Conventional immunosuppressants
Conventional immunosuppressants are the antifolate, antimetabolite, alkylating, and calcineurin-inhibiting agents (methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, azathioprine, mycophenolate mofetil, cyclophosphamide, cyclosporine, tacrolimus) plus systemic glucocorticoids that anchor treatment across rheumatoid arthritis, lupus, and vasculitis. Methotrexate is the first-line conventional synthetic disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis, hydroxychloroquine is background therapy for essentially all lupus, and cyclophosphamide is reserved for organ- or life-threatening disease.
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What this article covers
- Overview
Definition: conventional immunosuppressants are the nonbiologic agents for autoimmune rheumatic disease: the conventional synthetic disease-modifying antirheumatic drug (DMARD) class methotrexate…
- Epidemiology
Reach: essentially all patients with rheumatoid arthritis, systemic lupus erythematosus, and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis receive at least one of these agents.
- Risk factors
Thiopurine methyltransferase (TPMT) or NUDT15 deficiency before azathioprine: low or absent activity causes severe, potentially fatal myelosuppression at standard doses; concomitant allopurinol or…
- Pathophysiology
Folate pathway: methotrexate's rheumatologic dosing acts mainly through adenosine A2a upregulation, but shared folate depletion still explains mucosal and hematologic toxicity, mitigated by folic acid.
- Clinical features
Methotrexate pneumonitis: subacute dyspnea, dry cough, and fever with bilateral infiltrates; also linked to liver and lung fibrosis with prolonged use.
- Differential diagnosis
Methotrexate versus leflunomide as the anchor agent: similarly effective for rheumatoid arthritis, but leflunomide is used when methotrexate is not tolerated or is contraindicated (renal or hepatic disease).
- Diagnosis
This is a therapeutics topic, not a disease: starting an agent rests on disease-specific classification criteria (ACR/EULAR for rheumatoid arthritis, SLICC or EULAR/ACR for lupus, ANCA serology and…
- Management
Rheumatoid arthritis, first-line: start methotrexate 7.5-10 mg PO once weekly with folic acid 1 mg PO once daily, titrating toward 15-25 mg once weekly.
- Complications
Malignancy: higher cumulative cyclophosphamide doses raise risk for solid organ tumors and bladder cancer; azathioprine raises lymphoproliferative disease risk; hydroxychloroquine does not.
- Prognosis
Methotrexate remission rate: 30% to 50% of methotrexate-naive rheumatoid arthritis patients reach remission or low disease activity.
- Prevention
Hydroxychloroquine dose ceiling and retinal screening: do not exceed 5 mg/kg/day; baseline dilated retinal examination in the first year, then annual screening starting at 5 years (sooner with a higher dose or renal impairment).
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Related articles
- Biologic and targeted immunosuppressants
Biologic and targeted synthetic disease-modifying antirheumatic drugs block a single cytokine, receptor, or signaling enzyme and are escalated to after conventional synthetic agents such as methotrexate fail. A tumor necrosis factor inhibitor is generally first-line, chosen by target organ and comorbidity, with mandatory tuberculosis and hepatitis B screening before the first dose.
- Rheumatoid arthritis
Rheumatoid arthritis is a chronic systemic autoimmune disease causing symmetric small-joint polyarthritis of the hands and feet that spares the distal interphalangeal joints, with morning stiffness over an hour. Diagnosis combines the ACR/EULAR classification criteria with rheumatoid factor, anti-CCP antibody, and radiographs. Treat-to-target management anchors on methotrexate, escalating to a biologic or targeted synthetic disease-modifying antirheumatic drug when remission is not reached.
- Systemic lupus erythematosus
Systemic lupus erythematosus is a chronic multisystem autoimmune disease in which antinuclear and other autoantibodies drive immune-complex deposition and organ injury across skin, joints, kidneys, blood, serosa, and the nervous system. Diagnosis rests on a positive antinuclear antibody plus weighted 2019 EULAR/ACR criteria totaling 10 or more points. Hydroxychloroquine is lifelong first-line therapy for nearly every patient, with glucocorticoids and steroid-sparing immunosuppression added for moderate to severe or organ-threatening disease.
- Lupus nephritis
Lupus nephritis is immune complex glomerulonephritis arising from systemic lupus erythematosus, classified by kidney biopsy into ISN/RPS classes I through VI, with class III, IV, or V disease defined by proteinuria above 500 mg per 24 hours. Class-directed immunosuppressive induction pairs pulse glucocorticoids with mycophenolate mofetil or cyclophosphamide, followed by mycophenolate mofetil or azathioprine maintenance, on a background of hydroxychloroquine and renin-angiotensin-system blockade.
- Granulomatosis with polyangiitis
Granulomatosis with polyangiitis (GPA) is an antineutrophil cytoplasmic antibody (ANCA)-associated necrotizing granulomatous vasculitis of the upper airway, lower airway, and kidney, most often with cytoplasmic ANCA (c-ANCA) targeting proteinase 3 (PR3). Diagnosis rests on the clinical triad, ANCA serology, and tissue biopsy showing pauci-immune vasculitis, and treatment begins with high-dose glucocorticoids plus rituximab or cyclophosphamide for organ-threatening disease, followed by rituximab or azathioprine maintenance.