Lecture 7 Rheumatologic Disorders Rheumatoid Arthritis University of Nizwa College of Pharmacy and Nursing School of Pharmacy PHARMACOTHERAPY II PHCY 410 Lecture 7 Rheumatologic Disorders Rheumatoid Arthritis Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy University of Nizwa

Course Outcomes Upon completion of this lecture the students will be able to Describe etiology, clinical manifestations and diagnosis of rheumatoid arthritis. Develop skills for monitoring drug therapy and patient education in patients with rheumatoid arthritis. Explain drug related problems and develop pharmaceutical care plan in patients with rheumatoid arthritis.

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

Pathophysiology RA results from a dysregulation of the humoral and cell-mediated components of the immune system. Most patients produce antibodies called rheumatoid factors(seropositive). Immunoglobulins (Igs) can activate the complement system. 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. Activated B cells produce plasma cells, which form antibodies.

Vasoactive substances (histamine, kinins, prostaglandins) are released at sites of inflammation causes edema, warmth, erythema, and pain. 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. The end results may be loss of joint space, loss of joint motion, bony fusion (ankylosis), joint subluxation, tendon contractures, and chronic deformity.

CLINICAL PRESENTATION Nonspecific symptoms include fatigue, weakness, low-grade fever, loss of appetite, joint pain, stiffness and myalgias. 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. Extra-articular involvement include rheumatoid nodules, vasculitis, pleural effusions, pulmonary fibrosis, ocular manifestations, pericarditis, cardiac conduction abnormalities, bone marrow suppression, and lymphadenopathy.

DIAGNOSIS The American Rheumatism Association classification. Laboratory abnormalities that may be seen include normocytic, normochromic anemia thrombocytosis or thrombocytopenia leukopenia elevated erythrocyte sedimentation rate and C-reactive protein positive rheumatoid factor positive antinuclear antibodies Aspirated synovial fluid shows turbidity, leukocytosis, reduced viscosity, and normal or low glucose. Radiologic findings include soft tissue swelling and osteoporosis near the joint. First in the metacarpophalangeal and proximal interphalangeal joints of the hands and metatarsophalangeal joints of the feet.

RA Factor Rheumatoid Nodules

Treatment Desired Outcome 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. 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.

PHARMACOLOGIC THERAPY A disease-modifying antirheumatic drug (DMARD) should be started within the first 3 months of symptom onset. DMARDs should be used in all patients except those with limited disease. First-line DMARDs include methotrexate (MTX), hydroxychloroquine, sulfasalazine, and leflunomide. MTX is often chosen initially because long-term superior outcomes compared with other DMARDs and lower cost than biologic agents.

Leflunomide appears to have long-term efficacy similar to MTX. 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, or both. 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.

Biologic DMARD 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. Methotrexate Methotrexate is now considered the DMARD of choice. Methotrexate alone or in combination therapy is the initial treatment of choice for patients with aggressive disease at doses ranging from 7.5 to 15 mg administered weekly, orally, intramuscularly, or subcutaneously, in one dose or in three equal doses every 12 hours.

Folic acid doses up to 27.5 mg per week have been used. Once-weekly doses should be initiated within 3 months of diagnosis and increased gradually until symptomatic improvement or a maximum dose of 20 mg/week is reached. Concomitant folic acid is given routinely to reduce the risk of folate-depleting reactions induced by methotrexate therapy (e.g., stomatitis, myelosuppression, and elevations in LFTs). Folic acid doses up to 27.5 mg per week have been used. Folic acid also diminishes the risk of hyperhomocysteinemia and therefore may decrease the risk of cardiovascular disease.

Monitoring Parameters Patients are monitored every 2 weeks initially, then eventually every 6 weeks, for adverse effects from MTX. Monitoring of liver enzymes could be performed every 3 to 4 months because of the low risk of alterations in MTX therapy caused by liver toxicity. Sustained elevation of mean corpuscular volume in a patient treated with MTX may indicate folate deficiency and may predict MTX hematologic toxicity. Severe neutropenia, thrombocytopenia, anemia, and pancytopenia may develop with low doses of MTX, especially in those patients with old age, renal disease, hypoalbuminemia, and concomitant antiproliferative agents.

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 anti-inflammatory properties and reduce stiffness. COX-2 selective NSAIDs appear to have a lower potential to cause gastrointestinal ulceration. Do not slow disease progression or prevent bony erosions or joint deformity. Should be used as adjuncts to DMARD treatment.

Corticosteroids Corticosteroids have anti-inflammatory and immunosuppressive properties. Oral corticosteroids (e.g., prednisone, methylprednisolone) can be used to control pain and synovitis while DMARDs are taking effect (“bridging therapy”). This is often used in patients with unbearable symptoms when DMARD therapy is initiated. Low-dose, long-term corticosteroid therapy may be used to control symptoms in patients with difficult-to-control disease.

Dosage tapering and eventual discontinuation should be considered. Prednisone doses below 7.5 mg/day (or equivalent) are well tolerated but are not devoid of the long-term corticosteroid adverse effects. Dosage tapering and eventual discontinuation should be considered. Patients taking doses > 10 mg/day prednisone or equivalent are at an increased risk for significant adverse reactions such as bone loss (osteoporosis), Cushing’s syndrome, peptic ulcer disease, hypertension, weight gain, infection, mood changes, cataracts, dyslipidemia, and hyperglycemia

Pregnancy: Methotrexate use (FDA pregnancy category X) is associated with abortion, fetal myelosuppression, limb defects, and CNS abnormalities NSAIDs, low dose steroids are safe during pregnancy.

Algorithm for treatment of rheumatoid arthritis

Usual Doses and Monitoring Parameters Drug Usual Dose Initial Monitoring Tests Maintenance Monitoring Tests NSAIDs Celecoxib Diclofenac 200–400mgOD/BiD, 150-200mgTid/Qid Scr or BUN, CBC every 2–4 weeks after starting therapy for 1–2 months Same as initial plus stool guaiac every 6–12 months Methotrexate Oral or IM: 7.5–15 mg/wk Baseline: Liver function tests, CBC with platelets, Scr CBC with platelets, AST, albumin every 1–2 months Leflunomide Oral: 100 mg daily for 3 days, then 10–20 mg daily; or 10–20 mg daily without loading dose Baseline: ALT, CBC with platelets CBC with platelets and ALT monthly initially, and then every 6–8 weeks Hydroxychloroquine Oral: 200–300 mg twice daily; after 1–2 months may decrease to 200 mg once or twice daily Baseline: color fundus photography and automated central perimetric analysis Ophthalmoscopy every 9–12 months Sulfasalazine Oral: 500 mg twice daily, then increase to 1 g twice daily max Baseline: CBC with platelets, then every week for 1 month Same as initial every 1– 2 months