In 2022, the most noteworthy event was the announcement that the COVID-19 pandemic was over. That was reassuring news, although there have been 316 million reported cases this year, about 50% of all COVID cases to date. Canada saw an average of 48 COVID-related deaths per day post-pandemic.
The COVID-19 phenomenon continues to have important direct and indirect effects on the management of patients with multiple sclerosis. This year saw the widespread distribution of booster injections against COVID-19, including a novel bivalent vaccine targeting the Omicron variant (Bivalent COVID booster approved in Canada, NeuroSens, September 16, 2022). Boosters were shown to enhance the impaired vaccine response seen in MS patients treated with disease-modifying therapies (DMT) such as ocrelizumab, rituximab and the S1PR modulators, but only somewhat. Data presented at ECTRIMS reported that among patients who were seronegative after the first vaccine series, only 17% on ocrelizumab and 47% on fingolimod seroconverted when a booster was administered (Upcott et al. ECTRIMS 2022; P343).
A separate study found that if patients contracted COVID after a booster injection, their symptoms were generally more severe and protracted if they were taking ocrelizumab rather than natalizumab or fingolimod (Gallo et al. ECTRIMS 2022; P560). This finding appeared to be supported by a retrospective study at the St. Michael’s Hospital MS in Toronto (Solomon et al. Mult Scler Relat Disord 2022;58:103509). Overall, 11.3% of MS patients with COVID required hospitalization, but one-third of these were receiving treatment with ocrelizumab.
The impact of DMTs on vaccine response served to highlight questions about whether profound immunosuppression is required to control MS and if chronic B cell suppression is safe. Indeed, a study of rituximab showed that some degree of B cell reconstitution (>5 cells/mm3) was generally not associated with a recurrence of disease activity; this may be due in part to the prolonged time to recovery of the memory B cell subset with anti-CD20 therapies (Dorcet et al. J Neurol 2022;269:5443-5453).
One approach to minimize potential safety issues with high-efficacy DMTs was to reduce drug exposure with extended-interval dosing (EID). In the NOVA trial of natalizumab, MRI outcomes were generally similar with q6wk versus q4wk dosing at week 72 (although there were two highly-active outliers) (Foley et al. Lancet Neurol 2022;21:608-619); and there was no difference in the effect of treatment on brain volume change (Arnold et al. ECTRIMS 2022; P350). Similarly, there was no change in annualized relapse rate in patients switched to a regimen of ocrelizumab administered q9mth (Perugini et al. ECTRIMS 2022; P741). Moreover, a German pilot study found that less frequent ocrelizumab dosing (q46wk) prevented much of the decline in Ig levels seen with standard dosing (Schuckmann et al. ECTRIMS 2022; P748).
A lower cumulative dose can also be achieved with the standard regimen of ofatumumab (20 mg/month SC). A small study presented at ECTRIMS reported that the COVID vaccine response during ofatumumab therapy was 54% with two vaccines, and 70% following a booster injection (Hendin et al. ECTRIMS 2022; P345). The ALITHIOS study also reported that COVID was generally mild-to-moderate in severity among ofatumumab-treated patients who were partially or fully vaccinated (Cross et al. Neurol Ther 2022;11:741-758).The improved vaccine response and lower infection risk may be attributable in part to the modest effect of ofatumumab on immunoglobulins. A long-term safety study showed that IgG levels remained stable and IgM levels remained above the lower limit of normal during 3.5 years of treatment with ofatumumab (Hauser et al. Mult Scler 2022;28:1576-1590).
Also noteworthy was a small study that reported that 100% of patients on cladribine responded to a booster injection, although IgG levels were initially lower in the cladribine group compared to controls (Brill et al. ECTRIMS 2022; P744).
The pandemic interrupted the general trend to the earlier use of high-efficacy therapies in MS, which was widely advocated this year by several groups (Filippi et al. J Neurol 2022; 269:5382-5394). A treatment goal has been to achieve no evidence of disease activity (NEDA) (Rotstein et al. Neurol Neuroimmunol Neuroinflamm 2022;9:e200032), with a survey showing that neurologists primarily escalate treatment to target inflammatory activity (Saposnik et al. Mult Scler Relat Disord 2022;58:103404).
However, the evidence is mixed whether the composite metrics used in NEDA (relapses, MRI lesions, EDSS worsening) are sufficiently prognostic of disability progression. Coupled with this is the growing awareness that conventional treatments that target inflammation have limited effectiveness against disease progression that occurs independently of relapse activity (PIRA) (Kappos et al. JAMA Neurol 2020;77:1132-1140).
Accordingly, the past year saw a shift away from the emphasis on ‘disease activity’ to the limitations of ‘no evidence’, i.e. what you see may not be what you get. Novel imaging techniques have underscored the importance of pathophysiological processes underlying disease progression, such as leptomeningeal enhancement, microglial activation, and slowly expanding or ‘smouldering’ lesions (the preferred term now being ‘mixed active and inactive lesions’). Of particular importance are paramagnetic rim lesions (PRL), which demonstrate an iron rim from deposition of iron-rich phagocytes at the lesion edge. This year, PRLs were reported to be prognostic of clinical worsening in subjects with radiologically isolated syndrome and MS (Lim et al. ECTRIMS; O093; Polvinen et al. ECTRIMS 2022; O160), which may support the treatment of high-risk RIS. Studies also showed that PRLs are present in a majority of MS patients (RRMS 57%, SPMS 80%), and that even one PRL is predictive of EDSS worsening (Nistri et al. ECTRIMS 2022; P111).
There is some evidence that current DMTs, such as anti-CD20 agents and S1PR modulators, can slow the development of PRLs (Eisele et al. Mult Scler 2022;28:2294-2298). Additional benefit may be seen with novel therapies in development that target the innate immune system. A phase III trial of masitinib reported a modest slowing of EDSS worsening in progressive MS (Vermersch et al. Neurol Neuroimmunol Neuroinflamm 2022;9:e1148). Also promising are Bruton’s tyrosine kinase inhibitors (BTKi), four of which (evobrutinib, tolebrutinib, remibrutinib, fenebrutinib) are currently in phase III testing; phase II results were presented this year (Vermersch et al. ECTRIMS 2022; P731; Kuhle et al. ECTRIMS 2022; EP1021; Reich et al. ECTRIMS 2022; P297; Oh et al. ECTRIMS 2022; P308). As this year of EndCOVID draws to a close, expectations will be high for these new classes of therapy as additional data become available in 2023.