Share

September 2021; 8 (5) ArticleOpen Access

Impact of Disease-Modifying Treatments of Multiple Sclerosis on Anti–SARS-CoV-2 Antibodies

An Observational Study

Kévin Bigaut, Laurent Kremer, Thibaut Fabacher, Livia Lanotte, Marie-Celine Fleury, Nicolas Collongues, Jerome de Seze
First published July 28, 2021, DOI: https://doi.org/10.1212/NXI.0000000000001055
Full PDF
Citation
Permissions

Make Comment

See Comments

Downloads
1150

Share

Abstract

Objective To compare the humoral response after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with multiple sclerosis (MS) receiving different disease-modifying treatments (DMTs).

Methods Patients with MS with coronavirus disease 2019 (COVID-19) and available anti–SARS-CoV-2 serology were included. The primary endpoint was the anti–SARS-CoV-2 immunoglobulin G (IgG) index. The multivariate analysis was adjusted for COVID-19 severity, SARS-CoV-2 PCR result, and the time between COVID-19 onset and the serology.

Results We included 61 patients with available IgG index. The IgG index was lower in patients with fingolimod or anti-CD20 monoclonal antibodies compared with patients without treatment (p < 0.01), patients with interferon β-1a or glatiramer (p < 0.01), and patients with another DMT (p = 0.01). The IgG index was correlated with the time between COVID-19 onset and serology (r = −0.296 [−0.510; −0.0477], p = 0.02).

Conclusions Humoral response after COVID-19 was lower in patients with MS with fingolimod or anti-CD20 mAb. These patients could therefore be at risk of recurrent infection and could benefit from anti–SARS-CoV-2 vaccination. The humoral response after vaccination and the delay before vaccination need to be evaluated.

Classification of Evidence This study provides Class IV evidence that patients treated with fingolimod or anti-CD20 monoclonal antibodies for MS have a lower humoral response after COVID-19 compared with patients without DMTs or with another DMTs.

Glossary

COVID-19=
coronavirus disease 2019;
DMT=
disease-modifying treatment;
EDSS=
Expanded Disability Status Scale;
IgG=
immunoglobulin G;
IQR=
interquartile range;
SARS-CoV-2=
severe acute respiratory syndrome coronavirus 2

Since 2019 and the pandemic outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the related disease (coronavirus disease 2019 [COVID-19]), physicians have been particularly concerned about patients with multiple sclerosis (MS) on disease-modifying treatments (DMTs), especially those with anti-CD20 monoclonal antibodies, such as ocrelizumab or rituximab.1,2 Indeed, patients with rituximab, ocrelizumab, or fingolimod had a higher risk of infection and a reduced humoral response to vaccines.3,4

The objective of our study was to analyze the humoral response after SARS-CoV-2 infection according to different DMTs.

Methods

Patients

Patients from MS centers in Alsace (France) were included prospectively in the French registry of COVID-19 in patients with MS or neuromyelitis optica spectrum disorder (NCT04355611, approval from the ethics committee of Sorbonne University #CER-2020–19).

COVID-19 diagnostic criteria were positive SARS-CoV-2 PCR on nasopharyngeal swab, thoracic CT abnormalities suggesting of COVID-19 (ground-glass opacities), rapidly evolving anosmia or ageusia without rhinitis or nasal obstruction, or COVID-19 typical symptoms (association of cough, fever, and asthenia) in an epidemic zone of COVID-19.

Data

Collected data were age, sex, Expanded Disability Status Scale (EDSS) score, DMT, comorbidity, date of COVID-19 onset, results of SARS-CoV-2 PCR, COVID severity, and date and results of SARS-CoV-2 serology.

DMTs were grouped as: “no treatment,” “no risk” (interferon β-1a and glatiramer acetate), “low risk” (teriflunomide, dimethyl fumarate, natalizumab, methotrexate, and mycophenolate), and “moderate to high risk” (fingolimod, rituximab, and ocrelizumab).

