Rheumatoid Arthritis

Gary S. Firestein, M.D.
University of California, San Diego, School of Medicine

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition

• Chronic inflammation of the peripheral joints of unknown etiology, generally symmetrical and involving the small joints of the hands and feet

Key Clinical Features

• Acute or insidious onset, usually insidious followed by polyarticular involvement
• Three quarters of patients are female
• Small joints of hands and feet are usually involved at onset
• Morning stiffness > 1 hr
• Arthritis of > three joint areas (proximal interphalangeal, metacarpophalangeal, wrist, elbow, knee, ankle, metatarsophalangeal) for more than 6 weeks
• Arthritis of > three hand joints
• Symmetrical arthritis
• Rheumatoid nodules
• Serum rheumatoid factor and anti-citrullinated peptide antibodies
• Radiographic changes (marginal erosions and joint space narrowing)
• Accelerated atherosclerosis, with increased cardiovascular events

back to top

• Seronegative spondyloarthropathies, such as psoriatic arthritis
• Systemic lupus erythematosus
• Polymyalgia rheumatica
• Viral arthritis (e.g., parvovirus B19, hepatitis B or C)
• Metabolic disorders (e.g., gout, calcium pyrophosphate deposition)
• Septic arthritis
• Osteoarthritis

back to top

• Physical examination of joints
  • Swelling, warmth, tenderness, limited range of motion
• X-ray
  • Often normal or shows juxta-articular osteopenia in early cases
  • Useful for following disease progression
  • Bone erosions at margins of the joint are most specific
  • Joint space narrows as articular cartilage is lost
• Magnetic resonance imaging
• Can detect pannus invasion of joints
• Detection of early erosions
• Ultrasonography
• Can detect pannus invasion of joints
• To confirm synovitis and identify increased blood flow
• Can be performed in examination room by rheumatologist
• Laboratory tests
• Mild normochromic, normocytic anemia and elevated platelet count usually present; leukocyte count generally normal
• Erythrocyte sedimentation rate and C-reactive protein level are usually elevated in active rheumatoid arthritis (RA) and are useful in monitoring disease activity and response to therapy
• Serum chemistry usually normal
• 80–85% of RA patients test positive for rheumatoid factor (RF), but specificity for RA is low and test may not be positive during first 6–9 mo
• Antibodies to cyclic citrullinated peptides (CCPs) more specific (85–90%) could be a useful diagnostic test in some cases
• Synovial fluid usually straw colored and mildly turbid with white blood cell count from 2 to 10,000/μL; rarely diagnostic

back to top

• Consultation to confirm diagnosis and plan treatment
• Advance rapidly from nonsteroidal antiinflammatory drugs (NSAIDs) to methotrexate (and beyond, if necessary) early, before joint damage occurs
• Oral prednisone in low doses (10 mg or prednisone or less) to control symptoms as bridge therapy until disease-modifying antiarrhythmic drugs become effective
• Rapidly increase methotrexate to 20–25 mg/wk over 2 to 3 months
• Methotrexate will not adequately control symptoms in 70% of patients; indications for advancing therapy:
  • Morning stiffness lasting > 30 min
  • Continued pain
  • Evidence of active synovitis on physical examination
  • Progressive erosion and deformities
• Combination therapy
  • Methotrexate + tumor necrosis factor (TNF) blocker
  • Methotrexate + sulfasalazine ± hydroxychloroquine
  • Methotrexate + leflunomide
• Inadequate response to TNF blockers
• Methotrexate + abatacept
• Methotrexate + rituximab
• Methotrexate + tocilizumab
• Alternative management algorithms
  • Early triple therapy (e.g., sulfasalazine, hydroxychloroquine, methotrexate)
  • Early high-dose corticosteroid therapy with tapering dose over several months, combined with methotrexate and sulfasalazine; patients improve rapidly due to steroid, but difficult to assess efficacy of second-line drugs
  • For recalcitrant cases, immunosuppressive agents such as azathioprine or cyclosporine or experimental approaches can be used

