Highlights
- •An association between intercurrent infections and MS disease activity has been often reported.
- •There is uncertainty as to whether this is causality or mere temporal coincidence.
- •The SARS-CoV-2 pandemic can represent a model to assess the relationship between infections and MS disease activity.
- •In our cohort no differences in MS disease activity are observed between MS patients exposed and not exposed to SARS-CoV-2.
Abstract
Introduction
An association between intercurrent viral respiratory infections and exacerbations of Multiple Sclerosis (MS) disease activity has been proposed by several studies. Considering the rapid spread of SARS-CoV2 worldwide and the systematic effort to immediately detect all incident cases with specific diagnostic tests, the pandemic can represent an interesting experimental model to assess the relationship between viral respiratory infections and MS disease activity.
Aims and Methods
In this study, we have performed a propensity score matched case-control study with a prospective clinical/MRI follow-up, on a cohort of relapsing-remitting MS (RRMS) patients who tested positive for SARS-CoV2 in the period 2020–2022, with the aim to evaluate if the SARS-CoV2 infection influences the short-term risk of disease activity. Controls (RRMS patients not exposed to SARS-CoV-2, using 2019 as the reference period) were matched 1:1 with cases for age, EDSS, sex and disease-modifying treatment (DMT) (moderate efficacy vs high efficacy). Differences in relapses, MRI disease activity and confirmed disabilty worsening (CDW) between cases in the 6 months following the SARS-CoV-2 infection, and controls in a similar 6 months reference period in 2019 were compared.
Results
We identified 150 cases of SARS-CoV2 infection in the period March 2020 - March 2022, out of a total population of approximately 1500 MS patients, matched with 150 MS patients not exposed to SARS-CoV2 (controls). Mean age was 40.9 ± 12.0 years in cases and 42.0 ± 10.9 years in controls, mean EDSS was 2.54±1.36 in cases and 2.60±1.32 in controls. All patients were treated with a DMT, and a considerable proportion with a high efficacy DMT (65.3% in cases and 66% in controls), reflecting a typical real world RRMS population. 52.8% of patients in this cohort had been vaccinated with a mRNA Covid-19 vaccine. We did not observe a significant difference in relapses (4.0% cases, 5.3% controls; p = 0.774), MRI disease activity (9.3% cases, 8.0% controls; p = 0.838), CDW (5.3% cases, 6.7% controls; p = 0.782) in the 6 months after SARS-CoV-2 infection between cases and controls.
Conclusion
Using a propensity score matching design and including both clinical and MRI data, this study does not suggest an increased risk of MS disease activity following SARS-CoV-2 infection. All MS patients in this cohort were treated with a DMT, and a considerable number with a high efficacy DMT. These results therefore may not be applicable to untreated patients, for which the risk of increased MS disease activity after SARS-CoV-2 infection may not be excluded. A possible hypothesis explaining these results could be that SARS-CoV2 is less prone, compared to other viruses, to induce exacerbations of MS disease activity; another possible interpretation of these data might be that DMT is able to effectively suppress the increase of disease activity triggered by SARS-CoV2 infection.
Keywords
1. Introduction
The association between intercurrent viral respiratory infections and exacerbations of Multiple Sclerosis (MS) disease activity has been suggested by several studies, hypothesizing a bystander effect following the activation of the host immune response (
Sibley et al., 1985
; Andersen et al., 1993
; Panitch, 1994
; De Keyser et al., 1998
; Edwards et al., 1998
; Buljevac et al., 2002
; Correale et al., 2006
); it is yet less clear whether particular viruses are more or less associated with MS exacerbations risk (Steelman, 2015
).Prior to the SARS-CoV-2 pandemic, never before a viral respiratory infection had been so intensively screened for on the wide general population in Europe, and systematically diagnosed with specific laboratory tests in a huge effort to immediately detect and quarantine all incident cases (even those asymptomatic or with minimal symptoms). The SARS-CoV-2 pandemic can therefore represent an interesting model to assess the temporal relationship between intercurrent viral respiratory infections and exacerbations of MS disease activity.
