ARTHRITIS, RHEUMATOID (RA)

ARTHRITIS, RHEUMATOID (RA) - Konstantinos Deligiannidis, MD, MPH; Joseph R. Stenger, MD
BASICS
DESCRIPTION
Chronic systemic inflammatory disease (typically joint-involving) of unknown cause. Articular inflammation may be remitting, but if continued, usually results in joint damage and disability. Characteristic extra-articular manifestations include rheumatoid nodules, arteritis, neuropathy, scleritis, pericarditis, and splenomegaly.
• System(s) Affected: Musculoskeletal; Hematologic/lymphatic/immunologic; Cardiovascular; Nervous; Pulmonary; Renal
ALERT
Geriatric Considerations
• Increased contribution/interaction of age-related comorbidities; pericarditis, septic arthritis, Sjogren syndrome more common
• Less tolerance to drugs; increased incidence of hydroxychloroquine-associated maculopathy, D-penicillamine rash, and sulfasalazine-induced nausea/vomiting
Pregnancy Considerations
• Use effective contraception with DMARDs. Modify regimen with pregnancy or breast-feeding.
• Labor/delivery pose no serious problems, unless severe mechanical joint disease.
• >75% improve during pregnancy, but relapse in 6 months. Occasionally, 1st episodes occur during pregnancy.
• Fetal abnormalities not increased
EPIDEMIOLOGY
• Predominant age: 3rd-6th decades
• Predominant sex
- Female > Male (2:1; overall incidence and prevalence of articular manifestations)
- Male > Female (systemic disease)
Prevalence
• US population: 0.3-1.5%
• Native Americans: 3.5-5.3%
RISK FACTORS
• HLA-DR4
• Family history
• Native American ethnicity
• Age 20-50 years
Genetics
• Seropositive RA aggregates in families
• Increased relative risk of 4-5 times for HLA-DR4 positive person; African Americans tend not to exhibit this tendency.
ETIOLOGY
Antibody-complement complex results in intra-articular inflammation.
ASSOCIATED CONDITIONS
• Sjogren syndrome
• Felty syndrome
• Increased incidence of infections, lymphomas, renal and cardiovascular disease
• Renal disorders from therapy.
• Amyloidosis from chronic inflammation


DIAGNOSIS
SIGNS AND SYMPTOMS
• American College of Rheumatology diagnostic criteria (5 of the 7 must be present; 1st 4 must be continuous >6 weeks)
- Morning stiffness >1 hour's duration
- Arthritis of 3 or more joint groups with soft-tissue swelling or fluid
- Swelling involving 1 or more of the following joint groups: wrists, proximal interphalangeal, metacarpophalangeal
- Symmetrical joint swelling
- Subcutaneous nodules
- Positive rheumatoid-factor test
- Radiographic changes consistent with RA
• General
- Joints: Wrists, knees, elbows, shoulders, ankles, and subtalar joints (most often involved) with swelling, heat, deformity, pain on passive motion, morning stiffness. 70% show radiologic signs of joint damage within 3 years of onset.
- Systemic: Fatigue, depression, malaise, anorexia, rheumatoid nodules, ocular disease, lymphadenopathy, splenomegaly, entrapment neuropathies, osteoporosis.
- Patients experience symptoms an average of 36 weeks before diagnosis.
TESTS
Lab
• Hematocrit: Mild anemia (of chronic disease)
• ESR: Usually elevated
• C-reactive protein: Direct measure of impact of IL-6 on liver cells
• Rheumatoid factor: >1:80 in 70-80% of patients with RA
- RF tests are assays for IgM Ab.
- Poor screening tool with positive predictive value of only 20% in asymptomatic persons. In patients with rheumatologic symptoms, positive predictive value is 80%.
- Not useful for monitoring course of illness
• Antinuclear antibody: Present in 20-30%
• Electrolytes, creatinine, liver function, urinalysis to assess organ comorbid states
• Synovial fluid
- Yellowish-white, turbid, poor viscosity
- Mucin clot poor owing to degradation of hyaluronic acid by lysosomal enzymes
- WBC increased (3,500-50,000)
- Protein: ~4.2 g/dL (42 g/L)
- Serum-synovial glucose difference 30 mg/dL (1.67 mmol/L)
• Drugs that may alter lab results: Prior treatment with immunosuppressives may "normalize" results.
• Disorders that may yield false-positive RF results: Sjogren syndrome, mixed cryoglobulinemia, parasitic infections (e.g., malaria), liver disease, endocarditis, acute viral infections (e.g., mononucleosis, influenza, rubella)
Imaging
• Radiograph films are useful in following disease progression.
