Article summary
Patients at any stage of multiple sclerosis can be irreversibly disabled not only by disease progression independent of recurrent activity, but also by exacerbation associated with recurrence.
A new study published online Dec. 19 found that patients with multiple sclerosis (MS) who had disease progression independent of recurrent activity (PIRA) within the first five years of being diagnosed had severe The risk of developing the disorder was significantly higher. Department of Neurology, JAMA.
PIRA after the first demyelinating event had worse outcomes, especially when occurring early in the disease course.
The findings suggest that irreversible disability can manifest through both relapse-associated exacerbations and PIRA at any stage. Even in patients without a formal diagnosis of secondary progressive multiple sclerosis, PIRA is associated with a predominant underlying neurodegenerative component, which appears to be the most important mechanism. The study author writes.
“We observed that having at least one PIRA event at any time during the disease course was strongly associated with an unfavorable long-term prognosis, especially if the first PIRA event occurred within the first 5 years of disease. It was done,” said the study’s director. The researcher, Carmen Tur, MD, PhD, is a neurologist at the Catalan Multiple Sclerosis Center (Cemcat) at the Val Her Devon Institute in Barcelona, Spain.
“If that happens, the risk of reaching a noticeable level of disability (score 6.0 on the Expanded Disability Status Scale (EDSS)) is 26 times higher than for patients presenting with PIRA late in the disease.”
She added that the study “reveals the importance of progression in the absence of MS relapses even in the very early stages of the disease.”
“This may contradict the notion that relapsing-remitting MS is characterized by relapses (with varying degrees of subsequent recovery) with no apparent progression in between,” said Dr. Tur. “This study raises a very important question for multiple sclerosis researchers and clinicians: Should the current clinical classification of multiple sclerosis be changed?”
Survey details
A long-term study conducted from 1 January 1994 to 31 July 2021 included 1,128 patients from one research center in Barcelona who had a first demyelinating event.
“This study raises a very important question for multiple sclerosis researchers and clinicians: Should the current clinical classification of multiple sclerosis be changed?” —DR. Carmen Tur
“The timely detection of PIRA will not only influence advice and treatment choices, but also our efforts to develop therapies that target the pathophysiological mechanisms responsible for their progression.” ”—DR. Ludwig Kappos
The investigators aimed to estimate the risk of developing PIRA after symptom onset and to explore potential clinical and MRI predictors at the time of this event.
They also evaluated long-term outcomes in these patients and examined potential associations between the timing of the first event or the presence of recent inflammatory activity preceding it and long-term disability outcomes. was intended to
The investigators reviewed data on clinical and neuroimaging features during the first demyelinating bout, assessed the annual increase in EDSS after the first bout, and compared time to first PIRA and time to EDSS score of 6.0. We adjusted the hazard ratios for the predictors of .
They found that 25% of patients who experienced their first attack of MS developed at least one PIRA event during their disease course, and 10% within the first 5 years after symptom onset. .
Of all PIRA patients, 86 of 277 (31%) had early onset and 73 of 144 (51%) developed active PIRA.
The researchers noted that patients with PIRA were slightly older, had more brain lesions, and were more likely to have oligoclonal bands than those without PIRA. Age at first attack was the only predictor of her PIRA (p< 0.001 every decade older).
PIRA patients were eight times more likely to achieve a high disability score of 6.0 on the EDSS 6.0 (p = 0.001) than without PIRA.
Early PIRAs showed a steeper annual rate of increase in EDSS than late PIRAs (p < 0.001), a 26 times higher risk of reaching EDSS 6.0 from the first attack (p = 0.009).
The main strengths of this study are its large sample size, uniquely long follow-up, and the high quality of the clinical and MRI data collected over many years, Dr. Tur said, adding, “All these factors contribute to this important We were able to investigate a number of important issues: aspects of the clinical progression of MS.”
However, she noted that some of the diagnostic criteria and procedures performed in clinics have changed over the years, and that is one of the limitations of the study. considered treatment exposure, but did not evaluate its effects in detail, Dr. Tur said, adding that this needs to be investigated in future studies.
Expert commentary
“This is an important study based on long-term follow-up of a thoroughly observed cohort of people presenting with a first episode suggestive of multiple sclerosis at a large multiple sclerosis center in Barcelona,” said Ludwig. Kappos, MD, FEAN, FAAN, corresponding author of the editorial accompanying the study.
Dr. Kappos, professor of neurology and director of the University Hospital in Basel, Switzerland and the Basel Center for Clinical Neuroimmunology and Neuroscience Research at the University of Basel, said the median follow-up time of 10.5 years was impressive. says.