A few previous studies have investigated the relationship between SARS-CoV-2 infection and risk of new demyelinating events, or between SARS-CoV-2 infection and risk of clinical relapses in patients with MS (
Verstrepen et al., 2020
; Yavari et al., 2020
; Corrêa et al., 2021
; Zhang et al., 2021
; Etemadifar et al., 2021
; Barzegar et al., 2021
; Garjani et al., 2021
; Michelena et al., 2022
; Ismail and Salama, 2022
; Etemadifar et al., 2022
; Bsteh et al., 2022
; Babtain et al., 2022
; Conway et al., 2022
; Kim et al., 2022
; Lotan et al., 2022
). Many published studies were however limited to small case series, often lacked a matched control group, and did not include MRI data.In this study, we have performed a propensity score matched, case-control, observational study with a clinical and MRI follow-up, in a cohort of patients with relapsing-remitting MS (RRMS) who tested positive for SARS-CoV-2 in 2020–2022, with the aim to evaluate if the SARS-CoV-2 infection influences the short-term risk of clinical/MRI disease activity.
2. Materials and methods
All incident cases of SARS-CoV-2 infection observed in RRMS patients followed at the MS Center of the AOU Città della Salute e della Scienza di Torino, the largest hospital in the Piedmont region of northern Italy, in the period March 2020 - March 2022 were included in the study. Clinical and MRI data for cases and controls were obtained from a database (part of the Italian MS register) in which patient data in the MS Center are routinely recorded, currently including 900 patients.
SARS-CoV-2 infection was considered confirmed if the patient tested positive with an EMA-approved antigenic or molecular test.
As per standard clinical practice, all RRMS patients undergoing disease-modifying therapy (DMT) are evaluated at least every 6 months (including Expanded Disability Status Scale (EDSS) scoring performed by certified neurologists), and perform MRI at least yearly, acquired with the same magnet in each patient, according to established guidelines (
Wattjes et al., 2021
).- Wattjes M.P.
- Ciccarelli O.
- Reich D.S.
- et al.
Magnetic Resonance Imaging in Multiple Sclerosis study group; Consortium of Multiple Sclerosis Centres; North American Imaging in Multiple Sclerosis Cooperative MRI guidelines working group. 2021 MAGNIMS-CMSC-NAIMS consensus recommendations on the use of MRI in patients with multiple sclerosis.
Lancet Neurol. 2021; 20: 653-670
Clinical evaluation (including EDSS) performed within 6 to 9 months after SARS-CoV-2 infection was compared to the last clinical evaluation within 6 months before the SARS-CoV-2 infection. Brain gadolinium-enhanced MRI performed within 6 to 9 months after the SARS-CoV-2 infection was compared to a reference MRI performed within 6 months before the SARS-CoV-2 infection.
Controls (MS patients not exposed to SARS-CoV-2) were selected from the total population of MS patients followed at the MS Center of the AOU Città della Salute e della Scienza di Torino, using a 1:1 propensity score matching for age, EDSS, sex and DMT (moderate efficacy vs high efficacy) (
Benedetto et al., 2018
). Moderate efficacy therapies were defined as β-interferon, glatiramer acetate, teriflunomide, dimethylfumarate. High efficacy therapies (HET) were defined as S1P modulators, antiCD20 mAbs, natalizumab, alemtuzumab, cladribine. The reference period used for controls was 2019, prior to the pandemic, in order to exclude the possibility of unidentified SARS-CoV-2 infections. The first recorded visit in 2019 was considered as the effective date of study inclusion. The time frame for MRI assessment was the same used for cases.In order to evaluate the influence of the SARS-CoV2 infection on the risk of short-term clinical/MRI disease activity, we assessed the differences in relapses, MRI disease activity and confirmed disability worsening (CDW) between cases in the 6 months following the SARS-CoV-2 infection, and controls in a similar 6 months reference period in 2019. Relapses were defined as symptoms/signs typical of an acute CNS inflammatory demyelinating event, with duration at least 24 h, in absence of fever/infection. MRI disease activity was defined by T1 Gd+ lesions, or new/enlarging T2 lesions, compared to the previous reference MRI. CDW (defined as a 1.0-point EDSS increase if baseline EDSS < 5.5, or a 0.5-point increase if baseline EDSS ≥ 5.5, confirmed 3 months apart) was assessed by comparing EDSS assessed 6 months after the SARS-CoV-2 infection, with the last EDSS assessed within 6 months before the infection. We chose a 6 months period as the most informative on the possible influence of the SARS-CoV-2 infection on MS disease activity, believing a longer period would have also detected disease activity possibly unrelated to the infection.
