Progression Independent of Relapse Activity (PIRA) in Patients with Relapsing Multiple Sclerosis

Background: Accumulation of disability in multiple sclerosis (MS) may occur as relapse-associated worsening (RAW) or as steady progression independent of relapse activity (PIRA), regarded as a feature of primary and secondary progressive MS. Using two Phase III trials comparing ocrelizumab and interferon (IFN) β-1a in a typical relapsing MS (RMS) population, we investigated the relative contribution of RAW and PIRA to overall confirmed disability accumulation (CDA), assessed baseline prognostic factors of PIRA and RAW, and respective effects of the two treatments. Methods: CDA, PIRA, and RAW events were assessed in the pooled intent-totreat population of the OPERA I and II trials. CDA was defined using a composite measure that included a defined increase in Expanded Disability Status Scale, Timed 25-Foot Walk, or 9-Hole Peg Test confirmed after ≥12 or ≥24 weeks. RAW events were defined as a confirmed worsening occurring ≤90 days after onset of a protocol-defined relapse. Findings: PIRA events were the main contributors to 12/24-week composite CDA after 96 weeks. Of this overall risk, 78·7% to 88·9% corresponded to PIRA while 13·0% to 21·1% was explained by RAW events. Acute baseline lesional MRI activity only predicted RAW, whereas PIRA was predicted by baseline T1 and T2 lesion burden, whole brain and cortical grey matter atrophy, disease duration, male sex, baseline disability, and perceived quality of life. Very few patients experienced both RAW and PIRA. Compared with IFN β-1a, ocrelizumab reduced the risk of composite CDA, composite PIRA, and composite RAW events confirmed at 12/24 weeks. Interpretation: A considerable proportion of overall accumulation of disability in RMS is not related to overt relapses. This indicates an underlying progressive course in this typical RMS population and challenges the current clinical distinction of relapsing and progressive forms of MS. Ocrelizumab was superior to IFN β-1a in preventing both RAW and PIRA. Funding Statement: F. Hoffmann-La Roche Ltd, Basel, Switzerland. Declaration of Interests: L Kappos’s institution, the University Hospital Basel, has received research support and payments that were used exclusively for research support for Prof. Kappos’s activities as principal investigator and member or chair of planning and steering committees or advisory boards for trials sponsored by Actelion, Addex, Almirall, Bayer HealthCare Pharmaceuticals, CSL Behring, F. Hoffmann-La Roche Ltd and Genentech, Inc., GeNeuro SA, Genzyme, Merck, Mitsubishi Pharma, Novartis, Octapharma, Ono Pharmaceutical, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB, and XenoPort; has received license fees for Neurostatus products; and has received research grants from the European Union, Novartis Research Foundation, Roche Research Foundation, Swiss Multiple Sclerosis Society, Innosuisse, and Swiss National Research Foundation. JS Wolinsky has served on advisory boards, data monitoring or steering committees, has consulting agreements from the following entities: AbbVie, Acorda Therapeutics, Actelion, Alkermes, Biogen, Bionest, Brainstorm Cell Therapeutics, Celgene, Clene Nanomedicine, EMD Serono, Forward Pharma A/S, GeNeuro, GW Pharma Ltd, MedDay Pharmaceuticals, Novartis Pharmaceuticals, Otsuka, PTC Therapeutics, Roche Genentech, and Sanofi Genzyme; royalties are received for outlicensed monoclonal antibodies through UTHealth from Millipore Corporation. G Giovannoni has received honoraria from AbbVie, Atara Biotherapeutics, Bayer HealthCare, Biogen, Canbex Therapeutics, F. Hoffmann-La Roche Ltd, Five Prime Therapeutics, Genzyme, GlaxoSmithKline, GW Pharmaceuticals, Merck, Merck Serono, Novartis, Protein Discovery Laboratories, Synthon, Teva, UCB, and Vertex; research grant support from Biogen, Ironwood, Merck Serono, Merz, and Novartis; and compensation from Elsevier. DL Arnold has received personal fees for consulting from Acorda, Biogen, F. Hoffmann-La Roche Ltd, MedImmune, Mitsubishi, Novartis, Receptos, and Sanofi-Aventis; grants from Biogen and Novartis; and an equity interest in NeuroRx Research. Q Wang is an employee of F. Hoffmann-La Roche Ltd. C Bernasconi is a contractor for F. Hoffmann-La Roche Ltd. F Model is an employee and shareholder of F. Hoffmann-La Roche Ltd. H Koendgen is an employee and shareholder of F. Hoffmann-La Roche Ltd M Manfrini is an employee of F. Hoffmann-La Roche Ltd. S Belachew was an employee of F. Hoffmann-La Roche Ltd. during the completion of the work related to this manuscript. S Belachew is now an employee of Biogen (Cambridge, MA, USA), which was not in any way associated with this study. SL Hauser serves on the board of trustees for Neurona and on scientific advisory boards for Alector, Annexon, Bionure, Molecular Stethoscope, and Symbiotix, and has received travel reimbursement and writing assistance from F. Hoffmann-La Roche Ltd for CD20-related meetings and presentations.