Starting intensive therapy early in multiple sclerosis (MS) produced better long-term outcomes in real-life settings, an observational study in Wales found.
Five years after symptom onset, disability scores were lower among young MS patients who received early treatment with high-efficacy monoclonal antibodies than patients who started with moderate-efficacy treatment, reported Neil Robertson, MD, of University Hospital of Wales in Cardiff, and colleagues in JAMA Neurology.
In recent years, nearly a dozen drugs have been shown to suppress disease activity in relapsing-remitting MS, noted co-author Emma Tallantyre, PhD, also at Cardiff University.
"However, the medications differ considerably in their efficacy and safety; the drugs with the strongest effect are often associated with the most worrisome risks," Tallantyre said.
As result, there's uncertainty about how to treat MS in its early stages, with high-efficacy early intensive therapies often reserved for those with rapidly evolving, severe disease, Tallantyre noted. But the results of this cohort study suggest "that existing thresholds for this therapeutic approach may be too high, and the delay imposed by escalation strategies may result in lost therapeutic opportunity," she added.
"Beyond looking at Medication A versus Medication B, this study examines overall treatment approach or philosophy," observed Daniel Ontaneda, MD, of the Cleveland Clinic, who was not part of the study. "Do you start low and escalate as needed, or do you start more with effective medications from the get-go?"
"This study shows very convincing evidence that treating early makes a difference," Ontaneda told MedPage Today. "It goes beyond just control of relapses. It makes a difference in terms of how much disability you accrue overall."
In this analysis, Robertson and colleagues studied 592 MS patients in southeast Wales with an average age of 27 at symptom onset. They used a database that captured an estimated 97% of all MS cases in the region from 1998 to 2016 and looked at clinical exam data, prescription records, and Expanded Disability Status Scale (EDSS) scores.
The researchers classified monoclonal antibodies -- alemtuzumab (Lemtrada) and natalizumab (Tysabri) -- as high-efficacy treatment. All other therapies were considered moderate efficacy, including interferons, glatiramer acetate (Copaxone), dimethyl fumarate (Tecfidera), fingolimod (Gilenya), and teriflunomide (Aubagio). Ocrelizumab (Ocrevus) was not licensed in the U.K. during the study period and not included.
Overall, 104 patients started with high-efficacy and 488 patients started with moderate-efficacy treatment. The groups had similar baseline characteristics, but the mean baseline EDSS score was 4.2 in the high-efficacy cohort and 3.5 in the moderate-efficacy cohort (EDSS scores range from 0 to 10, with higher numbers representing higher levels of disability.)
Of the 488 patients in the moderate-efficacy group, 58 (11.9%) escalated to a high-efficacy agent during the follow-up period, mainly due to relapses. The median time to escalation was 2.4 years.
In total, 179 patients (41 in the high-efficacy group and 138 in the moderate-efficacy group) had EDSS scores available at baseline and at 5-year follow-up. The mean change in EDSS score was lower in the high-efficacy group than moderate group (0.3 vs 1.2) at 5 years. This remained significant after adjusting for relevant covariates (β = −0.85, 95% CI −1.38 to −0.32, P=0.002).
The median time to sustained accumulation of disability (SAD) was 6.0 years for the high-efficacy and 3.14 years for moderate-efficacy group (P=0.05), but the hazard of reaching SAD was not statistically significant after adjusting for potential confounders. For patients in the moderate group who escalated to high-efficacy agents as second-line treatment, the median time to SAD was 3.3 years; 60% of these patients reached SAD while on initial moderate-efficacy treatment.
There were no treatment-related deaths in the study. Of patients who received alemtuzumab, 47% of patients developed autoimmunity, but no serious infections occurred. Patients who received natalizumab had no serious adverse events and no cases of progressive multifocal leukoencephalopathy. Patients who received moderate-efficacy agents had seven serious adverse events: three cases of necrotic skin reactions, one case of anaphylaxis, and three severe infections.
Based on these and other findings, the DELIVER-MS trial -- a multi-center prospective study of therapy algorithms for MS -- has started to evaluate treatment approaches with the drugs mentioned in this study, plus ocrelizumab and off-label rituximab (Rituxan).
Meanwhile, better escalation approach procedures need to be developed, Robertson noted. "These need to detect where first-line treatments are failing to slow the progression of the disease and respond by moving patients to more effective therapies without people developing permanent disability," he said.
The research had limitations commonly found in cohort studies, such as a lack of uniformly acquired imaging or adverse event data, the authors noted. It also was subject to hidden biases, Ontaneda pointed out: "There are reasons some patients were started on higher-effective medications that we don't know."
Researchers disclosed relevant relationships with Novartis UK, Biogen, Teva Pharmaceutical Industries, Roche, MedDay Pharma, Genzyme, and Merck & Co.
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