Disability progression unrelated to relapses in relapsing-remitting multiple sclerosis: insights from the Swiss multiple sclerosis cohort study
ECTRIMS Online Library. Lorscheider J. 09/13/19; 279536; 273
Johannes Lorscheider
Johannes Lorscheider
Contributions
Abstract

Abstract: 273

Type: Scientific Session

Abstract Category: Therapy - Tools for detecting therapeutic response

J. Lorscheider1, P. Benkert2, S. Schädelin2, Ö. Yaldizli1, T. Derfuss1, P. Lalive3, C. Pot3, S. Müller4, J. Vehoff4, T. Sinnecker1, J. Würfel5, L. Achtnichts6, O. Findling6, K. Nedeltchev6, R. Du Pasquier7, G. Disanto8, C. Zecca8, C. Kamm9, A. Salmen10, A. Chan10, C. Granziera1, C. Gobbi8, L. Kappos1, J. Kuhle1, Swiss Multiple Sclerosis Cohort Study

1Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel and University of Basel, 2Clinical Trial Unit, University Hospital Basel, Basel, 3University Hospital of Geneva (HUG), Geneva, 4Cantonal Hospital St. Gallen, St. Gallen, 5Medical Image Analysis Center (MIAC AG) and Department for Biomedical Engineering, Basel, 6Cantonal Hospital Aarau, Aarau, 7University Hospital of Lausanne (CHUV), Lausanne, 8Neurocenter of Southern Switzerland, Civic Hospital, Lugano, 9Cantonal Hospital Lucerne, Lucerne, 10Department of Neurology, Inselspital Bern, University Hospital and University of Bern, Bern, Switzerland