Comorbidities associated with severe COVID-19 were cardiovascular disease, pulmonary disease, diabetes, obesity (body mass index > 30 kg/m2), and smoking.

COVID-19 severity was scored on a 7-point ordinal scale:5

  • 1–2 = not hospitalized

  • 1, normal activities

  • 2, reduction of daily activities

  • 3–7 = hospitalized

  • 3, hospitalized but without supplemental oxygen

  • 4, required supplemental oxygen

  • 5, noninvasive ventilation or high-flow oxygen

  • 6, invasive mechanical ventilation or extracorporeal membrane oxygenation

  • 7, death

SARS-CoV-2 Antibody Detection

Serum samples were tested using the Abbott or Roche chemiluminescent immunoassay detecting immunoglobulin G (IgG) against the SARS-CoV-2 spike protein. Tests were classified as positive or negative with a threshold according to the manufacturer's instructions in the range of 0.72–1.54 U/mL.

Statistical Analysis

The primary endpoint was the IgG index, and the secondary endpoint was the serologic status (negative or positive).

We excluded from the analysis patients with a SARS-CoV-2 serology within 6 weeks after the onset of COVID-19 because immunization against the virus was potentially not finished.

For the multivariate analysis, we selected variables with p < 0.20 in the univariate analysis among the following variables: age, sex, EDSS score, DMT, comorbidity, results of SARS-CoV-2 PCR, COVID severity, and the time between COVID-19 onset and serology. If a quantitative variable was not normally distributed, we changed it to a categorical variable according to the median. The candidate covariates were included in a linear regression model for the anti–SARS-CoV-2 IgG index endpoint and a logistic regression model for the serologic status endpoint (R software).

Data Availability

Anonymized data will be shared on request from any qualified investigator.

Results

In our registry in the period of the study, 94 patients were infected by SARS-CoV-2, a serology with IgG index >6 weeks from the COVID-19 onset was available for 61 patients, and a serology without IgG index (only qualitative result: positive or negative) >6 weeks from the COVID-19 onset was available for 64 patients. Two patients from the registry died of COVID-19. No patients were vaccinated because no vaccines were available in France during the period of the study. DMTs were introduced in the 3 months before COVID-19 onset for only 3 patients and in the 6 months for 6 patients. Descriptive results are summarized in Table 1.

View this table:
Table 1

Descriptive Characteristics of the Cohort

Anti–SARS-CoV-2 Antibodies

After univariate analysis (eTable 1, links.lww.com/NXI/A537), we selected the following relevant variables: DMT group (no treatment, no risk, low risk, and moderate to high risk), time between COVID-19 onset and the serology (≤168 and >168 days), COVID severity (grade 1–2 and grade ≥3), and the result of SARS-CoV-2 PCR (negative, positive, or not performed). The longer the time between COVID-19 onset and the serology, the lower the IgG index (r = −0.296 [−0.510; −0.0477], p = 0.02; Figure, A). Only 1 patient had a high dose of corticosteroid within the month before the onset of COVID-19 (grade of severity = 1). This variable was therefore not included in the model.

Figure
Figure Anti–SARS-CoV-2 IgG Index According to Time and DMTs

(A) Anti–SARS-CoV-2 IgG index according to the time from the onset of COVID-19. Statistical analysis was performed using a Pearson correlation coefficient r. (B) Anti–SARS-CoV-2 IgG index according to the DMT group (no treatment; no risk: interferon β-1a and glatiramer acetate; low risk: teriflunomide, dimethyl fumarate, natalizumab, methotrexate, and mycophenolate; and moderate to high risk: fingolimod, rituximab, and ocrelizumab). The analysis was adjusted for COVID-19 severity score, SARS-CoV-2 PCR result, and the time between the onset of COVID-19 and the serology using a linear regression model. COVID-19 = coronavirus disease 2019; DMT = disease-modifying treatment; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.

