Conventional Synthetic DMARDs

Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) suppress immune-mediated joint inflammation and slow structural damage in rheumatoid arthritis and other inflammatory diseases. Methotrexate is the anchor drug, with hydroxychloroquine, sulfasalazine and leflunomide used alone or in combination. Early treatment (within 3 to 6 months of symptom onset) gives the best results.

Mechanism. Methotrexate inhibits dihydrofolate reductase and raises adenosine; leflunomide blocks pyrimidine synthesis; sulfasalazine and hydroxychloroquine have broader immunomodulatory effects, including reduced antigen presentation and cytokine release. Onset is slow, 4 to 12 weeks.

Combinations. Methotrexate plus hydroxychloroquine plus sulfasalazine (triple therapy) is as effective as many biologic combinations in rheumatoid arthritis and is much cheaper.

Other drugs. Azathioprine, ciclosporin, mycophenolate, gold and penicillamine for selected diseases (connective tissue disease, vasculitis, uveitis); low-dose prednisolone (5 to 10 mg) or short courses to bridge until DMARDs act.

• First-line. Methotrexate as the first DMARD for rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis and many other inflammatory diseases.
• Alternative. Leflunomide or sulfasalazine when methotrexate is not tolerated; hydroxychloroquine for mild disease, lupus and pregnancy.
• Specialist. Triple therapy; combination with biologic or targeted synthetic agents when disease stays active after 3 to 6 months.
• Emergency. None; severe flares are treated with glucocorticoid (intramuscular methylprednisolone 120 mg or oral prednisolone 20 to 30 mg).

Treatment targets. Aim for remission or low disease activity (DAS28 under 2.6 or 3.2), assessed every 1 to 3 months, with escalation if the target is not met by 3 months or improvement is under 50% at 3 months.

Principles. Treat early, escalate promptly, use glucocorticoid bridging only briefly, screen for tuberculosis, hepatitis B and C and HIV before biologic therapy, and vaccinate before immunosuppression.

Contraindications. Pregnancy (methotrexate, leflunomide); significant liver disease; severe renal impairment (methotrexate); active serious infection; marrow failure; sulfonamide allergy (sulfasalazine); G6PD deficiency (sulfasalazine, relative).

Serious adverse effects. Marrow suppression, hepatotoxicity, interstitial pneumonitis (methotrexate), retinal toxicity (hydroxychloroquine), rash and hypersensitivity, hypertension and neuropathy (leflunomide), serious infection and malignancy risk.

Major interactions. Trimethoprim-sulfamethoxazole with methotrexate (severe marrow failure); NSAIDs and penicillins with methotrexate (reduced renal clearance); warfarin with leflunomide and sulfasalazine; live vaccines are avoided.

Common prescribing errors.

• Daily instead of weekly methotrexate (fatal overdose).
• Missing folic acid.
• Co-prescribing trimethoprim-sulfamethoxazole with methotrexate.
• Waiting too long to escalate.
• Not screening before biologic therapy.

Special groups.

• Pregnancy: hydroxychloroquine and sulfasalazine (with folic acid) are acceptable; stop methotrexate 3 months and leflunomide 2 years (or wash out) before conception.
• Breastfeeding: hydroxychloroquine and sulfasalazine acceptable.
• Children: methotrexate 10 to 15 mg/m2 weekly for juvenile idiopathic arthritis.
• Older adults: reduce doses for renal function; closer monitoring.
• Kidney: avoid methotrexate under 30 mL/min; adjust others.
• Liver: avoid methotrexate and leflunomide.
• East Africa: screen for tuberculosis, hepatitis B and HIV before treatment; csDMARDs are the main affordable option; confirm availability of folic acid and blood monitoring; lower alcohol intake.

Monitoring. Full blood count, creatinine and liver tests every 2 to 4 weeks for 3 months, then every 3 months; blood pressure (leflunomide); eye examination after 5 years (hydroxychloroquine); chest symptoms.

Referral and escalation. Active disease after 3 months of optimal csDMARD; abnormal blood tests; new breathlessness or cough; pregnancy.

Comparison with alternative classes. csDMARDs are cheap, orally available and effective for most patients, but slow to act. Biologic and targeted agents act faster in refractory disease at much higher cost.