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J Neurol Neurosurg Psychiatry. 2017 Aug;88(8):639-647. doi: 10.1136/jnnp-2017-315603. Epub 2017 Jun 1.

Immunotherapies in neuromyelitis optica spectrum disorder: efficacy and predictors of response.

Author information

1
Institut für Neuroimmunologie und Multiple Sklerose (INIMS), Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
2
Klinik und Poliklinik für Neurologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
3
Institute of Clinical Neuroimmunology, Ludwig Maximilian University, Munich, Germany.
4
Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
5
Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany.
6
Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.
7
NeuroCure Clinical Research Center and Clinical and Experimental Multiple Sclerosis Research Center, Charité Universitätsmedizin Berlin, and Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
8
Department of Neurology, Asklepios Fachklinikum Teupitz, Teupitz, Germany.
9
Department of Neurology and Clinical and Experimental Multiple Sclerosis Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany.
10
Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
11
Department of Neurology, University Hospital Würzburg, Würzburg, Germany.
12
Department of Neurology, Jena University Hospital, Jena, Germany.
13
Department of Neurology, University Hospital Essen, Essen, Germany.
14
Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
15
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
16
Department of Neurology, University Hospital Regensburg, Regensburg, Germany.
17
Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany.
18
Department of Neurology, University of Ulm, Ulm, Germany.
19
Department of Neurology, Goethe University Frankfurt, Frankfurt, Germany.
20
Department of Neurology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
21
Department of Neurology, University of Münster, Münster, Germany.
22
Department of Neurology, University of Leipzig, Leipzig, Germany.
23
Department of Neurology, Klinikum Bayreuth, Bayreuth, Germany.
24
Department of Neurology, SRH Krankenhaus Sigmaringen, Sigmaringen, Germany.
25
Department of Neurology, University of Rostock, Rostock, Germany.
26
Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany.
27
Department of Neurology, Hannover Medical School, Hannover, Germany.

Abstract

OBJECTIVE:

To analyse predictors for relapses and number of attacks under different immunotherapies in patients with neuromyelitis optica spectrum disorder (NMOSD).

DESIGN:

This is a retrospective cohort study conducted in neurology departments at 21 regional and university hospitals in Germany. Eligible participants were patients with aquaporin-4-antibody-positive or aquaporin-4-antibody-negative NMOSD. Main outcome measures were HRs from Cox proportional hazard regression models adjusted for centre effects, important prognostic factors and repeated treatment episodes.

RESULTS:

265 treatment episodes with a mean duration of 442 days (total of 321 treatment years) in 144 patients (mean age at first attack: 40.9 years, 82.6% female, 86.1% aquaporin-4-antibody-positive) were analysed. 191 attacks occurred during any of the treatments (annual relapse rate=0.60). The most common treatments were rituximab (n=77, 111 patient-years), azathioprine (n=52, 68 patient-years), interferon-β (n=32, 61 patient-years), mitoxantrone (n=34, 32.1 patient-years) and glatiramer acetate (n=17, 10 patient-years). Azathioprine (HR=0.4, 95% CI 0.3 to 0.7, p=0.001) and rituximab (HR=0.6, 95% CI 0.4 to 1.0, p=0.034) reduced the attack risk compared with interferon-β, whereas mitoxantrone and glatiramer acetate did not. Patients who were aquaporin-4-antibody-positive had a higher risk of attacks (HR=2.5, 95% CI 1.3 to 5.1, p=0.009). Every decade of age was associated with a lower risk for attacks (HR=0.8, 95% CI 0.7 to 1.0, p=0.039). A previous attack under the same treatment tended to be predictive for further attacks (HR=1.5, 95% CI 1.0 to 2.4, p=0.065).

CONCLUSIONS:

Age, antibody status and possibly previous attacks predict further attacks in patients treated for NMOSD. Azathioprine and rituximab are superior to interferon-β.

KEYWORDS:

Aquaporin-4 antibody; Azathioprine; Neuromyelitis optica spectrum disorder; Rituximab; Therapy

