Antimetabolite Immunosuppressants

Antimetabolite immunosuppressants block purine synthesis and lymphocyte proliferation. Azathioprine, mycophenolate mofetil and mycophenolic acid are the main drugs, and methotrexate and leflunomide belong to the same group. They maintain remission in lupus, vasculitis, inflammatory bowel disease, autoimmune hepatitis and uveitis, and prevent transplant rejection.

Mechanism. Azathioprine is converted to 6-mercaptopurine and thioguanine nucleotides, which block DNA synthesis. Mycophenolate inhibits inosine monophosphate dehydrogenase, selectively blocking lymphocyte purine synthesis.

Pharmacokinetics. Azathioprine is metabolised by thiopurine methyltransferase (TPMT) and NUDT15 and by xanthine oxidase. Mycophenolate mofetil is converted to mycophenolic acid with enterohepatic recirculation, and half-life about 17 hours.

Azathioprine.

• Start 1 mg/kg daily, increase to 2 to 2.5 mg/kg daily over 4 to 6 weeks (1 to 2 mg/kg in many rheumatic conditions).
• Check TPMT (and NUDT15 where available) before starting; absent activity means avoid; reduced activity means a 25 to 50% lower dose.
• Reduce to 25% of dose with allopurinol or febuxostat, or avoid.
• Onset takes 6 to 12 weeks.

Mycophenolate mofetil.

• Transplant 1 g twice daily (up to 1.5 g twice daily).
• Lupus nephritis 1 to 1.5 g twice daily; start 500 mg twice daily and increase over 2 to 4 weeks.
• Mycophenolic acid (enteric-coated) 720 mg is equivalent to 1 g of mofetil.

Take mycophenolate on an empty stomach. Separate from antacids, iron and colestyramine by 2 hours.

• First-line. Maintenance after cyclophosphamide or rituximab in vasculitis; lupus nephritis (mycophenolate); transplant combination therapy; steroid-sparing in autoimmune hepatitis and inflammatory bowel disease (azathioprine).
• Alternative. Switch between azathioprine and mycophenolate for intolerance or inadequate response.
• Specialist. Myasthenia gravis, interstitial lung disease in systemic sclerosis, scleroderma, uveitis, pemphigus.
• Emergency. None.

Selection. Mycophenolate is the more effective choice in lupus nephritis; azathioprine is preferred in pregnancy and in men or women planning pregnancy.

Contraindications. Azathioprine: absent TPMT or NUDT15 activity, hypersensitivity, concurrent allopurinol without dose reduction. Mycophenolate: pregnancy and women who might become pregnant without strict contraception, hypersensitivity, severe infection.

Serious adverse effects.

• Marrow suppression (leucopenia, thrombocytopenia, anaemia), mainly in the first months.
• Nausea, vomiting, diarrhoea (mycophenolate); hepatotoxicity and pancreatitis (azathioprine).
• Infection (including cytomegalovirus, herpes zoster), skin cancer and lymphoma.
• Hypersensitivity syndrome with azathioprine; mycophenolate embryopathy and miscarriage.

Major interactions. Allopurinol and febuxostat with azathioprine (severe marrow failure); co-trimoxazole and ACE inhibitors increase leucopenia risk; warfarin response reduced; rifampicin and antacids reduce mycophenolate levels; live vaccines.

Common prescribing errors.

• Starting azathioprine without TPMT or NUDT15 testing.
• Full dose azathioprine with allopurinol.
• Prescribing mycophenolate without pregnancy counselling and contraception.
• Skipping blood tests in the first 3 months.
• Switching brands of mycophenolate without advice.

Special groups.

• Pregnancy: azathioprine acceptable; mycophenolate contraindicated (stop 6 weeks before conception).
• Breastfeeding: azathioprine acceptable; avoid mycophenolate.
• Children: weight-based dosing; specialist.
• Older adults: start lower; marrow risk.
• Kidney: reduce mycophenolate in severe impairment; adjust azathioprine.
• Liver: monitor liver tests; use with caution.
• East Africa: TPMT testing is seldom available, so start low (25 to 50 mg daily) and check counts at 1, 2 and 4 weeks; co-trimoxazole prophylaxis with azathioprine needs close count monitoring; watch for HIV, hepatitis B and tuberculosis.

Monitoring. Full blood count, liver tests and creatinine weekly for the first 4 weeks, then every 2 weeks to 3 months, then every 3 months. Stop and review for white cells under 3.5 x 10^9/L, neutrophils under 1.6 x 10^9/L, platelets under 140 x 10^9/L, or transaminases over twice the upper limit.

Referral and escalation. Fever, sore throat, mouth ulcers or bruising; severe vomiting or diarrhoea; jaundice; pregnancy; new skin lesions.

Comparison with alternative classes. Antimetabolites are cheap, oral and suitable for long-term maintenance, but slow to act and marrow toxic. Calcineurin inhibitors act faster but are nephrotoxic; biologics are targeted and costly.