Rheumatoid Arthritis

Abdellatif Aly Mohamed

 LEARNING OBJECTIVES

• Recognize the symptoms and characteristics of rheumatoid arthritis

(RA).
• Compare and contrast available pharmacologic therapies for RA.
• Design individualized therapeutic regimens and monitoring plans
for patients with RA.
 Definition

Rheumatoid arthritis is a common autoimmune, inflammatory disease characterized by synovial

inflammation and hyperplasia (“swelling”), autoantibody production (rheumatoid factor and
anti–citrullinated protein antibody [ACPA]), cartilage and bone destruction (“deformity”), and
systemic features, including cardiovascular, pulmonary, psychological, and skeletal disorders.
EPIDEMIOLOGY
Most common systemic inflammatory disease
Prevalence: 1-2%
Occurrence:
Genetics Environment
 Any age but the frequency increases with age,
peaks between 30-50 years.
Also observed in both elderly
persons and children.
 3:1 in females but similar after menopause
Unknown etiology
 Interplay between genetic predisposition and
environmental triggers
 Possible triggers - Mycoplasma, Clostridia,
Epstein-Barr virus, Protease species
• Genetic Factors
• Female
• Anti-citrullinated protein antibodies (ACPA)
• Rheumatoid factor (RF)
• Human leukocyte antigen (HLA)-DRB1, HLA-DRB4
Environmental Factors
• Advanced age
• Smoking
• Silica exposure
• Comorbidities
– Diabetes mellitus type 1 and 2, inflammatory lung disease, dyslipidemia
• Lower education level
PATHOPHYSIOLOGY
• Autoimmune disease
 Lack of differentiation between self and non-self tissues
 Destruction of synovial and connective tissues

• Pannus
 Inflamed, proliferating synovium
 Invades cartilage and bone surface  joint destruction
 Characteristic of RA
 PATHOPHSYIOLOGY(2)
LYMPHOCYTES
B Lymphocytes
• Origin: bone marrow
• Produce rheumatoid factor
and anticyclic citrullinated
peptide
• Attract neutrophils to sites of
injury
• Act an APCs to stimulate T
cells and activate the
immune process
APCs = antigen-presenting cells
PRO-INFLAMMATORY
CYTOKINES
T Lymphocytes TNF α, IL-1, IL-6, IL-17
• Origin: thymus • Initiate and continue
• Produce cytokines and inflammatory process
cytotoxins • Stimulate osteoclast
• Further promote formation
inflammation and tissue • Suppress osteoblasts and
destruction bone formation
• Stimulate macrophages to
release prostaglandins and
cytotoxins
All the major immunologic elements play fundamental roles in the initiation, propagation, and maintenance of the autoimmune process
of RA. It involves T and B lymphocytes, antigen-presenting cells (eg, B cells, macrophages, dendritic cells), and numerous cytokines.
Aberrant production and regulation of both pro-and anti-inflammatory cytokines and cytokine pathways are found in RA.
T cells are assumed to play a pivotal role in the initiation of RA, and the key player in this respect is assumed to be the Th1 CD4 cells. (T
helper 1 cells produce IL-2 and interferon gamma.) These cells may subsequently activate macrophages and other cell populations,
including synovial fibroblasts. The latter 2 populations are the main producers of the proinflammatory cytokines TNF-alpha and IL-1 that
appear to be the major driving forces of inflammation.
B cells are important in the pathologic process because they may serve as antigen-presenting cells and activated T cells, produce
numerous autoantibodies (eg, RF, to citrullinated proteins), and secrete cytokines.
Elimination of populations of B cells with monoclonal antibodies (eg, rituximab) offers another effective therapeutic option.
Early and intermediate molecular mediators of inflammation include tumor necrosis factor alpha (TNF-a), interleukins IL-1, IL-6, IL-8
and IL-15, transforming growth factor beta, fibroblast growth factor and platelet-derived growth factor.
Synovial macrophages and dentritic cells function as antigen presenting cells by expressing MHC class II molecules, leading to the
production of immunoglobins, rheumatoid factors of the IgG and IgM class and complement components by B-Lymphocytes. Once
triggered, the immune response causes inflammation of the synovium, leading to edema, vasodilation and infiltration by activated T-cells
(mainly CD4 in nodular aggregates and CD8 in diffuse infiltrates). The disease progresses in concert with formation of granulation tissue
at the edges of the synovial lining (pannus) with extensive angiogenesis and production of enzymes that cause tissue damage.
Once the inflammatory reaction is established, the synovium thickens, the cartilage and the underlying bone begins to disintegrate and
evidence of joint destruction accrues. Although the articular structures are the primary sites, other tissues are also affected
PATHOPHSYIOLOGY(3)
Promotion of Extra-articular Complications
DIAGNOSIS
Clinical presentation