Background: Recently, data from the randomised clinical trial of ocrelizumab in relapsing-remitting multiple sclerosis (RRMS) and the Tysabri Observational Program demonstrated that a substantial proportion of disability worsening events occurs unrelated to relapse activity. Hence, our aim was to analyse disability progression independent of relapse activity (PIRA) in a well-characterised observational cohort.
Methods: Using the Swiss Multiple Sclerosis Cohort Study, we included patients with RRMS and ≥3 prospective visits with available EDSS and Functional System (FS) scores. Confirmed disability worsening (CDW) was defined as EDSS increase of ≥1.5 steps if baseline EDSS step was 0, ≥1.0 step if 1.5-5.5, or ≥0.5 steps if >5.5, confirmed after ≥6 months. A roving baseline approach was applied to maximise sensitivity (Kappos et al., MSJ 2018), whereas re-baselining and a fixed baseline were used for a more conservative estimate. For PIRA, absence of a relapse between baseline, index event and confirmation visit was required. Influence of exposure to disease modifying treatment (DMT) was both modeled as categorical and as time-dependent covariate and analysed with Cox proportional hazards models adjusted for gender, age, disease duration, baseline EDSS and pre-baseline relapse activity. DMT was categorised in highly effective DMT, i.e. monoclonal antibodies, oral DMT and platform injectables.
Results: We included 917 RRMS patients with a median follow-up of 4.6 years. The roving baseline approach identified 198 (22%) patients experiencing CDW. Of these, 131 fulfilled the definition for PIRA (66% of patients with CDW, 14% of all eligible patients). The number of identified PIRA and CDW decreased when using a fixed baseline (92/157, 59%) or re-baselining (93/157, 59%). Highly effective DMT was associated with a lower risk for CDW (hazard ratio [HR] 0.4, 95% confidence interval [CI] 0.2-0.7, p< 0.001) compared to no treatment. However, we observed only a trend regarding PIRA (HR 0.5, 95% CI 0.3-1.1, p=0.08), which disappeared when modelling treatment as a time-dependent covariate (HR 0.8, 95%CI 0.4-1.4, p= 0.393).
Conclusion: A relevant proportion of patients classified as RRMS experienced PIRA within a 5-year period, accounting for 59-66% of all CDW events. While highly effective DMT reduced the risk of CDW, we could not demonstrate a consistent effect on PIRA in patients with RRMS in our prospectively followed cohort study.
Disclosure: J.L. has received research support from Biogen and served on advisory boards for Roche and Teva. P.B. reports no conflicts of interest. S.S. reports no conflicts of interest. Ö.Y.'s institution (University Hospital Basel) received honoraria for lectures from Teva, Novartis and Bayer Schering exclusively used for funding of research or educational courses. T.D. received speaker fees, research support, travel support, and/or served on Advisory Boards or Steering Committees of Novartis Pharma, Merck Serono, Biogen, Teva, Bayer-Schering, GeNeuro, Mitsubishi Pharma, MedDay, Roche, and Genzyme. P.L. received honoraria for speaking from Biogen, CSL Bering, Merck Serono, Novartis, Sanofi-Aventis, Teva; consulting fees from Biogen, Geneuro, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, Teva; research grants from Biogen, Merck Serono, Novartis. C.P. reports no conflicts of interest. S.M. received fees for travel, speaker honoraria and consulting services and/or research support from Almirall, Bayer, Biogen, Celgene, Genzyme, Merck, Novartis, Roche, and Teva.. J. V. has received honoraria and travel expenses from Biogen, Bayer, Teva, Novartis, Genzyme (Sanofi Aventis), Almirall and Merck. T.S. has received travel support from Actelion, Alkermes, and Roche. He is an employee of the MIAC AG in Basel. J.W. CEO of MIAC AG Basel, Switzerland. He served on scientific advisory boards of Actelion, Biogen, Genzyme-Sanofi, Novartis, and Roche. He is or was supported by grants of the EU (Horizon2020), Swiss National Research Foundation German, Federal Ministeries of Education and Research (BMBF) and of Economic Affairs and Energy (BMWI). L.A. Served on scientific advisory boards for Cellgene, Novartis Pharmaceuticals, Merck, Biogen, Sanofi Genzyme, Roche and Bayer; received funding for travel and/or speaker honoraria from Cellgene, Biogen, Sanofi Genzyme, Novartis, Merck Serono, Roche, Teva and the Swiss MS Society; and research support from Biogen, Sanofi Genzyme, and Novartis. O.F. reports no conflicts of interest. K.N. reports no conflicts of interest. R.D. has served on scientific advisory boards for Biogen, Merck Serono, Teva, and Novartis; has received funding for travel or speaker honoraria from Abbvie, Biogen, Teva, Merck Serono, and Bayer Schering Pharma. G.D. reports no conflicts of interest. C.Z. reports no conflicts of interest. C.K. received honoraria for lectures/consulting and/or grants for studies from Biogen, Novartis, Teva, Merck-Serono, Genzyme, Bayer Schweiz AG and the Swiss MS society. A.S. received speaker honoraria and/or travel compensation for activities with Almirall Hermal GmbH, Biogen, Merck, Novartis, Roche and Sanofi Genzyme, not related to this work. A.C.received compensation for activities with Actelion, Almirall, Bayer, Biogen, Celgene, Sanofi-Genzyme, Merck, Novartis, Roche, Teva, all for hospital research funds. He receives research support from Biogen, Sanofi-Genzyme and UCB. The University Hospital Basel (USB), as the employer of Ch.G., has received the following fees which were used exclusively for research support: (i) advisory board and consultancy fees from Actelion and Roche; (ii) speaker fees from Biogen and Genzyme-Sanofi. Before my employment at USB, I have also received speaker honoraria and travel funding by Novartis. C.G. reports no conflicts of interest. The University Hospital Basel, as the employer of L.K., has received and dedicated to research support fees for board membership, consultancy or speaking, or grants in the past 3 years from Actelion, Advancell, Allozyne, Bayer, Bayhill, Biogen Idec, BioMarin, CSL Behring, Eli Lilly EU, Genmab, GeNeuro SA, Gianni Rubatto Foundation, Glenmark, Merck Serono, MediciNova, Mitsubishi Pharma, Novartis, Novartis Research Foundation, Novo Nordisk, Peptimmune, Roche, Roche Research Foundation, Santhera, Sanofi-Aventis, Swiss MS Society, Swiss National Research Foundation, Teva Pharmaceutical Industries Ltd, UCB, and Wyeth. J.K´s institution received research support from Swiss MS Society, Biogen, Novartis, Roche, Genzyme, and Merck Serono; he received research support from Bayer AG, Celgene, Genzyme, Novartis, Roche Pharma (Schweiz) AG, Swiss National Research Foundation, ECTRIMS, University of Basel, and Swiss MS Society.