• Bone scan is appropriate if aseptic necrosis suspected.
• CT/MRI are useful in specific situations such as cervical-spine symptoms.
DIFFERENTIAL DIAGNOSIS
• Sjogren syndrome
• Sarcoidosis
• Systemic lupus erythematosus
• Psoriatic arthritis
• Vasculitis
• Gout/pseudogout
• Seronegative polyarthritis
• Polymyositis
• Erosive osteoarthritis
• Reiter syndrome
• Behcet syndrome
• Lyme disease
• Scleroderma
• Chronic infection
• Occult malignancy
TREATMENT
GENERAL MEASURES
• Key elements include ongoing evaluation of
- Disease activity and extent of synovitis
- Structural damage
- Psychosocial functional status
• Intervene before joint damage occurs.
• Emphasize
- Exercise and mobility
- Reduction of joint stress
- General health care
Activity
Encourage full activity, but patient should avoid heavy work or exercise during active phases.
MEDICATION (DRUGS)
First Line
• No one disease-modifying antirheumatic drug (DMARD) is consistently better than another, but methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide preferred over gold, D-penicillamine, azathioprine, and cyclosporine, based on relative risks/benefits.
• Combinations of DMARDs may be more effective than individual drugs.
• Start DMARDs within 2 months if patient has ongoing joint pain/morning stiffness, active synovitis, or persistent increase in ESR and/or C-reactive protein despite appropriate-dose NSAIDs.
• Early disease or acute/chronic inflammations
- Aspirin or other NSAID; try various classes.
- Prednisone/prednisolone: 5-15 mg/d for severe disease or to minimize disease activity while waiting for DMARDs to act, when temporary decrease in activity is anticipated, or to control active disease when NSAIDs/DMARDs have failed. Generally to be used only for short periods, or intermittently. Low-dose prednisolone is more effective than NSAIDs (1)[A].
• Persistent disease activity (chronic synovitis, morning stiffness, increased ESR and/or C-reactive protein, extra-articular disease): Add DMARDs to above-mentioned anti-inflammatories; hydroxychloroquine or sulfasalazine often are 1st choice. When second-line agent's therapeutic level is reached, decrease prednisone slowly.
- Minocycline: Effective with active mild/moderate disease (2)[A], and twice as effective as hydroxychloroquine in patients also treated with low-dose prednisone. Serious problems are rare.
- Intra-articular steroids: Rarely used.
- Antimalarials: Hydroxychloroquine (Plaquenil) 400 mg qhs for 2-3 months, then 200 mg at bedtime; 6-month trial usual (3)[A].
- Auranofin (Ridaura): 6-10 mg/d PO; re-evaluate in 6 months or 1 g total
- Injectable gold (Aurolate): Weekly for 22 weeks, then every 2-4 weeks
- Sulfasalazine: 500 mg/d, increase to 2 g/d over 1 month; max: 2-3 g/d; 6-month trial (4)[A].
- Penicillamine (D-penicillamine): 250 mg/d, increase slowly to 750-1,000 mg/d; 9-month trial with 8-12 weeks at maximum dosage. However, has dose-related side-effects (5)[A].
- Azathioprine: Because of toxicity, reserve for persons not responsive to other DMARDs.
- Methotrexate (Rheumatrex): 5-15 mg per week PO; 3-6-month trial. For steroid-dependent disease or after other measures fail. The DMARD with most predictable benefit. Has many significant side effects (6)[A] but the addition of folate to methotrexate reduces liver toxicity and allows reduction of methotrexate without lessening effectiveness, although it requires 10-20% increase in dosage.
- Protein A immunoadsorption (Prosorba): For moderate to severe RA in patients failing other DMARDs; removes antibodies responsible for RA activity. Majority respond in 9-21 weeks; costly.
- Hyaluronate (Hyalgan, Hyalgan G-F20): Hyaluronic acid substitute. For pain relief; variable responses. Currently limited to knee disease. Exact role in RA unclear; expected therapy duration 6-12 months.
- Infliximab (Remicade), adalimumab (Humira), and etanercept (Enbrel): Tumor necrosis factor inhibitors. Administered intravenously bimonthly (infliximab), biweekly (adalimumab), or twice weekly subcutaneously (etanercept). Optimal dosage and duration of treatment unclear. Short- and long-term toxicity low. Adalimumab is more beneficial with persistent disease activity, whereas infliximab and etanercept also can be used in early disease. Adalimumab with methotrexate is effective, but unclear with other DMARDs (7-9)[B]. Costly. Check PPD prior to treatment.
