually presents as
persistent dryness of the mouth and eyes.
Epidemiology:
• Prevalence: The overall prevalence of SS is 0.1 to 4 %.
• Age of onset: The disease may occur at all ages but typically has its onset in the fourth
to sixth decades of life.
• Sex: SS primarily affects white perimenopausal women, with a female:male ratio ranging from
20:1
Clinical Findings
Sicca Features
keratoconjunctivitis sicca (dry eyes), xerostomia (dry mouth)
1. Mouth:
➢ Xerostomia (Oral dryness): the key feature in the diagnosis of primary SS,
occurring in more than 95% of patients.
➢ Oral soreness, adherence of food to the mucosa, and dysphagia.
➢ Infection: The lack of salivary antimicrobial functions accelerate local infection (eg,
candidiasis), tooth decay, periodontal disease, and angular cheilitis.
o ON Examination:
➢ In the early stages, the mouth may appear moist, but as the disease progresses,
the usual pooling of saliva in the floor of the mouth disappears.
➢ Tongue: the surface of the tongue becomes red and lobulated, with partial or
complete depapillation
➢ In advanced disease, the oral mucosa appears dry and glazed and tends to form
fine wrinkles.
➢ Salivary gland enlargement: (30% of patients)
✓ Bilateral, non-tender swelling of the major salivary glands & generally
asymptomatic.
✓ Parotid gland swelling usually represents supervening bacterial parotitis or
ductal obstruction from a sialolith or mucus plug.
✓ Slowly progressive enlargement of the glands should raise concern for the
presence of glandular lymphoma, particularly when asymmetric.
Sjogren Syndrome 199

2. Eyes :
➢ Xerophthalmia, the subjective feeling of ocular dryness, produces sensations of
itching, grittiness, soreness, and dryness.
➢ Photosensitivity, erythema, eye fatigue, or decreased visual acuity.
➢ Environmental irritants such as smoke, wind, air conditioning, and low humidity may
exacerbate ocular symptoms.
➢ Infection: Tears also have inherent antimicrobial activity and SS patients are more
susceptible to ocular infections such as blepharitis, bacterial keratitis, and
conjunctivitis.
➢ Slitlamp examination :
✓ Keratoconjunctivitis sicca: Diminished tear secretion may lead to
chronic irritation and destruction of corneal and bulbar conjunctival epithelium
✓ Filamentary keratitis, marked by mucus filaments that adhere to
damaged areas of the corneal surface (In severe cases).
✓ Severe ocular complications may include corneal ulceration,
vascularization, and opacification.
Extraglandular Manifestations
1. General manifestations:
✓ Fever, generalized pain, fatigue, weakness (which are the most debilitating clinical features of primary SS).
✓ Sleep disturbances, anxiety, and depression. (may have a much greater impact on the quality of life of patients than sicca
features).
2. Musculoskeletal System: 3. Skin:
✓ Mostly generalized arthralgias & myalgias, is seen in 25– ✓ Cutaneous dryness -- Palpable purpura, urticarial lesions.
75% of patients. ✓ Ro-associated polycyclic lesions.
✓ Less frequently: ✓ Vasculitis: small-vessel vasculitis, the vasculitis may be
• An intermittent symmetric arthritis primarily characterized by either a lymphocytic vasculitis or
affecting small joints. leukocytoclastic vasculitis.
• Clinical myopathy is rare.
4. LUNG: 5. CVS:
✓ Obstructive chronic pneumopathy (bronchial/bronchiolar ✓ Raynaud phenomenon: In 13% of cases
involvement). ✓ Pericarditis & pericardial effusions (usually mild and
✓ Interstitial pneumopathy. asymptomatic)
✓ Autonomic cardiovascular disturbances.
6. GUT: 7. Neurological System:
✓ Altered esophageal motility,dysphagia, chronic gastritis, ✓ Mixed polyneuropathy, pure sensitive neuropathy,
and malabsorption. mononeuritis multiplex
✓ Associated hepatitis C virus infection, primary biliary ✓ Cranial nerve involvement (V, VIII, and VII) & Rarely White
cirrhosis, type 1 autoimmune hepatitis. matter lesions.
✓ Liver function tests may be elevated in 10–20% of patients
with primary SS.

8. Other Organs:
➢ Nephro-Urologic Involvement:
✓ Renal dysfunction: including mild proteinuria, reduced creatinine clearance in, and distal renal tubular acidosis in.
✓ Interstitial cystitis.
➢ Ears: Sensorineural hearing loss
➢ Thyroid: Autoimmune thyroiditis (1/3 of patients)
✓ Subclinical hypothyroidism is the most frequent finding, especially in patients with antithyroid autoantibodies
(suggesting previous Hashimoto thyroiditis).
➢ Nose and throat: Nasal dryness, chronic cough

➢ SS patients may be divided into two groups with different prognoses:
A. Predominantly peri-epithelial lesions (such as interstitial nephritis or liver or lung disease)
<<<< usually progresses very slowly, with no rapid deterioration in salivary
function or dramatic changes in sicca symptoms.
B. Predominantly extraepithelial expression (glomerulonephritis, polyneuropathy, and vasculitis)

<<<<suffer higher morbidity and mortality.
NB: Cryoglobulinemia probably plays a central etiopathogenic role in this latter group of patients, contributing to the
development of the main extraepithelial manifestations.
➢ Lymphoma is considered as the main complication (5%) in the natural history of SS.
➢ Prognostic Factors that predict poor outcome:

1. Lymphadenopathy and Fever.
2. Skin vasculitis, peripheral neuropathy.
3. Anemia, lymphopenia and low C4 levels.

Investigations
➢ CBC:
✓ Normochromic, normocytic anemia.
✓ Mild leucopenia & thrombocytopenia.
➢ ESR & CRP:

✓ Raised ESR (>50 mm/h) in 20–30% of cases, especially in patients with
hypergammaglobulinemia
✓ Normal values of CRP
➢ Liver function tests:

✓ Raised transaminases (associated with hepatitis C virus or autoimmune hepatitis).
✓ Raised alkaline phosphatase and/or bilirubin (associated with primary biliary cirrhosis).
➢ Urinalysis:
✓ Proteinuria (glomerulonephritis).
➢ Serum protein:
✓ Hypergammaglobulinemia
✓ Monoclonal band
➢ Serology:
Autoantibodies and Clinical Significance in (SS)
Autoantibody Prevalence in SS
1. ANA < 80%
2. Rheumatoid factor 50%
3. Anti-Ro/SSA 30-60%
4. Anti-La/SSB 20-40%
5. Antimitochondrial antibodies Associated with primary biliary cirrhosis
6. Antithyroid antibodies Associated with thyroiditis
7. Anti-dsDNA Associated with SLE
8. Anticentromere Associated with a limited form of systemic sclerosis.
9. Low Complement (C3 & C4) levels 10–20% of patients.
The most common being directed against the Ro/SSA and La/SSB ribonucleoprotein complexes in 60% to 80% of patients.
The anti-Ro/SSA and anti-La/SSB antibody profile present at diagnosis generally remains unchanged during the subsequent
disease course.
Anti-Ro/SSA and anti-La/SSB antibodies are associated with a higher prevalence of extra-glandular features and more extensive
lymphoid infiltrates in the salivary glands.
❖ Assessment of Oral Involvement

➢ Salivary Gland Biopsy (a highly specific test for the diagnosis of SS)
✓ Focal lymphocytic sialadenitis, defined as multiple, dense aggregates of 50
or more lymphocytes in perivascular or periductal areas in the majority of sampled
glands, is the characteristic histopathologic feature of SS.
➢ Sialometry:
✓ It can be used to quantitate saliva production. An unstimulated whole salivary flow
rate of ≤1.5 mL/15 minutes meets criterion for xerostomia.
➢ Sialography:
✓ It will outline the salivary duct anatomy but It is not routinely used in clinical practice
because it is an invasive procedure with complications that include duct rupture,
pain, and infection.
➢ Scintigraphy: a radionuclide technique for measuring salivary gland function.
➢ Ultrasonography and MRI: Can detect anatomic abnormalities in the salivary glands
of patients with primary Sjögren’s syndrome.
❖ Assessment of Ocular Involvement

➢ Schirmer test (Quantitative assessment of tear formation)
✓ Via placement of filter paper in the lower conjunctival sac.
✓ The test can be performed with or without the instillation of anesthetic drops to prevent
reflex tearing.
✓ The test result is positive when less than 5 mm of paper is wetted after 5
minutes.
➢ Rose bengal staining (For the corneal surface integrity)

✓ Rose bengal scoring involves the placement of 25 mL of rose bengal solution in the
inferior fornix of each eye and having the patient blink twice.
✓ Slitlamp examination detects destroyed conjunctival epithelium due to desiccation.
✓ Ocular surface staining can also performed with lissamine green (for the conjunctiva)
and fluorescein (for thecornea).

2016 ACR/EULAR classification criteria for 1ry SS
Requirements: The classification of primary SS applies to any individual who meets the inclusion criteria, does not
have any of the conditions listed as exclusion criteria, and has a score of ≥ 4 when the weights from the five criteria
items are summed
Item Weight / Score

1. Labial salivary gland with focal lymphocytic sialadenitis and focus score ≥ 1 3
2. Anti-SSA (Ro) + 3
3. Ocular staining score ≥ 5 (or van Bijsterfeld score ≥ 4) on at least one eye 1
4. Schirmer ≤ 5 mm/5min on at least one eye 1
5. Unstimulated whole saliva flow rate ≤ 0.1 ml/min5 1
❖ Inclusion Criteria:
Inclusion criteria are applicable to any patient with at least 1 symptom of ocular or oral dryness, defined as a
positive response to at least 1 of the following:
(1) Have you had daily, persistent, troublesome dry eyes for more than 3 months?
(2) Do you have a recurrent sensation of sand or gravel in the eyes?
(3) Do you use tear substitutes more than 3 times a day?
(4) Have you had a daily feeling of dry mouth for more than 3 months?
(5) Do you frequently drink liquids to aid in swallowing dry food?
Or
in whom there is suspicion of Sjogren's syndrome from the EULAR SS Disease Activity Index questionnaire (at least 1
domain with a positive item)
❖ Exclusion Criteria
Exclusion criteria include prior diagnosis of any of the following, which would exclude diagnosis of SS and participation
in SS studies or therapeutic trials because of overlapping clinical features or interference with criteria tests:
(1) History of head and neck radiation treatment.

(2) Active hepatitis C infection (with confirmation by PCR).
(3) AIDS.
(4) Amyloidosis.
(5) Sarcoidosis.
(6) Graft-versus-host disease.
(7) IgG4-related disease.

ACR 2012 classification Criteria for Sjogren syndrome

I. Ocular symptoms: a positive response to at least one of the following questions:
a) Have you had daily, persistent, troublesome dry eyes for more than 3 months?
b) Do you have a recurrent sensation of sand or gravel in the eyes?
c) Do you use tear substitutes more than three times a day?
II. Oral symptoms: a positive response to at least one of the following questions:
a) Have you had a daily feeling of dry mouth for more than 3 months?
b) Have you had recurrently or persistently swollen salivary glands as an adult?
c) Do you frequently drink liquids to aid in swallowing dry food?
III. Ocular signs: objective evidence of ocular involvement defined as a positive result for at
least one of the following two tests:
a) Schirmer test, performed without anesthesia (5 mm in 5 minutes)
b) Rose bengal score or other ocular dye score (4 according to the van Bijsterveld scoring system)
IV. Histopathology: (In minor salivary glands, obtained through normal-appearing mucosa & evaluated by an expert histopathologist)
➢ Focal lymphocytic sialoadenitis: multiple, dense aggregates of 50 or more
lymphocytes in perivascular or periductal areas ,with ≥ 1 focus/4 mm2
V. Salivary gland involvement: a positive result for at least one of the following
diagnostic tests:
a) Unstimulated whole salivary flow (1.5 mL in 15 minutes).
b) Parotid sialography showing the presence of diffuse sialectasias (punctate, cavitary,
or destructive pattern), without evidence of obstruction in the major ducts.
c) Salivary scintigraphy showing delayed uptake, reduced concentration, and/or
delayed excretion of tracer
VI. Autoantibodies: presence in the serum of the following autoantibodies:

a) Antinuclear antibodies
b) Rheumatoid factor
c) Antibodies to Ro/SS-A or La/SS-B antigens, or both
❖ Rules for Classification

▪ For a primary Sjögren’s diagnosis:
a. Any 4 of the 6 criteria, must include either item IV (Histopathology) or VI (Autoantibodies)
b. Any 3 of the 4 objective criteria (III, IV, V, VI)
▪ For a secondary Sjögren’s diagnosis:

In patients with another well-defined major connective tissue disease, the presence of one symptom (I
or II) plus 2 of the 3 objective criteria (III, IV and V) is indicative of secondary
SS.
❖ Exclusion Criteria
1. Past head and neck radiation treatment
2. Hepatitis C infection
3. Acquired immunodeficiency syndrome (AIDS)
4. Pre-existing lymphoma
5. Sarcoidosis
6. Graft versus host disease
7. Current use of anticholinergic drugs
❖ ACR 2012 criteria for Sjögren syndrome

Diagnosis of Sjögren syndrome requires at least 2 of the following 3 findings:
1. Positive serum anti-SSA and/or anti-SSB antibodies or positive rheumatoid factor and antinuclear antibody
titer of at least 1:32
2. Ocular staining score of at least 3
3. Presence of focal lymphocytic sialadenitis with a focus score of at least 1 focus/4 mm2 in labial salivary
gland biopsy samples


Non-Sicca Manifestations Suggestive of Sjögren Sydrome

Clinical features Analytic features
1. Chronic fatigue. 1. Elevated ESR
2. Fever of unknown origin. 2. Hypergammaglobulinemia
3. Raynaud phenomenon. 3. Leukopenia and thrombocytopenia.
4. Peripheral neuropathy. 4. Serum and/or urine monoclonal
5. Leukocytoclastic vasculitis. band
6. Parotid or submandibular gland swelling. 5. Positive antinuclear antibodies or
rheumatoid factor in an
7. Pulmonary fibrosis.
asymptomatic patient.
8. Mother of a baby born with congenital
heart block.

Treatment of Sjogren Syndrome

❖ Treatment of Sicca manifestations:
➢ Treatment of sicca manifestations is mainly symptomatic (replacement or stimulation of glandular
secretions) and is typically aim to limit the damage resulting from chronic involvement.
❖ Conservative measurements:
➢ Good dental care, with frequent use of fluoridated toothpaste and mouthwash.
➢ Sugar-free (not just sugarless) gum, mints, or candies may stimulate salivary flow
without increasing the risk of dental caries.
➢ Nystatin for ttt of oral candidiasis
➢ The patient is advised to avoid:
✓ Central heating, air conditioning & windy environments.
✓ Medications that reduce tear and saliva production (antihistamines, antidepressants,
muscle relaxers, and other drugs with anticholinergic properties)
✓ Alcohol, and smoking, should be avoided whenever possible.
✓ Glucocorticoid-containing ophthalmic solutions should be avoided because
they may induce corneal lesions or promote infection.
❖ For Dry Eye:

➢ Tear substitutes:
✓ Help to replace moisture, and effective for patients with mild or moderate symptoms.
✓ Preservative-free formulations help avoid the irritation that can occur with frequent use.
✓ Lubricating ointments and methylcellulose inserts are usually reserved for nocturnal
use.
➢ Artificial tears: In moderate-to-severe xerophthalmia, in dosing intervals as often as
hourly is highly recommended.
➢ Restasis : An ophthalmic preparation of cyclosporine, 0.05%, which has been approved
by the FDA for the treatment of keratoconjunctivitis sicca.
➢ Surgery: Occlusion of the puncta

• In severe cases occlusion of the puncta to block tear drainage and thus retain
existing tears.
• Temporary through the insertion of plugs (collagen or silicone) or permanent
occlusion by electrocautery.
❖ For Dry Mouth:

➢ Stimulation of saliva flow:
 Indication: For patients with SS who have residual salivary gland function,
stimulation of saliva flow with a secretagogue is the treatment of choice and at
present is the most efficacious means to prevent long-term oral complications.

 Dose:
✓ Pilocarpine (Salagen) : 5mg/ three times daily.
✓ Cevimeline: 30 mg three times daily
 Mechanism of action: These agents stimulate the M3 muscarinic receptors
present on salivary & lacrimal glands, leading to increased secretory function.
 Side effects: Sweating and flushing, visual disturbances, increased urination,
nausea,abdominal pain, and diarrhea.
 Contraindications: Narrow-angle glaucoma, asthma, or on beta blockers.
❖ Treatment of extraglandular features:
➢ Mild disease:
▪ Patients with fatigue and minor musculoskeletal symptoms of SS (arthralgias,
myalgias).
▪ Treated with: NSAIDs + HCQ (low dose steroids may be needed).
➢ For patients with moderate extraglandular involvement:

▪ Mainly arthritis, extensive cutaneous purpura, and non-severe peripheral
neuropathy.
▪ Treated with: Low dose steroids: 0.5 mg/kg/d of prednisone HCQ.
➢ For patients with internal organ involvement:

▪ Pulmonary alveolitis, glomerulonephritis, or severe neurologic features
▪ Treated with: A combination of Steroids and immunosuppressive agents (MTX,
Cyclophosphamide, azathioprine, or mycophenolate mofetil) is suggested.
➢ Biological agents:
▪ Rituximab (anti-CD20):
✓ A monoclonal agent approved for the treatment of B-cell lymphoma.
✓ The specific target of rituximab (B cells) suggests that this agent may play a role in
modifying the etiopathogenic events of patients with primary SS, a disease
characterized by B-cell hyperactivity.
✓ Rituximab has shown promise in for improvement in fatigue, sicca symptoms and
disease activity.
▪ Recent studies have demonstrated the lack of efficacy of tumor necrosis factor
inhibitors in primary SS.

Treatment algorithm for Sjogren’s syndrome.

Etiology & Pathogenesis
RISK FACTORS FOR SS

Genetic Factors
➢ Primary SS is immunogenetically associated with HLA-DRB1*0301 and DRB1*1501,
and serologically associated with antibodies to Ro/SS-A and La/SS-B.
➢ Secondary SS is diagnosed when there is accompanying evidence of another

connective tissue disease, most frequently RA. The immunogenetic and serologic
findings are usually those of the accompanying disease (e.g., HLA-DR4-positive if
associated with RA).
Infection:
➢ A virus infection participates in the pathogenesis of SS through inducing chronic
inflammation, a source of exogenous antigen that triggers autoimmunity, or a
molecular mimic of the candidate autoantigen.
➢ Viruses that have been considered include Epstein–Barr virus (EBV), Coxsackie virus,
human immunodeficiency virus (HIV), and hepatitis C virus (HCV).
Pathogenesis:
➢ The manifestations of SS result from a predominantly lymphocytic cell infiltration of
glandular and non-glandular organs.
➢ The cellular infiltration of the lacrimal glands and salivary glands interferes with the
production of tears and saliva, respectively.
➢ Cellular infiltration of other organs, such as the lungs and gastrointestinal tract, results in
a variety of major organ manifestations.
❖ Cellular Immunopathology
➢ Over 90% of the infiltrating cells are CD4+ T lymphocytes with memory phenotype
(T-helper) (70%) and CD20+ B lymphocytes (20%).
➢ The remaining 10% are an admixture of plasma cells, CD8+ T lymphocytes, T

regulatory cells, natural killer cells, and dendritic cells.
❖ Autoantibodies
➢ Most patients with SS develop increased circulating polyclonal immunoglobulins and
autoantibodies.
➢ These autoantibodies includes the highly non-specific RF and ANA, and the more
specific anti-Ro (SS-A) and anti-La (SS-B) antibodies, which are more highly
associated with 1ry SS and SLE.

NB
▪ The clinical hallmarks of Sjogren’s syndrome are keratoconjunctivitis sicca (dry eyes),
xerostomia (dry mouth) and parotid gland swelling.
▪ Extraglandular features of primary Sjogren’s syndrome include fatigue, Raynaud’s
phenomenon, polyarthralgia/ arthritis, interstitial lung disease, neuropathy, and purpura.
▪ The characteristic histopathologic finding: A chronic mononuclear cell infiltration of the
lacrimal and salivary glands is
▪ The most frequent cause of sicca features is the chronic use of dry drugs (mainly
antihypertensive, antihistamine, and antidepressant agents), especially in the elderly.
▪ Reduced salivary volume interferes with basic functions such as speaking or eating.
▪ Life-threatening vasculitis is also closely related to cryoglobulinemia.
▪ The clinical course of Raynaud phenomenon in primary SS is milder than in other systemic
autoimmune diseases such as systemic sclerosis. Vascular complications (eg, digital loss, digital
pulp pitting, or fingertip infarctions) are uncommon.
▪ Pancreatic involvement, usually asymptomatic, is demonstrated by altered pancreatic function
tests. Some patients may present with chronic pancreatitis.
▪ Nonspecific sialadenitis is quite common in biopsy samples of minor salivary glands in healthy
control populations (sialoadenitis is the key histopathologic feature of SS, this finding in the absence of symptoms
and markers suggestive of SS should be interpreted with caution).
▪ Anti-Ro/SS-A and anti-La/SS-B antibodies do not appear to have a pathogenic role in disease
mechanisms despite their diagnostic and prognostic significance
▪ Anti-Ro antibody positivity is believed to be a risk factor for pulmonary disease in SS.
▪ Anti-Ro and -La antibodies may be associated with fetal heart block during the pregnancies of
women with SS.
▪ The variability in the presentation of SS may partially explain delays in diagnosis of up to 9 years
from the onset of symptoms.
➢ 1ry or 2ry??
✓ When sicca symptoms appear in a previously healthy person, the syndrome is classified as
primary SS.
✓ When sicca features are found in association with another systemic autoimmune disease,
most commonly rheumatoid arthritis, systemic sclerosis, or systemic lupus erythematosus,
it is classified as secondary SS.


Mustafa Elmenawy
Basic
Rheumatology
Systemic sclerosis
Systemic sclerosis
Definition: Chronic multi-systemic autoimmune disease of unknown etiology
characterized by functional and structural abnormalities in small blood vessels, and
progressive fibrosis of the skin and visceral organs.
Epidemiology:
• Prevalence: The overall prevalence of systemic sclerosis is 250 /1 million persons

• Incidence: approximately 18 to 20 cases per million population per year
• Race: Higher in non-Caucasian individuals (African American, Asian, and Hispanic).
• Age of onset: The average age at onset is between 35 and 50 years.
• Sex: The female-to-male ratio is 7 : 1
Clinical Findings
A-General manifestations:
Fatigue, anorexia & possible weight loss
B- Skin Manifestations:
(The hallmark feature of SSc is thickened skin)
➢ Puffy hands: the first symptom following the onset of Raynaud’s phenomenon.
➢ This is followed by thickening of the skin start distally and progressing
proximally, affecting the upper extremities more than the lower.
➢ Skin manifestations also include:

✓ Swollen hands (and sometimes feet).
✓ Pruritus (Occurs in the early inflammatory phase and usually lasts for weeks to months).
✓ Hyper- and/or hypopigmentation ("salt and pepper" appearance).
✓ Calcinosis.
✓ Telangiectasias.
✓ Dermal ulcers.
✓ Digital tip pitting scars, and digital tip gangrene.
✓ Masked facies (small oral and orbital apertures, and vertical furrowing of the perioral skin are
consequences of skin and soft tissue fibrosis).
Calcinosis
❖ It consists of cutaneous deposits (firm, irregular, and generally nontender) of basic calcium phosphate.
❖ Sites: occur in the hands (especially over the PIP joints and fingertips), periarticular tissue,
and over bony prominences (especially the extensor surface of the elbows and knees)
❖ They can become inflamed, infected, or ulcerated or may discharge a chalky white material.
Systemic Sclerosis 215

NB:
➢ Skin thickening and hardening due to increased collagen and extra-cellular matrix deposition in the dermis.
➢ Active skin involvement might persist for the first 12 to 18 months of the disease, with no further clinical signs
of inflammation or progressive skin fibrosis seen after this interval.
➢ During this later stage, the skin begins to repair and can return to normal texture or, in areas most severely
affected (e.g., the fingers and hands), it can become thin and atrophic.
➢ During this recovery phase, new robust hair growth is seen, particularly on the forearms, and itching and pain
disappear, consistent with spontaneous resolution of disease activity.
➢ After years from disease onset, the skin rarely relapses again into an active phase and gradually can recover
normal texture and color.
➢ Patients who, over time, experience the establishment of a phenotype that is limited to the fingers (plus or
minus facial changes) do not undergo conversion to the diffuse form of the disease.
Modified Rodnan Skin Score (MRSS)

 The amount of skin thickening can be quantified by performing a "skin
score,".
 The skin is pinched between the examiner's thumbs in 17 specified areas
of the patient's body:
✓ Face –– Anterior chest – Abdomen.
✓ 2 upper arm – 2 Forearm – 2 Hands – 2 Fingers.
✓ 2 Thigh – 2 Leg – 2 Feet.
 Each area is graded from 0 to 3.
0 ➔ No involvement.
1 ➔ Mild involvement = Possible thick.
2 ➔ Moderate involvement = Difficult thick and mobile.
3 ➔ Severe involvement =very thick and More fixed.
 Interpretation:
Normal (0) – Mild (1-14) – Moderate (15-29) - Severe (30-39) – Very severe (≥ 40)
 A higher skin scores correlate with greater degrees of internal organ

involvement and worse overall prognosis.
C- Raynaud phenomenon:
(The first manifestation of the disease in almost every patient).
➢ Risk factors: Stress and cold temperatures induce an exaggerated vasoconstriction
of the small arteries, arterioles, and arteriovenous shunts of the skin of the digits.
➢ Presented clinically by:
✓ Pallor and cyanosis of the digits, followed by a reactive hyperemia after
rewarming.
✓ Attacks of Raynaud phenomenon in patients with scleroderma are often painful
and frequently lead to digital ulcerations, gangrene, or amputation (Unlike episodes of
uncomplicated primary Raynaud phenomenon).
D- Lung Involvement:
(the leading cause of death & responsible for 60% of scleroderma-related deaths)
➢ Interstitial pulmonary fibrosis (due to inflammatory alveolitis) typically more common in
patients with early diffuse scleroderma.
➢ Pulmonary hypertension: typically, more common in patients with long-standing

limited disease (may lead to right heart failure).
➢ Lung involvement (both types) usually presents as:
✓ Dyspnea & fatigue on exertion, (but can be asymptomatic early in the course of the lung disease).
✓ Chest pain or syncope (less common)
✓ Fine crackles at the lung bases (its presence may indicate stable fibrosis and not active disease).
✓ Pulmonary HTN: systolic murmur of tricuspid regurgitation and signs of right
heart failure (e.g., right-sided parasternal heave, prominent and elevated jugular venous pulse, hepatomegaly,
and signs of fluid overload with peripheral edema).
Factors associated with Increased risk of developing Pulmonary HTN

▪ Limited skin disease.---Late age at onset of scleroderma.
▪ The presence of numerous telangiectasias, --- Low diffusing capacity.
▪ The presence of anti-U3-RNP antibody.
E- Renal Involvement
(Scleroderma renal crisis): in 10% of patients.
➢ SRC was the most common cause of death in SSc prior to the introduction of (ACE)
inhibitors and still remains an important source of patient morbidity in SSc.
➢ It is characterized by the sudden onset of:
✓ Malignant hypertension (Headache, altered vision, fatigue, confusion).
✓ Microvascular hemolysis, proteinuria & microscopic hematuria.
✓ An abrupt rise in creatinine.
✓ Renal failure and death can occur if SRC not treated.
Patients at high risk:

▪ Patients in the early stages of diffuse scleroderma, particularly those treated with
glucocorticoids. (For this reason, it is recommended that use of corticosteroids be
avoided or that doses less than 15 mg daily be used if necessary).
▪ The presence of anti-RNA polymerase III antibodies.
G- Cardiac Involvement:
(Usually subclinical & can be demonstrated by objective testing eg, Echo or ECG),
➢ Palpitations: Arrhythmias
➢ Dyspnea on exertion: Cardiomyopathy with diastolic dysfunction & Heart failure
➢ Chest pain: Pericarditis & Pericardial effusions.
➢ Focal myocardial fibrosis is the hallmark of primary heart involvement in scleroderma.

F- Gastrointestinal Involvement
➢ Asymptomatic (mild constipation).
➢ Difficult chewing (because of decreased facial flexibility & Perioral skin tightening).
➢ Difficult mastication (because of decreased saliva production).
➢ Gastroesophageal reflux disease with dysphagia (in the majority of patients):
✓ Patients often complain a sensation of food getting stuck in the mid-
esophagus & that they must drink liquids to swallow solid food,
particularly dry food such as meat or bread.
✓ Atypical chest pain or cough.
➢ In the later course of the disease (if the upper gastrointestinal disease left untreated) can cause:
✓ Esophagitis & esophageal ulceration with bleeding.
✓ Esophageal stricture, or Barrett esophagus.
➢ Constipation alternating with diarrhea: Lower bowel dysmotility slows the

movement of bowel contents, allowing bacterial overgrowth, diarrhea, and
malabsorption.
NB:
 Gastrointestinal affection dysfunction results from atrophy of the gastrointestinal tract wall smooth muscle that
occurs in the absence of significant tissue fibrosis or vascular insult.
 Reflux and dysphagia occur because of dysmotility of the esophagus and stomach (gastroparesis).
H- Musculoskeletal Involvement:
➢ Musculoskeletal symptoms range from mild arthralgias to frank nonerosive
arthritis with synovitis resembling rheumatoid arthritis.
➢ Limited range of motion: due to sclerosis of the skin of the fingers or limbs and
contractures of the joints.(Contractures of the PIP and MCP joints are most common, and rarely, contractures
of the DIP)
➢ Flexion contractures of fingers, wrists, and elbows appear as a result of dermal

sclerosis and fibrosis with atrophy of underlying tissues.
➢ Myopathy: Muscle weakness is a common complaint due to:

✓ Pain & prolonged muscle disuse.
✓ Slowly progressive fibrosis of striated muscle.
✓ Malnutrition.
▪ In the early edematous phase of diffuse scleroderma, patients often are diagnosed with carpal tunnel syndrome as a result
of soft tissue swelling and inflammation in the hand and wrist area.
▪ In the later stage diffuse scleroderma: there is distal bone resorption, osteolysis, and periarticular calcinosis.
▪ Erosive arthritis is commonly associated with periarticular Calcinosis
▪ X-ray finding: erosion - joint space narrowing, periarticular osteopenia , acro-osteolysis, flexion contracture , and
calcinosis.

I- Other Symptoms
➢ Sicca complex (dry eyes and dry mouth) are common in patients with scleroderma
but are usually not as severe as in patients with primary Sjögren syndrome.
➢ Thyroid diseases: It is reported in 10% to 15% of patients with scleroderma.
➢ Pain is very common and usually is associated with digital ulcers, fibrosis of
tendons, joint contractures, or musculoskeletal disease.
➢ Depression is common among patients with scleroderma and reflects other factors
such as degree of pain, personality traits, and lack of good social support systems.
➢ Sexual dysfunction:
✓ Erectile dysfunction is very common among men with scleroderma
✓ In women symptoms include: vaginal dryness and dyspareunia secondary to a
narrowed, fibrotic introitus.
NB
 The word scleroderma literally means "hard skin" and describes the most
dramatic clinical feature of the disease—namely, skin fibrosis.
 The degree of skin involvement is highly variable. Many patients with
limited scleroderma have only subtle cutaneous findings (eg, mild
sclerodactyly).
 The most frequent symptoms are (in descending order) Raynaud

phenomenon, gastroesophageal reflux with or without dysmotility, skin
changes, swollen fingers, and arthralgias.
 Signs of classic inflammatory events are often present during the

initial phase of the disease, but later, an indolent subclinical
fibrotic process is dominant and gradually causes organ damage.
 Scleroderma renal crisis, the most common cause of death in SSc prior
to the introduction of angiotensinconverting enzyme (ACE) inhibitors
and still remains an important source of patient morbidity in SSc.
 If patients do progress to ESRD, ACE inhibition should be continued
into the phase of dialysis; some patients demonstrate renal recovery
even after several months of dialysis.
 Patients with Raynaud phenomenon and features atypical for primary

Raynaud phenomenon should be evaluated for the possibility of
scleroderma or another connective tissue disease.
 Complications of scleroderma that result clearly from vascular
dysfunction include PAH, scleroderma renal crisis (SRC), and Raynaud’s
phenomenon (RP).
LABORATORY FINDINGS
1-CBC: Anemia is very common in Scleroderma.
2-Acute phase reactant: marked elevation in ESR & CRP
3-Urine analysis: Proteinuria & microscopic hematuria with scleroderma renal crisis
Autoantibodies and Clinical Significance in Scleroderma

Autoantibody Prevalence Associated Clinical Features
1. ANA < 95% Non specific
2. Anti-Scl-70 (anti- 20-40 • Highly specific for scleroderma - worse prognosis
topoisomerase I) • Associated with Lung disease, diffuse skin involvement
3. Anti-centromere 20-40% • CREST syndrome, digital ulcerations/digital loss.
• Pulmonary HTN
4. Anti-RNA polymerases 4–20% • Diffuse skin involvement, scleroderma renal crisis, cardiac
disease - worse prognosis
5. Anti-U3-RNP (anti- 10% Lung disease & diffuse skin involvement
fibrillarin)
6. Anti-U1-RNP 5% Associated with mixed connective tissue disease

7. Anti-B23 10% Pulmonary HTN
8. Anti-Pm-Scl 10% Limited cutaneous involvement, myositis
Special Tests (for evaluation of organ affection)

➢ Pulmonary function testing (PFT): The most sensitive measure for the development of ILD.
▪ Patients should have PFTs (spirometry, lung volumes, and diffusing capacity) performed at
baseline and then every 4–12 months depending on symptoms.
▪ Finding: Approximately 80% of patients with scleroderma have restrictive

ventilatory defects with or without a reduction in diffusing capacity.
▪ Role of PFTs:
✓ Assessing the degree of respiratory impairment due to ILD & coexistent of
pulmonary HTN.
✓ Assess for disease progression and response to therapy.
➢ High-resolution chest CT scans:

▪ The earliest and most common abnormality: increased subpleural lung
attenuations in the absence of distinct architectural distortion (usually found in the
posterior & basilar portion of the lungs).
▪ With progression of the disease: ground glass opacities are seen.

▪ Subsequent detection of a fine reticular pattern often precedes overt pulmonary
fibrosis.
➢ Transthoracic echocardiogram (TTE):

▪ The best noninvasive assessment for the presence of Pulmonary Hypertension
▪ A baseline echocardiogram is recommended in all SSc patients and should be
repeated yearly.
➢ BAL: bronchoalveolar lavage or right heart catheterization may be performed to

determine degree of activity or severity of disease in those patients with abnormal
screening studies and cardiopulmonary symptoms.
➢ Barium swallow or upper gastrointestinal endoscopy:

▪ Indicated in:
✓ Patients with atypical symptoms.
✓ Poor responses to proton pump inhibitors.
✓ Long-standing untreated symptoms.
✓ Unnecessary in a patient with scleroderma who has symptomatic
gastroesophageal reflux alone.
▪ Role of endoscopy: To assess reflux esophagitis, candidiasis, Barrett’s esophagus,

and strictures of the lower esophageal area.
▪ Plain x ray erect on the abdomen: detect small intestinal dysmotility and pseudo-
obstruction.
➢ Nailfold capillary Examination:

▪ Normally: the nailfold capillaries should be thin, linear, and uniform.
▪ In patients with scleroderma:
➢ Early disease: Capillary dilation (giant capillaries), microhemorrhages,
and some disorganization of the capillary network are typical of early
disease.
➢ Later stages: Capillary dropouts, avascular areas, and signs of
neoangiogenesis disorganized capillaries.
▪ Role OF NFC: To identify disease progression as loss of capillary density is

correlated with development of pulmonary hypertension and digital ulcers.
▪ Method:
✓ To examine the nailfold capillaries, a drop of either microscope oil or
lubricant jelly is placed on the nail bed.
✓ An ophthalmoscope, set at minus 20–40 diopters (40 green) is used as a
microscope to visualize the capillaries.
▪ Nail fold capillary changes are not specific for scleroderma & can be seen
in other connective tissue diseases such as dermatomyositis and mixed connective
tissue disease.

The ACR /EULAR criteria for the classification of systemic sclerosis 2013
Definitions of the SSc classification criteria items.

Item Definition
Skin thickening Skin thickening or hardening not due to scarring after injury, trauma, etc.
Puffy fingers Swollen digits - a diffuse, usually nonpitting increase in soft tissue mass of the digits extending beyond the normal
confines of the joint capsule. Normal digits are tapered distally with the tissues following the contours of the digital bone and
joint structures. Swelling of the digits obliterates these contours. Not due to other reasons such as inflammatory dactylitis.
Finger tip ulcers Ulcers or scars distal to or at the PIP joint not thought to be due to trauma.
or pitting scars Digital pitting scars are depressed areas at digital tips as a result of ischemia, rather than trauma or exogenous causes.
Telangiectasia Telangiectasia(e) in a scleroderma like pattern are round and well demarcated and found on hands, lips, inside of the mouth,
and/or large matt-like telangiectasia(e).
Telangiectasiae are visible macular dilated superficial blood vessels; which collapse upon pressure and fill slowly when pressure is
released; distinguishable from rapidly filling spider angiomas with central arteriole and from dilated superficial vessels.
Abnormal nailfold Enlarged capillaries and/or capillary loss with or without peri-capillary hemorrhages at the nailfold and may be seen on the cuticle.
capillary pattern
PAH Pulmonary arterial hypertension diagnosed by right heart catheterization according to standard definitions.
Interstitial lung Pulmonary fibrosis on HRCT or chest radiograph, most pronounced in the basilar portions of the lungs, or
disease Presence of `Velcro' crackles on auscultation not due to another cause such as congestive heart failure.
Raynaud's Self report or reported by a physician with at least a two-phase color change in finger(s) and often toe(s) consisting of pallor,
phenomenon cyanosis and/or reactive hyperemia in response to cold exposure or emotion; usually one phase is pallor.
Scleroderma Anti-centromere antibody or centromere pattern on antinuclear antibody (ANA) testing; anti-topoisomerase I
specific Ab antibody or anti-RNA polymerase III antibody. Positive according to local laboratory standards.

The ACR diagnostic criteria for scleroderma 1980

➢ Thickened (sclerodermatous) skin changes proximal to the metacarpophalangeal joints (proximal areas include the
face).
Or at least two of the following:
➢ Sclerodactyly.
➢ Digital pitting (residual loss of tissue on the finger pads due to ischemia).
➢ Pulmonary fibrosis (chest radiograph; HRCT)
CREST Criteria
➢ A diagnosis of scleroderma can also be made if the patient has three of the five features of the CREST syndrome
1. Calcinosis 2. Raynaud’s phenomenon
3. Esophageal dysmotility 4.. Sclerodactyly 5. Telangiectasias
Minor criteria:
➢ Patients must have all of the following 3:
1. Definite Raynaud phenomenon.
2. Abnormal nailfold capillary loops.
3. The presence of autoantibodies known to be associated with scleroderma (anticentromere,
antitopoisomerase (Scl-70), and anti-RNA polymerase III).
➢ Patients with minor criteria only are classified as as undifferentiated connective disease with scleroderma
features or early scleroderma or a mild expression of the disease.
 Scleroderma sine sclerosis: Although more than 95% of SSc patients have evidence of skin thickening, a small
proportion will have scleroderma sine sclerosis, characterized by Raynaud’s phenomenon, typical GIT signs and
symptoms, positive autoantibodies, and/or telangiectasias -with prognosis is similar to those with limited
cutaneous SSc.
 Mixed connective tissue disease: features of Systemic lupus erythematosus, Systemic sclerosis, and
Polymyositis in the presence of anti-U1 RNP antibodies.
 Overlap syndrome
✓ Patients have features of more than one of the six classic systemic autoimmune rheumatic diseases
(SLE, SSc, polymyositis [PM], dermatomyositis, rheumatoid arthritis [RA], and SS).
✓ The most common overlap syndromes are polyarthritis, myositis, sicca complex, and hypothyroidism.
✓ Less common are primary biliary cirrhosis, autoimmune hepatitis, vasculitis,rheumatoid arthritis, and
anti-neutrophil cytoplasm antibody (ANCA)-associated pauci-immune glomerulonephritis.

Scleroderma clinical types & classification
Diffuse cutaneous systemic sclerosis Limited cutaneous systemic sclerosis

(dcSSc) (lcSSc)
Skin thickening proximal to the elbows and/or Symmetrical skin thickening limited to the areas
knees in addition to distal extremity involvement
below the elbows and knees and involving the
(truncal skin may also be involved). face/neck
Rapid onset of disease following the appearance
Slowly progressive disease start years after
of Raynaud’s phenomenon the onset of Raynaud’s phenomenon
Significant visceral disease: lungs, heart, Later and less severe development of visceral
gastrointestinal, and/ or kidneys disease & late development of pulmonary
hypertension.
Absence of anticentromere antibodies. Association with anticentromere antibodies
Association with anti-topoisomerase I & Anti-
RNA polymerases
Dilated Capillary loops without dropout Dilated Capillary loops with dropout
Overall poor prognosis, with survival 40% - Relatively good prognosis with survival >70%
60% at 10 years. at 10 years.
Localized scleroderma
➢ Morphea (one or more patches of thickened skin).
➢ Linear scleroderma (a line of thickened skin affecting one or more extremities).
➢ Scleroderma en coup de sabre, which is a distinct subset of linear disease that affects the forehead and face.

❖ Raynaud phenomenon
1. Primary Raynaud phenomenon
2. Systemic lupus erythematosus
3. Vibration-hand syndrome
4. Medication-induced
5. Chemotherapy (eg, cisplatin or bleomycin)
6. Sympathomimetics
7. Thoracic outlet syndrome
8. Cryoglobulinemia/cryofibrinogenemia/cold agglutinins
9. Systemic vasculitis.
10. Chilblains
❖ Skin thickening
1. Scleredema
2. Scleromyxedema
3. POEMS syndrome
4. Eosinophilic fasciitis
5. Graft-versus-host disease
6. Eosinophilia-myalgia syndrome
7. Morphea
8. Nephrogenic fibrosing dermopathy
9. Diabetic cheiroarthropathy
❖ Overlapping clinical features

1. Systemic lupus erythematosus
2. Sjögren syndrome
3. Inflammatory myopathies
4. Rheumatoid arthritis.

❖ The prognosis in scleroderma is highly variable, and survival is influenced by disease
subtype, degree of internal organ involvement, and comorbid conditions.
❖ Prognostic factors that predict poor outcome:

✓ Older age at disease onset.
✓ Diffuse skin disease.
✓ The presence of pulmonary disease (particularly PAH).
✓ Renal or cardiac involvement.
✓ Severe GI failure.
✓ The presence of anemia.


➢ Regular pulmonary function testing.
➢ High resolution computed tomography (CT) of the chest.
➢ Echocardiography for pulmonary arterial hypertension (PAH).
➢ Renal function and blood pressure: serve as prime indicators of scleroderma renal
crisis in early diffuse disease.
➢ Raynaud’s condition score for severity of Raynaud’s phenomenon
➢ Rodnan skin score with a visual analogue scale (VAS) score of the patient’s
assessment of skin activity, a VAS score of the physician’s assessment of skin activity,
and measures obtained by a durometer.
Medsger Systemic Sclerosis Severity Scale


Treatment of scleroderma
Some important principles to keep in mind when treating patients with scleroderma:
❖ No single drug has been found to treat all of the manifestations of scleroderma, so management is
based on the symptoms and disease manifestations of each individual patient and is often organ-
specific.
❖ Each patient with scleroderma is unique with regard to disease features and prognosis
❖ Scleroderma skin disease tends to reach peak involvement over the first 18–24 months, but then
gradually improves.
❖ Routine screening and early intervention for internal organ manifestations may significantly reduce
morbidity and mortality.
❖ Defining the disease subtype and level of disease activity are most important in establishing optimal
management.
A- Skin care:
➢ Frequent topical application of an emollient preparation.
➢ Periodic cleansing with soap and water.
➢ Topical antibiotics for any traumatic skin ulceration.
➢ Physical therapy is important to prevent severe skin and joint contractures and to
help patients with activities of daily living.
➢ Medications:
✓ Methotrexate, Cyclophosphamide& mycophenolate mofetil
✓ Improves skin changes & skin score in early diffuse SSc
➢ For pruritus: Low-dose prednisone (<15 mg/day)

B- Scleroderma Renal Crisis (SRC)

 High risk patients: Scleroderma patients with early diffuse skin changes and
prednisone use and they should have their blood pressure monitored several
times a week.
 ACEI:
✓ ACEI therapy is needed to control blood pressure as quickly as possible, with a
target blood pressure of 130/80 mm Hg or lower.
✓ If blood pressure remains high, patients may require hospitalization for the
management of medications and close monitoring of blood pressure and renal
function.
 Sever resistant cases: ARBs or Calcium channel blockers or a Prostacyclin analogue.
 Prognosis: Despite the current availability of effective therapy and aggressive

management, approximately 40% of patients with SRC have poor outcomes (death
within 6 months or permanent dialysis), likely due to under-recognition of early
symptoms and signs.
 Currently no evidence supports the prophylactic use of ACE inhibitors in

patients with scleroderma who are at risk for SRC.
 Several studies have shown that use of an ACE inhibitor before the onset of SRC
was associated with worse outcome, including higher mortality.
Management of scleroderma renal crisis.

