Connective tissue

disorders

Dr Josephine Ojoo
MBChB FRCP CCST(Resp) Dip HIV Med
Senior Lecturer
Maseno University
 Objectives
• by end of lecture you should:

• Know the most common autoimmune CTDs

• Know who are most affected

• How CTDs present

• How to investigate the CTDs

 CTDs
• Autoimmune rheumatic/ connective tissue disorders

Include diverse syndromes such as:

• Systemic Lupus Erythematosus (SLE)

• Systemic Sclerosis (SS)

• Polymyositis and Dermatomyositis.

• Mixed Connective Tissue Disease (MCTD)

• Sjögren Syndrome (SjS)

• Relapsing Polychondritis
 Systemic lupus erythematosus
(SLE)
• Chronic, multisystem, inflammatory autoimmune
disorder

• Results in rheumatologic, dermatological and end - organ

manifestations

• 70- 90% in women (usually of child-bearing age).

• Can affect patients of any age, including neonates

 Epidemiology
• USA prevalence is 20 to 150 cases/100,000

• In women, prevalence rates vary from 164 (white) to 406

(African American)/100,000

• Estimated incidence rates are 1-25/100,000 in North

America, South America, Europe and Asia

• Due to improved detection of mild disease, the incidence

nearly tripled from1960-2000
 Aetiology
• Both genetic and environmental components

• Female sex strongly influences pathogenesis.

• Irreversible break in immunological tolerance manifested

by immune responses against endogenous nuclear
antigens.

• Some drugs cause a reversible lupus-like syndrome.

Drug induced lupus
• Antiarrhythmics - Procainamide and quinidine

• Antibiotics – Minocycline , isoniazid, rifabutin

• Antifungals - Griseofulvin and voriconazole

• Anticonvulsants - Valproate, ethosuximide, carbamazepine, and hydantoins

• Hormonal therapy - Leuprolide acetate

• Antihypertensives - Hydralazine, methyldopa, and captopril

• Anti-inflammatories - Penicillamine and sulfasalazine

• Antipsychotics - Chlorpromazine

• Cholesterol-lowering agents - Lovastatin, simvastatin (DISCLE), atorvastatin, and gemfibrozil

• Biologics - Interleukins, interferons, TNF-α (etanercept, infliximab, adalimumab) and rituximab

• Inhalers - Tiotropium bromide inhaler

• Chemotherapy agents -Docetaxel, paclitaxel, cabazitaxel (DISCLE), gemcitabine (DISCLE)

• Other drug categories - Ophthalmic timololiazid cause a reversible lupus-like syndrome.

 Pathophysiology
• Genetic factors

• Epigenetic factors:changes in gene expression

• Environmental factors
• UV light
• viral infections

• Hormonal factors
• oestrogen or prolactin
• Damage results in cell apoptosis releasing nucleic antigens

• Dendritic cells present autoantigens released by apoptotic

cells to T cells leading to their activation.

• Activated T cells in turn help B cells to produce antibodies to

these self-constituents
• Damage results in cell apoptosis releasing nucleic antigens

• Dendritic cells present autoantigens released by apoptotic cells to

T cells leading to their activation.

• Activated T cells in turn help B cells to produce antibodies to

these self-constituents

• Immune responses against endogenous nuclear antigens are

characteristic of SLE
 Disease mechanisms
• Immune complexes and complement activation pathways
mediate effector function and tissue injury.

• Immune complexes deposited in tissue resulting in tissue

injury.

• Tissue damage is mediated by

• recruitment of inflammatory cells
• reactive oxygen intermediates
• production of inflammatory cytokines
• modulation of the coagulation cascade.
Natural history and
course
Presentation
• Onset

abrupt with fever

insidious over months or years with episodes of arthralgias

and malaise.

• Vascular headaches, epilepsy, or psychoses may be initial

findings.

• Manifestations referable to any organ system may appear.

• Periodic exacerbations (flares) may occur.

Clinical manifestations in a series of 1000 European SLE patients
 Presentation
Common manifestations may include

• Joint: arthralgias and arthritis

• Skin: malar and other rashes

• Organs: renal or CNS , pleuritis or pericarditis,

• Vascular: Raynaud’s vasculitis

• Hematologic cytopenias
 Joint manifestations
• Range from intermittent arthralgias to acute polyarthritis

• Occur in about 90% of patients and may precede other

manifestations by years.

