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Ovid: Oxford Handbook of Respiratory Medicine

Authors: Chapman, Stephen; Robinson, Grace; Stradling, John; West, Sophie Title: Oxford Handbook of Respiratory Medicine, 1st Edition Copyright ©2005 Oxford University Press > Table of Contents > Part 3 – Supportive care > Chapter 55 – Immunosuppressive drugs Chapter 55 Immunosuppressive drugs P.626
Patient advice and monitoring Immunosuppressive drugs are used mainly in the management of pulmonary vasculitis, but also in asthma, sarcoidosis, and interstitial lung diseases. Centres differ in their use of these drugs and local guidelines are often available. General advice for patients on immunosuppressive drugs

  • Increased risk of infections and increased likelihood of severe infections. Check FBC if develop febrile illness
  • May have atypical presentation of infections
  • Avoid live vaccines, such as measles, mumps, rubella, BCG, yellow fever, oral typhoid, oral polio
  • If never had varicella zoster:
    • Avoid contacts with chicken pox or shingles
    • Consider passive immunization
    • Immunoglobulin therapy if exposed
    • Hospital treatment with close monitoring if develop chicken pox
  • Avoid measles exposure. Prophylaxis with immunoglobulins if exposed.
Summary of tests to perform before and during immunosuppressive drug treatment
Drug Check before starting Follow-up
Corticosteroids BP, glucose. Consider bones/osteoporosis BP, glucose if symptoms of diabetes.
Azathioprine FBC, LFT FBC every 2 weeks for 3 months, then month. LFT monthly.
Methotrexate FBC, U&E, LFT CXR Folic acid Bloods every 2 weeks for 3 months, then monthly.
Cyclophosphamide FBC, U&E, LFT Urine dip Semen store Check all every week for 1 month, then every 2 months.

Corticosteroids and azathioprine Corticosteroids

  • First-line treatment for suppressing inflammation. At high doses, also cause immunosuppression
  • IV methylprednisolone (500–1000 mg/day) for 3–5 days can be used for aggressive induction of remission, e.g. Wegener’s granulomatosis, followed by maintenance oral steroids (prednisolone 30–40 mg/day). Usually taken in the morning as they may disturb sleep
  • Dose should be slowly reduced when control of the disease is achieved. Gastric and bone protection may be necessary as the patient will be on high doses for some months. Also ensure BP and glucose are controlled
  • Ensure patients have steroid treatment card.

Side-effects include skin and hair thinning, obesity, cataracts, diabetes, and aseptic bone necrosis. Inform patient of these and document. PCP infection can occur secondary to steroid treatment, particularly with high doses for prolonged periods. Some centres therefore use PCP prophylaxis. Steroids and osteoporosis Current guidelines suggest patients being started on long-term steroids, with one other osteoporosis risk factor (such as being over 65, or having had a previous osteoporotic fracture), should also start on a bisphosphonate. In other patients, bone mineral density should be checked via DEXA scan of hip and spine after 6 months treatment with 7.5 mg or more of prednisolone per day, and offer lifestyle advice and bisphosphonates if this is reduced. (see Royal College of Physicians guidelines, http://www.rcplondon.ac.uk) Azathioprine

  • Mainly used as a steroid-sparing agent, or when vasculitis is under control to enable cyclophosphamide to be stopped
  • Cytotoxic drug, less effective than cyclophosphamide. May be reasonable alternative if side effects of cyclophosphamide are unacceptable
  • Maximal effect on disease may not be evident for 6–9 months, but can be used long-term
  • For vasculitis, start with 2 mg per kg/day after cyclophosphamide. Maximum dose usually around 150–200 mg/day
  • Check FBC every 2 weeks for 3 months, then monthly. Check LFTs monthly. Stop treatment if WCC < 3, platelets < 100, or ALP and transaminases 3 × normal. Restart when they recover.

Side-effects include sore mouth, ulcers, nausea and vomiting, diarrhoea, skin rash, alopecia (rare). Most respond to stopping the drug and restarting at a lower dose. Interacts with allopurinol and leads to increased toxicity. P.628
Methotrexate and cyclophosphamide Methotrexate

  • Can be used as a second-line treatment
  • Dose: 7.5–20 mg once/week. Usual starting dose is 10 mg. Can increase after 6 weeks to 15 mg
  • Baseline CXR. Monitor FBC, U&E, and LFTs every 2 weeks for 3 months then monthly. Give folic acid 5 mg 3–4 days after dose.

Side-effects include mouth ulcers, skin rashes, nausea, macrocytosis, myelosuppression, pneumonitis (dyspnoea and dry cough). Avoid if significant renal or hepatic impairment, or if pleural effusions or ascites, as it can accumulate in these fluids. Stop if WCC < 3, platelets < 100, transaminases 3 × normal, pneumonitis. Cyclophosphamide

  • The primary cytotoxic drug used for treating systemic vasculitis. Used particularly if there are life- or organ-threatening features, such as requiring ventilation for lung vasculitis, systemic features, or renal involvement
  • Causes immunosuppression without anti-inflammatory effects
  • Takes 12–14 days to work; hence is combined with high-dose steroids at the beginning of treatment. When combined with steroids, it induces remission of vasculitis in 95% of patients
  • Oral cyclophosphamide is used if possible in active vasculitis, at a dose of 2 mg/kg
  • Pulsed intravenous cyclophosphamide is given if patients cannot take oral preparations, using doses of around 0.375–1 g/m2 every 2–4 weeks. The lowest white cell count occurs 10 days after a pulse. Non-randomized studies have shown that pulsed doses give a lower cumulative dose than oral regimes, are as likely to induce remissions, and cause fewer adverse effects, but have a non-significantly higher vasculitis relapse rate
  • If giving IV cyclophosphamide, patients should be well hydrated before and after, and given Mesna, which chelates with the urotoxic cyclophosphamide metabolite, acrolein. Dose varies according to the cyclophosphamide dose and is available on product literature. Give during cyclophosphamide infusion and also 4 and 8 hours after. Also prescribe anti-emetics. Dose may need reduction with renal failure
  • Haemorrhagic cystitis is a potentially serious side-effect of cyclophosphamide therapy. Perform a baseline urine dip for blood prior to treatment (although note that microscopic haematuria is common with active vasculitis). Check routinely for macroscopic haematuria in patients receiving IV cyclophosphamide and, if it is present, stop drug and arrange cystoscopy (rare if Mesna is used, and rare with oral cyclophosphamide regimes)
  • Check blood counts at least weekly for 4 weeks (FBC, U&E, LFT). Then check every 2 months and ensure results are seen. Withhold or reduce treatment if leucopenic, until bone marrow recovers
  • P.629

  • Treatment likely to last for 6 months. Longer courses are no more effective and carry the risk of side-effects from the cumulative dose. Cyclophosphamide is not recommended for more than one year as total overall dose has cumulative side-effects. Induce remission with cyclophosphamide and prednisolone and maintain remission with prednisolone and another immunosuppressant.

Side-effects include nausea, vomiting, hair thinning or alopecia, bone marrow suppression (2%), leucopenia, haemorrhagic cystitis, transitional cell carcinoma of bladder, infertility, lymphoma (0.7%), and leukaemia, pulmonary and bladder fibrosis. Risks of cystitis and bladder cancer increase with increasing cumulative dose. Treat patient with minimum dose required to maintain remission. Semen storage for men prior to starting treatment.

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