Rheumatoid Arthritis

1. RheumatoidArthritis Rowa’ Al Ramahi

2. DEFINITION • Rheumatoid arthritis (RA) is a chronic and usually progressive inflammatory disorder of unknown etiology characterized by polyarticular symmetric joint involvement and systemic manifestations.

3. CLINICAL PRESENTATION • Nonspecific prodromal symptoms that develop insidiously over weeks to months may include fatigue, weakness, low-grade fever, loss of appetite, and joint pain. Stiffness and myalgiasmay precede development of synovitis. • Joint involvement tends to be symmetric and affect the small joints of the hands, wrists, and feet; the elbows, shoulders, hips, knees, and ankles may also be affected.

4. CLINICAL PRESENTATION • Joint stiffness typically is worse in the morning, usually exceeds 30 minutes, and may persist all day. • On examination, joint swelling may be visible or may be apparent only by palpation. The tissue feels soft, spongy, and warm and may appear erythematous, especially early in the disease course

5. Chronic joint deformities may involve subluxationsof wrists, metacarpophalangealjoints, and proximal interphalangealjoints (swan neck deformity, boutonnière deformity, and ulnar deviation). • Extra-articularinvolvement may include rheumatoid nodules, vasculitis, pleural effusions, pulmonary fibrosis, ocular manifestations, pericarditis, cardiac conduction abnormalities, bone marrow suppression, and lymphadenopathy.

6. DIAGNOSIS • A working group of the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) developed the 2010 Rheumatoid Arthritis Classification Criteria (Arthritis Rheum 2010;62:2569–2581). The six new criteria are intended to diagnose the disease earlier so patients can be started on disease-modifying treatments sooner to prevent erosive damage and improve outcomes. Two criteria are considered essential by the panel: at least one joint with definite clinical synovitis(swelling) and absence of disease that would better explain the synovitis.

7. DIAGNOSIS • The remaining criteria are evaluated on a scoring system, with a combined score of 6 or more indicating that the patient has definite RA: joint involvement, serology, acute phase reactants, and duration of symptoms. These criteria differ substantially from the previous 1987 criteria; symmetric joint involvement and the presence of structural joint damage or rheumatoid nodules are not required, and the new criteria set a lower threshold for the number of involved joints.

8. Laboratory abnormalities that may be seen include normocytic, normochromic anemia; thrombocytosisor thrombocytopenia; leukopenia; elevated erythrocyte sedimentation rate and C reactive protein; positive rheumatoid factor (60–70% of patients); positive anticycliccitrullinated peptide antibody (50–85% of patients); and positive antinuclear antibodies (25% of patients). • Examination of aspirated synovial fluid may reveal turbidity, leukocytosis, reduced viscosity, and normal or low glucose relative to serum concentrations.

9. Radiologic findings early in the disease course may include soft tissue swelling osteoporosis near the joint (periarticularosteoporosis). Erosions occurring later in the disease course are usually seen first in the metacarpophalangealand proximal interphalangealjoints of the hands and metatarsophalangealjoints of the feet.

10. DESIRED OUTCOME • The ultimate goal of RA treatment is to induce a complete remission, although this may be difficult to achieve. • The primary objectives are to reduce joint swelling, stiffness, and pain; preserve range of motion and joint function; improve quality of life; prevent systemic complications; and slow destructive joint changes.

11. NONPHARMACOLOGIC THERAPY • Adequate rest, weight reduction if obese, occupational therapy, physical therapy, and use of assistive devices may improve symptoms and help maintain joint function. • Patients with severe disease may benefit from surgical procedures such as tenosynovectomy, tendon repair, and joint replacements. • Patient education about the disease and the benefits and limitations of drug therapy is important.

