Background: Except for ocrelizumab, treatment options in primary progressive multiple sclerosis (PPMS) are lacking, as randomized clinical trials failed to show efficacy in reducing disability progression in this patient population.
Objective: To investigate the effectiveness of disease-modifying treatment (DMT) on hard disability outcomes (EDSS 6 and 7) in a real-life population of PPMS patients.
Methods: Using the Italian MS Registry, we selected PPMS patients with at least three EDSS evaluations and three years of follow-up. Study baseline was defined as the first EDSS evaluation for untreated patients and the date of the first DMT initiation for treated patients. The impact of DMT on the risk of reaching EDSS 6 and 7 was assessed as a dichotomous variable (yes versus no) and as a time-dependent covariate through multivariable Cox regression models (adjusted for age at baseline, sex, first EDSS score, symptoms at onset, annualized visit rate, annualized relapse rate). We compared outcomes with an as-treated analysis and used propensity-score matching (PSM) to select cohorts with comparable baseline characteristics. DMT-exposure was also evaluated in terms of quartiles of exposure.
Results: Of the 1214 patients we included 671 females, mean ± Standard Deviation baseline age 48.7 ± 11.1 years, mean EDSS score 4.1 ± 1.8, 790 (65%) received a DMT during the follow-up (57% platform and 43% highly active treatments). In the whole sample, after a mean follow-up of 11.6 ± 6.3 years, 994 (82%) patients reached EDSS 6 and 539 (44%) EDSS 7. In the multivariable Cox regression models, the use of DMT analyzed as a dichotomous variable did not influence the risk of reaching EDSS 6 (aHR=1.1, 95% CI 0.95-1.28, p=0.181) and EDSS 7 (aHR = 0.93, 95% CI 0.77-1.12. p = 0.454). However, longer DMT exposure significantly reduced the risk of reaching EDSS 7 (aHR = 0.73, 95% CI 0.56-0.95, p =0.021). Of note, patients in the upper quartile of DMT exposure compared with those with shorter DMT exposure were younger at baseline (mean age 44.1 ± 10.6 years; p < 0.001) and received the first DMT closer to the disease onset (mean time to first DMT 6.8 years ± 6.1 ; p=0.002). All these findings were confirmed in the PSM analysis.
Conclusion: Our results suggest that longer exposure to DMT may delay time to wheelchair in PPMS patients. Moreover, treating younger patients and reducing the delay to treatment initiation may improve the patients’ long-term disability outcomes. To optimize treatment decision-making in PPMS further profiling of the best candidates to treatment is needed.