Since 1974, azathioprine (AZA) has been approved for use as a disease-modifying antirheumatic drug (DMARD) in rheumatoid arthritis (RA). Intravenous (IV) AZA has been found to be effective as induction therapy for Crohn’s disease, an inflammatory bowel condition (1). Based on this experience, we designed a study with the primary aim of evaluating the safety and utility of a single IV loading dose of AZA, followed by maintenance oral AZA, in patients with active, refractory RA.

This was an open-label, single-center study involving 10 adult patients with treatment-resistant RA (1 man, 9 women; mean age 47.6 years). All were in functional class I, II, or III as defined by the American College of Rheumatology (ACR)(2). Patients had active disease at the time of enrollment, as evidenced by 9 joints that were painful or tender on motion, 6 swollen joints, morning stiffness of 45 minutes, and an elevated C-reactive protein level. The protocol was reviewed and approved by the Institutional Review Board, and informed consent was obtained from all patients before screening and treatment. Two patients who were homologous low for thiopurine methyltransferase activity were excluded from enrollment because of prior reports of severe neutropenia in such patients following AZA treatment (3). A total of 1,800 mg (22.5–36.0 mg/kg body weight) of IV AZA was administered as a constant-rate infusion. A 1,800-mg loading dose of IV AZA would be comparable with an oral AZA loading dose of at least 3,600–4,390 mg, given an oral bioavailability of 41–50%(1). Following the single-dose IV administration, oral AZA was given to patients beginning at 50 mg/day; after 4 weeks, the dosage was increased to as much as 150 mg/day (range 1.7–2.5 mg/kg/day). Followup visits with clinical assessments occurred at weeks 2, 4, 8, 16, and 24. Total red blood cell 6-thioguanine nucleotide (RBC 6-TGN) concentrations were measured based on the conversion of 6-TGN to the free 6-thioguanine base (4). Treatment failure was recorded if another DMARD had to be substituted or added, or prednisone or equivalent at a dosage of 10 mg/day had to be administered, during the followup period. The ACR core set of disease activity measures for at least 20% improvement (5) was used to assess clinical response. Success of the treatment was defined at the outset as clinical improvement, by the ACR 20% criteria, in at least 7 of the 10 patients who received IV AZA, without subsequent disease relapse by week 24 when compared with baseline.