Confirmed disability progression as a marker of permanent disability in multiple sclerosis

Sifat Sharmin 1, Francesca Bovis 2, Charles Malpas 1 3, Dana Horakova 4, Eva Kubala Havrdova 4, Guillermo Izquierdo 5, Sara Eichau 5, Maria Trojano 6, Alexandre Prat 7 8, Marc Girard 7 8, Pierre Duquette 7 8, Marco Onofrj 9, Alessandra Lugaresi 10 11, Francois Grand'Maison 12, Pierre Grammond 13, Patrizia Sola 14, Diana Ferraro 14, Murat Terzi 15, Oliver Gerlach 16, Raed Alroughani 17, Cavit Boz 18, Vahid Shaygannejad 19, Vincent van Pesch 20 21, Elisabetta Cartechini 22, Ludwig Kappos 23, Jeannette Lechner-Scott 24 25, Roberto Bergamaschi 26, Recai Turkoglu 27, Claudio Solaro 28, Gerardo Iuliano 29, Franco Granella 30 31, Bart Van Wijmeersch 32, Daniele Spitaleri 33, Mark Slee 34, Pamela McCombe 35 36, Julie Prevost 37, Radek Ampapa 38, Serkan Ozakbas 39, Jose Luis Sanchez-Menoyo 40, Aysun Soysal 41, Steve Vucic 42, Thor Petersen 43, Koen de Gans 44, Ernest Butler 45, Suzanne Hodgkinson 46, Youssef Sidhom 47, Riadh Gouider 47, Edgardo Cristiano 48, Tamara Castillo-Triviño 49, Maria Laura Saladino 50, Michael Barnett 51, Fraser Moore 52, Csilla Rozsa 53, Bassem Yamout 54, Olga Skibina 55 56, Anneke van der Walt 55 56, Katherine Buzzard 55 56, Orla Gray 57, Stella Hughes 58, Angel Perez Sempere 59, Bhim Singhal 60, Yara Fragoso 61, Cameron Shaw 62, Allan Kermode 63 64 65, Bruce Taylor 66, Magdolna Simo 67, Neil Shuey 68, Talal Al-Harbi 69, Richard Macdonell 70, Jose Andres Dominguez 71, Tunde Csepany 72, Carmen Adella Sirbu 73, Maria Pia Sormani 2, Helmut Butzkueven 55 56, Tomas Kalincik 1 3

Affiliations

doi: 10.1111/ene.15406

Abstract

Background and purpose: The prevention of disability over the long term is the main treatment goal in multiple sclerosis (MS); however, randomized clinical trials evaluate only short-term treatment effects on disability. This study aimed to define criteria for 6-month confirmed disability progression events of MS with a high probability of resulting in sustained long-term disability worsening.

Methods: In total, 14,802 6-month confirmed disability progression events were identified in 8741 patients from the global MSBase registry. For each 6-month confirmed progression event (13,321 in the development and 1481 in the validation cohort), a sustained progression score was calculated based on the demographic and clinical characteristics at the time of progression that were predictive of long-term disability worsening. The score was externally validated in the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial.

Results: The score was based on age, sex, MS phenotype, relapse activity, disability score and its change from baseline, number of affected functional system domains and worsening in six of the domains. In the internal validation cohort, a 61% lower chance of improvement was estimated with each unit increase in the score (hazard ratio 0.39, 95% confidence interval 0.29-0.52; discriminatory index 0.89). The proportions of progression events sustained at 5 years stratified by the score were 1: 72%; 2: 88%; 3: 94%; 4: 100%. The results of the CLARITY trial were confirmed for reduction of disability progression that was >88% likely to be sustained (events with score ˃1.5).

Conclusions: Clinicodemographic characteristics of 6-month confirmed disability progression events identify those at high risk of sustained long-term disability. This knowledge will allow future trials to better assess the effect of therapy on long-term disability accrual.

Keywords: CLARITY; clinical trial; functional system impairment; risk scoring; sustained disability progression.