C- Approach to lung disease in scleroderma
Interstitial Lung Disease

➢ The most reliable tool for monitoring ILD over time is serial measurements of FVC.
➢ A decline in FVC of more than 10% from baseline is often indicative of disease activity
and is associated with increased mortality.
➢ Patients who need treatment:
❖ Patients with a restrictive pattern on PFTs.
❖ Patients with interstitial fibrosis on high-resolution CT.
❖ Patients with active Alveolitis: (increased neutrophils or eosinophils on BAL or ground glass
opacities on CT).
➢ Medications:
❖ Treatment with CYC as a daily oral regimen or as monthly IV therapy until control of
disease is achieved(6monthes) & followed by maintenance treatment with AZA or
MMF (immunosuppressive with anti-proliferative effects on inflammatory cells and in particular on activated T
and B lymphocytes)

D- Management of pulmonary HTN
Pulmonary hypertension associated with CTDs

❖ Vasodilator medication which helps in Improving exercise capacity, time to clinical
worsening and haemodynamic parameters in patients with PAH.
A. Prostaglandins
➢ Iloprost (a stable prostacyclin analog)
✓ Dose:(0.5–2 ng/kg/min intravenous infusion) for 3–5 consecutive days.
B. Phosphodiesterase Inhibitors:
➢ Examples: (sildenafil, tadalafil, and vardenafil)
➢ Side effects: Flushing, dyspepsia, diarrhoea, headache and myalgia.
C. Endothelin-Receptor Inhibitors: Bosentan

➢ Endothelin is a potent vasoconstrictor produced by a variety of cells including
endothelial cells, smooth muscle cells, leukocytes & macrophages.
➢ Endothelin receptor antagonist drugs (ie, bosentan) have been developed to
prevent this potent vasoconstriction.
➢ Limited use of bosentan because of its Liver toxicity, availability, and the expense.

E- Management of Gastrointestinal Disease

❖ Upper gastrointestinal symptoms: (Gastroesophageal reflux and esophageal dysmotility)
➢ Important instruction for patients that can reduce the symptoms:
✓ Eat small, frequent meals.
✓ Do not eat meals within 2–3 hours of bedtime.
✓ Keep the head of the bed elevated.
✓ Avoid aggravating factors (eg, tobacco, alcohol, and caffeine).
➢ PPI: (omeprazole 20–40 mg once or twice daily).
➢ Prokinetic (such as metoclopramide): indicated in those with persistent symptoms

& many patients respond to relatively low doses, (at bedtime alone).
➢ Given the increased risk of neurologic complications with the use of metoclopramide,
many clinicians recommend domperidone as a relatively safer alternative when long
term prokinetic treatment is needed.
➢ Upper GIT endoscopy: for patient with severe dysphagia or symptoms

unresponsive to the above measures.
❖ Lower gastrointestinal symptoms: (less frequent but often more difficult to manage)
➢ Avoiding a constipation-diarrhea cycle through
✓ Adequate fiber ingestion.
✓ Over-the-counter preparations (stool softener) such as loperamide.
✓ For sever constipation: periodic doses of osmotic laxatives (polyethyleneglycol)
➢ Antibiotics: Persistent, frequent diarrhea may be a sign of bacterial overgrowth that

requires treatment with antibiotics (eg, metronidazole).

Current Recommendations for Treatment of Scleroderma
Manifestation 1st line therapy Alternative line

Raynaud’s Vasodilators (CCB or PDE5 inhibitors) PDE5 inhibitors,
phenomenon Anti-platelet Prostacyclin
Endothelin antagonists
Hypertensive renal ACE inhibitors ARBs -- CCB,
disease prostacyclin, renal
transplant (wait at least 24 mo)
GI involvement Upper GI EGD to treat stenosis and/or GAVE
Dental/periodontal care, Total parenteral nutrition
lifestyle modifications,
proton pump inhibitors -- prokinetics
Lower GI: Probiotics -- rotational antibiotics

Skin Mycophenolate mofetil -- cyclophosphamide IVIG, ATG,
Research trial (severe cases)
Interstitial lung Mycophenolate mofetil -- cyclophosphamide Research trial
disease
Pulmonary arterial PDE5 inhibitors, Combination therapy,

hypertension Endothelin antagonists, Atrioseptostomy,
Prostacyclin. lung transplant,
Soluble guanylate-cyclase stimulators Research trial
Cardiac involvement Heart failure therapy-- diuretics, CCB Immunosuppression

(myocardial inflammation)
Joints -- Muscles Prednisone,-- methotrexate, IVIG (if contractures and rubs are
TNF inhibitors present),
PT/OT
Psychosocial Anti-depressants, pain control, sleep control Support group

NB NB NB
 Disease onset in elderly individuals is well described; it is uncommon for the disease to become manifest before
the age of 25 years.
 Older age at onset is associated with increased risk for multisystem disease and, in particular, pulmonary
arterial hypertension (PAH).
 A negative antinuclear antibody test makes the diagnosis of scleroderma very unlikely.
 Anticentromere antibodies generally are predictors of a favorable prognosis.
 The presence of anticentromere antibodies can also be seen in patients with primary Sjogren’s syndrome who
do not have scleroderma.
 Anti-RNA polymerase III antibodies are associated with rapid and aggressive diffuse skin disease and renal
involvement.
 These patients have the worst cutaneous involvement, with rapid widespread skin disease associated with signs
and symptoms of deep tissue fibrosis involving joints, tendons, and muscles.
 The most common endocrine problem associated with scleroderma is thyroid disease especially in patients with
limited scleroderma who have CREST syndrome and in those with long-standing disease.
 Flexion contractures of the fingers, wrist, elbows, shoulders, hips, knees, and ankles are complications that can
occur within a few months of onset of disease activity.
 A “fibrosing” myopathy without inflammation, along with skin and joint disease, leads to loss of strength and
flexibility with Significant disability occurs in early stage disease.
 In addition, osteolysis or bony resorption of the tips or tufts of the fingers, middle phalanges, distal radius, and
ulna bones (less commonly, the distal clavicle, ribs, mandible, and distal toes)These tests are
imperative to detect signs and symptoms of new organ-system involvement and to monitor the response or adverse
reactions to therapies.
 D-penicillamine: some early, uncontrolled observations suggested that D-penicillamine may be beneficial.
 Haematopoietic stem cell transplantation (HSCT): *
Role: Improvement of skin involvement and stabilization of lung function in patients with SSc.
 The importance of transforming growth factor beta (TGF-beta) expression in the pathogenesis of scleroderma has
prompted the evaluation of agents that either trap or block TGF-beta.


RISK FACTORS FOR Scleroderma
Genetic Factors
➢ There is increased risk of developing the disease in first degree relatives of a
scleroderma patient higher (2%) than the general population.
➢ Genetic variants associated with scleroderma

A) Major Histocompatibility Complex (MHC) genes: It appears that haplotypes HLA
DRB1*1104, DQA1*0501 & DQB1*0301 are the strongest
B) Non-MHC genes: The protein tyrosine phosphatase nonreceptor 22 (PTPN22),

which has been associated with SLE, myasthenia gravis, vitiligo,and Addison’s
disease
Environmental Agents and Drugs Implicated in Scleroderma-like Syndromes
➢ Infection: viruses such as human cytomegalovirus (hCMV) , parvovirus B19 & EBV
have been implicated as potential triggers for SSc.
➢ Chemicals
• Silica,Heavy metals, Mercury
• Organic chemicals
• Vinyl chloride, Benzene, Trichloroethylene
➢ Drugs: Bleomycin, Pentazocine, Taxol &Cocaine.

➢ Dietary Supplement/Appetite Suppressants
• L-tryptophan (contamination)
• Mazindol , Fenfluramine, Diethylpropion
Pathology
The pathologic hallmarks of SSc are
Vasculopathy- Fibrosis - Autoimmunity
❖ Vasculopathy:
➢ A non-inflammatory proliferative/obliterative vasculopathy affecting
small arteries and arterioles in multiple vascular beds, loss of capillaries
(rarefication).
➢ Vascular injury and activation are the earliest and possibly primary events in the
pathogenesis of SSc.
➢ Vascular damage is present before fibrosis and can be detected in involved and
uninvolved skin, indicating a generalized process.

➢ In late stages of the disease, extensive fibrin deposition and perivascular fibrosis
cause progressive luminal occlusion, and there is striking paucity of small blood
vessels in lesional tissue.
➢ Loss of vascular supply leads to chronic tissue hypoxia.
➢ Vasculopathy is responsible for Raynaud’s phenomenon, scleroderma renal crisis,
and pulmonary artery hypertension.
➢ The organs most prominently affected by obliterative vasculopathy are the
heart, lungs, kidneys, and intestinal tract.
➢ Scleroderma renal crisis: There is intimal hyperplasia and vasospasm of cortical arteries ,which
leads to activation of the renin-angiotensin system and accelerated hypertension.
❖ Fibrosis
➢ Fibrosis is characterized by accumulation of excessive amounts of type I
collagen and other fibrillar collagens, fibronectin, elastin, proteoglycans, and other
connective tissue molecules in the extracellular matrix (ECM).
➢ In SSc, interstitial and vascular fibrosis in the skin and parenchymal organs
contributes directly to their progressive dysfunction and eventual failure.
➢ Fibrosis is responsible for thickened skin, pulmonary parenchymal disease, and

gastrointestinal dysmotility.
➢ The organs most prominently affected by Fibrosis the skin, lungs,
gastrointestinal tract, heart, tendon sheath, perifascicular tissue
surrounding skeletal muscle, and in some endocrine organs, such as the thyroid
gland.
❖ Autoimmunity
➢ Inflammatory cell accumulation is generally absent in long-standing SSc but may be
prominent in patients with early-stage disease.
➢ Infiltrates are located predominantly around blood vessels and are composed
primarily of CD4+ T lymphocytes, dendritic cells (DCs), and
monocytes/macrophages.
➢ T-Cell abnormalities:
✓ predominantly CD4+T cells and express the activation marker class II MHC
antigen DR.
✓ An altered balance between T helper type 1 (Th1) and T helper type 2 (Th2)
cytokines in aberrant response to tissue injury.
✓ T cells polarized to a Th2 pattern secrete abundant IL-4, IL-5, and IL-13.
✓ The Th2 cytokines are profibrogenic because they can directly stimulate collagen
synthesis and myofibroblast trans-differentiation, and induce TGF-β, a powerful
modulator of immunoregulation and ECM accumulation.
➢ Transforming growth factor beta (TGFβ),:

✓ TGFβ produced by activated lymphocytes and monocytes, plays a crucial role in
SSc related fibrosis:
▪ It stimulates the extracellular matrix synthesis.
▪ Decreases the production of collagen degrading metalloproteinases
▪ Stimulates the production of protease inhibitors (as tissue inhibitor of
metalloproteinases-1), which prevent break-down of the extracellular matrix.
Vasculopathy
✓ An initial vascular insult results in endothelial cell (EC) injury and activation, with reversible functional changes,
increased expression of adhesion molecules, and enhanced leukocyte diapedesis resulting in perivascular
inflammation.
✓ Damaged endothelium promotes platelet aggregation and thrombin release and shows impaired production of
vasodilators such as nitric oxide (NO), increased production of vasoconstrictors such as endothelin-1 (ET-1), and
release of reactive oxygen species (ROS).
✓ Consequent vasoconstriction and defective vasodilation aggravate vascular damage, leading to irreversible and
progressive vascular wall remodeling, luminal occlusion, platelet aggregation, in situ thrombosis, and tissue
hypoxia. Loss of blood vessels may be further compounded by insufficient vasculogenesis.

Fibrosis
✓ Fibrosis is the end result of immune dysregulation and vascular damage and hypoxia.
✓ Injury causes vascular damage, perivascular inflammation, and innate immune signaling, with
oxidative stress, secretion of inflammatory and fibrogenic cytokines and chemokines,
autoantibodies, fibroblast activation, and myofibroblast accumulation.
✓ Circulating mesenchymal progenitor cells traffic to and accumulate within the lesional tissue and
transdifferentiate into fibrotic fibroblasts, accelerating matrix accumulation.
✓ Tissue hypoxia, matrix remodeling, and stiffness further contribute to fibroblast activation, which
causes disruption of tissue architecture and organ failure.

Autoimmunity
✓ An inciting event such as infection, oxidative damage, necrotic/apoptotic cell debris, or environmental
toxins causes activation of dendritic cells, possibly via Toll-like receptors (TLRs).
✓ Activated dendritic cells produce type I interferon (IFN), which causes T helper (Th)2 T cell polarization,
monocyte differentiation to an alternately activated (M2) phenotype, and B cell activation with plasma cell
maturation and production of autoantibodies.
✓ Autoantibodies form immune complexes that in turn further induce type I IFN production via TLR signaling.
Th2-polarized T cells and M2 macrophages secrete profibrotic chemokines and cytokines, inducing
fibroblast activation.
✓ Additional T cell subsets such as regulatory T cells and Th17 also may be involved.The production of
TGFβ is consistently upregulated in SSc, maintaining fibroblasts from SSc patients in an activated state.
✓ SSc fibroblasts on the other hand express increased number of TGFβ receptors, enhancing collagen
production.


Mustafa Elmenawy
Basic
Rheumatology
Raynaud phenomenon
Raynaud phenomenon
Definition: Raynaud phenomenon (RP) is an exaggerated response to cold
temperatures that results in transient digital ischemia.
Epidemiology:
• Age & Sex: It is most common in females with an age of onset between 15 and 30
years.
• Prevalence: RP occurs in 3% to 15% of the general population.
Raynauds clinical types & classification

➢ Primary RP
Occurs in the absence of any associated disease or definable cause (it is nearly an exaggeration
of normal physiologic responses to cold environmental temperatures or emotional stress or both, rather than a disease).
➢ Secondary RP
✓ It is associated with an underlying pathologic condition or disease that alters
regional blood flow through one or all of the following:
• Damaging blood vessels.
• Interfering with neural control of the circulation.
• Changing either the physical properties of the blood or the levels of
circulating mediators that regulate the digital and cutaneous circulation.
✓ The most common causes of secondary RP are:

• Scleroderma.
• Systemic lupus erythematosus.
• Other connective tissue disorders.
Pathophysiology
❖ When humans are exposed to cold temperatures, the body will sacrifice the viability of peripheral tissues by shifting
blood flow from the skin and other organs to maintain a stable core body temperature.
❖ A unique circulatory system exists in the skin, especially in the hands, feet, and areas of the face that includes both
thermoregulatory and nutritional blood vessels. In these areas of the body, local blood flow is regulated by a complex
interaction of neural signals, cellular mediators, and circulating vasoactive molecules.
❖ Temperature responses are principally mediated through the sympathetic nervous system by rapidly altering blood flow
through arteriovenous shunts in the skin.
❖ During hot weather, these shunts open (vasodilate), allowing heat to dissipate.
❖ In cool weather, the shunts constrict, shifting blood centrally and helping maintain a stable core body temperature.
Raynaud phenomenon 241

❖ Mechanism of RP:
✓ The vasoconstriction of digital arteries, precapillary arterioles, and cutaneous arteriovenous shunts leads to a
sharp demarcation of skin pallor and cyanosis of the digits (as a result of the deoxygenation of sluggish venous
blood flow).
✓ This ischemic phase is followed by recovery of blood flow that appears as cutaneous erythema, secondary to rapid
reperfusion of the digits.
Clinical Findings
➢ Risk factors: Stress and cold temperatures induce an exaggerated
vasoconstriction of the small arteries, arterioles, and arteriovenous shunts of the skin
of the digits.
➢ Sites:
✓ The fingers are most commonly affected.
✓ Attacks also occur in the toes and areas of the face.
➢ Presented clinically by:
✓ Sudden onset of cold digits associated with Pallor(white) and cyanosis(blue)
followed by a reactive hyperemia (Erythema) after rewarming.
✓ RP attacks typically begin in a single finger and then spread to other digits of the
same or both hands. (middle three fingers are the most commonly involved digits).
✓ In Patients with secondary RP the attack usually accompanied by pain, digital

ischemia, fingertip ulceration, and tissue necrosis (due to secondary processes causing direct
vessel damage).
Clinical Features suggest primary Raynaud Phenomenon

1. Symmetric intermittent RP attacks. 2. Normal nailfold capillary microscopy.
3. No evidence of peripheral vascular disease - tissue gangrene or digital pitting.
4. No Lab. abnormality (Negative antinuclear antibody test and normal ESR)
Clinical Features suggest Secondary Raynaud Phenomenon

1. Male sex. 2. Age of onset >40 years
3. Pain associated with attacks 4. Asymmetry of digits affected.
5. Signs of tissue ischemia (digital ulcerations)
6. Signs or symptoms of other diseases (rheumatic endocrine, etc)
7. Abnormal laboratory tests (positive antinuclear antibodies, cryoglobulins)
Findings would suggest early SSc with new onset RP:

1. Positive nucleolar staining ANA, anticentromere, or anti-Scl-70 antibody.
2. Nailfold capillary abnormalities of capillary drop out or dilatation.
3. Tendon friction rubs.
4. Digital edema or puffy hands.
5. Dilated, patulous esophagus (esophageal hypomotility)

Approach for diagnosis of RP

❖ Examination:
➢ All patients with a history of RP should be asked about symptoms suggestive of an
autoimmune disease, such as:
 Dry eyes or mouth (Sjögren syndrome).
 Painful joints or morning stiffness (arthritis).
 Rashes, photosensitivity, or cardiopulmonary abnormalities (SLE)
 Skin tightening, respiratory distress, or gastrointestinal disease (scleroderma).
➢ Careful examination for signs of a secondary process should include:

✓ Examination of the pulses.
✓ Auscultation over large arteries.
✓ Examination for evidence of tissue ischemia or inflammatory skin lesions.
✓ Nailfold capillary microscopy.
❖ Laboratory Findings
➢ Primary RP:
✓ Patients who are young when symptoms begin with a normal history and
physical examination, can be considered to have primary RP.
✓ These patients can be monitored clinically, and no further laboratory testing
is needed.
➢ Secondary RP: If a secondary cause of RP is suspected, appropriate testing is
recommended, including:
✓ ESR & CRP.
✓ CBC.
✓ ANA.
✓ Anticentromere antibodies: strongly associated with limited scleroderma
(CREST syndrome)
✓ Serum chemistries.
✓ Thyroid function tests.
✓ Serum and urine protein electrophoresis.
✓ Testing for cryoglobulins or cryofibrinogens.
➢ Nailfold capillary Examination:

▪ Normally: the nailfold capillaries should be thin, linear, and uniform.
▪ In patients with 2ry Raynauds:
➢ Early disease: Capillary dilation (giant capillaries), microhemorrhages,
and some disorganization of the capillary network are typical of early disease.
➢ Later stages: Capillary dropouts, avascular areas, and signs of
neoangiogenesis disorganized capillaries.
▪ Method:
✓ To examine the nailfold capillaries, a drop of either microscope oil or
lubricant jelly is placed on the nail bed.
✓ An ophthalmoscope, set at minus 20–40 diopters (40 green) is used as a
microscope to visualize the capillaries.

Approach for diagnosis of Raynaud’s phenomenon

❖ The diagnosis of RP is clinical, based on a patient's report of sudden, episodic color
changes of the digits provoked by cold temperature or emotional stress.
➢ Acrocyanosis:
✓ It is a condition seen when the patient has cold hands and feet with persistently
cyanotic skin.
✓ Acrocyanosis is aggravated by cold temperatures but there are none of the episodic
attacks or sharp demarcations of color changes observed in RP.
➢ Worker on vibratory machines:

✓ Repeated mechanical stress on the nerves or vessels in the hand or fingers may
also cause sensitivity to the cold temperature.
✓ Use of tools that vibrate, carpal tunnel syndrome, or neuropathy should be
considered in a patient who complains of color changes of the hands and
numbness with or without sensitivity to the cold.
➢ Hyperviscosity syndromes:
✓ Hyperviscosity syndromes should also be considered in the differential diagnosis.
RP in these patients results from sluggish blood flow through cutaneous and
digital vessels.
✓ Patients may also have cold-sensitive proteins; RP is common among patients
with cryoglobulinemia.
Secondary Causes of Raynaud Phenomenon

❖ Rheumatologic ❖ Hematologic disorders
✓ Systemic sclerosis (scleroderma) ✓ Cryoglobulinemia
✓ Systemic lupus erythematosus ✓ Paraproteinemia
✓ Rheumatoid arthritis ✓ Polycythemia
✓ Sjögren syndrome ✓ Cold agglutinins
✓ Polymyositis---- Vasculitis
❖ Mechanical ❖ Endocrine disorders
✓ Vibration injury ✓ Hypothyroidism
✓ Frostbite ✓ Carcinoid syndrome
✓ Thoracic outlet syndrome ✓ Pheochromocytoma
✓ Vascular embolus or occlusion
❖ Drugs
✓ Sympathomimetic drugs (decongestants, diet pills)
✓ Serotonin agonists (sumatriptan)
✓ Chemotherapeutic agents (bleomycin, cisplatin, carboplatin, vinblastine)
✓ Ergotamine tartrate – Caffeine - Nicotin

Treatment of Raynaud’s phenomenon

❖ Preventive Strategies
 Keeping the hands and feet warm: (wearing several layers of loose-fitting clothing, gloves, stockings, and
headwear in cold temperatures is very important).
 Avoidance of:
➢ Cold temperatures, damp windy weather.
➢ Rapid shifts in temperature.
➢ Medications that have the potential to vasoconstrict the peripheral arteries:
✓ Sympathomimetic drugs
✓ Serotonin agonists.
✓ Clonidine and narcotics
✓ Macrolide antibiotics and protease inhibitors.
➢ Smoking: because nicotine reduces cutaneous and digital blood flow.
❖ Vasodilator Therapy
➢ Medications are indicated in the treatment of RP if:
✓ There are signs of critical tissue ischemia (eg, digital ulcers).
✓ The quality of life of the patient is affected to the degree that normal functions
are restricted.
➢ Medication are used to reduces the frequency and severity of attacks by improving
digital blood flow
A. Calcium Channel Blockers (reduces the frequency and severity of attacks by about one-third).
➢ CCB are the most popular pharmacologic treatment for RP (especially in the patients with primary RP).
➢ In general, no medication has proved to be more effective or safer than the calcium channel blockers.
➢ Slow-release preparations are preferred because they are as effective and safer than the rapid-release
medications.
➢ If one calcium channel blocker is ineffective, another calcium channel blocker may be tried.
➢ There is no evidence that combinations of calcium channel blockers are better than a single drug.
➢ Examples:
• Amlodipine (Regcor) 5–20 mg/d
• Nifedipine (Epilat) 10-30mg/d
➢ Currently, amlodipine is preferred over nifedipine because amlodipine
exerts less negative inotropy on the heart.
➢ SE: The most significant side effects from CCB are:
✓ Headache, hypotension & tachycardia.
✓ Lower extremity edema.
B. Angiotensin-Converting Enzyme Inhibitors

➢ Improve digital blood flow by increasing kinins and causing vasodilation.

C. Prostaglandins
➢ Prostacyclin are vasodilators used in the treatment of severe cases of RP (secondary
to scleroderma or with digital ulcers).
➢ Iloprost (a stable prostacyclin analog)
✓ Dose:(0.5–2 ng/kg/min intravenous infusion) for 3–5 consecutive days.
✓ Provide relief for several weeks following treatment & help in healing digital
ulcers.
D. Phosphodiesterase Inhibitors:
➢ Phosphodiesterase type 5 inhibitors reduce the severity and frequency of RP and
improve healing of digital ulcers.
➢ Examples: (sildenafil, tadalafil, and vardenafil)
➢ Side effects: Flushing, dyspepsia, diarrhoea, headache and myalgia.
E. Endothelin-Receptor Inhibitors: Bosentan

➢ Endothelin is a potent vasoconstrictor produced by a variety of cells including
endothelial cells, smooth muscle cells, leukocytes & macrophages.
➢ Endothelin receptor antagonist drugs (ie, bosentan) have been developed to
prevent this potent vasoconstriction.
➢ Indicated in patients with multiple digital ulcers despite use of CCB, PDE-5
inhibitors or iloprost therapy.
➢ Currently, bosentan is used for the treatment of pulmonary hypertension.
➢ Limited use of bosentan because of its Liver toxicity, availability, and the expense.
F. Sympatholytic Agents:
➢ Sympathetic adrenergic stimulation, particularly 2-adrenergic receptors on the
digital arteries, play an important role in control of digital blood flow.
➢ Therefore, in severe RP block sympathetic tone in the hope of inducing
vasodilation of digital vessels.
➢ Sympatholytic agents may be helpful in the treatment of RP, but the vasodilation
lessens over time and side effects are often intolerable.
❖ Sympathectomy:
➢ Mechanism: surgical sympathectomy is used to ligate the sympathetic nerves
that cause vasoconstriction.
➢ Procedures: Both proximal (cervical) and localized (digital) sympathectomy can be
used in the treatment of RP.
➢ Indication: the procedure is limited to patients with severe RP, especially those who
are in an active ischemic crisis and are not responding to medical management.
➢ SE: A proximal sympathectomy may not be fully effective and this procedure is
associated with significant risks including neuralgia, Horner syndrome, and decreased
localized sweating. Therefore a localized digital sympathectomy is the preferred
procedure.
➢ Most of the available evidence shows that RP attacks recur several weeks to months
following either proximal or digital sympathectomy.
Approach for Treatment of Raynaud’s phenomenon
NB
❖ An exaggerated response to cold temperatures that results in transient

digital ischemia.
❖ Complications of digital tissue ischemia may occur in patients with
secondary Raynaud phenomenon, leading to recurrent digital ulcerations,
rapid deep tissue necrosis, and amputation.
❖ Avoidance of cold temperatures is crucial to the management of Raynaud
phenomenon. The entire body must be kept comfortably warm.
❖ Medications are indicated if there are signs of critical tissue ischemia
(eg, digital ulcers) or if the quality of life of the patient is so
affected that normal function is restricted.
❖ If a patient meets criteria for primary RP and no new symptoms develop
over 2 years of follow-up, the development of secondary disease is
unlikely.
❖ The presence of abnormal nailfold capillaries on microscopy is the best
predictor of secondary RP.

Mustafa Elmenawy
Basic
Rheumatology
Vasculitis
Vasculitis
➢ The vasculitis are a group of complex disorders characterized by inflammation of blood
vessel walls that can lead to ischemia and organ damage.
➢ A vasculitis is considered primary when no underlying etiology such as infection,

connective tissue disease, drugs, or malignancy has been identified, and secondary
when the vasculitis is considered a consequence of one of these comorbidities or
exposures.
CLASSIFECATIONS:
Chapel Hill Consensus Conference 2012 classification

1. Large Vessel Vasculitis 5. Single-Organ Vasculitis
✓ Giant cell arteritis. ✓ Cutaneous leukocytoclastic
angiitis
✓ Takayasu’s arteritis ✓ Cutaneous arteritis
✓ Primary CNS vasculitis
✓ Isolated aortitis
2. Medium Vessel Vasculitis 6. Vasculitis Associated with
Systemic Disease
✓ Classical PAN.
✓ Lupus vasculitis
✓ Rheumatoid vasculitis
✓ Kawasaki disease
✓ Sarcoid vasculitis
✓ Others (e.g., IgG4-related aortitis)
3. Small-Vessel Vasculitis 7. Vasculitis Associated with
➢ Anti-neutrophil Cytoplasmic Antibody– Probable Etiology
Associated Vasculitis ✓ HCV–associated cryoglobulinemic
vasculitis
✓ Microscopic polyangiitis
✓ HBV–associated vasculitis
✓ Granulomatosis with polyangiitis ✓ Syphilis-associated aortitis
✓ Eosinophilic granulomatosis with polyangiitis ✓ Drug-associated immune complex
➢ Immune Complex Small Vessel Vasculitis vasculitis
✓ Anti-glomerular basement membrane disease ✓ Drug-associated ANCA-
✓ Cryoglobulinemic vasculitis associated vasculitis
✓ IgA vasculitis (Henoch-Schِnlein purpura) ✓ Cancer
✓ Hypocomplementemic urticarial vasculitis
4. Variable Vessel Vasculitis

✓ Behçet’s disease
✓ Cogan’s syndrome
VASCULITIS 249
➢ Large generally denotes the aorta and its major branches (and the corresponding vessels in the venous circulation in some
forms of vasculitis, e.g., Behçet’s disease).
➢ Medium refers to vessels that are smaller than the major aortic branches yet still large enough to contain four elements: (1)
an intima, (2) a continuous internal elastic lamina, (3) a muscular media, and (4) an adventitia.
➢ Small-vessel vasculitis, which incorporates all vessels below macroscopic disease, includes capillaries, postcapillary
venules, and arterioles.
VASCULITIS 250
Typical Clinical Manifestations of Large-Medium- Small-Vessel Involvement by Vasculitis

Large Medium Small
• Limb claudication (Fatigue & • Cutaneous nodules • Purpura - Urticaria
Discomfort) • Ulcers • Vesiculobullous lesions
• Asymmetric blood pressures • Livedo reticularis • Glomerulonephritis
• Absence of pulses • Digital gangrene • Alveolar hemorrhage
• Bruits • Mononeuritis multiplex • Cutaneous extravascular
• Aortic dilation • Microaneurysms necrotizing granulomas
• Renovascular hypertension • Renovascular hypertension • Splinter hemorrhages
• Uveitis/episcleritis/scleritis
General Clinical Features Suggesting Vasculitis

➢ Vasculitis can result in clinical syndromes that vary in severity from a minor self-limited
rash to a life-threatening multisystem disorder. (Depending on the size, distribution, and severity of the
affected vessels)
➢ Subacute onset: Usually manifestations builds over weeks or months (patients with vasculitis will
struggle to define the month or the season in which their nonspecific symptoms accumulated sufficiently to become
memorable).
1- Constitutional symptoms :
▪ Fatigue, Fever& Sweat.
▪ Loss of weight & Loss of appetite.
▪ Arthralgia & Myalgia.
2- Pain: Originate from many different sources, such as arthritis; myalgia; or infarction
of a digit, nerve, bowel, or testicle.
3- Laboratory finding :
✓ A markedly elevated ESR.
✓ Anemia of chronic disease.
4- Specific Organ affection :
➢ Skin  Livedo reticularis, palpable purpura, nodules, ulcers, gangrene
➢ Peripheral nervous  Mononeuritis multiplex, polyneuropathy

system
➢ CNS  Stroke, seizure, encephalopathy
➢ Kidney  Hypertension, proteinuria, hematuria, renal failure
➢ Heart  Myocardial infarction, cardiomyopathy, pericarditis, arrhythmia
➢ Lung  Cough, chest pain, hemoptysis,Dyspnea.

➢ Eyes  Blindness, scleritis
➢ Gastrointestinal tract  Pain, bleeding, perforation
VASCULITIS 251
Work up for suspected Case of Vasculitis
Common Laboratory Tests in Vasculitis

Test Result Disease Association
➢ ESR • Usually high, especially in giant cell arteritis
➢ Creatinine • Elevated by renal forms of vasculitis
➢ Urinalysis • Often abnormal, red blood cell casts caused by
vasculitis of the glomeruli
➢ Viral markers • HCV - HBV
➢ Serum cryoglobulins • Present in cryoglobulinemia
➢ Complement levels • Low in SLE, cryoglobulinemia
➢ Immunoelectrophoresis • Monoclonal gammopathies common in hepatitis C-
related vasculitis
➢ Antineutrophil cytoplasmic • Positive in WG, MPA, Churg-Strauss syndrome
antibodies
➢ Specific Tests:
➢ Biopsy of involved tissues is the most common method for establishing definitively
the diagnosis of vasculitis.
➢ Skin, peripheral nerves, airways, arteries, kidney, and gut are the most commonly
sampled tissues.
VASCULITIS 252
Giant cell arteritis

Definition: Granulomatous arteritis of the aorta and its major branches with a predilection
of the extracranial branches of the carotid artery (mostly involves the temporal artery).
Epidemiology:
• Age of onset: Usually occur in pts over 50 (the mean age at onset of GCA and PMR is approximately
79 years, with a range of approximately 50 to 90 years of age)
• Incidence: GCA is the most common form of systemic vasculitis in
adults. and often associated with PMR.
Pathogenesis
➢ Infiltration of blood vessels by macrophages
and T Cells, undergo granulomatous
organization and form giant cells: intimial
hyperplasia & lumen occlusion with activation of
dendritic cells in response to antigen.
➢ T helper 1 and T helper 17 will secret
interferon gamma& inteleukin 17
➢ The adventitia is also infiltrated with
macrophages that secrete IL-1, IL-6, and
transforming growth factor (TGF)-β. The media
is populated mostly by macrophages that, in
contrast to those in other layers, produce matrix
metalloproteinases and oxygen-free radicals.
➢ Production of matrix metalloproteinases and
lipid peroxidation agents by macrophages in the
media results in the destruction of elastic
laminae.
➢ The vessel attempts to counter the tissue destruction by elaborating a variety of growth
factors including PDGF, vascular endothelial growth factor (VEGF), and TGF-β, which
prompt smooth muscle cells in the media to revert from a contractile phenotype to a
secretory one and migrate to the intima.
➢ Proliferation of the intimal smooth muscle cells results in occlusion of the lumen.
VASCULITIS 253
Clinical Findings
A- Headach:
✓ Described as a dull, aching pain of moderate severity, localized over the temporal area
✓ Patients usually describe tenderness of the scalp, especially when they comb or brush
their hair.
B- Jaw Claudication: (The most specific symptom for GCA)

✓ Pain in the masseter muscles associated with protracted chewing (vasculitis of its blood
supply).
✓ Typically noticed when eating foods that requires vigorous chewing.
✓ Detection of jaw claudication may be increased by “the chewing gum test” in
which jaw discomfort is provoked by the patient chewing gum at a rate of one chew
per second for 2-3 minutes.
C- Visual Symptoms:(About 1/3 of patients present with visual symptoms, chiefly diplopia or visual loss).
✓ Visual loss is the most feared complication of GCA because it is usually
irreversible.
✓ The direct cause of visual loss in GCA is usually occlusion of the posterior ciliary artery
supplies blood to the optic nerve head.
✓ Usually preceded by episodes of blurred vision or amaurosis fugax (but visual loss can
develop abruptly).
D- Abnormal temporal artery (Develops in 50% of pts):
✓ The temporal artery may be enlarged, difficult to compress, nodular or pulsless.
✓ Decreased pulse or unequal arm blood pressures or bruits in about 15 – 20 % of
patient (due to axillary or subclavian disease).
E- Constitutional symptoms:
F- Atypical manifestations: (Approximately affect 40% of patients)

▪ Fever of Unknown Origin (40% of patients) ▪ Tumor-like lesions
associated with rigors and sweats. ✓ Breast mass
✓ Ovarian and uterine mass
▪ Respiratory (10% of patients). ▪ Neurologic:
✓ Dry cough may reflect inflammation ✓ Mononeuritis multiplex most commonly
within the arteries adjacent to cough affects the shoulder, producing sudden
centers. weakness and pain that mimics a C5
✓ Tongue & dental pain- pain - glossitis. radiculopathy.
✓ Stroke – TIAs – dementia –
hallucinations.
VASCULITIS 254
▪ Large artery disease (25% of patients):

✓ The most commonly affected vessels include the vertebral, carotid, subclavian, and axillary
arteries, and the aorta.
✓ Presenting symptoms includes transient ischemic attack, cerebrovascular accident,
hand ischemia, and arm or leg claudication.
✓ Thoracic aortic aneurysm develops an average of 7 years after the diagnosis of
GCA.
▪ Others:
✓ Myocardial infarction-Microangiopathic hemolytic anemia
Work Up
➢ Laboratory:
➢ ESR: highly elevated especially in the presence of PMR.
➢ CRP: elevated.
➢ CBC: Normochromic normocytic anemia
➢ An increased alkaline phosphatase level in 1/3 of patients.
➢ Radiology:
➢ Color duplex ultrasonography: show a characteristic "halo" of edema or stenosis of
the temporal artery.
➢ MR angiography or CT angiography can assess larger-artery disease (Patients who have
signs of subclavian and axillary disease manifested by arm claudication, unequal arm blood pressures, and supraclavicular or
axillary bruits).
➢ Positron emission tomography scanning can demonstrate occult large-vessel
inflammation.
➢ Biopsy:
➢ Temporal artery biopsy is the “gold standard” for diagnosing GCA (the sensitivity of
temporal artery biopsy is approximately 90% to 95%).
➢ Because GCA does not involve the artery in a continuous fashion, temporal artery
biopsy should be directed to the symptomatic side, if evident.
ACR criteria for the classification of Giant Cell Arteritis:

Sensitivity 93.5% - Specificity 91%.
➢ Age at onset > 50 years: Development of symptoms or findings beginning aged 50 years or
older.
➢ New headache: New onset of, or new type of, localized pains in the head.
➢ Temporal artery abnormality: Temporal artery tenderness to palpation or decreased
pulsation, unrelated to atherosclerosis of cervical arteries.
➢ Increase ESR: ESR > 50mm/h by Westergren method.
➢ Abnormal artery biopsy: Biopsy specimen with artery showing Vasculitis characterized by a
predominance of mononuclear infiltration or granulomatous inflammation.
The presence of any 3 or more criteria makes the diagnosis
VASCULITIS 255
TREATMENT:
➢ Oral glucocorticiodes :
➢ Start Prednisone (40–60 mg/d) in any pts with strong suspicion of GCA to prevent
loss of vision.
➢ The initial effective dose of prednisone should be continued until all reversible
symptoms, signs, and laboratory abnormalities have reverted to normal (usually takes 2 to
4 weeks).
➢ Tapering: the dose can be gradually reduced by a maximum of 10% of the total dose
each week or every 2 weeks.
➢ Maintenance: Most patients with GCA have a chronic disease that requires
prednisone treatment for at least 1 year and often for several years.
➢ Because vision loss is almost always permanent, initiate corticosteroid therapy as
early as possible, even before the biopsy is performed (temporal artery biopsy is not altered by
corticosteroid therapy for at least 2 weeks).
➢ High-dose intravenous methylprednisolone :

➢ (1000 mg/d) for 3–5 days for pts with suspected GCA who have experienced
transient visual loss for a few hours.
➢ Visual loss of more than 1 day's duration is almost always permanent (however
recovery is recorded in some pts).
➢ Asprin: From 81- 325 mg/d reduces the risk of blindness and stroke.
➢ MXT:The best gulucocorticoides sparing drug for GCA (10-15mg orally/weekly).
➢ Tocilizumab: In 2017 a humanized monoclonal anti-IL6receptor antibody (Tocilizumab),

was approved for GCA.
Optic disc in fundoscopic exam :

➢ In the first few hours after infarction: the disc appears
normal even in the presence of profound visual loss.
➢ Later:- disc pallor and swelling, cotton-wool spots, and
flame-shaped intraretinal hemorrhages .
➢ Over weeks or months, the disc becomes atrophic.
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Polymyalgia Rheumatica (PMR)

➢ PMR is defined as pain and stiffness in the neck, shoulders, and hip-girdle area that are usually much worse in the
morning.
➢ Between 30% and 50% of patients with GCA develop PMR.
➢ Approximately 10% to 15% of patients who appear to have only PMR have positive temporal artery biopsies.
➢ In the absence of symptoms of GCA (e.g.headache, jaw claudication, visual symptoms, high fever), PMR by itself does
not appear to cause vision loss and responds to low doses of glucocorticoids.
➢ Criteria to diagnose PMR 1984:
1. Age >50 years.
2. Aching and stiffness for at least 1 month, affecting at least two of the three above-mentioned areas (ie,
shoulders, neck, and pelvic girdle)
3. Morning stiffness lasting at least 1 hour.
4. ESR >40 mm/h
5. Exclusion of other diseases except GCA.
6. Rapid response to prednisone (20 mg/d).
➢ Treatment of PMR:
✓ Patients with PMR (without symptoms or signs or biopsy evidence of GCA) are usually treated initially
with prednisone 10 to 20 mg/day or equivalent.
✓ Once the symptoms, signs, and laboratory abnormalities of PMR have resolved (usually after 2 to 3 weeks of
therapy), the daily dose of prednisone can be slowly tapered.
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Takayasu Arteritis
Definition: Granulomatous arteritis of the aorta and its major branches.
Epidemiology:
• Age of onset: Usually occur in pts younger than 50 (The median patient age at onset is 25 years)
• Incidence: it occurs most commonly in Japan, China, India, Southeast Asia &
Mexico (Whereas the incidence of TA in Japan is nearly 150 per million per year, it is only 0.2 to 2.6 per million in
Western Europe and North America).
Pathogenesis
➢ TA is thought to result from an autoimmune panarteritis (granulomatous inflammation affecting all
layers of the vessel) that targets large elastic-containing arteries.
➢ The inflammatory injury mediated by activated T cells, macrophages, and cytokines
results in proliferation of the intima and of smooth muscle cells in the media, leading to
occlusion and stenosis of the artery.
➢ Overproduction of inflammatory cytokines, such as interleukin-6, results in fever and
other constitutional symptoms.
➢ The late phase of TA, similar to that of GCA, is characterized by intima proliferation
with superimposed atherosclerosis,medial necrosis with scarring, and adventitial
fibrosis.
➢ The inflammatory involvement in TA can be continuous or segmental, with skip areas of
normal vessel interposed between involved areas.
➢ Most patients with TA possess anti-endothelial cell antibodies that can damage vessels
by inducing endothelial inflammatory cytokine production, adhesion molecules, and
apoptosis.
Clinical Findings
A. Vascular manefistations :
1. Bruit: 80%
✓ Frequently over the carotid arteries, but also often develop in the supraclavicular
space (reflecting subclavian disease), along the flexor surface of the upper arm (from axillary
artery disease), or in the abdomen (from renal or mesenteric artery vasculitis).
2. Claudication: 50%
✓ Manifested in young women by fatigue and pain in the arm while exercising or
blow-drying hair.
✓ Upper extremity claudication more than lower extremity claudication
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3. Bl. Pressure: Unequal arm blood pressures & Hypertension

4. Pulse: widened pulse pressure
5. Carotodynia
6. Aortic regurgitation.
B. Constitutional symptoms:
C. Systemic manifestations:
▪ Cardiac (35% of patients): Visual abnormality: (Rare)
✓ Angina (vasculitis of the coronary arteries). ✓ When present, visual symptoms chiefly result from
✓ Myocarditis. retinal ischemia produced by narrowing or
✓ Congestive HF occlusion of the carotid arteries.
▪ Neurologic: ▪ Respiratory (3% of patients).

✓ LIGHT headness. ✓ dyspnea – chest pain.
✓ Stroke – TIAs – dementia.
✓ TA rarely causes peripheral neuropathies.
▪ Cutaneous manifestations (Less than 10% patients)
✓ Erythema nodosum is most common, but purpura, livedo reticularis, and
ulceration may rarely occur.
Work Up
➢ Laboratory:
➢ ESR & CRP: elevated.
➢ CBC: - Normochromic normocytic anemia.
- Thrombocytosis (in 1/3 of patients) is often mild but may exceed 800,000/L.
➢ Renal abnormalities (usually result from hypertension).

✓ An elevated serum creatinine (Fewer than 10% of patients).
✓ Mild proteinuria or hematuria (1/4 of patients).
➢ Radiology:
➢ The earliest detectable abnormality in TA is thickening of the vessel wall
from inflammation
➢ MRI & Color duplex ultrasonography: most sensitive& non-Invasive (can detect the
inflammatory thickening of the aorta or its branches that precedes changes in the caliber of the vessels' lumen).
➢ Conventional angiography: gold standard for diagnosis of TA
✓ Invasive and provides the least sensitive method for visualizing wall thickness
✓ Detect stenoses (80%), occlusions, dilatation, and other vascular wall
irregularities characteristic of Takayasu arteritis.
➢ Biopsy: Of aorta and other affected artries show granulomatous vasculitis with giant cells
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ACR criteria for the classification of TAKAYASU Arteritis:

Sensitivity 91% - Specificity 98%.
➢ Age at onset ≤ 40 years:
➢ Claudication of extremities: Development and worsening of fatigue and discomfort in muscles of
one or more extremity while in use, especially the upper extremities
➢ Decreased brachial artery pulse.
➢ BP difference >10 mm Hg (in systolic blood pressure between arms)
➢ Bruit over subclavian arteries or aorta
➢ Arteriogram abnormality: narrowing or occlusion of the entire aorta, its primary branches, or
large arteries in the proximal upper or lower extremities, not due to
arteriosclerosis,fibromuscular dysplasia, or similar causes; changes usually focal or segmental.
Criteria for active disease include new onset or worsening of two or more of the following:
1. Fever or other systemic features (in the absence of other cause)
2. Elevated ESR.
3. Symptoms or signs of vascular ischemia or inflammation (e.g., claudication, absent pulse, and carotidynia)
4. Typical angiographic lesions.
TREATMENT:
20% of TA patients have a self-limited disease but the rest have a relapsing-remitting or progressive course requiring
chronic corticosteroid and/or immunosuppressive therapy.
➢ Start Prednisone (40–60 mg/d OR 1mg/kg/d).
4 weeks).
➢ Maintenance: Prednisone 5-10 mg/d over 4–6 months.
➢ immunosuppressive therapy (As steroids sparing or in combination with it)

➢ MXT: The best gulucocorticoides sparing drug (10-15mg orally/weekly).
➢ Others: AZA (2 mg/kg per day), MMF (2000 mg/day) OR Cyclosporine.
➢ Cyclophosphamide is rarely used to treat Takayasu arteritis because of its toxicity.
➢ Treatment of complications :
➢ Management of hypertension, congestive heart failure, angina, or aortic
regurgitation.
➢ Vascular surgery & Angioplasty.
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Polyarteritis Nodosa
Definition: Necrotizing inflammation of small or medium arteries (without
glomerulonephritis) or vasculitis of arteries arterioles, capillaries or venules (PAN mostly involves a
medium size-vessels).
Epidemiology:
• Age of onset: PAN can occur at any age, but the most common age range at
diagnosis is 40 to 60 years
• Sex: Females and males equally affected.
• Incidence: 2 to 9 per million in Europe and the United States.
✓ PAN develops in 1% to 5% of patients with HBV infection which confers an
approximately 1000-fold increase in risk compared with the background
population
✓ The epidemiology of PAN has changed over time. Effective hepatitis B virus
(HBV) immunization programs, improved blood screening for HBV, have
substantially reduced the true incidence of PAN.
Pathogenesis
➢ In HBV-related PAN, the postulated mechanism of vasculitis includes direct vessel
injury by replicating virus or deposition of immune complexes.
➢ Deposition of immune complexes leads to activation of the complement cascade,
resulting in an inflammatory response and subsequent endothelial damage.
Clinical Findings
▪ Constitutional symptoms: (70% of patients). ▪ Renal: (40% of patients).

