Advertisement

Comparison of efficacy and tolerability of azathioprine, mycophenolate mofetil, and lower dosages of rituximab among patients with neuromyelitis optica spectrum disorder

Published:December 30, 2017DOI:https://doi.org/10.1016/j.jns.2017.12.034

      Highlights

      • AZA, MMF and lower dosages of RTX were compared in ARR, EDSS, CD19+ B-cell, AQP-4-IgG titre and adverse reactions.
      • The time to first relapse, the number of relapse-free and AQP-4-IgG titre were also recorded in the follow-up.
      • Lower dosages of RTX is more effective in decreasing the CD19+ B-cell counts and AQP-4-IgG titre than the others.

      Abstract

      Objective

      To observe and compare the efficacy and tolerability of azathioprine (AZA), mycophenolate mofetil (MMF) and lower dosages of rituximab (RTX) among patients with neuromyelitis optica spectrum disorder.

      Methods

      In this prospective cohort, AQP4-IgG-seropositive patients with neuromyelitis optica spectrum disorder (NMOSD) were enrolled and randomly divided into three groups, using AZA, MMF or lower dosages of RTX (defined as 100 mg RTX intravenous injection, once per week for 4 consecutive weeks) respectively. Annualized relapse rate (ARR), EDSS scores, CD19+ B-cell counts in peripheral blood, serum AQP-4-IgG titre and drug adverse reactions were compared between three groups.

      Results

      In the AZA group (n = 22), MMF group (n = 30) and RTX group (n = 20), 54.5%, 60.0% and 65.0% of patients reached a relapse-free state and EDSS score improved in 90.9%, 83.3% and 90.0% of patients respectively. In addition, there was significant reduction in ARR in all the three groups. Reduced dosage of RTX exerted a significant effect in reducing CD19+ B-cell counts (P < 0.01). Compared with the AZA group, the MMF group and the RTX group decreased the AQP-4-IgG titre evidently and caused fewer adverse events. Neither the Kaplan-Meier survival curves nor the Cox proportional hazard model indicated a significant difference in relapse among the three groups (P > 0.05).

      Conclusions

      AZA, MMF and reduced dosages of rituximab are all effective in reducing ARR and improving the clinical symptom of patients with NMOSD. Lower dosages of RTX are more effective than the others in decreasing the CD19 B-cell counts. MMF and reduced RTX decrease AQP-4-IgG titre more and cause fewer adverse events than AZA. However, more multicentre studies are still needed to find more effective therapeutic regimen.

