A RANDOMIZED CLINICAL TRIAL OF 2-WEEK METHOTREXATE DISCONTINUATION IN RHEUMATOID ARTHRITIS PATIENTS VACCINATED WITH INACTIVATED SARS-COV-2 VACCINE

  1. Carlo S R Araujo
  2. Ana C Medeiros-Ribeiro
  3. Carla G S Saad
  4. Karina R Bonfiglioli
  5. Diogo S Domiciano
  6. Andrea Y Shimabuco
  7. Matheus R Silva
  8. Emily F N Yuki
  9. Sandra G Pasoto
  10. Tatiana N Pedrosa
  11. Leonard Kupa
  12. Gioanna Zou
  13. Rosa M R Pereira
  14. Clovis A Silva
  15. Nadia E Aikawa
  16. Eloisa Bonfa

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Abstract

Objectives

To evaluate the effect on immunogenicity and safety of 2-week methotrexate(MTX) discontinuation after each dose of the Sinovac-CoronaVac vaccine versus MTX maintenance in rheumatoid arthritis(RA) patients.

Methods

This was a single-center, prospective, randomized, investigator-blinded, intervention study (# NCT04754698 , CoronavRheum), including adult RA patients(stable CDAI<10, prednisone<7.5mg/day), randomized(1:1) to withdraw MTX(MTX-hold) for 2 weeks after each vaccine dose or maintain MTX(MTX-maintain), evaluated at D0, D28 and D69. Co-primary outcomes were anti-SARS-CoV-2 S1/S2 IgG seroconversion(SC) and neutralizing antibody(NAb) positivity at D69. Secondary outcomes were GMT and changes in disease activity scores. For immunogenicity analyses, we excluded patients with baseline positive IgG/NAb, and, for safety reasons, those unable to hold MTX twice(CDAI>10 at D28).

Results

Randomization included 138 patients with 9 exclusions(5 COVID-19, 4 protocol violations). Safety evaluation included 60(MTX-hold) and 69(MTX-maintain) patients. Further exclusions consisted of 27 patients[13(21.7%) vs. 14(20.3%),p=0.848] with positive baseline IgG/NAb and 10 patients(21.3%) in MTX-hold with CDAI>10 at D28. At D69, a higher increase in SC[29(78.4%) vs 30(54.5%),p=0.019] was observed in MTX-hold(n=37) in comparison to MTX-maintain(n=55), with parallel augmentation in GMT[34.2(25.2-46.4) vs 16.8(11.9-23.6),p=0.006]. No differences were observed for NAb positivity[23(62.2%) vs 27(49.1%),p=0.217]. Longitudinal variations in disease activity scores were alike in both groups(CDAI,p=0.144; DAS28-CRP,p=0.718).

Conclusion

We provided novel data that 2-week MTX withdrawal after each vaccine dose improves anti-SARS-CoV-2 immunogenicity. The comparable longitudinal variations of disease activity in both groups suggest that discontinuation is a feasible and efficient strategy in well-controlled RA patients, and may be even safer for vaccines with longer interval between doses or single dose schedules.

Funding

FAPESP/CNPq/B3-Bolsa de Valores-Brasil.

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  1. ScreenIT

    SciScore for 10.1101/2021.11.23.21266785: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: The study was conducted in accordance with the Declaration of Helsinki and local regulations, and was approved by the institutional and national ethics committee (CAAE: 42566621.0.0000.0068).
    Consent: Patients with CDAI<10 proceeded to the enrollment station, where the unblinded researchers revised the protocol, explained the procedures, collected the informed consent and conducted the randomization, which was performed on the web-based software “The REDcap
    Sex as a biological variablenot detected.
    RandomizationStudy design: This was a single-center, randomized, investigator-blind, intervention study performed at the rheumatology outpatient clinic of a tertiary center.
    BlindingRandomization and masking: Investigators responsible for disease activity measures, statisticians and laboratory personnel were blinded to the allocation groups.
    Power AnalysisStatistical analysis: The sample size calculation was based on the 2009 non-adjuvanted influenza A/H1N1 primo vaccination in a large cohort of RA patients under MTX, which induced SC rate of 46%, [36].

    Table 2: Resources

    Antibodies
    SentencesResources
    The co-primary outcomes were seroconversion (SC) rates for anti-SARS-CoV-2 S1/S2 IgG and neutralizing antibodies (NAb) positivity at D69.
    anti-SARS-CoV-2 S1/S2 IgG
    suggested: None
    Software and Algorithms
    SentencesResources
    All statistical analyses were performed using Statistical Package for the Social Sciences, version 20.0 (IBM-SPSS for Windows. 20.0. Chicago, IL, USA).
    Statistical Package for the Social Sciences
    suggested: (SPSS, RRID:SCR_002865)

    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:
    The final small sample size of the study is related to the high rate of refusals to participate and the rigorous exclusion criteria, and is an important limitation of this trial. However, the larger than expected benefit of MTX withdrawal allowed the identification of a significant difference between groups for SC and GMT. We provide herein novel evidence of an increment of approximately 25% in anti-SARS-CoV-2 antibodies induced by Sinovac-CoronaVac vaccine with temporary MTX withdrawal. Such improvement is very similar to the 20% increase first described regarding MTX discontinuation for 2 weeks after influenza vaccine,[15], and could therefore partially reduce the deleterious effects in seroconversion induced by MTX reported for Sinovac-CoronaVac vaccine,[12] and BNT162b2 mRNA COVID-19,[13, 16]. This immunogenicity enhancement was observed even with a high frequency of combined DMARD therapy and corticosteroids, factors that could further impair immune response to COVID vaccine,[12-13]. Importantly, MTX dose was comparable between the groups and all patients had doses above 10mg/week, in line with the observation that only patients with doses greater than 7.5mg/week benefited from MTX withdrawal after influenza vaccine,[15]. Concerning combination therapy, the distribution of drugs was alike between the groups, equalizing possible additional harmful effects of different DMARD. We also deliberately excluded patients under rituximab, due to well-known effect on humoral immuno...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04754698Active, not recruitingCOVID-19 CoronaVac in Patients With Autoimmune Rheumatic Dis…

    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

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  2. Version published to 10.1101/2021.11.23.21266785v1 on medRxiv