✓ Fatigue, Fever& Sweat. ✓ Renin-mediated hypertension (Due to
✓ Loss of weight & Loss of appetite. involvement of renal artery and/or intra-renal
✓ Arthralgia & Myalgia. arterioles).
✓ Proteinuria and hematuria
▪ GIT: (50%of patients). ▪ Neurologic: (55% of patients).
✓ Postprandial abdominal pain ✓ Mononeuritis multiplex most
("intestinal angina") due to Involvement of the commonly affects the sural, peroneal,
mesenteric arteries &May be complicated by mesenteric radial, and ulnar nerves.
✓ Foot or wrist drop may be the first
infarction motor symptoms.
✓ PAN may be detected at cholecystectomy or ✓ Rare: encephalopathy and strokes.
appendectomy in the absence of other
disease manifestations
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▪ Skin: (45%of patients). (Cutaneous manifestation is a feature of PAN share it with small vessels vasculitis and differntiate
them from large vessel vasculitis).
✓ Livedo reticularis: with a diffuse distribution over the extremities and buttocks, does not blanch with
pressure.
✓ Nodules, papules, and ulcers over the lower extremities (near the malleoli, calf muscles
and the dorsal surfaces of the feet.)
✓ Digital ischemia & splinter hemorrhages.
▪ Others:
✓ Testicular pain due to ischemic orchitis is a classic feature
✓ Tachycardia - Congestive heart failure and myocardial infarction.
✓ Eyes (scleritis), pancreas, ureters, breasts, and ovaries.
▪ Complications:
✓ Advanced mononeuritis multiplex with Residual nerve dysfunction (muscle
weakness or painful neuropathy).
✓ Bowel perforation -- Rupture of a mesenteric microaneurysm
Work Up
➢ Laboratory:
➢ ESR & CRP: highly elevated-- ESRs in excess of 100 mm/h are frequently found
- Moderate leukocytosis &Thrombocytosis.
➢ Renal abnormalities (usually result from renal artery involvement).

✓ An elevated serum creatinine.
✓ Mild proteinuria or hematuria (Red blood cell casts suggest glomerulonephritis and are therefore
atypical).
➢ HBV: +ve
➢ Liver functions: Hepatic artery involvement common in PAN which can lead mild to
moderate elevations in serum hepatic transaminases.
➢ Complement level C3 & C4:

✓ Low in patients with PAN associated with HBV.
✓ Elevated in patients with idiopathic PAN.
➢ Serology:
✓ Negative result for RF- ANA (anti-Ro, -La, -Sm, -RNP)
✓ ANCA: Occasionally positive on immunofluorescence testing (low titers of
perinuclear [P-ANCA] immunofluorescence)
➢ Radiology: MR & CT angiography -- Conventional angiography:

➢ The classic findings are vascular wall inflammation & necrosis in segmental
distribution leads to multiple small aneurysms, vessel ectasia, and focal
occlusive lesions in medium-sized vessels.
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➢ Sites typically for the renal and mesenteric arteries.

➢ MR and CT angiography are less invasive alternatives to conventional angiography
but are much less sensitive in demonstrating microaneurysms.
➢ Biopsy:
➢ Pan-arteritis characterized by transmural necrosis and fibrinoid necrosis (a homogeneous,
eosinophilic appearance of the blood vessel wall), With infiltration by polymorphonuclear cells,
lymphocytes and granulocytes.
➢ Site of the biopsy: specimens of the skin that capture lobules of subcutaneous fat (In the skin,
medium-sized arteries lie within the deep dermis and in the subdermal adipose tissue)
ACR criteria for the classification of Polyarteritis Nodosa:

Sensitivity 93.5% - Specificity 91%.
1. Weight loss ≥4 kg.
2. Livedo reticularis.
3. Testicular pain or tenderness.
4. Myalgias, weakness, or leg tenderness.
5. Diastolic blood pressure >90 mm Hg
6. Elevated blood urea nitrogen or creatinine levels : (creatinine≥ 1.5mg/dl)
7. Hepatitis B virus: HBs Antigen or antibody.
8. Arteriographic abnormality: Aneurysm or occlusions of the visceral arteries.
9. Abnormal artery biopsy: Biopsy of a small- or medium-sized artery
containing polymorphonuclear neutrophils or granulocytes.
TREATMENT:
➢ Non-hepatitis B Virus Polyarteritis Nodosa
➢ Start Prednisone (1mg/kg/d) up to 60 mg/day.
4 weeks).
➢ Maintenance: Prednisone 7.5-10mg /day for 18-24 months.
➢ Immunosuppressive therapy (Cyclophosphamide)

➢ Indicated for patients whose disease is refractory to corticosteroids or who have
serious involvement of major organs.
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➢ Induction: pulse Cyclophosphamide (15 mg/kg) per pulse Every 2-3 weeks for 3-6
months.
➢ Maintenance: Azathioprine 2 mg/kg/day for 18-24 months, then stop.
➢ Hepatitis B Virus related Polyarteritis Nodosa:

• Start with oral prednisone (1 mg/kg/d) to suppress the inflammation tapered rapidly
over approximately 2 weeks.
• Then Antiviral therapy (eg, lamivudine 100 mg/d) & Plasmapheresis.
• Seroconversion of hepatitis B antibody status was associated with complete remission
and no relapse.
Prognosis:
➢ PAN is generally considered to be a "one-shot" disease (In contrast to the ANCA-
associated vasculitides, which are more prone to recurrences).
➢ For patients with HBV-associated PAN, seroconversion to anti-HBe antigen antibody
usually signals the end of the active phase of vasculitis.
➢ Among those with idiopathic PAN, disease recurrences are observed in about 10% of
cases.
NB
➢ The diagnosis of GCA should be considered in any patient older than 50 years who
experiences loss of vision, diplopia, scalp tenderness new form of headache, jaw claudication
➢ GCA risk increase with varicella zoster infection & smoking.
➢ TA risk increase with previous exposure to Mycobacterium tuberculosis.
➢ Congestive heart failure and renal failure are the most common causes of death in TA
➢ In the CHCC definition, PAN is a medium-vessel disease; by comparison, MPA is
predominantly a small-vessel disease that includes glomerulonephritis and pulmonary
capillaritis.
➢ In PAN, the most common organ manifestation is neurologic with mononeuritis multiplex,
followed by skin lesions, abdominal pain from mesenteric ischemia, and renal infarction.
Testicular pain due to ischemic orchitis is a classic feature but uncommon.
➢ Vasculitis Associated with Granulomatous Inflammation
✓ Giant cell arteritis--Takayasu’s arteritis.
✓ Cogan’s syndrome
✓ Granulomatosis with polyangiitis
✓ Eosinophilic granulomatosis with polyangiitis
✓ Primary angiitis of the central nervous system.
✓ Rheumatoid vasculitis.
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Differential Diagnosis of
Giant Cell Arteritis Takayasu Arteritis Polyarteritis Nodosa
Other Diseases that Can Affect the Aorta
➢ Other forms of vasculitis: ➢ Other forms of vasculitis: ➢ Other forms of vasculitis:
✓ Takayasu’s arteritis. ✓ GCA, ✓ ANCA–associated vasculitis.
✓ ANCA–associated vasculitis. ✓ Cogan syndrome. ✓ Cryoglobulinemia.
✓ Polyarteritis nodosa. ✓ Buerger disease. ✓ Isolated vasculitis of peripheral
✓ Primary angiitis of the CNS. ✓ Behçet disease nerves.
➢ Infections: ➢ Rheumatic diseases: ➢ Rheumatic diseases:

✓ Occult infections-Tuberculosis, ✓ Relapsing polychrondritis. ✓ Systemic lupus erythematosus
✓ Bacterial endocarditis. ✓ Ankylosing spondylitis. ✓ Rheumatoid arthritis (with
✓ HIV. ✓ Rheumatoid arthritis. rheumatoid vasculitis).
✓ SLE. ✓ Mixed connective tissue disease
➢ Others: ✓ Catastrophic APL.
✓ Lymphoma & multiple myeloma ➢ Infections: ✓ Still disease.
✓ Systemic amyloidosis. ✓ Syphilis.
✓ Other vascular disorders ➢ Infections:
causing anterior ischemic ➢ Others: ✓ Bacterial endocarditis.
optic neuropathy. ✓ Sarcoidosis. ✓ Deep fungal infections
✓ Retroperitoneal fibrosis. (histoplasmosis, blastomycosis)
➢ DD of Polymyalgia Rheumatica ✓ Neurofibromatosis,
✓ Early rheumatoid arthritis. ✓ Atherosclerosis. ➢ Others:
✓ Polymyositis -- Fibromyalgia. ✓ Inflammatory abdominal ✓ Lymphoma
✓ Complication of medication aortic aneurysm ✓ Sarcoidosis
Statins ✓ inflammatory bowel disease, ✓ Inflammatory bowel disease
✓ Endocrine: Hypothyroidism ✓ Congenital coarctation, ✓ Erythema nodosum
✓ Remitting seronegative Marfan syndrome. ✓ Cholesterol emboli
synovitis with pitting edema ✓ Fibromuscular dysplasia.
Cutaneous Polyarteritis Nodosa

✓ Cutaneous PAN is a localized chronic arteritis affecting small arteries and/or arterioles in the panniculus (medium vessels) and in
the dermo-subcutaneous junction.
✓ Unlike systemic PAN, cutaneous PAN is usually a more chronic disease.
✓ Indistinguishable between systemic PAN and cutaneous PAN, but the absence of venule involvement in cutaneous PAN is an
important distinction.
Microscopic Polyangiitis Versus Polyarteritis Nodosa

✓ Patients with MPA had a greater frequency of purpura (26%) compared with a frequency of only 19% in patients with PAN.
✓ Urticaria was more common in patients with PAN (6% vs. 1.2%).
✓ The presence or absence of HBV infection–influenced skin manifestations was less common (with a rate of only 30%) in HBV
positive patients compared with HBV-negative patients (54%).
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ANCA-associated vasculitides
Definition:
➢ Granulomatosis with polyangiitis (GPA) (Wegener’s Granulomatosis): Small- to medium-sized
vasculitis characterized by Necrotizing granulomatous inflammation involving the respiratory
tract. Necrotizing glomerulonephritis is common.
➢ Microscopic polyangiitis (MPA): Small- to medium-sized vasculitis characterized by Necrotizing

inflammation involving the respiratory tract-Necrotizing glomerulonephritis is very common
Without granulomatous inflammation.
➢ Eosinophilic granulomatosis with polyangiitis (EGPA) (Churg–Strauss Syndrome): Small- to medium-

sized vasculitis characterized by Necrotizing granulomatous inflammation involving the
respiratory tract and Eosinophilic-rich infiltration.
Epidemiology:
▪ Overall incidence of AAV approximately 10 to 30 individuals per million per year.
▪ Slight male predominance (male to female, 1.5 : 1).
▪ These diseases are rare in childhood and the incidence increases with age.
▪ The peak incidence occurring in people between 55 and 70 years of age.
▪ GPA is the most prevalent AAV & EGPA is the least prevalent of the AAV.
Clinical Findings
▪ Non-specific Constitutional symptoms:
- Fatigue, Fever& Sweat. - Loss of weight & Loss of appetite.
- Arthralgia, Myalgia and/or Arthritis (Migratory pattern).
▪ Lung:
- Nonspecific pulmonary infiltrates - alveolar hemorrhage - pulmonary fibrosis - pleural effusions.
- In GPA: Nodular, cavitary lesions.
- In EGPA: More than 90% of patients have histories of ASTHMA
▪ kidney
- Glomerulonephritis (small-vessel vasculitis of the kidney).
- EGPA is less likely to cause end-stage renal disease than other forms of AAV.
▪ Ear-Nose-Throat:
- Persistent Rhinitis & Sinusitis.
- GPA & EGPA:
✓ Brown nasal crusts; nasal obstruction; nasal septal perforation; saddle-nose deformity.
✓ Conductive hearing loss (due to granulomatous inflammation in the middle ear).
✓ Subglottic stenosis.
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▪ Skin: Palpable purpura – ulcers - vesiculobullous lesions - splinter hemorrhages.

▪ Peripheral nerves: Sensory or motor mononeuritis multiplex.
▪ Uncommon:
✓ Mesenteric vasculitis.
✓ Valvular heart lesions (GPA) - Congestive heart failure (EGPA).
✓ Strawberry gums. (GPA).
✓ Orbital pseudotumor; scleritis (often necrotizing) conjunctivitis; keratitis. anterior uveitis.
(GPA)
Laboratory:
▪ ESR& CRP: highly elevated with good correlation to disease activity.
▪ CBC:
✓ Anemia (Normochromic, normocytic) -- acute, severe anemias with alveolar hemorrhage
✓ Leukocytosis (Mild to moderate, usually not exceeding 18 x 109/L) .
✓ Thrombocytosis (Moderate to severe, ranging from 400 x 109/L to >1000 x 109/L).
✓ In EGPA: Eosinophilia (before treatment)
▪ Eosinophil counts may comprise as much as 60% of the total WBCs.
▪ Eosinophil counts are usually sensitive markers of disease flares.
▪ Respond very quickly to treatment with high doses of glucocorticoids.
▪ Serum IgE levels: Most patients with EGPA have elevated serum IgE levels.
▪ Serology:
✓ Rheumatoid factor: Positive in 40–50% of patients (leading to diagnostic confusion with rheumatoid arthritis)
✓ C3 & C4: Complement levels are normal to elevated in WG.
✓ ANA: negative.
▪ Urine analysis:
✓ Hematuria (ranging from mild to high) & Red blood cell casts.
✓ Proteinuria (nephritic range proteinuria in a small minority).
▪ ANTINEUTROPHIL CYTOPLASMIC ANTIBODY (ANCA)

➢ Two types of assays for ANCA:
1. Immunofluorescence:
2. Enzyme immunoassay
➢ With immunofluorescence, three principal patterns of fluorescence are recognized:
❖ Cytoplasmic (C-ANCA):
✓ Usually corresponds to the detection of PR3-ANCA (proteinase 3- ANCA) by enzyme immunoassay.
✓ Associated most strongly with Granulomatosis with polyangiitis (GPA).
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❖ Perinuclear (P-ANCA):
✓ Usually corresponds to the presence of MPO-ANCA (myeloperoxidase- ANCA) by enzyme immunoassay.
✓ Associated mostly with MPA, EGPA and renal-limited vasculitis.
✓ Mostly positive with drug-induced AAVs (with very high titers of MPO-ANCA).
✓ Occurs in approximately 10% of patients with GPA.
❖ Atypical patterns:
➢ Regardless of the immunofluorescence pattern, positive immunofluorescence assays should be

confirmed by the performance of enzyme immunoassays for the specific antibodies associated
with vasculitis: PR3- and MPO-ANCA.
➢ The positive predictive value of ANCA is only in the range of 50% to 70%.
Radiology:
➢ Chest CT scan:
✓ Indication: Patients with confirmed or strongly suspected diagnoses of Granulomatosis with
polyangiitis (GPA).
✓ Up to one-third of patients with GPA have asymptomatic pulmonary lesions on radiologic
imaging.
✓ Lung nodules are typically multiple and bilateral and have a tendency to cavitate.
✓ Usually located in the periphery of the lung and may appear to be wedge-shaped and
pleural-based. (They may therefore be mistaken for pulmonary emboli or lung malignancies)
Biopsy:
➢ Biopsy of an involved organ gold standard for diagnosing GPA.
➢ The tissue necrosis associated with GPA is frequently so extensive within diseased tissues
that it is termed "geographic necrosis."
➢ Among the organs commonly involved in GPA, those most likely to yield tissue that permits a
diagnosis are (in descending order): lung, kidney, and upper respiratory tract (nose or sinuses).
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Criteria for Classification of AAV

ACR 1990 criteria for the classification of Granulomatosis with polyangiitis (GPA)
➢ Nasal or oral inflammation (painful or painless oral ulcers, purulent or bloody nasal discharge)
➢ Abnormal chest radiograph (nodules, fixed infiltrates, cavities)
➢ Urinary sediment (microhematuria or red cell casts)
➢ Biopsy: Granulomatous inflammation within wall of artery or in perivascular or extravascular
area.
➢ ANCA testing: Positive antibodies to PR-3 (added to modified criteria59)
ACR 1990 criteria for the classification of Eosinophilic Granulomatosis with polyangiitis
(EGPA)
➢ ASTHMA: History of wheezing or diffuse high-pitched rales on expiration
➢ Eosinophilia: >10% > on white blood cell differential count
➢ Mononeuropathy or polyneuropathy.
➢ Radiograph: Non-fixed pulmonary infiltrates.
➢ Paranasal sinus abnormality: sinus pain or tenderness or radiographic opacification of sinuses.
➢ Biopsy: Extravascular eosinophils (biopsy from artery, arteriole or venule)
The presence of any 4or more criteria makes the diagnosis
Differential Diagnosis of AAV

➢ Other forms of vasculitis: ➢ Rheumatic diseases: ➢ Infections:
✓ Polyarteritis nodosa. ✓ SLE. ✓ Bacterial endocarditis.
✓ Henoch-Schönlein purpura. ✓ Rheumatoid arthritis. ✓ Mycobacterial diseases.
✓ Mixed cryoglobulinemia. ✓ Relapsing polychondritis. ✓ Fungal infections
✓ Giant cell arteritis. (histoplasmosis,
✓ Goodpasture syndrome. ➢ Others:
blastomycosis,
✓ Nasopharyngeal carcinoma
➢ Hypereosinophilic disorders ✓ Hodgkin disease coccidioidomycosis)
✓ Chronic eosinophilic pneumonia. ✓ Non-Hodgkin lymphoma ✓ Streptococcal pneumonia with
✓ Eosinophilic gastroenteritis. ✓ Angiocentric lymphoma glomerulonephritis.
✓ Eosinophilic fasciitis, ("lymphomatoid granulomatosis") ✓ Sepsis.
✓ Hypereosinophil syndrome. ✓ Sarcoidosis
✓ Eosinophilic leukemia.
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TREATMENT of AAV
I. Severe disease: (defined as an immediate threat to either the function of a vital organ or to the patient's life such as
glomerulonephritis, alveolar hemorrhage, or vasculitic neuropathy)
➢ Induction therapy: (3-6monthes)

➢ High-dose intravenous methylprednisolone: (500-1000 mg/d) for 3–days
followed by:
✓ Oral glucocorticoids: Prednisone (40–60 mg/d) for at least one month then
✓ Tapering: the dose can be gradually reduced by a maximum of 10% of the total
dose each week or every 2 weeks.
➢ Cyclophosphamide: (for those with normal renal function)

✓ Oral (2 mg/kg/d) OR intermittently (15 mg/kg per pulse monthly).
➢ Maintenance therapy: (1-2years)

➢ AZA (2 mg/kg per day) OR MMF (2000 mg/day) OR MTX (10-15mg/weekly).
➢ Low-dose glucocorticoid therapy (0.1-0.2 mg/kg/day).
II. Limited disease: (All cases that are not sever – no threat to life or vital organ)
➢ Oral glucocorticoids: Prednisone (0.3–0.5mg/kg/d).
➢ Immunosuppressive therapy (As steroids sparing or in combination with it)
✓ AZA (2 mg/kg per day). OR
✓ MTX (10-15mg/weekly).
III. Resistant cases:

➢ RITUXIMAB.
➢ Plasmapharesis.
NB
❖ As Regard GPA
➢ Three pathologic hallmarks: granulomatous inflammation, vasculitis, and necrosis.
➢ Classic clinical features include:
✓ Persistent upper respiratory tract and ear "infections" that do not respond to antibiotic therapy.
✓ Persistent Rhinitis & Sinusitis and decreases in hearing.
✓ Rapidly progressive glomerulonephritis.
✓ Typically presents in a subacute fashion.
✓ Most commonly associated with C-ANCA.
❖ As Regard EGPA
➢ The classic hallmarks are Asthma, eosinophilia, and systemic vasculitis.
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➢ Only 40% of patients produce detectable ANCA.

➢ After the diagnosis of CSS has been made, three disease phases are often recognizable:
1. Prodrome: Characterized by the presence of allergic disease (typically asthma or allergic rhinitis). This phase
often lasts for several years.
2. Eosinophilia/tissue infiltration: Tissue infiltration by eosinophils is observed in the lung, GIT, and other tissues.
3. Vasculitis: Systemic necrotizing vasculitis affects a wide range of organs (heart, lungs, peripheral nerves & skin).
➢ MPA is the most common cause of the pulmonary-renal syndrome of alveolar hemorrhage and glomerulonephritis.
➢ MPA most commonly associated with P-ANCA.
❖ As Regard Treatment of AAV

➢ Daily cyclophosphamide administration is more likely to result in durable remissions than intermittent (ie, monthly) dosing.
➢ Remission can often be maintained with less toxic medications such as AZA / MTX
➢ Methotrexate is not an appropriate first-line treatment for patients with severe involvement of the kidney, lung, or other vital
organs and should not be used in patients with significant renal dysfunction (eg, a serum creatinine of >2.0 mg/dL).
➢ Vaccination: to prevent the infections
✓ All patients with AAV should receive prophylaxis against Pneumocystis jiroveci pneumonia with either single-
strength trimethoprim-sulfamethoxazole or 100 mg/d of dapsone.
Clinical significance of Anti Neutrophil Cytoplasmic Antibody (ANCA)
➢ Positive ANCA serologies are extremely useful in suggesting the diagnosis in the proper clinical setting.
➢ Positive immunofluorescence assays without confirmatory enzyme immunoassays for anti-PR3 or anti-MPO
(myeloperoxidase) antibodies are of limited utility.
➢ Histopathology remains the gold standard for diagnosis in most cases.
➢ Treatment of ANCA-associated vasculitis should never be predicated upon ANCA serologies or titers alone.
➢ Negative ANCA assays do not exclude ANCA-associated vasculitis (because between 10% and 50% of patients with ANCA-
associated vasculitis may be ANCA-negative).
➢ Persistence of ANCA in the absence of clinical indications of active disease does not indicate a need for continued treatment.
➢ In a patient who was ANCA-positive during active disease, persistent ANCA-negativity provides reassurance—but no
guarantee—that the disease is not active. If disease flares occur in such patients, they are usually limited.
➢ A patient who becomes ANCA-positive again following a period of clinical quiescence associated with negative ANCA assays
may be at an increased risk for a disease flare.
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Immune Complex–Mediated Vasculitis
❖ Key Points
➢ Vasculitis mediated by immune complexes (ICs) includes a heterogeneous group of
disorders linked by inefficient or dysregulated clearance of ICs.
➢ The most common types of IC-mediated vasculitis are:
✓ Hypersensitivity vasculitis.
✓ Henoch-Schِnlein purpura (HSP).
✓ Mixed cryoglobulinemia.
➢ Rarer forms of IC-mediated vasculitis are:

✓ Hypocomplementemic urticarial vasculitis.
✓ Erythema elevatum diutinum.
✓ IgG4- related disease.
➢ Connective tissue disorders such as systemic lupus erythematosus, Sj ِgren’s
syndrome, and rheumatoid arthritis can be associated with IC-mediated vasculitis.
➢ The most prominent feature is Cutaneous involvement of small blood vessels (but
extracutaneous involvement occurs in some forms).
➢ The classic cutaneous finding is palpable purpura, but a variety of other skin
lesions may be found including pustules, vesicles, urticaria, and small ulcerations.
➢ Direct immunofluorescence studies of involved blood vessels demonstrate
characteristic types and patterns of immunoglobulin (Ig) and complement
deposition.
➢ Hypersensitivity vasculitis usually results from a reaction to a medication or an
infection.
➢ HSP is associated with purpura, arthritis, glomerulonephritis, and colicky
abdominal pain. IgA deposition is found within blood vessel walls.
➢ Cryoglobulinemic vasculitis is most often associated with long-standing hepatitis C
virus infection.
Pathophysiology:
➢ Immune complex solubility is determined by the ratio of antibody to antigen.
➢ When antibody and antigen are present in equal proportion, large immune complexes
are formed, which are identified easily and removed by the reticuloendothelial system.
➢ When there is a slight excess of antigen, however, the immune complexes precipitate
from solution, and become trapped in characteristic areas—either the capillary beds
(such as those found in the skin, kidneys, or lungs), or the endothelium of medium-sized
blood vessels previously damaged by turbulent blood flow.
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➢ Pathogenic immune complexes formed between antigen and antibodies tend to occur
during periods of antigen excess. When the immune complexes precipitate into the
tissues, they fix complement, leading to an intense immune reaction.
➢ In immune complex vasculitis, immune complexes deposit in the vascular endothelium

or in capillary beds, such as those found in the skin, kidneys, or lungs.
➢ Complement fixation and local inflammation recruit neutrophils, which attempt to engulf
the immune complexes.
➢ During this process, the neutrophils degranulate, releasing lysosomal enzymes and
oxygen free radicals that cause tissue necrosis.
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Mixed cryoglobulinemia (MC)

Cryoglobulinemic Vasculitis
❖ Definitions:
➢ Cryoglobulins: are immunoglobulins (Ig) that precipitate from the serum at low
temperatures.
➢ Cryoglobulins, detectable to a varying degree in a wide array of inflammatory conditions,
are not invariably pathogenic.
➢ Cryoglobulinemic Vasculitis: In some patients cryoglobulins deposit in the small- and
medium-sized blood vessels and activate complement, leading to cryoglobulinemic
Vasculitis
➢ Cryoprecipitates are comprised most commonly of IgG and IgM (either singly, or in the case of
mixed cryoglobulinemia, together).
➢ Occasionally IgA may be associated with clinically relevant cryoglobulin syndromes.
➢ The term "mixed cryoglobulinemia" was coined to differentiate types II and III (both of
which contain mixtures of both IgG and IgM) from type I (which contains only a single monoclonal
antibody).
➢ Hepatitis C virus (HCV) infections are now known to be associated with approximately
90% of all cases of MC (essential MC)
➢ The symptoms and signs of MC-associated vasculitis are caused by the vascular
deposition of cryoprecipitate components.
❖ Types of Cryoglobulinemia
➢ Classified according to the clonality of the IgM component and the presence of
rheumatoid factor (RF)
Subtype RF Monoclonality Associated Diseases
Positivity
Type I No Yes (lgG or lgM) Hematopoietic malignancy (multiple myeloma,
macroglobulinemia)
Type II Yes Yes (polyclonal lgG, monoclonal lgM) Hepatitis C (other infection, Sjögren syndrome,
Type III Yes No (polyclonal lgG and lgM) systemic lupus erythematosus)
Clinical Findings
A triad of signs and symptoms: purpura, arthralgias, and myalgias.
with periods of remission and exacerbation
➢ Skin:
✓ Palpable purpura with a predilection for the lower extremities (the rash is also found sometimes
on the upper extremities, trunk, or buttocks).
✓ Cutaneous ulcers may heal with scarring.
✓ Hyperpigmentation over the involved areas of skin often develops in patients with
long-standing, recurrent cutaneous vasculitis.
➢ Musculoskeletal:
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✓ Arthralgias and myalgias are a prominent symptom in most cases of MC (Frank arthritis
is much less common than arthralgias).
✓ The typically involved joints are the PIP, MCP joints and the knees.
➢ Renal (20%):
✓ Mostly presented as asymptomatic microscopic hematuria, proteinuria, and
variable degrees of renal insufficiency.
✓ Less commonly: acute nephrotic syndrome and acute nephritic syndrome.
✓ The most frequent histologic picture is membranoproliferative glomerulonephritis,
(which can mimic lupus nephritis).
➢ Peripheral neuropathy: sensory involvement predominates over motor nerve disease.
➢ Type I cryoglobulinemia:
✓ Rarely presents with signs and symptoms of vasculitis.
✓ When symptomatic it may be associated with a hyperviscosity syndrome affect
mainly CNS (dizziness, confusion, headache, and stroke) & Skin (livedo reticularis, acrocyanosis, and digital
gangrene).
Work Up
➢ Laboratory:
➢ ESR & CRP: elevated (moderate to severe).
- Thrombocytopenia.
➢ Rheumatoid factor: mostly positive (IgMs).
➢ ANA: Positive in the majority of cases.
➢ C3, C4: Low, particularly C4 levels. (Because complement proteins are involved in the formation of immune complexes)
➢ Anti-HCV Antibodies: positive in 90% of cases.
➢ Urine analysis: proteinuria or hematuria (if kidney affected).
➢ Cryoglobulins (a white precipitate at the bottom of the tube)
✓ Assays for cryoglobulins are associated with a high false-negative rate, caused
principally by insufficient care in handling.
✓ After phlebotomy, the blood sample must be transported to the laboratory at 37°C
and allowed to clot at that same temperature.
✓ Specimens are then centrifuged at 37°C and stored at 4°C for up to 1 week.
✓ The presence of cryoglobulins is indicated by the development of a white
precipitate at the bottom of the tube.
➢ Cryocrit (The percentage of the serum occupied by the cryoprecipitate)
✓ The percentage of serum comprised by cryoglobulins may be determined by the
centrifugation of serum at 4°C.
✓ The cryocrit may then be measured in precisely the same fashion as a hematocrit.
✓ Cryocrit levels should not dictate therapeutic decisions(correlates poorly with clinical status).
➢ Biopsy: Direct immunofluorescence (DIF) biopsy of the skin shows:
➢ An immune complex–mediated leukocytoclastic vasculitis, with deposition
of IgG, IgM, C3, and other immunoreactants in and around the walls of small- and
medium-sized vessels.
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TREATMENT:
➢ Treatment of the underlying causes: Such as infection (HCV), Autoimmune disorder or
Malignancy.
➢ Symptomatic treatment: mild cases

➢ NSAIDs for arthralgias and arthritis.
➢ Low-dose glucocorticoids for cutaneous vasculitis and peripheral neuropathy.
➢ Sever Resistant cases: (necrotizing vasculitis involving vital organs in a dangerous fashion)
➢ Higher-dose glucocorticoids plus Rituximab: With gradual tapering of the

glucocorticoids over several weeks &regular treatment with rituximab (e.g., every 6
months) to prevent disease return. (The rationale behind rituximab use in cryoglobulinemia is that peripheral
B lymphocyte depletion will lead to a reduction in plasma cells that produce cryoglobulins)
➢ Plasmapheresis.
➢ Lower survival rates are observed with age over 60 years, male gender, and renal
involvement.
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Hypersensitivity Vasculitis
❖ Definition: Hypersensitivity vasculitis (the most common form of vasculitis) refers to a
heterogeneous group of syndromes (including serum sickness and drug induced vasculitis)
characterized by immune complex deposition in capillaries, postcapillary venules, and
arterioles.
❖ Key points:
➢ Cause: Precipitants such as medications and infections are often identifiable, but
approximately 40% of cases have no definable cause.
➢ Hypersensitivity vasculitis that occurs without systemic manifestations is
sometimes referred to as cutaneous vasculitis or cutaneous leukocytoclastic angiitis.
➢ The term serum sickness, on the other hand, is reserved to describe a systemic
illness, including rash and arthralgias, which occurs 1 to 2 weeks after exposure to a
drug or foreign antigen.
➢ Any medication can be associated with the induction of a hypersensitivity vasculitis
but the most common are antibiotics (particularly penicillins and cephalosporins),
Diuretics and anti-hypertensive agents.
➢ Differential diagnosis:
✓ Primary forms of vasculitis (such as Henoch-Schönlein purpura, microscopic polyangiitis, or
Wegener granulomatosis).
✓ Secondary vasculitis such as mixed cryoglobulinemia caused by hepatitis C.
Clinical Presentation
➢ The typical history for a drug-induced hypersensitivity vasculitis is the occurrence of clinical
symptoms approximately 7 to 14 days after starting a new medication.
➢ Cutaneous manifestations:
✓ Purpura:
• The most common symptoms
• Distributed usually in a symmetric fashion over dependent regions of the
body, particularly the lower legs (and, in recumbent patients, over the buttocks) because of
the increased hydrostatic pressure in such areas.
• Either palpable or nonpalpable.
✓ Papules, urticaria/angioedema, erythema multiforme.
✓ Vesicles, pustules, ulcers, and necrosis.
➢ Musculoskeletal:
✓ Arthralgias and myalgias may occures (Frank arthritis is much less common than arthralgias), with a
predominance for large joints.
Work Up
➢ Laboratory:
➢ ESR & CRP: elevated (Mild).
➢ CBC & C3, C4: within normal.
➢ Rheumatoid factor, ANA & Anti-HCV Antibodies: all are NEGATIVE.
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of IgG, IgM, C3, and other immunoreactants in and around the walls of small- and
medium-sized vessels.
❖ Light microscopy examination: an inflammatory infiltrate primarily composed of

mononuclear or polymorphonuclear cells & Leukocytoclastic vasculitis.
❖ The optimal time for skin biopsy is 24 to 48 hours after the appearance of a lesion. Biopsies should be
obtained from a non-ulcerated site.
ACR criteria for the classification of Hypersensitivity Vasculitis:

➢ Age >16 years
➢ Use of a possible offending medication in temporal relation to symptoms
➢ Palpable purpura
➢ Maculopapular rash
➢ Biopsy of a skin lesion showing neutrophils around an arteriole or venule
Therapy
➢ Removal of the inciting agent is the only reliable therapy.

➢ Mild cases treated simply with leg elevation and the administration of H1 antihistamines.
➢ Low dose glucocorticoids for refractory or more severe cases.
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Henoch-Schönlein Purpura
❖ Definition: Henoch–Schönlein purpura (HSP) is an immune complex–mediated form of
small vessel vasculitis that is associated strongly with IgA deposition within blood vessel
walls
❖ Epidemiology:
➢ Age & sex: Usually affect children younger than 5 years of age with a male:female
ratio of 2:1.
➢ Incidence: HSP is the most common form of systemic vasculitis in children,
with an annual incidence of 140 cases per million persons.
➢ Causes: the true etiology remains unknown, but many cases of HSP are reported to
occur after upper respiratory tract infections. (Group A streptococci, mycoplasma, Epstein–Barr virus,
varicella).
Acute onset of fever (an upper respiratory tract infection), palpable purpura on the lower extremities and buttocks abdominal
pain, arthritis, and hematuria
➢ Skin: Palpable purpura on the lower extremities and buttocks.
➢ Joints: Arthritis affect large joints, especially the knees and ankles in Migratory patterns.
➢ GIT: Colicky abdominal pain (GIT vasculitis) usually occurs within a week after the onset of rash.
➢ Kideny: Mild self-limited glomerulonephritis is common.
Work Up
➢ Laboratory:
➢ ESR & CRP: elevated (Mild).
➢ CBC: usually normal (Mild to moderate leukocytosis common)
➢ Serum IgA level: 60% of patients have an elevated serum IgA (IgA1).
➢ Urine analysis: hematuria, proteinuria & red blood cell casts.
➢ Rheumatoid factor, ANA & Anti-HCV Antibodies: all are NEGATIVE.
➢ C3, C4: within normal

of IgA in and around the walls of small sized vessels.
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ACR criteria for the classification of Henoch-Schِnlein Purpura (IgA Vasculitis)

➢ Palpable purpura
➢ Age at onset <20 years
➢ Bowel angina
➢ Vessel wall granulocytes on biopsy
Therapy
➢ In mild cases of HSP, no specific therapy is necessary.

➢ NSAIDs: should be avoided as it can aggravate gastrointestinal symptoms .
➢ Moderate glucocorticoid doses (prednisone 20-30 mg/day) may be used in patients with
disabling symptoms or refractory purpura
➢ Severe renal disease: high-dose glucocorticoids plus MMF

➢ Dapsone (100 mg/d) may be effective in cases of HSP (through interference with the interactions of IgA and neutrophils).
➢ Prognosis
➢ Multiple episodes of recurrent skin disease may occur over months, but the disease
subsides and resolve completely over a few months to a year.
➢ In a minority of patients, some evidence of permanent renal damage persists in the
form of proteinuria and hematuria.
➢ Less than 5% of patients develop renal failure as a result of IgA vasculitis.
Diagnostic algorithm for immune

complex–mediated small vessel
vasculitis.
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Hypocomplementemic Urticarial Vasculitis Syndrome

➢ Definition
➢ Urticaria: an IgE-mediated hypersensitivity reaction to a variety of stimuli, including
medications, infection, and other triggers.
➢ Acute urticaria manifests as pruritic wheals that resolve days after the allergen is
removed.
➢ Chronic urticaria is an autoimmune condition that is probably driven by an
autoantigen and may require immunosuppressive therapy in addition to antihistamines
to prevent recurrence.
➢ Urticarial vasculitis describes a form of small vessel vasculitis that is characterized by

the appearance of urticarial wheals & frequently associated with moderate pain,
burning, and tenderness in addition to pruritus.
➢ Whereas common urticaria typically resolves completely within 24 to 48 hours, UV

lesions may take days to resolve completely, often leaving residual hyperpigmentation;
they may worsen without therapy.
➢ Types of Urticarial vasculitis:

A. Normo-complementemic urticarial vasculitis: self-limited hypersensitivity vasculitis
in which the principal skin manifestation is urticaria.
B. Hypocomplementemia urticarial vasculitis: chronic cutaneous (urticarial) vasculitis

that has certain overlapping features with SLE:
✓ Low serum complements & autoantibodies.
✓ An interface dermatitis characterized by immunoreactant deposition
(complement and immunoglobulins) at the dermal-epidermal junction in a
pattern essentially identical to the lupus band test.
C. Hypocomplementemia urticarial vasculitis syndrome (HUVS): a severe form of

the disease associated with extracutaneous manifestations.
❖ Presentation: low complement levels and urticaria for a period of at least 6
months, as well as some or all of the following:
• Arthralgias(arthritis) --- Glomerulonephritis ----- Uveitis.
• Angioedema--chronic obstructive pulmonary disease—pleurisy-- pericarditis.
➢ Therapy
 Mild cases respond to therapies commonly used for the treatment of SLE,
including:
▪ Low-dose prednisone.
▪ Hydroxychloroquine.
 Serious cases, particularly those presenting with glomerulonephritis or other forms

of serious organ involvement: require treatment with high doses of glucocorticoids
and biologic agents, such as TNF inhibitors or B cell depletion.
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Behçet disease
Definition: Behçet’s disease (BD) is a complex, multisystem auto-immune disease,
named for the Turkish dermatologist who in 1937 described the syndrome as a triad of
recurrent oral aphthous ulcers, genital ulcers, and ocular inflammation.
Epidemiology:
• Age: Usually occur in young people (patients are in their 20s or 30s when symptoms first develop).
• Sex:
✓ Men and women can be equally affected with slight male predominance of BD
in Middle Eastern and Mediterranean countries, and female predominance in
Japan and Korea.
✓ BD in men tends to follow a more severe clinical course with greater disease-
associated morbidity, particularly with vascular involvement.
• Prevalence:
✓ The highest prevalence along the “Silk Route,” extending from Japan to the
Middle Eastern and Mediterranean countries.
✓ The prevalence of BD is highest in Turkey, with up to 420 per 100,000
inhabitants affected, followed by Iran, Israel, China, and Korea.
✓ The lowest prevalence of BD is seen in the United Kingdom, Germany,
Portugal, and the United States (US), ranging from 0.12 to 6.4 per 100,000
people.
Pathogenesis
❖ Genetic factors associated with BD
✓ HLA_B51: genetic studies have revealed high prevalence of the human leukocyte
antigen (HLA)-B51 allele in patients living along the Silk Road (HLA-B51 seen in about 50% of
individuals with BD)
➢ HLA-A26 is also associated with increased susceptibility to BD, as well as a higher

prevalence of posterior uveitis in Korean patients with BD and poor visual prognosis in
Japanese patients with BD-associated uveitis
➢ About 31% of individuals with BD reporting positive family history.
❖ Environmental risk factors associated with BD: Some bacterial and viral infections
have been identified as possible environmental triggers of BD (via lymphocyte activation).
✓ Streptococcus sanguis and herpes simplex virus (HSV) type 1 Streptococcal
infections.
✓ Other bacteria including Escherichia coli, Staphylococcus aureus, Mycoplasma
fermentans, and Helicobacter pylori have also been identified
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❖ Main pathological changes in BD result from:

➢ Vasculitis: most of the damage in Behçet disease results from blood vessel
inflammation, justifying the disease's classification as a form of vasculitis.
✓ Behçet disease typically affects the small- and medium-sized vessels, and
✓ Also, it is one of the rare forms of vasculitis capable of also affecting large
arteries. Arterial inflammation can lead to occlusion, aneurysm, or rupture.
✓ Behçet disease joins Wegener granulomatosis and Buerger disease in being a
form of vasculitis that has a predilection for involving veins and causing venous
thrombosis.
➢ An abnormal reactivity of neutrophils and lymphocytes: Which responsible for

many of the pathologic changes—including ulceration of the mouth and gut.
❖ Main cellular changes in BD:

➢ The major lymphocytes implicated in BD are T lymphocytes (cytotoxic T cells, Th1 cells,
regulatory T (Treg) cells, and Th17 cells) acting as key players.
➢ Interleukin production: there is Increased serum levels of IL-17 & IL-23 in patients
with BD.
➢ Heat shock proteins (HSPs) and alterations in neutrophil and macrophage activity
leading to activation of the innate immune response and Th1 stimulation.
➢ HSPs may increase expression of vascular endothelial growth factor by T cells,
contributing to endothelial cell damage and vasculitis.
Clinical Findings
A. Mucocutaneuos:
1. Oral ulceration:
✓ The hallmark of the disease -- the earliest manifestation -- required for the diagnosis.
✓ Sites: the ulcers most frequently affect the buccal mucosa, tongue, lips,
gingivae, palate, tonsils, uvula, or pharynx.
✓ Number: During an attack, patients usually have two to five lesions, but some
patients may have a single ulcer or too many to count (Shallow or deep with a white or
yellow base and red halo. They vary in size from 1–20 mm).
✓ Oral ulcers are be so painful but usually heal without scarring over 10–20
days.
2. Erythema nodosum:
✓ Erythema nodosum occurs most commonly in women.
✓ Erythema nodosum in Behçet disease tends to ulcerate and heal with
scarring and hyperpigmentation (compared with erythema nodosum associated with
sarcoidosis and inflammatory bowel disease, which does not ulcerate and heals without scarring).
3. Pseudofolliculitis and acneiform nodules develop frequently over the neck and
face.
4. Migratory thrombophlebitis also commonly occurs in Behçet disease.
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B. Ocular (pan-uveitis): (60% of patients):

✓ One of the hallmark manifestations -- occur early in the course -- the most common causes of
disability.
✓ Behçet disease is one of the few autoimmune diseases that can cause both
anterior and posterior uveitis.
✓ Anterior uveitis typically presents with a red eye, intense photophobia, and blurred
vision. (The anterior uveitis may be so intense that a grossly visible layer of pus in the anterior chamber (hypopyon)
develops).
✓ The posterior uveitis and vasculitis of the carotid and retina occur less commonly
but cause a greater threat to vision.
✓ Recurrent or persistent ocular inflammation frequently leads to visual loss.
▪ Joints: (50% of patients): ▪ Large vessel (40%):

✓ Peripheral arthritis (monarticular or ✓ A major cause of morbidity and
polyarticular- usually not deforming) mortality.
✓ Spondylitis: usually presents as ✓ Deep venous thrombosis (DVT) is the
sacroiliitis (with low back or buttock most common large vascular lesion.
pain). ✓ Affect both arterial & venous systems.
▪ CNS (20%): The neurologic features are ▪ Genital ulcers

variable and includes: ✓ Genital ulcers of BD are similar in
✓ Headache and confusion (from appearance to oral lesions, but can be
recurrent sterile meningitis) and deeper and demonstrate a higher
meningoencephalitis. tendency to scar.
✓ Stroke (thrombotic or hemorrhagic). ✓ They favor the scrotum and penis in men
✓ TIAs – dementia – seizures - and vulva or vaginal mucosa in women
psychiatric disease & personality and are associated with severe pain,
changes.
dyspareunia, strictures, and fistulae.
▪ GIT (25%):
✓ Appear at any time, typically emerges several years after the onset of oral ulcers.
✓ Most commonly presents as aphthous ulcers affecting the ileum and cecum (any portion
of the gut from the mouth to the anus can be involved).
✓ The most frequent manifestations of bowel involvement are pain, anorexia, rectal
bleeding, vomiting, and diarrhea.
✓ Ischemia of the bowel (vasculitis of the medium- and large-sized mesenteric arteries).
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International Study Group for Behçet’s Disease

➢ Recurrent oral ulceration (herpetiform ulceration or minor or major aphthous ulcer recurring ≥ 3 times
in one 12-month period)
Plus two of
➢ Recurrent genital ulceration or scarring.
➢ Eye lesions (anterior uveitis, posterior uveitis, retinal vasculitis)
➢ Skin lesions (erythema nodosum, pseudofolliculitis, papulopustular lesions, acneiform nodules
in post-adolescent patients).
➢ Positive pathergy test
International Criteria for Behçet’s Disease (2008)