In the multivariate analysis, the IgG index was significantly lower in the moderate to high risk DMT group compared with the other groups (Table 2 and Figure, B). Similarly, patients who had a severe COVID-19 (grade ≥3) had a higher IgG index than patients who did not (p = 0.02, Table 2). This analysis also confirmed that the IgG index decreased with time (p = 0.03, Table 2).

View this table:
Table 2

Predictive Factors of the Humoral Response After COVID-19 in Multivariate Analysis

For the serologic status in multivariate analysis (Table 2), serology was more often negative in the moderate to high risk DMT group (8/15 patients; 4/6 patients with anti-CD20 mAb; and 4/9 patients with fingolimod) than in the group without treatment (3/16 patients, p = 0.04) and the low-risk group (5/25 patients, p = 0.05), but no differences were found with the no-risk DMT group (1/8 patients, p = 0.15). Serology was more often negative after 168 days (p < 0.01). No differences were found for the result of PCR.

Patients With Repeated Serologies

At least 2 serologies were available in 15 patients. The mean time from COVID-19 onset to serology 1 was 95.3 ± 57.7 days and to serology 2 was 271.3 ± 84.3 days. The IgG index remained low for 2 of 4 patients in the moderate to high risk DMT group, whereas it increased before decreasing over time in the other groups (eFigure, links.lww.com/NXI/A537).

Discussion

We reported here a reduced humoral response after COVID-19 in patients treated with anti-CD20 mAb and fingolimod compared with patients without DMT or with other DMTs.

These results are consistent with previous case reports or case series, which suggest an absence or a poor humoral response after COVID-19 in patients with anti-CD20 mAb.6,-,9 Indeed, depleting B cells from pre–B cells to mature B cells, ocrelizumab affects humoral responses to infection and, subsequently, antibody production.3 A case series on DMTs in SARS-CoV-2 antibody-positive patients with MS showed that among the 14 patients, 6 patients were treated with fingolimod, suggesting a humoral response.10 However, in our study, 4 of 9 patients with fingolimod had a negative serology, suggesting a reduced humoral response, as previously demonstrated with immune responses against influenza vaccine.4

Thus, our results suggest that patients with fingolimod or anti-CD20 mAb could be at risk of reinfection with SARS-CoV-2. However, a study showed that patients with asymptomatic or mild COVID-19 had memory T-cell responses without detectable circulating antibodies leading to potential prevention of recurrent infection.11 In view of the high proportion of patients with a score of 1–2 on the COVID-19 severity scale in our cohort (≈90%), these patients could be protected by cellular mechanism than humoral mechanism.

Our study has some limitations. First, the time between the onset of COVID-19 and the anti–SARS-CoV-2 serology was not predetermined and was dependent on the availability of the serology. Second, only the humoral immunity was analyzed and not the cellular immunity, which plays an important role in the defense against viruses and the protection against COVID-19 through vaccination.12 Third, repetitive anti–SARS-CoV-2 serologies were not systematically performed and were available for only 13 patients, thus limiting the interpretation of the humoral response over time.

In conclusion, the humoral response after COVID-19 was lower in patients with MS with fingolimod or anti-CD20 mAb. Consequently, these patients could be at risk of recurrent infection and could benefit from anti–SARS-CoV-2 vaccination. The humoral response after vaccination and the delay before vaccination need to be evaluated.

Study Funding

The authors report no targeted funding.

Disclosure

The authors declare no disclosures relevant to the manuscript. Go to Neurology.org/NN for full disclosures.

Acknowledgment

The authors thank Thomas Senger for his assistance in collecting data.

Appendix Authors

Table

Footnotes

  • Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.

  • The Article Processing Charge was funded by the authors.

