Rheumatoid Arthritis Pharmacology

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease with onset typically between 30 and 55 years. Unlike osteoarthritis (mechanical wear of articular surfaces), RA begins with synovial membrane damage and inflammation, progresses to pannus (fibrovascular) tissue formation, and ultimately causes bone destruction and joint fusion.

Treatment addresses three goals: pain/symptom control, inflammation reduction, and disease progression modification.

NSAIDs inhibit cyclooxygenase (COX) enzymes. Cell damage releases phospholipids; phospholipase converts them to arachidonic acid; COX converts arachidonic acid to prostaglandins, especially PGE2 (mediates pain and inflammation). COX-1 is constitutive — its inhibition causes gastric and renal side effects. COX-2 is inducible at inflammation sites — its inhibition is anti-inflammatory. COX-2 produces PGI2 (prostacyclin); inhibition increases thrombosis risk. Key NSAIDs: ibuprofen; diclofenac (slightly COX-2 selective; GI risk; oral and topical); celecoxib (highly COX-2 selective; reduced GI effects; increased cardiovascular thrombosis risk).

Glucocorticoids are powerful anti-inflammatory and immunosuppressive agents. The endogenous corticosteroid is cortisol. They alter gene transcription to produce anti-inflammatory effects, can serve as bridge therapy, and at high doses function as DMARDs. Long-term oral use causes cushingoid features, osteoporosis (decreased collagen synthesis), and HPA suppression. Key agents: prednisone (main for RA); dexamethasone (most potent); triamcinolone (intra-articular, short-term). Corticosteroids must be tapered rather than stopped abruptly because chronic use suppresses the HPA axis — abrupt cessation risks Addison-like disease.

DMARDs have slow onset (weeks to months), reduce disease progression or induce remission, reduce joint damage, and cause immunosuppression requiring blood monitoring. They lack direct analgesic or anti-inflammatory effects; bridge therapy with NSAIDs or glucocorticoids is required until DMARD effects appear.

Xenobiotic DMARDs: methotrexate (first-choice DMARD; folate antagonist targeting rapidly dividing cells; onset 3-6 weeks; monitor for pancytopenia, hepatotoxicity); cyclosporin (calcineurin inhibitor; reduces T-cell proliferation; also used for transplant rejection; hypertension and renal toxicity are major concerns).

Biological DMARDs target specific immune pathways: infliximab and adalimumab (monoclonal antibodies against TNF-alpha); rituximab (anti-CD20 mAb, depletes B cells); etanercept (soluble TNF receptor). All biological DMARDs cause immunosuppression and increase infection risk.