Review article| Volume 33, P22-32, August 2019

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Efficacy and tolerability of azathioprine for neuromyelitis optica spectrum disorder: A systematic review and meta-analysis


      • Azathioprine was inferior to rituximab for neuromyelitis optica spectrum disorder (NMOSD).
      • Current efficacy data for azathioprine compared to other studied drugs were very limited.
      • Azathioprine was linked to frequent adverse events which may lead to intolerance.
      • At present, azathioprine may be offered as second-line treatment option for patients with NMOSD.



      Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory and autoimmune disorder of the central nervous system that typically presents with optic neuritis and myelitis. Azathioprine (AZA) is one of the available immunotherapies with purported beneficial effects for patients with NMOSD. At present, there are no systematic reviews that extensively pooled the effects of AZA compared to other interventions for this condition. The objective of this study, therefore, is to determine the efficacy and safety of AZA in patients with NMOSD using systematic review of relevant studies.


      Major health electronic databases, which included CENTRAL, MEDLINE, EMBASE, Scopus, LILACS,, and HERDIN, were searched from May 2017 to November 2018 for relevant studies involving adult and pediatric patients with NMOSD. Randomized controlled trials, and either prospective or retrospective cohort designs that assessed the reduction or prevention of relapse or disability and the occurrence of adverse events related to AZA use compared to placebo or to other active drugs were considered. Assessment of risk of bias was performed using the Cochrane Collaboration tool and Newcastle–Ottawa Scale.


      From a total of 273 records, 9 relevant studies (1 randomized controlled trial (RCT), 3 prospective cohort studies, 5 retrospective studies) which involved a total of 977 patients, were included. One RCT and several observational studies revealed that AZA regimen may be inferior to rituximab in terms of annualized relapse rate, reduction of disability as measured by the expanded disability status scale (EDSS), risk for relapse and relapse-free rate. Efficacy data were very limited in the comparison of AZA to mycophenolate mofetil (MMF), to cyclophosphamide, and to interferon-β for patients with NMOSD. Occurrence of any adverse event, elevated liver enzymes/hepatoxicity, leukopenia and hair loss associated with AZA use were significantly greater compared to MMF, which may lead to medication noncompliance.


      AZA improves relapses and disability in patients with NMOSD but this regimen is associated with relatively frequent adverse events based on limited published evidences. More well-conducted clinical trials are necessary to establish with certainty the beneficial and harmful effects of AZA in patients with NMOSD.



      ADE (adverse drug events), AQP4-IgG (aquaporin-4-immunoglobulin G), ARR (annualized relapse rate), AZA (azathioprine), CENTRAL (Cochrane Central Register of Controlled Trials), CI (confidence interval), CYP (cyclophosphamide), EDSS (expanded disability status scale), EFNS (European Federation of Neurological Societies), EMBASE (Excerpta Medica dataBASE), F:M (female-to-male ratio), HERDIN (Health Research and Development Information Network), HRR (hazard risk for relapse), INFβ (interferon-β), IPND (International Panel for NMO Diagnosis), LILACS (Literatura Latino-Americana e do Caribe em Ciências da Saúde), MeSH (Medical Subject Headings), MMF (mycophenolate mofetil), MOOSE (Meta-analysis Of Observational Studies in Epidemiology), NMO (neuromyelitis optica), NMOSD (neuromyelitis optica spectrum disorder), NOS (Newcastle–Ottawa Scale), PCS (prospective cohort studies), PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses), RCS (retrospective cohort studies), RCT (randomized controlled trial), RFR (relapse-free rate), RR (risk ratio), RTX (rituximab), SD (standard deviation), TPMT (thiopurine methyltransferase)
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