By Jai S. Perumal, MD
Assistant Professor of Neurology, Weill Cornell Medical College; Assistant Attending Neurologist, New York-Presbyterian Hospital
Dr. Perumal reports she is a consultant for Biogen and Genzyme.
SYNOPSIS: In a multicenter, observational, retrospective “real world” analysis of a large cohort of relapsing multiple sclerosis (MS) patients, the authors found that being on disease-modifying therapy decreased the risk of long-term disability progression in both pediatric and adult MS patients.
SOURCE: Amato MP, Fonderico M, Portaccio E, et al. Disease-modifying drugs can reduce disability progression in relapsing multiple sclerosis. Brain 2020;143:3013-3024.
Although several disease-modifying treatments (DMT) currently are approved for the treatment of relapsing and remitting multiple sclerosis (MS), based on clinical trials, it is important that we have a better understanding of their benefit in a real-world scenario. Therapeutic trials enroll patients who fit within certain criteria of age, disease duration, disability, and other restrictive baseline characteristics, and the duration of these studies is often just two to three years. Hence, an assessment of these treatments in patients in clinical practice and evaluation of longer-term outcomes would provide important data to better to gauge the true impact of these medications.
Amato et al conducted a retrospective, multicenter analysis of patients with prospectively collected information in an Italian database. The patients were divided into three cohorts based on their age at disease onset: pediatric-onset MS (POMS) for disease onset ≤ 18 years, adult-onset MS (AOMS) for > 18 years to < 50 years of age, and late-onset MS (LOMS) for patients who were diagnosed at age 50 years or older. They identified 460 POMS, 6,574 AOMS, and 382 LOMS patients who fit the criteria to be included in the analysis. Inclusion criteria for the study were: 1) first neurological examination within three years of symptom onset; and 2) a minimum of five years of follow-up after the diagnosis. Primary progressive MS patients were excluded from the study. The primary outcome was 12-month confirmed disability worsening (CDW) based on an increase in the Expanded Disability Status Scale (EDSS) score.
They also evaluated time to reach an EDSS of 4, which is a milestone that indicates limitation in function. CDW was defined a ≥ 1 point increase in EDSS for those with a baseline between 1 and 5, and ≥ 1.5 in those with a baseline EDSS of 0. Multivariate Cox regression models were used to assess predictors of reaching CDW. DMT exposure was divided into quartiles based on duration of treatment. They divided the treatments into moderately effective (interferons, glatiramer acetate, dimethyl fumarate, teriflunomide, and azathioprine) and highly effective (monoclonal antibodies, mitoxantrone, cladribine, and fingolimod). The majority of patients in this study were on a moderately effective treatment. The mean follow-up was about 12 years for POMS, 11 years for AOMS, and nine years for LOMS. Treatment for all of these groups was started within three years of symptom onset.
Based on the regression analysis, the authors reported that the most significant predictor of long-term disability in POMS and AOMS was treatment with DMT. Increasing treatment exposure resulted in a stepwise reduction in disability progression. For LOMS, there was a trend toward treatment benefit. DMT reduced the risk of CDW with a progressive risk reduction in the different treatment quartiles (adjusted hazard ratio [aHR], 8.0; 95% confidence interval [CI], 3.3-17.9 in POMS; aHR, 6.3; 95% CI, 4.9-8.0 in AOMS; P < 0.0001; and aHR, 1.9; 95% CI, 0.9-4.1; P = 0.07 in LOMS). A higher number of relapses was associated with an increased risk of long-term disability.
The authors concluded that their large study with long-term follow-up demonstrates that DMT can reduce the risk of long-term disability and that the longer the patient was on treatment, the greater the benefit. They also emphasized that their data strongly support the use of DMT in pediatric patients, where the medications are used off-label because they are not specifically approved for use in the pediatric population. POMS patients who were started on DMT earlier and continued it for a longer duration had a greater reduction of risk of disability progression.
This large, multicenter study of “real-world” data in MS demonstrates that starting and staying on DMT has significant impact on long-term disability. Most therapeutic clinical trials in MS are of two to three years’ duration and, hence, are better suited to gauge the impact of treatments on relatively more immediate outcomes like MRI lesions or relapses. Disability outcomes measures in these trials are suboptimal, and it is from long-term follow-up data like the current study that we can obtain a much better understanding of the impact of DMT on disability from MS. Also, the measure of CDW used here was defined as worsening confirmed over a 12-month period vs. the three to six months that typically is used in clinical trials. They also included POMS, where there is a relative dearth of information when compared to DMT trials in adults with MS.
This analysis also shows that in patients with relapsing disease, there is cumulative benefit to longer treatment duration. As we have more and more treatment options available, it is imperative that we use them optimally early in the disease course to make a meaningful difference in long-term disability in patients with MS.