• Morning stiffness > 30 minutes

• Decreased range of motion and grip strength
Warm and tender joints with decreased range of motion

• Stenosing flexor tenosynovitis (trigger fingers)

Symmetrical synovitis in small joints; metacarpophalangeal, proximal interphalangeal, second through
fifth metatarsophalangeal, thumb interphalangeal, wrist

• Extraarticular involvement
• Laboratory abnormalities
1- Most patients with the disease have an insidious onset. It may begin with systemic features, such as fever, malaise,
arthralgias, and weakness, before the appearance of overt joint inflammation and swelling.
2-A small percentage of patients (approximately 10) have an abrupt onset with the acute development of synovitis and extra-
articular manifestations. Spontaneous remission is uncommon, especially after the first 3-6 months.
3- Joint involvement is the characteristic feature of patients with RA. In general, the small joints of the hands and feet are
affected in a relatively symmetric distribution. Joints show inflammation with swelling, tenderness, warmth, and decreased
range of motion.
4- Atrophy of the interosseous muscles of the hands is a typical early finding. Joint and tendon destruction may lead to the
following irreversible deformities:
A. ulnar deviation
B. boutonnière
C. swan-neck deformities
D. hammer toes, and occasionally joint ankylosis.
5- Other musculoskeletal manifestations include: Tenosynovitis, Tendon rupture commonly involving the 4th and 5th digital
extensor tendons at the wrist),Periarticular osteoporosis, generalized osteoporosis, systemic chronic inflammation,
immobilization-related changes or corticosteroid therapy, Carpal tunnel syndrome and Muscle atrophy from disuse.
6- Most commonly affected joints, in decreasing frequency are: 1-MCP 2- Wrist 3- PIP 4-Knee 5- MTP 6- Shoulder 7-Ankle
8-Cervical spine 9-Hip 10-Elbow 11-Temporomandibular.
Joint Involvement and radiographic changes
 EXTRAARTICULAR INVOLVEMENT
• Skin manifestations
Subcutaneous nodules (Rheumatoid nodules), vasculitic lesions palpable purpura or skin ulceration
• Pulmonary complications
pleural effusions, interstitial fibrosis, nodules (Caplan syndrome), and bronchiolitis obliterans-organizing pneumonia.
• Cardiac involvement
Myocardial infarction, asymptomatic pericardial effusions are common. Rarely-pericarditis, constrictive pericarditis.
Myocarditis, coronary vasculitis, valvular dx, and conduction defects.
• Ocular involvement
Keratoconjunctivitis siccais common in RA and is often the initial manifestation of secondary Sjögren syndrome. The eye
may also have episcleritis, uveitis, and nodular scleritis that may lead to scleromalacia
• Hematologic manifestation
anemia, thrombocytosis, and eosinophilia. Leukopenia in patients with Felty’s syndrome (splenomegaly, neutropenia and
thrombocytopenia).
• Neurologic manifestations
nerve entrapment, carpal tunnel syndrome, mononeuritis multiplex, and cervical myelopathy.
Rheumatoid nodule
•These are small subcutaneous nodules present
at the extensor surfaces of hand, wrist, elbow
and back in rheumatoid arthritis patients.

•Characteristics feature of rheumatoid arthritis

•A marker of disease activity

•Can be present even if other features of

rheumatoid Arthritis are absent
LABORATORY FINDINGS
• ↑ erythrocyte sedimentation rate (ESR)
• ↑ C-reactive protein (CRP)
• (+) Rheumatoid factor (RF)
• (+) Anticyclic citrullinated peptide (anti-CCP)
• Synovial fluid: turbid with many leukocytes
• Radiographic imaging
 ARA Diagnostic Criteria

1. Joint morning stiffness more than 1 hour

2. Arthritis of 3 or more joints
3. Arthritis of hand joints
4. Symmetrical Arthritis
5. Rheumatoid nodules
6. Seropositivity for RF
7 Radiographic changes
 RA Classification Criteria
• Collaboration of the American College of
Rheumatology (ACR) and the European League
Against Rheumatism (EULAR)
• 4 different domains in scoring algorithm
• Aimed at newly presenting patients who:
– Have ≥ 1 joint with clinical synovitis
– Synovitis is not better explained by another disease
> 6/10 for classification of definite RA SCORE
Joint involvement 1 large joint 0
2-10 large joints 1
1-3 small joints 2
4-10 small joints 3
> 10 joints (at least one small) 5
Serology (> 1) Negative RF and negative anti-CCP Abs 0
Low-positive RF or low-positive anti-CCP Abs 2
High-positive RF or high-positive anti-CCP Abs 3
Acute phase reactants Normal ESR and normal CRP 0
Abnormal ESR or abnormal CRP 1
Symptom duration < 6 weeks 0
> 6 weeks 1

