Treatment of primary progressive multiple sclerosis (PPMS) with disease-modifying therapies (DMTs) for patients experiencing relapse or with disease activity is linked to a significant reduction of long-term disability risk, new research shows.
“Taken as a whole, the results of our and previous studies suggest that the occurrence of inflammatory activity is relatively frequent and can represent a modifiable determinant of long-term disability accrual even in progressive MS,” write the investigators, led by Emilio Portaccio, MD, Department of Neuroscience, University of Florence, Italy.
Importantly, the benefits of DMTs among those with disease activity were observed across drug classes, even though ocrelizumab is currently the only DMT that is approved for PPMS.
“Our study results suggest that the off-label use of other DMTs in patients with PPMS with persistent inflammatory activity may be taken into consideration if ocrelizumab is contraindicated,” the researchers note.
The findings were published online July 25 in JAMA Neurology.
While a variety of DMTs are approved for the treatment of relapsing-remitting MS (RRMS), randomized trials have generally not shown similar benefits among patients with PPMS ― which is why only ocrelizumab is currently approved for the indication.
The lack of benefit could be because DMTs target inflammatory activity, which may be less prominent in PPMS than in RRMS, the investigators write.
To further study the effects of DMT treatment on risk of long-term disability in a real-world population of patients with PPMS, the researchers evaluated 409 patients in the Italian MS Register in the multicenter, double-blind, phase 3 ORATORIO trial.
The patients (mean age, 43 years; 55% women) were matched in the propensity-score analysis. Of these, 288 had been treated with DMTs, and 121 had not. There were no other significant differences in baseline characteristics.
With a mean follow-up of 10.6 years, 37% of the patients (n = 152) had reached the study’s outcome of an Expanded Disability Status Scale (EDSS) score of 7.0 or higher, which indicates wheelchair dependence. There was no significant difference for this outcome between the treated and untreated groups.
The key characteristics associated with reaching the 7.0 or higher EDSS score included having a higher EDSS score at baseline (adjusted hazard ratio [aHR], 1.32; P < .001), having relapses (aHR, 2.37; P = .009), and treatment with DMTs (aHR, 1.75; P = .03).
However, the only variable associated with a significantly reduced risk of reaching disability of EDSS 7.0 or higher was the use of DMT for patients who had experienced relapse activity (aHR, 0.33; P = .004).
Of note, there were no significant differences in the results based on different DMT classes, including those considered to be moderately effective: interferon beta-1a, interferon beta-1a/1b, glatiramer acetate, dimethyl fumarate, teriflunomide, methotrexate, and azathioprine; and those considered highly effective: ocrelizumab, rituximab, natalizumab, alemtuzumab, mitoxantrone, cyclophosphamide, cladribine, and fingolimod.
Identifying Inflammatory Activity “Crucial”
In a further analysis of 277 patients for whom MRI data were available at baseline, the results were similar. Risk of having an EDSS score of 7.0 or higher on follow-up was associated with having a higher EDSS score at baseline (aHR, 1.35; P = .002), DMT exposure (aHR, 3.61; P = .004), and presence of clinical and/or MRI activity (aHR, 2.14; P = .07).
Again, DMT in combination with the presence of clinical and/or MRI disease activity was associated with a significantly reduced risk of becoming wheelchair dependent (aHR, 0.30; 95% CI, 0.11-0.82; P = .02).
While the link between relapse activity and improved outcomes may appear counterintuitive, such activity in patients who are receiving a DMT “cannot be compared with that occurring without treatment,” the investigators note.
“For instance, it is possible that the number of relapses without treatment would have been higher than that observed during DMT,” they write.
Furthermore, the increased risk of disability associated with DMT exposure alone may reflect its use for patients who are not necessarily experiencing inflammatory activity, they add.
This higher risk of later disability with DMTs “may reflect the choice of neurologists to treat patients with more aggressive disease (for instance, rapidly progressing MS), despite the absence of clear inflammatory activity, and may reflect an indication bias and the lack of efficacy of DMTs in inactive PPMS,” the researchers write.
“Therefore, it would be crucial to identify, at the time of treatment introduction, patients who may experience persistent inflammatory activity in order to maximize the benefit-risk balance,” they add.
The investigators note that among participants in whom there was MRI or clinical disease activity at baseline, the majority (about 80%) continued to experience inflammatory events over time, underscoring the importance of spotting the activity.
Commenting for Medscape Medical News, Tomas Kalincik, MD, PhD, head of the MS Center, Department of Neurology, at the Royal Melbourne Hospital, Australia, said the study importantly adds to evidence supporting the benefits of DMTs for patients with PPMS and disease activity.
“This is a valuable study, which confirms the findings of the previous studies of registry data and subgroup analyses of randomized controlled trials in primary progressive MS,” said Kalincik, who was not involved with the research.
“The study from the Italian MS Registry shows that disease-modifying therapies, which are used to control inflammation, are more effective among patients with primary progressive MS who also present with clinical attacks,” he added.
Kalincink noted the findings underscore that “episodic, localized inflammation of the CNS serves as a potentially treatable target [and] by addressing this inflammation with therapy, neurologists are able to slow down the progression of disability in people with progressive MS.”
He also pointed out that the authors noted that most patients in the study had received less potent therapies.
“Therefore, the potential of the contemporary, high-efficacy therapies to control progression in active primary progressive MS is probably even greater than what is shown by this study,” Kalincik said.
Nevertheless, consideration of the patient’s full picture is ultimately necessary in decision-making, he added.
“The decision still depends on a highly individualized balancing of risks vs benefits, but it is appropriate that recommendations should now include individualization of therapy informed by the evidence of the potentially preventable inflammatory episodes,” said Kalincik.
The Italian iMedWeb database received funding in the form of annual research grants from the Italian University and Research Ministry, Merck Serono, Novartis, and Biogen. Portaccio has received travel grants for participation in advisory boards and/or speaking activities from Biogen, Merck, Sanofi Genzyme, Novartis, Roche, Celgene, and Teva. He has also served on the editorial board of Frontiers in Neurology and Brain Sciences. Disclosures for the other investigators are fully listed in the original article. Kalincik’s disclosures include co-authoring two prominent studies on MS and disability outcomes.
JAMA Neurol. Published online July 25, 2022. Abstract