The aim of this study was to identify risk factors associated with an increased lethality of COVID-19 in patients with MS. We fitted meta-regression analyses of observational studies published so far, paying attention to avoid data duplication, and by handling data in the more appropriate way to deal with a rare event such as death (i.e. double arcsine transformation) .
We estimated a pooled death rate of 1.97%, a slightly lower proportion as compared with a published systematic review reporting a 3.0% death rate among patients with suspected/confirmed COVID-19 cases . However, this latter review included also conference abstracts, case report and case series , instead we choose to not include articles other than observational cohort studies to prevent the risk data duplication.
Other than age and presence of comorbidities—which are two known risk factors shared with the general population —we identified several MS-specific determinants influencing the lethality of COVID-19, namely a progressive disease course and current treatment with different DMTs (anti-CD20 agents, interferon beta, teriflunomide).
Notably, male sex and EDSS score did not associate with higher death rate, unlike prior studies [12, 39]. The low variability both in proportions of males (interquartile range 28–31%) and in median EDSS score (ranging from 1.0 to 3.5) among the included cohorts may, at least partially, explain this discrepancy. Moreover, in contrast with prior studies, our analysis did not show an increased risk of severe or fatal COVID-19 among untreated patients [31, 36], neither a decreased risk among those treated with fumarates and natalizumab .
MS-specific determinants of death risk of COVID-19
Patients with progressive disease course and worse disability level have an increased risk of severe or fatal COVID-19 [9, 11] that is in line with previous observations on infections in general, especially those affecting the respiratory tracts [40,41,42].
Furthermore, our data indicate a diverse effect on lethality of COVID-19 from different DMTs used in MS. Anti-CD20 agents showed a detrimental effect, while interferon beta and teriflunomide had a protective effect on the death risk.
Prolonged anti-CD20 treatment has been associated with hypogammaglobulinemia and impaired B-cell reconstitution that, in turn, may lead to increased infection risk , regardless of the underlying pathological condition. In a large cohort study, patients with MS treated with rituximab experienced a higher rate of serious infections than those under other DMTs . Pivotal phase III trials showed a higher incidence of respiratory tract infections in ocrelizumab arm than placebo arm and interferon beta arm in patients with primary progressive and relapsing–remitting, respectively .
Several smaller studies included in our analysis did not document any significant effect of anti-CD20 agents on COVID-19 severity [20, 22, 26, 27, 29, 30, 32, 33], whilst the three largest studies showed a significant association [34, 36, 37]. Other two large studies (not included in our meta-regression to prevent data duplication), one combining data from Italy and France  and the other one aggregating data from 12 data-sources in 28 different countries , confirmed an increased risk for severe COVID-19 in patients treated with anti-CD20 agents. However, these studies were inconclusive concerning the risk of death from COVID-19, probably due to low statistical power to explore rare events.
Interestingly, anti-CD20 agents were the most prevalent DMTs, not only in the pooled cohort (almost 20%), but also in many of the included studies [20, 22, 27, 30,31,32,33,34,35,36,37]. While one can argue about the possibility of selection or reporting bias, another plausible explanation might encompass an increased susceptibility to SARS-COV-2 infections due to current treatment with anti-CD20 agents .
The protective role of interferon beta on the death risk from COVID-19 is not surprising. Type I interferons are abundantly secreted in response to viral infections, and for this reason they are considered as a potential treatment for COVID-19 . Individuals exhibiting low type I interferon secretion capacity are more vulnerable to SARS-COV-2 infection and life-threatening COVID-19 pneumonia . Other than inborn errors, autoimmune diseases (including MS) can be linked with altered production of type I interferons . Of note, a lower risk of pneumonia has been observed in patients currently treated with interferon beta in a large cohort of MS cases followed for an average time of 8.5 years .
The protective effect of teriflunomide on death rate, as by the present meta-regression, reinforces the putative antiviral role of inhibiting the pyrimidine biosynthesis to suppress transcription and replication of several viruses . However, this latter finding should be interpreted with caution, as the antiviral role of teriflunomide is just hypothetical and, differently from interferon beta, not yet supported by clinical data.
Despite the robust methodological and statistical approach, we are aware that our study has some limitations.
First, the clinical and statistical heterogeneity of the samples, resulting from pooling data from mixed MS cohorts.
Second, we included observational studies that, for their intrinsic nature, suffer from limited internal validity as affected by hidden confounding factors and reporting bias , as for example in regard to the aforementioned high prevalence of patients treated with anti-CD20 agents.
Third, we should consider the availability bias due to the absence of some data, thus forcing us to reduce the pooled sample size when analyzing several variables (comorbidities, EDSS score, progressive course) and not to fit several meta-regressions exploring the death risk in relation with lymphocyte count, recent steroid exposure, timing from the last anti-CD20 administration, and timing from pulsed immune-reconstitution therapy with alemtuzumab or cladribine.
Lastly, when interpreting our meta-regressions, we should take into account the ecological fallacy of such an approach , considering that the association found in pooled data does not necessarily reflect the association found in individual patient data reported by cohort studies included in our analyses [20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37]. Nevertheless, our findings appear biologically and clinically plausible, in line with those from larger observational studies [11, 34, 36, 37, 39].
Despite the aforementioned limitations, we believe our study may have relevant clinical implications. Clinicians and patients with MS and should be made aware of a possible increased lethality of COVID-19 in case of advancing age, presence of comorbidity, and progressive disease course.
Risk mitigation plans should be implemented in patients treated with anti-CD20 agents, also considering the recent report of a reduced humoral response to anti-COVID-19 vaccination in patients receiving ocrelizumab [53, 54]. When applicable, ocrelizumab and rituximab should be started after anti-COVID-19 vaccination, unless the risk:benefit ratio supports the need for an urgent treatment . In patients already on treatment with anti-CD20 agents, the timing of vaccination should be scheduled with a delay of at least 3 months from the last administration, according to the most recent recommendations . Interferon beta, and to a lesser extent, teriflunomide, should be considered among the first treatment options in older patients with comorbidity who require lower-efficacy DMTs . Notably, all the aforementioned suggestions came from expert consensus rather than clinical evidence, therefore they should be interpreted with caution and cannot be considered as guidelines until validation by ‘ad hoc’ studies.