Pausing methotrexate improves immunogenicity of COVID-19 vaccination in elderly patients with rheumatic diseases

  1. Amanthi Nadira Arumahandi de Silva
  2. Leonie Maria Frommert
  3. Fredrik N Albach
  4. Jens Klotsche
  5. Veronika Scholz
  6. Lara Maria Jeworowski
  7. Tatjana Schwarz
  8. Alexander ten Hagen
  9. Jan Zernicke
  10. Victor Max Corman
  11. Christian Drosten
  12. Gerd-Rüdiger Burmester
  13. Robert Biesen

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Abstract

To study the effect of methotrexate (MTX) and its discontinuation on the humoral immune response after COVID-19 vaccination in patients with autoimmune rheumatic diseases (AIRD).

Methods

In this retrospective study, neutralising SARS-CoV-2 antibodies were measured after second vaccination in 64 patients with AIRD on MTX therapy, 31 of whom temporarily paused medication without a fixed regimen. The control group consisted of 21 patients with AIRD without immunosuppressive medication.

Results

Patients on MTX showed a significantly lower mean antibody response compared with patients with AIRD without immunosuppressive therapy (71.8% vs 92.4%, p<0.001). For patients taking MTX, age correlated negatively with immune response (r=−0.49; p<0.001). All nine patients with antibody levels below the cut-off were older than 60 years. Patients who held MTX during at least one vaccination showed significantly higher mean neutralising antibody levels after second vaccination, compared with patients who continued MTX therapy during both vaccinations (83.1% vs 61.2%, p=0.001). This effect was particularly pronounced in patients older than 60 years (80.8% vs 51.9%, p=0.001). The impact of the time period after vaccination was greater than of the time before vaccination with the critical cut-off being 10 days.

Conclusion

MTX reduces the immunogenicity of SARS-CoV-2 vaccination in an age-dependent manner. Our data further suggest that holding MTX for at least 10 days after vaccination significantly improves the antibody response in patients over 60 years of age.

Article activity feed

  1. Version published to 10.1136/annrheumdis-2021-221876
  2. Version published to 10.1101/2021.11.17.21266441v3 on medRxiv
  3. Version published to 10.1101/2021.11.17.21266441v2 on medRxiv
  4. ScreenIT

    SciScore for 10.1101/2021.11.17.21266441: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsConsent: All patients provided written informed consent.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Additionally, IgG antibodies against nucleocapsid, receptor binding domain (RBD), full spike and the S1 domain of the spike protein were tested using SeraSpot® Anti-SARS-CoV-2 IgG microarray-based immunoassay (Seramun Diagnostica GmbH, Heidesee, Germany) and served here for further validation purposes.
    IgG antibodies against nucleocapsid, receptor binding domain (RBD)
    suggested: None
    Anti-SARS-CoV-2 IgG
    suggested: None
    The association between timing and duration of MTX-hold at the two vaccinations and neutralisation results were estimated by linear regression analyses (anti-RBD-IgG concentrations or neutralizing antibody levels by neutralisation result) and logistic regression analyses (anti-RBD-IgG concentration >1 S/CO or neutralization capacity ≥30%)adequate neutralisation result) adjusted for duration between blood sampling and second vaccination and considering the clustering of the two vaccinations within a patient.
    anti-RBD-IgG
    suggested: None
    Software and Algorithms
    SentencesResources
    Statistical analyses were performed using Graphpad Prism 9.2.0 and STATA 12.1.
    Graphpad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    STATA
    suggested: (Stata, RRID:SCR_012763)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Limitations of our study were small case numbers and the retrospective design, which is why our findings should be validated in a randomized controlled trial in the future. Also, T-cell-response were not part of our study design, however, according to current studies, it can be assumed that measuring antibody levels is an adequate mean to determine vaccine immunogenicity 18. In addition, we used multivariable statistical models analyses to additionally adjust for the potential confounders MTX monotherapy and MTX dose. A strength of our study was that we validated all our neutralisation test results with an additional test system measuring anti-RBD-IgG. We did not assess the safety of pausing MTX in our cohort, but current data do not indicate a significantly higher flare occurrence or disease activity in association with MTX discontinuation of two weeks 19. In conclusion, we present real-world data that is of clinical relevance regarding upcoming booster vaccination campaigns initiated by several countries. We determined age and MTX-hold as the main factors influencing antibody response during SARS-CoV-2 vaccinations and both aspects should be regarded when discussing MTX regimens. Our data suggest that, if possible, patients older than 60 years of age should hold MTX for at least 10 days after receiving a COVID-19-vaccination.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  5. Version published to 10.1101/2021.11.17.21266441v1 on medRxiv