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Rheumatology 2001; 40: 831-832
© 2001 British Society for Rheumatology
Letters to the Editor |
Azathioprine toxicity mimicking a relapse of Wegener's granulomatosis
Department of Rheumatology, University of Lübeck and Rheumaklinik Bad Bramstedt, Germany
SIR, We report a patient with severe generalized Wegener's granulomatosis (WG) including crescentic glomerulonephritis (GN) at diagnosis, in whom maintenance of remission therapy with azathioprine resulted in acute deterioration of renal function combined with high fever, constitutional symptoms, rheumatic complaints and an increase in inflammatory parameters mimicking a relapse of WG. We report this case to heighten awareness that symptoms reminiscent of a vasculitis relapse can be caused by azathioprine toxicity.
The diagnosis of WG was established in December 1996 in a 63-yr-old man with GN (serum creatinine up to 3.5 mg/dl) and focal necrotizing GN without immunodeposits in biopsy but with involvement of the upper and lower respiratory tracts, skin and peripheral nervous system, and rheumatic complaints. Indirect immunofluorescence showed a cANCA (antineutrophil cytoplasmic antibodies with cytoplasmic labelling pattern) titre of 1:256 (ELISA for proteinase-3, 129 U/ml; normally <20 U/ml). Treatment to induce remission was started with daily cyclophosphamide (CYC) 2 mg/kg combined with prednisone 1 mg/kg. Extended interdisciplinary staging in January 1998 showed no clinical, imaging or serological signs of WG activity [1]. Serum creatinine was stable at 1.5 mg/dl (creatinine clearance 68 ml/min) without any abnormalities in urine sediment. The cANCA titre was 1:128, the level of soluble interleukin 2 receptor 540 U/ml (normally <420) [2]. Maintenance of remission therapy with azathioprine 150 mg/day (1.5 mg/kg/day) plus 2 mg prednisone/day was initiated. Ten days later the patient complained of fever (39.7°C) without clinical signs of infection, headache, myalgia or arthralgia. He was admitted to another hospital because of an acute increase in serum creatinine to 5.2 mg/dl. The following laboratory parameters were increased: erythrocyte sedimentation rate 130 mm/h, white blood cell count 12000/µl, aspartate transaminase 25 U/l, alanine transaminase 24 U/l, gamma glutamyltransferase 158 U/l, C-reactive protein 12.9 mg/dl. The urine showed leucocyturia but no erythrocyturia or proteinuria. There were no signs of WG activity in other organ systems. Multiple urinary and blood cultures were sterile. The cANCA titre was stable at 1:128. Assuming that a renal relapse of WG had occurred, CYC (100 mg/day) and prednisone (100 mg/day) were restarted, combined with three haemofiltrations. Over the next 2 weeks the serum creatinine returned to its former level of 1.6 mg/dl, all inflammatory parameters returned to their original values and the patient felt well. The cANCA titre remained unchanged (1:128). He received CYC until October 1998 and a reduced prednisone dose of 3 mg/day between February and October 98 without any signs of active WG. We then switched the patient to azathioprine again (150 mg/day). Within a few hours fever rose to 39.8°C, accompanied by malaise, arthralgia and myalgia. The inflammatory parameters increased. The serum creatinine climbed to 3.0 mg/dl and the cANCA titre was low (1:64). Urinalysis revealed leucocyturia but no erythrocyturia or proteinuria. A kidney biopsy showed no signs of GN, but did disclose extensive interstitial oedema with interstitial infiltration by polymorphonuclear cells. After cessation of azathioprine and without further therapy, the serum creatinine returned to 1.6 mg/dl and all other parameters returned to normal. The diagnosis of azathioprine toxicity due to interstitial nephritis was established. Maintenance of remission therapy was continued with methotrexate 7.5 mg/week. The patient was still in complete remission at the last evaluation in October 2000.
Azathioprine is frequently used in the treatment of autoimmune diseases, especially to maintain remission of vasculitis previously induced by CYC; this treatment was recently used in a large multicentre controlled study initiated by the European Vasculitis Study Group [3]. Toxic effects of azathioprine include myelosuppression and hepatotoxicity, both conditions apparently related to mutations in thiopurine methyltransferase [4]. Azathioprine-induced hypersensitivity includes fever, leucocytosis, pancreatitis, hepatitis, hypotension and shock [5–9]. Acute interstitial nephritis with renal insufficiency is rare [5–9]. As in our case, most reported cases have had reduced renal function at the start of azathioprine therapy [5–7, 9]. Case reports that include renal biopsies describe a predominantly polymorphonuclear interstitial infiltrate [5], similar to our case. The first reaction develops within 1 week to a few months and rechallenge leads to an acute response, usually within a few hours [5–9]. The response to rechallenge can be very severe and potentially life-threatening. This temporal course and the clinical features resembling those of a type-III hypersensitivity reaction favour an allergic reaction rather than a direct toxic effect to azathioprine.
In conclusion, this case highlights the potential of misdiagnosing symptoms of azathioprine toxicity in the management of vasculitis patients. Patients with residual impaired renal function may be at higher risk of developing this side-effect than patients with normal renal function. In the present case, diagnosis of azathioprine toxicity was based on the absence of elevated surrogate markers [2, 10] of WG activity, the lack of activity in other organ systems, the rapid increase in creatinine without nephritic sediment and, most importantly, on the demonstration of interstitial nephritis in kidney biopsy. For patients with impaired renal function, a small open study has been suggested to test the possibility that leflunomide may be effective as an alternative to azathioprine for the maintenance of remission for vasculitis [11].
Notes
Correspondence to: E. Reinhold-Keller, Poliklinik für Rheumatologie der Universität zu Lübeck, Rheumaklinik Bad Bramstedt GmbH, Oskar Alexander Strasse 26, D-24576 Bad Bramstedt, Germany. 
References
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