• Most polyarthritis non-destructive and non deforming

• In long-standing disease, deformities without bone

erosions may develop
Jacoud-type arthropathy. Deformities in the hands closely
resemble those seen in rheumatoid arthritis. Distinguished by
absence of erosions on radiographs and their reducibility
 Subacute cutaneous lupus
lesions.
Typical features include
symmetric, widespread,
superficial, and non-scarring
lesions.
Involvement of the neck,
shoulders, upper chest, upper
back, and extensor surface of the
hand is common.
 Renal manifestations
• Can develop at any time and may be the only manifestation
of SLE

• It may be benign and asymptomatic or progressive and

fatal. Lesions range in severity from a focal, usually benign,
glomerulitis to a diffuse, potentially fatal,
membranoproliferative glomerulonephritis.

• Common manifestations include proteinuria (most often),

an abnormal urinary sediment manifested by RBC casts and
leukocytes, hypertension, and edema.
 MRI showing cerebrovascular disease

Acute
transverse
myelitis

Thrombosis in the sagittal sinus

 Haematologic
• Anemia, leukopenia and thrombocytopenia

• In patients with antiphospholipid antibodies arterial or

venous thrombosis, thrombocytopenia, obstetric
complications occur.

• Thromboses probably account for many of the

complications of SLE, including obstetric complications.
 Obstetric manifestations
• Early and late fetal loss

• In patients with antiphospholipid antibodies, the risk of

recurrent miscarriages is increased.

• SLE flares are common during pregnancy.

• Pregnancy should be timed for when disease is in remission

• During pregnancy, the patient should be monitored closely

for any disease flare or thrombotic events
 Differentials
• Early-stage SLE can mimic other CTDs, including RA if arthritic
symptoms predominate.

• Mixed CTD can mimic SLE but also may involve features of
systemic sclerosis, rheumatoid-like polyarthritis, and
polymyositis

• Infections (eg, bacterial endocarditis, histoplasmosis) can mimic

SLE and may develop as a result of treatment-caused
immunosuppression

• Disorders such as sarcoidosis and paraneoplastic syndromes can

also mimic SLE
 Investigations
• Diagnosis requires clinical and serologic criteria.
immunosuppressants

• Laboratory testing differentiates SLE from other

connective tissue disorders.
Prevalence of serological features in a series of 1000 SLE patients
 Antiphospholipid antibodies
Include:

• Anticardiolipin antibodies

• lupus anticoagulant

Associated with:

• arterial or venous thrombosis, thrombocytopenia

• during pregnancy, spontaneous abortion or late fetal death

Thrombosis in the sagittal sinus in patient
with antiphospholipid syndrome
 Investigations
• Full haemogram

• Hemolytic anemia

• Leukopenia: < 4000/mm3

• Lymphopenia: < 1000/mm3

• Thrombocytopenia < 100,000/mm3

• Low C3, low C4 or low CH50

• ESR
 Progression
• The course chronic, relapsing, and unpredictable.

• Remissions may last for years.

• If the initial acute phase is controlled the long-term

prognosis is usually good

• The 10-yr survival in most developed countries is > 95%.

• Improved prognosis is in part due to earlier diagnosis and

more effective therapies.
 Complications
• Disease and therapy related

• Early damage is mostly related to disease whereas

• Late damage is usually related to complications of

longstanding disease and immunosuppressive therapy
 Complications SLE
• alopecia • avascular necrosis

• fixed erythema • tendon rupture

• cognitive dysfunction • Jaccoud’s arthropathy

• valvular heart disease

 Late complications
• infections

• atherosclerosis

• malignancies

• osteoporosis

• Increased risk of coronary artery disease can contribute

to premature death.
Systemic sclerosis (SSc)
 Systemic sclerosis (SSc)
• Characterized by diffuse fibrosis, degenerative changes,
and vascular abnormalities in the:

• skin

• joints

• internal organs (especially the esophagus, lower GI

tract, lungs, heart, and kidneys)
 SSc symptoms
The most common initial symptoms and signs:

• Raynaud phenomenon

• insidious swelling of the distal extremities with gradual

thickening of the skin of the fingers

• Polyarthralgia is also prominent

• GI disturbances (eg, heartburn, dysphagia) or respiratory

complaints (eg, dyspnea) are occasionally the first
manifestations.
 Skin
• Symmetrical swelling and induration

• It may be confined to the fingers (sclerodactyly) and

hands, or it may affect most or all of the body

• Telangiectases may appear on the fingers, chest, face,

lips, and tongue

• Swelling and eventually skin tightening and contractures

of the fingers.
 Raynaud
phenomenon
skin eventually becomes taut, shiny, and hypopigmented or hyperpigme
• Mask like facies

• Telangiectases
 Internal organs
• Esophageal dysfunction most frequent visceral disturbance, occurs in
most patient

• Lung involvement generally progresses indolently, but is a common

cause of death. Pleurisy can occur

• Heart failure, Pericarditis with effusion

• Cardiac arrhythmias are common

• Severe, often sudden renal disease (renal crisis) may occur

• Lung, heart, and kidney involvement accounts for most deaths

 Diagnosis
• Diagnosis is clinical, but laboratory tests help with confirmation

• Serum ANA and Scl-70 antibody should be obtained.

