Immunosuppressive drugs
- DOI:
- 10.1093/med/9780198703860.003.0054
Immunosuppressive drugs are used mainly in the management of pulmonary vasculitis, but also in asthma, sarcoidosis, and ILD. Centres differ in their use of these drugs, and local guidelines are often available. A summary of tests to perform before and during immunosuppressive drug treatment is shown in Table 54.1.
Table 54.1 Summary of tests to perform before and during immunosuppressive drug treatment of respiratory disease
Drug |
Check before starting |
Follow-up |
|---|---|---|
Corticosteroids |
|
BP, glucose if symptoms of diabetes |
Azathioprine |
FBC, LFT, TPMT test (see text) |
FBC every 2 weeks for 3 months, then monthly LFT monthly |
Methotrexate |
|
Bloods every 2 weeks for 3 months, then monthly |
Cyclophosphamide |
|
Check all every week for 1 month, then every 2 months |
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 and atypical pathogens
• Avoid live vaccines such as measles, mumps, rubella, BCG, yellow fever, oral typhoid, oral polio
• If never had varicella-zoster:
• Avoid contacts with chickenpox or shingles
• Consider passive immunization
• Immunoglobulin therapy if exposed
• Hospital treatment, with close monitoring, if develop chickenpox
• Avoid measles exposure. Prophylaxis with immunoglobulins if exposed.
Corticosteroids and azathioprine
Corticosteroids
• First-line treatment for suppressing inflammation. At high doses, also cause immunosuppression. Ineffective as sole therapy for induction of remission in systemic vasculitis
• IV methylprednisolone (500–1, 000mg/day) for 3–5 days can be used for aggressive induction of remission, e.g. GPA, followed by maintenance oral steroids (prednisolone 30–40mg/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.
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 who will be on 7.5mg/day or more for >3 months, consider checking bone mineral density via DEXA scan of hip and spine, and offer lifestyle advice and bisphosphonates if this is reduced (T score –1.5 or lower).
(See Royal College of Physicians guidelines, available at 
http://www.rcplondon.ac.uk, and National Osteoporosis Society at http:www.nos.org.uk.)
Azathioprine
• Mainly used as a steroid-sparing agent or when vasculitis is under control to enable cyclophosphamide to be stopped. Is a pro-drug for 6-mercaptopurine. Takes ~4 weeks to work
• 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
• TPMT testing should be performed prior to commencement. TPMT breaks down azathioprine to an inactive product. 90% of the population have normal TPMT levels and 10% have intermediate activity, so azathioprine should be given with caution; 0.3% have no TPMT activity, and azathioprine should be avoided
• For vasculitis, start with 2mg/kg/day after cyclophosphamide. Maximum dose usually around 150–200mg/day
• As steroid-sparing regime: could start 50mg od for 2 weeks, increasing to 100mg od for 2 weeks if FBC satisfactory, and increasing to 150mg od (or 75mg bd) after further 2 weeks if FBC satisfactory. Reduce prednisolone by 5mg every 4 weeks
• Check FBC every 2 weeks for 6 weeks, then at 2 and 4 weeks after each dose increase, and thereafter 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. If taken for a number of years, then increased risk of some types of cancers, including skin. Advised to contact doctor if any concerns about new skin problems. Interacts with allopurinol and leads to increased toxicity.
Methotrexate and cyclophosphamide
Methotrexate
• Can be used as a second-line treatment
• Dose: 7.5–25mg once/week. Usual starting dose is 10mg. Can increase after 6 weeks to 15mg, in increments of 2.5mg weekly
• Baseline CXR. Monitor FBC, U&E, and LFTs every 2 weeks for 3 months, then monthly. Give folic acid 5mg 3–4 days after dose to reduce toxicity.