Abstract: 273

Type: Scientific Session

Abstract Category: Therapy - Tools for detecting therapeutic response

J. Lorscheider1, P. Benkert2, S. Schädelin2, Ö. Yaldizli1, T. Derfuss1, P. Lalive3, C. Pot3, S. Müller4, J. Vehoff4, T. Sinnecker1, J. Würfel5, L. Achtnichts6, O. Findling6, K. Nedeltchev6, R. Du Pasquier7, G. Disanto8, C. Zecca8, C. Kamm9, A. Salmen10, A. Chan10, C. Granziera1, C. Gobbi8, L. Kappos1, J. Kuhle1, Swiss Multiple Sclerosis Cohort Study

1Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel and University of Basel, 2Clinical Trial Unit, University Hospital Basel, Basel, 3University Hospital of Geneva (HUG), Geneva, 4Cantonal Hospital St. Gallen, St. Gallen, 5Medical Image Analysis Center (MIAC AG) and Department for Biomedical Engineering, Basel, 6Cantonal Hospital Aarau, Aarau, 7University Hospital of Lausanne (CHUV), Lausanne, 8Neurocenter of Southern Switzerland, Civic Hospital, Lugano, 9Cantonal Hospital Lucerne, Lucerne, 10Department of Neurology, Inselspital Bern, University Hospital and University of Bern, Bern, Switzerland

