In clinical MS studies, disease progression is usually measured by the increase in the EDSS score. Now an increase in the EDSS score can occur as a result of a clinical relapse. Take, for example, a relapse with severe optic neuritis, which only partially regresses and leaves a visual impairment as a disability. In this case, the increase in disability is purely dependent on the relapse. Alternatively, there may also be an increase in disability independent of relapses. And indeed, not a few patients, especially in later stages of the disease, report an increase in disability despite treatment with an MS drug.
Meanwhile, it is becoming increasingly clear that such relapse-independent progression not only exists in patients in later, secondary progressive phases of the disease, but can already be observed in the relapsing phase of the disease. To this end, a very interesting study was published in the renowned Journal JAMA Neurology (Kappos et al. JAMA Neurol. 2020; 77 (9): 1 – 9) at the beginning of 2020.
The authors around Ludwig Kappos re-evaluated the data from the OPERA study program (these were the approval studies of Ocrelizumab, in which the effect of Ocrelizumab versus Interferon-Beta was studied in purely relapsing patients) and investigated to what extent the disability progression of the examined RRMS patients was attributable to MS relapses or occurred independently of relapses. Overall, a smaller proportion of patients treated with Ocrelizumab showed disability progression compared to the group treated with Interferon-beta (21% vs 29%). Upon reanalysis, it was found that this disability progression was predominantly due to relapse-independent deterioration. In numerical terms, this progression was independent of relapses (=PIRA) in 78% of the Interferon patients with disability progression and even in 88% of the Ocrelizumab patients with disability progression. And very importantly: all of these were patients with relapsing MS in a relatively early phase of the disease.
Therefore, the monoclonal antibody Ocrelizumab is capable of extremely efficiently suppressing inflammatory disease relapses and the associated increase in disability. Unfortunately, the results also show that relapses play hardly any role as drivers of clinical disability in highly effectively treated patients.
In summary, we can currently suppress inflammatory activity extremely efficiently – and this should be done consistently whenever possible – but we still lack concepts to slow down or prevent relapse-independent progression. Although there is little doubt that relapse-independent progression is directly related to the initial inflammatory activity, over the course of the disease this phenomenon seems to become independent. Therefore, efficient anti-inflammatory action is particularly important in the early phases of the disease – and this concept is not yet implemented consistently enough in practice. The new development of drugs must focus on the prevention of PIRA – perhaps this will be achieved by drugs that more effectively suppress inflammation in brain tissue. The detection of PIRA in different study cohorts and the discussion on how to prevent progression was very present in the current ECTRIMS contributions and will definitely influence the current discussion about the therapy of the disease.
