Worse recovery from acute attacks and faster disability accumulation highlights the unmet need for improved treatment in patients with late-onset neuromyelitis optica spectrum disorders (COPTER-LO study)

Julian Reza Kretschmer ¹ Daria Tkachenko ¹ Tania Kümpfel ² Joachim Havla ² Daniel Engels ² Friedemann Paul ^3,4 Patrick Schindler ^3,4 Judith Theresia Bellmann-Strobl ^3,4 Achim Berthele ⁵ Katrin Giglhuber ⁵ Clarissa Zappe ⁵ Luisa Klotz ⁶ Lisa Lohmann ⁶ Eva Dawin ⁶ Makbule Senel ⁷ Hayrettin Tumani ⁷ Florian Then Bergh ⁸ Clemens Warnke ⁹ Markus Kraemer ^10,11 Annette Walter ¹² Antonios Bayas ¹³ Uwe K. Zettl ¹⁴ Ann-Sophie Lauenstein ¹⁵ Yavor Yalachkov ¹⁶ Thorleif Etgen ¹⁷ Matthias Kaste ¹⁸ Felix Luessi ¹⁹ Stefan Gingele ²⁰ Sarah Passoke ²⁰ Martin S Weber ²¹ Jörn Peter Sieb ²² Axel Haarmann ²³ Patrick Oschmann ²⁴ Veit Rothhammer ²⁵ Christian Geis ²⁶ Markus C Kowarik ²⁷ Peter Kern ²⁸ Matthias Grothe ²⁹ Heike Stephanik ³⁰ Klemens Angstwurm ³¹ Frank Hoffmann ³² Ulrike Wallwitz ³² Brigitte Wildemann ³³ Sven Jarius ³³ Jan-Patrick Stellmann ^34,35,36 Thivya Pakeerathan ³⁷ Carolin Schwake ³⁷ Ilya Ayzenberg ³⁷ Ingo Kleiter ^37,38 Katinka Fischer ¹¹ Orhan Aktas ¹¹ Marius Ringelstein ^11,39 Vivien Häußler ³⁴ Corinna Trebst ²⁰ Martin W Hümmert ^20*