      Keywords

      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 access
      One-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 Journal of the Neurological Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Wingerchuk D.M.
        • Hogancamp W.F.
        • O'Brien P.C.
        • et al.
        The clinical course of neuro-myelitis optica (Devic's syndrome).
        Neurology. 1999; 53: 1107-1114https://doi.org/10.1212/WNL.53.5.1107
        • Wingerchuk D.M.
        • Lennon V.A.
        • Pittock S.J.
        • et al.
        Revised diagnostic criteria for neuromyelitis optica.
        Neurology. 2006; 66: 1485-1489https://doi.org/10.1212/01.wnl.0000216139.44259.74
        • Wingerchuk D.M.
        • Banwell B.
        • Bennett J.L.
        • et al.
        International panel for NMO diag-nosis. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders.
        Neurology. 2015; 85: 177-189https://doi.org/10.1212/WNL.0000000000001729
        • Lennon V.A.
        • Wingerchuk D.M.
        • Kryzer T.J.
        • et al.
        A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis.
        Lancet. 2005; 364: 2106-2112https://doi.org/10.1016/S0140-6736(04)17551-X
        • Lennon V.A.
        • Kryzer T.J.
        • Pittock S.J.
        • et al.
        IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel.
        J. Exp. Med. 2005; 202: 473-477https://doi.org/10.1084/10.1084/jem.20050304
        • Jeong I.H.
        • Park B.
        • Kim S.H.
        • et al.
        Comparative analysis of treatment outcomes in patients with neuromyelitis optica spectrum disorder using multifaceted endpoints.
        Mult. Scler. 2016; 22: 881-884https://doi.org/10.1177/1352458515587752
        • Kleiter I.
        • Gold R.
        Present and future therapies in neuromyelitis optica spectrum disorders.
        Neurotherapeutics. 2016; 13: 70-83https://doi.org/10.1007/s13311-015-0400-8
        • Mealy M.A.
        • Wingerchuk D.M.
        • Palace J.
        • et al.
        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
        • Kitley J.
        • Palace J.
        Therapeutic options in neuromyelitis optica spectrum disorders.
        Expert. Rev. Neurother. 2016; 16: 319-329https://doi.org/10.1586/14737175.2016.1150178
        • Pellkofer H.L.
        • Krumbholz M.
        • Berthele A.
        • et al.
        Long-term follow-up of patients with neuromyelitis optica after repeated therapy with rituximab.
        Neurology. 2011; 76: 1310-1315https://doi.org/10.1212/WNL.0b013e3182152881
        • Kim S.H.
        • Kim W.
        • Li X.F.
        • et al.
        Repeated treatment with rituximab based on the assessment of peripheral circulating memory B cells in patients with relapsing neuromyelitis optica over 2 years.
        Arch. Neurol. 2011; 68: 1412-1420https://doi.org/10.1001/archneurol.2011.154
        • Yang C.S.
        • Yang L.
        • Li T.
        • et al.
        Responsiveness to reduced dosage of rituximab in Chinese patients with neuromyelitis optica.
        Neurology. 2013; 81: 710-713https://doi.org/10.1212/WNL.0b13 e3182a1aac7
        • Kleiter I.
        • Hellwig K.
        • Berthele A.
        • et al.
        Failure of natalizumab to prevent relapses in neuromyelitis optica.
        Arch. Neurol. 2012; 69: 239-245https://doi.org/10.1001/archneurol.2011.216
        • Kim S.H.
        • Kim W.
        • Li X.F.
        • et al.
        Does interferon beta treatment exacerbate neurom-yelitis optica spectrum disorder?.
        Mult. Scler. 2012; 18: 1480-1483https://doi.org/10.1177/1352458512439439
        • Min J.H.
        • Kim B.J.
        • Lee K.H.
        Development of extensive brain lesions following fingolimod (FTY720) treatment in a patient with neuromyelitis optica spectrum disorder.
        Mult. Scler. 2012; 18: 113-115https://doi.org/10.1177/1352458511431973
        • Costanzi C.
        • Matiello M.
        • Lucchinetti C.F.
        • et al.
        Azathioprine: tolerability, efficacy, and predictors of benefit in neuromyelitis optica.
        Neurology. 2011; 77: 659-666https://doi.org/10.1212/WNL.0b013e31822a2780
        • Elsone L.
        • Kitley J.
        • Luppe S.
        • et al.
        Long-term efficacy, tolerability and retention ra-te of azathioprine in 103 aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder patients: a multicentre retrospective observational study from the UK.
        Mult. Scler. 2014; 20: 1533-1540https://doi.org/10.1177/1352458514525870