12. PHARMACOLOGIC THERAPY • General Approach • A disease-modifying antirheumaticdrug (DMARD) should be started within the first 3 months of symptom onset. DMARDs should be used in all patients except those with limited disease. Early use of DMARDs results in a more favorable outcome and can reduce mortality. • First-line nonbiologic DMARDs include methotrexate(MTX), hydroxychloroquine, sulfasalazine, and leflunomide. The order agent selection is not clearly defined, but MTX is often chosen initially because long-term data suggest superior outcomes compared with other DMARDs and lower cost than biologic agents. Leflunomide appears to have long-term efficacy similar to MTX.

13. Combination therapy with two or more nonbiologicDMARDs may be effective when single-DMARD treatment is unsuccessful. Recommended combinations include (1) MTX plus hydroxychloroquine, (2) MTX plus leflunomide, and (2) MTX plus sulfasalazine. • Biologic agents with disease-modifying activity include the anti-TNF agents etanercept, infliximab, adalimumab, certolizumab, and golimumab; the costimulationmodulator abatacept; the IL-6 receptor antagonist tocilizumab; and rituximab, which depletes peripheral B cells. Biologic DMARDs are effective for patients who fail treatment with other DMARDs

14. DMARDs that are less frequently used include anakinra (an IL-1 receptor antagonist), azathioprine, penicillamine, gold salts (including auranofin), minocycline, cyclosporine, and cyclophosphamide. These agents have either less efficacy or higher toxicity, or both. • NSAIDs and/or corticosteroids may be used for symptomatic relief if needed. They provide relatively rapid improvement compared with DMARDs, which may take weeks to months before benefit is seen. However, NSAIDs have no impact on disease progression, and corticosteroids have the potential for long-term complications.

15. NonsteroidalAntiinflammatoryDrugs • NSAIDs act primarily by inhibiting prostaglandin synthesis, which is only a small portion of the inflammatory cascade. They possess both analgesic and antiinflammatory properties and reduce stiffness, but they do not slow disease progression or prevent bony erosions or joint deformity. NSAIDs should seldom be used as monotherapy for RA; instead, they should be viewed as adjuncts to DMARD treatment.

16. Nonbiologic DMARDs • METHOTREXATE • MTX inhibits cytokine production and purinebiosynthesis, which may be responsible for its antiinflammatory properties. Its onset is relatively rapid (as early as 2–3 wk), and 45% to 67% of patients remained on it in studies ranging from 5 to 7 years. • Toxicities are GI (stomatitis, diarrhea, nausea, and vomiting), hematologic (thrombocytopenia and leukopenia), pulmonary (fibrosis and pneumonitis), and hepatic (elevated enzymes and rarely cirrhosis). Concomitant folic acid may reduce some adverse effects without loss of efficacy.

17. Nonbiologic DMARDs • Liver injury tests (aspartateaminotransferase [AST] or alanineaminotransferase [ALT]) should be monitored periodically, but a liver biopsy is recommended during therapy only in patients with persistently elevated hepatic enzymes. MTX is teratogenic, and patients should use contraception and discontinue the drug if conception is planned. • MTX is contraindicated in pregnant and nursing women, chronic liver disease, immunodeficiency, pleural or peritoneal effusions, leukopenia, thrombocytopenia, preexisting blood disorders, and creatinine clearance <40 mL/min.

18. LEFLUNOMIDE • Leflunomide(Arava) inhibits pyrimidinesynthesis, which reduces lymphocyte proliferation and modulation of inflammation. Its efficacy for RA is similar to that of MTX. A loading dose of 100 mg/day for the first 3 days may result in a therapeutic response within the first month. The usual maintenance dose of 20 mg/day may be lowered to 10 mg/day in cases of GI intolerance, complaints of hair loss, or other dose-related toxicity.

19. LEFLUNOMIDE • The drug may cause liver toxicity and is contraindicated in patients with preexisting liver disease. The ALT should be monitored monthly initially and periodically thereafter. Leflunomide may cause bone marrow toxicity; a complete blood cell count with platelets is recommended monthly for 6 months, then every 6 to 8 weeks thereafter. It is teratogenicand should be avoided during pregnancy.

