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We read with interest the recent article by Lennard on the role of thiopurine methyltransferase (TPMT) enzyme in predicting azathioprine related toxicity in patients with inflammatory bowel disease (IBD) (Gut 2002;51:143–6). He concludes that measurement of TPMT activity has no specific role in identifying the risk of significant bone marrow toxicity in long term users of azathioprine. This conclusion is in agreement with other published work and emphasises the importance of ongoing haematological monitoring in IBD patients receiving this drug.1 The importance of haematological monitoring in the early detection and prevention of azathioprine related toxicity is well recognised.2 However, the duration of early monitoring is a matter of controversy. The current British National Formulary guidelines recommend that patients undergo blood tests on at least a weekly basis for the initial four weeks of therapy. The drug’s manufacturers recommend a more stringent monitoring policy and in their view, initial monitoring should continue for the first eight weeks of treatment. The American College of Gastroenterology guidelines recommend a slightly different approach, with fortnightly blood counts for the initial three months of therapy.3 The key issue in determining the value of these different approaches to monitoring is the time of onset of potentially life threatening bone marrow suppression following initiation of azathioprine treatment. These data are not available for patients with IBD.
In a retrospective study, we analysed the time of onset of all drug related toxicity in IBD patients post initiation of azathioprine therapy. A total of 110 consecutive IBD patients with a history of azathioprine use were identified (table 1). Patients were identified from the hospital inpatient enquiry system, IBD clinic, and pharmacy records. Mean azathioprine dose was 2 mg/kg/day (range 1–3). Mean age of the patients on azathioprine was 38.11 years (18–76). Seventeen of 110 patients (15%) suffered from azathioprine related early toxicity (table 1). Mean azathioprine dose in those showing drug toxicity was 100 mg/day (50–150). Most (77%) drug related toxic events manifested within the first 12 weeks of therapy (fig 1). However, the mean time of onset of drug related toxicity depended on the side effect observed. For example, most drug related nausea was observed within two weeks of commencing treatment while all cases of deranged liver function tests were detected within eight weeks of treatment onset. Significantly, this was not true for bone marrow suppression. The mean duration of treatment in the two patients who experienced this side effect was 11 weeks (range 10–12). Both cases occurred outside the “stringent” eight week monitoring period recommended by the drug’s manufacturer. Hence identification of bone marrow suppression would have been delayed using the current British and manufacturer’s guidelines. Three further episodes of neutropenia were identified during long term (>3 months) treatment in three patients who continued on maintenance azathioprine (mean duration 101 weeks/patient, range 2 weeks to 5 years). In our practice, we feel that significant toxicity during the early (<3 months) period of therapy could have been missed by strictly following existing guidelines.
Early detection of abnormalities in asymptomatic patients helped in dose adjustment with resolution of side effects. In addition, early detection of azathioprine related bone marrow suppression is likely to save lives. We recommend that gastroenterologists employ an extended (three month) period of intensive haematological monitoring after initiation of azathioprine therapy in IBD. Although neutropenia is occasionally observed beyond this point, intensive monitoring for the duration of treatment, which may continue for years, is clearly not practical from a patient or service perspective. However, this serves to emphasise the importance of continuous patient education concerning “alarm symptoms” throughout the duration of azathioprine therapy.
Measurement of thiopurine methyltransferase (TPMT) status, prior to the start of azathioprine therapy, has a role in identifying the TPMT deficient patient at risk of severe myelosuppression and TPMT heterozygous individuals who are prone to early myelosuppression.1,2 The risk of azathioprine toxicity is well recognised but, as the authors state, the duration of early monitoring is a matter of controversy. The matter for debate is the time of onset of potentially life threatening myelosuppression. Quasim et al state that this information is not available for patients with inflammatory bowel disease (IBD). However, data can be derived from observations in other patients groups which may serve as useful guidelines for this time interval.
Reports of azathioprine induced severe myelosuppression in the TPMT deficient patient indicate that bone marrow toxicity is recorded after 3–10 weeks (median 4) of azathioprine therapy.1,3,4 In these reports the drug dosage varied from 1 to 2.9 mg/kg (median 1.7). One patient taking azathioprine at a dosage of 1 mg/kg developed myelosuppression (white blood cell count (WBC) 1.6×109/l, platelets 25×109/l) at 10 weeks1 while another dosed at 1 mg/kg developed myelosuppression (WBC 3.8×109/l, platelets 80×109/l) by seven weeks.4 For the patient with an intermediate TPMT activity (heterozygotes with one variant and one wild-type allele), Black and colleagues2 reported leucopenia (leucocyte counts 0.9–2.9×109/l) within one month of starting azathioprine (2–3 mg/kg) as second line therapy for rheumatic disease.
Specifically for the patient with Crohn’s disease, Colombel and colleagues5 have reported that TPMT deficient individuals experience leucopenia or thrombocytopenia within 1.5 months of azathioprine therapy (100–150 mg/day) and that TPMT heterozygotes developed toxicity after 1–18 months (median 4) of therapy. Similar observations have been made by Schwab and colleagues6 who reported myelosuppression in a TPMT deficient Crohn’s patient after 1.75 months of azathioprine at 1.5 mg/kg and in two TPMT heterozygous patients after 2.5 and 3 months of therapy at dosages of 1.0 and 1.5 mg/kg, respectively. The additional observation that those individuals with wild-type alleles (“normal” TPMT activity) can experience myelosuppression after weeks or years of azathioprine therapy5,6 illustrates the multifactorial nature of myelosuppression in this patient group and supports the need for continued vigilance with respect to blood count monitoring. The drug manufacturer’s guidelines, as stated in the Association of the British Pharmaceutical Industry (ABPI) medicines compendium,7 advise that at a minimum, complete blood counts should be monitored weekly during the first eight weeks of therapy. The guidelines then continue, “this frequency may be reduced during later therapy to monthly intervals, or at least at intervals no longer than three months”.
The data presented in the reports above indicate, particularly for the patient on low dose azathioprine in whom TPMT status is unknown, close adherence to the ABPI guidelines and continuation of, at a minimum, weekly full blood counts during the first three months of treatment. Because severe bone marrow toxicity can be precipitated by the addition of aminosalicylate derivatives8 to the azathioprine regimen, the drug manufacturer’s more stringent blood count monitoring scheme should be considered following such adjustments in the combination therapy of refractory IBD.