A Vall d'Hebron study opens the door to change the classification of multiple sclerosis

Research has found that a significant number of patients with the Relapsing-Remitting variant have Progression Independent of Relapse Activity episodes.


A study from the Vall d'Hebron University Hospital published in JAMA Neurology has prompted several scientists to open the door to change the classification of multiple sclerosis (MS). Currently, patients are mainly divided into two categories according to how the pathology manifests itself: Primary Progressive, considered a minority, is characterized by a gradual, constant and irreversible development of symptoms from the onset; and Remitting-Recurrent, the majority, is characterized by an initial phase with acute outbreaks and periods of normality intercalated. During the "calm" intervals the patient typically recovers functions and abilities. After this initial relapsing-remitting phase, the pathology of some patients evolves into a new category called Secondary Progressive, characterized by a constant and irreversible clinical worsening, similar to Primary Progressive. Classically, the diagnosis of Secondary Progressive MS is associated with advanced stages of the disease and high levels of disability.

The new study, led by researchers from the Multiple Sclerosis Center of Catalonia (CEMCAT) and the Clinical Neuroimmunology research group of the Vall d'Hebron Research Institute (VHIR), could be the definitive blow to the phenotypic classification of the pathology. The article shows how, from the onset of the disease and when disability is still minimal or moderate, a non-negligible number of patients classified as relapsing-remitting present episodes of worsening independent of outbreaks. In much the same way as occurs in the progressive forms (primary and secondary). Therefore, the traditional classification becomes meaningless.

Progression independent of flare-ups

One of the key ideas behind the current classification is that patients with the relapsing-remitting version do not worsen between outbreaks. They may experience permanent sequelae from the damage done during the episode. Even so, once the maximum possible level of recovery is reached (about three months after the attack), the patient should remain stable until the next flare-up. The new study found that one in four patients will experience at least one incident of Progression Independent Relapse Activity (PIRA) in the first twelve years. PIRA has been defined as any rise in the level of dependence experienced by the patient during the period between flares without any external cause being identified. This worsening has to be significant enough to change their assessment on the disability scale (EDSS).

The study has shown that having a PIRA episode translates into a more severe prognosis, which is reflected in a faster evolution of patients on the disability scale. For example, they reach EDSS level 6 earlier, which means that they have a disability that prevents them from performing daily activities and forces them to need some type of aid, cane or crutch, to walk more than 100 meters. This poor prognosis is increased if the first PIRA incident occurs within five years after the first episode of demyelination. Myelin is the sheath substance that protects most nerves in the nervous system. Its destruction leaves the nerves more vulnerable and less functional. Suffering demyelination without any cause independent of MS is considered a key symptom for diagnosing the pathology. In fact, many studies use this first episode of demyelination to mark the onset of the disease.

The number of patients with PIRA increases with the number of years they have had the disease: thus, during the first five years they represent 8% of the total, after 12 years they will represent 25% and after 22 years, 50% of the patients will have suffered an episode. At present, these patients are classified as Remitting-Recurrent, but it is possible that this will change in the future. The numbers are significant enough that a team from the University of Basel, based on the results of the study, has written an editorial proposing a change of classification. The team believes that the current classification has been useful in deciding which patients would benefit most from existing drugs. These treatments focused on modifying the behavior of the pathology, e.g., preventing or delaying the onset of new flares. However, new therapeutic efforts are currently focused on reducing the disability caused by the disease and a new, more precise model is needed to administer them correctly and effectively, possibly taking into account the appearance of phenomena such as PIRA, and focusing on the functional consequences of the evolution of the pathology.


One in four patients will experience at least one incident of PIRA in the first twelve years.  Therefore, the traditional classification becomes meaningless.

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