Large joints = shoulders, elbows, hips, knees, ankles

Small joints = metacarpophalangeal joints, proximal interphalangeal joints, metatarsophalangeal joints, thumb, wrists
 Conditions with RF in the serum
1. Autoimmune rheumatic diseases RF (IgM)
2. Rheumatoid arthritis 70%
3. Systemic lupus erythematosus 25%
4. Sjdgren's syndrome 90%
5. Systemic sclerosis 30%
6. Polymyositis/dermatomyositis 50%
7. Juvenile idiopathic arthritis Variable
8. Viral infections
9. Hepatitis
10. Infectious mononucleosis
11. Chronic infections
12. Tuberculosis
13. Leprosy
14. Infective endocarditis
15. Syphilis
 RA VERSUS OSTEOARTHRITIS
RHEUMATOID ARTHRITIS
• Morning stiffness > one
hour, worse with activity
• ↑ incidence females (3:1)
• ~ Age
• ↑ ESR
• Systemic symptoms
• ~ Obesity
• Wrists, hands, feet
• Symmetrical
OSTEOARTHRITIS
• Morning stiffness < 30
minutes, resolves with activity
• Equal gender prevalence
• ↑ Age
• Normal ESR
• Local symptoms
• ↑ Obesity
• Hands, knees, hips, spine
• Asymmetrical
 Disease severity
Mild disease
•Arthralgias
•>3 inflamed joints
•Mild functional limitation
•Minimally elevated ESR & CRP
•No erosions/cartilage loss
•No extraarticular disease i.e. anemia
 Moderate Disease
•6-20 Inflamed joints
•Moderate functional limitation
•Elevated ESR/CRP
•Radiographic evidence of
inflammation
•No extraarticular disease
 Severe Disease
•>20 persistently inflamed joints
•Rapid decline in functional capacity
•Radiographic evidence of rapid progession of bony erosions
and loss of cartilage
•Extraarticular disease:
• AOCD, Hypoalbuminemia
PREDICTORS OF WORSE OUTCOME
• Older age
• Female gender
• Genotype (HLA-DRB1)
• Worse physical functioning
• Cigarette smoking
 PROGNOSTIC FACTORS
• Functional limitation
• Extraarticular disease
• RF and/or anti-CCP antibody positivity
• Bony erosions on radiographic imaging
• Management of comorbidities

Disease duration and activity are also important when assessing prognosis
 CASE #1
• MJ is a 36 year old female who presents to her PCP c/o joint
pain in her hands and wrists (~6 joints) that has persisted for
the past 2 months. She receives little relief from OTC NSAIDs,
and on examination, the joints on both hands appear red and
swollen. Laboratory testing shows positive RF and anti-CCP
antibodies (high-positive) and ↑ ESR.

What signs and symptoms are indicative of RA?

What is MJ’s score using the 2010 ACR classification criteria for
definite RA?
TREATMENT
 Treatment Goals
Maintain function for activities of daily living

Maximize quality of life

Prevent joint destruction

Control disease activity

Induce remission of disease

Management
Nonpharmacologic Treatment
• Smoking cessation
• Rest
• Physical therapy, occupational therapy
• Weight loss
• Surgery
• Tenosynovectomy, tendon repair, joint replacement
 1. NSAIDs
• Anti-inflammatory, analgesic effects
• Inhibition of COX-1 and COX-2
• No disease modification
• Common products
– Celeboxib, ibuprofen, naproxen
 2. Corticosteroids
• Controls RA symptoms quickly
• Potent inhibitory effects of pro-inflammatory cytokines  some
disease modifying activity (anti-erosive)
• Useful for early disease before DMARD activity present, acute
flares, combination maintenance therapy
• Long-term adverse events limit use
• Systemic
Proposed
Dose per day in
– Prednisone Dosing
prednisone equivalents
Nomenclature
– Prednisolone
– Methylprednisolone sodium succinate
Low dose ≤7.5 mg
– Methylprednisolone acetate
• Intra-articular Medium dose >7.5 mg, ≤30 mg

