Klinik und Poliklinik für Innere Medizin I der Universität Regensburg,
1 Rheumazentrum Baden-Baden and
2 Abteilung für klinische Chemie, Universitätsklinikum Göttingen, Germany
SIR, Azathioprine has been used as a disease-modifying drug in rheumatology for several years. A disadvantage of its application is the delayed onset of the therapeutic response. Intravenous azathioprine has been found to be effective as induction therapy for Crohn's disease. In a pilot study [1], twelve patients with Crohn's disease were treated with an i.v. loading dose. Healing of fistulae and improvement of inflammatory disease was seen after 4 weeks of treatment in the majority of patients.
On the basis of this experience, we designed a study with the primary aim of evaluating the safety of an i.v. loading dose of azathioprine followed by maintenance oral azathioprine in patients with different inflammatory rheumatic diseases. This was an open-label, single-centre study involving 11 adult patients (eight women, three men) with different rheumatic diseases [three with myositis, three with systemic sclerosis, three with systemic lupus erythematosus (SLE) and two with rheumatoid arthritis (RA)]. All patients suffered from active disease requiring immunosuppressive treatment. The study protocol was approved by the local ethics committee. All patients gave written informed consent. Before the initiation of treatment, the activity of thiopurinemethyltransferase (TPMT), an inactivating enzyme in the metabolism of azathioprine, was determined. TPMT activities of all patients included in the trial were in a range (9.220.7 nmol/ml red blood cellsxhour) considered to be safe for azathioprine treatment [2].
As suggested by Sandborn et al. [1] for the therapy of Crohn's disease, we treated our patients with a loading dose of 1800 mg azathioprine as a continuous infusion over 36 h (50 mg/h). Given the incomplete oral bioavailability of azathioprine (4150%) [1], 1800 mg of i.v. azathioprine would correspond to an oral dose of 36004390 mg of the drug. The dose and the duration of the infusion were as defined by Sandborn et al. following phase I and II studies using an investigational 6-mercaptopurine preparation in patients with solid tumours, assuming a body surface area of 1.73 m2 for the average adult [1, 3]. Patients were hospitalized for 36 h of i.v. treatment and a treatment-free interval of 36 h for additional safety. Subsequently, oral azathioprine was administered in a dose of 11.5 mg/kg body weight per day. After 4 weeks of azathioprine treatment, the daily dose was increased to 22.5 mg/kg body weight if treatment was well tolerated and no adverse events occurred. On day 0 and 24, 36, 48 and 72 h after the initiation of treatment, measurements of the concentration of 6-TGN (thioguanine nucleotides) (the effective azathioprine metabolite) in erythrocytes, serum amylase and serum lipase concentrations were determined and liver function tests and blood counts were performed. Erythrocyte 6-TGN concentration, blood count, white blood cell count, creatinine and C-reactive protein were determined and liver function tests and urinalysis were performed 1, 2, 4, 6 and 8 weeks after the beginning of treatment. To assess treatment outcome and adverse events, patients were interviewed and physical examinations were performed at the time of inclusion in the trial, before discharge from the hospital and during follow-up visits.
In two of three patients with dermatomyositis, the combination of prednisolone and azathioprine led to a decrease in serum levels of muscle enzymes, leukocytes and inflammatory proteins. Clinical examination showed an improvement in myalgias, muscle weakness and cutaneous manifestations. In all patients with systemic sclerosis we observed a rapid improvement of digital ulcers. In two of three patients with SLE, serum anti-double-stranded-DNA antibody levels decreased slightly after the initiation of treatment with azathioprine. No convincing clinical improvement was seen during the short follow-up period. One patient with RA and detectable anti-nuclear antibodies showed a reduction of joint inflammation during follow-up.
Adverse events following i.v. azathioprine treatment were rare. In two patients we found transient leukopenia as low as 2.1 leukocytes/nl. One of these patients had a history of lymphopenia in the context of SLE with autoimmune haemolytic anaemia and thrombocytopenia. The other patient suffering from dermatomyositis presented with a disease-related leukopenia of 3.4 leukocytes/nl. In both patients the leukocyte count decreased temporarily after the initiation of treatment. One patient with SSc suffered from cephalalgias during the time of azathioprine infusion. Severe adverse events leading to discontinuation of the treatment were not seen in our patients.
In agreement with Matteson et al. [4], who used the same protocol for the treatment of patients with refractory, active RA, i.v. azathioprine was well tolerated in our group of patients. Unlike Matteson et al., we saw clinical or serological improvement in the majority of patients. Peak erythrocyte 6-TGN levels of the two patients not responding to therapy were below the median of the whole group. In order to demonstrate a superior and faster clinical effect of parenteral compared with oral initiation of azathioprine treatment in patients with rheumatic diseases, further studies with a more homogeneous group of patients and azathioprine dosages individualized according to erythrocyte 6-TGN concentration should be performed. The promising results of the pilot study on patients with Crohn's disease [1] disease have been refuted by a larger, placebo-controlled trial in which a loading dose of azathioprine did not decrease the time to response in patients with Crohn's disease [5].
Notes
Correspondence to: A. Pickenpack, Klinik und Poliklinik für Innere Medizin I, Klinikum der Universität Regensburg, 93042 Regensburg, Germany.
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