• ¹ Hannover Medical School, Hanover, Germany
• ² Institute for Clinical Neuroimmunology, LMU Munich University Hospital, Munich, Bavaria, Germany
• ³ Charité University Medicine Berlin, Berlin, Baden-Wurttemberg, Germany
• ⁴ Max Delbrück Center for Molecular Medicine, Helmholtz Association of German Research Centers (HZ), Berlin, Baden-Wurttemberg, Germany
• ⁵ Department of Neurology, University Hospital rechts der Isar, Technical University of Munich, Munich, Bavaria, Germany
• ⁶ Department of Neurology, University Hospital Münster, Muenster, North Rhine-Westphalia, Germany
• ⁷ Department of Neurology, Ulm University Medical Center, Ulm, Germany
• ⁸ Department of Neurology, University Hospital Leipzig, Leipzig, Lower Saxony, Germany
• ⁹ Clinic and Polyclinic for Neurology, University Hospital of Cologne, Köln, North Rhine-Westphalia, Germany
• ¹⁰ Klinik für Neurologie, Alfried Krupp Krankenhaus, Essen, North Rhine-Westphalia, Germany
• ¹¹ Department of Neurology, University Hospital Düsseldorf, Düsseldorf, North Rhine-Westphalia, Germany
• ¹² Department of Neurology, Herford Hospital, Herford, Germany
• ¹³ Department of Neurology and Clinical Neurophysiology, Medical School, Augsburg University, Augsburg, Baden-Württemberg, Germany
• ¹⁴ Department of Neurology, University Hospital Rostock, Rostock, Mecklenburg-Vorpommern, Germany
• ¹⁵ DKD Helios Hospital Wiesbaden, Wiesbaden, Germany
• ¹⁶ Department of Neurology, University of Frankfurt, Frankfurt, Germany
• ¹⁷ Department of Neurology, Klinikum Traunstein, Traunstein, Germany
• ¹⁸ Department of Neurology, Nordwest-Hospital Sanderbusch, Sande, Germany
• ¹⁹ Department of Neurology, University Medical Centre, Johannes Gutenberg University Mainz, Mainz, Rhineland-Palatinate, Germany
• ²⁰ Department of Neurology, Hannover Medical School, Hannover, Lower Saxony, Germany
• ²¹ Department of Neurology, University Medical Center Göttingen, Goettingen, Lower Saxony, Germany
• ²² Helios Hanseklinikum, Stralsund, Germany
• ²³ Department of Neurology, University Hospital Würzburg, Würzburg, Bavaria, Germany
• ²⁴ Department of Neurology, Bayreuth Clinic, Bayreuth, Bavaria, Germany
• ²⁵ Department of Neurology, FAU Erlangen-Nuremberg, Erlangen, Germany
• ²⁶ Department of Neurology, University of Jena, Jena, Germany
• ²⁷ Department of Neurology & Stroke, Hertie-Institute for Clinical Brain Research, Tübingen, Baden-Württemberg, Germany
• ²⁸ Department of Neurology, Asklepios Expert Clinic Teupitz, Teupitz, Germany
• ²⁹ Department of Neurology, University of Greifswald, Greifswald, Germany
• ³⁰ Department of Neurology, Faculty of Medicine, Otto von Guericke University Magdeburg, Magdeburg, Saxony-Anhalt, Germany
• ³¹ Department of Neurology, University Medical Center Regensburg, Regensburg, Bavaria, Germany
• ³² Department of Neurology, Hospital Martha-Maria, Halle, Germany
• ³³ Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany
• ³⁴ Institut für Neuroimmunologie und Multiple Sklerose (INIMS), Universitätsklinikum Hamburg-­Eppendorf (UKE), Hamburg, Germany
• ³⁵ CEMEREM, APHM, Hôspital de la Timone, Marseille, Marseille, France
• ³⁶ CRMBM, Aix Marseille Univ, CNRS, Marseille, Marseille, France
• ³⁷ Department of Neurology, Ruhr University Bochum, Bochum, North Rhine-Westphalia, Germany
• ³⁸ Marianne-Strauss-Klinik, Behandlungszentrum für Multiple Sklerose Kranke, Berg, Germany
• ³⁹ LVR Klinik Düsseldorf, Germany, Düsseldorf, Germany

ObjectiveThis study analyzed clinical characteristics, attack recovery and long-term disability accumulation in late-onset (LO ≥ 50 years at onset) versus early-onset (EO < 50 years) NMOSD. MethodsThis multicenter cohort study included demographic and clinical data from 446 NMOSD patients collected from 35 German Neuromyelitis Optica Study Group (NEMOS) centers. Time to disability milestones was estimated through Kaplan-Meier analysis and Cox proportional hazard regression models adjusted for sex, year of onset, immunotherapy exposure and antibody status. Generalized estimating equations (GEE) were used to compare attack outcomes.ResultsOf the 446 NMOSD patients analyzed (83.4% female, 85.4%, AQP4-IgG-positive, median age at disease onset = 43 years), 153 had a late-onset (34.3%). AQP4-IgG+ prevalence was higher in LO- than in EO-NMOSD (94.1% vs. 80.9%, p<0.001). Optic neuritis at onset was more frequent in EO-NMOSD (27.4% vs. 42.6%, p<0.002), whereas myelitis was more common in LO-NMOSD (58.4% vs. 37.9%, p<0.001). Both groups had similar annualized attack rates (AAR, 0.51 vs. 0.54, p=0.352), but attack recovery was poorer (complete remission in 15.6% vs. 27.4%, p<0.001) and relapse-associated worsening (RAW) was higher in LO-NMOSD (RAW: 3 vs. 0.5, p<0.001). Long-term immunotherapy use was comparable. LO-NMOSD exhibited faster progression to disability endpoints (EDSS 4: HR = 2.64, 95% CI=1.81–3.84).InterpretationLO-NMOSD patients presented more often with myelitis, experienced worse attack outcomes and faster disability accumulation, despite comparable AAR, acute attack treatment and long-term treatment regimens. Accordingly, therapeutic strategies for attack and prophylactic treatment in LO-NMOSD have to be improved.