PMID:
28572277
PMCID:
PMC5537514
DOI:
10.1136/jnnp-2017-315603
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Competing interests: AB has received honoraria for consultancy or lectures and travel reimbursement from Bayer HealthCare, Biogen, Merck Serono, Mylan, Roche, Novartis and Teva, and grant support from Bayer HealthCare and Chugai. AG has received travel reimbursement from Sanofi Genzyme. BH reports grants from Chugai, grants, personal fees and non-financial support from Roche, personal fees and non-financial support from Biogen, personal fees and non-financial support from Novartis, personal fees and non-financial support from Merck, and personal fees and non-financial support from Bayer. BW has received grants from the German Ministry of Education and Research, Dietmar Hopp Foundation, Biogen, Biotest, Merck, Novartis Pharmaceuticals and Teva Pharma, personal fees from Biogen, Merck, Novartis Pharmaceuticals, Teva Pharma, Bayer HealthCare and Genzyme. CG received honoraria for lectures, travel reimbursement and grant support from Merck Serono, Teva, Novartis and CSL Behring. CT has received honoraria for consultation and expert testimony from Bayer Vital GmbH, Biogen Idec/Biogen GmbH, Genzyme GmbH and Novartis Pharmaceuticals/Pharma GmbH. FL reports travel expenses from Teva Pharma. FlP reports grants from BIH‐Charité Clinical Scientist Program funded by the Charité–Universitätsmedizin Berlin and the Berlin Institute of Health and non-financial support from ECTRIMS-Travel grant 2014. FrP reports grants and personal compensations from Alexion, Bayer, Biogen, Shire, Novartis, Medimmune, Merck and Genzyme. FTB reports grants and others from Bayer, personal fees and others from Biogen Idec, grants and personal fees from CSL Behring, grants from Fresenius, personal fees and others from Genzyme Sanofi, others from Merck Serono, grants, personal fees and others from Novartis, grants, personal fees and others from Teva, grants and others from Actelion, and grants from the German Ministry of Education and Research. HPH received, with approval of the Rector of Heinrich-Heine-University and the CEO of University of Düsseldorf Hospital, honoraria for consulting, serving on steering committees and speaking from Biogen, Geneuro, Genzyme, Medimmune, Merck, Novartis, Opexa, Receptos/Celgene, Roche, Sanofi and Teva. IK has received honoraria for consultancy or lectures and travel reimbursement from Bayer HealthCare, Biogen Idec, Chugai, Novartis, Shire and Roche, and grant support from Biogen Idec, Novartis, Chugai and Diamed. JHF received grant support and honoraria from Novartis, Bayer Vital, Merck, Biogen, Sanofi-Genzyme and Roche. JH reports personal fees and non-financial support from Sanofi Genzyme, Bayer HealthCare, Merck and Novartis Pharma. JPS received honoraria for consultancy or lectures, travel reimbursement and grant support from Biogen, Merck Serono, Novartis, Genzyme and Medimmune. KH reports grants and personal fees from Bayer HealthCare, grants and personal fees from Biogen, grants and personal fees from Teva, grants and personal fees from Merck Serono, grants and personal fees from Novartis, grants and personal fees from Almirall. KLY has nothing to disclose. KR has received research support from the German Ministry of Education and Research (BMBF/KKNMS, Competence Network Multiple Sclerosis) and Novartis, as well as speaking fees and travel grants from Guthy Jackson Charitable Foundation, Bayer HealthCare, Biogen Idec, Merck Serono, Sanofi-Aventis/Genzyme, Teva Pharmaceuticals, Roche and Novartis. LZ has nothing to disclose. MK received grant support, travelling expenses and scientific advisory board honoraria from Novartis, Novartis Foundation, Genzyme, Bayer, Roche and Biogen. MM has received grants from Biogen, Novartis; personal fees from Bayer Vital, Biogen, Genzyme, Merck Serono, Novartis, Sanofi-Aventis and Teva; and non-financial support from Biogen. MR received speaker honoraria from Novartis and Bayer Vital GmbH, and travel reimbursement from Bayer Schering and Biogen Idec. MSch has nothing to disclose. MSt reports grants and personal fees from Bayer HealthCare, personal fees from Baxter/Baxalta, grants and personal fees from Biogen, personal fees from CSL Behring, grants and personal fees from Genzyme, personal fees from Grifols, personal fees from Merck, personal fees from Roche, grants and personal fees from Novartis, personal fees from Sanofi, and grants and personal fees from Teva. NB has received grants from Alexion Pharmaceuticals, Inc. ON has nothing to disclose. RAL reports grants and personal fees from Biogen, personal fees from Bayer, grants and personal fees from Novartis, grants and personal fees from Merck, personal fees from TEVA, personal fees from Roche, personal fees from Genzyme. SJ has received a research grant from the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). MR received speaker honoraria from Novartis and Bayer Vital GmbH, and travel reimbursement from Bayer Schering and Biogen Idec. TF received honoraria for consultancies (including data monitoring committees and advisoryboards) from Novartis, Biogen, Bayer, AstraZeneca, Janssen, SGS and Pharmalog. TK reports personal fees from Biogen, grants from Novartis, personal fees from Genzyme and from Merck-Serono. UHO reports grants from Genzyme, grants from Zambon, and others from Merck Serono, Bayer, Biogen, Teva and Novartis. UZe has patents, whether planned, pending or issued, broadly relevant to the work. UZi reports personal fees from Biogen Idec GmbH, grants from Biogen Idec GmbH, personal fees from Bayer Vital GmbH, personal fees from Bristol Myers Squibb GmbH, personal fees from CorTec GmbH, personal fees from Medtronic GmbH, grants from Servier, grants from Janssen Pharmaceuticals NV and personal fees from Takeda.

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