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Azathioprine is often used to prevent relapses in patients with neuromyelitis optica (NMO), but data on its efficacy are limited. These researchers retrospectively examined open-label azathioprine use in 99 patients with NMO. Treating clinicians optimized azathioprine dose by testing for thiopurine methyltransferase (TPMT) genetic variation (which affects drug metabolism), by prescribing concurrent high-dose corticosteroids for the initial 6 months and low-dose corticosteroids for breakthrough disease activity, and by considering body weight and hematologic parameters. Median follow-up was 22 months (range, 12–180).
Annualized relapse rates (ARRs) were assessed in 70 patients with at least 12 months of follow-up. ARR decreased significantly from 2.18 before treatment, to 0.52 in those treated with ≥2.0 mg/kg/day and 0.82 in those treated with <2.0 mg/kg/day; the difference between these treatment groups was significant. About one third of patients were free of relapses on treatment. In 52 patients, concomitant prednisone was prescribed (median starting dose, 60 mg, tapered over a median of 12 months). Among all patients, ARR declined from 0.51 in the first year to 0.27 subsequently. An increase of >5 points in mean corpuscular volume (MCV) was associated with a decline in ARR during treatment. The median Expanded Disability Status Scale score was 3.5 both before and after treatment. Azathioprine was discontinued in 38 patients: 22 because of adverse effects, 13 because of inadequate efficacy, and 3 after developing lymphoma.
Costanzi C et al. Azathioprine: Tolerability, efficacy, and predictors of benefit in neuromyelitis optica. Neurology 2011 Aug 16; 77:659.
Comment
Although this trial of azathioprine use in NMO was not randomized or controlled, the authors raise several issues that are critical to optimizing this therapy. Azathioprine remains a reasonable treatment option for NMO because of its low cost and because several retrospective studies suggest efficacy. Disadvantages include a delay in effect necessitating at least several months of prednisone, the need for detailed monitoring, gastrointestinal intolerability for some, and an uncommon association with lymphoma (3% in this series).
Titration to biologic effect is important. The authors advocate a weight-based dose of 2.5 to 3.0 mg/kg/day after determining TPMT status, and then monitoring MCV. Other clinicians titrate to white cell count ≥3000 per mm3, or lymphocyte count ≥1000 per mm3.
Oral immunosuppressive agents (azathioprine and mycophenolate mofetil) can be used particularly in patients without frequent relapses and with ≥6 months of concomitant prednisone. For those with rapid and severe relapses, rituximab provides a more rapid therapeutic effect. For aggressive NMO, rituximab might be useful initially to gain disease control before instituting azathioprine or another purine inhibitor.