I. Epidemiology

  1. Prevalence 1-2%
  2. Female : Male 2.5:1
  3. Typical age of onset 25-55yo

II. Pathology

  1. Involves humoral, cellular, and non-immune mechanisms
  2. Synovial membrane hypertrophy with overgrowth of granulation tissue ("pannus") over articular surfaces; eventually leading to destruction of articular cartilage & bone
  3. Cytokine activation results in release of proteolytic enzymes & other damaging substances in the joint

III. Clinical features

  1. Diagnostic criteria as of 1987: at least 4 of the following; 1-4 must be present x > 6wks
    1. Morning joint stiffness
    2. Arthritis of 3 or more joint areas
    3. Arthritis of hand joints (wrists, MCP, or PIP)
    4. Symmetrical arthritis
    5. Rheumatoid nodules
    6. Postive serum RF
    7. Radiographic changes c/w RA (see below)
  2. Can be insidious or sudden in onset and with wide range in severity
  3. Typically polyarticular though may be oligo- or rarely, monoarticular
  4. Distinguishing characteristics from osteoarthritis
    1. Involvement of MCP joints, wrists, elbows, MTP joints, and ankles
    2. Warmth, swelling, and erythema of the joints
    3. Synovial hypertrophy ("doughy" feel) on exam
    4. Joint deformity, e.g. ulnar deviation at MCP's
    5. Joint sx typically wax & wane in concert
  5. Extra-articular features
    1. Fatigue and other constitutional sx
    2. Subcutaneous nodules
    3. Thoracic involvement
      1. Pulmonary nodules
      2. Interstitial lung disease
      3. Pleural effusion
    4. Carpal tunnel syndrome
    5. Sjogren's syndrome
    6. Vasculitis
    7. Neuropathy
    8. Pericarditis
  6. May overlap clinically with Polymyalgia Rheumatica or fibromyalgia
  7. Poor prognostic indicators: positive RF, elevated ESR, extra-articular features, rapid erosive changes

IV. Laboratory findings

  1. Rheumatoid factor "positive," i.e. elevated, in about 85% of pts with RA and 1-5% of patients without (false-positive rate increases with age)
  2. Elevated ESR
  3. Elevated C-Reactive Protein
  4. Anemia
  5. WBC's in synovial fluid: us. 5-50k/ul
  6. Antinuclear antibodies may be positive in about 35% of patients with RA
  7. Anti-cyclic citrullinated peptide (anti-CCP) Ab-More specific than rheumatoid factor for RA

