Key Facts

Immunosuppressants are essential for transplant survival and control of autoimmune diseases. Their use requires balancing efficacy against significant risks including infection, malignancy, and organ toxicity.

Classification

• Antimetabolites: azathioprine (purine), methotrexate (folate), mycophenolate (IMPDH)
• Calcineurin inhibitors: ciclosporin, tacrolimus — block T-cell activation
• mTOR inhibitors: sirolimus, everolimus — block T-cell proliferation
• Biologic agents: anti-TNF, anti-IL-6, anti-CD20, anti-IL-17, anti-IL-23, JAK inhibitors
• Alkylating agents: cyclophosphamide — severe autoimmune/vasculitis
• Corticosteroids: see dedicated topic

Pathophysiology

• Immune-mediated diseases: aberrant T-cell and/or B-cell activity → tissue damage
• Immunosuppressants target specific steps in immune activation/proliferation
• Transplant: prevent T-cell mediated rejection of donor organ
• Side effects: consequence of global immune suppression — infection, malignancy (lymphoma, skin cancer)

Common Indications

• Transplant: tacrolimus + mycophenolate + prednisolone (standard triple therapy)
• Rheumatoid arthritis: methotrexate (first-line DMARD), biologics if refractory
• IBD: azathioprine, methotrexate; anti-TNF (infliximab, adalimumab) for moderate-severe
• SLE: hydroxychloroquine (all patients), azathioprine, mycophenolate, rituximab, belimumab
• Vasculitis: cyclophosphamide (induction), azathioprine/rituximab (maintenance)
• Psoriasis: methotrexate, ciclosporin, biologics (anti-TNF, anti-IL-17)

Major Side Effects by Drug

• Azathioprine: bone marrow suppression (especially if TPMT-deficient), hepatotoxicity, GI upset, pancreatitis, increased lymphoma risk
• Methotrexate: bone marrow suppression, hepatic fibrosis/cirrhosis, pneumonitis, mucositis, teratogenic
• Mycophenolate: GI (diarrhoea), bone marrow suppression, teratogenic
• Ciclosporin: nephrotoxicity, hypertension, hyperlipidaemia, gingival hyperplasia, hirsutism, tremor
• Tacrolimus: nephrotoxicity, diabetes, neurotoxicity (tremor, headache), hypertension
• Anti-TNF: infection (TB reactivation), demyelination, heart failure exacerbation, lupus-like syndrome

Red Flags

• Sore throat + fever on azathioprine/methotrexate: urgent FBC — exclude agranulocytosis/pancytopenia
• Breathlessness on methotrexate: exclude pneumonitis — CXR, urgent review; stop methotrexate
• Rising creatinine on ciclosporin/tacrolimus: nephrotoxicity — check trough levels, reduce dose
• Signs of infection in immunosuppressed patient: may be atypical; low threshold for investigation

Before Starting

• FBC, LFTs, U&Es: baseline for all immunosuppressants
• TPMT level: MANDATORY before azathioprine (homozygous deficiency → fatal bone marrow toxicity)
• DPYD testing: before 5-FU/capecitabine (not standard immunosuppressant but important pharmacogenomic test)
• CXR: baseline before methotrexate (pneumonitis monitoring)
• Hepatitis B & C serology: reactivation risk with immunosuppression
• TB screening (IGRA): before starting anti-TNF or other biologic agents
• Varicella immunity: check and vaccinate if non-immune before starting immunosuppression
• Pregnancy test: methotrexate, mycophenolate are teratogenic

Monitoring

• Azathioprine: FBC weekly for 4 weeks, then fortnightly for 8 weeks, then monthly; LFTs monthly
• Methotrexate: FBC, LFTs, U&Es — fortnightly until stable for 6 weeks, then monthly; annual CXR
• Ciclosporin/tacrolimus: trough drug levels; U&Es (creatinine), BP, glucose, lipids — regularly
• Biologics: FBC, LFTs, CRP; clinical monitoring for infection

Special Tests

• Drug levels: ciclosporin, tacrolimus (trough levels essential — narrow TI)
• Liver biopsy/FibroScan: if long-term methotrexate and concern about fibrosis
• HRCT chest: if methotrexate pneumonitis suspected

Key Prescribing Points

• Azathioprine: 1–3 mg/kg/day; check TPMT first; if heterozygous → reduce dose; if homozygous deficient → contraindicated
• Methotrexate: 7.5–25 mg ONCE weekly (prescribe specific day); folic acid 5 mg the day after MTX (or weekly except MTX day)
• Mycophenolate: 1–1.5 g BD; effective contraception mandatory (teratogenic)
• Ciclosporin: 2–5 mg/kg/day in divided doses; TDM; CYP3A4 interactions
• Tacrolimus: 0.1–0.2 mg/kg/day BD initially (transplant); TDM essential; CYP3A4 interactions

Infection Prevention

• Vaccinations: update BEFORE starting immunosuppression; live vaccines contraindicated once immunosuppressed
• PJP prophylaxis: co-trimoxazole 480 mg OD — for patients on high-dose steroids + another immunosuppressant
• Annual influenza and COVID-19 vaccination
• Hepatitis B prophylaxis: if HBsAg positive or past infection (anti-HBc positive) → antiviral cover

Pregnancy

• Azathioprine: considered relatively safe in pregnancy (used in IBD, transplant)
• Methotrexate: CONTRAINDICATED — stop ≥3 months before conception (men and women)
• Mycophenolate: CONTRAINDICATED — stop ≥6 weeks before conception; switch to azathioprine
• Ciclosporin, tacrolimus: can be continued in pregnancy with specialist advice

Referral Criteria

• Specialist prescribing: all immunosuppressants should be initiated by or in conjunction with specialist
• Shared care: many immunosuppressants managed in primary care with specialist oversight (shared care protocols)
• Urgent referral: suspected bone marrow toxicity, pneumonitis, severe infection

• Transplant immunosuppression: graft survival >90% at 5 years (kidney); lifelong treatment
• Methotrexate in RA: 60–70% achieve significant improvement; slows joint damage
• Biologic agents: transformed outcomes in RA, IBD, psoriasis — major reductions in disease activity
• Infection: most important complication — opportunistic infections (PJP, CMV, TB) require vigilance
• Malignancy: small increased long-term risk of lymphoma and skin cancer with immunosuppression
• TPMT testing: prevents azathioprine-related deaths from bone marrow failure — pharmacogenomic success story

Immunosuppressant Monitoring Summary

Biologic Agents Summary