Side Effects of Immunosuppressants

AZA and 6-MP inhibits the proliferation of T and B lymphocytes, thereby reducing cytotoxic T cells and plasma cells. During AZA or 6MP, 6-thioguanine nucleotides accumulate slowly in tissues, probably accounting for the protracted action of these drugs upon their suspension. This intracellular accumulation of 6-thioguanine nucleotides is responsible for the cytotoxic effects of these drugs by the inhibition of purine synthesis, nucleotide interconversions, DNA and RNA synthesis and chromosomal replication. Measurements of erythrocyte 6-thioguanine may be helpful in optimising the dose of AZA/6-MP for a clinical response without myelosuppressive effects.

In has been suggested that leukaemic patients deficient in TPMT are at increased risk of myelotox-icity [39], but this does not necessarily apply to IBD. In one study, 31 of 41 IBD patients with AZA-induced myelosuppression did not carry a TPMT mutation. Evidence that TPMT activity predicts other side effects or outcome is limited, and so far, it cannot be recommended as a prerequisite to therapy [40].

AZA should be introduced at a low dose, 0.5-1.5 mg/kg daily, and increased gradually within 2 weeks to 2.5 mg/kg daily. Blood monitoring (haematology and liver function tests) should be performed weekly until the maintenance dose is reached, and monthly thereafter. The equivalent dose of 6-MP is initially 0.25-0.5 mg/kg daily, increasing to 1.0-1.5 mg/kg daily. If white blood cells decrease below 3 000/mm3 or platelets below 120 000/mm3, the drug should be discontinued or the dose reduced until these parameters normalise. Furthermore, if liver biochemistry (and/or serum amylase) exceeds more than 50% of the upper normal limit, AZA/6MP should be discontinued, and then cautiously reintro-duced.

Both AZA and 6-MP are considered slow-acting drugs, with an effect expected after 12-17 weeks. A recent study suggests that AZA works faster than previously believed, showing effects after 4 weeks [41]. In any case, for their slow onset of action, these drugs have no place as a monotherapy in acute relapses of UC. Allopurinol blocks the metabolism of 6-MP by the inhibition of xanthine-oxidase, so that patients on allopurinol should receive half doses of AZA/6-MP.

Side-effects of immunosuppressants can be categorised as (1) bone-marrow suppression, 2) short-term effects and 3) long-term effects. The side-effects occur in about 10-15% of patients with IBD and are either dose-dependent (bone marrow suppression) or idiosyncrasic (pancreatitis, allergic reactions or hepatitis).

Severe leukopenia, although rare (around 3%), may develop suddenly and unpredictably in between blood tests, even during long-term treatment. Side effects detected with short-term use often occur with in the first week of treatment and include pancreatitis (3.3% of patients), allergic reactions including rash, idiosyncratic hepatitis with cytonecrosis, cholestasis or insidious onset of liver dysfunction (3.3%) and infections (7.4%). Pancreatitis resolves upon drug withdrawal but recurs on retreatment, which precludes the use of either AZA or 6MP.

Some 5-10% of patients stop treatment on their own mainly during the first month. Nausea, vomiting and malaise are the most common problems especially if the dose is increased too fast. Infections are the theoretical risk of the long-term use of these agents, but their incidence is not higher than with high-dose prednisolone.

In patients on long-term immunosuppressants one may expect an increase incidence of neoplastic diseases. Actually, a prospective study of 1 349 non-transplant patients receiving AZA, including 280 patients with IBD, showed a significant increase in non-Hodgkin's lymphoma, squamous cell carcinoma and other tumours (overall risk increased by a factor of 1.6) [42]. In contrast, reports from St Mark's Hospital (755 patients) and Oxford (2 205 patients) showed a risk of neoplasia comparable with the general population, but after a treatment of only 1 year [43, 44].

A recent meta-analysis found a fourfold increase risk of lymphoma in IBD patients on azathioprine/6-MP possibly as a result of the drugs, the severity of the disease, or a combination of the two [45]. In any case, decision analysis suggests that in IBD, the benefits of AZA outweigh the risk of lymphoma [46, 47].

The main mistake in the use of anti-metabolites is probably undertreatment [29]. Three forms of undertreatment are still rampant. The first is waiting too long to introduce these agents. One relapse noted during or soon after an attempted steroid withdrawal is an indication for the introduction of anti-metabolites. Likewise, neither cyclosporine nor infliximab should be used without a previous introduction of anti-metabolites in the expectation that they will be needed over the long-term.

The second mistake is underdosing. The habit of administering 6-MP or azathioprine at a fixed dosage of 50 mg/day should have long been abandoned. A reasonable starting dose of 6-MP is 1.5 mg/kg/day and of azathioprine 2.5-3 mg/kg/day. Even more important, is not giving up with these drugs until being sure that they have been administered at the maximal doses. By definition, the dose has been pushed up enough either when success is achieved or when mild leukopenia has occurred (WBC in the 3 000-4 000/mm3 range). If there is uncertainty about efficacy, adsorption, or adherence, additional information can be gained by looking for a substantial increase in MCV or by measuring drug metabolites.

The last mistake is an early suspension of the drug. No "safe" number of years has been established after which these medications can be withdrawn without the risk of relapse. Moreover, it is of critical importance not to suspend 6-MP or azathioprine during pregnancy. Safety in pregnancy has been unequivocally established via published experience [48]. Indeed, the risk to pregnancy is infinitely greater from relapse of disease than from adverse effect of treatment.

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