V. Radiologic findings: periarticular demineralization, erosions in periarticular bone, joint space narrowing

VI. Treatment

  1. Physical therapy for strengthening and flexibility
  2. Heat/cold may help reduce discomfort; TENS has also been used
  3. Podiatry referral if deformities are leading to secondary problems, e.g. painful calluses, etc.
  4. Aerobic conditioning (evidence?)
  5. Meds for symptomatic relief
    1. NSAIDS--for many years considered drugs of first choice
      1. Have the advantages of prompt action and reasonable long-term safety
      2. Don't seem to alter natural history of the disease
    2. Corticosteroids
      1. Can inject locally for mono- or oligoarticular flares
      2. Usually used in nrief courses of systemic steroids for polyarticular flares
      3. Chronic use at low dose (5-10mg/d) c/w placebo (alone or in combination with a DMARD) ass'd with sig. less joint tenderness, radiologic damage, and use of NSAIDs long-term randomized trials in pts with recent dx of RA (Ann. Int. med. 136:1, 2002--JW; Arth. Rheum. 52:3371, 2005--JW; Arth. Rheum. 52:3360, 2005--JW)
      4. If need to use systemic steroids chronically, use minimal dose possible and see chapter on corticosteroids (link above) for info on prevention of steroid-induced osteoporosis
      5. Long-term (3mo-2y) use of low-dose (equivalent to 15mg/d prednisolone or less) for RA was not found to be associated with sig. increase in adverse outcomes (fx, cataracts, or other major outcomes) in one meta-analysis (BMJ 316:811, 1998--JW)
  1. "Statin" Medications for rheumatoid arthritis
    1. In a study of 116 pts with active inflammatory RA despite use of DMARDs randomized to atorvastatin 40mg/d vs. placebo, at 6mos, the atorvastatin recipients had small but sig. reductions in overall disease-activity scores; also sig. improvements c/w placebo in swollen joint count and various lab markers of inflammation (Lancet 363:2015, 2004--JW)
  2. "Disease-modifying Anti-Rheumatic Drugs" ("DMARD's")
  1. General principles
  1. Generally require 1-6mos for therapeutic effect
  2. Can be used in combination with NSAIDs, corticosteroids, or other each other
  3. Consider screening for HIV, if risk factors are present, before using immunosuppressants like steroids or methotrexate
  4. Initial therapy with hydroxychloroquine, methotrexate, or gold produced (plus NSAIDS as needed) better functional outcomes and lower sed rates at 1y than initial therapy with NSAIDS (Ann. Int. Med 124:699, 1996-JW)
  5. Combination therapy with methotrexate (7.5-17.5mg Qwk), sulfasalazine 500 BID, and plaquenil 200mg BID gave better reduction in sx and no greater incidence of drug toxicity than methotrexate alone or sulfasalazine plus plaquenil (NEJM 334:1287, 1996-JW)
  6. Choice of initial DMARD--In a 1y study in 508 pts with early RA randomized to the following 4 medication regimens, the 3rd & 4th regimens were associated with sig. better outcomes in terms of disease scores, functional abilities, and radiographic progression (Arth. Rheum. 52:3381, 2005--JW):
    1. Start w/methotrexate alone, switch to sulfasalazine alone if response inadequate
    2. Start w/methotrexate alone, add sulfasalazine if response is inadequate
    3. Start with methotrexate + sulfasalazine + prednisone 60mg/d tapering over 7wks to 7.5mg/d
    4. Start with methotrexate + infliximab
  1. Hydroxychloroquine (Plaquenil) 200-400 mg/d--can cause rash, GI disturbance, and retinal toxicity (ophthalmologic monitoring often advised--visual fields, color vision Q6-12mos); can cause hemolysis in pts with G6PD deficiency; takes 3-6mos to become effective
  1. Sulfasalazine (Azulfidine) 2-3g divided BID--can cause leukopenia, anemia, elevated LFT's, rash, decreased sperm counts in men, and nausea. Enteric-coated form has less GI toxicity. May cause hemolysis in pts with G6PD deficiencyOverall, more toxic than hydroxychloroquine
  1. Methotrexate 7.5-25mg/wk PO, SQ, or IM
    1. Folic acid 1-4mg QD may decrease toxicity (primarily hepatotoxicity) though may impair efficacy slightly, requiring slightly higher doses (results from a randomized study in 434 pts with RA--Arth. Rheum. 44:1515, 2001--JW)
