Immunosuppressive Drugs

Immunosuppressive drugs suppress adaptive and innate immune responses to prevent organ rejection, treat autoimmune and inflammatory disease, and control graft-versus-host disease.

Classes include glucocorticoids, calcineurin inhibitors, antimetabolites, mTOR inhibitors, alkylating agents, costimulation blockers, biologics and induction antibodies. Combination therapy lowers the dose, and so the toxicity, of each drug.

Mechanism. Glucocorticoids suppress inflammatory gene transcription; calcineurin inhibitors block T cell interleukin 2 production; antimetabolites block lymphocyte purine synthesis; mTOR inhibitors block T cell proliferation; alkylating agents damage DNA in dividing cells; antibodies deplete or block lymphocytes.

Pharmacokinetics. Narrow therapeutic range drugs (tacrolimus, ciclosporin, sirolimus) need blood level monitoring and have many CYP3A4 and P-glycoprotein interactions.

Principles of use.

• Use steroid-sparing combinations and taper glucocorticoids to the lowest effective dose.
• Screen for tuberculosis, hepatitis B and C, HIV and Strongyloides before starting.
• Vaccinate beforehand (inactivated vaccines; avoid live vaccines during treatment).
• Give prophylaxis against Pneumocystis (co-trimoxazole 480 mg daily) with high-dose steroids or combination therapy, and bone protection with prolonged steroids.

• First-line. Glucocorticoid for flares and induction; azathioprine or mycophenolate for maintenance; tacrolimus for transplant maintenance.
• Alternative. Switch when side effects, inadequate control or pregnancy planning require a change.
• Specialist. Cyclophosphamide or rituximab for life-threatening vasculitis or lupus nephritis; induction antibodies in transplantation.
• Emergency. Pulse methylprednisolone 500 to 1000 mg intravenously for 3 days in severe organ-threatening flare or acute rejection.

Selection. Match drug to disease, organ, pregnancy plans, liver and kidney function, infection risk and monitoring capacity. Avoid unnecessary immunosuppression in latent infection.

Contraindications. Active uncontrolled infection; specific drug contraindications (each drug has its own list); live vaccines during treatment; pregnancy with teratogenic drugs (mycophenolate, cyclophosphamide, methotrexate).

Serious adverse effects.

• Opportunistic and serious infection (Pneumocystis, cytomegalovirus, tuberculosis, fungal, herpes zoster).
• Skin cancer and lymphoma with long-term use.
• Marrow suppression, nephrotoxicity, hepatotoxicity, hypertension, diabetes and dyslipidaemia.
• Glucocorticoid toxicity: osteoporosis, adrenal suppression, cataract, myopathy, psychiatric effects.

Major interactions. Azole antifungals, macrolides, diltiazem, verapamil (raise calcineurin and mTOR inhibitor levels); rifampicin, carbamazepine, phenytoin (lower them); allopurinol with azathioprine (marrow failure); live vaccines.

Common prescribing errors.

• Stopping glucocorticoids suddenly.
• Missing screening and prophylaxis.
• Prescribing interacting drugs without adjusting levels.
• Allopurinol with azathioprine at full dose.
• No sun protection or skin checks.

Special groups.

• Pregnancy: azathioprine, tacrolimus, ciclosporin and prednisolone (low dose) are compatible; mycophenolate, cyclophosphamide and methotrexate are avoided.
• Breastfeeding: azathioprine, tacrolimus and prednisolone are compatible.
• Children: specialist dosing; growth effects with steroids.
• Older adults: lower doses; infection and bone risks.
• Kidney: avoid nephrotoxic combinations; adjust doses.
• Liver: reduce doses of calcineurin and mTOR inhibitors.
• East Africa: tuberculosis, hepatitis B, HIV and strongyloidiasis are common, so screen and treat first; Pneumocystis prophylaxis with co-trimoxazole may also protect against toxoplasmosis and malaria; trough level monitoring may be unavailable, which limits use of tacrolimus, ciclosporin and sirolimus.

Monitoring. Blood count, liver and kidney tests, drug levels, glucose, lipids, blood pressure, bone density, skin examination and infection review, with frequency set by agent.

Referral and escalation. Fever or infection; falling counts; graft dysfunction; toxic drug levels; pregnancy; new masses or skin lesions.

Comparison with alternative classes. Immunosuppressive drugs are broad and effective but increase infection and cancer risk, whereas targeted biologics act on narrower targets with different risks. Combining drugs reduces individual toxicity.