Conflict of interest statement

The authors report the following relationships: speaker honoraria, advisory board or steering committee fees, research support and/or conference travel support from Almirall (G.Iz., M.Tr., R.B., C.So., J.L.SM), Bayer (P.S., V.V.P., L.K., J.LS., R.B., G.Iu., MSl, RAl, RAm, J.L.SM, T.P., S.H., C.R., B.T., M.Si., N.S., P.M., T.C., S.E., M.Tr., M.Te., E.Cr.), BioCSL (T.K., K.B.), Biogen (A.L., D.H., P.G., P.S., D.F., H.B., J.LS., F.Gm., F.Gr., S.H., M.B., O.Gr., B.S., C.So., C.Sh., B.T., N.S., P.M., M.P.S., O.Ge., O.S., S.E., K.B., M.Tr., G.Iz., G.Iu., MSl, M.Si., RAl, R.Am., E.Cr.), Celgene (E.K.H.), Genzyme‐Sanofi (T.K., A.L., M.P.S., O.Gr., O.Ge., O.S., S.E., K.B., M.Tr., M.Te., C.So., G.Iz., G.Iu., F.Gm., F.Gr., MSl, RAl, E.Cr.), GSK (RAl), Innate Immunotherapeutics (A.K.), Merck/EMD (D.H., E.K.H., G.Iu., M.Tr., A.L., P.G., P.S., D.F., T.K., M.Te., R.Am., H.B., C.B., V.V.P., L.K., J.LS, R.B., C.So., G.Iz., F.Gr., B.V.W., D.S., MSl, RAl, J.L.SM., T.P., S.Ho., E.Cr., M.B., C.R., O.Gr., B.S., Y.F., A.K., M.Si., T.C., M.G., P.D., F.M., M.P.S., O.Ge., O.S., S.E., K.B.), Mitsubishi (F.Gm.), Mylan (A.L.), Novartis (D.H., E.K.H., G.Iz., M.Tr., M.G., P.D., A.L., F.Gm., P.G., P.S., D.F., T.K., M.Te., R.Am., H.B., CB, V.V.P., L.K., J.LS., R.B., C.So., G.Iu., F.Gr., B.V.W., D.S., MSl, J.P., RAl, J.L.SM, T.P., S.H., E.Cr., M.B., F.M., C.R., O.Gr., Y.F., C.Sh., A.K., BT, MSi, NV, NS, PM, TC, MPS, OS, FB, SE, K.B.), ONO Pharmaceuticals (FGm), Roche (DH, EKH, GIz, AL, TK, MTe, RAl, CB, VVP, LK, FGr, BVW, T.P., ECr, Y.F., B.T., T.C., M.P.S., S.Ho., S.E., K.B.), Teva (D.H., E.K.H., G.Iz., G.Iu., M.Tr., M.G., P.D., A.L., F.Gm., P.G., P.S., D.F., T.K., M.Te., R.T., C.B., V.V.P., L.K., J.LS., R.B., C.So., B.V.W., D.S., J.P., R.Am., J.L.SM., C.R., Y.F., A.K., M.Si., T.C., C.A.S., M.P.S., O.Ge., O.S., S.E., K.B.), WebMD (T.K.), UCB (L.K.), GeNeuro (M.P.S.), Medday (M.P.S.), Fondazione Italiana Sclerosi Multipla (A.L.), Grifols (K.B.), Actelion (R.Am.).

Figures

FIGURE 1 Flow diagram of patients and 6‐month confirmed progression events included in the analyses

FIGURE 1 Flow diagram of patients and 6‐month confirmed progression events included in the analyses

FIGURE 2 (a) Histogram of the sustained progression scores in the internal validation cohort. n represents the number of patients with each integer progression score. (b) The risk of 6‐month confirmed progression events being sustained over time stratified by the sustained progression score in the internal validation cohort. Example: A progression event confirmed over 6 months was recorded in a 40‐year‐old male diagnosed with RRMS, who presented with a two‐step increase in EDSS from step 5.5 to 7.5, in the absence of a relapse during the preceding month, with five neurological domains affected and worsening in pyramidal (1 unit), cerebellar (2 units) and sensory (2 units) functional system scores. The sustained progression score in this patient was estimated as 2.001 [Colour figure can be viewed at wileyonlinelibrary.com] show full caption

FIGURE 2 (a) Histogram of the sustained progression scores in the internal validation cohort. n represents the number of patients with each integer progression score. (b) The risk of 6‐month confirmed progression events being sustained over time stratified by the sustained progression score in the internal validation cohort. Example: A progression event confirmed over 6 months was recorded in a 40‐year‐old male diagnosed with RRMS, who presented with a two‐step increase in EDSS from step 5.5 to 7.5, in the absence of a relapse during the preceding month, with five neurological domains affected and worsening in pyramidal (1 unit), cerebellar (2 units) and sensory (2 units) functional system scores. The sustained progression score in this patient was estimated as 2.001 [Colour figure can be viewed at wileyonlinelibrary.com] show full caption

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