        • Jacob A.
        • Matiello M.
        • Weinshenker B.G.
        • et al.
        Treatment of neuromyelitis optica with mycophenolate mofetil: retrospective analysis of 24 patients.
        Arch. Neurol. 2009; 66: 1128-1133https://doi.org/10.1001/archneurol.2009.175
        • Huh S.Y.
        • Kim S.H.
        • Hyun J.W.
        • et al.
        Mycophenolate mofetil in the treatment of ne-uromyelitis optica spectrum disorder.
        JAMA Neurol. 2014; 71: 1372-1378https://doi.org/10.1001/jamaneurol.2014.2057
        • Chen H.
        • Zhang Y.
        • Shi Z.
        • et al.
        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
        • Torres J.
        • Pruitt A.
        • Balcer L.
        • et al.
        Analysis of the treatment of neuromyelitis optica.
        J. Neurol. Sci. 2015; 351: 31-35https://doi.org/10.1016/j.jns.2015.02.012
        • Xu Y.
        • Wang Q.
        • Ren H.T.
        • et al.
        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
        • Chen H.
        • Qiu W.
        • Zhang Q.
        • et al.
        Comparisons of the efficacy and tolerability of mycophenolate mofetil and azathioprine as treatments for neuromyelitis optica and neuromyelitis optica spectrum disorder.
        Eur. J. Neurol. 2016; 24: 219-226https://doi.org/10.1111/ene.13186
        • Qiu W.
        • Kermode A.G.
        • Li R.
        • et al.
        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
        • Sahasranaman S.
        • Howard D.
        • Roy S.
        Clinical pharmacology and pharmacogenetics of thiopurines.
        Eur. J. Clin. Pharmacol. 2008; 64: 753-767https://doi.org/10.1007/s00228-008-0478-6
        • Watanabe S.
        • Misu T.
        • Miyazawa I.
        • et al.
        Low-dose corticosteroids reduce relapses in neuromyelitis optica: a retrospective analysis.
        Mult. Scler. 2007; 13: 968-974https://doi.org/10.1177/1352458507077189
        • Kham S.K.
        • Soh C.K.
        • Liu T.C.
        • et al.
        Thiopurine S-methyltransferase activity in three major Asian populations: a population-based study in Singapore.
        Eur. J. Pharmacol. 2008; 64: 373-379https://doi.org/10.1007/s00228-007-0426-x
        • McLeod H.L.
        • Siva C.
        The thiopurine S-methyltransferase gene locus-implications for clinical pharmacogenomics.
        Pharmacogenomics. 2002; 3: 89-98https://doi.org/10.1517/14622416.3.1.89
        • Allison A.C.
        • Eugui E.M.
        Mycophenolate mofetil and its mechanisms of action.
        Immunopharmacology. 2000; 47: 85-118https://doi.org/10.1016/S0162-3109(00)00188-0
        • Lv Q.K.
        • Liu J.X.
        • Li S.N.
        • et al.
        Mycophenolate mofetil modulates differentiation of Th1/Th2 and the secretion of cytokines in an active Crohn's disease mouse model.
        Int. J. Mol. Sci. 2015; 16: 26654-26666https://doi.org/10.3390/ijms161125985
        • Eickenberg S.
        • Mickholz E.
        • Jung E.
        • et al.
        Mycophenolic acid counteracts B cell proliferation and plasmablast formation in patients with systemic lupus erythematosus.
        Arthritis Res. Ther. 2012; 14: R110https://doi.org/10.1186/ar3835
        • Tobin W.O.
        • Pittock S.J.
        Rituximab therapy in neuromyelitis optica: moving toward a personalized medicine approach.
        JAMA Neurol. 2015; 72: 974-977https://doi.org/10.1001/jamaneurol.2015.1421
        • Collongues N.
        • Brassat D.
        • Maillart E.
        • et al.
        Efficacy of rituximab in refractory neuromyelitis optica.
        Mult. Scler. 2016; 22: 955-959https://doi.org/10.1177/1352458515602337
        • Radaelli M.
        • Moiola L.
        • Sangalli F.
        • et al.
        Neuromyelitis optica spectrum disorders: long-term safety and efficacy of rituximab in caucasian patients.
        Mult. Scler. 2016; 22: 511-519https://doi.org/10.1177/1352458515594042
        • Kim S.H.
        • Huh S.Y.
        • Lee S.J.
        • et al.
        A 5-year follow-up of rituximab treatment in patients with neuromyelitis optica spectrum disorder.
        JAMA Neurol. 2013; 70: 1110-1117https://doi.org/10.1001/jamaneurol.2013.3071
        • Kim S.H.
        • Jeong I.H.
        • Hyun J.W.
        • et al.
        Treatment outcomes with rituximab in 100 patients with neuromyelitis optica: influence of FCGR3A polymorphisms on the therapeuticresponse to rituximab.
        JAMA Neurol. 2015; 72: 989-995https://doi.org/10.1001/jamaneurol.2015.1276