RHEUMATOID ARTHRITIS, PATHOPHYSIOLOGY, CLINICAL PRESENTATION, DIAGNOSIS, TREATMENT

Rheumatoid arthritis

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

PATHOPHYSIOLOGY

• RA results from dysregulation of humoral and cell-mediated immunity. Most patients produce antibodies called rheumatoid factors; these seropositive patients tend to have a more aggressive course than seronegative patients.
• Immunoglobulins (Ig) activate the complement system, which amplifies the immune response by enhancing chemotaxis, phagocytosis, and release of lymphokines by mononuclear cells that are then presented to T lymphocytes. Processed antigen is recognized by the major histocompatibility complex proteins on the lymphocyte surface, resulting in activation of T and B cells.
• Tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and IL-6 are proinflammatory cytokines important in initiation and continuance of inflammation.
• Activated T cells produce cytotoxins and cytokines, which stimulate further activation of inflammatory processes and attract cells to areas of inflammation. Macrophages are stimulated to release prostaglandins and cytotoxins. T-cell activation requires both stimulation by proinflammatory cytokines as well as interaction between cell surface receptors, called costimulation. One such costimulation interaction is between CD28 and CD80/86.
• Activated B cells produce plasma cells, which form antibodies that, in combination with the complement system, result in accumulation of polymorphonuclear leukocytes. These leukocytes release cytotoxins, oxygen-free radicals, and hydroxyl radicals that promote damage to synovium and bone.
• Signaling molecules are important for activating and maintaining inflammation. Janus kinase (JAK) is a tyrosine kinase responsible for regulating leukocyte maturation and activation. JAK also has effects on production of cytokines and immunoglobulins.
• Vasoactive substances (histamine, kinins, prostaglandins) are released at sites of inflammation, increasing blood flow and vascular permeability. This causes edema, warmth, erythema, and pain, and facilitates granulocyte passage from blood vessels to sites of inflammation.
• Chronic inflammation of synovial tissue lining the joint capsule results in tissue proliferation (pannus formation). Pannus invades cartilage and eventually the bone surface, producing erosions of bone and cartilage and leading to joint destruction. End results may be loss of joint space and joint motion, bony fusion (ankylosis), joint subluxation, tendon contractures, and chronic deformity.

CLINICAL PRESENTATION

• Nonspecific prodromal symptoms developing over weeks to months include fatigue, weakness, low-grade fever, anorexia, and joint pain. Stiffness and myalgias may precede development of synovitis.
• Joint involvement tends to be symmetric and affect small joints of the hands, wrists, and feet; elbows, shoulders, hips, knees, and ankles may also be affected.
• 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 apparent only by palpation. Tissue is soft, spongy, warm, and may be erythematous. Joint deformities may involve subluxations of wrists, metacarpophalangeal joints, and proximal interphalangeal joints (swan neck deformity, boutonnière deformity, and ulnar deviation).
• Extra-articular involvement may include rheumatoid nodules, vasculitis, pleural effusions, pulmonary fibrosis, ocular manifestations, pericarditis, cardiac conduction abnormalities, bone marrow suppression, and lymphadenopathy.

DIAGNOSIS

• The American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) revised criteria for diagnosis of RA in 2010. These criteria are intended for patients early in their disease and emphasize early manifestations. Late manifestations (bone erosions, subcutaneous nodules) are no longer in the diagnostic criteria. Patients with synovitis of at least one joint and no other explanation for the finding are candidates for assessment. The criteria use a scoring system with a combined score of 6 or more out of 10 indicating that the patient has definite RA.
• Laboratory abnormalities include normocytic, normochromic anemia; thrombocytosis or thrombocytopenia; leukopenia; elevated erythrocyte sedimentation rate and C-reactive protein; positive rheumatoid factor (60%–70% of patients); positive anticitrullinated protein antibody (ACPA) (50%–85% of patients); and positive antinuclear antibodies (25% of patients).
• Aspirated synovial fluid may reveal turbidity, leukocytosis, reduced viscosity, and normal or low glucose relative to serum concentrations.
• Early radiologic findings include soft tissue swelling and osteoporosis near the joint (periarticular osteoporosis). Erosions later in the disease course are usually seen first in the metacarpophalangeal and proximal interphalangeal joints of the hands and metatarsophalangeal joints of the feet.

TREATMENT

• Goals of Treatment: The ultimate goal is to induce complete remission or low disease activity. Additional goals are to control disease activity and joint pain, maintain ability to function in daily activities, slow destructive joint changes, and delay disability.

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.