Two points for each One point for each
✓ Oral aphthosis ✓ Skin lesions
✓ Genital aphthosis ✓ Neurologic manifestations
✓ Ocular lesions ✓ Vascular manifestations
✓ Positive pathergy
Diagnosis established by score ≥ 4
Differential Diagnosis of Behçet disease

❖ The DD of recurrent oral and genital aphthous ulceration includes:
1. Complex aphthosis (the label given to patients who suffer from almost constant mouth ulcers or
recurrent oral and genital ulcers in the absence of Behçet disease).
2. Infection: Herpes simplex virus -- HIV disease
3. Autoimmune diseases : SLE -- Crohn disease – reactive arthropathy.
4. Cyclic neutropenia.
5. Drugs: NSAIDs
6. Vitamin or other nutrient deficiencies (including iron, zinc, folate, and vitamins B1, B2, B6, or B12).
7. PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis).
8. MAGIC syndrome (mouth and genital ulcers with inflamed cartilage).
❖ The DD of Erythema nodosa includes:

1. Sarcoidosis
2. Inflammatory bowel disease.
3. Recative arthritis.
4. Syphilis.
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Work Up
➢ Laboratory:
➢ No specific blood test abnormalities
➢ During attacks of active inflammation: Elevated ESR & CRP - Normochromic
normocytic anemia & mild leukocytosis (Nonspecific markers of inflammation).
➢ Elevated levels of serum IgD.
➢ Radiology:
➢ CT& MRI: for patients with neurologic disease.
➢ Angiograms or MR angiography can demonstrate large-artery thrombosis and
aneurysm, typically seen in the chest or abdomen.
➢ Biopsy: Biopsies of mucocutaneous lesions and gastrointestinal ulcers reveal a

neutrophilic vascular reaction (True vasculitis is rare).
➢ Pathergy test: Highly specific for BD (sensitivity 60% & specificity 87%)
1. Pathergy is an excessive skin response to trauma, reflecting neutrophil

hyperreactivity.
2. Pathergy is suggested if there is a history of red papules, pustules, or sterile abscesses after
therapeutic injections, at intravenous catheter sites, or after minor skin trauma.
3. Testing for pathergy can be done with a sterile 20-gauge needle, used to penetrate the
cleansed skin perpendicularly to a depth of approximately one quarter of an inch, rotated briefly on its axis, and
then removed.
4. After 48 hours, the appearance of an erythematous papule or pustule at the
puncture site constitutes a positive test.
5. The volar forearm is usually chosen for the test and sensitivity is greater when three
needle punctures are made.
6. The positivity of the test may vary during the course of the disease and is more
likely to be positive at times of active disease.
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TREATMENT:
❖ Treatment of BD depends on:
✓ The organ system(s) involved and severity of involvement.
✓ Frequency of recurrences.
✓ Disease duration.
✓ Age at disease onset and sex.
❖ Aim of treatment:
✓ Reduce or prevent recurrences.
✓ Prevent irreversible organ damage.
✓ Improve quality of life.
❖ Poor prognostic factors:

✓ Young age at disease onset.
✓ Male sex.
✓ Ocular, vascular, CNS involvement.
❖ Inflammatory eye disease: ➢ Azathioprine (or MMF) and systemic corticosteroids (prednisone 0,5-1mg/day).
❖ Severe eye disease: ➢ Azathioprine (or MMF ) and systemic corticosteroids (prednisone 0,5-1mg/day).
(defined as >2 lines of drop in visual In combination with either
acuity on a 10/10 scale and/or retinal Cyclosporine A or anti-TNF agents (Infliximab or Adalimumab) & in
vasculitis or macular involvement). severe resistant eye disease Infliximab or Rituximab are recommended.
Local Eye therapy: ➢ Topical steroids drops --- Intravitreal steroids (in combination with systemic therapy)
❖ CNS involvement: ➢ Pulse steroid (High-dose intravenous methylprednisolone 1000 mg/d for 3–5 days) followed by
gradual tapering on high dose oral steroids. +
➢ Immunosuppressive therapy (Azathioprine or MMF) & in severe resistant
cases anti-TNF agents are recommended.
➢ Cyclosporine A should not be used in BD patients with CNS involvement.
❖ Mucocutaneous Disease ➢ Predominant oral and genital ulcers: Topical measures (Topical or intralesional
corticosteroids-- Topical sucralfate & Local anesthetics).
➢ Predominant erythema nodosum: Colchicine is preferred.
➢ Recurrent & resistant cases: Colchicine – AZA – Low dose oral steroids – Dapson
❖ Vascular involvement: ➢ High dose oral steroids + Immunosuppressive therapy (Azathioprine,
Cyclosporine A or Cyclophosphamide) & in severe resistant cases anti-
TNF agents are recommended.
❖ Arthritis ➢ Colchicine --- (NSAIDs or low dose steroids as 2nd line).
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Last Eular Recommendations for management of Behcet disease
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Primary Angiitis of the Central Nervous System

(PACNS)
❖ Definition: PACNS is rare vasculitis that is confined only to the brain, meninges, or
spinal cord.
❖ EPIDEMIOLOGY
✓ The incidence of PACNS is estimated at 2.4 cases per 1 million person-years.
✓ PACNS occurs more commonly in men than women at a ratio of 2:1.
✓ The average age of patients with PACNS is 50 years.
❖ Presentation:
➢ PACNS is divided into two subsets:
1. Granulomatous angiitis of the central nervous system (GACNS).
2. Atypical PACNS.
➢ Common presentation includes: headache, encephalopathy, and multiple strokes.
➢ Mass like lesions (a rare manifestation of PACNS that occurs in less than 5% of cases. presented with a
solitary cerebral mass).
❖ Diagnostic Criteria (A definite diagnosis of PACNS requires the following):
1. Clinical: Symptoms and signs of an acquired neurologic deficit consistent

with the diagnosis of PACNS (eg, headache, confusion, and multiple
strokes).
2. Biopsy: A brain or spinal cord biopsy demonstrating vasculitis in the
absence of infection.
3. Exclusion: No evidence of a systemic vasculitis or another disorder that
could cause the clinical picture, despite a thorough investigation.
➢ In the absence of a positive biopsy, the patient should meet the other two
criteria and has an angiogram with classic changes of vasculitis in
multiple intracranial vessels.
❖ Work Up: Spinal fluid, brain and vascular imaging, and brain biopsy are central to the
diagnosis of PACNS and the process of ruling out other diseases.
➢ Spinal fluid:
✓ CSF findings are nonspecific in PACNS, their value lies in ruling out other
diseases.
✓ Elevated protein levels, modest lymphocytic pleocytosis, and occasionally
oligoclonal bands and elevated IgG synthesis characterize the CSF in 80% to
90% of patients.
✓ Typically, the CSF findings include those of an aseptic meningitis picture with
negative staining for microorganisms.
➢ Brain biopsy, cerebral angiogram & MRI are an important part of the evaluation to
confirm the diagnosis and rule out mimics.
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❖ DD
➢ Reversible cerebral vasoconstriction syndrome:
✓ It is an important mimic of PACNS characterized by thunderclap
headaches, normal CSF, and abnormal cerebral angiogram in
which the changes resolve within 12 weeks.
✓ RCVS occurs more frequently in women than men.
➢ Infection.
➢ lymphoproliferative disease,
➢ Primary systemic vasculitis & connective tissue disease
➢ Thromboembolic disease.
❖ Treatment
➢ Induction therapy: (3-6monthes)
✓ High-dose intravenous methylprednisolone: for 3–days followed by Oral
glucocorticoids: Prednisone (40–60 mg/d) for at least one month then tapering.
✓ Cyclophosphamide pulse monthly.
➢ Maintenance therapy: (1-2years) AZA +Low-dose glucocorticoid therapy
ERYTHEMA ELEVATUM DIUTINUM

❖ Definition: Erythema elevatum diutinum (EED) is an extremely rare, chronic, recurrent
leukocytoclastic vasculitis limited to the skin.
❖ Presentation:
➢ The disorder affects both men and women in middle age.
➢ Lesions: Plaques with annular or nodular appearance -- purple, red, or brown.

➢ Erupting lesions may be associated with stinging, burning, or tenderness, and may be
accompanied by systemic symptoms.
➢ Sites: the lesions have a predilection for the skin overlying the small joints of the
hands and the knees, they can also affect the buttocks. The trunk is generally spared.
➢ Histopathology: leukocytoclastic vasculitis with a perivascular neutrophilic infiltrate,

then mature lesions demonstrate (perivascular or onion-skin like fibrosis, Capillary proliferation and
cholesterol containing histiocytes may also be seen).
❖ Associations: EED has been associated with various connective tissue diseases,
rheumatoid arthritis, other forms of vasculitis (such as GPA), HIV infections, and
paraproteinemias (particularly IgA).
❖ Treatment:
✓ Proper management of any associated disorder.
✓ Dapsone (100 mg/day) or Sulfapyridine
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Rheumatoid Vasculitis
❖ General Key points:
 Rheumatoid vasculitis (RV) is a medium-vessel vasculitis that occurs in patients with
"burnt-out" but previously severe rheumatoid arthritis (RA).
 Vasculitis rarely occurs in autoimmune diseases or connective tissue diseases
(CTDs) without overt manifestations of the underlying disorder.
❖ Pathogenesis
➢ Immune complex deposition and antibody-mediated destruction of endothelial cells
both appear to contribute to RV.
➢ Certain human leukocyte antigen (HLA)-DR4 alleles that predispose patients to
severe RA may also heighten patients' susceptibility to RV.
➢ Cigarette smoking increases the risk of RV.
➢ RV resembles polyarteritis nodosa because it leads to multiorgan dysfunction in
the skin, peripheral nerves, gastrointestinal tract, and other organs.
❖ Risk factors: Chronic diseases (eg, diabetes, atherosclerosis, and hypertension) play an
important role in promoting vascular occlusion, but the central issue in RV is necrotizing
inflammation of blood vessels.
❖ Clinical Findings
➢ Skin: (the most common manifestation of RV)
✓ Palpable purpura, cutaneous ulcers (particularly in the malleolar region) & digital infarctions.
➢ Nervous System:
✓ Mononeuritis multiplex. (CNS manifestations such as strokes, seizures are less common).
➢ Eyes:
✓ Retinal vasculitis (common but frequently asymptomatic).
✓ Necrotizing scleritis and peripheral ulcerative keratitis.
➢ Disease Hx:
✓ The typical patient has long-standing RA characterized by:
_Rheumatoid nodules. _Destructive joint disease. _High titers of RF.
✓ The diagnosis of RV should be considered in any patient with RA in whom new

constitutional symptoms, skin ulcerations, serositis, digital ischemia, or symptoms
of sensory or motor nerve dysfunction develop.
✓ ESR & CRP: highly elevated but not specific.
✓ Rheumatoid factor: High titer.
✓ Others: Hypocomplementemia, antinuclear antibodies, atypical ANCAs (by
immunofluorescence testing but not enzyme immunoassay;) are all detected more
frequently in patients with RV than in those with RA alone.
❖ Special Tests (The diagnosis must be established by tissue biopsy whenever possible).
✓ Deep skin biopsies (full-thickness biopsies that include some subcutaneous fat)
taken from the edge of ulcers are very useful in detecting the presence of medium-
vessel vasculitis.
✓ Nerve conduction studies help identify involved nerves for biopsy.
✓ Muscle biopsies (eg, of the gastrocnemius muscle) should be performed
simultaneously with nerve biopsies.
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❖ Treatment
 Therapy must reflect the severity of organ involvement.
 Sever disease manifestations such as cutaneous ulcers, vasculitic neuropathy, and
inflammatory eye disease: Pulse Glucocorticoids and\or Cyclophosphamide
NB
➢ Rheumatoid vasculitis (RV) must be distinguished from the isolated, periungual digital
vasculitis that, in the absence of severe involvement, does not require intensive, vasculitis-
specific therapy.
➢ Isolated digital vasculitis in patients with rheumatoid arthritis, characterized by splinter-like
lesions in the periungual region (Bywaters’ lesions), is not necessarily associated with a
poorer prognosis than rheumatoid arthritis without digital vasculitic lesions and does not
require specific therapy for vasculitis.
COGAN’S SYNDROME
❖ DEF: Cogan’s syndrome refers to the association of non-syphilitic interstitial keratitis
and immune-mediated inner ear disease, resulting in audio-vestibular dysfunction.
❖ Age & sex: The disorder affects men and women equally at any age, but typically in their
third and fourth decade.
❖ Presentation:
Patients typically present with red painful eyes and/or hearing loss concurrently or within 4 months.
 Sudden bilateral hearing loss (shows a down-sloping progressive pattern on audiograms)

 Ménière’s-like vertigo and tinnitus.
 Vestibular testing shows bilateral cochlear dysfunction.
 Ocular: Painful red eyes (Scleritis or uveitis).
 Aortitis: Aortic involvement (12%) is the most serious manifestation of Cogan’s
syndrome and accounts for most deaths.
 Systemic manifestations include headache, fever, arthralgia, and vasculitis.
❖ Treatment:
➢ Oral glucocorticiodes: (40–60 mg/d OR 1mg/kg/d): The initial effective dose of
should be continued until all reversible symptoms, signs, and laboratory
abnormalities have reverted to normal (usually takes 2 to 4 weeks) then gradual tapering.
➢ Immunosuppressive therapy (As steroids sparing or in combination with it): MXT, AZA or MMF.
➢ Some patients have only a single episode and are free of active disease thereafter.
➢ The more typical course is one of waxing and waning symptoms for months or years.
❖ Prognosis: the vertigo and ataxia may improve, the hearing loss is usually permanent.
VASCULITIS 293
Kawasaki’s Disease (KD)

❖ Definition: Kawasaki’s disease is the second most prevalent form of pediatric
systemic vasculitis that occurs in young children and may be associated with the
development of coronary arteritis and aneurysm formation (years ago was known as mucocutaneous
lymph node syndrome or infantile polyarteritis nodosa).
❖ Epidemiology:
➢ Age & sex: 80% of cases occurring in children younger than 5 years of age
with male: female ratio is 1.5:1.
➢ Incidence: Incidence rates vary greatly across ethnicity (Asian children have the highest rates,
with 218/100,000 in Japan and 113/100,000 in Korea, compared with 5 to 13/100,000 in Western countries).
❖ Etiology:
➢ Genetic variation in pro-inflammatory genes and matrix metalloproteinases are
thought to play a role in susceptibility and disease severity.
➢ Infection: KD is consistent with an infectious cause (but no infectious etiology has been proven) due to:
✓ Clinical features that resemble infection (fever, lymphadenopathy).
✓ Epidemic occurrences and the seasonal variation of the disease (the illness appears
in late winter and spring).
CLINICAL FEATURES
➢ Onset & course:
✓ KD strikes quickly, runs a furious course over a few weeks, and then apparently resolves
within 1 month.
✓ KD is a monophasic, self-limited inflammatory condition with recurrence rate 1% to 3%.
✓ The cardiac complications are the leading cause of acquired heart disease in childhood in
Western countries.
Diagnostic guide lines for Kawasaki’s Disease

➢ Fever for >5 days (Mostly high grade, spiking)
Plus Four of
➢ Bilateral conjunctivitis (nonpurulent)
➢ Cervical lymphadenopathy (acute & non purulent)
➢ Rash: polymorphous rash typically involves the trunk
➢ Changes in the lips or oral cavity (0ne or more of the following)
✓ Diffuse congestion of oral and pharyngeal mucosa.
✓ A strawberry appearance to the tongue
✓ Erythema and fissuring of the lips.
➢ Changes in peripheral extremities/perineal area (0ne or more of the following)
✓ Erythema of the palms and soles.
✓ Edema of the hand and\or feet.
✓ Desquamation of the finger tips.
➢ Diagnosis can be also made by fever and <4 principal criteria if coronary artery
abnormalities are detected by echocardiogram or coronary angiography
VASCULITIS 294
➢ Cardiac manifestations: (catastrophic heart complications occur in only a small minority of patients <5%).
✓ Heart lesions may include myocarditis, pericarditis, aneurysmal dilatation and
thrombosis of the coronary arteries, and myocardial infarction.
✓ Cardiac manifestations of KD result from a severe pan-vasculitis, leading to
narrowing of the coronary lumina.
➢ Unusual disease features:

✓ Sterile pyuria & urethritis --- Diarrhea & abdominal pain --- Obstructive jaundice.
✓ Arthralgia & arthritis --- Aseptic meningitis.
Atypical KD: Incomplete KD :

➢ The term atypical KD has been used to ➢ The term Incomplete KD has been
describe both older children and young applied to any patient felt to have KD
infants presenting outside the typical age but who did not fulfill classical criteria.
range of 2 to 5 years, as well as those (These are often diagnosed by echocardiogram
presenting with features other than the findings).
classical criteria.
➢ CBC: Leukocytosis – Thrombocytosis – Anemia.
➢ ESR & CRP: Elevated.
➢ Elevated plasma lipids & serum transaminases.
➢ Hypoalbuminemia—Hyponatremia.
❖ RECOMMENDED THERAPY.
➢ Acute Stage: Aspirin 80–100 mg/kg/day in 4 divided doses until the 14th day of illness
+ IVIG 2 g/kg in 1 dose over 10–12 hours
➢ Convalescent Stage (>14th illness day; afebrile patient)

✓ ASA at 3–5 mg/kg/day in a single dose.
✓ Discontinue 6–8 weeks after onset of illness after verifying that no coronary
abnormalities are present by echocardiography.
✓ Chronic Treatment for Patients with Coronary Aneurysms

✓ ASA 3–5 mg/kg/day in a single dose.
✓ Some physicians use warfarin or heparin in combination with antiplatelet therapy in
patients with severe coronary findings or past evidence of coronary thrombosis.
✓ Acute Coronary Thrombosis: Prompt fibrinolytic therapy with streptokinase,

urokinase, or tissue plasminogen activator by a tertiary care center under the
supervision of a cardiologist.
VASCULITIS 295
Buerger’s disease (thromboangiitis obliterans)

❖ DEF: It is an inflammatory vaso-occlusive disease that predominantly affects the
vascular supply to the lower limbs in young adult male tobacco smokers.
❖ Pathology:
✓ In most cases Buerger’s disease affects small arteries and veins in the distal
extremities.
✓ There is a transmural infiltration of polymorphonuclear leukocytes and lymphocytes
with preservation of the internal elastic lamina.
✓ Thrombosis and microabscesses can be found in the vessel wall
❖ Presentation:
 Sites: The disease typically begins distally, with symptoms worse in the tips of the
toes (and fingers), but it progresses to larger, more proximal vessels over several
years.
 Ischemia affects both distal lower & upper extremities
✓ Start with paresthesia or pain on exposure to cold.
✓ Later on: most cases evolve rapidly, however, with increasing ischemic
(claudicant) limb pain, digital cyanosis, splinter hemorrhages, and skin
vesicles.
✓ Digital ulcers occur especially after minor trauma.
✓ Usually, Buerger’s disease does not cause proximal leg claudication.
 Superficial phlebitis occurs in about 1\3 of patients and may be the first symptom.
❖ Typical angiographic changes includes:

✓ Multiple bilateral areas of narrowing or occlusion in the digital, palmar, plantar, ulnar,
radial, tibial, and peroneal arteries.
✓ Small collateral vessels around the occlusion can appear to be corkscrew shaped.
✓ More proximal lesions resemble atherosclerotic occlusion.
❖ Differential diagnosis:
1. Atherosclerosis, hyperviscosity syndrome & Thoracic outlet syndrome.
2. Scleroderma, Takayasu’s arteritis & other rheumatic diseases.
3. Embolic disease including cholesterol emboli and atrial myxomas.
4. Ergot toxicity.
❖ Treatment
➢ The most important treatment is to stop smoking.
➢ Affected limbs must be protected from trauma and cold.
➢ Ulcers and cellulitis often require antibiotics and local wound management.
➢ Calcium channel blockers and pentoxifylline.
➢ Intravenous prostacyclin is effective and superior to aspirin for rest pain or ischemic
ulcers.
➢ Sympathectomy seems to provide little or no long-term benefit and is not usually
recommended.
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Mononeuritis multiplex
❖ Definition: it is a distinctive peripheral neuropathy in which multiple peripheral nerves
are infarcted one at a time (The most characteristic nervous system manifestation of vasculitis).
❖ Causes:
✓ Mononeuritis multiplex is one of the physical findings in medicine of great differential
diagnostic value.
✓ In the absence of diabetes or multiple compression injuries, mononeuritis multiplex
usually means the patient has some form of vasculitis.
✓ The nerve infarctions result from vasculitis of the vasa nervorum, causing ischemia
of a nerve.
✓ Vasculitis most likely to cause mononeuritis multiplex:
-- Polyarteritis nodosa -- Microscopic polyangiitis.
-- Churg-Strauss syndrome -- Wegener granulomatosis.
❖ Clinical presentation:
✓ Almost all patients will have sensory abnormalities (numbness & paresthesia) and
about half will have weakness as well.
✓ Mononeuritis multiplex is usually bilateral & asymmetric (The right hand may demonstrate a
median nerve infarct while the left hand has an ulnar nerve lesion).
Mononeuritis multiplex Nonspecific peripheral neuropathy

The onset of mononeuritis multiplex is strikingly Develop so slowly that the patient cannot
memorable: The patient will often recall the day accurately date the onset of the
that his foot drop or wrist drop began. neuropathy.
Numbness & paresthesia bilateral & The patient experiences numbness and
asymmetric tingling in a symmetric, stocking or glove
distribution
On examination, the damage from mononeuritis Examination of these patients usually fails
multiplex can be mapped to individual, named to identify the involvement of large, named
nerves (eg, the peroneal, tibial, ulnar, radial, or nerves.
median nerves).
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VASCULITIS 298
Basic
Rheumatology
Familial Autoinflammatory
Syndrome.
Adult Stills Disease

FAMILIAL AUTOINFLAMMATORY SYNDROMES
Key points:
➢ Systemic inflammatory disorder Characterized by Recurrent episodes of
inflammatory symptoms such as fever, abdominal pain, diarrhea, rash,
or arthralgia.
➢ Between the fever episodes, patients with most of these syndromes generally feel
healthy and function normally.
➢ The inflammatory episodes occur without an obvious trigger, although some patients
note a relationship to physical stimuli (e.g., exposure to cold), emotional stress, or the
menstrual cycle.
➢ The episodes resolve spontaneously in days or weeks & Patients go undiagnosed
for years.
When a patient has had recurrent fever episodes for more than 2 years, an infection or a malignant disorder is unlikely.
Autoinflammatory syndromes 299



Familial Mediterranean Fever
Key points:
➢ Systemic inflammatory disorder Characterized by recurrent episodes of peritonitis,
pleuritis, and arthritis, usually with fever.
➢ Prevalence: FMF is the most prevalent disorder among the hereditary autoinflammatory
syndromes, with more than 10,000 patients affected worldwide.
➢ Genetics:
• It occurs primarily in people originating from the Mediterranean basin, including
Armenians, Sephardic Jews, Arabs, and Turks.
• FMF is an autosomal recessively inherited disorder.
• Unknown gene on the short arm of chromosome 16, named the
Mediterranean fever (MEFV) gene.
• There are five common mutations, accounting for the majority of FMF
chromosomes.
• In approximately 30% of patients, only one or no mutations in the MEFV gene can
be detected
➢ Age of onset: At the onset of the disease
✓ 50-60% are younger than 10 years.
• 80-95% are younger than 20 years,
✓ 5-10% are older than 20 years at onset.
✓ Onset in persons older than 40 years is rare.
➢ Sex: In adults, FMF is more prevalent in men than in women, with a male-to-
female ratio of 2:1
PATHOGENESIS:
➢ The MEFV gene encodes for a protein of 781 amino acids, known as pyrin
➢ The pro-inflammatory cytokine IL-1β is central in the pathogenesis of FMF.
➢ This cytokine is expressed as an inactive precursor, which is cleaved by caspase-1 to yield the active IL-
1β.
➢ Caspase-1 itself first needs to be activated through the interaction with protein complexes called
inflammasomes.
➢ The major inflammasome complex involved in the activation of caspase-1 and IL-1β is the cryopyrin
➢ Pyrin has an inhibitory effect on caspase-1–mediated activation of IL-1β, through its prevention of the
formation of the cryopyrin inflammasome.
➢ FMF mutations are thought to interfere with the inhibiting interactions of pyrin,
resulting in decreased regulation of IL-1β activation
➢ Individuals with normal pyrin/marenostrin levels may have the ability to deactivate the target chemotactic factor when it is
produced in response to an inflammatory stimulus.

➢ Patients with FMF lack this ability, resulting in uninhibited activity of the chemotactic factor and episodes of inflammation
(with accompanying fever) in the peritoneum, pleura, and joints.
➢ These inflammatory episodes lead to the excess production of amyloid A protein from the acute phase and reactant
serum amyloid A with subsequent deposition in the kidneys; however, only patients with specific MEFV haplotypes develop
amyloidosis.
Clinical Findings
➢ The inflammatory attacks of FMF usually last 1 to 3 days.
➢ The frequency can vary widely; 2 to 4 weeks is the most common interval
➢ Symptoms of serositis (i.e., peritonitis, pleuritis, synovitis) are the main feature of FMF attacks, usually
accompanied by fever.
1. Fever: (Usually the initial symptom with incidence of 100%).

➢ Temperatures rise rapidly to 38-40°C.
➢ Temperature increases may occur before other manifestations & In mild attacks,
it may be the only manifestation.
2. Peritoneal symptoms (Almost all patients with FMF)

➢ Acute abdominal pain, rigidity & vomiting.
➢ Patients with FMF frequently have symptoms which mimic with appendicitis or
cholecystitis and commonly undergo appendectomies and cholecystectomies to
avoid miss diagnosis
➢ In many cases, patients develop constipation during the attack and diarrhea
after the attack resolves.
➢ Even with recurrent attacks, adhesions are rare.
3. Pleural and pericardial symptoms: (25-80%)

➢ Pleurisy: chest pain, cough, transient effusion
➢ Pericarditis (least common)
4. Arthritis: (30-70%).
➢ Usually affect on large joint such as the knee, ankle, or wrist.
➢ May be the only symptom.
➢ The joints are normal between attacks
5. Myalgia:
➢ Generalized myalgias, often coinciding with fever spikes.
➢ May last for 3-6 weeks
6. Skin: (30%).: Most often as erysipelas-like skin lesions on the shins or feet
7. Uncommon manifestations:RARE
➢ Acute scrotal swelling and tenderness
➢ Aseptic meningitis
➢ An increased frequency of Henoch-Schönlein purpura and polyarteritis nodosa
is reported in persons with FMF

LABORATORY FINDINGS
1. During an inflammatory attack, there is marked elevation an acute phase reactant:
which includes:
✓ Marked elevation in ESR, CRP & plasma fibrinogen.
✓ Polymorphonuclear leukocytosis.
2. Serum amyloid A protein: Elevated
3. Proteinuria in patients with FMF is highly suggestive of renal amyloidosis.
4. Genetic testing (MEFV mutation)

✓ Symptomatic patients with at least one MEFV mutation should be considered to
have FMF.
✓ Genetic laboratories usually screen for the five most common mutations, and
rare mutations are missed.
✓ MEFV mutations occur on both alleles in only 70% of typical cases, whereas
in the remaining 30%, only one or no mutation can be detected,
✓ Patients with no gene mutations who meet criteria for FMF should be offered a
trial of colchicine.
Mortality/Morbidity
❖ Amyloidosis: Before the institution of colchicine therapy, proteinuria, followed
by nephrotic syndrome and mortality was almost universal by age 50 years in
North African patients.
❖ Appendectomies: Many patients with undiagnosed FMF have undergone

appendectomy because the severity of the peritoneal episodes seemed to indicate
appendicitis.
❖ Chronic arthritis: Approximately 5% of patients with FMF develop chronic arthritis

that sometimes leads to destructive arthritis of hips or knees.
❖ Fertility and pregnancy: Approximately one third of female patients with FMF are
infertile, and 20-30% of pregnancies result in fetal loss.

CLASSIFICATION CRITERIA
➢ FMF is still primarily a clinical diagnosis.
➢ These criteria were validated in a population with a high prevalence of FMF
and a low prevalence of the other autoinflammatory disorders.
➢ Typical attacks† with peritonitis (generalized)

➢ Typical attacks with pleuritis (unilateral) or pericarditis
Major criteria ➢ Typical attacks with monoarthritis (hip, knee, ankle)
➢ Typical attacks with fever alone
➢ Incomplete abdominal attack
➢ Incomplete attacks‡ involving chest pain
Minor criteria ➢ Incomplete attacks involving monoarthritis
➢ Exertional leg pain
➢ Favorable response to colchicine
Exclusion ➢ Infections
criteria ➢ Malignancies
➢ Other rheumatic diseases
Diagnosis
➢ Requirements for diagnosis of familial Mediterranean fever are:
≥1 major criteria or ≥2 minor criteria.
Sensitivity &
95%
Specificity
Typical attacks are defined as recurrent (≥3 of the same type), Febrile (≥38° C), and short (lasting between 12 hours and 3
days).
Incomplete attacks are defined as painful and recurrent attacks not fulfilling the criteria for a typical attack..
Treatment
❖ Colchicine
➢ Colchicine is the first-line treatment for patients with FMF.
➢ It prevents inflammatory attacks completely in 60% to 75% of patients, and reduces
the number of attacks in an additional 20% to 30% & prevents amyloidosis.
➢ DOSE: The average dose in adults is 0.5mg twice daily but may be increased to 3
mg if no response is seen at the lower dose.
➢ Colchicine has proven to be safe during pregnancy and breastfeeding.
❖ Other drugs: During a fever attack, oral or intramuscular NSAIDs can be used for
pain relief, while glucocorticoids have limited efficacy.

MEVALONATE KINASE DEFICIENCY

(HYPER-IGD SYNDROME)
➢ Prevalence:
• It is an autosomal recessively inherited disorder, but it is far less prevalent than
FMF. Approximately
• 75% of patients are from Western Europe, and 50% are from the Netherlands and
France.
• Most patients with MKD are of Caucasian origin.
➢ Genetics:
• MKD is caused by mutations in the gene encoding for the enzyme mevalonate
kinase, located on the long arm of chromosome 12.
• Patients are most often compound heterozygotes for two missense mutations
➢ Sex: Men and women are equally affected
Clinical Findings
➢ The inflammatory attacks occur, on average, once every 4 to 6 weeks (vary from patient to patient or in an individual patient).
1. Fever:
➢ 90% of patients with MKD (HIDS) experience their first fever episode in the
first year of life.
➢ These episodes become most frequent in childhood and adolescence.
➢ Factors that provoke a fever episode: Vaccination, minor trauma,
surgery, and physical or emotional stress are
➢ The fevers often begin with cold chills and a sharp increase in body
temperature.
➢ The fever disappears spontaneously after 3 to 5 days, although it may take
longer before the symptoms in joints or skin disappear completely.
➢ The high fevers may lead to seizures, especially in young children.
2. Other finding:
➢ Cervical lymphadenopathy.
➢ Abdominal pain with vomiting and diarrhea.
➢ Headache, Myalgia, Arthralgia& Arthritis (principally large joints).
➢ Splenomegaly and hepatomegaly
➢ Skin rash with erythematous macules and papules or petechiae.
➢ Painful aphthous ulcers in the mouth, vagina, or scrotum (40%).
OUTCOME
❖ The long-term outcome in HIDS is relatively benign in most patients.
❖ In some patients, the fever episodes occur less frequently and become less severe
later in life, starting from late adolescence.
❖ Joint destruction, Amyloidosis & abdominal adhesions are a rare complication.

Diagnostic Indicators of Hyper-IgD Syndrome

➢ MKD is diagnosed on the basis of a combination of characteristic clinical
findings and continuously elevated IgD concentrations (>100 IU/mL).
➢ More than 80% of MKD patients combine a high concentration of IgD with
high IgA levels
➢ Elevated erythrocyte sedimentation rate and leukocytosis

➢ Abrupt onset of fever (≥38.5° C)
At Time of ➢ Recurrent attacks
Attacks
➢ Lymphadenopathy (especially cervical)
➢ Abdominal distress (e.g., vomiting, diarrhea, pain)
➢ Skin manifestations (e.g., erythematous macules and papules)
➢ Arthralgias and arthritis
➢ Splenomegaly
➢ Incomplete attacks‡ involving chest pain
Constantly ➢ Elevated IgD (above upper limit of normal) measured on two occasions
Present at least 1 mo apart.
➢ Elevated IgA (≥2.6 g/L)
Specific ➢ Mutations in mevalonate kinase gene

Features ➢ Decreased mevalonate kinase enzyme activity
Treatment
➢ IL-1β inhibition (e.g., anakinra) reduces disease severity and is currently the
most promising therapy
➢ HMG-CoA reductase inhibitor simvastatin showed a beneficial effect of this

drug, with a reduction in number of days of illness in five out of six patients.
➢ Favorable preliminary experience with the TNF antagonist etanercept has been
reported as well as with the IL-6 antagonist tocilizumab
➢ Some individual patients have been reported to have benefited from treatment with
corticosteroids, colchicine, intravenous immunoglobulin, or
cyclosporine, but these results have not been repeated in most patients.

TUMOR NECROSIS FACTOR RECEPTOR–ASSOCIATED

PERIODIC SYNDROME (TRAPS)
➢ Prevalence:
• It is an autosomal dominant inherited disorder.
• It is found primarily in patients from northwestern Europe (a large family from Irish
and Scottish).
➢ Genetics:
• Mutations are found in the gene for the type I TNF receptor (TNFRSF1A), which
is located on the short arm of chromosome
Clinical Findings
➢ A high, spiking fever can be accompanied by skin lesions, myalgia and arthralgia, abdominal distress, and ocular
symptoms.
1. Fever:
➢ High, spiking
➢ There is a large variation in duration and frequency of the fever episodes in
TRAPS.
➢ On average, attacks last 3 to 4 weeks and recur two to six times each year, but
episodes also may be limited to a few days.
2. Skin lesions: The most common cutaneous manifestation is a centrifugal, migratory,

erythematous patch, which may overlie a local area of myalgia.
3. Myalgia: Located primarily in the muscles of the thighs, but it may migrate during the
fever episode, affecting all of the limbs and the torso, face, and neck.
4. Arthralgia
➢ Arthralgia primarily affects large joints, including hips, knees, and ankles.
➢ Frank synovitis is rarer, and when it does occur it is nonerosive, asymmetric,
and monoarticular.
5. Abdominal distress
➢ Abdominal pain occurs in 92% of TRAPS patients during inflammatory attacks
➢ Vomiting &Constipation.
6. Ocular symptoms.
➢ Ocular involvement is characteristic in TRAPS, and it may involve conjunctivitis,
periorbital edema, or periorbital pain in one or both eyes.
➢ Severe uveitis and iritis have been described, and any TRAPS patient with
ocular pain should be examined for these complications.

OUTCOME
❖ Reactive AA amyloidosis is the principal systemic complication of TRAPS. It occurs in
approximately 15% to 25% of patients if untreated and generally leads to renal
impairment.
Diagnostic Indicators of TRAPS

➢ Recurrent episodes of inflammatory symptoms spanning >6 monthes duration
(several symptoms generally occur simultaneously)
a. Fever
b. Abdominal pain
c. Myalgia (migratory)
d. Rash (erythematous macular rash occurs with myalgia)
e. Conjunctivitis or periorbital edema
f. Chest pain
g. Arthralgia or monoarticular synovitis.
➢ Episodes last >5 days on average (although variable).

➢ Responsive to glucocorticosteroids but not colchicine.
➢ Affects family members in autosomal dominant pattern.
➢ Any ethnicity may be affected.
Treatment
➢ NSAIDs and glucocorticoids in high doses (>20 mg/day of oral prednisone)
alleviate the symptoms of fever and inflammation in most TRAPS patients,
although they do not alter the frequency of attacks.
➢ They can be used beneficially at times of attack, and glucocorticoids usually can be
tapered in the course of 1 or 2 weeks, as tolerated.
➢ Anti–IL-1 therapy is considered to be the most effective.

➢ TNF inhibitor (etanercept), has been partially successful in reducing disease
severity

cryopyrin-associated periodic syndrome (CAPS)

➢ Prevalence:
• It is found primarily in large families from Europe and North America with
extensive pedigrees,
➢ Genetics:
• The autosomal dominant cryopyrin-associated periodic syndrome (CAPS)
encompasses three clinical syndromes that all have been traced to mutations in
one common gene on the long arm of chromosome 1.
1. Familial cold autoinflammatory syndrome (FCAS).
2. Muckle-Wells syndrome (MWS).
3. Chronic infantile neurologic cutaneous andarticular syndrome (CINCA), also known as neonatal-
onset multisystemic inflammatory disease (NOMID).
• FCAS the mildest and CINCA the most severe form
Clinical Findings
Familial Cold Autoinflammatory Syndrome
➢ FCAS is characterized by episodes of rash, fever, and arthralgia after generalized exposure to cold
➢ The delay between cold and onset of symptoms varies from 10 minutes to 8 hours.
➢ A typical feature of FCAS is the requirement of cold exposure to trigger the symptoms.
➢ Age of onset: These episodes start at an early age, with 95% of patients having had their first fever episode in the first year
of life—60% within the first days of life. The symptoms tend to become less severe with advancing age.
1. Fever:
➢ The subsequent fever attack varies in length, depending on the degree of cold
exposure; generally, it lasts a few hours to a maximum of 3 days.
2. Rash:
➢ The rash usually starts on the exposed extremities and, in most episodes,
extends to the remainder of the body.
➢ It consists of erythematous macules and plaques urticarial lesions, and
sometimes petechiae and can cause a burning or itchy sensation.
3. Arthralgia:(93%): most often affects the hands, knees, and ankles but can also involve
feet, wrists, and elbows.
4. Other symptoms: Conjunctivitis (84%) during a fever episode, myalgia, profuse
sweating, drowsiness, headache, extreme thirst, and nausea.
Diagnostic Criteria for Familial Cold Autoinflammatory Syndrome

1. Recurrent intermittent episodes of fever and rash that primarily follow generalized cold exposures
2. Autosomal dominant pattern of disease inheritance
3. Age of onset <6 mo
4. Duration of most attacks <24 hr
5. Presence of conjunctivitis associated with attacks
6. Absence of deafness, periorbital edema, lymphadenopathy, and Serositis.

Muckle-Wells Syndrome
➢ Patients have recurrent episodes of fever, abdominal pain, myalgia, urticarial rash and
conjunctivitis, frequently accompanied by arthralgia, arthritis with limb pain, or both.
➢ Attacks start in adolescence and can be provoked by hunger, fatigue, and, sometimes, exposure to cold.
➢ The inflammatory episodes generally last 24 to 48 hours and start with ill-defined malaise and transient chills and rigor,
followed by aching or lancinating pains in the distal limbs and larger joints.
➢ The most feared complication of the inflammatory attacks is type AA amyloidosis, which affects the kidneys first, leading to
proteinuria and subsequent rapid progression to renal failure.
Chronic Infantile Neurologic Cutaneous and Articular Syndrome
➢ A rare congenital disorder defined by the presence of the triad of:

(1) Neonatal-onset skin lesions,
(2) Chronic aseptic meningitis
(3) Recurrent fever along with joint symptoms.
➢ Other clinical feature of CINCA:

▪ Central nervous system involvement (seizures, spasticity, or transient episodes of
hemiplegia.
▪ Ocular manifestations are prominent: (may lead to visual impairment).
✓ Optic disc changes such as optic disc edema, pseudopapilledema, and
optic atrophy.
✓ Anterior segment manifestations such as chronic anterior uveitis
➢ Age of onset: the symptoms in CINCA begin right after birth or in the first months
of life with a generalized skin rash.
➢ Course & Prognosis:

✓ The disease follows an unpredictable course with persistent nonpruritic and
migratory rash with fever, hepatosplenomegaly, and lymphadenopathy.
✓ The prognosis of these patients is grave unless treated aggressively; 20% die in
childhood because of infections, vasculitis, and amyloidosis.
Treatment
➢ Anti–IL-1 therapy is considered to be the most effective.
➢ Previously, high-dose oral corticosteroids were often used and could be modestly
beneficial in some patients.
➢ NSAIDs, disease-modifying anti-rheumatic drugs, and cytotoxic drugs generally do
not help.
➢ Placebo-controlled trials of IL-1β antibody canakinumab in patients with CAPS the
efficacy of an injection of 150 mg canakinumab once every 2 months

BLAU SYNDROME/EARLY-ONSET sARCOIDOSIS

Also known as:
• Familial granulomatous arthritis, and early-onset sarcoidosis (BS/EOS).
• Pediatric granulomatous arthritis
Prevalence & Genetics:

• Caused by mutations in the nucleotide-binding oligomerization domain 2/caspase
recruitment domain 15 gene (NOD2/CARD15)
• Sporadic cases were often classified as EOS precisely because of the absence of
affected relatives.
Clinical Findings
➢ Consists of recurrent granulomatous inflammations affect three typical sites affected are joints, eyes, and skin.
➢ Onset is generally before age 5 years In familial cases.
➢ The major long-term complications are joint deformity and visual impairment
1. Arthritis:
• Granulomatous polyarticular arthritis or tenosynovitis.
• The most frequently involved joints at presentation are wrists, ankles, knees, and
proximal interphalangeal joints.
2. Eye:
• Acute anterior uveitis or a panuveitis which tends to follow a chronic, persistent
course
• Cataracts, secondary glaucoma, and significant visual impairment can result.
3. Skin:
• A papular, erythematous skin rash with associated dermal granulomas, usually
generalized and intermittent, on the trunk and extremities.
4. Other symptoms:
• Generalized lymphadenopathy & recurrent fever.
• Cranial neuropathies.
• Interstitial lung disease.
Diagnosis
➢ The most important aspect of diagnosis is histologic evidence of granulomas at the
site of inflammation (can be obtained by biopsy of any involved site, of which skin is least invasive).
➢ Genetic testing is available for NOD2/CARD15 mutations.
Treatment
➢ A good response to the TNF inhibitor infliximab was described in case reports.
➢ The panuveitis is usually managed by topical, subconjunctival, or systemic
corticosteroids.
➢ There tends to be a poor response to NSAIDs.

PYOGENIC STERILE ARTHRITIS, PYODERMA GANGRENOSUM,

AND ACNE SYNDROME
Prevalence & Genetics:

• Caused by mutations in the CD2- binding protein 1 (CD2BP1) gene as the cause of
PAPA syndrome.
• CD2BP1, also known as proline-serine-threonine phosphatase interacting protein 1
(PSTPIP1), is highly in neutrophils.
Clinical Findings
➢ Symptoms of:
1. Pyogenic sterile arthritis.
2. Pyoderma gangrenosum.
3. Severe cystic acne.
➢ Lesions generally occur at the site of mild physical trauma.

➢ The inflammation can be severe and eventually may lead to destruction of joints,
muscle, and skin.
➢ Fever is not prominent in this syndrome.
➢ Onset is usually from age 1 to 16 years.
Diagnosis
➢ No specific diagnostic test exists.
➢ Diagnosis is based on a finding of the typical constellation of symptoms and a positive
family history.
Treatment
➢ High-dose steroids: have a positive effect on the pyoderma gangrenosum &
Pyogenic arthritis but may be associated with increased acne.
➢ Varying results have been reported with anti-cytokine treatment.
➢ The TNF inhibitor & the IL-1 inhibitor anakinra was reported to be beneficial.
DEFICIENCY OF THE IL-1 RECEPTOR ANTAGONIST

➢ It is a more recent discovery of a monogenetic disorder in the group of autoinflammatory diseases.
➢ All patients were homozygous for mutations affecting the gene encoding the IL-1 receptor antagonist (IL-1ra), designated
IL1RN.
➢ These mutations resulted in an absence of secretion of IL-1ra.
➢ The patients showed signs of unopposed IL-1 signaling, leading to overproduction of other inflammatory cytokines and
chemokines.
➢ The clinical phenotype is present at birth or in the first month of life.
➢ Features include primarily cutaneous pustulosis and sterile pustulous osteomyelitis.
➢ Patients do not present with fever.
➢ The diagnosis is made by a combination of the clinical features and an impressive response to anakinra.