– Triamcinolone acetonide High dose >30 mg, ≤100 mg

Very high dose >100 mg

Pulse therapy ≥250 x 1-3 days

 3- DMARDs
• Retard or halt the progression of RA
 Sustained suppression of inflammation
• Initiate < 3 months of symptom onset
 Improve outcomes
 Reduce mortality
• All patients except those with limited disease
• Slow onset with regard to symptom management
• Methotrexate
• Leflunomide
• Hydroxychloroquine
• Sulfasalazine
• Minocycline
 • Methotrexate (MTX)
• Mechanism of Action
dihydrofolate reductase inhibitor
Folate antimetabolite  inhibits purine synthesis
May inhibit cytokine production and stimulate adenosine release
Initial therapy of choice: most likely to induce long-term response
Dose: 7.5-15mg PO once weekly
Onset: 2-3 weeks
• Dosing and Administration
Initiation: 7.5 mg once per week or 2.5 mg bid three days per week, titrate up by 2.5 mg every 2weeks
Consider parenteral admin with doses ≥ 15 mg
Combine with folic acid supplementation
• Adverse effects: diarrhea, N/V, stomatitis, thrombocytopenia >
leukopenia, ↑ LFTs*
• Folic acid 1-3mg PO daily
 Decreases toxic effects without compromising efficacy
• Contraindications:
 Pregnancy
 Liver or kidney disease
 Alcohol use
 Blood dyscrasias
 Effusions
 LEFLUNOMIDE
• Inhibits pyrimidine synthesis  decreased lymphocyte
proliferation
• Similar long-term efficacy to MTX
• Dose: 100mg PO daily x 3 days, then 20mg daily
• Onset: 4 weeks
• Adverse effects: ↑ LFTs, pancytopenia
• Enterohepatic recycling prolongs elimination half life
 Cholestyramine can rapidly decrease plasma levels
• Contraindications:
 Pregnancy
 Pre-existing liver disease
 HYDROXYCHLOROQUINE
• Inhibits PMN migration and eosinophil chemotaxis; impairs Ag-Ab
reactions
• Least potent, but best tolerated
 Recommended for patients without poor prognostic factors, low disease
activity, duration < 24 months
• Dose: 200-300mg PO BID x 1-2 months, then can decrease to
200mg daily or BID
• Onset: 6 weeks
• Adverse effects: diarrhea, N/V,
ocular toxicity, rash, alopecia
• Limited monitoring
• Contraindications:
 Vision changes from therapy
 SULFASALAZINE
• Prodrug  5-aminosalicylic and sulfapyridine
 MOA unknown
• First DMARD: similar efficacy to MTX
• Dose: 500mg-1000mg PO daily initially, then 1000mg PO BID
(max 3000mg daily)
• Onset: 8 weeks
• Use limited by adverse effects
 MINOCYCLINE

• Tetracycline antibiotic; may inhibit metalloproteinases

• Mild disease without poor prognostic factors
 Limited data
• Dose: 100-200mg PO daily
• Adverse reactions: minimal
 CASE #1
• MJ is diagnosed with RA. After diagnosis, she is referred to a
rheumatologist who wishes to start her on a DMARD as soon as possible.
She does not have any pertinent PMH and has a sulfa allergy. She also
mentions that she and her husband are trying to get pregnant.

Out of the non-biologic DMARDs, what is the best option for initial therapy for
MJ?
 SUMMARY: DMARDs
DRUG DOSE MONITORING

• Baseline LFTs, CBC, SCr/BUN, hepatitis

Methotrexate PO/IM: 7.5-15mg weekly panel
• CBC, AST/ALT, albumin q1-2 months

PO: 100mg daily x 3 days, then 10-20 daily OR • Baseline LFTs, CBC
Leflunomide 10-20 mg daily w/o LD CBC, AST/ALT monthly, then q6-8 weeks
•

PO: 200-300mg BID x 1-2 months, then can ↓ • Baseline eye exam
Hydroxychloroquine to 200mg daily or BID Ophthalmoscopy q9-12 months
•

