High-dose intravenous azathioprine pulse treatment in refractory Wegener's granulomatosis.

SIR, in Wegener’s granulomatosis (WG) standard therapy with cyclophosphamide (CYC) is limited by treatment-associated shortand long-term morbidity and mortality as well as insufficient response in about 10% of all cases [1]. Several therapeutic regimes have been used for refractory disease with varied results, including monoclonal antibodies to TNF[2] and different surface markers of T-cells (CD4, CD 52) [3] and B-cells (CD20) [4]. We report two patients with WG responding insufficiently to standard therapy, TNF blockade and rituximab in succession, but treated successfully with intravenous (i.v.) azathioprine (AZA). Both participants who were treated gave their informed consent. They fulfilled the Chapel Hill Consensus Conference definition [5] and the ACR criteria [6] for WG. Diagnosis was based on a typical clinical presentation and biopsy findings, supported by the presence of cANCA/PR3-ANCA. Sufficient activity of thiopurine methyltransferase (TPMT), an inactivating enzyme in the metabolism of AZA, was determined before treatment. AZA (1200mg in 1000ml NaCl 0.9% i.v., corresponding to 17mg/kg body weight) was given over a 24-h period (50ml/h) once monthly with antiemetic prophylaxis (ondansetron). Additive AZA was given orally (100mg per day) in weeks 2 and 3 between each pulse, with regular monitoring of the white blood cell count. After completing six pulses, therapy was continued with daily AZA (100–150mg/day) orally. Patient 1, a 33-yr-old female with WG and predominantly ENT involvement, was started on CYC (1300mg every 6 weeks i.v.) and prednisolone (PRD). Because of the development of an increasing retro-orbital mass after 9 months of CYC, therapy was intensified by adding infliximab (5mg/kg body weight every 6 weeks). Continuing and wearing right-sided supraorbital pain with an increasing demand for PRD (60mg/ day) was attributed to massive progress of the retrobulbar granuloma. Thus, CYC and infliximab were stopped after 28 weeks of combined treatment and rituximab (375mg/m) was started in combination with MTX (20mg/week i.v.) instead. In addition to further progress of the retro-orbital mass, a necrotizing and destructive inflammation of the right-sided lower eyelid soon appeared (Fig. 1). The decision was made to change treatment to i.v. azathioprine pulse therapy (1.2 g). After the first two i.v. applications, less pain and better vision were reported by the patient. Strong improvement continued up to the sixth AZA pulse, and regression of endonasal and orbital disease activity and a better motility of the right eye were documented during the next 12 months (Birmingham Vasculitis Activity Score (BVAS) 1:0, BVAS 2:3). The second patient, a 43-yr-old male, was diagnosed as having WG presenting with remitting scleritis, subglottic stenosis, sensory neuropathy and a retro-orbital granuloma of the right eye with incipient visual loss. Therapy with CYC (150mg/day orally) and PRD was initiated. After continuous treatment for 6 months the progressive retrobulbar granulomatous lesion continued to threaten his vision. Standard therapy was intensified by adding infliximab (5mg/kg every 6 weeks). After 12 months of combined therapy, lesions of the right eye had led to a wearing orbital pain and almost extinct visual capacity. In addition, a smaller granuloma of the left eye developed under intensified treatment. Treatment was stopped and local corticosteroid retrobulbar injections were given in the right eye. Rituximab infusions (375mg/m) were started at monthly intervals; CYC was continued and PRD doses remained high (25mg/day). The inflammatory process and the orbital granulomas remained unchanged after four consecutive rituximab applications. Facing progressive visual loss even of the left eye, therapy was switched to i.v. AZA pulse therapy. Changes were noted after two infusions, and during further treatment the retrobulbar pain disappeared totally, progression of the orbital masses stopped and repeated MRIs showed regression and scarring of the granulomas (BVAS 1:0, BVAS 2:0). We report the successful induction of remission by i.v. AZA pulse therapy in two patients with refractory WG during standard treatment. Intravenous AZA was used initially in inflammatory bowel disease as a loading dose to decrease the time to response and was later proved to be safe and of clinical benefit in a pilot study in patients with ulcerative colitis [7, 8]. AZA is a purine analogue and its postulated mechanism of action is apparently at the level of DNA [9]. As demonstrated recently, AZA and its metabolites play a unique role in the control of T-cell apoptosis by the modulation of Rac1 activation upon CD28 costimulation [10]. Binding of AZA metabolites to the small GTP-binding Rac1 leads to decreased activation of Rac1 target genes, such as NFB and bcl-XL, leading to a mitochondrial pathway of apoptosis.