Accounting for disease modifying therapy in models of clinical progression in multiple sclerosis.
Identifying predictors of clinical progression in patients with relapsing-remitting multiple sclerosis (RRMS) is complicated in the era of disease modifying therapy (DMT) because patients follow many different DMT regimens. To investigate predictors of progression in a treated RRMS sample, a cohort of RRMS patients was prospectively followed in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB). Enrollment criteria were exposure to either interferon-β (IFN-β, n=164) or glatiramer acetate (GA, n=114) for at least 6 months prior to study entry. Baseline demographic and clinical features were used as candidate predictors of longitudinal clinical change on the Expanded Disability Status Scale (EDSS). We compared three approaches to account for DMT effects in statistical modeling. In all approaches, we analyzed all patients together and stratified based on baseline DMT. Model 1 used all available longitudinal EDSS scores, even those after on-study DMT changes. Model 2 used only clinical observations prior to changing DMT. Model 3 used causal statistical models to identify predictors of clinical change. When all patients were considered using Model 1, patients with a motor symptom as the first relapse had significantly larger change in EDSS scores during follow-up (p=0.04); none of the other clinical or demographic variables significantly predicted change. In Models 2 and 3, results were generally unchanged. DMT modeling choice had a modest impact on the variables classified as predictors of EDSS score change. Importantly, however, interpretation of these predictors is dependent upon modeling choice.
Department of Neurology, Partners Multiple Sclerosis Center, Brigham and Women's Hospital, Harvard Medical School, Brookline, MA 02115, USA. bchealy@partners.org
Brian C
BC
Healy
David
D
Engler
Taha
T
Gholipour
Howard
H
Weiner
Rohit
R
Bakshi
Tanuja
T
Chitnis
D000328:Adult; D017668:Age of Onset; D000368:Aged; D015331:Cohort Studies; D003627:Data Interpretation, Statistical; D004185:Disability Evaluation; D018450:Disease Progression; D005260:Female; D000068717:Glatiramer Acetate; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007370:Interferon Type I / Q000627:therapeutic use; D016899:Interferon-beta / Q000627:therapeutic use; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009103:Multiple Sclerosis / Q000188:drug therapy*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy; D010455:Peptides / Q000627:therapeutic use; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D011994:Recombinant Proteins; D012727:Sex Characteristics; D016896:Treatment Outcome; D055815:Young Adult
D007166:Immunosuppressive Agents; D007370:Interferon Type I; D010455:Peptides; D011994:Recombinant Proteins; D000068717:Glatiramer Acetate; D016899:Interferon-beta