ADULT STILLS DISEASE

Definition: Systemic inflammatory disorder of unknown etiology characterized by daily
high spiking fever, fleeting rash, arthritis and systemic manifestations.
Epidemiology:
• Prevalence: rare disease account for 0.1 % of 100,000 of population
• Age of onset: bimodal peak 15-25 and 35-45
• Sex: Females and males are equally affected.
PATHOGENESIS:
1. Genetics:
- Some observations support association with HLA B 17B18 ,B35 and DR2.
- Other support association with HLA B14 and DR7.
2. Environmental factors:
- Infectious agents: rubella ,mumps ,EBV ,CMV ,Influanza ,HCV HBV ,HIV .
- Microbial agents: mycoplasma pneumonia –chlamydia – brucella abortus.
3. Cytokines:
- Ptns with active ASD had elevated serum level of IL1 - IL6 - IL18 – TNF alpha –
IFN gamma.
- Over production of these cytokines may account for fever, leucocytosis and acute
phase protein production .
COURSE of the disease

1- Self-limiting or monophasic pattern:
➢ Single disease episode with systemic symptoms; fever, rash, serositis, hepato- and
splenomegaly.
➢ Most patients achieve complete remission within one year.
2- Intermittent or polycyclic systemic pattern:

➢ Recurrent disease flares with systemic symptoms, with or without articular
symptoms.
➢ Complete remission of symptoms between flares.
➢ Subsequent flares tend to be less severe and of shorter duration, and may be years
apart.
3- Chronic articular pattern:
➢ Persistent active disease with predominantly articular symptoms.
➢ Patients may have severe, destructive arthritis, 67%.
Clinical Findings
1. Fever: (Usually the initial symptom of ASD with incidence of 96%).
➢ Sudden onset daily spiking high fever, peak once daily in the late afternoon
or early evening generally exceeding 39°C and lasting under 4 hours, returning
to normal in 80% of patients even without antipyretic treatment.
➢ Sometimes has a double quotidian pattern, with highest spikes occurring
in the late afternoon or early evening.
2. Rash: (73%).
➢ An evanescent salmon-pink, macular or maculopapular eruption.
➢ Predominantly involving proximal limbs and trunk.
➢ Usually emerges with the fever, especially in the evenings.
➢ The rash may be mildly pruritic, and is often confused with drug allergy.
➢ Koebner phenomenon: The rash can exhibit the Koebner phenomenon, and as
a result may occur especially in areas subject to friction, i.e. tight clothing.
3. Arthritis: (70-95%).
➢ Pattern: initially mild, oligoarticular and transient, evolving over a period of
several months into a more severe, destructive, symmetrical and polyarticular
form.
➢ Affected joints:
✓ Mainly: knees, wrists and ankles.
✓ Other: elbows, shoulders, hips, interphalangeal-, MCP, MTP and
temporomandibular joints may also be involved.
4. Myalgia: (60-90%).
✓ Generalised myalgias, often coinciding with fever spikes .
✓ serum creatinine kinase and aldolase may be slightly elevated .
5. Liver disease: (50-70%).
✓ Hepatomegaly & elevated liver enzymes partly secondary to the use of (NSAIDs).
✓ Fatal fulminant liver failure has been described in ASD.
6. Pharyngitis: (70%).
7. Lymphadenopathy and splenomegaly:(50%).
8. Cardiopulmonary disease:
➢ Pleuritis, pericarditis and transient pulmonary infiltrates, occurring in 30% of
ptns.
➢ Rare:
✓ Sever interstitial lung disease and progression to acute respiratory distress
syndrome (ARDS).
✓ cardiac tamponade and myocarditis.

9. Hematologic manifestations:RARE
➢ Pancytopenia may be due to the hemophagocytic (macrophage activation)
syndrome.
➢ Thrombotic thrombocytopenic purpura and/or the hemolytic uremic syndrome
can occure.
LABORATORY FINDINGS
1-CBC:
➢ Leukocytosis: typical finding - markedly elevated > 15 x 10³.
➢ Thrombocytosis
➢ Normocytic normochromic anemia:
➢ Pancytopenia: may be due to the hemophagocytic (macrophage activation)
syndrome.
➢ ↑ intravascular coagulation: clotting should be monitored in active disease.
2-Acute phase reactant: Marked elevation in ESR & CRP.
3-Liver functions:
➢ Elevated ALT, AST, lactate dehydrogenase and bilirubin are seen in 75% of patients
with ASD.
4-Serum ferritin: (normal range 40-200 ng/ml)

➢ Ferritin is an acute phase reactant, produced by the histiocyte - macrophage system
under influence of IL-1β, IL-18, TNF-α and IL-6 and is also released by damaged
hepatocytes.
➢ Elevated in 70% of ptns with ASD and correlate with disease activity .
➢ Fivefold the upper limit of normal (1000 ng/ml) used to suggest ASD.
➢ Very high levels are present in other diseases, like hemochromatosis, infections and malignancies.
5-Glycosylated ferritin :
➢ More specific than serum ferritin for the diagnosis ASD.
➢ Normally: In healthy subjects 50-80% of ferritin is glycosylated which is dropped to
lower than 20% due to saturation of the glycosylation mechanism.
➢ Remains low in both the active phase of the disease and in remission.
Radiographic findings
➢ No radiographic finding is specific for ASD.
➢ The classic radiographic finding, seen in 41% of patients with ASD:
✓ A non-erosive intercarpal and carpometacarpal joint space narrowing of the
wrist.
✓ Bilateral in 69%.
✓ Typically, present 6 months after disease onset.
➢ Developing to bony ankylosis in 25% in 1.5 to 3 years
CLASSIFICATION CRITERIA
Yamaguchi criteria
A. Major criteria ➢ Fever of at least 39ºC, intermittent, lasting one week or longer
➢ Arthralgias or arthritis, lasting two weeks or longer
➢ Typical rash
➢ Leukocytosis (10,000/μL or greater), with 80% or more
granulocytes
B. Minor criteria ➢ Sore throat

➢ Recent development of significant lymphadenopathy
➢ Hepatomegaly or splenomegaly.
➢ Elevated liver enzymes

➢ Negative tests for ANA and rheumatoid factor
C. Exclusion ➢ Infections
criteria ➢ Malignancies
➢ Other rheumatic diseases
D. Diagnosis ➢ The Diagnosis ASD is established with the presence of five
criteria or more, with at least two major criteria present.
E. Sensitivity &
Sensitivity:96% & Specificity:92%
Specificity
Fautrel criteria
Major criteria 1. Spiking Fever.
2. Arthralgias.
3. Transient erythematous rash
4. Sore throat
5. Polymorphonuclear cells (80% or more)

6. Glycosylated ferritin (20% or less)
Minor criteria Maculopapular rash

Leukocytosis (10,000/μL or greater)
Diagnosis ➢ Presence of four or more major criteria

or
➢ Three major + two minor criteria.
F. Sensitivity &
Sensitivity:80% & Specificity:98%
Specificity

Granulomatous disorders Malignancy
• Sarcoidosis • Leukemia
• Idiopathic granulomatosis hepatitis • Lymphoma
• Crohn’s disease • Angioblastic lymphadenopathy
Vasculitis Infection
• Serum sickness • Viral infection (e.g., hepatitis B,
• Polyarteritis nodosa rubella, parvovirus,EBV, CMV, HIV)
• Subacute bacterial endocarditis
• Wegener’s granulomatosis
• Chronic meningococcemia
• ITP • Gonococcemia
• Tuberculosis
• Takayasu’s arteritis
• Lyme disease
Connective tissue disease • Syphilis
• Systemic lupus erythematosus • Rheumatic fever
• Mixed connective tissue disease
PROGNOSIS
➢ Predictors of chronic disease at disease onset are:
✓ Rash ----- Polyarthritis ----- Involvement of shoulders and hips.
➢ Patients with a chronic articular disease have a worse prognosis and more
disability.
➢ Patients with systemic disease have a favorable prognosis.
➢ Most common causes of death in ASD ----- Amyloidosis.

Treatment
1. NSAIDs and aspirin:
- Fist-line therapy for musculoskeletal symptoms and fever.
- Effective in controlling disease activity in only 7-15% of patients with ASD.
2. Glucocorticoids:
- Most patients require steroids at some point in the course of the disease
- The usual prednisone dose is 0.5 to 1.0 mg/kg/day.
- Pulse methylprednisolone therapy indicated for severe disease, refractory to
oral steroids
3. Immunomodulating drugs
➢ The use of immunomodulating drugs should be reserved for severe cases refractory to a combination of NSAIDs and
steroids, or when a reduction in the requirement of steroids is required.
A- Methotrexate :
- Methotrexate seems especially effective for treatment of polyarthritis in ASD,
with complete remission of arthritis in many cases
B- Cyclosporine.
C- Sulfasalazine:
D- Intravenous immunoglobulin :
4. Anti-tumour necrosis factor alpha

• Infliximab (Remicade):
• Etanercept (Enbrel): Less effective than infliximab.
5. Anti IL-6: Tocilizumab: dramatic decrease in inflammatory parameters and systemic

and articular symptoms.
6. Anakinra: (kineret) : IL-1 receptor antagonist.


Mustafa Elmenawy
Basic
Rheumatology
Osteoarthritis
OsteoArthritis
Definition: OA is a slowly progressive degenerative joint disease affecting the cartilage,
joint lining, ligaments, and bone. OA characterized by gradual loss of articular
cartilage, combined with thickening of the subchondral bone, bony outgrowths
(osteophytes) at joint margins, and mild, chronic nonspecific synovial inflammation.
Epidemiology:
• Prevalence:
✓ Osteoarthritis in an estimated 12% of the adult population (>age 25 years) overall.
✓ Symptomatic knee OA in 7% to 24% and hip OA in 8% to 11% of those > 45 years of age.
✓ Radiographic knee OA in 14% to 37%; hip OA in 11% to 27%; first MTP OA in 12% to 35%
✓ Radiographic hand osteoarthritis in 67% of women and 55% men over age 55 years.
✓ Between 10% and 30% of patients with osteoarthritis are significantly disabled/
• Age of onset: Based on radiographic criteria, osteoarthritis occurs in 30% of affected

individuals aged 45-65 years and in more than 80% by their eighth decade of life, although most are
asymptomatic.
RISK FACTORS OF OSTEOARTHRITIS
A- Genetic Factors:
✓ Genetics plays a role in increasing the risk of some joints to 1ry OA.
✓ OA of the hips and hands often runs in families, while knee OA is more often the
consequence of joint injury and loading history.
✓ Polymorphisms in several other genes may contribute incremental risk for RA.
B- AGE:
✓ Age is the risk factor most strongly correlated with OA.
✓ The risk of primary osteoarthritis increase with aging.
✓ Patients are often asymptomatic. Approximately 80-90% of individuals older than
65 years have evidence of radiographic primary osteoarthritis.
✓ These age-related tissue changes are most likely due to decrease in chondrocytes’
ability to maintain and repair the tissue.
C- SEX:
✓ Before the age of 50 years, Women have a lower prevalence of OA than men
(Chondrocytes have functional estrogen receptors. Women on estrogen replacement therapy have less hip
osteoarthritis and knee osteoarthritis).
✓ After the age of 55 years, the prevalence of osteoarthritis is higher among
women than among men with a female-to-male incidence ratio of 2:1.
Osteoarthritis 321
✓ Women are especially susceptible to osteoarthritis in the DIP joints of the fingers and
Knee OA.
✓ Erosive osteoarthritis more common in women, with a female-to-male ratio of about
12:1.
D- Obesity:
➢ Obesity is a clear risk factor for the development of osteoarthritis, especially of the
knee.
➢ Mechanism:
✓ Obesity increases the forces across weight-bearing joints and alters joint
mechanics by causing varus stress at the knee and changes in posture and gait.
✓ Obesity not only increases the forces at weight-bearing joints, but may also
change posture, gait, and physical activity level, any or all of which may further
contribute to altered joint biomechanics.
✓ Adipose tissue is a source of proinflammatory cytokines including leptin,
adiponectin, resistin, IL-1, IL-6, and TNF-α ➔ Negative effects on chondrocyte
function.
E- Joint Malalignment and Trauma
➢ Joint malalignment or trauma may lead to rapid development of OA, or it may initiate
a slow process that results in symptomatic OA years later.
➢ Altered joint geometry interferes with nutrition of the cartilage and alters load
distribution, either of which may result in altered biochemical composition of the
cartilage, irrespective of age.
➢ Repetitive trauma at a subfracture level has been shown to accelerate remodeling
in the zone of calcified cartilage, with reduplication of the tidemark and thinning of the
noncalcified zone, resulting in stiffening of the subchondral bone, increased wear of
the overlying cartilage, and, ultimately, development of OA.
➢ Joint incongruence (e.g., malreduced intra-articular fractures, developmental
dysplasia of the hip and recurrent dislocation of the patella) can lead to early-onset
OA.
➢ Local factors, such as stresses related to joint use and joint deformity, also
influence the development of OA.
➢ Certain occupations/sports causing repetitive high impact loading:

✓ Pneumatic drill operators (shoulders, elbows), Ballet dancers (ankles), Boxers
(MCP joints) and Basketball players (knees).
Osteoarthritis 322
Classification of osteoarthritis:
Primary OA
(Idiopathic, Predilection for 1st CMC, DIP, PIP, knee, and hip joint.)
❖ Localized:
➢ Hands:
✓ Heberden and Bouchard nodes [nodal]
✓ Erosive interphalangeal arthritis [nonnodal].
✓ Scaphometacarpal and scaphotrapezial.
➢ Feet:
✓ Hallux valgus, hallux rigidus, contracted toes [hammer/ cock-up toes.
✓ Talonavicular.
➢ Knee:
✓ Medial compartment - Lateral compartment - Patellofemoral compartment
➢ Hip:
✓ Eccentric (superior) - Concentric (axial, medial) - Diffuse (coxae senilis)
➢ Spine (particularly cervical and lumbar)
✓ Apophyseal
✓ Intervertebral (disk)
✓ Spondylosis (osteophytes)
✓ Ligamentous (hyperostosis [Forestier disease or DISH])
➢ Other single sites (e.g., shoulder, temporomandibular, sacroiliac, ankle, wrist, acromioclavicular).
❖ Generalized: includes three or more areas listed above (Kellgren-Moore)

1. Small (peripheral) and spine.
2. Large (central) and spine.
3. Mixed (peripheral and central) and spine.
Secondary OA
A. Metabolic disorders: B. Mechanical & local factors:
1. Crystal-associated arthritis. 1. Slipped capital femoral epiphysis.
2. Acromegaly. 2. Femoroacetabular impingement.
3. Ochronosis. 3. Epiphyseal dysplasias.
4. Hemochromatosis. 4. Legg-Calvé-Perthes disease.
5. Wilson’s disease. 5. Congenital dislocation.
6. Hyperparathyroidism. 6. Congenital hip dysplasia.
7. Ehlers-Danlos syndrome. 7. Limb-length inequality.
8. Gaucher’s disease. 8. Hypermobility syndromes.
9. Diabetes. 9. Avascular necrosis/osteonecrosis.
10. Genu varum
C. Post-traumatic: D. Inflammatory joint diseases:
1. Joint trauma (e.g., ACL tear). 1. RA /Other inflammatory arthropathies.
2. Fracture through joint. 2. Crystalline arthropathy (gout)
3. Prior joint surgery (Meniscectomy, ACL). 3. History of septic arthritis.
4. Charcot joint (neuropathic arthropathy).
Osteoarthritis 323

Normal cartilage
The Normal Cartilage has two main components:
➢ The extracellular matrix:
✓ The extracellular matrix is rich in collagens (mainly types II, IX, and XI) and
proteoglycans (mainly aggrecan).
✓ The matrix components are responsible for the tensile strength and
resistance to mechanical loading of the articular cartilage.
➢ Isolated chondrocytes: which lie in the matrix.
Passage of Normal Cartilage to Aging Cartilage:
1. Stress fractures of the collagen network which lead to fissures that develop in
cartilage during aging.
2. Several structural and biochemical changes involving the noncollagenous

component of the matrix occur during aging. These changes alter biomechanical
properties of the cartilage that are essential for the distribution of forces in the
weight-bearing zone.
3. Aging cartilage contains:

✓ Less water, which alters the biochemical properties of the cartilage.
✓ Less chondrocytes, which decreases the capacity of cartilage to synthesize
matrix.
✓ Altered collagens properties.
✓ Impaired vascularization & perfusion.
 Pathological changes occurs as following:
 Target tissue: OA is a disease in which most or all of the joint structures are
affected by pathology, but the primary tissue affected is the thin rim of
hyaline articular cartilage interposed between the two articulating bones.
Phase 1: Edema and Microcracks:

✓ The first recognizable change in OA is edema of the extracellular matrix.
✓ The cartilage loses its smooth aspect, and microcracks appear.
✓ There is a focal loss of chondrocytes, alternating with areas of chondrocyte
proliferation.
Phase 2: Fissuring and Pitting:
✓ The microcracks deepen perpendicularly in the direction of the forces of tangential
cutting and along fibrils of collagen.
✓ Vertical clefts form in the subchondral bone cartilage.
Osteoarthritis 324
Phase 3: Erosion:
✓ Fissures cause fragments of cartilage to detach and “fall” into the articular cavity,
creating osteocartilaginous loose bodies.
✓ The loose bodies cause the mild synovial inflammation of OA.
Finale result:
✓ Sclerosis of the subchondral bone, due to the apposition of small strips of new bone.
✓ Osteophytes form around this zone, their surface covered with fibrilar cartilage.
✓ Reduced joint space.
PATHOGENESIS
➢ The physiologic homeostasis of the articular cartilage is driven by chondrocytes, which

synthesize collagens, proteoglycans, and proteinases.
➢ Osteoarthritis results from a failure of chondrocytes within the joint to

synthesize a good quality matrix, in terms of resistance and elasticity, and to
maintain the balance between synthesis and degradation of the extracellular
matrix.
➢ Chondrocyte hypertrophy can contribute to the progression of OA via effects including:

✓ Dysregulation of matrix repair.
✓ Upregulation of matrix metalloproteinase 13 (MMP-13).
✓ Promotion of pathologic calcification.
➢ The imbalance between synthesis and degradation of the extracellular matrix is

caused by:
✓ Increasing synthesis of proteinases that breakdown collagens and aggrecans.
✓ Decreased synthesis of natural inhibitors of these proteinases, the tissue
inhibitor of metalloproteinases (TIMPs).
➢ Synovial tissue and chondrocyte activation:

✓ Synovial cells phagocytize the fragments of cartilage released into the joint, which
causes synovial inflammation.
✓ OA synovial cells become capable of producing a range of mediators that are
released in the cavity, such as MMPs and cytokines, which in turn can alter the
cartilage matrix and activate chondrocytes.
Enzymes Involved in Cartilage Degradation

➢ Matrix metalloproteinase MMPS
✓ The main proteinases involved in the destruction of cartilage in OA are the MMPs.
✓ They are synthesized by chondrocytes and synoviocytes under the influence of
cytokines.
✓ MMPs produced by the chondrocyte and released into the extracellular matrix are
activated by an enzyme cascade.
Osteoarthritis 325
✓ This enzymatic cascade is regulated by natural inhibitors, including the TIMPs and
the inhibitors of the plasminogen activator.
✓ MMP-13 is elevated in OA joint tissues, particularly in articular cartilage
➢ Cathepsins:
✓ They are enzymes that can degrade type II collagen and proteoglycans
✓ Cathepsins are stored in chondrocyte lysosomes and released into the pericellular
microenvironment.
Cytokines Involved in Cartilage Degradation

➢ Inflammatory cytokines provide essential biomechanical signals that stimulate
chondrocytes to release cartilagedegrading enzymes.
➢ Proinflammatory cytokines synthesized by chondrocytes and synoviocytes bind to
specific receptors on chondrocytes.
➢ Interleukin (IL) 1:
✓ It is the pivotal cytokine released during inflammation of the osteoarthritic joint.
✓ IL-1 alters the quality of the cartilage matrix by decreasing synthesis of type II
and IX collagens while increasing the synthesis of type I and type III collagens.
➢ Other cytokines are released,including chemokines (IL-8, GRO alpha, MIP-1 alpha and
MIP-1 beta).
➢ Some of these cytokines and chemokines may be:
✓ Regulatory [e.g., IL-6, IL-8, lymphocyte inhibitory factor (LIF)].
✓ Inhibitory (e.g., IL-4, IL-10, IL-13, interferon gamma).
➢ IL-1 receptor antagonist, IL- 4, IL10, and IL-13 prevent the secretion of some MMPs and
may increase the synthesis of TIMPs.
Osteoarthritis 326
Osteoarthritis 327
Clinical Findings
Characteristic sites:
✓ In the peripheral skeleton include the hand (distal interphalangeal joint, proximal
interphalangeal joint, and first carpometacarpal joint (base of the thumb).
✓ In weight bearing joints: Knee, Hip, Cervical & Lumbar spine.
Symptoms:
➢ PAIN:
✓ Joint pain brought on and exacerbated by activity and relieved with rest.
➢ Stiffness:
✓ Stiffness (gelling) that is self-limited upon awakening in the morning (usually less
than 30 min.) or when rising from a seated position after an extended period of
inactivity .
➢ Disability: there is increasing difficulty with previously routine activities:
✓ In an osteoarthritic hand or finger ,tasks such as gripping, holding, or writing
with a pen or pencil, putting car keys in and turning the ignition switch, lifting a
gallon of milk out of the refrigerator, or removing a pot of water from the stove
become difficult tasks.
✓ In osteoarthritis involving the hip joint, patients may have some difficulty
crossing their legs or putting on a pair of shoes
✓ In patients with knee osteoarthritis: Patients will have difficulty in climbing
stairs, squatting and flexed knee positions ,also joint instability or "giving way"
is common, sometimes leading to falling or near-falling events.
➢ Absence of prominent constitutional symptoms.
Signs:
➢ Crepitus (a grating sensation with motion).
➢ Bony enlargement at the joint margin. (suh as Heberden nodes)
➢ Tenderness to palpation over the joint line.
➢ Reduction in joint ROM (later on).
➢ Swelling with or without effusion.
Generalized OA (GOA):
➢ Kellgren and Moore provided the first clinical description of GOA, involving primarily
Heberden’s nodes and the CMC joints, with the spine, knees, hips, and feet involved
in descending frequency.
➢ GOA can be also defined as one of the following:

✓ More than three joint sites affected.
✓ Multiple hand joint involvement.
✓ Nodal hand OA with other joint involvement.
Osteoarthritis 328
Complications
1) Microcrystalline arthropathy (knee and hand joints): Gout & Pseudogout.
2) Ruptured Baker cyst (pseudothrombophlebitis syndrome in the knee)
3) Bursitis: Anserine bursitis (knee) --Trochanteric bursitis (hip).
4) Symptomatic meniscal tear (locking/instability).
5) Muscle weakness and wasting.
6) Ligamentous laxity
7) Deformity (such as Genu varus).
differential diagnosis:
➢ The following disorders should also be considered in the differential diagnosis:
1. Crystalline arthropathies (ie, gout and pseudogout)

2. Inflammatory arthritis (eg, rheumatoid arthritis)
3. Seronegative spondyloarthropathies (eg, psoriatic arthritis and reactive
arthritis)
4. Septic arthritis or postinfectious arthropathy
5. Fibromyalgia
6. Tendonitis
✓ The presence of joint pain brought on by activity and relieved with rest suggests
the existence of osteoarthritis.
✓ The absence of constitutional signs and symptoms and the presence of bony
enlargement and tenderness at the joint margin reinforce this clinical impression.
✓ The pattern of joint involvement:

➢ Osteoarthritis has a predilection for the knees, hips, and distal
interphalangeal, proximal interphalangeal, and first carpometacarpal joints of
the hands.
➢ This distribution of joint involvement distinguishes osteoarthritis from such
inflammatory forms of arthritis as rheumatoid arthritis, psoriatic arthritis, and
gout, which have different sites of involvement.
Osteoarthritis 329
➢ Joint space narrowing: due to loss of articular cartilage.
➢ Osteophytes formation.
➢ Subchondral cysts.
➢ Bony sclerosis (eburnation) at the joint line.
➢ Deformities: - Deformities of Heberden/Bouchard nodes.
➢ Erosions: Gull wing sign in erosive osteoarthritis
➢ Vacuum sign in degenerative disc disease (a collection of nitrogen in a degenerated disc space).
Kellgren and Lawrence system for classification of osteoarthritis of knee

➢ Grade 0: No radiographic features of OA are present.
➢ Grade 1: Doubtful joint space narrowing (JSN) and possible osteophytic lipping.
➢ Grade 2: Definite osteophytes & possible JSN on AP weight-bearing radiograph.
➢ Grade 3: Moderate Multiple osteophytes, definite JSN, some sclerosis, possible bony deformity.
➢ Grade 4: Large osteophytes, marked JSN, severe sclerosis & definite bony deformity.
A grade of 2 is generally considered diagnostic of OA.
MRI on the affected joint:

➢ More accurate diagnosis for OA.
➢ An MRI-based definition of tibiofemoral OA requires either:
The presence of both definite osteophytes and full-thickness cartilage loss or
one of these and one of the following features:
✓ A subchondral bone marrow lesion or cyst.
✓ Meniscal diseas (subluxation, maceration, or horizontal tear).
✓ Partial thickness cartilage loss.
✓ Bone attrition.
LABORATORY FINDINGS
➢ There is NO specific laboratory test used in clinical practice to confirm a diagnosis of osteoarthritis.
➢ Routine laboratory blood testing, including CBC, ESR,CRP and autoantibodies (rheumatoid factor and
antinuclear antibody) are within their NORMAL values.
➢ Arthrocentesis (synovial fluid analysis):Non-inflammatory synovial fluid (<1000 WBC/mm3) and the
crystals visible by light microscopy are absent.
Osteoarthritis 330
NB
 Crepitus symptom is likely more indicative of patellofemoral than tibiofemoral disease.
 In cases in which there is prominent involvement of the metacarpophalangeal (MCP) joints, evaluation for
hypothyroidism and hemochromatosis.
 SOURCE OF PAIN IN OA:
➢ Bone:
✓ Osteophytic periosteal elevation
✓ Vascular congestion of subchondral bone, leading to increased intraosseous pressure.
✓ Crepitus (a rough or crunchy sensation)
➢ Muscles:
✓ Fatigue in muscles that cross the joint.
✓ Periarticular muscle spasm
➢ Capsule:
✓ Synovitis with activation of synovial membrane nociceptors
✓ Joint effusion and stretching of the joint capsule
➢ Others:
✓ Overall joint contracture
✓ Torn menisci
✓ Inflammation of periarticular bursae
✓ Psychological factors.
 Angular misalignment is the most potent risk factor for deterioration of the joint structure because it increases the
degree of focal loading, creating a vicious cycle of joint damage, contributing to the development and progression of single
compartment osteoarthritis of the knee.
 About 65% of the weight-bearing load is transmitted through the medial compartment in a normally aligned knee, which explains
the greater frequency of tibiofemoral medial knee osteoarthritis.
 Varus misalignment increases the risk of joint space narrowing threefold to fourfold
Osteoarthritis 331
Classification criteria for OA
The sensitivity and specificity of the ACR hip criteria are estimated to be 91% and 89%,
The sensitivity and specificity of ACR knee criteria are estimated to be 91% and 86%.
Osteoarthritis 332
2016 ACR Revised Criteria for Early Diagnosis of Knee OA
a.In the presence of 3 points out of 10 with at least 1 point from Domain II along with all entry criteria, the diagnosis of knee OA can be
established.
b. Exclusion criteria are including: 1) moderate to significant knee synovitis 2) Hot or red knee 3) history and/or physical examination
findings compatible with the internal derangement of knee.
c. Knee pain that is initiated or increased with knee activity/exercise and finished or decreased with knee resting
d. Clear fluid with normal viscosity accompanied by WBC count less than 2000/mm3 with less than 25% PMN
e. It must be ignored in the presence of osteophyte in knee X-Ray
Osteoarthritis 333
Treatment of OA
Aim of Treatment:
The goals of medical therapy are to:
➢ Control pain (to provide a sufficient level of symptom improvement to allow healthy levels of physical activity and
exercise that, in turn, may help to prevent function loss and disability)..
➢ Improve function.
➢ Minimize disability.
➢ Enhance health-related quality of life.
➢ Minimize the risk of drug-associated toxicity, particularly that which may result from
nonsteroidal anti-inflammatory drug (NSAID) therapy.
Non-Pharmacologic Treatment
A-Patient education &Life style modification:
✓ Weight loss (Patients with a body mass index >25 should lose a minimum of 5%
of their body weight)should be encouraged for all persons with knee or hip
osteoarthritis (to reduce pain and slow progression of OA).
✓ Proper position: avoid knee flexion for long time-support your neck and back
while sitting or sleeping.
✓ Adjust furniture, such as raising a chair or toilet seat.

✓ Avoid repeated motions of the joint, especially frequent bending & squatting.
B-Exercise:
✓ Exercise for OA should include: range of motion, strengthening and aerobic
exercise.
✓ Exercise can improve muscle strength, decrease joint pain and stiffness, and
lower the chance of disability due to OA.
C-Physical therapy:
✓ Heat or cold therapy can help relieve OA symptoms for a short time.
✓ Therapeutic ultrasound, and pulsed electromagnetic field therapy.
D-Assistive device:
➢ Unloading the joint during activity through ( Decrease pain & deformity across the joint):
✓ Cane or walker can unload an affected knee or hip and diminish pain with
walking (in the hand opposite to the affected joint for partial weight bearing).
✓ Neoprene sleeves & fitted valgus braces, designed to decrease the varus
malalignment across the knee for knee osteoarthritis patients with varus deformity.
✓ Appropriate footwear &Lateral-wedged insoles (for genu varum)

Osteoarthritis 334
Systemic Pharmacologic Therapy

A-Non-Narcotic Analgesic Medication Acetaminophen (paracetamol)
➢ Indication: The most recent ACR & EULAR guidelines for the medical management
of OA suggest acetaminophen (paracetamol) as an effective initial approach
for mild-to-moderate pain. As well as the best long-term choice.
✓ Acetaminophen preferred over NSAIDs due to:

 The superior safety profile for acetaminophen.
 Its over-the-counter availability and low cost,
 Concerns about the potential cardiovascular and gastrointestinal effects
of NSAIDs,
✓ Doses of acetaminophen: 1000-3000 mg/ day and the minimally effective dose
should be used.
B-Nonsteroidal Anti-Inflammatory Drugs (NSAIDs):
➢ Indication: for persons with OA and pain that is refractory to regularly

dosed non-narcotic analgesia & non-pharmacologic measures.
➢ Mechanism:
 NSAIDs inhibit the enzymatic activity of cyclooxygenase (COX),
which is essential for the production of prostaglandins.
 Two isoforms of this enzyme exists, with the COX-2 isoform being most
important for synthesis of prostaglandins that cause pain and
inflammation.
➢ Dose:
 It is recommended that a patient be started on the lowest therapeutic
dose and that the dose be gradually increased until:
✓ The response is satisfactory;
✓ The maximal recommended dose is reached.
✓ The patient experiences an adverse effect.
 If the response is inadequate at the full dose of a given NSAID, it may be
beneficial to try other NSAIDs.
 NSAIDs and acetaminophen may be used concurrently, and this
combination may be more effective than using either medication alone.
C-Narcotic Analgesic Medication
✓ Indication: for persons with severe OA and pain that is refractory to

regularly dosed non-narcotic analgesia,NSAIDs & non-pharmacologic measures.
Osteoarthritis 335
Localized Pharmacologic Therapy

A- Intra-articular corticosteroids
➢ Indication: Intra-articular administration of corticosteroids result in pain reduction in

OA joints, especially in joints that show signs of inflammation.
➢ The duration of a beneficial effect range from only a few days but may last for a few
months.
➢ Should not be repeated more than three times into the same joint in 1 year (A
greater frequency is discouraged as that intra-articular therapy may accelerate cartilage loss).
➢ Corticosteroid injection therapy should not be considered as a primary or scheduled

form of therapy, but rather as an adjunct to other pharmacologic and non-
pharmacologic treatment.
B- Intra-articular viscuo-supplementation (Hyaluronan)
✓ Synthetic and naturally occurring hyaluronic acid derivatives are administered intra-
articularly.
✓ Intra-articular hyaluronan may result in a modest improvement in symptoms.
✓ Two of these agents—Hyalgan and Synvisc—are approved for use in the United
States for OA of the knee.
✓ The response appears to be slightly better in knees at earlier stages of OA.
✓ Prescribe as a series of1 or 3 or 5 injections (depending on the product). Each
injection is administered one week apart.
✓ A potential adverse effect is the development of synovitis and effusion after the
injection.
C- Topical capsaicin
➢ Pain-relieving effect in osteoarthritic knees and hands by:
✓ Depleting substance P in peripheral sensory neurons.
✓ Increasing pain threshold
➢ Dose: The best effect is associated with adherence to the recommended schedule,
that is, application three to four times per day for at least 2 weeks for the
full effects to be appreciated.
➢ SE: Capsaicin may be highly irritating to mucous membranes; careful hand washing
after application helps to prevent mucous membrane contact.
➢ Burning at the applied site diminishes with regular use.
Osteoarthritis 336
Surgical Management:
➢ Indication of surgical interference: patients with symptoms and functional loss
refractory to nonsurgical pharmacologic and non-pharmacologic therapies:
➢ Severe pain unresponsive to medical therapy. For example:

✓ Consistently awakens from sleep as a result of pain.
✓ Cannot stand in one place for >20 to 30 minutes as a result of pain.
➢ Loss of joint function. For example:
✓ Cannot walk more than one block.
✓ Had to move to single story house or apartment because of inability to
climb stairs.
➢ Procedures:
✓ Total joint replacement: In patients with advanced OA coupled with severe
pain and reduced function, total joint replacement is a highly effective
intervention in the vast majority of patients, especially when the involved joint
is the hip or the knee.
✓ Osteotomy: usually recommended in young patients with a malaligned hip or

knee joint.
✓ Arthroscopy: indicated in patients with osteoarthritis of the knee that in whom

imaging reveals specific structural damage (eg, for repairing meniscal tears,
removing fragments of torn menisci that are producing symptoms).
Osteoarthritis 337
Others Druges used in OA
❖ Duloxetine: (Cymbalta)
✓ Duloxetine is selective serotonin-norepinephrine reuptake inhibitor.
✓ Duloxetine is effective in chronic (Neuropathic) musculoskeletal pain including pain
from OA & chronic lower back pain.
✓ Indication in OA: in patients with osteoarthritis who had persistent moderate pain
despite optimized NSAID therapy.
✓ Dose:
➢ Starting dose: 30 mg /Day for 1 week to allow for therapy adjustment
➢ Target dose: 60 mg /Day
❖ Diacerein
✓
Diacerein and its active metabolite rhein are anthraquinones related to senna
compounds.
✓ They inhibit the synthesis of IL-1β in human OA synovium, as well as the
expression of IL-1 receptors on chondrocytes.
✓ Considered as a slow-acting symptom-modifying and structure- or disease-modifying
drug for OA ( It also can lower rate of radiographic progression)
✓ Diarrhea is the main potential side effect.
❖ Avocado and soy unsaponifiables (ASUs)
➢ Considered as structure or disease modifiers in OA.

➢ These compounds are derived from unsaponifiable residues of avocado and soya
oils mixed in a 1:2 ratio.
✓ Partial reversal of IL-1β effects.
✓ Increased aggrecan synthesis
➢ The roles of IL-1β in OA are thought to include inhibition of prostaglandin synthesis
by chondrocytes and stimulation of matrix metalloproteinases (MMPs) and nitric
oxide production.
➢ MMPs and nitric oxide can degrade cartilage matrix and cause chondrocyte
apoptosis.
➢ Use of ASUs also reportedly results in inhibited production of IL-6, IL-8, and MMPs
and stimulation of collagen synthesis.
❖ Glucosamine sulfate:
✓ Glucosamine sulfate is a component of human articular cartilage (an intermediate in
mucopolysaccharide synthesis) that is administered orally.
✓ A modest effect in those with mild knee pain Oral dose: 500 mg 3 times a day.
Osteoarthritis 338
❖ Chondroitin Sulfate
✓ Oral chondroitin sulfate, a glycosaminoglycan composed of units of
glucosamine with attached sugar molecules (molecular mass of around
14,000), has also been used as therapy for hip and knee OA.
✓ The efficacy of glucosamine sulfate & Chondroitin sulfate in the medical

management of osteoarthritis is controversial.
❖ Ginger extracts
✓ Ginger actually contains very small amounts of salicylate.
✓ Ginger has been shown to have inhibitory effects on COX and lipoxygenase
❖ Tetracyclines
✓ Tetracyclines, apart from any antimicrobial effect, are inhibitors of tissue
metalloproteinases, perhaps owing to their ability to chelate calcium and zinc
ions.
✓ Doxycycline, another tetracycline derivative, has been shown to inhibit articular
cartilage collagenase activity.
Osteoarthritis 339
Osteoarthritis 340
Osteoarthritis 341
ACR Recommendtions
Osteoarthritis 342
Osteoarthritis 343
Osteoarthritis 344
➢ The assessment of a patient with osteoarthritis should include evaluations of pain

and function.
➢ Pain or disability assessment can be evaluated using a visual analog scale VAS.
➢ Pain also can be assessed indirectly by estimating the symptomatic treatment
required, such as the number of days per week that drugs are required or their
consistent dose usage.
➢ The activity causing pain should be specified (e.g., resting, nocturnal, stair climbing,
weight bearing).
Knee and hip assessment
The WOMAC (Western Ontario and McMaster Universities)
➢ WOMAC is used to assess pain and disability.

➢ It is a 24-item questionnaire with three subscales measuring
1. Pain (five items).

2. Stiffness (two items).
3. Physical function (17 items).
- Answers to each of the 24 questions are scored on five-point Likert scales (none
= 0, slight = 1, moderate = 2, severe = 3, extreme = 4).
- Total scores ranging from 0 to 96.
- The maximum possible scores for WOMAC, pain, stiffness, and function are 96
(most severe), 20, 8, and 68, respectively.
- Higher scores indicate greater disease severity.
The Knee Osteoarthritis Outcome Score (KOOS)
➢ KOOS has been validated more recently. It is a 42-item, self-administered, knee-

specific questionnaire covering several types of knee injury and osteoarthritis.
➢ It consists of five subscales (pain, other symptoms, function in daily living,
function in sport and recreation, and knee-related quality of life).
➢ Standardized answer options are given (five Likert boxes), and the response to each
question is scored from 0 to 4.
➢ A score of 0 to 100 is calculated for each subscale; 100 is the best result. A
difference of 10 points is considered to be clinically significant.
Osteoarthritis 345
The Western Ontario and McMaster Universities Arthritis Index (WOMAC)

Name: Date: Instructions: Please rate the
activities in each category according to the following scale of difficulty: 0 = None, 1 = Slight, 2 =
Moderate, 3 = Very, 4 = Extremely Circle one number for each activity
Pain 1. Walking 0 1 2 3 4
2. Stair Climbing 0 1 2 3 4
3. Nocturnal 0 1 2 3 4
4. Rest 0 1 2 3 4
5. Weight bearing 0 1 2 3 4
Stiffness 1. Morning stiffness 0 1 2 3 4
2. Stiffness occurring later in the 0 1 2 3 4
Physical 1. Descendingdaystairs 0 1 2 3 4
Function 2. Ascending stairs 0 1 2 3 4
3. Rising from sitting 0 1 2 3 4
4. Standing 0 1 2 3 4
5. Bending to floor 0 1 2 3 4
6. Walking on flat 0 1 2 3 4
surface
7. Getting in / out of car 0 1 2 3 4
8. Going shopping 0 1 2 3 4
9. Putting on socks 0 1 2 3 4
10. Lvinq in bed 0 1 2 3 4
11. Taking off socks 0 1 2 3 4
12. Rising from bed 0 1 2 3 4
13. Getting in/out of 0 1 2 3 4
bath
14. Sitting 0 1 2 3 4
15. Getting on/off toilet 0 1 2 3 4
16. Heavy domestic 0 1 2 3 4
duties
17. Light domestic 0 1 2 3 4
duties____/ 96 = __%
Total Score:
Comments / Interpretation (to be

completed by therapist only)
Osteoarthritis 346
Hand osteoarthritis assessment
➢ Impaired function in hand osteoarthritis can be assessed in clinical trials using the
Functional Index for Hand Osteoarthritis (FIHOA), and the Australian/Canadian
Osteoarthritis Hand Index (AUSCAN) has been validated more recently ( Table).
➢ The FIHOA is a 10-item, investigator-administered questionnaire that is relevant and
reliable and has been well validated externally and internally.
➢ The AUSCAN is a self-administered questionnaire investigating pain, stiffness and
function.
➢ This index has been designed specifically for use with hand osteoarthritis patients
with acceptable reliability, construct validity, and responsiveness.
Functional Index for Hand Osteoarthritis

Are you able to turn a key in a lock?
Are you able to cut meat with a knife?
Are you able to cut cloth paper with a pair of scissors?
Are you able to fit a full bottle with the hand?
Are you able to clench your fist?
Are you able to tie a knot?
For women: are you able to sew?
For men: are you able to use a screwdriver?
Are you able to fasten buttons?
Are you able to write for a long period of time?
Would you accept a handshake without reluctance?
Osteoarthritis 347
Osteoarthritis 348
Mustafa Elmenawy
Basic
Rheumatology
GOUT
CPPD
GOUT
Definition: Gout is a metabolic disorder of purine metabolism associated with
hyperuricemia and caused by the deposition of monosodium urate (MSU) crystals in and
around the tissues of joints.
Prevalence:
✓ The incidence of gout varies among populations, with an overall prevalence
ranging from less than 1% to 15.3%.
✓ The prevalence increases substantially with age and with increasing serum
urate concentration.
✓ The prevalence of gout which occurs predominantly among men and

postmenopausal women is approximately 2.7%.
✓ Gout prevalence rises with advancing age, reaching a level of 9% in men

older than 80 years of age, and 6% in women.
RISK FACTORS OF HYPERURICEMIA & GOUT

➢ Age:
✓ The peak age is 40-50 years in males & after 60 years in females.
✓ Gout is rare in males under age 30 & in premenopausal females.
➢ Sex: The male to female ratio: 5:1 due to estrogen effect on renal excretion.
➢ Genetic Factors: Genetics plays a role in increasing the risk of primary Gout.
➢ Family history:
✓ Family history of gout is present in 25-30%
✓ Early-onset gout (Juvenile gout), incidence if family history is 80%.
➢ Obesity: Obesity is a clear risk factor for the development of gout
➢ Others
✓ Purine & Fructose rich foods.
✓ Alcohol consumption.
✓ Medications.
GOUT & CPPD 349

Causes of Gout (Hyperuricemia):

Uric acid underexcretion:(90% of cases)
❖ Primary:
1. Idiopathic
2. Hyperactivity of URAT1 transporter.
3. Defects of ABCG2 transporter.
4. Familial Juvenile Hyperuricemic Nephropathy and Medullary Cystic Kideny
Disease: Autosomal dominant diseases characterized by early hyperuricemia
and progressive chronic kidney disease.
❖ Secondary hyperuricemia:
1. Decreased renal function (renal failure).
2. Dehydration.
3. Drugs:
✓ Diuretics: Thiazide diuretics & Loop diuretics ( by inhibition of MRP4).
✓ Low-dose salicylates, Nicotinic acid.
✓ Cyclosporine, Pyrazinamide, ethambutol and
4. Metabolic acidosis (ketoacidosis or lactic acidosis(.
5. Hypertension & Obesity.
6. Thyroid & Parathyroid diseases.
Urate Overproduction
❖ Primary:
1. Idiopathic.
2. Deficiency of HGPRT:
➢ Complete: (Lesch-Nyhan syndrome): An X-linked recessive disorder characterized by
extremely high levels of serum urate, gout flares, nephrolithiasis, mental retardation,
movement disorders and self-mutilation.
➢ Partial: (Kelley-Seegmiller syndrome): Present with hyperuricemia & gout but have limited
neurologic symptoms.
3. Superactivity of PRPP synthetase
❖ Secondary hyperuricemia:
1. Excessive purine consumption.
2. Myeloproliferative or lymphoproliferative disorders( leukemias & lymphomas)
3. Hemolytic diseases: Hemolytic anemia, sickle cell anemia, polythyemia vera, and thalassemia.
4. Sarcoidosis&Psoriasis
5. Glycogen storage diseases: types 1, 3, 5, and 7.
❖ Overproduction and underexcretion: Glucose-6-phosphatase deficiency & Fructose-1-phosphate-aldolase deficiency.

GOUT & CPPD 350
Physiology of uric acid
Simplified scheme of purine metabolism pathways.

5-phosphoribosyl 1-pyrophosphate (PRPP), inosine monophosphate (IMP), guanosine
monophosphate (GMP), adenosine monophosphate (AMP). Dark boxes enclose enzymes
involved in de novo synthesis, purine salvage and catabolism pathways. Purine nucleoside
phosphorylase (PNP), hypoxanthine-guanine phosphorybosil transferase (HGPRT),
adenine phosphorybosiltransferase (APRT), xanthine oxidase (XO) inosine monophosphate
dehydrogenase (IMPDH).
➢ Uric acid is normally produced as an end product of the degradation of purine

compounds
➢ Total body urate stores are approximately 1.2 g (range, 800 to 1600 mg) in healthy men
and about half this value in healthy women.
➢ Significantly, urate synthesis averages around 750 mg/day in men, and dietary purine
intake stimulates additional uric acid production.
➢ The amount of urate in the body depends on the balance between dietary intake,
synthesis, and excretion of this molecule.
➢ Uric acid is a weak acid (pKa = 5.8) that exists largely as urate, the ionized form, at
physiological pH. In general, the risk of supersaturation and crystal formation rises in
parallel with the concentration of urate in physiologic fluids.
➢ The solubility of urate in joint fluids is influenced by other factors as well, including
temperature, pH, cation concentration, articular hydration state, and the presence of
nucleating agents around which urate crystals may coalesce (e.g., nonaggregated
proteoglycans, insoluble collagens, and chondroitin sulfate).
GOUT & CPPD 351

Schematic illustration of renal re-absorption and excretion of uric acid.