• ANA are present in ≥ 90%

• Antibody to centromeric protein (anticentromere antibody) occurs in the serum of

a high proportion of patients with CREST syndrome and is detectable on the ANA

• Scl-70 antigen is a DNA-binding protein sensitive to nucleases.

• Rheumatoid factor also is positive in one third of patients.

• If lung involvement is suspected, pulmonary function testing, chest CT, and

echocardiography can begin to define its severity
 Prognosis
• The course depends on the type of SSc but is
unpredictable.

• Typically, progression is slow. Overall 10-yr survival is

about 65%.
Polymyositis and
dermatomyositis
 Polymyositis and
dermatomyositis
• Uncommon systemic rheumatic disorders

• The female:male ratio is 2:1.

• May appear at any age but occur most commonly from

age 40 to 60 or, in children, from age 5 to 15.
 Presentation
• Characterized by inflammatory and degenerative changes in
the muscles (polymyositis) or in the skin and muscles
(dermatomyositis)

• Manifestations include symmetric weakness, some

tenderness, and later atrophy, principally of the proximal limb
girdle muscles

• Muscle weakness indicates advanced myositis

• Complications can include visceral involvement and cance

 Skin
• The most specific skin signs are Gottron papules over the
knuckles and a periorbital heliotropic rash
Gottron papules
 Diagnosis
• Clinical findings

• Abnormalities on muscle tests:

• muscle enzymes(CK)

• MRI

• electromyography

• If necessary, do a muscle biopsy to confirm the diagnosis. muscle

biopsy.

• Screen patients ≥ 40 yr with dermatomyositis and patients ≥ 60 yr with

polymyositis for cancer.
Mixed connective tissue disease
(MCTD)
 MCTD
• Uncommon overlap syndrome

• MCTD occurs worldwide and in all races, with a peak

incidence in the teens and 20s

• About 80% of people who have this disease are women.

• In some patients, the disorder evolves into classic

systemic sclerosis or SLE.
 MCTD
• Characterized by clinical features of SLE, systemic sclerosis, and
polymyositis

• Common findings
• Hand swelling
• Raynaud phenomenon
• polyarthralgia
• inflammatory myopathy
• esophageal hypo motility
• pulmonary dysfunction are common

• Anticipate pulmonary hypertension.

 MCTD
• Very high titers of circulating antinuclear antibody to a
ribonucleoprotein antigen (U1 RNP)

• Typically ANA present

• anti-Sm and anti-DNA antibodies are absent.

• Diagnosis is by the combination of clinical features,

antibodies to ribonucleoprotein, and absence of
antibodies specific for other autoimmune diseases
Sjögren syndrome
 Sjögren syndrome
• A relatively common chronic, autoimmune, systemic,
inflammatory disorder of unknown cause

• SS occurs most frequently among middle-aged women

• Genetic associations have been found

• Classified as primary when there is no other associated

disease.

• In about 30% of patients with autoimmune disorders SS

develops and, in such cases, is classified as secondary.
 Sjögren syndrome
• Characterized by dryness of the mouth, eyes, and other
mucous membranes due to lymphocytic infiltration of the
exocrine gland and secondary gland dysfunction

• Can affect various exocrine glands or other organs

 Sjögren syndrome
• Suspect SS if patients have gritty or dry eyes or dry
mouth, enlarged salivary glands, peripheral neuropathy,
purpura, or unexplained renal tubular acidosis.

• Diagnosis is by specific criteria relating to eye, mouth,

and salivary gland involvement, autoantibodies, and
(occasionally) histopathology
 Systemic sclerosis (SSc)
• Rare chronic disease of unknown cause

• 4 times more common among women than men

• It is most common among people aged 20 to 50 and is

rare in children.
Relapsing polychondritis
 Relapsing polychondritis
• An episodic, inflammatory, and destructive disorder of
cartilage

• Men and women equally affected

• Onset typically is in middle age

• An association with RA, systemic vasculitis, SLE, and

other connective tissue disorders suggests an
autoimmune etiology.
 Relapsing polychondritis
• Primarily cartilage of the ear and nose but also the eyes,
tracheobronchial tree

• consider if patient may present with

• inflammation of the pinna or nasal cartilage

• Associated with respiratory tract chondritis or unexplained

arthritis, ocular inflammation, or auditory or vestibular
dysfunction.

• Diagnosis is by a combination of clinical, laboratory, imaging,

and sometimes biopsy findings
 Summary
• Most common autoimmune CTDs

• Know who are most affected

• How CTDs present

• How to investigate the CTDs