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Neuro-inflammation
Research paper
Immunotherapies in neuromyelitis optica spectrum disorder: efficacy and predictors of response
  1. Jan-Patrick Stellmann1,2,
  2. Markus Krumbholz3,4,
  3. Tim Friede5,
  4. Anna Gahlen6,
  5. Nadja Borisow7,
  6. Katrin Fischer8,
  7. Kerstin Hellwig6,
  8. Florence Pache7,9,
  9. Klemens Ruprecht9,
  10. Joachim Havla3,
  11. Tania Kümpfel3,
  12. Orhan Aktas10,
  13. Hans-Peter Hartung10,
  14. Marius Ringelstein10,
  15. Christian Geis11,12,
  16. Christoph Kleinschnitz11,13,
  17. Achim Berthele14,
  18. Bernhard Hemmer14,15,
  19. Klemens Angstwurm16,
  20. Kim Lea Young1,2,
  21. Simon Schuster2,
  22. Martin Stangel17,
  23. Florian Lauda18,
  24. Hayrettin Tumani18,
  25. Christoph Mayer19,
  26. Lena Zeltner4,
  27. Ulf Ziemann4,
  28. Ralf Andreas Linker20,
  29. Matthias Schwab12,
  30. Martin Marziniak21,1,
  31. Florian Then Bergh22,
  32. Ulrich Hofstadt-van Oy23,2,
  33. Oliver Neuhaus24,
  34. Uwe Zettl25,
  35. Jürgen Faiss8,
  36. Brigitte Wildemann26,
  37. Friedemann Paul7,9,
  38. Sven Jarius26,
  39. Corinna Trebst27,
  40. Ingo Kleiter6
  41. on behalf of NEMOS (Neuromyelitis Optica Study Group)
  1. 1 Institut für Neuroimmunologie und Multiple Sklerose (INIMS), Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
  2. 2 Klinik und Poliklinik für Neurologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
  3. 3 Institute of Clinical Neuroimmunology, Ludwig Maximilian University, Munich, Germany
  4. 4 Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
  5. 5 Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany
  6. 6 Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
  7. 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. 8 Department of Neurology, Asklepios Fachklinikum Teupitz, Teupitz, Germany
  9. 9 Department of Neurology and Clinical and Experimental Multiple Sclerosis Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany
  10. 10 Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
  11. 11 Department of Neurology, University Hospital Würzburg, Würzburg, Germany
  12. 12 Department of Neurology, Jena University Hospital, Jena, Germany
  13. 13 Department of Neurology, University Hospital Essen, Essen, Germany
  14. 14 Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
  15. 15 Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
  16. 16 Department of Neurology, University Hospital Regensburg, Regensburg, Germany
  17. 17 Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany
  18. 18 Department of Neurology, University of Ulm, Ulm, Germany
  19. 19 Department of Neurology, Goethe University Frankfurt, Frankfurt, Germany
  20. 20 Department of Neurology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
  21. 21 Department of Neurology, University of Münster, Münster, Germany
  22. 22 Department of Neurology, University of Leipzig, Leipzig, Germany
  23. 23 Department of Neurology, Klinikum Bayreuth, Bayreuth, Germany
  24. 24 Department of Neurology, SRH Krankenhaus Sigmaringen, Sigmaringen, Germany
  25. 25 Department of Neurology, University of Rostock, Rostock, Germany
  26. 26 Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany
  27. 27 Department of Neurology, Hannover Medical School, Hannover, Germany
  1. Correspondence to Professor Ingo Kleiter, Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Gudrunstr. 56, Bochum 44791, Germany; ingo.kleiter{at}rub.de

  • ↵1 Department of Neurology and Neurological Intensive Care, Isar-Amper-Clinic, Munich-East, Haar, Germany

  • ↵2 Department of Neurology, Klinikum Westfalen, Dortmund, 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.

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

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/jnnp-2017-315603

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    Footnotes

    • Contributors JPS, MK, CT, and IK designed the study, collected, analysed and interpreted the data and drafted and revised the manuscript. TF did statistical analysis and revised the manuscript. AG, NB, KF, KH, FlP, KR, JH, TK OA, HPH, MR, CG, CK, AB, BH, KA, KLY, SS, MSt, FL, HT, CM, LZ, UZi, RAL, MSch, MM, FTB, UHO, ON, UZe, JHF, BW, FrP and SJ collected and analysed the data and revised the manuscript critically for intellectual content. All authors approved the final version of the manuscript.