Arrows in the figure indicate the direction of transport of uric acid. Dotted and solid lines indicate re-absorption and secretion,
respectively.
➢ Uric acid transported from liver to kidney through the blood.
➢ Uric acid removal:
✓ From the kidney, 75% is filtered.
✓ Rest 25 % excreted in the GI tract (saliva, gastric juice, pancreatic secretions, and
bowel) and degraded there.
➢ Uric acid filtrated from the renal glomerular body is first re-absorbed by renal proximal
tubule cells. Renal urate transport consists of glomerular filtration followed by near complete reabsorption of filtered
urate (Resorption phase), subsequent secretion (Secretion phase) back into the tubule, with net renal excretion of 10% of
the filtered uric acid.
➢ Uric acid is eliminated, in part, from the blood circulation to urine by renal transporters.
➢ Both urate resorption & secretion are handled by the epithelial cells of the PCT.
➢ Renal urate excretion in normal adult men ingesting a purine-free diet averages
approximately 400 mg/day, with the normal range being between 250 and 750 mg/day
with a typical Western diet.
➢ Renal urate and extrarenal excretion can increase in adaptation to increased uric acid
generation (when serum urate concentrations rise above 12 to 14 mg/dL).
➢ As a result of the activities of URAT 1 and other transporters, 8% to 12% of the urate
filtered by the glomerulus is excreted as uric acid.
GOUT & CPPD 352


➢ Uric acid is a weak acid (pKa = 5.8) that exists largely as urate, the ionized form, at
physiological pH. In general, the risk of supersaturation and crystal formation rises in
parallel with the concentration of urate in physiologic fluids.
➢ Gout is a form of inflammatory arthritis triggered by the crystallization of uric acid

within the joints which occurs due to:
• Release of uncoated crystals (eg, due to partial dissolution of a microtophus caused
by changing serum urate levels)
• Precipitation of crystals in a supersaturated microenvironment (eg, release of urate
due to cellular damage).
➢ Neutrophilic synovitis is the hallmark of acute gouty attack.

➢ MSU interact with intracellular and surface receptors of local dendritic cells and
macrophages, serving as a danger signal to activate the innate immune system (This
interaction may be enhanced by immunoglobulin G (IgG) binding).
➢ Triggering of these receptors by MSU, results in the production of interleukin (IL)–1,
which in turn initiates the production of a cascade of pro-inflammatory cytokines,
including IL-6, IL-8, neutrophil chemotactic factors, and tumor necrosis factor (TNF)–
alpha.
➢ Neutrophil phagocytosis leads to another burst of inflammatory mediator production.
➢ Influx of polymorphonuclear leukocytes into the synovial fluid ------------> secrete
inflammatory cytokines that stimulate the synovial lining layer to become hyperplastic and
infiltrated with neutrophils, monocyte-macrophages, and lymphocytes.
➢ Subsidence of an acute gout attack is due to multiple mechanisms:

• The clearance of damaged neutrophils, recoating of urate crystals.
• The production of anti-inflammatory cytokines including, IL-1RA, IL-10, and
transforming growth factor (TGF)–beta.
TOPHACEOUS GOUT
➢ The tophus represents the most characteristic lesion of gout and can be found in the
synovium as well as elsewhere.
➢ Crystals in the tophi in synovium and elsewhere are needle shaped and often are
arranged radially in small clusters.
➢ Tophi are frequently associated with erosion of cartilage and bone.
➢ The histopathology of tophi shows foreign body granulomas surrounding a core of
amorphous mass or monosodium urate (MSU) crystals by mono- and multinucleated
macrophages, fibroblasts, and lymphocytes. Other components of tophi include lipids,
mucopolysaccharides, and plasma proteins.
GOUT & CPPD 353

Clinical Findings
▪ The natural history of gout can be divided into three distinct stages:
1. Asymptomatic hyperuricemia.
2. Acute and intermittent (or intercritical) gout.
3. Chronic tophaceous gout.
❖ Asymptomatic hyperuricemia:
▪ In extracellular fluids, 98% of uric acid is in the form of urate ion at pH 7.4.
▪ Clinical laboratories define hyperuricemia as a serum urate level that is greater
than two standard deviations above the mean value in a gender- and age-matched
healthy population.
▪ Using this standard, the upper limit for normal serum urate frequently is listed as
8.0 to 8.5 mg/dL.
▪ In physiologic terms, however, any level above 6.8 mg/dL is hyperuricemia
because it exceeds the soluble concentration of MSU in body fluid.
▪ In children: Serum urate levels are relatively low (2.0–4.0 mg/dL).
▪ In men, this value increases dramatically around the time of puberty to reach the
level they will maintain throughout adulthood.
▪ In women, serum urate levels gradually increase throughout early adulthood and do
not reach maximum levels until after menopause.
❖ Acute and intermittent (or intercritical) gout:

 Description of the acute attack:
➢ There is rapid onset of Pain, Warmth, Swelling, Erythema and Limited
ROM of the affected joint.
➢ Pain varies from faint tingling to sever aching pain lasts up to 12 hours.
➢ The attack may be associated with systemic symptoms as fever, malaise and chills.
 Affected Joints:
➢ The initial attack usually is monarticular and usually involves the first
metatarsophalangeal (MTP) joint (PODGRA) (in up to 50% of patients).
➢ Other frequently involved joints:
✓ In this early stage are the midfoot, ankles, heels, and knees
✓ Less commonly: the wrists, fingers, and elbows.
✓ Hip & shoulder joints usually spare from affection.
 The course of the attack:

➢ Acute gout varies from episodes of mild pain that resolve in several hours (“petit
attacks”) to severe attacks that last 1 to 2 weeks.
➢ With resolution of the acute attack, patient enters interval termed intercritical
period which is completely asymatomatic.
➢ Early in the acute intermittent stage, episodes of acute arthritis are infrequent, and
intervals between attacks sometimes last for years.
➢ Over time, the attacks typically become more frequent, longer in duration, and
involve more joints.
GOUT & CPPD 354

❖ Advanced Gout (chronic tophaceous gout)

➢ Advanced gout usually develops after 10 or more years of acute intermittent gout
➢ The transition from acute intermittent gout to chronic tophaceous gout occurs when
the intercritical periods no longer are free of pain.
➢ Presntation:
 Chronic gouty arthritis:
▪ Joints involvement usually polyarticular and asymmetrical.
▪ The involved joints become:
✓ Persistently uncomfortable and swollen.
✓ Stiffness or gelling sensation which increases by movement.
✓ The intensity of these symptoms is much less than during acute
flares.
▪ Acute gouty attacks continue to occur against this painful background, and
without therapy, they may recur as often as every few weeks.
 Gouty tophi: (the most characteristic lesion of advanced gout)

▪ Tophi are subcutaneous nodules due to urate deposition around the joint
bursa and cartilage.
▪ Sites: Tophi may be found anywhere over the body, but occur most
commonly in the fingers, wrists, ears, knees, olecranon bursa, and
such pressure points as the ulnar aspect of the forearm and the Achilles
tendon.
▪ Factors associated with the development of tophi:
✓ The duration and severity of hyperuricemia.
✓ Early age of gout onset.
✓ Long periods of active but untreated gout(an average of four attacks
per year).
✓ A greater tendency toward upper extremity and polyarticular episodes.
NB
➢ In men, the first attacks usually occur between the fourth and sixth decades of life. In women, the
age of onset is older and varies with several factors, including the age of menopause and the use of
thiazide diuretics.
➢ The difference in the duration of urate elevations is the main reason gout is a male-predominant
disease.
➢ Podagra: Involvement of the first MTP joint, which occurs eventually in 90% of individuals with gout
(Greek word mean “foot-trap).
➢ In rare cases: patients have been reported with tophi as their initial clinical manifestation).
➢ Clinically evident tophi may or may not be detected on physical examination during the first few years
of this stage of gout. However, periarticular tophi detected by (MRI) and synovial “microtophi”
discovered through the arthroscope certainly are present early in this stage of gout and may in fact be
present during the earlier acute intermittent phase of gout.
➢ Chronic gouty arthritis may be confused with RA due to diffuse polyarticular involvement of the small
joints in the hands and feet.
GOUT & CPPD 355

❖ Precipitating factors of acute gouty attack:

➢ Trauma:
✓ Trauma may be an inciting event for acute gouty episodes.
✓ The trauma may be as minor as a long walk and may not have caused pain
during the activity, but it caused intra-articular swelling.
✓ When the joint is allowed to rest, there is a relatively rapid efflux of free water from
the joint fluid.
✓ This results in a sudden increase in synovial fluid urate concentration, which
may allow precipitation of urate crystals and a gout attack. This mechanism may
explain why gouty attacks commonly occur at night.
➢ Drugs:
✓ A rapid increase or reduction in the serum urate level can provoke gouty attacks
✓ Allopurinol is the drug most often responsible for this effect.
• The mechanism for this paradoxic response appears to be the destabilizing
of microtophi in the gouty synovium when the urate concentration of the
synovial fluid is changed rapidly.
• As the microtophi break apart, crystals are shed into the synovial fluid and
the gouty episode is initiated.
✓ Thiazide diuretics selectively interfere with urate excretion at the proximal

convoluted tubule.
✓ Low dose aspirin (less than 2 g/day) also can raise serum urate levels, but
higher doses have a uricosuric effect and may lower the serum urate
concentration.
➢ Alcohol:
✓ Alcohol ingestion may predispose to gout through several mechanisms.
✓ The ingestion of any form of ethanol can raise uric acid production acutely by
accelerating the breakdown of intracellular adenosine triphosphate.
➢ Excessive Ingestion of Purines.
➢ Exposure to: Stress, Cold or Infection.
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Unusual presentations of Gout

❖ Early-Onset Gout:
➢ Between 3% and 6% of patients with gout have symptom onset before age 25.
➢ Most of cases have a genetic component & the incidence of family history is
approximately 80%.
➢ Early-onset gout shows a more accelerated clinical course, and requires more
aggressive antihyperuricemic therapy.
➢ Causes.
▪ Diseases associated with overproduction of urate in children and young adults
include:
1) Enzymatic defects in the purine pathway: The complete deficiencyof hypoxanthine-guanine
phosphoribosyltransferase (HGPRT) is an X-linked inherited inborn error of purine metabolism
with a characteristic clinical presentation known as the Lesch–Nyhan syndrome.
2) Glycogen storage diseases: types I, III, V, and VII
3) Hematologic disorders, such as hemoglobinopathies(Sickle cell disease,
betathalassemia) and leukemias.
▪ Conditions associated with uric acid underexcretion in young patients include:

1) A specific renal tubular disorder known as familial juvenile hyperuricemic
nephropathy.
2) Polycystic kidney disease, chronic lead intoxication, medullary cystic
disease, and focal tubulointerstitial disease.
❖ Normouricemic Gout:
➢ The most frequent explanations for apparent gout with normal levels of uric acid are
that:
(1) Gout is not the correct diagnosis: Several articular conditions can mimic gout closely,
including:
✓ Crystalline arthropathies of calcium pyrophosphate dehydrate (pseudogout),
✓ Basic calcium (apatite).
✓ Other causes of acute monoarthropathies, such as infection, sarcoidosis,
and trauma.
(2) The patient actually is chronically hyperuricemic but the serum urate is normal at the time it is
measured:
✓ A sustained serum urate level above 7.0 mg/dL provides a permissive
environment for MSU crystal formation, but people with acute and chronic
gout may have urate values below this biochemical definition of
hyperuricemia.
✓ One third (1/3) of people presenting with acute gout have a serum urate
below 7.0 mg/dL during the episode of severe pain (This condition probably results
from uricosuric effects of ACTH release and adrenal stimulation, which are caused by the stress of the painful
process).
GOUT & CPPD 357
❖ Gout in Organ Transplantation Patients(CYclosporine-induced Gout):

➢ Hyperuricemia develops in organ transplant recipients who routinely take
cyclosporine to prevent allograft rejection:
✓ 75% of heart transplant recipients develop hyperuricemia.
✓ 50% of kidney and liver transplant recipients develop hyperuricemia (because lower
doses of cyclosporine are used in these individuals).
➢ cyclosporine promotes decreased renal urate excretion and hyperuricemia (nephrotoxic

effects: tubulointerstitial injury and arteriolar hyalinosis)
➢ Differences between primary and cyclosporine-induced gout include:

1. Asymptomatic hyperuricemia progresses to clinical gout in only 1 in 30
subjects in the general population & cyclosporine-induced hyperuricemia leads
to gout in 1 in every 6 patients.
2. Marked shortening of the asymptomatic hyperuricemia and acute

intermittent gout stages, with the rapid appearance of tophi. The stage of
asymptomatic hyperuricemia lasts for 20 to 30 years in classic gout, but is
present for only 6 months to 4 years in cyclosporine-induced disease.
3. The duration of the acute intermittent stage is only 1 to 4 years in

transplant recipients, but it may last 8 to 15 years in classic gout.
4. Because organ transplant recipients use other medications, such as

systemic corticosteroids and azathioprine, their gouty symptoms frequently are more
atypical and less dramatic than those of patients with classic gout.
❖ Gout in Women:
➢ Women account for no more than 5% of all people with gout.
➢ 90% of women are postmenopausal at the time of their initial attack.
➢ Premenopausal gout:
✓ Usually has a strong hereditary component.
✓ Most women who develop gout before menopause have hypertension and renal
insufficiency.
✓ The rare woman with premenopausal gout and normal renal function should be
evaluated for the autosomally inherited familial juvenile hyperuricemic
nephropathy or the even more rare non–X-linked inborn errors of purine
metabolism.
➢ Serum urate concentrations in men are about 1 mg/dL higher on average than in
women, but after menopause the serum levels of uric acid in women tend to approach
those in men.
➢ The sex differences in uric acid levels may stem from the effects of estrogen on the
renal tubular handling of uric acid; premenopausal levels of estrogens in women
may promote more efficient renal clearance of urate.
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Gout and renal disease:

❖ Chronic urate nephropathy.
➢ Caused by deposition of MSU crystals in the real medulla and pyramids and is
associated with mild albuminuria.
➢ Risk factors: hypertension, diabetes, obesity, and ischemic heart disease.
❖ Acute uric acid nephropathy.( Acute renal failure)

➢ Caused by: marked and rapid increase in serum uric acid level which can lead to tubular
obstruction by urate crystals. (This occurs as an example in the acute tumor lysis syndrome, which
occurs in patients given chemotherapy for rapidly proliferating lymphomas and leukemias due to massive liberation of
purines during cell lysis, uric acid precipitates in the distal tubules and collecting ducts of the kidney.
➢ This form of acute renal failure can be distinguished from other forms by a ratio of
uric acid to creatinine greater than 1.0 in a random or 24-hour urine collection.
❖ Uric acid nephrolithiasis (Stones).

➢ Uric acid renal stones occur in 10% to 25% of all people with gout.
➢ The incidence correlates strongly with the serum urate level (reaches 50% when the serum
urate is above13 mg/dl).
➢ Symptoms of renal stones precede the development of gout in 40% of patients.
➢ Calcium-containing renal stones occur 10 times more frequently in gouty subjects than
in the general population.
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LABORATORY FINDINGS
1. Serum Uric acid:
✓ Normal serum uric acid level: 2-6mg/dl
✓ It is of limited value in establishing the diagnosis (The vast majority of hyperuricemic
subjects will not develop gout, and serum urate levels may be normal during gouty attacks).
✓ Serum urate determinations are helpful and necessary in following the effects of
antihyperuricemic therapy.
2. Synovial fluid examination:

 Synovial fluid analysis: Inflammatory picture (Leucocytosis with predominant neutrophiles-
with the average count between 15,000 and 20,000 cells/mm3.)
 Under polarized microscopy:

✓ The definitive diagnosis of gout is possible only by aspirating and inspecting synovial
fluid or tophaceous material and demonstrating characteristic MSU crystals.
✓ The crystals usually are bright needle or rod shaped crystals & negatively
birefringence (Yellow parallel to arrow).
✓ During acute attacks: The crystals usually are intracellular.
✓ During the intercritical periods: Small, truncated, extracellular crystals.
3. A 24-hour urine uric acid measurement:

✓ This measurement is useful for patients being considered for uricosuric therapy
(probenecid or sulfinpyrazone) or when the cause of marked hyperuricemia (>11
mg/dL) is being investigated.
✓ On a regular diet, urinary uric acid excretion of more than 800 mg in 24 hours
suggests a problem of urate overproduction.(n:300-600mg/day)
4. Acute phase reactant: Elevated ESR & CRP.
 In early course of the disease:
✓ The radiographic findings of gout often are unremarkable early in the disease course.
✓ Soft tissue swelling around the affected joint in acute gouty arthritis.
 Years after the 1st attack:

• Punched out erosion: erosions with an overhanging edge.
• The erosions are usually asymmetric and seen in the feet, hands, wrists, elbows, and
knees.
• Soft tissue tophi.
MSK ultrasonography:
✓ It shows a superficial, hyperechoic, irregular band on the surface of articular cartilage
(“Double contour sign” or “urate icing”) in gouty patients
✓ Tophi appear as non-homogeneous material surrounded by an anechoic rim.
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Diagnosis of GOUT
Definitive diagnosis
➢ The definitive diagnosis of gout is made by identifying monosodium urate crystals in
polymorphonuclear leukocytes in synovial fluid or from aspirates of tophi.
Presumptive diagnosis
➢ The presumptive diagnosis of gout can be made by the presence of the characteristic
triad of:
1. Hyperuricemia.
2. Acute monarticular arthritis.
3. A gratifying clinical response to therapy with colchicine, defined as complete
resolution of symptoms within 48 hours and no recurrence for 1 week.
American College of Rheumatology Criteria for the diagnosis of gout 1977
 Presence of characteristic urate crystals in joint fluid.

OR
 A tophus proved to contain urate crystals by chemical means or polarized light
microscopy.
OR
 The presence of 6 of the following 12 clinical, laboratory, and x-ray phenomena listed
below:
1. More than one attack of acute arthritis.
2. Maximal inflammation developed within 1 day.
3. Attack of monarticular arthritis.
4. Joint redness observed.
5. First metatarsophalangeal joint painful or swollen.
6. Unilateral attack involving first metatarsophalangeal joint.
7. Unilateral attack involving tarsal joint.
8. Suspected tophus.
9. Hyperuricemia (laboratory).
10. Negative culture of joint fluids for microorganisms during attack of joint
inflammation (laboratory). .
11. A symptomatic swelling within a joint (radiograph).
12. Subcortical cysts without erosions (radiograph).
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2015 ACR/EULAR Gout classification criteria
GOUT & CPPD 362

differential diagnosis:
1. Septic arthritis:
✓ Septic arthritis must always be considered in a patient with acute monoarticular
arthritis, especially with fever and leukocytosis.
✓ Joint aspiration is critical to rule out bacterial infection; treat suspicious cases with
antibiotics as for cellulitis.
✓ Gouty joints are more susceptible to bacterial infection, and the two conditions may
occur simultaneously.
2. hemarthrosis or fracture in the joint line may be confused with a gouty attack.
3. Cellulitis:
✓ Gout mimics cellulitis in that the affected area is swollen, erythematous, and
painful and may be accompanied by fever and leukocytosis.
✓ If cellulitis is suspected, the joint should not be aspirated through the overlying
skin infection to avoid seeding a secondary septic arthritis
✓ In some cases, it may be necessary to treat with antibiotics for 1-2 days while
awaiting blood cultures and other indications of infection before considering gout as
a leading diagnosis.
4. Other crystal-induced diseases such as those related to the deposition of calcium

pyrophosphate dihydrate crystals (pseudogout) or basic calcium phosphate crystals.
✓ Chronic gout may mimic RA because some chronic gout patients may display a
symmetric polyarthritis.
✓ They may also develop tophi in sites where rheumatoid nodules typically occur.
✓ In contrast to RA, chronic gout typically presents at an older age and is seronegative.
✓ Radiographs may show changes typical of gout. Large asymmetric erosions with
ballooning of the cortex and overhanging edges are more likely to be caused by gout
than by RA.
6. OTHERS: Some oligoarticular conditions that may involve only one joint early in the course
and be confused with gout: the peripheral arthritis associated with ankylosing
spondylitis, Reactive, psoriatic arthritis, and the arthritis of inflammatory bowel disease.
GOUT & CPPD 363

NB
 There is a higher prevalence of gout among individuals of lower family income levels, likely reflecting a greater number of risk factors
for gout—for example, obesity, hypertension, and a Western dietary pattern with a greater red meat component .
 Hyperuricemia & Food

➢ Diet can have significant effects on serum urate levels by serving as a source of dietary purines and by
altering the metabolic production and/or renal excretion of uric acid.
➢ Recent studies suggesting limited effect of purine intake on alterations serum urate (high purine intake
may result in, at most, changes in serum urate of about 1 mg/dL).
➢ Purine-Rich Foods
✓ Red meat & organs as liver and kidney.
✓ Selected seafood: Sardines, scallops, mackerel, herring and tuna.
✓ Vegetables: Beans, lentils, peas, spinach, asparagus or mushrooms.
✓ Sugary drinks with high-fructose such as non-diet sodas or fruit drinks.
✓ Alcohol: Beer and wine.
 Risk factors may explain several of the interesting clinical features of gout:
✓ Predilection for the first MTP joint, that is, podagra (caused by the lower temperature at this peripheral body site).
✓ Tendency to occur in osteoarthritic joints (because such joints contain nucleating debris).
✓ The frequency of nocturnal onset (the result of intra-articular dehydration that may occur at night).
 EFFECTS OF HYPERURICEMIA IN THE ABSENCE OF GOUT

➢ Adverse effects of hyperuricemia
• Increased risk for hypertension and cardiovascular disease:
✓ Soluble urate is biologically active, with effects on renal and vascular function.
✓ Soluble urate inhibits synthesis of the potent vasodilator nitric oxide; induces smooth muscle cell proliferation by
activating MAP kinases; and stimulates cyclooxygenase-2 and platelet-derived growth factor synthesis, all
contributing to arterial vasoconstriction.
✓ Soluble urate directly stimulate the renin-angiotensin system in the kidney and to induce renal interstitial and
tubular inflammation.
✓ recent clinical trials suggest that lowering serum urate levels may reduce the risk of myocardial infarction and slow
the progression of renal failure.
• Increase of insulin resistance in adipose Cells and drive gluconeogenesis in hepatocytes.
• Reductions in 1,25(OH)2 vitamin D3 synthesis.
• Urate serve as a biomarker in osteoarthritis.
➢ Beneficial effects: hyperuricemia may protect against neurologic diseases such as dementia, multiple
sclerosis, and Parkinson’s and Huntington’s diseases.
 Difference between Gouty erosion & erosions of RA:

✓ Gouty erosions usually are slightly removed from the joint, but rheumatoid erosions typically are in the immediate proximity of
the articular surface
✓ The joint space is preserved in gout until very late in the disease process.
✓ Juxta-articular osteopenia, a common and early finding in rheumatoid arthritis, is absent or minimal in gout.
✓ Abnormalities are usually asymmetrical in Gout but symmetrical in RA.
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GOUT & CPPD 365

Treatment of GOUT
Goals of Management:
➢ Treatment of acute attack: Providing rapid and safe pain relief.
➢ Preventing further attacks.
➢ Preventing formation of tophi and destructive arthritis.
➢ Detection and management of associated medical conditions.
✓ Weight loss.
✓ Physical exercise.
✓ Dietary modification.
✓ Stay well hydrated.
✓ Decrease alcohol intake.
✓ Smoking cessation
Treatment of acute Gouty attack

Providing rapid and safe pain relief.
A-Nonsteroidal Anti-Inflammatory Drugs (NSAIDs):
 NSAIDs are the most frequently used agents to treat gout because they are
so well tolerated.
 The selected NSAID should be started at its recommended maximal dose. The
dose may be lowered as symptoms resolve.
 Indomethacin (25-50mg 3/day) is historically the NSAID of choice for acute
gout, but other NSAIDs with anti-inflammatory effect can be used may be just as
effective.
B-COLCHICINE
➢ Colchicine is effective but less well tolerated than NSAIDs.
✓ Colchicine inhibits phagocytosis of urate crystals by neutrophils by
impairing microtubule function.
✓ Anti-inflammatory effects: The drug impairs neutrophil metabolism,
chemotaxis, and motility, and inhibits the release of chemotactic factor.
➢ Dose:
✓ Oral form: Usually given orally as 1 mg initially, followed by 0.5–0.6 mg orally every 1–2 hours
until:
 The patient improves or
 Abdominal discomfort / diarrhea develops or
 A total dose of 8 mg has been administered.
GOUT & CPPD 366

➢ Initiating Therapy (basic line evaluation):

✓ LFTs (ALT ,AST ,s.albumin).
✓ Serum creatinine.
➢ Colchicine is contraindicated in:

✓ Patients with serious gastrointestinal (not IV colchicines), cardiac, or renal
disease.
✓ Patients with either renal and liver disease or failure.
✓ Extrahepatic billary obstruction.
✓ Patients with blood dyscrasia or with a history of hypersensitivity reactions to the
drug.

1- Abdominal discomfort, nausea, and diarrhea (The most common SE of Oral colchicine).
➢ If these side effects develop, the drug should be stopped;>>> once the
gastrointestinal symptoms have resolved, the drug can be cautiously
restarted at a lower dose.
2-Myopathy:
➢ Neuromyopathy may complicate long-term daily colchicine use.
➢ The clinical presentation resembles polymyositis with proximal muscle
weakness and creatinine kinase (CK) enzyme elevations.
➢ Neuromyopathy requires stopping colchicine.
Intravenous colchicines:
• Indicated in: Persons who are recovering from surgery or for those in whom oral intake is not possible.
• Intravenous use of colchicine has the advantages of a rapid onset and no gastrointestinal toxicity,
provided oral colchicine is not being used simultaneously.
• The usual initial intravenous dose is 2 mg diluted in 20–50 mL of normal saline and administered
over 20 minutes through a well-functioning catheter (to avoid extravasation).
C-Glucocorticoids:
➢ Indication: for patients in whom colchicine or NSAIDs are contraindicated or
ineffective (patients with CKD).
➢ Oral: prednisone 20–40 mg/d. The dosage is usually tapered over 1–2 weeks after
symptoms resolve.
➢ Intramuscular or intravenous glucocorticoids provide alternatives for use in the
hospitalized patient who can take nothing by mouth (IM Triamcinolone: 60 mg then oral
prednisolone)
➢ Intra-articular injections: 10–40 mg of prednisone or 10 mg of triamcinolone.
GOUT & CPPD 367

Prophylactic therapy
Preventing further attacks.
➢ The goal of treatment is to maintain the serum urate level at 5.0 mg/dL or less.
➢ Maintaining the serum level at this target allows precipitated crystals to dissolve and be cleared.
➢ If the urate level remains above 7.0 mg/dL, supersaturated conditions will persist and urate
deposition will continue. In other words, lowering the serum urate from 10.0 mg/dL to 8.0 mg/dL will
not reverse the disease; it will only allow it to continue to progress at a slower rate.
➢ Prophylaxis is usually continued for 3-6 months after achieving target serum urate (with no acute
attacks have occurred for last 3 to 6 months).
➢ Indication of prophylactic therapy:

1. Tophus or tophi by clinical exam or imaging study.
2. Frequent attacks of acute gouty arthritis (≥ 2 attacks/year)
3. CKD stage 2 or worse.
4. Past urolithiasis.
GOUT & CPPD 368

A. Xanthine Oxidase Inhibitor (XOI): (1st line ttt for most patients)
✓ Blocks the production of uric acid by inhibiting the enzyme xanthine oxidase,
which catalyzes the conversion of hypoxanthine to xanthine and of xanthine to uric acid. these
reduces the level of uric acid in serum and urine.
➢ Dose:
1. Allopurinol
✓ Started: 100 mg orally each day, and increased by 100 mg weekly until
the serum uric acid level falls below 6 mg/dL or until the maximum
recommended daily dose (800 mg) is reached
✓ The maintenance dose of allopurinol in most patients with normal renal
function is 300 mg/d as a single daily dose.
2. Febuxostat
✓ Started: 80 mg orally each day, and increased up to 120 mg /d until
the serum uric acid level falls below 6 mg/dL.
✓ The maintenance dose of febuxostat 40-80 mg/d as a single daily dose.
✓ Maximum Antihyperuricemic effect is seen 5-7 days after initiation
➢ Allopurinol started at low dose because abrupt changes in serum urate levels can provoke gout
➢ Colchicine (0.6 mg/d orally) is often administered during the first 6 months of XOI treatment to reduce the chance of
provoking a gout flare when serum urate levels fall.
➢ Febuxostat: Is a potent new xanthine oxidase inhibitor that appears to have certain benefits compared to
allopurinol.
✓ It is metabolized by the liver so can may be used in patients with mild to moderate renal
insufficiency without dose adjustment.
✓ It can be used safely even in patients with mild to moderate hepatic insufficiency.
✓ No hypersensitivity reactions: the use of febuxostat in patients with a history of allopurinol
reactions has been safe, effective, and well tolerated.
B. Uricosuric drugs: (If XOI contraindicated or not tolerated)
➢ Indications: Uricosuric drugs are mostly effective in

✓ Patients who have good renal function (as uricosuric agents require good renal function
to be effective (glomerular filtration rate above 60 mL/min).
✓ Patients who have no history of nephrolithiasis (it should be avoided in patients with
a history of nephrolithiasis because stone formation is more likely due to the flooding of urine with uric acid).
✓ Patients who can avoid all salicylate ingestions (Salicylate use in doses in excess of
81 mg/d will interfere with the effectiveness of uricosuric agents.).
✓ Patients under 65 years of age.
➢ Doses:
1. Probenecid is started at a dosage of 500 mg twice a day and advanced
slowly up to a maximum dosage of 1 g twice a day or until the target urate level
is reached.
GOUT & CPPD 369

2. Sulfinpyrazone: is slowly advanced from 100 mg to approximately 800

mg/d in two or three divided doses until the desired level of serum urate is
reached.
3. Benzbromarone: is more potent and may be effective in the case of
moderate renal insufficiency.
➢ Side effects: The most common side effects of this agent are rash and
gastrointestinal upset.
C-Lesinurad (New uricosuric agent)

➢ Mechanism of action: a selective URAT1 inhibitor.
➢ Indication: treatment of hyperuricemia in patients with gout who have failed to
reach a target serum uric acid level of less than 6.0 mg/dL while taking allopurinol or
febuxostat.
➢ Dose: 400-600 mg daily either single or combination with allopurinol or Feboxostat.
D-Uricase (Urate oxidase) Pegloticase
➢ Chemical structure: Recombinant mammalian uricase linked to polyethyleneglycol

(PEG).
➢ Mechanism of action: Pegloticase facilitates the conversion of UA into allantoin
(More soluble) which leads to decrease serum uric acid
➢ Indication:
✓ Severe tophaceous gout.
✓ Refractory gout (>3 attacks/year) which cannot reach to <6 mg/dL with XOIs.
➢ Dose and administration: 8 mg IV infusion every 2 weeks.
Colchicine: (Prophylaxis against recurrent attacks of gout)

➢ Given as 0.5–0.6 mg 1–3 times a day reduces the frequencies of attacks by 75–85%.
➢ The use of prophylactic colchicine without controlling the hyperuricemia only allows tophi and destructive
arthritis to continue to develop without the usual warning signs of recurrent acute gouty attacks (so it should
not be prescribed unless a urate-lowering agent is added to the regimen).
➢ These small doses of colchicine rarely cause gastrointestinal side effects and appear to be relatively safe.
➢ The daily dose should not exceed 0.6 mg for those with renal insufficiency.
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Treatment of Asymtomatic hyperuricemia:

➢ The use of a xanthine oxidase inhibitor or uricosuric agent is not recommended in the treatment of asymptomatic
hyperuricemia (Hyperuricemia alone is rarely an indication for treatment).
➢ The identification of asymptomatic hyperuricemia should not be ignored.
✓ The cause should be determined.
✓ Any associated problems, such as hypertension, obesity, alcoholism, diabetes, or hyperlipidemia, should be managed.
➢ Indication of XOI in Asymptomatic hyperuricemia:
• Family history of gout..
• Serum Uric acid >11mg%.
• Uric acid in urine>1100mg/dl.
NB
➢ XOI & Azathioptine:
• Both allopurinol and febuxostat may have severe interactions with azathioprine.
• Azathioprine is metabolized by xanthine oxidase, and because these drugs inhibit that enzyme, the breakdown of
azathioprine is slowed, increasing the effective dose.
• If care is not taken, significant bone marrow toxicity can result.
➢ The combination of colchicine and cyclosporine has induced rhabdomyolysis, So when considering
chronic therapy, it is helpful to lower the doses of cyclosporine and eliminate the use of diuretics
➢ Because of its possible serious side effects, allopurinol is not indicated in the treatment of asymptomatic hyperuricemia.
➢ Since allopurinol has no anti-inflammatory effects, it has no role in the treatment of acute gouty arthritis.
➢ Drugs that Are Uricosuric in Humans:

• Probenecid—Benzbromarone-Calcitonin-Salicylates-Sulfinpyrazone-Dicumarol-Diflunisal-Estrogens
Fenofibrate-Phenolsulfonphthalein- Losartan -Meclofenamic acid
➢ Canakinumab:
✓ A humanized, monoclonal anti–IL-1β antibody.
✓ approved for patients with gout who experience frequent gout attacks (at least three attacks in the past 12
months) and in whom NSAIDs and colchicine are contraindicated, are not tolerated, or do not provide an
adequate response, and in whom corticosteroids are inappropriate.
✓ Dose: a single, subcutaneous injection of 150 mg.
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❖ Uric acid is the biologically active end product of human purine metabolism.
• Serum urate concentrations are determined by the balance between urate production
and elimination.
• The purine precursors come from exogenous (dietary) sources or endogenous
metabolism (synthesis and cell turnover).
• Hyperuricemia results from urate overproduction, urate under excretion, or a
combination of both.
• Hyperuricemia is defined as serum urate levels greater than 6.8 mg/dL, the limit of its
solubility in serum.
❖ Incidence:
• The annual incidence rate of gout is 4.9% for urate levels greater than 9 mg/dL, 0.5%
for values between 7 and 8.9 mg/dL, and 0.1% for values less than 7 mg/dL.
• For serum urate values greater than 9 mg/ dL, the cumulative incidence of gout
reaches 22% after 5 years.
❖ Pathogenesis:
• Gout pathogenesis requires the accumulation of monosodium urate at levels sufficient
to drive the precipitation of crystals.
• Monosodium urate crystals drive inflammatory responses, including activation of the
NLRP3 inflammasome, a multimolecular cytosolic complex that processes and generates
IL-1β.
• The initiation of gouty inflammation by local leukocytes induces an influx of neutrophils
into the joint; when neutrophils encounter urate crystals, they become activated and
propagate further inflammation.
❖ Gout& Autoimmune diseases:

• Gout is rarely seen in patients with rheumatoid arthritis, systemic lupus erythematosus,
or ankylosing spondylitis.
• The basis for the decreased concurrence of these disorders is unclear, although the
long-term use of NSAIDs or corticosteroids may mask the clinical features of gout in
some of these patients.
❖ Acute tumor lysis syndrome: defined as hyperuricemia, lactic acidosis, hyperkalemia,

hyperphosphatemia, and hypocalcemia and is most commonly observed in patients with aggressive,
rapidly proliferating tumors, including lymphoproliferative disorders and metastatic
medulloblastoma.
❖ Gout & Common Co-morbidities:

• Hyperuricemia and gout are frequently accompanied by obesity, hyperlipidemia, hypertension
and glucose intolerance.
• These associated conditions should be managed aggressively.
• Fenofibrate and losartan might be appropriate agents for the treatment of
hypertriglyceridemia and hypertension, respectively, in hyperuricemic people because
each has modest uricosuric effects.
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❖ Adiposity, Insulin Resistance,and Hyperuricemia

• An increased adiposity and the insulin resistance syndrome are both closely associated
with hyperuricemia.
• Weight reduction is associated with a decline in urate levels and risk of gout. Weight
reduction leads to lower de novo purine synthesis and lower serum urate levels.
• Exogenous insulin can reduce the renal excretion of urate in both healthy and
hypertensive subjects, thus providing an additional link between adiposity, insulin
resistance, type II diabetes, and gout. Insulin mayenhance renal urate reabsorption via
stimulation of urate–anion exchanger URAT1 and/or the Na+- dependent anion
cotransporter in brush border membranes of the renal proximal tubule.
❖ Alcohol and Gout

• Conditions associated with net adenosine triphosphate (ATP) degradation lead to
accumulation of adenosine diphosphate (ADP) and adenosine monophosphate (AMP),
which can be rapidly degraded to uric acid, leading to hyperuricemia.
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GOUT & CPPD 374

❖ Inadequate response of an acute gout attack to initial therapy:

➢ Defintion: < 20% improvement in pain score within 24 hours or < 50% improvement in pain score ≥ 24 hours after
initiating pharmacologic therapy.
➢ TTT options: Switching to another monotherapy recommended above or adding a second recommended agent.
➢ If not response: Use of a biologic IL-1 inhibitor as anakinra or canakinumab.
GOUT & CPPD 375

GOUT & CPPD 376

2016 updated EULAR evidence-based recommendations for the management of gout
GOUT & CPPD 377

Calcium pyrophosphate dihydrate (CPPD)

crystal deposition disease (Pseudogout)
Definition: CPDD is a metabolic arthropathy resulting from the deposition of

calcium pyrophosphate dihydrate (CPPD) in and around joints, especially in
articular and fibrocartilage.
RISK FACTORS OF CPPD

➢ Age:
✓ CPPD affect about 3% of people in their 60s and the prevalence
increases with age to affect about 50% of people in their 90s.
✓ When it occurs early, before the fourth decade, it usually is associated
with secondary causes such as an underlying metabolic disease or
familial causes.
➢ Sex: Women have a slightly higher incidence than men
➢ Genetic Factors: Genetics plays a role in increasing the risk of CPPD.
➢ Metabolic disorders including:

✓ Hyperparathyroidism& hypothyroidism.
✓ Hemochromatosis& Amyloidosis.
✓ Hypomagnesemia, and hypophosphatasia.
➢ Others
✓ Drugs: such as loop diuretics--proton pump inhibitors--calcineurin
inhibitors (cyclosporine, tacrolimus),
✓ Post-surgical short bowel syndrome.
✓ Joint trauma or deformity.
✓ Complication of primary knee OA.
✓ Low cortical bone density.
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Pathophysiology
➢ Changes in the cartilage matrix with aging play an important role in promoting CPPD
deposition:
✓ Overactivity of enzymes that breakdown triphosphates, such as nucleoside

triphosphate pyrophosphohydrolase.
✓ Increased adenosine triphosphate breakdown with resultant increased inorganic
pyrophosphate in the joints
✓ Therefore, inorganic pyrophosphate can bind calcium, leading to CPPD deposition
in cartilage and synovium.
➢ CPPD develops by the precipitation of calcium pyrophosphate crystals in and surround the
joint.
➢ Hyaline cartilage is affected most commonly, but fibrocartilage, such as the meniscal
cartilage of the knee, also can be involved.
➢ The crystals also can attract white blood cells which cause inflammation(synovitis) that
leads to joint pain, warmth and swelling.
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Clinical Findings
Pseudogout 25% Pseudo rheumatoid Pseudo-osteoarthritis. Pseudo neuropathic
arthritis. 5% 50% arthropathy.
Presented by Acute, typically Symmetrical polyarthritis Gradual onset of joint pain Severe destructive
monarticular of with morning stiffness and stiffness monoarthritis similar
inflammatory arthritis. to that seen in
Patient may have acute neuropathic joints.
attacks superimposed on
their chronic symptoms
Affected joints • Knee 50% of cases Small joint of the hand & knees are most commonly
wrist affected, followed by the
• 1st MTP wrists ,MCP joints, hips,
shoulders, elbows, and
ankles.
DD: Arthrocentesis High titer RF, Anticcp Ab, CPPD affect Uncommon sites These patients have
examination of synovial and radiographic evidence for OA - Wrist, MCP joint, no neurologic
fluid for crystals and of typical rheumatoid bony elbow, shoulder. abnormalities and
culture to differentiate erosions favor the present with a painful
X ray: Sever degeneration of monoarthritis,
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from gout & septic diagnosis of true radiocarpal or associated with

arthritis rheumatoid arthritis patellofemoral joint-space dramatic destructive
with Subchondral cyst & radiographic
intraarticular radiodense changes.
bodies.
❖ Asymptomatic chondrocalcinosis (lanthanic CPPD):

✓ Some individuals with radiographic or pathologic evidence of articular
chondrocalcinosis have no clinically apparent arthritis.
✓ This finding has been termed lanthanic CPPD deposition and is of uncertain
significance.
NB
➢ Rarely, CPPD crystal deposition occurs in the axial skeleton, which may lead to acute neck pain.
➢ At times, neck pain may be accompanied by stiffness and fever, mimicking meningitis.
➢ The ligamentum flavum has been the most regularly reported site of CPPD crystal deposition in the
spine contribute to encroachment of the spinal cord.
➢ Infrequently, lumbar spine involvement may give rise to an acute radiculopathy or neurogenic
claudication resulting from spinal stenosis.
➢ CPPD crystal deposition disease is associated with other diseases, especially hemochromatosis and
hyperparathyroidism.
➢ A small percentage of patients with CPPD deposition have low titers of circulating rheumatoid factor
which making diagnosis more confusing.
LABORATORY FINDINGS
5. Synovial fluid examination:
 Synovial fluid analysis: Inflammatory picture (Leucocytosis with predominant neutrophiles-
with the average count between 15,000 and 20,000 cells/mm3.)
 Under polarized microscopy:

✓ The definitive diagnosis of CPPD is possible only by aspirating and inspecting
synovial fluid and demonstrating characteristic CPPD crystals.
✓ The crystals usually are rhomboid-shaped and positively birefringent (they
appear blue when parallel to the long axis of the compensator and yellow when perpendicular).
✓ During acute attacks: The crystals usually are intracellular.

✓ During the intercritical periods: Small, truncated, extracellular crystals.
6. Acute phase reactant: Elevated ESR & CRP.
7. Hormone & Electrolyte level:

➢ The evaluation of a patient with newly diagnosed CPPD deposition should include
tests of serum calcium, phosphorus, magnesium, alkaline phosphatase, and
GOUT & CPPD 381

thyroid-stimulating hormone levels. (Because of the recognized association between CPPD

deposition and various metabolic diseases)
• Chondrocalcinosis:
✓ There characteristic punctate and linear densities in hyaline
articular cartilage or fibrocartilaginous tissues which are diagnostic
of CPPD crystal deposition.
✓ The most common sites of CPPD crystal deposition are the knees, wrist
(triangular cartilage of the radiocarpal joint) and the symphysis
pubis.
• There are degenerative changes in an uncommon site along with subchondral cyst
formation (isolated patellofemoral joint space narrowing or degenerative change in the wrist)
MSK ultrasonography:
✓ It shows a superficial, hyperechoic, irregular band on the surface of articular cartilage
(“Double contour sign” or “urate icing”) in gouty patients
Diagnostic criteria For Cppd
1. Demonstration of CPPD crystals and tissue or synovial fluid by definitive means

(for example, characteristic x-ray defraction or chemical analysis).
2 A. Identification of monoclinic or triclinic crystals showing no or weakly positive

birefringence by compensated polarized light microscopy.
2 B. Presence of typical radiographic calcifications.
3 A. Acute arthritis, especially of the knees or other large joints.

3 B. Chronic arthritis, especially of the knee, hip, wrist, carpus, elbow, shoulder, or
metacarpophalangeal joint, especially if accompanied by acute exacerbations.
Categories
Definite disease: Criteria 1 or 2A must be fulfilled
Probable disease: Criteria 2A or 2B must be fulfilled.
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Possible disease: Criteria 3A or B should alert the clinician to the possibility of

underlying CPPD deposition
NB
The chronic arthritis shows the following features helpful in differentiating it from
osteoarthritis:
Uncommon site—wrist, metacarpophalangeal, elbow, or shoulder joint.
Radiographic appearance—radiocarpal or patellofemoral joint space
narrowing, especially if isolated (patella "wrapped around" the femur).
Subchondral cyst formation for severity of degeneration—progressive, with
subchondral bony collapse and fragmentation with formation of intra-
articular radiodense bodies.
Osteophyte formation—variable and inconstant
Tendon calcifications—especially triceps, Achilles, obturators
Treatment of CPPD
Goals of Management:
➢ Treatment of acute attack: Providing rapid and safe pain relief.
➢ Preventing further attacks.
➢ Detection and management of associated medical conditions.
✓ Weight loss.
✓ Physical exercise.
✓ Dietary modification.
✓ Stay well hydrated.
✓ Decrease alcohol intake.
✓ Smoking cessation
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Treatment of acute attack

Providing rapid and safe pain relief.
A-Nonsteroidal Anti-Inflammatory Drugs (NSAIDs):
 NSAIDs are the most frequently used agents to treat CPPD because they
are so well tolerated.
 The selected NSAID should be started at its recommended maximal dose. The
dose may be lowered as symptoms resolve.
 Indomethacin (25-50mg 3/day) is historically the NSAID of choice for acute
gout, but other NSAIDs with anti-inflammatory effect can be used may be just as
effective.
B-COLCHICINE
➢ Colchicine is effective but less well tolerated than NSAIDs.
✓ Colchicine inhibits phagocytosis of urate crystals by neutrophils by
impairing microtubule function.
✓ Anti-inflammatory effects: The drug impairs neutrophil metabolism,
chemotaxis, and motility, and inhibits the release of chemotactic factor.
➢ Dose:
✓ Oral form: Usually given orally as 1 mg initially, followed by 0.5–0.6 mg orally every 1–2 hours
until:
 The patient improves or
 Abdominal discomfort / diarrhea develops or
 A total dose of 8 mg has been administered.

✓ LFTs (ALT ,AST ,s.albumin).
✓ Serum creatinine.
➢ Colchicine is contraindicated in:

✓ Patients with serious gastrointestinal (not IV colchicines), cardiac, or renal
disease.
✓ Patients with either renal and liver disease or failure.
✓ Extrahepatic billary obstruction.
✓ Patients with blood dyscrasia or with a history of hypersensitivity reactions to the
drug.

