Highlights
- •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.
Abstract
Background
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.
Methods
Major health electronic databases, which included CENTRAL, MEDLINE, EMBASE, Scopus, LILACS, ClinicalTrials.gov, 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.
Results
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.
Conclusion
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.
Keywords
Abbreviations:
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)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Multiple Sclerosis and Related DisordersAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- The efficacy and tolerability of mycophenolate mofetil in treating neuromyelitis optica and neuromyelitis optica spectrum disorder in Western China.Clin. Neuropharmacol. 2016; 39: 81-87https://doi.org/10.1097/WNF.0000000000000131
- Azathioprine: tolerability, efficacy, and predictors of benefit in neuromyelitis optica.Neurology. 2011; 77: 659-666https://doi.org/10.1212/WNL.0b013e31822a2780
- Pre-post effect sizes should be avoided in meta-analyses.Epidemiol. Psychiatr. Sci. 2017; 26: 364-368https://doi.org/10.1017/S2045796016000809
- Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data.Ann. Rheum. Dis. 2006; 65: 285-293https://doi.org/10.1136/ard.2005.038638
- Efficacy and safety of rituximab therapy in neuromyelitis optica spectrum disorders: a systematic review and meta-analysis.JAMA Neurol. 2016; 73: 1342-1348https://doi.org/10.1001/jamaneurol.2016.1637
- Long-term efficacy, tolerability and retention rate of azathioprine in 103 aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder patients: a multicentre retrospective observational study from the UK.Mult. Scler. J. 2014; 20: 1533-1540https://doi.org/10.1177/1352458514525870
- Thiopurine S-methyltransferase (TPMT) assessment prior to starting thiopurine drug treatment; a pharmacogenomic test whose time has come.J. Clin. Pathol. 2010; 63: 288-295https://doi.org/10.1136/jcp.2009.069252
Higgins J, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. Version 5; 2011.
- Adverse events of low- to medium-dose oral glucocorticoids in inflammatory diseases: a meta-analysis.Ann. Rheum. Dis. 2009; 68: 1833-1838https://doi.org/10.1136/ard.2008.100008
- Comparative analysis of treatment outcomes in patients with neuromyelitis optica spectrum disorder using multifaceted endpoints.Mult. Scler. J. 2016; 22: 329-339https://doi.org/10.1177/1352458515587752
- Treatment of neuromyelitis optica spectrum disorder: acute, preventive, and symptomatic.Curr. Treat Options Neurol. 2016; 18: 1-15https://doi.org/10.1007/s11940-015-0387-9
- Treatment of neuromyelitis optica: review and recommendations.Mult. Scler. Relat. Disord. 2012; 1: 180-187https://doi.org/10.1016/j.msard.2012.06.002
- The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.PLoS Med. 2009; 6https://doi.org/10.1371/journal.pmed.1000100
- Devic's neuromyelitis optica: a prospective study of seven patients treated with prednisone and azathioprine.Neurology. 1998; 51: 1219-1220https://doi.org/10.1212/WNL.51.4.1219
- The thiopurine S-methyltransferase gene locus - implications for clinical pharmacogenomics.Pharmacogenomics. 2002; 3: 89-98https://doi.org/10.1517/14622416.3.1.89
- Epidemiology of neuromyelitis optica in the United States.Arch. Neurol. 2012; 69: 1176-1180https://doi.org/10.1001/archneurol.2012.314
- Comparison of relapse and treatment failure rates among patients with neuromyelitis optica: multicenter study of treatment efficacy.JAMA Neurol. 2014; 71: 324-330https://doi.org/10.1001/jamaneurol.2013.5699
NCT03350633: Tocilizumab vs azathioprine in neuromyelitis optica spectrum disorders (TANGO) 2017. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03350633?cond=NCT03350633&rank=1. Published . (Accessed 1 December 2018).
- Comparison of the efficacy of azathioprine and rituximab in neuromyelitis optica spectrum disorder: a randomized clinical trial.J. Neurol. 2017; 254https://doi.org/10.1007/s00415-017-8590-0
- Azathioprine plus corticosteroid treatment in Chinese patients with neuromyelitis optica.J. Clin. Neurosci. 2015; 22: 1178-1182https://doi.org/10.1016/j.jocn.2015.01.028
- Clinical pharmacology and pharmacogenetics of thiopurines.Eur. J. Clin. Pharmacol. 2008; 64: 753-767https://doi.org/10.1007/s00228-008-0478-6
- EFNS guidelines on diagnosis and management of neuromyelitis optica.Eur. J. Neurol. 2010; 17: 1019-1032https://doi.org/10.1111/j.1468-1331.2010.03066.x
- Immunotherapies in neuromyelitis optica spectrum disorder: efficacy and predictors of response.J. Neurol. Neurosurg. Psychiatry. 2017; 88: 639-647https://doi.org/10.1136/jnnp-2017-315603
- Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group.JAMA. 2000; 283: 2008-2012
- Analysis of the treatment of neuromyelitis optica.J. Neurol. Sci. 2015; 351: 31-35https://doi.org/10.1016/j.jns.2015.02.012
- Low-dose corticosteroids reduce relapses in neuromyelitis optica: a retrospective analysis.Mult. Scler. 2007; 13: 968-974https://doi.org/10.1177/1352458507077189
Wells G., Shea B., O'Connell D., et al. The Newcastle–Ottawa scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. (Accessed 28 August 2017).
- The clinical course of neuromyelitis optica (Devic's syndrome).Neurology. 1999; 53: 1107-1114
- Revised diagnostic criteria for neuromyelitis optica.Neurology. 2006; 66: 1485-1489https://doi.org/10.1212/01.wnl.0000216139.44259.74
- International consensus diagnostic criteria for neuromyelitis optica spectrum disorders.Neurology. 2015; 85: 177-189https://doi.org/10.1212/WNL.0000000000001729
- Comparison of efficacy and tolerability of azathioprine, mycophenolate mofetil, and cyclophosphamide among patients with neuromyelitis optica spectrum disorder: a prospective cohort study.J. Neurol. Sci. 2016; 370: 224-228https://doi.org/10.1016/j.jns.2016.09.035
- Comparison of efficacy and tolerability of azathioprine, mycophenolate mofetil, and lower dosages of rituximab among patients with neuromyelitis optica spectrum disorder.J. Neurol. Sci. 2018; 385: 192-197https://doi.org/10.1016/j.jns.2017.12.034
- Effectiveness of low dose of rituximab compared with azathioprine in Chinese patients with neuromyelitis optica: an over 2-year follow-up study.Acta Neurol. Belg. 2017; 117: 695-702https://doi.org/10.1007/s13760-017-0795-6
Article info
Publication history
Published online: May 25, 2019
Accepted:
May 19,
2019
Received in revised form:
April 29,
2019
Received:
February 16,
2019
Identification
Copyright
© 2019 Elsevier B.V. All rights reserved.