- Leflunomide (Arava): Modifies T-cell function to decrease autoimmune activity. Benefits similar to sulfasalazine and methotrexate, but overall difference in side effects are not statistically significant from sulfasalazine, but are slightly increased compared to methotrexate (10)[A]. Dose: 20 mg/d. For patients not responding to traditional agents or for whom use of traditional agents has been limited by side effects.
- Interleukin-1 receptor antagonist (Anakinra): Dose 100 mg/d SQ. Adverse reactions include rash, pruritus, neutropenia, and severe infections. TNF inhibitors may be more effective. Costly.
• Contraindications: Avoid leflunomide in pregnancy.
• Precautions
- Consider proton pump inhibitors for patients on chronic NSAID therapy; give folic acid (1-2/d) for patients on methotrexate.
- Avoid NSAID combinations.
Second Line
• Combinations that may be useful for resistant disease
- Methotrexate and cyclosporine
- Gold salts and prednisone
- Methotrexate and hydroxychloroquine
FOLLOW-UP
PROGNOSIS
• Progressive decline in function.
• Complete remission defined as absence of
- Symptoms of active inflammatory joint pain
- Morning stiffness
- Fatigue
- Synovitis on physical exam
- Progression of damage shown on radiograph films
- Elevation of ESR
• Poor prognostic findings
- Moderate to severe disease: Persistent swelling of proximal interphalangeal joints, flexor tenosynovitis of hands, high ESR, RF, or C-reactive protein, large number of swollen joints, extra-articular disease, bone erosions or cartilage loss, subcutaneous nodules, and early decline in function
- Inheritance of shared epitope: RA homozygous for shared epitope on DR1 or DR4 HLA class 11 -chains have poor prognosis. However, impractical to assay routinely for these sequences
- Early or advanced age at disease onset
• 50% cannot function in primary job within 10 years of onset.
COMPLICATIONS
• Erosive arthritis and joint destruction
• Skin vasculitis
• Pericarditis
• Intracardiac rheumatoid nodules causing valvular, conduction abnormalities
• Pleural, subpleural disease; interstitial fibrosis
• Mononeuritis multiplex, median nerve entrapment
• Sjogren syndrome, scleral rheumatoid nodules
• Felty syndrome
REFERENCES
1. Gotzsche PC and Johansen HK. Short-term low-dose corticosteroids vs placebo and nonsteroidal anti-inflammatory drugs in rheumatoid arthritis. The Cochrane Database of Systematic Reviews 1, 2006.
2. Tilley BC. et al. Minocycline in rheumatoid arthritis. A 48-week, double-blind, placebo-controlled trial. Ann Intern Med 1995;122:81-89.
3. Suarez-Almazor ME, Belseck E, et al. Antimalarials for treating rheumatoid arthritis. [Systematic Review] Cochrane Musculoskeletal Group Cochrane Database of Systematic Reviews. 1, 2006.
4. Suarez-Almazor ME, Belseck E, et al. Sulfasalazine for treating rheumatoid arthritis. The Cochrane Database of Systematic Reviews 1, 2006.
5. Suarez-Almazor ME, Belseck E, Spooner CH. Penicillamine for treating rheumatoid arthritis. The Cochrane Database of Systematic Reviews 1, 2006.
6. Suarez-Almazor ME, Belseck E, et al. Methotrexate for treating rheumatoid arthritis. The Cochrane Database of Systematic Reviews 1, 2006.
7. Blumenauer BBTB, Burls A, et al. Infliximab for the treatment of rheumatoid arthritis. The Cochrane Database of Systematic Reviews 1, 2006.
8. Blumenauer B, Judd M, et al. Etanercept for the treatment of rheumatoid arthritis. The Cochrane Database of Systematic Reviews 1, 2006.
9. Navarro-Sarabia F, Ariza-Ariza R, et al. Adalimumab for treating rheumatoid arthritis. The Cochrane Database of Systematic Reviews 1, 2006.
10. Osiri M, Robinson VA, et al. Leflunomide for treating rheumatoid arthritis. The Cochrane Database of Systematic Reviews 1, 2006.
MISCELLANEOUS
Functional ability classification
• Class I: None
• Class II: Moderate
• Class III: Marked restriction, inability to perform most of usual activities
• Class IV: Incapacitation