The year 2023 was marked by a number of anniversaries and what may be a turning point in the approach to MS research and clinical practice.

It was the thirtieth anniversary of the phase III trial of interferon-β, the first of the disease-modifying therapies (DMT) (IFNB Study Group. Neurology 1993;43:655-661). It was also the twentieth anniversary of the initial approval of natalizumab, the tenth anniversary of teriflunomide and dimethyl fumarate (DMF), and the fifth anniversary of ocrelizumab becoming available in Canada for the treatment of PPMS.

The year began with the January publication of a paper that may have profound implications (Kuhlmann et al. Lancet Neurol 2023;22:78-88). The authors stated that it was time to discard the current MS phenotypes (RRMS, SPMS, PPMS); the new view is that MS is a continuum of pathophysiologic processes that vary among individuals over the clinical course. Key pathophysiologic mechanisms cited were non-resolving inflammation, sustained in part through microglial activation and leptomeningeal inflammation; ion channel redistribution; oxidative stress and mitochondrial dysfunction. In essence, the authors were advocating a mechanism-based approach based on objective findings rather than a reliance on clinical observation.

In part, this emphasis on the underlying pathophysiology was a recognition of the limitations of current therapies. DMTs have been employed thus far to target disease activity (relapses, MRI lesions) rather than specific disease mechanisms. However, it is now apparent that most disability progression is due to neurodegeneration that occurs despite potent immunosuppression.  Thus arose PIRA (progression independent of relapse activity), a concept (if not a term) that had its own fifth anniversary this year (Kappos et al. Mult Scler 2018;24:963-973). PIRA is a glimpse at the underlying neurodegeneration that is occurring and is highly prognostic of progression. A long-term study reported that 25% of patients had a PIRA event after a median of seven years (Tur et al. JAMA Neurol 2023;80:151-160). Early PIRA was associated with more rapid disability worsening and a 26-fold increased risk of reaching EDSS 6.0.

Thus we enter the Age of PIRA (Carlson & Fox. Neurol Clin 2024;42:39-54). From a mechanistic standpoint, targeting the compartmentalized inflammation and neurodegeneration will require an array of treatments – some in use, some in development or only imagined – throughout the clinical course to target the individual patient’s predominant disease mechanism(s).

The most promising of the novel therapies in development are Bruton’s tyrosine kinase (BTK) inhibitors, which block B cell activation and inhibit the activation of proinflammatory macrophages/microglia in the CNS. Unfortunately, the much-anticipated lead candidate, evobrutinib, failed to meet its primary endpoint in its two EVOLUTION phase III trials (www.emdgroup.com/en/news/evobrutinib-phase-lll.html). The annualized relapse rate for evobrutinib in the two studies (0.11, 0.15) was similar to what was seen with teriflunomide (0.11, 0.14). Evobrutinib performed as expected: the unadjusted ARR was the same in the phase II trial (0.11 vs. 0.14 for DMF) (Montalban et al. N Engl J Med 2019;380:2406-2417) and the same (0.11) in the 192-week open-label extension (Montalban et al. ECTRIMS-ACTRIMS 2023;P706). The problem for evobrutinib may lie in the study design, which used conventional rather than novel endpoints to evaluate efficacy. So as the year closes out, the future role of evobrutinib is uncertain. Also unclear is the impact of the failed trials on the development program for other agents in this class (e.g. tolebrutinib, fenebrutinib, remibrutinib and orelabrutinib). Additional details from the EVOLUTION trials should be forthcoming next year. Also expected are data from the tolebrutinib development program, which comprises the GEMINI 1 and 2 (relapsing MS), PERSEUS (PPMS) and HERCULES (non-relapsing SPMS) trials.

Until such time that therapies with novel mechanisms of action become available, earlier use of higher-efficacy DMTs may forestall PIRA and slow the accumulation of disability (Selmaj et al. J Neurol 2023; epublished October 18, 2023). The need for a new approach is especially acute for progressive MS. A U.S. survey reported this year that about 40% of progressive MS patients receive no treatment; among those receiving a DMT, over 50% experienced disability progression (Watson et al. Neurol Ther 2023;12:1961-1979).

The second key component of a mechanism-based approach is biomarkers and significant gains were made in 2023. Thus far, the most promising fluid biomarkers are neurofilament-light chain (NfL) and glial fibrillary acidic protein (GFAP). For example, the EPIC group reported that an increasing NfL level predicted relapse-associated disability worsening at one year, and non-relapse-associated worsening (i.e. PIRA) at two years (Abdelhak et al. JAMA Neurol 2023; epublished November 6, 2023). This supported the earlier observation by Ascherio and colleagues of elevated NfL six years prior to MS onset (Bjornevik et al. JAMA Neurol 2020;77:58-64).

Also noteworthy was an interesting observation from an analysis of ocrelizumab phase III studies (Bar-Or et al. EBioMedicine 2023:93:104662). Persistently elevated NfL levels during treatment with ocrelizumab were significantly associated with a risk of disability progression. While NfL is generally considered to be an indication of disease activity, this finding suggests that NfL is also a biomarker of progressive biology, although this aspect may be masked by inflammatory activity.

Numerous fluid biomarkers are currently being investigated, and it is likely that a panel of biomarkers will become a useful tool for diagnosis, prognosis and for predicting treatment response in clinical practice in the near future (Bose et al. Mult Scler Relat Disord 2023:74:104695).

Further insights were also gained from MRI studies of mixed active/inactive lesions (previously known as smouldering or slowly expanding lesions [SEL]) and paramagnetic rim lesions (PRL) (Krajnc et al. Mult Scler 2023;29:1406-1417); TSPO-PET studies of microglial activation (De Picker et al. Brain Behav Immun 2023;113:415-431); and optical coherence tomography (OCT) studies (Mirmosayyeb et al. J Neurol Sci 2023;454:120847). The International Panel met in 2023 to discuss revisions to the McDonald criteria, and it will be interesting to see which imaging metrics (central vein sign, PRL) and fluid biomarkers will be incorporated.