    • 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.

    • Ethics approval The local institutional review boards of the participating centres approved the study (first approval from the institutional review board at Charité Universitätsmedizin EA3/004/08).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Collaborators P Albrecht, University of Düsseldorf; O Aktas, University of Düsseldorf; K Angstwurm, University of Regensburg; I Ayzenberg, Ruhr-University Bochum; A Berthele, Technical University Munich; F Bischof, University of Tübingen; N Borisow, Charité University Medicine Berlin; T Böttcher, Bonhoeffer Klinikum Neubrandenburg; J Brettschneider, University of Ulm; M Buttmann, University of Würzburg; B Ettrich, University of Leipzig; J Faiss, Asklepios Klinik Teupitz; A Gass, University Hospital Mannheim; C Geis, University of Jena; K Guthke, Klinikum Görlitz; J Havla, Ludwig-Maximilians University Munich; H-P Hartung, University of Düsseldorf; K Hellwig, Ruhr-University Bochum; B Hemmer, Technical University Munich; F Hoffmann, Krankenhaus Martha-Maria Halle; U Hofstadt-van Oy, Klinikum Westfalen Dortmund; M Hümmert, Hannover Medical School; S Jarius, University of Heidelberg; M Kaste, Nordwest-Krankenhaus Sanderbusch; P Kermer, Nordwest-Krankenhaus Sanderbusch; P Kern, Asklepios Klinik Teupitz; C Kleinschnitz, University of Essen; I Kleiter, Ruhr-University Bochum; W Köhler, Fachkrankenhaus Hubertusburg; E Kolesilova, Asklepios Klinik Teupitz; M Krumbholz, Ludwig Maximilians University Munich; T Kümpfel, Ludwig Maximilians University Munich; S Langel, Landeskrankenhaus Rheinhessen; F Lauda, University of Ulm; M Liebetrau, Evangelische Bathildiskrankenhaus Bad Pyrmont GmbH; R Linker, University of Erlangen; W Marouf, Heliosklinik Stralsund; M Marziniak, Isar-Amper Klinik Ost Munich; S Meister, Universityof Rostock, Department of Neurology; A Melms, University of Erlangen; I Metz, University of Göttingen; C Mayer, University of Frankfurt; C Münch, Charité University Medicine Berlin; O Neuhaus, SRH Krankenhaus Sigmaringen; S Niehaus, Klinikum Dortmund; F Pache, Charité University Medicine Berlin; F Paul, Charité University Medicine Berlin; H Pellkofer, University of Göttingen; A Riedlinger, Asklepios Klinik Teupitz; M Ringelstein, University of Düsseldorf; L Röpke, University of Jena; SP Rommer, University of Vienna (Austria); K Ruprecht, Charité University Medicine Berlin; C Ruschil, University of Tübingen; S Schippling, University of Zürich (Switzerland); S Schuster, University ofHamburg; M Schwab, University of Jena; M Stangel, Hannover Medical School; J Stellmann, University of Hamburg; M Stoppe, University of Leipzig; F Then Bergh, University of Leipzig; C Trebst, Hannover Medical School; J Tünnerhoff, University of Tübingen; H Tumani, University of Ulm; C Veauthier, Charité University Medicine Berlin; A Walter, Klinikum Herford; KP Wandinger, Institute of Clinical Chemistry, Neuroimmunology Unit, and Department of Neurology, University Medical Center Schleswig-Holstein Campus Lübeck; MS Weber, University of Göttingen; R Weissert, University of Regensburg; B Wildemann, University of Heidelberg; C Wilke, Nervenzentrum Potsdam; A Winkelmann, University of Rostock, Department of Neurology; K Young, University of Hamburg; L Zeltner, University of Tübingen; C Zentner, Krankenhaus Martha-Maria Halle; U Zettl, University of Rostock, Department of Neurology, Neuroimmunological Section; U Ziemann, University of Tübingen.

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