PHARMACOLOGIC THERAPY

General Approach
• Start disease-modifying antirheumatic drugs (DMARDs) as soon as possible after disease onset because early treatment results in more favorable outcomes.
• DMARDs slow RA disease progression. Common nonbiologic DMARDs include methotrexate (MTX), hydroxychloroquine, sulfasalazine, and leflunomide. The order of 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.
• Combination therapy with two or more nonbiologic DMARDs may be effective when single-DMARD treatment is unsuccessful. Recommended combinations include
 (1) MTX plus hydroxychloroquine,
(2) MTX plus leflunomide,
(3) MTX plus sulfasalazine, and
(4) MTX plus hydroxychloroquine plus sulfasalazine.
• Biologic DMARDs include the anti-TNF agents etanercept, infliximab, adalimumab, certolizumab, and golimumab; the costimulation modulator abatacept; the IL-6 receptor antagonist tocilizumab; and rituximab, which depletes peripheral B cells. Biologic DMARDs have proven effective for patients failing treatment with nonbiologic DMARDs.
• Anti-TNF biologics may also be used in patients with early disease of high activity and poor prognostic factors, regardless of previous DMARD use. Features of poor prognosis include functional limitation, extra-articular disease (eg, rheumatoid nodules, vasculitis) positive rheumatoid factor or ACPA, or bone erosions. Anti-TNF biologics can be used as either monotherapy or in combination with other DMARDs. Use of biologics in combination with MTX is more effective than biologic monotherapy.
• DMARDs less frequently used include anakinra (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.
• Nonsteroidal anti-inflammatory drugs (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 potential for long-term complications.
Nonsteroidal Anti-inflammatory Drugs
• NSAIDs inhibit prostaglandin synthesis, which is only a small portion of the inflammatory cascade. They possess both analgesic and anti-inflammatory properties and reduce stiffness, but they do not slow disease progression or prevent bony erosions or joint deformit.

Nonbiologic DMARDs

Methotrexate
• Methotrexate (MTX) inhibits cytokine production and purine biosynthesis, and may stimulate adenosine release, all of which may lead to anti-inflammatory properties. Onset is as early as 2 to 3 weeks, and 45% to 67% of patients remained on it in studies ranging from 5 to 7 years.
• Concomitant folic acid may reduce some adverse effects without loss of efficacy. Monitor liver injury tests 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 of less than 40 mL/min (0.67 mL/s).
Leflunomide
• Leflunomide (Arava) inhibits pyrimidine synthesis, which reduces lymphocyte proliferation and modulation of inflammation. Efficacy for RA is similar to that of MTX.
• A loading dose of 100 mg/day for 3 days may result in 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, alopecia, or other dose-related toxicity.
• Leflunomide is contraindicated in patients with preexisting liver disease. It is teratogenic and must be avoided during pregnancy.
Hydroxychloroquine
• Hydroxychloroquine is often used in mild RA or as an adjuvant in combination DMARD therapy. It lacks the myelosuppressive, hepatic, and renal toxicities seen with some other DMARDs, which simplifies monitoring. 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.
• Periodic ophthalmologic examinations are necessary for early detection of reversible retinal toxicity.
Sulfasalazine
• Sulfasalazine use is often limited by adverse effects. Antirheumatic effects should be seen within 2 months.
• GI symptoms may be minimized by starting with low doses, dividing the dose evenly throughout the day, and taking it with food.
Minocycline
• Minocycline may inhibit metalloproteinases active in damaging articular cartilage. It may be an alternative for patients with mild disease and without features of poor prognosis.
Tofacitinib
• Tofacitinib (Xeljanz) is a nonbiologic JAK inhibitor indicated for patients with moderate to severe RA who have failed or have intolerance to MTX.
• The Food and Drug Administration (FDA)–approved dose is 5 mg twice daily as monotherapy or in combination with other nonbiologic DMARDs.
• Labeling includes black-box warnings about serious infections, lymphomas, and other malignancies. Live vaccinations should not be given during treatment.
• Long-term safety data and impact on radiographic joint damage are needed before tofacitinib’s place in the therapy will be clear.