Background: Recently, data from the randomised clinical trial of ocrelizumab in relapsing-remitting multiple sclerosis (RRMS) and the Tysabri Observational Program demonstrated that a substantial proportion of disability worsening events occurs unrelated to relapse activity. Hence, our aim was to analyse disability progression independent of relapse activity (PIRA) in a well-characterised observational cohort.
Methods: Using the Swiss Multiple Sclerosis Cohort Study, we included patients with RRMS and ≥3 prospective visits with available EDSS and Functional System (FS) scores. Confirmed disability worsening (CDW) was defined as EDSS increase of ≥1.5 steps if baseline EDSS step was 0, ≥1.0 step if 1.5-5.5, or ≥0.5 steps if >5.5, confirmed after ≥6 months. A roving baseline approach was applied to maximise sensitivity (Kappos et al., MSJ 2018), whereas re-baselining and a fixed baseline were used for a more conservative estimate. For PIRA, absence of a relapse between baseline, index event and confirmation visit was required. Influence of exposure to disease modifying treatment (DMT) was both modeled as categorical and as time-dependent covariate and analysed with Cox proportional hazards models adjusted for gender, age, disease duration, baseline EDSS and pre-baseline relapse activity. DMT was categorised in highly effective DMT, i.e. monoclonal antibodies, oral DMT and platform injectables.
Results: We included 917 RRMS patients with a median follow-up of 4.6 years. The roving baseline approach identified 198 (22%) patients experiencing CDW. Of these, 131 fulfilled the definition for PIRA (66% of patients with CDW, 14% of all eligible patients). The number of identified PIRA and CDW decreased when using a fixed baseline (92/157, 59%) or re-baselining (93/157, 59%). Highly effective DMT was associated with a lower risk for CDW (hazard ratio [HR] 0.4, 95% confidence interval [CI] 0.2-0.7, p< 0.001) compared to no treatment. However, we observed only a trend regarding PIRA (HR 0.5, 95% CI 0.3-1.1, p=0.08), which disappeared when modelling treatment as a time-dependent covariate (HR 0.8, 95%CI 0.4-1.4, p= 0.393).
Conclusion: A relevant proportion of patients classified as RRMS experienced PIRA within a 5-year period, accounting for 59-66% of all CDW events. While highly effective DMT reduced the risk of CDW, we could not demonstrate a consistent effect on PIRA in patients with RRMS in our prospectively followed cohort study.
Disclosure: J.L. has received research support from Biogen and served on advisory boards for Roche and Teva. P.B. reports no conflicts of interest. S.S. reports no conflicts of interest. Ö.Y.'s institution (University Hospital Basel) received honoraria for lectures from Teva, Novartis and Bayer Schering exclusively used for funding of research or educational courses. T.D. received speaker fees, research support, travel support, and/or served on Advisory Boards or Steering Committees of Novartis Pharma, Merck Serono, Biogen, Teva, Bayer-Schering, GeNeuro, Mitsubishi Pharma, MedDay, Roche, and Genzyme. P.L. received honoraria for speaking from Biogen, CSL Bering, Merck Serono, Novartis, Sanofi-Aventis, Teva; consulting fees from Biogen, Geneuro, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, Teva; research grants from Biogen, Merck Serono, Novartis. C.P. reports no conflicts of interest. S.M. received fees for travel, speaker honoraria and consulting services and/or research support from Almirall, Bayer, Biogen, Celgene, Genzyme, Merck, Novartis, Roche, and Teva.. J. V. has received honoraria and travel expenses from Biogen, Bayer, Teva, Novartis, Genzyme (Sanofi Aventis), Almirall and Merck. T.S. has received travel support from Actelion, Alkermes, and Roche. He is an employee of the MIAC AG in Basel. J.W. CEO of MIAC AG Basel, Switzerland. He served on scientific advisory boards of Actelion, Biogen, Genzyme-Sanofi, Novartis, and Roche. He is or was supported by grants of the EU (Horizon2020), Swiss National Research Foundation German, Federal Ministeries of Education and Research (BMBF) and of Economic Affairs and Energy (BMWI). L.A. Served on scientific advisory boards for Cellgene, Novartis Pharmaceuticals, Merck, Biogen, Sanofi Genzyme, Roche and Bayer; received funding for travel and/or speaker honoraria from Cellgene, Biogen, Sanofi Genzyme, Novartis, Merck Serono, Roche, Teva and the Swiss MS Society; and research support from Biogen, Sanofi Genzyme, and Novartis. O.F. reports no conflicts of interest. K.N. reports no conflicts of interest. R.D. has served on scientific advisory boards for Biogen, Merck Serono, Teva, and Novartis; has received funding for travel or speaker honoraria from Abbvie, Biogen, Teva, Merck Serono, and Bayer Schering Pharma. G.D. reports no conflicts of interest. C.Z. reports no conflicts of interest. C.K. received honoraria for lectures/consulting and/or grants for studies from Biogen, Novartis, Teva, Merck-Serono, Genzyme, Bayer Schweiz AG and the Swiss MS society. A.S. received speaker honoraria and/or travel compensation for activities with Almirall Hermal GmbH, Biogen, Merck, Novartis, Roche and Sanofi Genzyme, not related to this work. A.C.received compensation for activities with Actelion, Almirall, Bayer, Biogen, Celgene, Sanofi-Genzyme, Merck, Novartis, Roche, Teva, all for hospital research funds. He receives research support from Biogen, Sanofi-Genzyme and UCB. The University Hospital Basel (USB), as the employer of Ch.G., has received the following fees which were used exclusively for research support: (i) advisory board and consultancy fees from Actelion and Roche; (ii) speaker fees from Biogen and Genzyme-Sanofi. Before my employment at USB, I have also received speaker honoraria and travel funding by Novartis. C.G. reports no conflicts of interest. The University Hospital Basel, as the employer of L.K., has received and dedicated to research support fees for board membership, consultancy or speaking, or grants in the past 3 years from Actelion, Advancell, Allozyne, Bayer, Bayhill, Biogen Idec, BioMarin, CSL Behring, Eli Lilly EU, Genmab, GeNeuro SA, Gianni Rubatto Foundation, Glenmark, Merck Serono, MediciNova, Mitsubishi Pharma, Novartis, Novartis Research Foundation, Novo Nordisk, Peptimmune, Roche, Roche Research Foundation, Santhera, Sanofi-Aventis, Swiss MS Society, Swiss National Research Foundation, Teva Pharmaceutical Industries Ltd, UCB, and Wyeth. J.K´s institution received research support from Swiss MS Society, Biogen, Novartis, Roche, Genzyme, and Merck Serono; he received research support from Bayer AG, Celgene, Genzyme, Novartis, Roche Pharma (Schweiz) AG, Swiss National Research Foundation, ECTRIMS, University of Basel, and Swiss MS Society.

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