Drug Treatment for Rheumatoid Arthritis

• NSAIDs (response rate > 75%; onset of action < 2 wk; toxicities: gastric erosion [nonselective inhibitors], renal toxicity [both selective and nonselective inhibitors]; relative efficacy +). Examples include:
  • Ibuprofen
    • Dose: 400–800 mg t.i.d.–q.i.d.
  • Naproxen
    • Dose: 200–500 mg b.i.d.
• Methotrexate (response rate > 70%; onset of action 6–8 wk; toxicities: liver [fibrosis, elevated enzymes], teratogen, hematologic, oral ulcers, alopecia; relative efficacy +++)
  • Dose: begin at 7.5–10 mg once weekly, then increase to 25 mg/wk over 2–3 mo if necessary; if no response, increase up to 50 mg/wk orally
• Leflunomide (response rate 50%; onset of action 2–3 mo; toxicities: gastrointestinal, liver, skin rash, reversible hair loss, infection, immunosuppression; teratogen)
  • Dose: 10–20 mg/day
• Hydroxychloroquine (response rate 30–50%; onset of action 2–6 mo; toxicities: retinopathy, myopathy, hyperpigmentation)
  • Dose: 200 mg b.i.d.
• Sulfasalazine (response rate > 30%; onset of action 2–3 mo; toxicities: dyspepsia, hemolysis in glucose-6-phosphate dehydrogenase deficiency)
• Dose: 1 g b.i.d. or t.i.d.
• Prednisone (response rate > 90%; onset of action < 1 wk; toxicities: skin atrophy, cataracts, osteoporosis, avascular necrosis, infections, immunosuppression)
• Dose: 5–10 mg/day
• Anticytokines
  • TNF inhibitors
    • Etanercept (response rate 50–70%; onset of action 2–8 wk; toxicities: injection-site reactions or infusion reactions, infections, immunosuppression, possible lymphoma in children)
      • Dose: 25 mg twice a week or 50 mg/wk SC
    • Infliximab (response rate 50–70%; onset of action 2–8 wk; toxicities: injection-site reactions or infusion reactions, infections, immunosuppression, possible lymphoma in children)
      • Dose: 3–10 mg/kg IV q. 8 wk with methotrexate
    • Adalimumab (response rate 50–70%; onset of action 2–8 wk; toxicities: injection-site reactions or infusion reactions, infections, immunosuppression, possible lymphoma in children)
      • Dose: 40 mg SC q. 2 wk (can also be used with methotrexate)
    • Golimumab (response rate 50–70%; onset of action 2–8 wk; toxicities: injection-site reactions or infusion reactions, infections, immunosuppression, possible lymphoma in children)
      • Dose: 50 mg SC once a month with methotrexate
    • Certilizumab (response rate 50-70%; onset of action 2-8 wk; toxicities: injection-site reactions or infusion reactions, infections, immunosuppression, possible lymphoma in children)
      • Dose: begin at 200 mg SC q. 2 wk, followed by 200 mg SC q. 4 wk (as a single agent or with methotrexate)
  • Interleukin-6 (IL-6) inhibitor
  • Tocilizumab (response rate 50%-70%; onset of action 2-8 wk; toxicities: infusion reactions, infections, immune surveillance, increased liver enzymes, neutropenia, bowel perforations, lipid alterations)
  • Dose: 4-8 mg/kg every 4 wk
  • IL-1 inhibitor
  • Anakinra (response rate 30%; onset of action 1–3 mo; toxicities: injection-site reactions, infections)
  • Dose: 100 mg/day SC
  • T cell costimulation blocker
  • Abatacept (response rate 50–70%; onset of action 4-12 wk; toxicities: injection-site reactions, infections, immune surveillance)
  • Dose: 500–1,000 mg IV q. 4 wk
  • B cell depleter
  • Rixtuximab (response rate 50–70%; onset of action 4-12 wk; toxicities: infusion reactions, increased infections)
  • Dose: 500–1,000 mg IV q. 2 wk x 2
• Immunosuppressants
  • Azathioprine (response rate 30–50%; onset of action 2–3 mo; toxicities: hematologic, immunosuppression, infections, cholestasis)
    • Dose: 50–150 mg/day
  • Cyclosporine (response rate 30%; onset of action 2–3 mo; toxicities: renal [irreversible], hypertension, hypertrichosis, infections, immunosuppression)
    • Dose: 2.5–5.0 mg/kg/day

Physical Therapy

• Maintain activity
• Passive range-of-motion exercises help prevent contractures
• Isometric and isotonic exercises build muscle strength, help preserve function
• Low-impact aerobic training (such as swimming or other water exercises)

Surgery

• Indicated for intractable pain, impaired function; need for surgery has dramatically decreased with improvements in drug therapy
• Dorsal hand synovectomy may prevent extensor tendon ruptures
• In the hands and wrists, operations on periarticular structures (e.g., repair of capsules and replacement of tendons) may improve appearance and function
• Release of carpal tunnel compression usually relieves pressure on the median nerve
• Arthroscopic surgery to remove cartilaginous fragments and for partial synovectomy may be useful in large, accessible joints with proliferative synovitis
• Fusion to stabilize joint and relieve pain
• Total replacement for joints to restore function, can increase risk of thromboembolism in post-operative period

back to top

Best References

Aletaha D, et al. Ann Rheum Dis 2010;69:1580–8. [PMID 20699241]

Furst DE, et al. Ann Rheum Dis 2010;69 (Suppl 1):i2–29. [PMID 19995740]

Wolfe F, Michaud K. Arthritis Rheum 2007;56:2886–95. [PMID 17729297]

* To obtain additional drug information, click on the DrugInfo tab in the left column, or click on the following link: http://search.medscape.com/drug-reference-search?queryText=

November 2010