Biologic DMARDs

• Biologic DMARDs may be effective when nonbiologic DMARDs fail to achieve adequate responses but are considerably more expensive.
• Other than anakinra and tocilizumab, these agents have no toxicities requiring laboratory monitoring, but they do carry a small increased risk for infection, including tuberculosis. Tuberculin skin testing should be performed before treatment to detect latent tuberculosis.
• Biologic agents should be at least temporarily discontinued in patients who develop infections while on therapy until the infection is cured. Live vaccines should not be given to patients taking biologic agents.
TNF-α Inhibitors
• Inhibitors of TNF-α are generally the first biologic DMARDs used. About 30% of patients eventually discontinue use owing to inadequate efficacy or adverse effects. In such situations, addition of a nonbiologic DMARD may be beneficial if the patient is not already taking 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 increased infection risk.
• Congestive heart failure (HF) is a relative contraindication for anti-TNF agents due to reports of increased cardiac mortality and HF exacerbations. Patients with New York Heart Association class III or IV and an ejection fraction of 50% or less should not use anti-TNF therapy. Discontinue the drugs if 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. Discontinue therapy if patients develop neurologic symptoms suggestive of MS.
• TNF inhibitors are associated with increased risk of cancer, especially lymphoproliferative cancers. The drugs contain a black-box warning about increased risk of lymphoproliferative and other cancers in children and adolescents treated with these drugs.
✓ Etanercept (Enbrel) is a fusion protein consisting of two p75-soluble TNF receptors linked to an Fc fragment of human IgG1. It binds to and inactivates TNF, preventing it from interacting with the cell-surface TNF receptors and thereby activating cells. Clinical trials using etanercept in patients who failed DMARDs demonstrated responses in 60% to 75% of patients. It slows erosive disease progression more than oral MTX in patients with inadequate response to MTX monotherapy.
✓ 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 an antibody response to this foreign protein, MTX must be given orally in doses used to treat RA for as long as the patient continues infliximab. In clinical trials, the combination of infliximab and MTX halted progression of joint damage and was superior to MTX monotherapy. An acute infusion reaction with fever, chills, pruritus, and rash may occur within 1 to 2 hours after administration. Autoantibodies and lupus-like syndrome have also been reported.
✓ Adalimumab (Humira) is a human IgG1 antibody to TNF-α that is less antigenic than infliximab. It has response rates similar to other TNF inhibitors.
✓ Golimumab (Simponi) is a human antibody to TNF-α with activity and precautions similar to other TNF-α inhibitors.
✓ Certolizumab (Cimzia) is a humanized antibody specific for TNF-α with precautions and side effects similar to other TNF-α inhibitors.
Abatacept
• Abatacept (Orencia) is a costimulation modulator 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, abatacept inhibits interactions between the antigen-presenting cells and T cells, preventing T cells from activating to promote the inflammatory process.
Rituximab
• Rituximab (Rituxan) is a monoclonal chimeric antibody consisting of 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. Give methylprednisolone 100 mg 30 minutes prior to rituximab to reduce 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 optimal therapeutic outcomes.
Tocilizumab
• Tocilizumab (Actemra) is a humanized monoclonal antibody that attaches to IL-6  receptors, preventing the cytokine from interacting with IL-6 receptors. It is approved for adults with moderately to severely active RA who have failed to respond to one or more anti-TNF biologic agents. It is used as either monotherapy or in combination with MTX or another DMARD.
Anakinra
• Anakinra (Kineret) is an IL-1 receptor antagonist; it is less effective than other biologic DMARDs and is not included in the current ACR treatment recommendations. However, select patients with refractory disease may benefit. It can be used alone or in combination with any of the other DMARDs except TNF-α inhibitors.
Corticosteroids
• Corticosteroids have anti-inflammatory and immunosuppressive properties. They interfere with antigen presentation to T lymphocytes, inhibit prostaglandin and leukotriene synthesis, and inhibit neutrophil and monocyte superoxide radical generation.
• Oral corticosteroids (eg, prednisone and methylprednisolone) can be used to control pain and synovitis while DMARDs are taking effect (“bridging therapy”).
• Low-dose, long-term corticosteroid therapy may be used to control symptoms in patients with difficult-to-control disease. Prednisone doses below 7.5 mg/day (or equivalent) are well tolerated but are not devoid of long-term adverse effects. Use the lowest dose that controls symptoms. 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, taper the drug to the lowest effective dose.
• The intramuscular route is preferable in nonadherent patients. Depot forms (triamcinolone acetonide, triamcinolone hexacetonide, and methylprednisolone acetate) provide 2 to 6 weeks of symptomatic control. Onset of effect may be delayed for several days. The depot effect provides a physiologic taper, avoiding hypothalamicpituitary axis suppression.
• Intra-articular injections of depot forms may be useful when only a few joints are involved. If effective, injections may be repeated every 3 months. Do not inject any one joint more than two or three times per year.
• Adverse effects of systemic glucocorticoids limit long-term use. Consider dosage tapering and eventual discontinuation at some point during chronic therapy.

Eval uation of Therape utic 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 assessing response to therapy but is essential for detecting and preventing adverse drug effects.
• Ask patients about the presence of symptoms that may be related to adverse drug effects.