A study led by the Centre for Multiple Sclerosis of Catalonia (Cemcat) has analysed the usefulness of different measures that people with multiple sclerosis can perform themselves to detect worsening disability and progression independent of relapse activity, known as PIRA (Progression Independent of Relapse Activity).

The study, published in the journal Annals of Neurology, analysed data from 9,088 people with multiple sclerosis from the multicentre MS PATHS registry, with a mean follow-up of three years. The results show that these measures can identify a significant proportion of people with worsening disability and that the changes detected are associated with greater brain atrophy, an increase in lesion volume on magnetic resonance imaging and poorer quality of life.

Worsening disability in multiple sclerosis is not always related to the occurrence of new relapses. Some of this worsening disability occurs independently of relapses and can appear in both relapsing and progressive forms of the disease. Detecting it early is particularly relevant because it may go unnoticed when only relapses or certain clinical measures are taken into account.

“Disability in multiple sclerosis is complex and does not always manifest as a consequence of a relapse. This study shows that incorporating the patient’s perspective and simple tests that patients can perform themselves, assessing motor and cognitive function, can help us identify changes that may be less visible in a conventional clinical examination (performed by the clinician),” explains Dr Carmen Tur, neurologist at Vall d’Hebron University Hospital and researcher at Cemcat and the Vall d’Hebron Research Institute (VHIR), and lead author of the study.

Almost half of the people studied experienced some worsening during the study period

To assess progression, the researchers used the Patient-Determined Disease Steps (PDDS), a self-reported measure of disability similar to the Expanded Disability Status Scale (EDSS), which is the most widely used clinical tool to measure the degree of disability in people with multiple sclerosis. In addition, three tests that patients can administer themselves were used: a walking speed test, a manual dexterity test and a cognitive processing speed test.

During the three-year follow-up, 4,066 of the 9,088 people analysed (45%) experienced worsening in at least one of the self-reported or self-administered measures. Of these, 2,357 (58%) met the criteria for PIRA.

PIRA was detected across different domains. Specifically, 13% of the people studied showed PIRA according to the PDDS, 7% in tests related to motor walking function and 8% in the cognitive processing speed test. However, most of the people who experienced PIRA (79%) did so in only one of the measures. These results highlight that different tests can provide complementary information.

Cognitive progression may occur without worsening detected by the PDDS scale

One of the study’s key findings is the contribution of cognitive tests to the detection of progression. The processing speed test identified exclusively cognitive PIRA in 6% of the overall group studied and in approximately one fifth of the people who experienced an episode of PIRA.

This is particularly relevant because the PDDS, considered the self-reported EDSS, focuses mainly on physical disability and, especially as disability increases, places significant weight on walking ability. Therefore, some changes in other functions, such as cognition or manual dexterity, may be less reflected in this scale.

“One of the important contributions of this work is to show that not all people progress clinically in the same way or in the same areas of disability. Incorporating cognitive processing speed, walking or manual dexterity tests can provide additional information to the EDSS and allow for a more complete view of how disability evolves,” says Dr Mar Tintoré, Clinical Head of the Neurology Department at Vall d’Hebron University Hospital, Director of Cemcat, Principal Investigator of the VHIR Clinical Neuroimmunology group and co-leader of the project.

Self-administered measures are associated with changes observed on magnetic resonance imaging

To determine whether the worsening detected through these measures had clinical relevance, the researchers also analysed the evolution of different magnetic resonance imaging indicators.

People who experienced PIRA or other forms of worsening detected through self-reported and self-administered measures showed an evolution associated with greater loss of brain volume. These patients also showed a faster increase in T2 lesion volume compared with people who did not experience worsening.

These associations support the clinical relevance of the changes detected through the self-administered tests, as they are not merely a variation in a score, but rather these changes are associated with indicators of brain damage that can be observed through magnetic resonance imaging.

The study also analysed the relationship between progression detected through these tools and quality of life. To do so, different dimensions of the Neuro-QoL questionnaire were used, including aspects related to physical, cognitive and social functioning, as well as symptoms such as fatigue, sleep disturbances, anxiety or depression.

The results show that people who experienced clinical worsening (including PIRA) according to the self-reported and self-administered measures had poorer quality-of-life trajectories than people who did not experience progression.

A complementary tool to routine clinical assessment

In a subcohort of 279 people from Cemcat, the researchers were able to compare the self-administered measures with the EDSS and with relapses clinically determined by healthcare professionals. Agreement between the different measures was only partial. In particular, only some of the people with worsening according to the EDSS also experienced worsening in the self-administered tests, while the overlap between PIRA definitions based on the EDSS and those based on the self-administered measures was limited.

However, worsening detected through the PDDS was significantly associated with subsequent worsening according to the EDSS. Specifically, people with worsening in the PDDS were approximately three times more likely to experience worsening according to the EDSS in this subcohort.

Therefore, the authors suggest that these measures should not necessarily replace conventional clinical assessment, but rather can complement it and provide additional information about different dimensions of disability. According to the study’s conclusions, these tools may contribute to making the monitoring of multiple sclerosis progression more accessible and efficient both in clinical practice and in clinical trials.