Descriptive data were presented as counts (proportion) for categorical variables and mean ± standard deviation for continuous variables. The differences in presence/absence of relapses, presence/absence of MRI disease activity, presence/absence of CDW between cases and controls were assessed using the McNemar test. Propensity score matching and statistical analysis were performed with SPSS 17.0.
3. Results
We identified 156 cases of SARS-CoV-2 infection in RRMS patients in the period March 2020 - March 2022, out of a total population of approximately 1500 MS patients. After excluding 6 patients with no MRI available after SARS-CoV-2 infection, the remaining 150 cases were matched 1:1 with 150 controls (MS patients not exposed to SARS-CoV-2, as previously defined).
Mean age was 40.9 ± 12.0 years in cases and 42.0 ± 10.9 years in controls, mean EDSS was 2.54±1.36 in cases and 2.60±1.32 in controls. Male to female ratio was 0.32 in cases and in controls. Mean duration of disease was 9.1 ± 7.9 years in cases and 9.4 ± 6.3 years in controls. All patients were treated with a DMT. The proportion of patients treated with HET was 65.3% in cases and 66.0% in controls. Only few patients in this cohort were treated with a DMT with potential antiviral effects such as beta interferon or teriflunomide (10 patients treated with teriflunomide, 9 patients treated with betaIFN).
The anamnestic, clinical and MRI data of the study population are summarized in Table 1.
Table 1Characteristics of the study population.
| Cases | Controls | Cohen d | |
|---|---|---|---|
| Number | 150 | 150 | |
| Age | 40.9 ± 12.0 | 42.0 ± 10.9 | 0.09 |
| M:F ratio | 0.32 | 0.32 | |
| EDSS | 2.54±1.36 | 2.60±1.32 | 0.04 |
| High efficacy DMT | 98/150 (65.3%) | 99/150 (66.0%) | |
| Moderate efficacy DMT | 52/150 (34.7%) | 51/150 (34.0%) | |
| Disease duration | 9.1 ± 7.9 | 9.4 ± 6.3 | 0.04 |
| clinical relapses in the year prior to study inclusion | 12/150 (8.0%) | 15/150 (10.0%) | |
| MRI disease activity in the year prior to study inclusion | 22/150 (14.7%) | 18/150 (12.0%) |
Values for continuous variables are expressed as mean ± standard deviation.
EDSS = Expanded Disability Status Scale.
DMT = Disease Modifying Treatment.
We did not observe a significant difference,between cases in the 6 months after SARS-CoV-2 infection and controls, in the occurrence of clinical relapses (6/150 (4.0%) cases and in 8/150 (5.3%) controls (p = 0.774), MRI disease activity (14/150 cases (9.3%) and 12/150 controls (8.0%) (p = 0.838), CDW (8/150 cases (5.3%) and in 10/150 controls (6.7%) (p = 0.782). The results of the study are summarized in Table 2.
Table 2MS disease activity following SARS-CoV2 infection.
| Cases | Controls | p | |
|---|---|---|---|
| Number | 150 | 150 | |
| Clinical relapses | 6/150 (4.0%) | 8/150 (5.3%) | p = 0.774 |
| MRI disease activity | 14/150 (9.3%) | 12/150 (8.0%) | p = 0.838 |
| CDW | 8/150 (5.3%) | 10/150 (6.7%) | p = 0.782 |
Values for continuous variables are expressed as mean ± standard deviation.
CDW = Confirmed Disability Worsening.
No significant differences were observed in clinical relapses, MRI disease activity or CDW following SARS-CoV2 infection, between patients treated with a DMT with a potential antiviral effect (beta interferon, teriflunomide) and patients treated with other DMTs (Supplementary Table 1).
No deaths or hospitalizations due to Covid-19 were recorded in this cohort. A considerable proportion of patients in this cohort (52.8%) had been vaccinated with a mRNA Covid-19 vaccine, according to the national guidelines for MS patients (almost all unvaccinated patients did not receive the vaccine because it was not yet available). No significant differences were observed in clinical relapses, MRI disease activity or CDW following SARS-CoV2 infection, between vaccinated and unvaccinated patients (Supplementary Table 1).