20. Hydroxychloroquine lacks the myelosuppressive, hepatic, and renal toxicities seen with some other DMARDs, which simplifies monitoring. Its onset may be delayed for up to 6 weeks, but the drug should not be considered a therapeutic failure until after 6 months of therapy with no response. • Short-term toxicities include GI (nausea, vomiting, and diarrhea), ocular m(accommodation defects, benign corneal deposits, blurred vision, scotomas, night blindness, and preretinopathy), dermatologic (rash, alopecia, and skin pigmentation), and neurologic (headache, vertigo, and insomnia) effects. Periodic ophthalmologic examinations are necessary for early detection of reversible retinal toxicity.

21. Sulfasalazine use is often limited by adverse effects. Antirheumaticeffects should be seen in 2 months. • Adverse effects include GI (anorexia, nausea, vomiting, and diarrhea), dermatologic (rash and urticaria), hematologic (leukopenia and rarely agranulocytosis), and hepatic (elevated enzymes) effects. GI symptoms may be minimized by starting with low doses, dividing the dose more evenly throughout the day, and taking the drug with food.

22. OTHER NONBIOLOGIC DMARDS • Gold salts, azathioprine, penicillamine, cyclosporine, and cyclophosphamidecan be effective and may be of value in certain clinical settings. However, they are used less frequently today because of toxicity, lack of long-term benefits, or both.

23. Biologic DMARDs • TNF-α INHIBITORS • Inhibitors of the inflammatory cytokine TNF-α are generally the first biologic DMARDs used for RA treatment. About 30% of patients eventually discontinue their use due to inadequate efficacy or adverse effects. In such situations, addition of a nonbiologic DMARD may be beneficial if the patient is not already one. Choosing an alternative TNF inhibitor may benefit some patients; treatment with rituximab or abatacept may also be effective in patients failing TNF inhibitors. Combination biologic DMARD therapy is not recommended because of the increased risk for infection.

24. Biologic DMARDs • TNF-α INHIBITORS • Congestive heart failure (HF) is a relative contraindication for anti-TNF agents due to reports of increased cardiac mortality and HF exacerbations with several agents. Patients with a history of uncompensated HF or recent hospital admissions for HF should not use anti-TNF therapy. The drugs should be discontinued in patients whose HF worsens during treatment. • Anti-TNF therapy has been reported to induce a multiple sclerosis (MS)–like illness or exacerbate MS in patients with the disease. Patients with neurologic symptoms suggestive of MS should discontinue therapy.

25. TNF inhibitors are associated with increased risk of cancer, especially lymphoproliferativecancers. The drugs contain a black box warning about increased risk of lymphoproliferative and other cancers in children and adolescents treated with these drugs. • These drugs (and other biologic DMARDs) carry a small increased risk for infection. Tuberculin skin testing is recommended prior to treatment so that latent tuberculosis can be detected. These agents should be avoided in patients with preexisting infection and in those at high risk for developing infection. Treatment should be discontinued temporarily if an infection develops during therapy. No laboratory monitoring is required with anti-TNF agents.

26. Infliximab (Remicade) is a chimeric anti-TNF antibody fused to a human constant-region IgG1. It binds to TNF and prevents its interaction with TNF receptors on inflammatory cells. To prevent formation of antibodies to this foreign protein, MTX should be given orally in doses used to treat RA for as long as the patient continues on infliximab. In clinical trials, the combination of infliximab and MTX halted progression of joint damage and was superior to MTX monotherapy. Infliximabmay increase the risk of infection. An acute infusion reaction with fever, chills, pruritus, and rash may occur within 1 to 2 hours after administration. Autoantibodiesand lupus-like syndrome have also been reported.

27. Adalimumab (Humira) is a human IgG1 antibody to TNF that is less antigenic than infliximab. It has response rates similar to other TNF inhibitors. Local injection site reactions were the most common adverse event reported in clinical trials.

