Natural history of the revised ALS functional rating scale and its association with survival: the PRECISION-ALS Extant Study
Ruben P. A. van Eijk, Daphne N. Weemering, Sarah Opie-Martin, Jordi W. J. van Unnik, Alejandro Caravaca Puchades, Adriano Chiò, Philippe Corcia, Miriam Galvin, Orla Hardiman, Mark Heverin, Frederik Hobin, Oskar Holmdahl, Caroline Ingre, Nikita Lamaire, Éanna Mac Domhnaill, Harry McDonough, Umberto Manera, Christopher McDermott, Robert McFarlane, Mohammed Mouzouri, Fouke Ombelet, Mónica Povedano Panadés, Stefan Sennfält, Pamela J. Shaw, Carlos Pastor‐Vargas, Philip Van Damme, Rosario Vasta, Jan H. Veldink, Ammar Al-Chalabi, Leonard H. van den Berg
Abstract
Objective To characterize the natural history of the revised ALS functional rating scale (ALSFRS-R) over a 24-month period following initial assessment, and to assess its associations with survival.Methods Longitudinal ALSFRS-R measurements and survival data were obtained from seven population-based, European cohorts. Different models for the ALSFRS-R trajectory were evaluated, including tests for linearity and between-cohort differences. We employed a joint modeling framework to factor in mortality, thereby aiming to derive a more precise estimate of the population’s rate of decline, while simultaneously delineating its relationship with survival.Results In total, 7,030 patients were included who produced 31,746 ALSFRS-R measurements during a follow-up period of 10,285 person-years. There was substantial evidence for a non-linear time trend within all cohorts (all p < 0.001), with faster progression rates at the beginning of follow-up. The average rate over 24 months was 0.89 points per month; 95% of the patients had a rate between 0.04 and 1.96. Overall, two components of the ALSFRS-R trajectory were found to be associated with survival: (1) the actual value of the ALSFRS-R total score and (2) the rate of change at any given time (both p < 0.001).Conclusions Functional loss in ALS follows a decelerating trajectory, where the current functional status and the rate of change have a direct impact on the patient’ s probability of survival. Given the pivotal role of the ALSFRS-R in drug development, these results help to separate treatment benefit from the disease’s natural trajectory and to estimate the impact on survival.