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

Key Clinical Features

• Acute or insidious onset, usually insidious followed by polyarticular involvement
• Onset may be preceded by major infection, surgery, trauma, childbirth, or other event
• Hand and foot joints usually involved at onset
• Morning stiffness > 1 hr
• Arthritis of > 3 joint areas (PIP, MCP, wrist, elbow, knee, ankle, MTP)
• Arthritis of > 3 hand joints
• Symmetrical arthritis
• Rheumatoid nodules
• Serum rheumatoid factor
• Radiographic changes (erosions or bony decalcifications)

• SLE
• Polymyalgia rheumatica
• Viral arthritis
• Metabolic disorders (e.g., gout, calcium pyrophosphate deposition)
• Septic arthritis
• Seronegative spondyloarthropathies
• Psoriatic arthritis
• Osteoarthritis

• Physical exam of joints
  • Swelling, warmth, tenderness, limited range of motion
• X-ray
  • Often cannot detect early pathology
  • Useful for following disease progression
  • Shows bone erosions at margins of the joint
  • Shows cystlike radiolucencies in larger joints
• MRI
  • Can detect pannus invasion of joints
  • Best image for large joints
• No specific laboratory tests
• Serology
  • Mild normochromic, normocytic anemia and elevated platelet count usually present; leukocyte count generally normal
  • ESR and C-reactive protein level are usually elevated in active RA and are useful in monitoring disease activity and response to therapy
  • Serum chemistry usually normal
  • 80%–85% of RA patients are seropositive for rheumatoid factor (RF), but specificity for RA is low
  • CCP antibodies more specific (85%–90%) but less sensitive (50%–60%) for RA than RF; could be a useful diagnostic test in some cases
  • Synovial fluid usually straw colored and mildly turbid; rarely diagnostic

• Advance rapidly from NSAIDs to methotrexate for most patients
• 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 exam
• Progressive erosion and deformities
• Rapidly increase methotrexate to 20–25 mg/wk
• Combination therapy
  • Methotrexate + etanercept or infliximab
  • Methotrexate + sulfasalazine ± hydroxychloroquine
  • Methotrexate + leflunomide
  • Methotrexate + anakinra (usually reserved for patients who do not respond to methotrexate + TNF inhibitors)
• Prednisone is usually reserved for patients requiring adjunctive "bridge" therapy between trials of single-drug or combination therapies
• 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 or experimental approaches can be used

Drug Treatment for Rheumatoid Arthritis

• NSAIDs (response rate > 65%; onset of action < 2 wk; toxicities: gastric erosion [nonselective inhibitors], renal toxicity [both selective and nonselective inhibitors]; relative efficacy +)
  • Aspirin
    • Dose: 325–1,300 mg p.o, b.i.d.–q.i.d.
  • Ibuprofen
    • Dose: 400–800 mg t.i.d.–q.i.d.
  • Naproxen
    • Dose: 200–500 mg b.i.d.
  • Rofecoxib: fewer GI side effects than nonselective COX inhibitors
    • Dose: 12.5–25 mg q.d.
    • Cost/mo: $78
  • Methotrexate (response rate > 70%; onset of action 6–8 wk; toxicities: liver [fibrosis, elevated enzymes], hematologic, oral ulcers; relative efficacy +++)
    • Dose: begin at 7.5 mg once weekly, then increase to 15 mg/wk over 2–3 mo if necessary; if no response, increase to 20–25 mg/wk
    • Cost/mo: $33
  • Leflunomide (response rate 50%; onset of action 2–3 mo; toxicities: GI, liver, skin rash, reversible hair loss; teratogen—do not use in pregnancy; relative efficacy ++ to +++)
    • Dose: 20 mg/day
    • Cost/mo: $273
  • Hydroxychloroquine (response rate 30%–50%; onset of action 2–4 mo; toxicities: retinopathy, myopathy, hyperpigmentation; relative efficacy ++)
    • Dose: 200 mg b.i.d.
    • Cost/mo: $36
  • Sulfasalazine (response rate > 30%; onset of action 2–3 mo; toxicities: dyspepsia, hemolysis in glucose-6-phosphate dehydrogenase deficiency; relative efficacy ++)
    • Dose: 1 g b.i.d. or t.i.d.
    • Cost/mo: $38
  • Gold salts (response rate 30%; onset of action 3–6 mo; toxicities: skin rash, hematologic, renal; relative efficacy ++)
    • Dose: 50 mg/wk I.M. Χ 6 mo
• Anticytokines
  • TNF inhibitors
    • Etanercept (response rate 50%–70%; onset of action 2–4 wk ; toxicities: injection-site reaction, infections; relative efficacy +++)
      • Dose: 25 mg S.C. twice a week
      • Cost/mo: $1,145
    • Infliximab (response rate 50%–70%; onset of action 2–4 wk; toxicities: infections; relative efficacy +++)
      • Dose: 3–10 mg/kg I.V. q. 8 wk with methotrexate
    • Adalimumab (response rate 50%–70%; onset of action 2–4 wk; toxicities: injection-site reactions, infections; relative efficacy +++)
      • Dose: 40 mg S.C. q. 2 wk
    • Anakinra (response rate 30%; onset of action 1–3 mo; toxicities: injection-site reactions, infections; relative efficacy + to ++)
      • Dose: 100 mg/day S.C.
    • Prednisone (response rate > 90%; onset of action < 1 wk; toxicities: skin atrophy, cataracts, osteoporosis, avascular necrosis; relative efficacy +++)
      • Dose: 5–10 mg/day
      • Cost/mo: $8
• Immunosuppressants
  • Azathioprine (response rate 30%–50%; onset of action 2–3 mo; toxicities: hematologic, immunosuppression, cholestasis; relative efficacy ++)
    • Dose: 100–150 mg/day
    • Cost/mo: $7
  • Cyclosporine (response rate 30%; onset of action 2–3 mo; toxicities: renal (irreversible), hypertension, hypertrichosis, immunosuppression; relative efficacy ++)
    • 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
• Aerobic training (especially water exercises)

Surgery

• Indicated for intractable pain, impaired function
• Dorsal synovectomy may prevent extensor tendon ruptures
• Frayed menisci and other loose bodies that interfere with function can be removed
• In the hands and wrists, operations on periarticular structures (e.g., repair of capsules and replacement of tendons) may restore 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 or total replacement may be appropriate for gross deformity or destruction of a joint

Best References

Furst, et al: Ann Rheum Dis 62(suppl 2):2, 2003

Misichia, et al: Expert Opin Investig Drugs 11:7, 2002

Aletah, et al: Clin Exp Rheumatol 21(suppl 31):S169, 2003

July 2004