RHEUMATOID ARTHRITIS

                                       RHEUMATOID ARTHRITIS









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

• RA results from a dysregulation of the humoral and cell-mediated components of the immune system. Most patients produce antibodies called rheumatoid factors; these seropositive patients tend to have a more aggressive course than patients who are seronegative

. • Immunoglobulins (Igs) can 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. The 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 (TNF), interleukin-1 (IL-1), and IL-6 are proinflammatory cytokines important in the initiation and continuance of inflammation. • Activated T cells produce cytotoxins, which are directly toxic to tissues, and cytokines, which stimulate further activation of inflammatory processes and attract cells to areas of inflammation. Macrophages are stimulated to release prostaglandins and cytotoxins

 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 myalgias may 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.

• 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 and spongy and may appear erythematous and warm, especially early in the course of the disease. Chronic joint deformities commonly involve subluxations of the wrists, metacarpophalangeal joints, and proximal interphalangeal joints (swan-neck deformity, boutonniere deformity, ulnar deviation). 


TREATMENT 

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
 A disease-modifying antirheumatic drug (DMARD) should be started within the first 3 months of symptom onset (Fig. 4-1). 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 DMARDs include methotrexate (MTX), hydroxychloroquine, sulfasalazine, and leflunomide. The order of 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
 Biologic agents with disease-modifying activity include the anti-TNF agents (etanercept, infliximab, adalimumab), the IL-1 receptor antagonist anakinra, and rituximab, which depletes peripheral B cells. Biologic agents are effective for patients who fail treatment with other DMARDs.
• DMARDs that are less frequently used include azathioprine, penicillamine, gold salts (including auranofin), minocycline, cyclosporine, and cyclophosphamide. These agents have either less efficacy or higher toxicity.
 Combination therapy with two or more DMARDs may be effective when single-DMARD treatment is unsuccessful. Combinations that are particularly effective include (1) MTX plus cyclosporine, and (2) MTX plus sulfasalazine and hydroxychloroquine
• Nonsteroidal antiinflammatory 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 the potential for long-term complications.


Nonsteroidal Antiinflammatory Drugs

 • 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 do not slow disease progression or prevent bony erosions or joint deformity. They should seldom be used as monotherapy for RA; instead, they should be viewed as adjuncts to DMARD treatment

• Methotrexate

MTX inhibits cytokine production and purine biosynthesis, which may be responsible for its antiinflammatory properties.

• Leflunomide

• Leflunomide (Arava) inhibits pyrimidine synthesis, 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 doseof 20 mg/day may be lowered to 10 mg/day in cases of GI intolerance, complaints of hair loss, or other dose-related toxicity.

• Hydroxychloroquine 

• 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. 

• Sulfasalazine

• Sulfasalazine use is often limited by adverse effects. Antirheumatic effects should be seen in 2 months. • Adverse effects include GI (anorexia, nausea, vomiting, diarrhea), dermatologic (rash, urticaria), hematologic (leukopenia, rare agranulocytosis), and hepatic (elevated enzymes) effects.

• Penicillamine 

Onset may be seen in 1 to 3 months, and most responses occur within 6 months. Early adverse effects include skin rash, metallic taste, hypogeusia, stomatitis, anorexia, nausea, vomiting, and dyspepsia.

• • Cyclosporine

Reduces production of cytokines involved in T-cell activation and has direct effects on B cells, macrophages, bone, and cartilage cells. Its onset appears to be 1 to 3 months. Important toxicities at doses of 1 to 10 mg/kg/day include hypertension, hyperglycemia, nephrotoxicity, tremor, GI intolerance, hirsutism, and gingival hyperplasia.

Biologic Agents

• Etanercept (Enbrel)
It 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. Most clinical trials used etanercept in patients who failed DMARDs, and responses were seen in 60% to 75% of patients.

• Infliximab (Remicade) 

It is a chimeric anti-TNF antibody fused to a human constant-region immunoglobulin G1 (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.  

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• Adalimumab

(Humira) is a human IgG1 antibody to TNF that is less antigenic than infliximab.

• Anakinra

 (Kineret) is an IL-1 receptor antagonist (IL-1ra) that binds to IL-1 receptors on target cells, preventing the interaction between IL-1 and the cells. IL-1 normally stimulates release of chemotactic factors and adhesion molecules that promote migration of inflammatory leukocytes to tissues. 

• 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

• Rituximab
(Rituxan) is a monoclonal chimeric antibody 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.

Corticosteroids 

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 (see Table 4-2)

. • Patients should be questioned about the presence of symptoms that may be related to adverse drug effects