Patterns and Predictors of Multiple Sclerosis Phenotype Transitions: A Longitudinal Analysis Using the CLIMB Study
Gauruv Bose1, Nupur Greene2, Brian C. Healy3, Howard Weiner4, Lisa Farnett2, Keiko Higuchi2, Tanuja Chitnis4
1Brigham and Women’s Hospital; and University of Ottawa and Ottawa Hospital Research Institute, 2Sanofi, 3Brigham and Women’s Hospital Boston, 4Brigham and Women's Hospital; and Harvard Medical School
To investigate how people with multiple sclerosis (pwMS) transition between phenotypes, within the Comprehensive Longitudinal Investigation of MS at the Brigham and Women’s Hospital (CLIMB) Study. 
MS characteristics vary over time, but little is known about transitions and predictors of change among phenotypes
Retrospective analysis of US-based CLIMB Study. PwMS (18-65y) diagnosed between 2000/1/1–2010/12/31 were identified to allow ≥10y of data for descriptive and predictive analysis. PwMS were categorized by phenotype (relapsing-remitting MS[RRMS], primary-progressive MS[PPMS], active-secondary progressive MS[aSPMS], non-relapsing secondary-progressive MS[nrSPMS]). Demographics were extracted alongside disability scores (Expanded Disability Status Scale [EDSS]). Cox regression modelled time to MS diagnosis. Predictors of progression were determined by univariate analyses. 
Of 565 with initial RRMS diagnosis, 95 (16.8%) transitioned to SPMS (median time 10.4y [range: 1.3–21.3y]). 56/95 (58.9%) transitioned to nrSPMS, and never relapsed. Of 39 pwMS with any aSPMS diagnosis, 32/39 (82.1%) transitioned to nrSPMS by last visit. Relative risk for time to reach EDSS level 3, 4, or 6, was lowest for RRMS patients (hazard ratio [HR]: 0.84 0.73, 0.68, respectively; all P<0.0001), and highest for PPMS patients (HR: 5.5, 10.7, 15.0, respectively; all P<0.0001), respectively. Older age at MS onset (HR[95% CI]: 1.05 [1.03-1.07]), higher baseline EDSS (1.42 [1.26-1.62]), and higher number of DMT switches (1.21 [1.11-1.32]) were significant predictors of shorter time to nrSPMS diagnosis (all P<0.001). 
Overall, 41% of the RRMS cohort who transitioned to SPMS overlapped with an active phenotype (aSPMS), while the majority (59%) transitioned without relapses (nrSPMS). Those who transitioned through aSPMS tended to be younger and more likely to have DMT escalation vs. those who transitioned without relapse (nrSPMS). Defining nrSPMS in addition to aSPMS should facilitate better patient management and aid timely intervention to aid delaying patients entering the progressive stage of MS.