  • Received March 29, 2021.
  • Accepted in final form June 1, 2021.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

References

  1. 1.↵
    1. Louapre C,
    2. Collongues N,
    3. Stankoff B, et al.
    Clinical characteristics and outcomes in patients with coronavirus disease 2019 and multiple sclerosis. JAMA Neurol. 2020;70(9):1079-1088.
    OpenUrl
  2. 2.↵
    1. Sormani MP,
    2. De Rossi N,
    3. Schiavetti I, et al.
    Disease-modifying therapies and coronavirus disease 2019 severity in multiple sclerosis. Ann Neurol. 2021;89(4):e1999-e2008.
    OpenUrl
  3. 3.↵
    1. Bar-Or A,
    2. Calkwood JC,
    3. Chognot C, et al.
    Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: the VELOCE study. Neurology. 2020;95(14):e1999-e2008.
    OpenUrlPubMed
  4. 4.↵
    1. Kappos L,
    2. Mehling M,
    3. Arroyo R, et al
    . Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis. Neurology. 2015;84(9):872-879.
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. Cao B,
    2. Wang Y,
    3. Wen D, et al
    . A trial of lopinavir-Ritonavir in adults hospitalized with severe covid-19. N Engl J Med. 2020;382(19):1787-1799.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Maillart E,
    2. Papeix C,
    3. Lubetzki C,
    4. Roux T,
    5. Pourcher V,
    6. Louapre C
    . Beyond COVID-19: DO MS/NMO-SD patients treated with anti-CD20 therapies develop SARS-CoV2 antibodies?. Mult Scler Relat Disord. 2020;46:102482.
    OpenUrl
  7. 7.↵
    1. Thornton JR,
    2. Harel A
    . Negative SARS-CoV-2 antibody testing following COVID-19 infection in Two MS patients treated with ocrelizumab. Mult Scler Relat Disord. 2020;44:102341.
    OpenUrl
  8. 8.↵
    1. Conte WL
    . Attenuation of antibody response to SARS-CoV-2 in a patient on ocrelizumab with hypogammaglobulinemia. Mult Scler Relat Disord. 2020;44:102315.
    OpenUrl
  9. 9.↵
    1. Wallach AI,
    2. Picone MA
    . The presence of SARS-CoV2 antibodies in MS patients. Mult Scler Relat Disord. 2021;50:102793.
    OpenUrl
  10. 10.↵
    1. Mallucci G,
    2. Zito A,
    3. Baldanti F, et al
    . Safety of disease-modifying treatments in SARS-CoV-2 antibody-positive multiple sclerosis patients. Mult Scler Relat Disord. 2021;49:102754.
    OpenUrl
  11. 11.↵
    1. Sekine T,
    2. Perez-Potti A,
    3. Rivera-Ballesteros O, et al
    . Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19. Cell. 2020;183(1):158.e14-168.e14.
    OpenUrl
  12. 12.↵
    1. Sahin U,
    2. Muik A,
    3. Derhovanessian E, et al
    . COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses. Nature. 2020;586(7830):594-599.
    OpenUrlPubMed

Letters: Rapid online correspondence

No comments have been published for this article.
Comment

REQUIREMENTS

If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org

Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.

If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.

Submission specifications:

  • Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
  • Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
  • Submit only on articles published within 6 months of issue date.
  • Do not be redundant. Read any comments already posted on the article prior to submission.
  • Submitted comments are subject to editing and editor review prior to posting.

More guidelines and information on Disputes & Debates

Compose Comment

More information about text formats

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Author Information
NOTE: The first author must also be the corresponding author of the comment.
First or given name, e.g. 'Peter'.
Your last, or family, name, e.g. 'MacMoody'.
Your email address, e.g. higgs-boson@gmail.com
Your role and/or occupation, e.g. 'Orthopedic Surgeon'.
Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.
Publishing Agreement
NOTE: All authors, besides the first/corresponding author, must complete a separate Publishing Agreement Form and provide via email to the editorial office before comments can be posted.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

You May Also be Interested in

Back to top
Advertisement

Related Articles

  • No related articles found.

Topics Discussed

Alert Me

Recommended articles