Dr. Kappos said Neurology Today This study advances our understanding of disability in multiple sclerosis. Previous studies have shown that relapse-independent development of disability (PIRA) is unique to people with MS labeled as ‘secondary progressive’ or ‘primary progressive’, according to established consensus criteria. It has been demonstrated that it is not of Rather, it is “a key factor in disease progression in classic relapsing multiple sclerosis,” Dr. Kappos said.
Even though a clinically isolated syndrome is the early clinical manifestation of MS, this study reveals that PIRA appears more frequently than the incidence of relapse-related disability.
It is important to recognize that PIRA can occur even in the early stages of the disease.”MS patients experiencing PIRA are at a much higher risk of further disability progression and receive more intensive and possibly different targeted therapy.” ,” said Dr. Kappos.
“Timely detection of PIRA will influence advice and treatment choices, as well as our efforts to develop treatments that target the pathophysiological mechanisms responsible for progression.
As the editorial suggests, the field “has come a time to redefine the phenotypic characteristics of multiple sclerosis and develop more individualized treatment strategies that will lead to better long-term disability outcomes.” “There is,” said Corey C Ford, MD, PhD, FAAN, Professor Emeritus of Neurology. At the University of New Mexico Health Science Center in Albuquerque, he was not involved in the research.
Dr. Ford said Dr. Tur and her colleagues were commendable for following a large cohort of 1,128 MS patients from their first demyelinating event to identify factors that worsen clinical outcomes.
“MS has long been phenotypically classified into relapsing and progressive patterns for practical reasons. ,” he said. “This approach has led him to successfully identify more than 20 agents that are beneficial in early relapsed MS, but only a few agents have proven efficacy, albeit marginally, in late-progressive MS. Very little.”
As a result, insurers limit early use of certain highly effective drugs for MS to secondary stages, despite data showing that early, more aggressive treatment is superior to escalation strategies. often do. The study supports the need to develop and use specific drugs sooner in his 25% of patients with fast-growing relapses, Dr. Ford said.
More research is needed on whether treatment escalation is effective to prevent PIRA, says John L. Trotter, professor of neurology and clinic director at the MS Center for MS and MS at the University of Washington in St. said Robert T. Naismith, MD, FAAN, Director of Clinical Trials in Neuroimmunology. . Lewis.
“Traditionally, disease progression without recurrence was thought to be rare in early MS,” Dr. Naismith said. “Clinicians now appreciate that disease progression continues to occur in some MS patients, not just when transitioning to secondary progressive MS. This was a strong risk factor for higher disability scores and the need to use a cane for mobility.”
“For practical reasons, multiple sclerosis has been phenotypically classified into relapsing and progressive patterns. This approach has been successful in identifying more than 20 drugs that are effective in early relapsing MS, but with modest efficacy in late progressive MS. There are very few drugs that have been proven to
However, Dr. Kappos pointed out that failure incidence assessment is based on the EDSS. It may underestimate the symptoms of other important diseases such as cognitive impairment and fatigue. Another limitation is that we were unable to systematically assess the relationship between PIRA and her MRI signs of disease activity or tissue damage in the setting of this study.
Dr. Ford said future research efforts will likely target advanced imaging techniques to measure tissue damage in the central nervous system in its early stages. Other means of evaluating neurological function not included in the EDSS should also be evaluated in relation to detecting early progression. For example, he said it would be valuable to perform measurements of cognition, walking speed, and upper extremity function, as noted in his editorial.
“Traditionally, disease progression without recurrence was thought to be rare in early MS. Instead, clinicians recognize that disease progression occurs continuously.”—DR. Robert T. Naismith
What do the findings mean for clinical practice? Our disease-modifying therapies are most effective in early stages of multiple sclerosis, so treatment should be optimized in patients with worsening disease. ”
Disclosure
Dr. Tour received a grant from the ‘La Caixa’ Foundation Junior Leader incoming Fellowship, Fundación Merck Salud (Spain) 2021 Merck’s Award for the Investigation in MS, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación de España Proyecto de reported that Investigación, ECTRIMS 2015 ECTRIMS Postdoctoral Research Fellowship, and UK MS Society. Speaker honoraria from Roche and Novartis. non-financial support from Biogen; serving on the steering committee of the consensus group on the O’HAND trial and follow-on DMT.and members of the Editorial Board neurology.
Dr. Ford has received consulting fees from Ortley Bio LLC, TG Therapeutics, and River West Meeting Associates, Inc. Dr. Kappos has not disclosed. Dr. Naismith consulted with Genentech, Genzyme, Janssen, GW Therapeutics, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics..
