Progression Independent of Relapse Activity in Multiple Sclerosis

Disability progression independent of relapse activity (PIRA) -- sometimes referred to as silent progression -- is a key integrating concept in the contemporary view of multiple sclerosis (MS).

"The observation that progression can occur without preceding relapse in early relapsing remitting MS patients now has been replicated in multiple cohorts and is recognized as the most common cause of progression in relapsing patients," said Bruce Cree, MD, PhD, MAS, of the University of California San Francisco (UCSF). "This observation represents a sea change in our understanding about MS."

Silent Progression

In 2019, Cree and colleagues proposed the term "silent progression" to describe insidious accumulating disability independent of inflammatory activity in MS, based on data from the prospective UCSF EPIC cohort.

The group studied relapsing MS patients with long-term follow-up and found that relapses were associated with a transient increase in disability over 1-year intervals (P=0.012), but not with confirmed disability progression (P=0.551).

In addition, relative brain volume declined at a greater rate among patients with disability progression compared with patients who remained stable.

The high degree of effectiveness of MS therapies against clinical attacks made it possible to assess long-term outcomes when elements of focal disease were silenced, the researchers noted. This opened the door to a fundamental shift in thinking.

"Disability worsening was previously thought to be driven by relapses early in the disease course and only later was considered to be insidious after substantial disability had already accumulated," Cree observed.

"This two-stage model is incorrect," he pointed out. "What we call secondary progressive MS is very likely the same process that occurs once relapsing activity is suppressed by highly effective anti-inflammatory medications."

"In other words, secondary progressive MS is not secondary -- rather, progressive disability worsening runs parallel to relapsing activity and can be detected in the early stages of the illness," Cree said.

Defining PIRA

In 2023, researchers led by Ludwig Kappos, MD, of the University of Basel in Switzerland, sought to propose a harmonized definition of PIRA for general use based on a systematic review of PIRA literature.

"After the first descriptions of PIRA, numerous studies in different patient groups followed with the aim of better understanding this newly recognized phenomenon," said co-author Jannis Müller, MD, also of the University of Basel.

"However, there was no uniform definition of PIRA, which made it difficult to compare and interpret the studies," he continued. "We aimed to summarize the current knowledge on this phenomenon and proposed uniform diagnostic criteria for PIRA identification."

Kappos and colleagues based their criteria on a literature review of 48 studies. They estimated PIRA occurred in about 5% of patients with relapsing-remitting MS yearly, causing 50% or more of relapsing-remitting MS disability accrual. Compared with relapse-associated worsening, the proportion of PIRA increased with age and longer disease duration.

The review supported the early findings of Cree's group and others. "PIRA is responsible for the majority of the increase in disability from the earliest stages of MS," Müller said.

"This challenges the conventional dichotomy of multiple sclerosis into relapsing-remitting and progressive phenotypes and supports the notion that both mechanisms are present in all patients and at all stages, with an overlap of inflammatory and neurodegenerative aspects of the disease," he continued. Recognizing this phenomenon can help targeted and personalized therapies be developed, he added.

Kappos and co-authors recommended a composite measure that included upper limb function (for example, the 9-hole peg test), walking speed (the timed 25-foot walk test), and cognitive testing (information processing speed measured by the Symbol Digit Modalities Test).

Other recommendations included the use of data sets with scheduled, standardized clinical assessments at average intervals not exceeding 12 months, and interpretation of new or enlarging T2 lesions or gadolinium-enhancing T1 lesions as signs of acute activity and temporally associated with a clinical event only if imaging is acquired within 90 days.

Determinants to define or diagnose PIRA in both relapsing-remitting and progressive MS should include a baseline reference score updated with clinical events, classification of worsening as PIRA-related only if it is distinct from investigator-confirmed relapses in time, confirmation of apparent disability worsening 6 to 12 months after initial worsening, and a 12-to-24 month requirement for sustained PIRA, Kappos and colleagues added.

The definition of PIRA represents a trade-off of specificity and sensitivity, they noted. "If a higher specificity for PIRA is desired in a study, we recommend that disability accrual events are only considered as PIRA events in the absence of relapses between baseline/reference score and confirmation score," they wrote.

Since the term silent progression was first introduced, PIRA has been studied from several perspectives. One study showed that MS patients who had PIRA soon after a first demyelinating event were more likely to experience unfavorable long-term disability outcomes. Another reported that pediatric-onset MS patients had PIRA when they were relatively young. Researchers also have suggested that serum glial fibrillary acidic protein (GFAP) may be a prognostic biomarker for PIRA, as may spinal cord atrophy.

The implication of understanding PIRA is profound, Cree noted.

"If a medication can effectively prevent PIRA from occurring in relapsing MS, its use will presumably prevent the onset of what is recognized as secondary progressive MS," he said. "Clinical trials targeting PIRA as the primary endpoint have yet to be successfully undertaken but represent the new frontier for therapeutic efficacy."

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