2- Abdominal discomfort, nausea, and diarrhea (The most common SE of Oral colchicine).
➢ If these side effects develop, the drug should be stopped;>>> once the
gastrointestinal symptoms have resolved, the drug can be cautiously
restarted at a lower dose.
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2-Myopathy:
➢ Neuromyopathy may complicate long-term daily colchicine use.
➢ The clinical presentation resembles polymyositis with proximal muscle
weakness and creatinine kinase (CK) enzyme elevations.
➢ Neuromyopathy requires stopping colchicine.
Intravenous colchicines:
• Indicated in: Persons who are recovering from surgery or for those in whom oral intake is not possible.
• Intravenous use of colchicine has the advantages of a rapid onset and no gastrointestinal toxicity,
provided oral colchicine is not being used simultaneously.
• The usual initial intravenous dose is 2 mg diluted in 20–50 mL of normal saline and administered
over 20 minutes through a well-functioning catheter (to avoid extravasation).
C-Glucocorticoids:
➢ Indication: for patients in whom colchicine or NSAIDs are contraindicated or
ineffective (patients with CKD).
➢ Oral: prednisone 20–40 mg/d. The dosage is usually tapered over 1–2 weeks after
symptoms resolve.
➢ Intramuscular or intravenous glucocorticoids provide alternatives for use in the
hospitalized patient who can take nothing by mouth (IM Triamcinolone: 60 mg then oral
prednisolone)
➢ Intra-articular injections: 10–40 mg of prednisone or 10 mg of triamcinolone.
NB:
✓ No treatment is available to dissolve the crystal deposits.
✓ There is no equivalent to allopurinol or a uricosuric agent for the treatment of CPPD deposition disease. Until the
specific cause of this condition is determined, it is unlikely that a specific medicine will be found that removes the
crystals from joints.
✓ Other medicines may help some patients during severe attacks of calcium pyrophosphate crystal arthritis or with
the less common chronic inflammation that these crystals can cause. These drugs include hydroxychloroquine ,
methotrexate
✓ However, in patients with an associated metabolic condition, such as hyperparathyroidism, hemochromatosis, or
hypothyroidism, treatment of the underlying disease may decrease the number of attacks, but does not result in
resorption of crystals.
✓ The management of the pseudo-osteoarthritic form of CPPD deposition disease is similar to that for the
management of other forms of osteoarthritis, especially when acute attacks occur infrequently. Activity planning
and pacing, assistive devices, analgesic medication (eg, nonsteroidal anti-inflammatory drugs and intra-articular
glucocorticoid injections), and eventually surgery have all been proven to be effective tools.
GOUT & CPPD 385

Complications
✓ Progressive degenerative joint damage: CPPD crystal deposition disease can lead to progressive
degenerative damage to the joint. Findings may be severe with joint collapse and Charcot-like degeneration
✓ Acute attacks: Flares of pseudogout can follow general anesthesia and surgery, occurring most notably after
parathyroidectomy. The sudden decline in calcium may precipitate a flare of polyarticular inflammation with fever
and mental confusion.
GOUT & CPPD 386

Mustafa Elmenawy
Basic
Rheumatology
Metabolic Bone Diseases

Osteoporosis
Osteomalacia
Paget Disease
Metabolic Bone Disease
Important Definition
➢ Osteoporosis:
 WHO definition: Osteoporosis is a systemic skeletal disorder characterized by low
bone mass, deterioration of bone microarchitecture which leads to an increased risk
for fracture.
 (NIH) national institute of health definition: A disease of compromised bone strength
(bone mass and quality), resulting in an increased risk of fracture.
➢ Osteomalacia: softening of the bones due to impaired mineralization of bone matrix.
➢ Osteopetrosis: It is a clinical syndrome characterized by the failure of osteoclasts to resorb

bone which results in pathologic increase in bone density.
➢ Osteodystrophy:
✓ Abnormal development of bone due to chronic kidney disease (renal failure).
✓ It is marked by Impaired vitamin D metabolism, Elevated serum phosphorus
levels, Low or normal serum calcium levels, and Stimulation of parathyroid function.
✓ There may be any of various bone diseases, including osteitis fibrosa cystica,
osteomalacia, osteoporosis, and sometimes osteosclerosis.
➢ Modeling: It is the process that results in the achievement of bones’ characteristic shape
and overall structure.
➢ ReModeling: In which the gross shape of bone is altered by changes on periosteal or
endosteal surfaces (differs from modeling).
➢ Osteoclasts: The cells responsible for Resorption of bone.

➢ Osteoblasts: They are the pivotal bone cell, responsible directly for bone Formation.
➢ Compact or cortical bone: It is the bone found principally in the shafts (diaphyses) of long &
peripheral bones (about 80%of total skeleton).
➢ Trabecular or cancellous bone: It is the bone found principally at axial skeleton (the ends of long
bones, in vertebral bodies, and in flat bones). (about 20%of total skeleton).
Metabolic Bone Disease 387

Bone Structure and Function
Bone Structure:
There are two main types of bone
A. Compact or cortical bone (80%):
▪ Found principally in the shafts (diaphyses) of long & peripheral bones.
▪ It consists of overlapping parallel osteons surrounded by interstitial bone
and many lacunae containing osteocytes, which are connected between
each other and with the surfacing cells by myriads of canaculi.
▪ These osteocytes are distributed around the central Haversian canals,
which contain blood vessels, lymphatic vessels and connective tissue
B. Trabecular or cancellous bone(20%):

▪ Found principally at axial skeleton (the ends of long bones, in vertebral
bodies, and in flat bones).
▪ It has large spaces and is comprised of a meshwork of intercommunicating
trabeculae.
▪ Although trabecular bone accounts for the minority of total skeletal tissue,
it is the site of greater bone turnover due to its greater surface
area(trabecular bone turns over between 3 to 10 times more rapidly than cortical bone and is
therefore more sensitive to changes in bone resorption and formation).

Bone Matrix consists of:

▪ 25% water.
▪ 25% organic bone matrix consists predominantly (90%) of type I collagen,
other components (10%) are proteoglycan, osteocalcin and osteonectin.
▪ 50% crystalized mineral &the main mineral crystals are calcium
hydroxyapatite, which is deposited in along the lamellar gaps between
collagen fibers.
▪ Bone matrix also contains growth factors, such as IGF-I and II, for which
bone tissue is the largest reservoir.
▪ Each unit of collagen is formed as pro-collagen within the osteoblast and
consists of two alpha-1 chains and one alpha-2 chain twisted together in a triple helix.
Bone Cells:
▪ Bone consists of four types of cells that play a central role in bone turnover:
osteoclasts, osteoblasts, osteocytes and lining cells.
▪ Osteoclasts and osteoblasts are in low number present on bone, only at
locations with active bone turnover.
▪ Osteocytes are resident cells (as lining and periosteal cells) and present in
the entire bone volume.
A. Osteoclasts:
✓ The cells responsible for resorption of bone.
✓ Derived from hematopoietic stem cells (Osteoclasts are formed from macrophage,
monocytic precursor cells).
B. Osteoblasts:
✓ They are the pivotal bone cell, responsible directly for bone formation.
✓ Derived from local mesenchymal cells.
C. Osteocytes:
➢ They are small, flattened cells within the bone matrix, which are
connected to one another and to the lining cells on the bone surface by
a myriad of canaliculi.
➢ Osteocytes are very important in maintain the material and structural
strength of bone (response to mechanical loading).
➢ Derived from osteoblasts that have become entombed in lacunae in
the bone matrix during bone formation.
D. Lining cells:
➢ They cover the surface of the bone that is not remodeled. Their exact
function is still unknown.


Cellular Basis of Bone Remodeling
➢ The cellular mechanisms responsible for the adaptation of bone are modeling
(construction) and remodeling (reconstruction).
➢ Osteoclasts and osteoblasts form the bone multicellular unit (BMU) that
reconstructs endocortical, intracortical and trabecular bone.
➢ Bone loss occurs as a result of:
• Imbalance between the activity of osteoclasts and osteoblasts.
• Increase in the rate of initiation of new bone remodeling cycles (activation
frequency).
➢ Bone modeling produces a change in the size and shape of bone.
➢ During bone remodeling, resorption by osteoclasts (lasting about 3 weeks)
precedes bone formation by osteoblasts (over the following 3-4 months).
➢ The rate of remodeling differs across anatomical sites according to:

• The type of bone (cortical or trabecular).
• Physical loading.
• Proximity to a synovial joint.
• The presence of hemopoietic rather than fatty tissue in adjacent marrow.
➢ During childhood and adolescence

• Both processes (modeling and remodeling) are involved to establish the
peak bone strength.
• Bones grow by periostal apposition (growth in width) and by
endochondral ossification in the growth plate (growth in length), in which
PTH is one of the regulators.
• During childhood modeling occurs primarily on its outer (periosteal)
surface and is responsible for its size.
• Resorption is essential for the excavation of a marrow cavity and the
fashioning of cortical and trabecular bone.
➢ At puberty:
• Bone thickens because formation can occur on both the outer and inner
(endocortical) surfaces.
• The modeling and remodeling rates decrease as longitudinal growth
ceases with epiphyseal closure.
➢ In young healthy adults:

• The resorptive phase of the remodeling cycle removes damaged bone,
and the formation phase restores the structure.
• Each cycle is balanced and lasts 90-130 days.
• Bone resorption and formation are tightly coupled in time, location and
quantity, in which M-CSF and the RANKL/OPG balance are involved.
• After the remodeling cycle has completed, mineralization of new bone
will continue.
❖ This bone turnover is essential for:

✓ Maintaining bone health, preventing the accumulation of old bone, enabling
repairs to microfractures.
✓ Changing bone architecture in response to repeated loading.
✓ To provide calcium for calcium homeostasis when calcium uptake from the
intestine is suboptimal, such as in cases of deficiency of calcium intake
and/or vitamin D deficiency.
❖ Although bone mineral density predicts bone strength, many other skeletal
characteristics also contribute to bone strength such as:
✓ Bone macroarchitecture (shape and geometry).
✓ Bone microarchitecture (both trabecular and cortical).
✓ The degree of mineralization and microdamage accumulation.
✓ The rate of bone turnover, which can affect bone’s structural and material
properties.

The bone remodeling cycle:

1. The process of bone remodeling starts when the lining cells reveal the bone
surface upon activation.
2. Osteoclast precursors arrive at the site and become active osteoclasts as
they start to dig out a resorption pit (called a Howship’s lacuna).
3. When the osteoclasts have finished the process of resorption, osteoblasts

are attracted to the site and fill the lacuna with osteoid (unmineralized bone
matrix).
4. These osteoblasts lay down the organic matrix (mainly collagen type I), which
is subsequently mineralized.
5. At the end of this process old bone has been replaced by new bone. Bone
resorption and formation are coupled in this process.
6. Uncoupling of the remodeling cycle, so that either bone resorption or
formation in excess of the other leads to net bone change (gain or loss).

➢ Important factors for the osteoclastogenesis
o The macrophage colony-stimulating factor (M-CSF): produced by

osteoblasts.
o The receptor activator of the nuclear factor κB ligand (RANKL)

• It is expressed on osteoblasts surface.
• It interacts with its decoy receptor RANK, which is expressed on
osteoclast precursors and on mature osteoclasts, and promotes
osteoclast differentiation and activation.
o Osteoprotegerin (OPG),
• Present in the bone micro-environment,
• It is mainly secreted by osteoblasts and stromal cells.
• It is a decoy receptor for RANKL. OPG blocks the interaction of
RANKL with RANK and thus acts as a physiological regulator of
bone resorption.
➢ Factors affecting the osteoclastogenesis
A. Factors stimulate osteoclastogenesis (increase bone resorption)

enhance RANKL or inhibit OPG production
o Cytokines like IL-1β, IL-6, IL-7 and TNFα enhance RANKL
o 1.25-dihydroxyvitamine D3 enhances RANKL
o PTH enhance RANKL and inhibit OPG
o Glucocorticoids enhance RANKL and inhibit OPG
o Leptin, a protein involved in regulation of apatite
B. Factors inhibit osteoclastogenesis (decrease bone resorption)

enhance OPG or inhibit RANKL
o Estrogens enhance OPG production
o Tumor Growth Factor (TGF) enhance OPG production
o Interferon-gamma inhibits RANKL


Menopause AND Osteop0rosis:
✓ Estrogens play a central role in normal physiological bone remodeling.
✓ Estrogens inhibits osteoclastogenic proinflamatory cytokines (such as interleukin 1 (IL-1)

and tumor necrosis factor).
✓ Bone loss occurs as a consequence of estrogen deficiency in the

postmenopausal women (results in a remodeling imbalance with increase in bone
turnover).
✓ Estrogen deficiency lead to:

• Enhanced formation of functional osteoclasts as result of increase of
osteoclastogenic proinflamatory cytokines such as interleukin 1 (IL-1) and
tumor necrosis factor, which are regulated in a negative fashion by
estrogen.
• Loss of estrogen shortens the lifespan of osteoblasts and
osteocytes<<<This result in the accumulation of apoptotic osteocytes
within bone, which may increase bone fragility.
✓ The rate of loss is greatest soon after the menopause. The earlier the
menopause the greater the risk.
✓ Remodeling nearly doubles in the first year after menopause. This imbalance
leads to a progressive loss of trabecular bone in part due to increased
osteoclastogenesis.
✓ Age-related bone loss starts from 30 to 50 years of age in both men and women.
Loss from different bone sites occurs at different ages and at different rates.

Calcium Homeostasis and Hormonal Control

➢ More than 99% of the total body calcium resides in the skeleton.
➢ Serum calcium represents less than 1% of total body supply, but normal
serum calcium levels are extremely important for normal cellular function.
➢ The maintenance of normal serum calcium depends on the interplay of:

✓ Intestinal calcium absorption.
✓ Renal excretion.
✓ Skeletal mobilization or uptake of calcium.
➢ Serum calcium regulates and is regulated by three major hormones;:

✓ Parathyroid hormone (PTH).
✓ 1,25- dihydroxy vitamin D.
✓ Calcitonin.
1. PTH actions:
✓ On the kidney (main action): increase calcium reabsorption, phosphate
excretion, and 1,25-dihydroxy vitamin D production.
✓ On the bone to increase bone resorption.
2. 1,25-Dihydroxy vitamin D action:

✓ Potent stimulator of intestinal calcium (and phosphate) absorption.
✓ Stimulator of bone resorption
✓ Necessary for bone mineralization.
3. Calcitonin can directly inhibit osteoclastic bone resorption, but it plays a

relatively minor role in calcium homeostasis in normal adults.
➢ A number of feedback loops operate to control the level of serum calcium, PTH, and 1,25-dihydroxy
vitamin D.
➢ Low serum calcium levels stimulate 1,25-dihydroxy vitamin D synthesis directly through stimulation of
PTH release (and synthesis).
➢ The physiological response to increasing levels of PTH and 1,25-dihydroxy vitamin D is a gradual rise
in serum calcium level.
➢ A second set of feedback loops maintain serum calcium within a narrow physiological range.
➢ Disturbances in these control mechanisms or over/underproduction of PTH, 1,25- dihydroxy vitamin D,

calcitonin occurs in various clinical states, including osteoporosis.


NB
 More than 99% of the human body’s total calcium of approximately 1 kg is stored in bone.
 A small proportion of calcium is absorbed through the gut wall by passive diffusion, but most of the
calcium is absorbed actively through the action of 1.25-dihydroxy-vitamin D (1.25(OH) 2D) on
calbindin in the epithelial cells of the gut.
 Vitamin D is derived from dietary sources (10%) and from endogenous production in the skin
under the influence of sunlight.
 Hepatic 25-hydroxycholecalciferol (25-OHD) is the major circulating form of the vitamin and is
thought to be biologically inert, and is converted in the renal tubule cell to the metabolic active form
of the vitamin 1.25(OH)2D by 1α-hydroxylase, the activity of which is controlled chiefly by PTH.
 Both 25-OHD and 1.25(OH) 2D can be measured.

 25-OHD has a biological half-life of 2-3 weeks and is regarded as the more reliable indicator of
vitamin D status

The principal function of the PTH/1,25(OH)2D axis is to regulate calcium homeostasis.
Decrements in serum calcium levels stimulate PTH secretion by the PTG, which targets the kidney
to reduce urinary calcium excretion, stimulate 1α-hydroxylase activity, and enhance the fractional
excretion of phosphate (PO4), and targets bone to increase the efflux of calcium and phosphate.
The resulting increase in 1,25(OH)2D targets the gastrointestinal tract to increase dietary
absorption of calcium, which suppresses PTH.


Osteoporosis
➢ WHO definition: Osteoporosis is a systemic skeletal disorder characterized by low bone

mass, deterioration of bone microarchitecture which leads to an increased risk for fracture.
➢ (NIH) national institute of health definition: A disease of compromised bone strength (bone
mass and quality), resulting in an increased risk of fracture.
➢ Age: Bone loss in women begins before the onset of menopause, typically in the late third
and early fourth decades, and then accelerates for the 5–10 years after the menopause.
➢ Cause:
✓ Postmenopausal osteoporosis result from an estrogen-deficiency–induced
imbalance between bone formation and resorption such that resorption is favored
over formation.
✓ At least 10–20% of postmenopausal women have an additional secondary cause for
their bone loss beyond the estrogen deficiency of menopause.
➢ Presentation: Clinically, osteoporosis is diagnosed when bone mineral density (BMD) is

reduced or when fragility fractures (ie, fractures after little or no trauma) occur.

WHO Definition of Osteoporosis for Postmenopausal Women Based on DXA Measurements
T-score Number of SD above or below peak bone mass ("young normal")

according to race.
Z-score Number of SD above or below age-matched bone mass according
to gender and race.
Normal BMD T-score >–1
Low bone mass(osteopenia) BMD T-score < –1 and > –2.5
Osteoporosis BMD T-score< –2.5.
Severe osteoporosis BMD T-score<–2.5 with one or more fragility fractures
✓ T-score relates the BMD of the patient to peak bone mass for race and gender.
✓ Z-score relates the BMD of the patient to persons of the same age, gender, and race.
✓ The T-score is the more useful determination clinically.
✓ The lower of the two T-scores (spine or hip) is used for making the diagnosis.
✓ For each decline of approximately 1 standard deviation of BMD, there is a 1.3- to 3.0-fold increase
in the risk of fracture.
✓ Typically there is concordance between T-scores at both sites.
✓ Discordance can be due to artifactual elevation of the spinal measurement as a result of
degenerative arthritis, disc disease, or aortic calcification& in such cases, only measurements of
the hip and femoral neck should be used.


Clinical presentation
✓ Osteoporosis generally does not become clinically apparent until a fracture occurs.
✓ Two thirds of vertebral fractures are painless.
➢ Symptoms & signs in patients with painful vertebral fractures may include the
following:
• History of trauma: The episode of acute pain may follow a fall or minor trauma
• PAIN:
✓ Pain is localized to a specific, identifiable, vertebral level in the
midthoracic to lower thoracic or upper lumbar spine.
✓ Pain is often accompanied by paravertebral muscle spasms
exacerbated by activity and decreased by lying supine.
✓ Acute pain usually resolves after 4-6 weeks; in the setting of multiple
fractures with severe kyphosis, the pain may become chronic.
• On physical examination:
✓ With acute vertebral fractures, point tenderness over the involved vertebra
✓ Thoracic kyphosis with an exaggerated cervical lordosis (dowager hump)
✓ Subsequent loss of lumbar lordosis
✓ A decrease in height of 2-3 cm after each vertebral compression fracture
and progressive kyphosis.
➢ Symptoms & signs in patients with a hip fracture or Pelvis fracture may include
the following:
• Pain in the groin, posterior buttock, anterior thigh, medial thigh, and/or medial
knee during weight-bearing on the involved extremity.
• Diminished hip range of motion (ROM), particularly internal rotation and
flexion.
• On physical examination:
✓ Limited ROM with end-range pain on a FABER (flexion in abduction and
external rotation) hip joint test
✓ Decreased weight-bearing on the fractured side or an antalgic gait pattern
✓ External rotation of the involved hip while in the resting position
NB
 The most common osteoporosis-related fractures involve the thoracic and lumbar spine, the hip, and the distal radius.
 Ninety percent (90%) of all hip and spinal fractures are related to osteoporosis.
 The most frequent areas of spinal fracture are the thoracolumbar juncture (T12 and L1) and the mid-thoracic spine.
 Fractures of the humerus, ribs, pelvis,ankle, and clavicle also have been attributed to osteoporosis in 50% to 70% of
cases.
 Osteoporotic fractures result from a combination of decreased bone strength and an increased incidence of falls with
aging.
Clinical Evaluation
➢ The clinical evaluation of osteoporosis is dedicated to identifying lifestyle risk

factors for fracture pertinent physical findings, and secondary causes of
metabolic bone disease.
When taking the history>>careful attention to:

✓ Medication use (especially glucocorticoids)
✓ Smoking, alcohol intake.
✓ Dietary calcium intake.
✓ Family history of osteoporosis and fractures.
✓ Changes in height and weight.
✓ Reproductive history (particularly for evidence of hypogonadism).
The physical examination focuses on:

✓ Height loss.
✓ The presence of bone pain or deformity.
✓ Signs of anemia, hyperthyroidism, hypercortisolism, malnutrition, and other
disorders that cause secondary forms of osteoporosis.
Laboratory Evaluation
1. Serum chemistry:
✓ Calcium & Phosphorous.
✓ Albumin, Creatinine and total protein.
2. Serum 25-hydroxyvitamin D:
➢ Vitamin D deficiency is relatively common in elderly patients and contributes to
bone loss because it interferes with the absorption of calcium and phosphorus
and thus the mineralization of bone matrix.
3. Thyroid & parathyroid function tests.
4. Urinary calcium excretion:

✓ Urinary calcium measurements in a patient taking calcium supplements can
be informative as to the adequacy of therapy.
✓ Low urinary calcium excretion accompanies vitamin D deficiency & can be
due to underlying malabsorption or an extremely low calcium intake.
✓ High levels of urinary calcium excretion suggest idiopathic hypercalciuria,
which can be associated with renal stones and low BMD.
5. Urinary cortisol determination: Cushing syndrome is easily excluded by a 24-hour

urinary cortisol determination or overnight dexamethasone suppression testing.

6. Additional workup to be considered as clinically indicated:

A. Bone turnover markers:
➢ Bone Formation Markers:
✓ Bone-specific alkaline phosphatase.
✓ Osteocalcin (a noncollagenous matrix protein in bone, is produced
exclusively by osteoblasts).
✓ Procollagen I carboxyterminal propeptide.
✓ Procollagen I aminoterminal propeptide.
➢ Bone Resorption Markers:

✓ Aminoterminal telopeptide of type I collagen.
✓ Carboxyterminal telopeptide of type I collagen.
✓ Urinary pyridinolines.
B. Erythrocyte sedimentation rate (ESR).

C. Evaluation for gonadal insufficiency
D. Evaluation for hypercortisolism
E. Acid-base evaluation.
F. Serum and urine immunoelectrophoresis.

Imaging Evaluation
➢ DEXA Scan (Dual-energy x-ray absorptiometry)
Indications for Bone Densitometry
1. All women >65 yr regardless of additional risk factors
2. All postmenopausal women <65 yr who have one or more additional risk factors
for osteoporosis (besides menopause)
3. Estrogen-deficient women at risk for low bone density who are considering use
of estrogen or an alternative therapy, if bone density would influence the
decision
4. Women who have been on estrogen replacement therapy for prolonged periods
or to monitor the efficacy of a therapeutic intervention for osteoporosis
5. To diagnose low bone mass in glucocorticoid-treated individuals
6. To document reduced bone density in patients with vertebral abnormalities or
osteopenia on radiographs
7. To document low bone density in patients with asymptomatic primary or
secondary hyperparathyroidism
NB
 (DEXA) is the standard study used to establish or confirm a diagnosis of osteoporosis, to predict future
fracture risk, and to assess changes in bone mass over time.
 DXA is used to calculate bone mineral density (BMD) at the hip, wrist and spine.
 The central DXA sites—the hip and spine—are the optimal imaging locations for two reasons. First,
measurements at these sites are associated with superior precision. Second, the quantity of trabecular bone
at these sites correlates well with osteoporosis burden and fracture risk.
 Measurement at multiple sites increases the sensitivity for osteoporosis.
 This method can be used in both adults and children.
 Plain radiographs are inaccurate for the assessment of BMD. Bone loss must exceed 30% to 40% before it is
visible by x-ray.
➢ Quantitative CT scanning:
✓ This is used to measure BMD as a true volume density in g/cm3, which is not influenced
by bone size.
✓ This technique can be used in both adults and children but assesses BMD only at the
spine.
✓ Other limitations include significant radiation exposure, high cost, and possible
interference by osteophytes.
➢ Quantitative US of the calcaneus:

✓ This is a low-cost portable screening tool, but is not as accurate as other methods.

Fracture Risk Assessment (FRAX)

➢ Osteoporosis Foundation recommends performing a Fracture Risk Assessment (FRAX)
using a computer program that incorporates clinical risk factors for osteoporosis with
and without femoral neck BMD.
➢ FRAX provides a10-year risk of a hip fracture or a major osteoporotic fracture (i.e., hip,
proximal humerus, and wrist).
➢ The clinical risk factors included in the FRAX includes:

1. Age.
2. Weight.
3. Height.
4. History of a fracture as an adult.
5. Parental history of a hip fracture.
6. Current glucocorticoid use.
7. Secondary causes of osteoporosis.
8. Alcohol intake of more than two drinks a day.
9. Current smoker.
➢ These risk factors are added to femoral neck T-score for the 10-year fracture risk.
➢ Evaluation: a 10-year risk of hip fracture of 3% or more or a major osteoporotic

fracture of 20% or more is the threshold to recommend treatment.
➢ Advantages:
✓ Easily determined risk factors.
✓ Global validation & application in specific regions or nations.
➢ Limitations:
✓ It can lead to underestimates or overestimates of fracture risk in some patients
because it does not include all known risk factors and some risk factors are
superficial (e.g., glucocorticoid use is the question, but dose is not evaluated).
✓ The FRAX score is calibrated only for untreated patients, and thus results can be
misleading for patients who are already receiving pharmacologic therapy

Disease Course & Complications

➢ Postmenopausal osteoporosis can progress silently over years to a dangerously low
BMD and to bone strength so markedly reduced that the fracture threshold is
reached (fragility fractures can occur with minimal impact).
➢ Fractures of the spine:

✓ Fractures of the spine cause pain that is generally self-limited.
✓ Multiple vertebral fractures can lead to:
▪ Loss of height.
▪ Reduced thoracic expansion capacity and difficulty with breathing.
▪ Progressive thoracic kyphosis& ultimately increased frailty (Frailty itself
is a risk factor for fractures).
➢ Hip fractures
✓ Hip fractures have a more dramatic course and bad prognosis in the elderly
osteoporotic patient.
✓ Patients with hip fracture have decreased life expectancy & the overall mortality
in the first year after a hip fracture is approximately 20%.
✓ Hip fractures are life-altering events for elderly people. It is estimated that 50%
of patients who sustain a hip fracture do not live independently afterwards.

Osteoporosis in Women & Men <<< What is the difference???
➢ The morbidity and mortality of hip fractures are much greater in men than in
women…WHY??
✓ Because OP in men start in age elder than women so Osteoporotic fractures
occur in men at stages in their lives when they are more likely to be frail and are
less able to cope physically and emotionally with the loss of independence and
the risks of fracture repair surgery.
➢ Women have lower BMDs than men of the same age??

✓ Because of differences in the peak bone mass (Men achieve higher peak bone mass than do
women) & the rate of bone loss (the early rapid phase of menopause-related bone loss and).
✓ This leads to an earlier onset of the typical osteoporotic fractures (hip, vertebral, and Colles
fractures) in women compared with men.
✓ Men with low BMD experience the same fractures, but these fractures occur at later ages
(approximately 10 years on average) than they do in women.
✓ But once the early rapid phase of postmenopausal bone loss ends, the rate of bone loss slows.
Thereafter, the rates of bone loss in men and women are roughly comparable.
✓ In contrast to women, men do not experience a clear-cut, easily defined cessation of

gonadal function that raises awareness of risks for bone loss.
➢ Osteoporosis in men and gonadal functions??

✓ Replacing testosterone does not restore BMD to "normal" even in hypogonadal men and that
there are determinants of low BMD and fractures in men beyond hypogonadism.
✓ At least 80% of men with osteoporosis have one or more secondary causes of bone loss.
✓ Only 10–20% of men with low BMD have primary osteoporosis.These men are often middle-
aged and present with height loss and multiple fractures.
Osteoporosis in Children and Adolescents

• Disorders of bone fragility associated with increased fracture risk in children can be
divided into
➢ Primary osteoporosis (the defect is intrinsic to the bone tissue itself):

1. Osteogenesis imperfecta.
2. Idiopathic juvenile osteoporosis.
3. Osteoporosis pseudoglioma syndrome.
➢ Secondary osteoporosis (the defect arises in a tissue other than bone):

1. Immobilization-induced disease.
2. Inflammatory (rheumatic) diseases.
3. The use of glucocorticoids.

Glucocorticoid-Induced Osteoporosis
➢ Incidence:
✓ Osteoporosis is the most serious and disabling side effects of glucocorticoid therapy.
✓ Adverse skeletal events occur in approximately 50% of patients taking long-term
glucocorticoid therapy.
✓ Men and women of all ages and even children can lose bone while taking long-term
glucocorticoid therapy.
✓ Dose: Chronic therapy (3 months) with oral doses of >7.5 mg of prednisone daily (or
its equivalent) is associated with an increased risk of both vertebral and hip fractures.
✓ Rout of administration: The majority of patients receiving glucocorticoids take these

drugs orally. Other routes of administration (inhaled, intranasal, or topical) are less
likely to have deleterious skeletal consequences unless particularly high doses of long-
acting glucocorticoid preparations are used.
➢ The pathogenesis of glucocorticoid-induced osteoporosis:

✓ The most important effects appear to be a direct inhibitory effect on bone formation
(due to enhanced osteoblast and osteocyte apoptosis).
✓ In the first few weeks of such therapy, there is an increase in bone resorption, and
patients can lose considerable bone mass during this initial phase.
✓ Glucocorticoids antagonize the actions of vitamin D, especially in the intestine,

leading to reduced calcium absorption, and promote calcium excretion by the kidney,
producing marked hypercalciuria in some cases. These actions limit the amount of
calcium available to form bone matrix properly.
✓ Glucocorticoids also act on the pituitary to suppress gonadotropin production,

rendering most patients hypogonadal.
✓ Chronic glucocorticoid therapy promotes apoptosis (programmed cell death) of

osteoblasts and osteocytes.
✓ The prevention of bone loss is the ideal initial strategy Because when
glucocorticoids are discontinued, bone cannot replace the bone mineral that has been
lost, and it is impossible to rebuild bone microarchitecture.
ACR committee on Glucocorticoid-Induced Osteoporosis:

• Obtain baseline bone mineral density measurement when initiating long-term
(>6 months) glucocorticoid therapy
• Repeat measurement at 12 months (or 6 months) to ascertain ongoing bone
loss
• Monitor patients receiving therapy for osteoporosis annually.


Treatment of Osteoporosis
Preventive strategy
Lifestyle Modifications
➢ Target patient
✓ Lifestyle modifications indicated for all patients in whom the prevention of
bone loss and reducing fractures are desired.
➢ Methods
1. STOP: Patients should be encouraged to stop smoking and alcohol consumption.
2. Exercises:
 Regular weight-bearing exercise program & Walking: five times
weekly if possible for at least 30 and preferably 45 or 60 minutes each.
 Exercise improves well-being and neuromuscular coordination, which
can help condition reflexes to respond better to falls-also
 Physical activity produce strain on bone which stimulate the osteoblast.
3. Prevent falls and fractures by.

 Increasing the safety of the patient's immediate environment.
 Eliminating habits that are deleterious to skeletal integrity and that can
contribute to falls.
4. Nutritional Supplements:
➢ Calcium:
✓ Premenopausal women and men younger than 50 years without risk
factors for osteoporosis should receive a total of 1000 mg of calcium daily.
✓ Postmenopausal women, men older than 50 years, and other persons at
risk for osteoporosis should receive a total of 1200-1500 mg of calcium
daily.
➢ Vitamin D:
✓ Adults younger than 50 years should receive 400-800 IU of vitamin D 3
daily.
✓ All adults older than 50 years should receive 800-1000 IU of vitamin D 3
daily.
NB
1. Prevention of osteoporosis in premenopausal women: Increase calcium intake to 1000 mg elemental calcium per
day.
2. For postmenopausal women, men, and patients taking glucocorticoids long term 1000–1500 mg elemental calcium
per day (provided through the diet plus supplements).

Pharmacologic therapies
Bisphosphonates
Etidronate (Didronel), Pamidronate (Aredia), Alendronate (Fosamax), Risedronate
(Actonel), Ibandronate (Boniva), & Zoledronic Acid (Zometa)
❖ Mechanism of Action:
 Antiresorptive or anticatabolic agents.
 Bind to bone matrix at sites of active resorption and Inhibit bone resorption by
two mechanisms:
✓ Enhance osteoclast apoptosis.
✓ Interfere with osteoclast function: Aminobisphosphonates (eg,

pamidronate, alendronate, risedronate, ibandronate, and zoledronic acid) interfere
with osteoclast function by blocking the mevalonate pathway and the
geranylgeranylation of low-molecular-weight guanyl nucleotide (GTP)
binding proteins (GTPases). These proteins are involved in the
formation of the ruffled border of the osteoclast (a cellular structure that
enables the osteoclast to adhere tightly to bone matrix and allow resorption).
❖ Pharmacokinetics:
• Bioavailability: Poorly absorbed from the gastrointestinal tract—less than 5%
of the administered dose even on an empty stomach.

• Half-life: Depends on duration of therapy, specific compound, total amount
administered, and rate of bone remodeling.
• Clearance: Renally cleared without significant in vivo metabolism.

Drug Approved for dosing Efficacy

Alendronate • 70 mg orally once • Increases BMD at spine by 8% and
TTT & prevention of : weekly for hip by 3.5%.
osteoporosis. • Reduces the incidence of vertebral
✓ Postmenopausal • (35 mg/wk) for the fractures by 47% and nonvertebral
osteoporosis. prevention of fractures by 50% over 3 y.
postmenopausal
✓ Male bone loss
osteoporosis. • 35 mg orally once • Increases BMD at spine by 5.4% and
Risedronate
weekly hip by 1.6%.
✓ Steroid-induced
• Reduces vertebral fractures by 41%
osteoporosis
and nonvertebral fractures by 39%
. over 3 y.
Zoledronic Acid • 5 mg IV over 20 min • Increases BMD at spine by 4.3-5.1%

once yearly and hip by 3.1-3.5% compared with
placebo.
• Reduces the incidence of spine

fractures by 70%, hip fractures by
41%, and non-vertebral fractures by
25% over 3 y.
Ibandronate Treatment of • 150 mg orally once • Increases BMD at spine by 5.7-6.5%

postmenopausal monthly. and hip by 2.4-2.8%..
osteoporosis • 2 mg IV every 3 • Reduces vertebral fractures by 50%
months. with intermittent (non-daily) dosing
over 3 y.
• No effects on reduction of
nonvertebral fractures.
➢ Both serum calcium and 25-OHD levels should be monitored and

deficiencies should be restored to normal levels before treatment (to avoid
symptomatic hypocalcemia).
➢ Renal function should be assessed before start of treatment (S. creatinine

& creatinine clearance).
➢ Therapy can be initiated on the basis of bone mineral density

measurements or the history of fragility fractures in a patient at high risk for
bone loss.

➢ Monitoring Therapy:
➢ The efficacy of bisphosphonate therapy to increase bone mineral density
can be monitored on an annual or semiannual basis in patients with
osteoporosis.
➢ A reduction in bone resorption can also be assessed by measuring
biochemical markers of bone turnover (eg, urinary excretion of or serum
levels of N-telopeptide, osteocalcin, or bone-specific alkaline
phosphatase).
➢ In treating Paget disease of bone, regular monitoring of alkaline
phosphatase is advised along with periodic skeletal radiologic evaluation to
assess the response to therapy.
➢ Empty stomach: Oral bisphosphonates are best absorbed on an empty

stomach, 30–60 minutes before breakfast, with 8 oz of water and while
remaining upright.
➢ Discouraged in growing children Because bisphosphonates have a long

half-life in bone and significantly reduce skeletal remodeling, their use is
strongly discouraged in growing children (except in very unusual
circumstances) and in women of child-bearing age.
➢ CALCIUM + VIT D: Patients should receive adequate daily calcium and

vitamin D supplementation to treat osteoporosis.
➢ Renal insufficiency:
✓ Bisphosphonates should be used with great care, if at all, in patients
with renal insufficiency. (Long-term oral bisphosphonates are not recommended
in patients with serum creatinine >2.5 mg/dL or CrCl <35 mL/min).
✓ Patients with mild renal insufficiency (serum creatinine <2.5 mg/dL)

do not need doses of bisphosphonate adjusted for renal function.
✓ Renal function should be assessed before each dose of intravenous

bisphosphonate.
1- Gastrointestinal side effects:

➢ Daily, long-term alendronate and risedronate therapy may cause:
gastrointestinal irritation, especially abdominal pain, and less commonly,
esophagitis,ulceration, and bleeding.

➢ Weekly administration of both alendronate and risedronate or monthly

therapy with ibandronate reduce gastrointestinal adverse events.
➢ Careful clinical monitoring when use oral bisphosphonates with NSAIDs

because the potential for increased upper gastrointestinal adverse effects.
2- Minor adverse events included: headache, nausea, and body pain, which
have generally been mild.
3- Acute phase reactions:

➢ Characterized by joint pains, myalgias, and fever within 24–48 hours of the
infusion.
➢ It can develop in patients receiving intravenous bisphosphonates
(pamidronate, ibandronate, and zoledronic acid).
➢ Such reactions occur in <10% of patients receiving these therapies and are
self-limited.
4- Long term effect :

➢ Osteomalacia:
✓ Older first-generation bisphosphonates (eg, etidronate), when
used in high doses for conditions like Paget disease, must be
used with care.
✓ There is the potential for the accumulation of such agents in bone
over time with the subsequent induction of a mineralization defect,
low bone turnover, and frank osteomalacia.
➢ Osteonecrosis of the jaw:
✓ An uncommon but worrisome complication of therapy with
intravenous (zoledronic acid and pamidronate) and oral
(alendronate) therapy is osteonecrosis of the jaw.
✓ All potent anti-resorptive agents (bisphosphonates and RANKL
inhibitor) have been associated with osteonecrosis of the jaw
✓ Invasive dental procedures should be avoided while on
intravenous bisphosphonate treatment if possible.
➢ Atypical subtrochanteric fractures:
➢ Contraindications:
✓ Documented hypersensitivity.
✓ Inability to stand or sit upright for at least 30 min;
✓ Hypocalcemia.
✓ Esophageal abnormalities (eg, stricture, achalasia) that might
delay esophageal emptying.
✓ Pregnancy: category C.

➢ Other Uses in Rheumatic Diseases

1- Paget Disease of Bone:
➢ Alendronate & Risedronate are used in TTT of Paget disease as they are
approved to:
▪ Improves both the elevated alkaline phosphatase and the pain
due to Paget disease after 3 months of therapy.
▪ Enhance radiologic healing of pagetic bone lesions.
➢ Both oral Alendronate (40mg/day) & Risedronate (30mg/day) are
superior to etidronate (400 mg/d) in treatment of Paget disease.
2- Multiple myeloma & solid tumors:

✓ Bisphosphonates used in the prevention of skeletal complications
(bone pain, pathologic fractures, spinal cord compression, and
hypercalcemia) in patients with solid tumors and multiple myeloma.
✓ Hypercalcemia of malignancy: Intravenous bisphosphonates are
the treatment of choice (pamidronate & zoledronic acid).
NB
1. Ibandronate Studies with intravenous dosing (1 versus 2 mg every 3 months) showed greater effects on bone
mineral density and biochemical markers at the 2-mg dose, which is the approved dose.
2. Alendronate (70 mg/wk) is comparable to daily dosing (10 mg/d) as assessed by biochemical markers of bone
turnover and bone mineral density at the lumbar spine and hip.
3. Risedronate is not specifically approved by FDA for the therapy of osteoporosis in men.

Raloxifene
➢ Mechanisem of action:
✓ Raloxifene (Evista) belongs to a growing class of drugs called selective
estrogen response modulators (SERM), which differ from estrogen biochemically
and structurally but can act as estrogen agonists or antagonists depending on the
specific target tissues.
✓ Raloxifene was developed with the goal of capitalizing on the benefits of estrogen
in bone and eliminating or strongly diminishing the impact of estrogen-like
compounds on cardiovascular and breast cancer risks.
➢ Dose: Raloxifene (60 mg daily) is approved by the FDA for prevention recently and
treatment of osteoporosis in menopausal women.
➢ Efficacy:
✓ Significant increases in lumbar spine and femoral neck BMD: postmenopausal
women with osteoporosis treated with raloxifene (60 or 120 mg/d) for 3 years
demonstrated modest (2.1–2.7%) but significant increases in lumbar spine and
femoral neck BMD.
✓ Reduction of vertebral fractures by 30–50% compared with the placebo.
✓ No change in the overall incidence of non-vertebral fractures.
✓ Most suitable in women <70 y at moderate risk for osteoporosis who have
infrequent vasomotor symptoms of menopause (eg, hot flashes) and who are at
moderate-to-high risk for breast cancer.
➢ Side effect:
✓ Increased incidence of venous thrombosis.
✓ Additional adverse events that were increased in women taking raloxifene
included hot flashes, leg cramps, edema, and a flulike syndrome.
✓ Raloxifene was not associated with an increased risk of endometrial
carcinoma, vaginal bleeding, or mastalgia.
✓ Of interest: in the osteoporosis trials, raloxifene was associated with a
reduced incidence of breast cancer.

Calcitonin
✓ Calcitonin is a peptide hormone secreted by specialized cells in the thyroid
gland.
✓ Calcitonin acts directly to reduce bone resorption by binding to specific
receptors of the osteoclast.
✓ Salmon calcitonin is used for treatment of osteoporosis because it is more
potent and has a longer duration of action than human calcitonin.
➢ Dose & Indications:

1. Treatment of postmenopausal Osteoporosis:
✓ Especially in patients in whom bisphosphonates and estrogen are
contraindicated or not tolerated.
✓ Nasal spray (200 U/d) OR 100 IU IM/SC.
2. Analgesic effect: for patients who have acute painful vertebral fractures.
3. Not approved for prevention or for use in glucocorticoid-induced osteoporosis.
➢ Efficacy:
✓ Calcitonin has modest effects on spinal BMD.
✓ Increases BMD at lumbar spine by 1-1.5% & Reduce incidence of spine
fracture by 33% does BUT not reduce hip fractures,
➢ Side effect:
✓ Nasal irritation (congestion, discharge, or sneezing).
✓ Calcitonin has been linked to an Increased risk of cancer.

Teriparatide (Forteo)
✓ Teriparatide or parathyroid hormone (PTH) was approved by the FDA in
2002 for the treatment of osteoporosis in postmenopausal women and men.
✓ Relatively low doses activate parathyroid hormone receptors in bone to

produce anabolic effects that stimulate new bone formation.
✓ This therapy capitalizes on the ability of PTH to produce anabolic effects on
the skeleton to stimulate bone formation with the net effect of increased bone
mass and improved skeletal microarchitecture. when it is administered
intermittently in low doses.
✓ This is in contrast to continuous exposure to parathyroid hormone (Chronic

elevations of PTH, as occurs in primary hyperparathyroidism), which increases bone
resorption (catabolic effect) with a net effect of decreased trabecular bone
volume).
➢ Uses in Rheumatic Diseases

1- Postmenopausal Osteoporosis.
2- Osteoporosis in Men.
➢ Teriparatide is recommended to treat bone loss in the following groups:

✓ Patients with severe osteoporosis, especially accompanied by
fractures.
✓ Patients intolerant of other therapies for osteoporosis.
✓ Patients who have not responded to other drugs for osteoporosis as
evidenced by significant losses of BMD by DXA and/or the
development of fractures.
➢ Efficacy& Dose:
✓ Teriparatide: 20ug subcutaneously each day for a maximum of 2 years.
✓ Increases BMD at lumbar spine by 9-13% and hip by 3-6%

✓ Reduced the risk of spine fractures by 65% and nonspinal fractures by
54%.
➢ Treatment with teriparatide should be limited to 2 years because lack of
both safety and efficacy data with longer duration.
➢ How should teriparatide be best used to treat osteoporosis?
✓ It is anticipated that 2 years of therapy with this agent will be
followed by long-term therapy with antiresorptive drugs in an effort to
maintain the gains in BMD achieved with this anabolic agent.
➢ Adverse events due to teriparatide included: dizziness, leg cramps &

hypercalcemia.
➢ Contraindications: Teriparatide is contraindicated in:

1. Growing children (with open epiphyses).
2. Patients with bone metastases or those who have had skeletal irradiation.
3. Paget disease or an unexplained elevation in the alkaline phosphatase
value.
NB
1. Both of the above studies were terminated early due to results from standard carcinogenicity studies in rats
showing that lifelong daily injections of high-dose teriparatide induced osteosclerosis and a markedly increased
incidence of osteosarcomas.
2. Persistent elevations in serum calcium in teriparatide-treated patients generally can be managed with a dose
reduction in calcium and/or vitamin D.
Hormone Replacement Therapy (HRT):
➢ HRT refers to the combination of estrogen and progestin while estrogen

replacement therapy (ERT) involves the use of an estrogen preparation
exclusively, typically only in patients who have had a hysterectomy.
➢ Studies like the PEPI (Postmenopausal Estrogen/Progestin Interventions) trial

established the efficacy of various HRT and ERT regimens to prevent
postmenopausal bone loss at the spine and hip, based on DXA measurements
after 3 years of therapy.
➢ Side effects: Despite the positive effects of HRT on reducing fractures, the
negative non-skeletal outcomes have made HRT undesirable for treating
osteoporosis, given the availability of other options.
➢ Present recommendations are that HRT be used for as short a time as possible
after menopause, in the lowest possible doses, and mainly for the control of
vasomotor symptoms.