    2. Can cause hepatotoxicity, bone marrow suppression, hepatotoxicity, nausea, diarrhea, stomatitis, cutaneous necrotizing vasculitis, immunosuppression, teratogenesis, impaired fertility (in men and women), and interstitial pneumonitis
    3. Takes 4-6wks to take effect
    4. In a trial of 51 pts with RA in remission on weekly methotrexate x at least 9mos randomized to continue mtx weekly vs. go to Q2wks, there was no difference in likelihood of of relapse over 2y f/u (Arth. Rheum. 42:2160, 1999--AFP)
    5. May reduce cardiovascular mortality and overall mortality in RA
      1. In a nonrandomized prospective observational study of 1240 pts > 18o with RA followed for avg. 6y, those pts on MTX (mean dose 13mg/wk) had hazard ratio of 0.4 for overall mortality and 0.3 for CV mortality (both sig.).  Other DMARD's were not ass'd with sig. mortality benefit (Lancet 359:1173, 2002--JW)
  1. Gold 25-50mg IM Q 1-2wks--can cause marrow suppression, proteinuria, rash, stomatitis, leukopenia, thrombocytopenia, and rarely, enterocolitis, aplastic anemia, or interstitial pneumonitis.
  1. Minocycline for RA--better than placebo & possibly Hydroxychloroquine as well
    1. Minocycline 100 BID vs. placebo (both groups used NSAIDs as needed) in 46 pts with seropositive RA x < 1y who were also on NSAIDs showed higher rates of improvement (65% vs. 13%) after 3mos of tx (Arth. Rheum. 40:842, 1997-JW)
    2. 60 pts with RA diagnosed < 1y previously randomized to Minocycline 100mg BID vs. Hydroxychloroquine 200mg BID; all also put on Prednisone 5.0-7.5mg QD.  After 2y f/u, sig. improvement (50% improvement in ACR score) was sig. more likely in Minocycline group than Hydroxychloroquine group (60% vs. 33%); also minocycline gorup had sig. lower mean daily prednisone doses than hydroxychloroquine group (0.8mg/d vs. 3.2mg/d) (Arth. Rheum. 44:2235, 2001--JW)
  1. Leflunomide (Arava)
    1. A pyrimidine synthesis inhibitor; Prevents activation of T-lymphocytes; intended as an alternative to Methotrexate
    2. May cause nausea, diarrhea, rash, and alopecia
    3. May be associated with hepatotoxicity, particularly if used with methotrexate
    4. May be teratogenic; if pregnancy is desired, it is advised to d/c the drug and take cholestyramine 8g TID x 11d then verify that plasma levels of Leflunomide are < 0.02mg/L
    5. As effective in sx reduction as sulfasalazine (Lancet 353:259, 1999) and methotrexate (Arth. Rheum 41:S155, 1998) (UW Pharm Letter)
    6. Slightly better at sx reduction and quality-of-life measures than methotrexate in a 1y study in 508 pts with RA (Arth. Rheum. 44:1984, 2001--JW)
  1. Etanercept
    1. 234 pts with active RA failing DMARD's randomized to etanercept 10-25mg 2x/wk vs. placebo. Over 26wk f/u, sig. more etanercept pts experienced a 20% improvement in disease activity (by sx scores?); usually improvement noted within 2wks of initiating therapy. 25mg dose sig. better than 10mg dose (Ann. Int. Med. 130:478, 1999--AFP)
    2. Ass'd with sig. better clinical response in conjunction w/methotrexate than w/methotrexate alone in 89 pts with active RA despite 6mos of methotrexate (NEJM 340:253, 1999--JW)
    3. In a case series of 628 pts with RA on etanercept for median 25mo, no increase in adverse event rates compared with rates during short-term trials; clinical benefit seemed to be sustained during the observation period (J. Rheum. 28:1238, 2001--JW)
    4. Etanercept 10-25mg SQ 2x/wk ass'd with sig. more rapid improvement in sx but no diff. in sx at 12mos compared with weekly oral methotrexate in a 1y randomized trial of 632 pts with early RA (NEJM 343:1594, 2000--JW); in a followup paper describing 2y outcomes, etanercept group had sig. higher likelihood of 20% improvement on a standardized clinical score (72% vs. 59%) and sig. less incidence of significant radiographic progression (Arth. Rheum. 46:1443, 2002--JW)
    5. 686 pts with RA randomized to methotrexate, etanercept, or both.  At 6mos and 12mos, combination gropu had sig. better clinical outcomes and sig. less radiographic progression (Lancet 363:675, 2004--JW)
  1. Infliximab