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 1° cytotoxic drug used for treating systemic vasculitis
• Causes immunosuppression without anti-inflammatory effects
• Used particularly if there are life- or organ-threatening features, e.g. ventilation for lung vasculitis, systemic features, renal involvement
• 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 90% of patients
• Perform a baseline urine dip for blood prior to treatment (although note 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)
• PCP prophylaxis with co-trimoxazole is recommended (960mg 3×/week) in patients receiving cyclophosphamide and prednisolone
• Semen storage for men prior to starting treatment.
Usual treatment duration of cyclophosphamide is 3–6 months. Courses longer than 6 months should generally be avoided; they are no more effective and carry the risk of side effects from the cumulative dose. Induce remission with cyclophosphamide and prednisolone, and maintain remission with prednisolone and another immunosuppressant (azathioprine or methotrexate) for at least 2y.
Side effects
Haemorrhagic cystitis is a potentially serious side effect of cyclophosphamide therapy. Risk of bladder cancer is increased (and is greater with increasing cumulative dose), and indefinite monitoring of urinalysis 3–6-monthly after treatment with cyclophosphamide is recommended. Other side effects include nausea, vomiting, infection (including PCP), hair thinning or alopecia (reversible), bone marrow suppression (2%), leucopenia, infertility, lymphoma (0.7%) and leukaemia, pulmonary and bladder fibrosis. Risk of cervical cancer may be higher—recommend annual cervical smear for 3y and thereafter, as per population screening programme. Should not be taken in pregnancy or if breastfeeding. Men and women should avoid starting a family during, and for 6 months following, treatment with cyclophosphamide.
Oral cyclophosphamide
is used, if possible, in active vasculitis at a dose of 2mg/kg (up to 200mg/day). Reduce dose in elderly (by 25% if >60y and by 50% if >75y) and in setting of renal impairment.
Monitoring
Check FBC and renal function weekly for the first month, 2-weekly for 2nd and 3rd months, and monthly thereafter.
• If WCC <4 × 109/L, neutrophils <2 × 109/L, stop oral cyclophosphamide, and restart with dose reduced by at least 25mg when WCC recovered, and then monitor weekly for 4 weeks
• If prolonged (WCC <4 × 109/L, neutrophils <2 × 109/L for >2 weeks) or severe (WCC <1 × 109/L, neutrophils <0.5 × 109/L) leucopenia/neutropenia, stop cyclophosphamide, and restart at 50mg daily when WCC recovered; then increase to target dose weekly, WCC permitting
• If WCC is falling (<6 × 109/L and fall of >2 × 109/L since previous count), reduce dose by 25%.
Pulsed IV cyclophosphamide
is given if patients cannot take oral preparations, using doses of 15mg/kg (reduced for age and renal function, maximum dose 1, 500mg) every 2 weeks for the first three pulses, and then at 3-weekly intervals. The lowest WCC occurs 10 days after a pulse. A randomized study has shown that pulsed doses give a lower cumulative dose than oral regimes, but there is no difference in remission rates between the two. The infection rate is higher with oral regimes (European Vasculitis Study Group).
If giving IV cyclophosphamide, patients should be well hydrated before (1L normal saline) and after (3L/day oral fluids for 3 days) 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 8h after. Prescribe anti-emetics.
Monitoring
Check FBC and renal function on day of pulse or previous day.
• If WCC <4 × 109/L, neutrophils <2 × 109/L, postpone pulse until WCC >4 × 109/L, neutrophils >2 × 109/L, whilst checking FBC weekly, and reduce dose by 25%
• After first pulse, check FBC between days 10 and day of next pulse: reduce dose of next pulse by 40% of previous dose if WCC nadir 1–2 × 109/L or neutrophil nadir 0.5–1.0 × 109/L
• Reduce dose of next pulse by 20% of previous dose if WCC nadir 2–3 × 109/L or neutrophil nadir 1–1.5 × 109/L
• Thereafter, check FBC on day of pulse or previous day, unless dose adjustment when checked additionally at day 10.