Monoclonal Antibody (RANK Ligand Inhibitor)

Denosumab (prolia)
➢ Binds to RANKL, a transmembrane or soluble protein essential for the
formation, function, and survival of osteoclasts, the cells responsible for bone
resorption.
➢ Denosumab Monoclonal antibody that specifically targets RANK ligand, an

essential regulator of osteoclasts.
➢ Indicated for: prevention of fracture in postmenopausal women with

osteoporosis and high fracture risk (ie, history of osteoporotic fracture, failed
other treatments).
➢ Denosumab is a potent inhibitor of bone resorption with suppression of a

marker of osteoclast activity. CTX-1 is suppressed by nearly 90% a few
weeks after each injection,however, the suppression of bone turnover is
transient, and bone turnover and bone density return to baseline levels rapidly
if the injections of denosumab are discontinued
➢ Dosing: 60 mg SC every 6monthes for 36 months or 3 years
➢ Efficacy: the incidence of vertebral fractures, hip fractures, and major

osteoporotic fractures was reduced by 68%, 40%, and 20%, respectively.
Combination Therapy
➢ Combining two antiresorptive agents (e.g., a bisphosphonate combined with

estrogen or raloxifene) produces small additional gains in bone mineral density;
but not reduces the risk of fracture more than treatment with a single agent.
➢ Combining parathyroid hormone or teriparatide with an antiresorptive agent

appears to lessen the BMD response to teriparatide.
➢ Cyclic parathyroid hormone therapy (3 months on and 3 months off) produced

similar gains in BMD to daily therapy in patients receiving alendronate.
➢ When therapy with parathyroid hormone is stopped, BMD begins to decline, but
following parathyroid hormone or teriparatide treatment with a bisphosphonate
appears to produce additional gains.

Treatment Failures
✓ Noncompliance is a common explanation for treatment failure.

✓ If noncompliance is not the explanation, then the clinician must decide whether the
fracture was expected or unexpected in the context of the individual patient.
✓ The clinician must consider:

• The length of therapy.
• Underlying risk factors contributing to the patient's bone loss.
• Baseline BMD values.
• The degree of trauma.
• Other medications and conditions that might exacerbate the fracture risk or
bone loss.
✓ The clinician must also decide whether the initial work-up was sufficient and
whether possible secondary causes were considered and properly eliminated.
✓ On many occasions, especially in postmenopausal women, treatment failures

prompt the first thorough investigation to exclude secondary causes of low BMD
(eg, primary hyperparathyroidism, multiple myeloma, vitamin D deficiency, or celiac
sprue).

OSTEOPOROSIS INDUCED BY OTHER MEDICATIONS
❖ Aromatase inhibitors
➢ Aromatase inhibitors in women undergoing breast cancer treatment are
associated with bone loss.
➢ These agents prevent the conversion of androgen to estrogen, resulting in low
serum estrogen levels and increased bone remodeling.
➢ Preventive treatment should be initiated in women with normal or low bone

mass and no history of fractures.
➢ Zoledronic acid and denosumab have been reported to be quite effective in

this patient population.
➢ Recombinant Human PTH (rhPTH 1-34): can be used to build up bone mass
If a woman continues to lose bone mass while taking aromatase inhibitors
despite compliance with potent anti-resorptive agents, and if the patient has not
been treated with radiation to the skeleton as part of the breast cancer protocol
❖ Gonadotropin-releasing hormone antagonists

➢ Gonadotropin-releasing hormone antagonists are used to treat women with
endometriosis and men with prostate cancer.
➢ These compounds induce bone loss by lowering estrogen levels, resulting in
accelerated bone turnover
➢ Treatment with calcium and vitamin D supplementation and a bisphosphonate

(zoledronic acid, alendronate, risedronate, or denosumab) should be initiated.
➢ BMD of the lumbar spine and hip should be measured at least once a year while
patients receive androgendeprivation maintenance therapy.


Paget disease
➢ Definition: Paget disease is a localized disorder of bone remodeling that typically
begins with excessive bone resorption followed by an increase in bone formation.
➢ Age: Mostly affect people in their fifth & sixth decade of life (rare in persons younger than 25 years).
➢ Sex: Both men and women are affected, with a 3:2 male-to-female ratio
➢ Prevalence:
✓ Greatest prevalence (3-4%) in Europe (predominantly England, France, and
Germany), Australia, and New Zealand.
✓ Very rare (0.01-0.02%), in Asian countries, especially China, India, and Malaysia,
and in the Middle East and Africa.
Pathogenesis
➢ Sites
✓ Paget disease can affect every bone in the skeleton, with an affinity for the
axial skeleton, long bones, and the skull.
✓ The skeletal sites primarily affected: the pelvis, lumbar & thoracic spine,
femur, sacrum, skull, tibia, and humerus. (The hands and feet are very rarely involved).
➢ Phases of Paget disease:

1. Lytic phase
✓ An increase in bone resorption with an abnormality in the osteoclasts (more
numerous and have many more nuclei) found at the site of bony involvement.
✓ This result in a bone turnover rate up to 20 times more rapid than normal.
2. A second phase (known as the mixed phase)

✓ A phase of rapid increases in bone formation with numerous osteoblasts,
which are increased in number but remain morphologically normal.
✓ The newly made bone is abnormal; the newly formed collagen fibers are deposited
in a haphazard fashion rather than linearly (as with normal bone formation).
3. The sclerotic phase

✓ Bone formation dominates and the bone that is formed has a disorganized
pattern (woven bone) and is weaker than normal adult bone.
✓ This woven bone pattern allows the bone marrow to be infiltrated by excessive
fibrous connective tissue and blood vessels, leading to a hypervascular bone state.
❖ The end result of these three phases is a structurally disorganized mosaic

of bone (woven bone), which is weaker mechanically, larger, less compact, more
vascular, and more susceptible to fracture than normal adult lamellar bone.

❖ Most persons with Paget disease are asymptomatic, In these patients, the disease is
detected based on the incidental finding of:
✓ An elevated serum alkaline phosphatase level.
✓ Characteristic radiographic abnormality.
❖ Paget disease may present with:
➢ Bone pain is the most common complaint.
➢ Pathologic fractures:
✓ May be traumatic or spontaneous. Most pagetic bone fractures heal normally
✓ The femur is the most common pagetic bone to fracture.
➢ Skeletal deformities:
✓ Spinal stenosis or kyphosis.
✓ Hyperexpansion of the skull (an increase in head size with frontal bossing, enlarged maxilla),
✓ Dental malocclusion.
➢ Neurologic manifestations:
✓ Hearing loss: The most common neurologic problem is, which is due to
compression of cranial nerve VIII and cochlear dysfunction.
✓ Dysesthesias and weakness due to nerve-root compression.
✓ Headache, Vertigo &Tinnitus.
➢ Others:
✓ Increased skeletal warmth over affected bone.
✓ Secondary OA.
✓ Congestive heart failure,
❖ Mortality/Morbidity
➢ Morbidity due to Paget disease can be extensive and most commonly results
from bone pain, osteoarthritis, and fractures.
➢ The increased mortality rate is due complications of the disease, especially

fractures and sarcoma.
➢ Most patients with Paget disease who develop sarcoma die within 3 years of
diagnosis.

Work up
❖ Laboratory Evaluation:
➢ Elevated Bone-specific Alkaline phosphatase levels: (markers of bone formation).
✓ BSAP is more specific than total alkaline phosphatase for Paget disease.
✓ Measuring total alkaline phosphatase levels may be useful in patients with normal
liver function.
➢ Elevated Bone Resorption Markers:

✓ Aminoterminal telopeptide of type I collagen (N –telopeptide).
✓ Carboxyterminal telopeptide of type I collagen (C-telopeptide).
✓ Urinary pyridinolines (Deoxypyridinoline).
➢ Serum Calcium, phosphorus, and PTH levels: usually remain Normal.
❖ Imaging:
➢ The radiographic appearance of pagetic bone shows mixed area of both a
radiolucency (osteolysis) & sclerosis (excessive bone formation).
➢ The skull: area of radiolucent lesion (osteoporosis circumscripta) & area of

increased density (coarsened trabecula).
➢ Other specific findings for Paget disease:

▪ V-shaped pattern discriminating between healthy and pagetic bone in the
long bones of the skeleton known as "the blade of grass" lesion.
▪ Brim sign: which is the thickened iliopectineal line in the pelvis;
▪ Cotton wool pattern in the skull characteristic of the mixed phase of Paget
disease.
▪ framed vertebrae: enlargement of the vertebral bodies with thickened
cortical shells and vertical striations.
❖ Biopsy:
➢ Bone biopsies may be indicated to evaluate for malignant transformation.
➢ The major histologic feature of Paget disease is: abnormal bony architecture
with increased osteoid volume and replacement of the normal marrow
with fibrous tissue.
➢ The 3 distinct phases in Paget disease may all exist separately or in the same bone
at one time.
❖ Radionuclide bone scans: helpful for documenting the extent of the disease.

Management
❖ Aim of treatment is to:

✓ Control disease activity.
✓ Minimize or prevent disease progression (suppression of the enhanced bone resorption and skeletal
turnover)
✓ Decrease complications from the disease.
❖ Indications for Treatment of Paget’s Disease
✓ Bone Pain.
✓ Progressive skeletal deformity
✓ Fractures.
✓ Skull involvement.
✓ Neurologic compromise.
✓ Periarticular disease.
✓ Hypercalcemia OR Recurrent renal calculi to hypercalciuria
✓ High-output congestive heart failure (Rare).
❖ Bisphosphonates
Drug dosing
Alendronate 40 mg orally daily.
Etidronate disodium 200- to 400-mg doses once-daily for 6 months.

The course should not exceed 6 months, but repeat courses can be given after rest
periods, preferably of 3 to 6 months’ duration
Zoledronic Acid 5 mg IV over 20 min once yearly
Risedronate sodium 30-mg tablet taken once daily for 2 months

Pamidronate disodium 30-mg IV infusion over 4 hours for 3 consecutive days
Or
60 mg over 2 to 4 hours for 2 consecutive days
❖ Calcitonin
✓ Calcitonin is a peptide hormone secreted by specialized cells in the thyroid gland.
✓ Calcitonin acts directly to reduce bone resorption by binding to specific receptors
of the osteoclast.
✓ Salmon calcitonin and human calcitonin inhibit the function of osteoclasts, which
are active in the pagetic process
➢ Dose:100 IU IM/SC and after 6 months of therapy, the patient may receive a maintenance
dose of 50 to 100.

❖ Monitoring treatment
• Response to therapy is monitored by:
✓ Reduction of symptoms.
✓ Maintenance of the alkaline phosphatase level in a mid-normal range, with
retreatment once values rise 25% above normal.
• Bone markers should be rechecked 2-3 months following bisphosphonate

treatment.
❖ Other
➢ Adequate intake of calcium and vitamin D especially in patient are receiving
bisphosphonate therapy.
➢ NSAIDs and acetaminophen may be effective for pain management.
❖ Surgical Care
➢ Indications for surgical treatment of Paget disease include bony deformities,
pathologic fractures, nerve compression, and degenerative arthritis, particularly of
the hip or knee.
➢ Total hip replacement and tibial osteotomy are effective for relieving pain and restoring
mobility.
➢ Bisphosphonates, should be used preoperatively to try to reduce disease activity in order
to prevent severe blood loss during surgery.
NB
 The spine is the second most commonly involved site of Paget disease.
 Paget disease is a localized disorder that may be:

✓ Monostotic (affecting only one bone)- about one third of all Paget disease cases.
✓ Polyostotic (affecting 2 or more bones).
 Paget disease does not spread from one bone to another, and new sites of involvement are rare after the initial
diagnosis; but lesions may continue to progress if left untreated.
 The juvenile form of Paget disease differs greatly from the adult version. Juvenile Paget disease is
characterized by widespread skeletal involvement and has distinctly different histologic and radiologic features.
 The hypervascularity of bone that may result from Paget disease may cause excessive bleeding following
fractures or surgery
 If increases in pain or BSAP levels are noted or if pathological fractures occur, further imaging studies are
important to help exclude neoplasms, including sarcomas and giant cell tumors.

OsteoMalacia
➢ Definition:
❖ Osteomalacia: Softening of the bones due to impaired mineralization of bone
matrix.
❖ Rickets applies to the defective mineralization of bone and the cartilaginous growth
plate in growing children.
Causes of Osteomalacia and Rickets
❖ Vitamin D Deficiency or Dysfunction

➢ Reduced Availability:
✓ Nutritional deficit.
✓ Reduced exposure to ultraviolet light
✓ Malabsorption (gastrointestinal or biliary disease or surgical resection).
➢ Alteration in Metabolism:
✓ Reduced 25-hydroxyvitamin D from: liver or gastrointestinal disease,Nephrotic
syndrome, or use of anticonvulsant drugs
✓ Reduced 1,25-dihydroxyvitamin D from renal disease or vitamin D–dependent
rickets type I.
➢ Alteration in Action on Target Tissues: Vitamin D–dependent rickets type II.
❖ Phosphate Deficiency
➢ Decreased availability: dietary deficiency and phosphate-binding antacids
➢ Decreased renotubular phosphate reabsorption
➢ Familial:
✓ X-linked hypophosphatemic rickets.
✓ Adult-onset vitamin D–resistant osteomalacia
➢ Acquired:
✓ Hypophosphatemic osteomalacia (phosphate diabetes)
✓ Oncogenic osteomalacia
➢ Generalized renotubular disorders.
❖ Acidosis
✓ Renotubular acidosis
✓ Ureterosigmoidostomy
✓ Carbonic anhydrase inhibitors (acetazolamide)
❖ Miscellaneous Mineralization Defects
✓ Inhibitors of mineralization—fluoride, bisphosphonates (e.g.,etidronate), and
chronic renal failure (aluminum)
✓ Hypophosphatasia
➢ Pathogenesis
• The most common cause of osteomalacia is reduced sunlight exposure since
ultraviolet light stimulates conversion of 7-dehydrocholesterol in the skin to form
cholecalciferol.
• Vitamin D occurs in only small quantities in most foods, except oily fish, so the
amount present in the average diet is generally insufficient to meet requirements.
➢ PAIN:
✓ Generalized pain involving the pelvis, spine, ribs, or lower extremities.
✓ Pain may be elicited by deep palpation of the tibia, ribs, or pubic ramus.
➢ Proximal muscle weakness, which may result in an antalgic or waddling gait and
difficulty ambulate.
➢ Skeletal deformities such as bowing of the long bones, kyphoscoliosis, or pelvic

abnormalities.
➢ Skeletal deformities in children ( RICKETS):

✓ Growth disturbances,
✓ Bowing of the long bones, and Short stature.
✓ Frontal bossing: Bony deformities of the skull with widened cranial sutures
(craniotabes),
✓ Pigeon chest
✓ Thickened costochondral junctions (rachitic rosary)
✓ Indentation of the margins of the ribs (Harrison's grooves).
➢ History of a malabsorptive process such as

✓ Gastrectomy
✓ Intestinal resection.
✓ Sprue.
✓ Primary biliary cirrhosis, or
✓ Pancreatic deficiency may lead to the identification of vitamin D deficiency and
osteomalacia.
➢ Complications:
▪ Due to impaired renal production of 1,25(OH)2D:
✓ Renal osteodystrophy.
✓ Mixed osteomalacia
✓ Osteitis fibrosa cystica.
▪ Secondary hyperparathyroidism ( due to Chronic vitamin D deficiency).

Work up
❖ Laboratory Evaluation:
➢ Decreased serum calcium levels slightly (In vitamin D deficiency states, the serum calcium levels are
usually normal or slightly decreased because PTH levels rise rapidly as a compensatory response to impaired calcium
absorption).
➢ Decreased serum phosphate, (principally in patients with decreased renotubular reabsorption of phosphate).
➢ Elevated PTH (in renal insufficiency phosphate retention),
➢ Elevated Alkaline phosphatase levels: (in patients with osteomalacia without hepatobiliary disease).
❖ Imaging:
➢ Pseudofractures or Looser's zones: which are transverse lines of rarefaction
through the cortices, with incomplete healing in the ribs, scapulae, long bones or
pubic rami. (Pseudofractures, however, may be indistinguishable from those associated with osteogenesis
imperfecta or Paget's disease).
➢ Vertebral fractures or Protrusio acetabuli.
❖ Biopsy: bone biopsy with a double tetracycline label: increased osteoid and
delayed mineralization of bone.
NB
Rare causes of osteomalacia

 Oncogenic osteomalacia or rickets
• It is a vitamin D–resistant process associated with certain neoplasias, principally small, benign mesenchymal or
endodermal tumors and, infrequently, certain malignant tumors (e.g., multiple myeloma; prostatic, oat cell, breast
carcinomas).
• Such patients typically present with:
o Decreased renotubular phosphate reabsorption,.
o Hypophosphatemia,
o Muscle weakness,
o Diminished 1,25(OH)2D levels, and
o Normocalcemia.
 The following condition can cause osteomalacia due to a direct inhibition of mineralization.
• Aluminum intoxication
• Bisphosphonates (in patients with Paget’s disease receiving etidronate and high dose pamidronate).
• Excessive intake of fluoride

Management
Vitamin D less than 20 ng/mL

❖ Rapid correction: (High loading doses)
➢ Oral 6000-10000 IU per day of vit D3 or D2 (better vitD 3) or 50000 IU per week for 8-
12 weeks.
➢ Higher doses needed in the following cases: (50000 IU twice weakly for 8-12 weeks)
✓ Very low level of vit D with severe symptoms of deficiency.
✓ Clinical lab and radiological evidence of Osteomalacia.
✓ Before start potent anti resorptive drugs ( denosumab , Zolendronate and teripatide)
❖ Maintenance dose:
➢ 800 to 1000 IU vit D3 per day.
➢ Higher maintenance doses (2000 IU daily) needed in the following cases

(high risk group):
✓ Obese--Dark skin—Smoker.
✓ Persistent non sun exposure in future.
✓ Concomitant medications interfere with vit D catabolism.
✓ Malabsorption syndrome (eg by pass surgery)
Vitamin D 20-30 ng/mL

➢ Elective correction with maintenance dose of 600 IU to 800 IU per day may be
sufficient to maintain level.
➢ No need for high loading dose.
➢ If symptomatic OR high risk group:

▪ Loading: 50000 IU per week for 8 weeks.
▪ Maintenance: 800 to 2000 IU vit D3 per day.
❖ Monitoring treatment
• Re check serum calcium after one month of last loading dose.
• Re assy 25 OH vit D after 6-12months.
✓ If target level is obtained so decrease maintenance dose to 800 IU per day or
1000 IU per day in high risk groups.
✓ If not reached , increase dose according to vit D level.
• Serum alkaline phosphatase: sometimes rise initially as mineralisation of bone
increases, but eventually fall to within the normal range as the bone disease heals.
• Every 1000 IU per day rise serum 25 OH vit D 10ng/ml within 3 to 6 months.

Concomitant use of Calcium and vit D
➢ Ca is replacement therapy that means if serum ca is low give Ca, If serum Ca is

normal so don't give it.
➢ Concomitant Ca and Vit D is indicated in:

✓ Osteoporosis or Ostemalacia
✓ During steroid treatment.
✓ Serum Ca is low.
✓ Malabsorption need Ca supplement up to 4 gm/ day.
✓ Vit D deficiency in pregnancy 1000 to (although NHS guidelines mentioned that Ca supplement increase
risk of hypercalcemia and pre birth so advice 700mg / day from diet and Give supplement ; if there is risk of preeclampsia).
In patients with renal insufficiency or failure
➢ Treatment should be with active form 1,25 OH vit D ( Calcitriol). (In advanced renal
failure (eGFR <30 ml/ min), calcitriol (1,25 dihydroxyvitamin D) production may be low due to diminished glomerular
filtration, loss of the 1 alpha hydroxylase).
➢ A phosphate binder (calcium acetate or calcium carbonate) should be used after

meals to decrease intestinal phosphate absorption.
➢ Calcium citrate therapy should not be used because it augments aluminum
absorption.
➢ CKD with (eGFR) >30 mL/min who have no biochemical evidence for chronic kidney
disease-metabolic bone disease (hyperparathyroidism, hyperphosphatemia) should
have similar vit. D supplementation as patients with normal renal function.
➢ Avoid use Ca supplements with history of renal stones.

NB
 Raw vit D (VitD3 and Vit D2) is the form of choice for vit D deficiency replacement
rather than active vit. D (Calcitriol).
 Vit D3 is better than vit D2:
✓ vit D3 is more sensitive to hepatic enzymes than vit D2 with subsequent more
active vit D production.
✓ It has slower clearance from body than vit D2.
 Vit D 3 capsules is preferred to some extent than tablets due its fatty content with better
absorption (bear in mind may be a cause if target level is not reached).
 Oral Vit D is better than IM (IM with unpredictable bioavailability and may be stored
in adipose tissue in obese patients with subsequent incomplete absorption of the total
injected dose).
 Dialy loading dose 5000 to 6000 IU / day or 50000 IU / weekly is recommended than
200000 IU monthly as a loading dose for vit D deficiency replacement
 Calcitriol (one alpha) is form of choice in following conditions:

✓ Diseases with decrease activity of 1alpha Hydroxylase enzyme such as Renal failure;
nephrotic syndrome ; CKD; hypophosteamic rickets and other vit D resistance rickets .
✓ Hypoparathryodism
✓ Malabsorption syndrome not responding to high loading dose of vit D 3 or calcidiol (25
OH vit D)
➢ For patients using calcitriol as a supplement, 25(OH)D levels do not indicate
clinical vitamin D status. (Calcitriol is associated with a fairly high incidence of hypercalcemia, so the
serum calcium should be monitored carefully. Monitoring serum 1,25 di OH vitamin D levels is not useful.
➢ In patients with severe liver disease: Use of the active metabolite of 25-OHD (Calderol) may
occasionally be necessary in resistant patients or in those with severe liver disease who cannot achieve
activation of this metabolite.
➢ In patients with hypophosphatemia and disorders of renotubular phosphate

reabsorption: Mineralization of bone occurs with phosphate therapy and moderately high doses of 1,25(OH)2D, the
latter being necessary to prevent the secondary hyperparathyroidism associated with phosphate therapy.

Mustafa Elmenawy
Basic
Rheumatology
Fibromyalgia
Fibromyalgia
Definition: FM is a disorder characterized by chronic widespread musculoskeletal pain of
associated with debilitating fatigue, unrefreshing sleep, cognitive complaints, depression,
and anxiety.
Epidemiology:
• Prevalence: Chronic pain and fatigue that have no clear organic cause are extremely
prevalent in the general population, especially among women and persons of lower
socioeconomic status.
 Regional pain, 20%;
 Widespread pain, 11%
 Fibromyalgia: 3–5% in females and 0.5–1.6% in males.
 Chronic fatigue, 20%.
• Age of onset: The average age of onset is approximately 30 to 55 years, but FM can
affect any age.
✓ FM can be diagnosed in children (adolescents & most commonly in girls).
✓ The prevalence of FM in children is approximately 1.5%.
• Sex: Females account for 70% to 90% of patients.
RISK FACTORS OF Fibromyalgia

 The cause fibromyalgia is UNKNWON, but it most likely involves a variety of factors
working together. These may include:
A- Genetic Factors:
✓ Increasing evidence supports the existence of a genetic predisposition to FM. First-
degree relatives of individuals with FM display an eightfold higher risk of FM than the
general population.
✓ Female sex: young and middle-aged females most at risk.
B- Environmental triggers may include

• Infections. Some illnesses appear to trigger or aggravate fibromyalgia.
• Physical or emotional trauma. Post-traumatic stress disorder has been linked to FM.
• Non-specific behavioral factors, such as Smoking, Obesity, Stress exposures &
Sleep abnormalities.
C- Fibromyalgia and other diseases: FM frequently coexist with:
✓ Systemic lupus erythematosus (>⅓) & Rheumatoid arthritis (1/4).
✓ Chronic fatigue syndrome.
✓ Irritable bowel syndrome.
✓ Multiple other regional pain syndromes.
✓ Psychiatric conditions, especially (depression, anxiety).
Fibromyalgia 439
Pathogenesis
❖ The two intrinsic mechanisms associated with the risk of developing chronic painful
musculoskeletal disorders:
1. Central sensitization and generalized pain magnification: may be related to
sensitization of afferent pathways in the peripheral or CNS that process coded
pain information or impairment in the inhibitory systems of the CNS.
2. Psychological factors include enhanced somatic awareness or the perception
and interpretation of sensory information, anxiety, depression, perceived stress,
and catastrophizing.
 Abnormalities in Pain and Sensory Processing

 Decrease in the pain perception threshold: associated with:
✓ Reduced discrimination of a nociceptive quality from a nonnociceptive
quality (eg, touch, warmth, cold).
✓ Reduced threshold for pain tolerance.
 Abnormalities in pain processing:

✓ Excess excitatory neurotransmitters (eg, substance P, glutamate levels in the insula).
✓ Low levels of inhibitory neurotransmitters (eg, serotonin and norepinephrine) in
descending antinociceptive pathways in the spinal cord.
✓ Maintained enhancement of temporal summation of second pain.
✓ Dopamine dysregulation.
 Low level of Serotonin and ATP:
✓ Serotonin is a neurotransmitter which has linked to sleep, pain perception,
headaches, and mood disorders. Lower-than-normal levels of serotonin
have been observed in patients with fibromyalgia.
✓ ATP is necessary to move and then hold serotonin in platelets.
 High level of Substance P:

✓ Substance P is a neurotransmitter that is released when axons are
stimulated.
✓ Elevated levels of substance P increase the sensitivity of nerves to pain or
heighten awareness of pain.
✓ In patients with fibromyalgia, levels of substance P in the CSF are 2 to 3
times higher than normal.
 Hypothalamic–Pituitary and Autonomic Dysfunction:
Fibromyalgia 440
1. PAIN:
➢ The hallmark of FM is widespread chronic pain (above and below the waist and on both sides of the body
for longer than 3 months).
➢ Pain is described as "exhausting," "miserable," or "unbearable." “throbbing,” “stabbing,”
and “burning.”.
➢ Pain is typically present on most days almost all day & the intensity may wax and wane.
➢ Pain is typically exacerbated by physical activity & may worsened with changes in the
weather.
➢ The patient may complain that a light touch is unpleasant (allodynia, defined as pain with stimulation that
should not be painful).
➢ The pain usually radiates diffusely from the axial skeleton over large areas of the body,
primarily in muscles.
➢ The pain usually accompanied with:
 Non-dermatomal paresthesias -- Morning stiffness — Arthralgia.
 Subjective sense of joint swelling. (Synovitis is not confirmed by physical examination unless another
coexisting rheumatic disease is present).
2. Regional pain syndromes: such as headache, temporomandibular joint pain,

irritable bowel syndrome, dysmenorrhea & chronic pelvic pain.
3. Fatigue:
➢ Marked fatigue with usual activities (almost universal and may dominate the clinical picture).
➢ Exhaustion after mild exercise.
➢ Subjective muscle weakness (not confirmed by loss of muscle power or elevated creatinine kinase levels).
➢ Restless legs syndrome.
4. Sleep distrubance:
➢ Poor sleep almost always is present, and the patient awakens unrefreshed.
➢ Sleep apnea & Specific sleep abnormalities may be demonstrable, particularly a-
wave intrusion into slow d-wave non-REM sleep.
➢ Hyper-somnolence during the day.
5. Psychological Troubles:
➢ Huge psychological burdens of stress and distress that may precede chronic pain.
➢ Difficulty in dealing with the usual stresses of daily life.
➢ Feelings of anxiety & depression.
6. Cognitive impairment (fibro-fog):

➢ Difficulty finding the right word & difficulty concentrating.
➢ Decreased short-term memory & forgetting names.
Fibromyalgia 441
2016 Revisions to the 2010 Diagnostic Criteria for Fibromyalgia

➢ Widespread pain index (WPI): In how many areas has the patient had pain during the past
week (Score will be between 0 and 19).
 Jaw- Shoulder girdle -- Upper arm -- Lower arm (both sides of the body Rt. & Lt.).
 Hip (buttock, trochanter) – Upper leg – Lower leg (both sides of the body Rt. & Lt.).
 Axial region: Neck -- Upper back -- Lower back – Chest – Abdomen.
➢ Symptoms Severity Scale (SSS) Score: Ask For each of the following over the past 7 days (The
total symptom severity scale (SSS)score: between 0 and 12)
0 1 2 3
 Fatigue No problem Slight or mild problem, or Moderate, considerable Severe, continuous, life
intermittent. problem, often present disturbing.
 Waking unrefreshed No problem Slight or mild problem, or Moderate, considerable Severe, continuous, life
intermittent. problem, often present disturbing
 Cognitive symptoms No problem Slight or mild problem, or Moderate, considerable Severe, continuous, life
intermittent. problem, often present disturbing
 Headaches 0=No problem 1=Problem
 Pain or cramps in 0=No problem 1=Problem
lower abdomen
 Depression 0=No problem 1=Problem
Patient satisfies modified 2016 fibromyalgia criteria if the following 3 conditions are met:
(1) Widespread pain index (WPI) ≥ 7 and symptom severity scale (SSS) score ≥ 5 OR WPI of 4–6
and SSS score ≥ 9.
(2) Generalized pain: pain in at least 4 of 5 regions, must be present, (Jaw, chest, and abdominal pain are not
included in generalized pain definition).
(3) Symptoms have been generally present for at least 3 months.
A diagnosis of fibromyalgia is valid irrespective of other diagnoses & A diagnosis of fibromyalgia

does not exclude the presence of other clinically important illnesses
ACR 1990 criteria for the classification of FM

➢ A history of chronic widespread pain (for at least 3 months) involving both sides of
the body and the axial skeleton above and below the waist,
Plus
➢ Pain in 11 of 18 Tender Point Sites on physical examination:
 Occiput -- Low cervical – Trapezius – Supraspinatus -- Second rib.
 Lateral epicondyle -- Gluteal -- Greater trochanter—Knee.
➢ Digital palpation should be performed with an approximate force of 4 kg.

➢ For a tender point to be considered “positive,” the subject must state that the
palpation was painful. “Tender” is not to be considered “painful.”
Fibromyalgia 442
Fibromyalgia 443
Work Up
➢ Consider fibromyalgia when a patient complains of the following :
✓ Widespread pain for longer than 3 months .
✓ Fatigue associated with usual daily activities .
✓ Sleep disturbances .
✓ Changes in personality and mood .
✓ Multiple symptoms that cannot be easily explained.
➢ In assessing patients with fibromyalgia Specifically, assess the following :

✓ Onset, location, and nature of pain, together with ameliorating and exacerbating factors .
✓ Sleep quality .
✓ Current and past stressors .
✓ Adverse experiences during childhood, such as physical, emotional, or sexual abuse.
✓ A detailed social and behavioral history
✓ How the patient deals with the usual stresses of daily life, feelings of anxiety, and feelings of
depression .
✓ The presence of regional pain syndromes, such as temporomandibular joint pain, irritable
bowel syndrome, and chronic pelvic pain. These disorders overlap with fibromyalgia and
very frequently coexist in the same patient.
❖ Physical examination: general exam, joint exam including back, tender point
evaluation for allodynia, manual muscle strength, neurologic exam including deep
tendon reflexes.
❖ Laboratory examination:
✓ There is NO specific laboratory test used in clinical practice to confirm a
diagnosis of FM.
✓ Routine laboratory blood testing, including CBC, ESR,CRP ,autoantibodies (rheumatoid factor and
antinuclear antibody) thyroid-stimulating hormone levels, creatine kinase, S.GPT & S.GOT are within
their NORMAL values.
➢ Rheumatologic disorder ➢ Neurologic disorder ➢ Endocrine disorder ➢ Psychiatric disorder

✓ SLE,a rheumatoid arthritis, Sjögren ✓ CTS ✓ Hypothyroidisma ✓ Anxiety
syndromea ✓ Cervical radiculopathy ✓ Non-IDDM ✓ Depression.
✓ Polyarticular osteoarthritis, Cervical cord compression ✓ Hyperparathyroidism
degenerative spondylosis ✓ Metabolic myopathies as ➢ Drugs ➢ Chronic infection: SBE,
✓ Polymyalgia rheumatica myasthenia gravis. ✓ Statine brucellosis, hepatitis C,
✓ Polymyositis, statin myopathy ✓ Multiple sclerosis ✓ Antimalarials. HIV
✓ Regional pain syndromes ✓ Tapering of steroids.
✓ Osteomalacia
✓ Hypermobility syndromes
Fibromyalgia 444
NB
 Regional myofascial pain syndrome:
✓ It is a localized pain syndrome characterized by the presence of a trigger point.
✓ Upon palpation of the trigger point, severe local tenderness and radiation of pain into characteristic regions is elicited. Though
the discomfort of the myofascial pain syndrome remains regional, it is usually more widespread than bursitis or tendinitis.
✓ Regional myofascial pain syndrome most commonly involves the unilateral lower back, neck, shoulder, or hip region.
 Hypersensitivity and multiple chemical sensitivity syndrome (odors, bright lights, loud noises, medications). May occurs with FM
 FM symptoms occurring for the first time in a patient older than 55 to 60 years are usually due to a disease other than FM (e.g.,
infection, neoplasia, and arthritis).
 Pain sensitivity in women: Fibromyalgia is most common in women. Among the mechanisms that may contribute to increased pain
sensitivity in women are the following :
✓ Differences in primary afferent input to the CNS, with developmental and menstrual cycle–dependent enhancement
✓ Developmental and phasic gonadal-hormonal modulation of pain regulatory systems, stress-induced analgesia, and opioid
receptors
✓ Higher levels of trait and state anxiety
✓ Increased prevalence of depression
✓ Use of maladaptive coping strategies
✓ Increased behavioral activity in response to pain.
 Overlap between FM and autoimmune disorders:

✓ Symptoms that can be seen in both FM and autoimmune disorders include not only arthralgias, myalgias, and fatigue, but also
morning stiffness and a history of subjective swelling of the hands and feet.
✓ In addition, symptoms suggestive of Raynaud’s phenomenon (characterized, in contrast to true Raynaud’s phenomenon, by
paleness or erythema of the entire hand rather than only specific digits), malar flushing (in contrast to a fixed malar rash), and
livedo reticularis are all common in FM, and can mislead the practitioner to suspect an autoimmune disorder.
✓ Persons with established autoimmune disorders also commonly exhibit comorbid symptoms of FM.
✓ Up to 25% of persons with systemic inflammatory disorders, such as systemic lupus erythematosus (SLE), rheumatoid arthritis
(RA), and ankylosing spondylitis, also meet ACR criteria for FM.
✓ Because both inflammatory and non-inflammatory mechanisms cause symptoms in this setting, FM should be suspected when an
individual with an autoimmune disorder has persistent complaints despite normal inflammatory indices, or when symptoms are
unresponsive to anti-inflammatory regimens.
Fibromyalgia 445
Treatment of Fibromyalgia
❖ Aim of Treatment:
➢ The therapeutic goal is care not cure.
➢ Improves physical, functional status and self-reported fibromyalgia symptoms (overall
well-being, tender point count, self-reported pain, depression, state-trait anxiety, and
self-efficacy).
❖ Education and Lifestyle Measures:
➢ Begin education at the first visit, emphasizing that an active role for the patient in the
treatment plan is essential.
➢ Encourage self-efficacy (the belief that the patient can control pain and fatigue through self-management).
➢ It is often helpful to educate patients about the waxing and waning nature of FM and
ask that they make note of their personal triggers so that they better understand the
linkage between environment, behaviors, and FM symptoms.
➢ Reassuring patients that the pain they are experiencing is due to altered
neurophysiology of pain processing rather than tissue destruction may relieve anxiety.
➢ Reduce stress:
✓ Develop a plan to avoid or limit overexertion and emotional stress.
✓ Allow yourself time each day to relax.
✓ Try stress management techniques, such as deep-breathing exercises or
meditation.
➢ Get enough sleep:
✓ Getting sufficient sleep is essential (to improve associated fatigue).
✓ Practice good sleep habits, such as going to bed and getting up at the same time
each day and limiting daytime napping.
➢ Exercise regularly:
✓ Gradual and regular exercises such as walking, swimming, biking and water
aerobics. A physical therapist can help you develop.
✓ Home exercise program: Stretching, good posture and relaxation exercises also
are helpful.
✓ High-intensity fitness programs should be avoided because they are associated
with increased pain and fatigue, with consequent poor compliance.
➢ Pace yourself. Keep your activity on an even level. If you do too much on your good
days, you may have more bad days. Moderation means not "overdoing it" on your good
days, but likewise it means not self-limiting or doing "too little" on the days when
symptoms flare.
➢ Maintain a healthy lifestyle:
✓ Eat healthy foods & Limit your caffeine intake.
✓ Do something that you find enjoyable and fulfilling every day.
Fibromyalgia 446
❖ Therapeutic programs:
➢ Physical Therapy -- Aquatic Therapy -- Massage Therapy
➢ Acupuncture -- Yoga -- Meditation
➢ Cognitive Behavioral Therapy.
Pharmacologic TTT:
❖ Medications approved by FDA for treatment of FM:
➢ Dual reuptake inhibitors (serotonin-norepinephrine reuptake inhibitors [SNRI]): Increase serotonin and
norepinephrine at synapses in the descending analgesia pathways.
 Duloxetine (Cymbalta): start 20 to 30 mg in the morning with food. Titrate

monthly to 60 mg/day or effect.
✓ use in FM patients with depressed mood and fatigue or
osteoarthritis of the back and knees
 Milnacipran (Savella): start 12.5 mg in the morning with food. Increase by

12.5 mg every 3 to 7 days to effect. Typical dose: 50 mg twice a day.
✓ use in FM patients with cognitive dysfunction (fibrofog) and fatigue
➢ Anticonvulsant: bind to ligand on voltage-gated calcium channels letting less calcium in,
which decreases the release of excitatory neurotransmitters (glutamate, substance P).
 Pregabalin (Lyrica): start 50 mg with food before bed. After 1 week, increase
to 50 mg BID and titrate dose to effect. Typical dose: 75 to 150 mg BID (max dose
225 mg BID).
✓ Use in FM patients with profound sleep disturbance and/or
neuropathic pain symptoms.
❖ Other effective Medications in treatment of FM:
➢ Tricyclic antidepressant:
✓ Low-dose TCAs improve the sleep disturbance, pain, and tender points in a
proportion of patients with FM.
✓ Antidepressant drugs are especially useful in fibromyalgia because of the high
prevalence of comorbid depression.
 Amitriptyline: (10 to 25 mg) 2 hours prior to bedtime. This dose may be
increased by 10 to 25 mg increments at 2-week intervals & the usual effective
dose is 25 to 100 mg daily.
➢ Side effects: morning drowsiness, dry mouth, and constipation (due to the TCA’s
anticholinergic and antihistamine activities).
➢ Antiepileptic drugs:
✓ Many patients also require an antiepileptic drug, particularly when marked
allodynia and hyperalgesia are present.
✓ Antiepileptic drugs ameliorate both pain sensitivity and serve as adjunctive
medications for disturbed sleep and depression.
Fibromyalgia 447
 Gabapentin: Escalate weekly by 300-mg increments from 300 mg at

bedtime to 600 mg 3 times daily.
 Topiramate, escalating at weekly intervals from 25–50 mg at bedtime to
100–200 mg twice daily, is also useful for migraine prophylaxis and may
facilitate weight loss.
➢ A selective serotonin reuptake inhibitor SSRI:
 Fluoxetine: 10–40 mg every morning.
 Sertraline: 50 mg every morning.
➢ Anxiolytics Drugs: Anxiety disorders are common in fibromyalgia, thus anxiolytics of

different durations of action are frequently useful adjuncts.
 Clonazepam (long half-life), escalate after 3 days from 0.25 mg twice daily
to a maximum of 4 mg/d.
 Lorazepam (medium half-life), 2–3 mg/d given 2 or 3 times daily.
 Alprazolam (short half-life), 0.25–0.5 mg 2 or 3 times daily.
➢ Other Medications:
 cyclobenzaprine (10–20 mg at bedtime) Muscle relaxants generally
provide only short-term benefit.
 Venlafaxine (dual reuptake inhibitor) start at 50-100 mg/d divided twice
daily (maximum 375 mg/d)
➢ Fatigue:
 Fatigue generally improves with effective treatment of pain, depression, and
sleep disturbances in combination with a graded aerobic exercise program.
 Modafinil (100–200 mg/d) may benefit those patients in whom
overwhelming fatigue is a persistent complaint.
NB
 Opioids, corticosteroids, NSAIDs, benzodiazepines, and nonbenzodiazepine hypnotics, guaifenesin, S-Adenosylmethionine, melatonin,
magnesium, and DHEA are not effective and should be avoided.
 Potential side effects from medications used to treat FM.

✓ All SNRIs may increase risk for suicidal ideation upon initiation.
✓ Serotonin syndrome: Many of the drugs (SNRIs, SSRIs, tramadol, others) can increase the chance of developing serotonin
syndrome when used together or at high doses.
✓ SNRIs, milnacipran: nausea, vomiting which are lessened by giving it with food. Insomnia, dizziness, high BP, and liver and renal
dysfunction can occur.
✓ Pregabalin, gabapentin, TCAs: fatigue, somnolence, dizziness, weight gain, dry mouth, hyponatremia (TCAs).
✓ Tramadol: fatigue, somnolence, dizziness, nausea, headache, high BP, and liver and renal dysfunction.
Fibromyalgia 448
Prognosis and Outcome

➢ Overall, patients with FM typically have a lifelong problem with chronic pain.
➢ Overall, about 30% to 40% of patients will have 40% to 50% relief of their
pain. However, this is an average response as some patients get excellent symptom
relief, whereas some get none.
➢ Assisting patients in the self-management of their symptoms, reducing health care–
seeking behaviors, and improving healthy behaviors are important goals of treatment.
➢ Perhaps the most important function of the rheumatologist is to confirm the diagnosis and
determine if the patient has a comorbid rheumatic condition that should be treated.
Fibromyalgia 449

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2021

Rheumatoid Arthritis 1-42

A-General manifestations: Fatigue, possible weight loss &low-grade fevers.

 Distribution of involved joints:

Hand examination Foot examination

 Other joints involvement:

➢ Hip joint: (in 20% of patients).

✓ Entrapment neuropathy: carpal tunnel syndrome and tarsal tunnel syndrome

✓ Peripheral neuropathy & Mononeutitis multiplex: due to small vessel vasculitis

3- Rheumatoid nodules(subcutaneous nodules) >>> in 25% of patients:

3. Caplan’s syndrome: RA+ multiple pulmonary nodules+ Pneumoconiosis.

4. Bronchiolitis obliterans: also called constrictive bronchiolitis. Patients have

Patterns of cervical spine involvement:

Variant of Rheumatoid arthritis

B-Juvenile chronic arthropathy: (Still's disease)

C-Adult Still's disease:

D-Caplan’s syndrome: Rheumatoid arthritis+ pulmonary nodules+Pneumoconiosis

 Microcytic hypochromic anemia(iron deficiency anemia) due to GIT Bleeding.

B- Pancytopenia:: (Leukopenia &Thrombocytopenia): which result from:

2-Acute phase reactant: Marked elevation in ESR & CRP.

3. RF +Ve in abouts 50%_60% of cases at 1st presentation and additional 25%

4. RF can be detected by:

6. Differential of a Positive Rheumatoid Factor:

B-Anti-Cyclic Citrullinated Peptide Antibodies (anti-CCP).

1. Autoantibodies directed against citrullinated proteins, so-called anticyclic

5. The process of citrullination:

C-Antinuclear antibody (ANA): +ve in 30% of cases.

The Synovial Fluid Analysis:

✓ Synovial fluid in RA is inflammatory:

Ultrasonography: Early detection of synovitis, erosion & effusions.

Bone scanning: Findings may help to distinguish inflammatory from noninflammatory

Classification criteria(2010) for rheumatoid arthritis Score

B. Serology (at least 1 test result is needed for classification)

C. Acute-phase reactants (at least 1 test result is needed for classification)

A score of ≥ 6/10 is needed for classification of a patient as having definite RA

1987 Criteria for Classification of Rheumatoid Arthritis (American Rheumatism

2016 ACR/EULAR revised criteria for too early diagnosis of RA

A. Entry criteria; No other prominent diagnosis is proposed according to the patient’s

2. Calcium Pyrophosphate Dihydrate Deposition Disease (Common)

7. Musculoskeletal Pain of Thyroid Disease (Common)

8. Viral Infection (Common)

9. Rheumatic Fever (Uncommon)

10. Bacterial Endocarditis (Uncommon)

 This synovitis probably is caused by the deposition of circulating immune complexes.

11. Lyme Disease (Common in Endemic Areas)

12. Relapsing Seronegative Symmetric Synovitis with Pitting Edema (Uncommon)

13. SAPHO syndrome:

14. Sarcoidosis (Uncommon)

 In chronic granulomatous sarcoidosis:

15. Malignancy (Uncommon)

16. Multicentric Reticulohistiocytosis (Rare)

17. Pigmented Villonodular Synovitis (Rare)

Prognosis & Outcome:

Prognostic Factors that predict poor outcome

Epidemiology, Pathology & Pathogenesis

RISK FACTORS OF RHEUMATOID ARTHRITIS

Nongenetic Risk Factors:

✓ Modifying environmental factors such as: Climate_trauma_psychological stress.

2. HCV also is associated with increased risk of RA.

The intimal lining layer contains two types of cells:

The Synovium Changes in Rheumatoid Arthritis:

1. Increased cellularity & vascularity.

3. Vascular proliferation & Hyperplasia of synovial lining: lead to increase

5. The Synovial Fluid changes