28. Certolizumab (Cimzia) is a humanized antibody specific for TNF-α. • Golimumab (Simponi) is another human antibody to TNF-α

29. Abatacept (Orencia) is a costimulationmodulator approved for patients with moderate to severe disease who fail to achieve an adequate response from one or more DMARDs. By binding to CD80/CD86 receptors on antigen presenting cells, abataceptinhibits interactions between the antigen presenting cells and T cells, preventing T cells from activating to promote the inflammatory process. The drug is well tolerated, with infusion reactions, headache, nasopharyngitis, dizziness, cough, back pain, hypertension, dyspepsia, urinary tract infection, rash, and extremity pain reported more frequently in clinical trials.

30. RITUXIMAB • Rituximab(Rituxan) is a monoclonal chimericantibody consisting of mostly human protein with the antigen-binding region derived from a mouse antibody to CD20 protein found on the cell surface of mature B lymphocytes. Binding of rituximab to B cells results in nearly complete depletion of peripheral B cells, with a gradual recovery over several months. • Rituximab is useful in patients failing MTX or TNF inhibitors. Methylprednisolone100 mg should be given 30 minutes prior to rituximabto reduce the incidence and severity of infusion reactions. Acetaminophen and antihistamines may also benefit patients who have a history of reactions. MTX should be given concurrently in the usual doses for RA to achieve the best therapeutic outcomes.

31. TOCILIZUMAB • Tocilizumab(Actemra) attaches to IL-6 receptors, which prevents the cytokine from interacting with cells. It has been used as monotherapy or in combination with MTX. Infusion reactions, increased plasma lipids, and increased infections have been reported.

32. ANAKINRA • Anakinra(Kineret) is an IL-1 receptor antagonist; it is considered to be less effective than other biologic DMARDs and is not included in the current ACR treatment recommendations. It can be used alone or in combination with any of the other DMARDs except for TNF blocking agents.

33. Corticosteroids have antiinflammatoryand immunosuppressive properties. They interfere with antigen presentation to T lymphocytes, inhibit prostaglandin and leukotriene synthesis, and inhibit neutrophiland monocytesuperoxide radical generation. • Oral corticosteroids (e.g., prednisone and methylprednisolone) can be used to control pain and synovitiswhile DMARDs are taking effect (“bridging therapy”). This is often used in patients with debilitating symptoms when DMARD therapy is initiated. Low-dose, long-term corticosteroid therapy may be used to control symptoms in patients with difficult-tocontrol disease.

34. Prednisone doses below 7.5 mg/day (or equivalent) are well tolerated but are not devoid of the long-term corticosteroid adverse effects. The lowest dose that controls symptoms should be used. Alternate-day dosing of low-dose oral corticosteroids is usually ineffective in RA. • High-dose oral or IV bursts may be used for several days to suppress disease flares. After symptoms are controlled, the drug should be tapered to the lowest effective dose.

35. The intramuscular route is preferable in nonadherentpatients. Depot forms (triamcinoloneacetonide, triamcinolonehexacetonide, and methylprednisoloneacetate) provide 2 to 6 weeks of symptomatic control. • The onset of effect may be delayed for several days. The depot effect provides a physiologic taper, avoiding hypothalamic-pituitary axis suppression.

36. Intraarticularinjections of depot forms may be useful when only a few joints are involved. If effective, injections may be repeated every 3 months. No one joint should be injected more than two or three times per year. • Adverse effects of systemic glucocorticoidslimit their long-term use. Dosage tapering and eventual discontinuation should be considered at some point in patients receiving chronic therapy.

37. EVALUATION OF THERAPEUTIC OUTCOMES • Clinical signs of improvement include reduction in joint swelling, decreased warmth over actively involved joints, and decreased tenderness to joint palpation. • Symptom improvement includes reduction in joint pain and morning stiffness, longer time to onset of afternoon fatigue, and improvement in ability to perform daily activities. • Periodic joint radiographs may be useful in assessing disease progression. • Laboratory monitoring is of little value in monitoring response to therapy but is essential for detecting and preventing adverse drug effects . • Patients should be questioned about the presence of symptoms that may be related to adverse drug effects