    1. Infliximab ass'd with sig. higher likelihood of clinical improvement (52% vs. 17%) in a 1y randomized trial in 428 pts iwth longstanding RA; all pts also got weekly oral methotrexate (NEJM 343:1640, 2000--JW)
    2. In combination with metothrexate reduces joint damage more than methotrexate alone ("ATTRACT" trial, presented at Am. Coll. Rheum meeting per AFP 5/15/01)
    3. In a study in 487 pts with newly-diagnosed RA with inadequate clinical responses to 3-4mos of methotrexate monotherapy randomized to add either (sulfazalazine + hydroxychloroquine) vs. (infliximab IV) x 24mos.  At 1y, the infliximab pts had sig. higher likelihood of "good clinical response" (measured on a standard scale) (39% vs. 25%) (Lancet 374:459, 2009-JW)
  2. Adalimumab
    1. In a 24-week randomized trial in 271 pts with active rheumatoid arthritis on methotrexate, adalimumab 40mg SQ Q2wks was ass'd with 20% improvement in ACR clinical criteria in 67% of pts vs. 15% w/placebo ("ARMADA" trial; Arth. Rheum. 48:35, 2003-cited in Med. Lett. 45:25, 2003)
    2. In a study in 799 methotrexate-naive pts with early mod-to-severe RA randomized to adalimumab, methotrexate, or both, after 2y, the combination pts had sig. higher incidence of a 50% improvement in disease activity compared with adalimumab alone or methotrexate alone (59% vs. 37% and 43%, respectively).  Combination pts had sig. higher incidence of serious infectious (RR 3.0) (Arth. Rheum. 54:26, 2006--JW)
  3. Tocilizumab (Actemra)
    1. An interleukin-6 inhibitor (binds to IL-6 receptors)
    2. Administered IV Q4wks
    3. Can be used with methotrexate or DMARDs
    4. Camn be associated with upper respiratory tract inhections, headache, HTN, increased ALT, neutropenia, thrombocytopenia, dyslipidemia, and GI perforations
  1. Azathioprine 1-2.5mg/kg/d
    1. A purine analog
    2. Can cause nausea, vomiting, abdominal pain, hepatitis, bone marrow depression, and possibly increased risk of lymphoma; may be teratogenic
  1. Plasmapheresis--Limited data that may decrease sx in refractory severe RA
  2. Anakinra (Kineret)
    1. Interleukin-1 receptor antagonist
    2. Ass'd with increased remission rates in RA pts in combination w/methotrexate c/w methotrexate alone in a 24wk randomized trial (Arth. Rheum. 46:614, 2002--JW)
    3. May cause leukopenia
  1. Abatacept (Orencia)
    1. Inhibits T-cell Activation
    2. In a study in 258 pts with RA incompletely responsive to etanercept or infliximab randomized to Abatacept IV Q14d x 3 then Q28d x 6mos vs. placebo, Atabacept recipients had sig. greater symptomatic and functional improvement than placebo recipients (NEJM 353:1114, 2005--JW)
  2. Chaperonin 10 (aka "Heat-shock protein 10")
    1. A mitochondrial protein that inhibits toll-like receptors (TLRs), inflammatory mediators in synovial tissue
    2. In a study in 23 pts with active, treatment-resistant RA (most on other DMARDs and prednisone) randomized to one of 3 different doses of chaperonin-10 x 12wks, there were sig. improvements in disease activity scores, more in the higher-dose groups (Lancet 368:855, 2006--JW)
  3. Less frequently used--d-penicillamine (fairly toxic), cyclophosphamide (long-term use increases risk of malignancy), and cyclosporine
  1. Joint replacement surgery and/or synovectomy when sx are lifestyle-limiting and not controlled by meds
  2. Prosorba column--an antibody-adsorbing column used with prasmapheresis
    1. Consists of Protein A, derived from staphylococcus, which binds IgG and IgG-immune complexes
    2. Ass'd with symptomatic improvement in pts with RA (Med. Lett. 41:69, 1999)
    3. Must take pt off any ACEI's because apheresis releases bradykinins, whose breakdown is blocked by ACEI's and thus may trigger severe hypotension
  3. Treatment of early RA
    1. In a study in 236 patients with untreated early RA randomized to methotrexate + (prednisone 10 mg/d vs. placebo), at 2y, a sig. greater proportion of the combined-treatment pts had no evidence of joint damage on x-rays (78% vs. 67%) and also sig. lower pain scores. (Ann. Int. Med. 156:329, 2012-JW)
  4. Consider support groups, psychotherapy, vocational counseling as appropriate