4. Discussion
Considering the rapid spread of the virus worldwide during the pandemic and the high propensity to immediately perform diagnostic tests on large numbers in the general population, probably an event that has never occurred in history to date for a viral respiratory infection, the SARS-CoV-2 pandemic can represent an ideal model to assess the temporal relationship between intercurrent viral respiratory infections and MS disease activity. In previous studies, the assessment of this temporal relationship was often limited by the retrospective identification of intercurrent viral infections (open to recall biases), and, for those studies with a prospective design, often by the lack of a laboratory confirmation of the infection (relying only on self-reported symptoms by the patient). In addition, older studies usually did not include MRI data and evaluated only clinical exacerbations, therefore with limited sensitivity for MS disease activity. Furthermore, only 3 studies included patients treated with DMTs (betaIFN) and none included patients treated with higher efficacy DMTs (
Edwards et al., 1998
; Buljevac et al., 2002
; Correale et al., 2006
).Using a propensity score matching design and including both a clinical and MRI evaluation of MS disease activity, this study does not suggest an increase in MS disease activity after the SARS-CoV-2 infection.
This study has some potential limitations. The sample size is not as large as a multicentric study could have reached. It should be noted, however, that with this sample size we should have easily detected an increase of the risk of MS disease activity with the magnitude reported in previous studies following other viral infections, which was in most studies about 2–3 fold (
Andersen et al., 1993
; Panitch, 1994
; Edwards et al., 1998
; Buljevac et al., 2002
; Correale et al., 2006
). Also, we can not exclude the possibility of other intercurrent unidentified viral infections, which may also have had an impact on the risk of disease activity. We can not be sure if these results are generalizable to infections by other types of coronaviruses, or to infections by other respiratory viruses, or are specific only for the SARS-CoV-2 infection.These results can reassure MS patients about the absence of significant risks of the exposure to SARS-CoV-2 in relation to MS disease activity. It should however be considered that all MS patients in our cohort were treated with a DMT, and a considerable number with a high efficacy therapy. These results therefore may not be applicable to untreated patients, for which the risk of increased MS disease activity after SARS-CoV-2 infection may not be excluded. This is an important difference from most older studies on the relationship between intercurrent viral infections and exacerbations of MS, which were performed on untreated MS patients cohorts (
Andersen et al., 1993
; Panitch, 1994
; Edwards et al., 1998
; Buljevac et al., 2002
). A possible hypothesis explaining these results could be that SARS-CoV2 is less prone, compared to other viruses, to induce exacerbations of MS disease activity. Another possible hypothetical interpretation of these results could be that DMT is able to effectively suppress the increase of disease activity triggered by SARS-CoV2 infection.Ethical approval
All patients gave their written consent for inclusion in the MS Center database (which is part of the Italian Multiple Sclerosis register) and for use of the recorded clinical data. Local ethics committee (Comitato Etico interaziendale AOU Città della Salute e della Scienza di Torino, AO Ordine Mauriziano, ASL Città di Torino) approval protocol 0039998 and 0039993.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Data availability
The dataset analyzed in this study is available from the corresponding author on reasonable request.
CRediT authorship contribution statement
Marco Vercellino: Conceptualization, Methodology, Formal analysis, Writing – original draft, Project administration. Chiara Bosa: Data curation, Investigation. Anastasia Alteno: Data curation, Investigation. Francesco Muccio: Data curation, Investigation. Stella Marasciulo: Data curation, Investigation. Paola Garelli: Data curation, Investigation. Paola Cavalla: Supervision, Writing – review & editing.
Declaration of Competing Interest
Marco Vercellino and Paola Cavalla have received research funding and speaker fees from Merck Serono, Roche, Novartis, Biogen, Sanofi. The other Authors declare that there is no conflict of interest regarding this study.
Acknowledgements
We wish to thank the Italian Multiple Sclerosis register and its Scientific Committee (Prof. Maria Trojano, Prof. Mario Alberto Battaglia, Dr. Marco Capobianco, Prof. Maura Pugliatti, Dr. Monica Ulivelli, Dr. Paola Mosconi, Dr. Claudio Gasperini, Prof. Francesco Patti, Prof. Maria Pia Amato, Dr. Roberto Bergamaschi, Prof. Giancarlo Comi). We also thank Dr. Daniele Dell'Anna for invaluable support.
Appendix. Supplementary materials
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Article info
Publication history
Published online: April 09, 2023
Accepted:
April 8,
2023
Received in revised form:
March 5,
2023
Received:
November 27,
2022
Identification
Copyright
© 2023 Elsevier B.V. All rights reserved.