Sulfasalazine PO: 500mg BID, then ↑ to 1000mg BID • Baseline CBC

• CBC weekly x 1 month, then q1-2 months

Minocycline PO: 100-200mg daily • LFTs, BUN/SCr with long-term treatment

 BIOLOGIC DMARDs
• Infliximab
• Etanercept
• Adalimumab
• Golimumab
• Certolizumab
• Anakinra
• Abatacept
• Ritubimab
• Toclizumab
• Tofacitinib
Drug Targets:
•TNF α
•IL-1
•IL-6
•B cells
•JAK
• Genetically engineered protein molecules that target pro-
inflammatory cytokines or lymphocytes
• Not considered first line therapy
 High disease activity with poor prognostic factors
• May be effective when non-biologic DMARDs have failed
• Expensive
 TNF α INHIBITORS
• Inactivate TNF α, preventing interaction with receptor and inhibiting
immune cell activation
• Increased infection risk
 Tuberculosis: must test prior to initiation
 Avoid live vaccines
• Multiple sclerosis-like illness
• Increased risk for lymphoma and other cancers
• Contraindication: NYHA class III-IV heart failure
DRUG DOSE ADVERSE COMMENTS
REACTIONS
Infliximab IV: 3 mg/kg at 0, 2, & 6 Infusion reactions: flu- Given with MTX to prevent
weeks, then q8 weeks like symptoms Ab formation (superior to
monotherapy)
Etanercept SQ: 50mg once weekly Local injection-site • Avoid in MS
OR 25mg two times a reactions Preferred with HCV
week May slow erosive disease
> MTX

Adalimumab SQ: 40mg every 2 weeks Local injection-site Less antigenic than
reactions infliximab
Golimumab SQ: 50mg once a month Local injection site Given in combination with
IV: 2 mg/kg at 0 & 4 reactions MTX
weeks, then q8 weeks
Certolizumab SQ: 200mg at 0, 2, & 4 • Local injection site Given as monotherapy or
weeks, then every 2 reactions in combination with MTX
weeks Nausea
 B CELL DEPLETING AGENT
Rituximab
• Depletes peripheral B cells by binding CD20
• Recovery takes several months – intermittent therapy
• For patients who have failed MTX therapy or TNF α inhibitors (second line)
• Also preferred in recently treated solid malignancy and PMH of treated lymphoma or skin melanoma
• Better outcomes when given with MTX
• Dose: 1000mg IV at 0 and 2 weeks
• Adverse reactions:
• Infusion reactions – pre-medicate*
• HBV reactivation – screen prior to initiation
• Black box warning for fatal infusion reactions

*Acetaminophen, diphenhydramine, and methylprednisolone 30 minutes prior to infusion

 CD80/CD86 CO-STIMULATOR MODULATOR

• Abatacept
• Binds to antigen-presenting cells, preventing interaction with T cells and subsequent T cell activation
• For patients who have failed MTX therapy or TNF α inhibitors
 Response rate of 50% in clinical trials
 Weight-based dosing: IV infusion at 0, 2, & 4 weeks, then q4 weeks
 < 60kg: 500mg
 60-100kg: 750mg
 > 100kg: 1000mg
 Alternative: 125mg SQ weekly
 Adverse reactions: headache, nausea, nasopharyngitis, infection, infusion reactions
 INTERLEUKIN-6 INHIBITOR
Tocilizumab
• IL-6 receptor antagonist, reducing production of
cytokines and acute phase reactants
• For patients who have failed MTX therapy or TNF α
inhibitors
• Can be as monotherapy or in combination with MTX
 JANUS KINASE (JAK) INHIBITOR
Inhibits cytokine production, which is integral to lymphocyte function
Place in RA therapy unclear

• Xeljanz (tofacitinib)
• FDA approved in 2012
 Moderate to severe RA refractory to MTX
• Versus placebo and MTX: significantly less symptoms and
improved physical function
• Dose: 5mg PO BID
 COMBINATION THERAPY
• Typically effective when monotherapy fails
• May be appropriate initially in moderate to high disease
activity
• Biologics in combination with MTX may be more effective than
biologic monotherapy
• Combination therapy with > one biologic is not recommended
• JF is a 63 year old female who was recently diagnosed with RA. PMH
significant for osteoporosis. She reports difficulty performing her daily
activities and painful, swollen joints that keep her up at night. She has high
disease activity with the presence of bony erosions on imaging.

What RA treatments would you consider for JF?

What other recommendations might you make?
 EVALUATION OF THERAPY
• Clinical signs and symptoms of RA
 Swelling, warmth, and tenderness
 Pain, stiffness, and functional limitations
 Radiographic imaging
• Adverse effects and other drug monitoring
• American College of Rheumatology Improvement Criteria
 ACR20: 20% improvement in disease activity
 ACR50: 50% improvement in disease activity
The ACR20 is a composite measure defined as both improvement of 20% in the number of tender and number of swollen
joints, and a 20% improvement in three of the following five criteria: patient global assessment, physician global assessment,
functional ability measure [most often Health Assessment Questionnaire (HAQ)], visual analog pain scale, and erythrocyte
sedimentation rate or C-reactive protein (CRP).

ACR50 and ACR70 are the same instruments with improvement levels defined as 50% and 70% respectively versus 20% for
ACR20.