Two-week methotrexate discontinuation in patients with rheumatoid arthritis vaccinated with inactivated SARS-CoV-2 vaccine: a randomised clinical trial

  1. Carlo Scognamiglio Renner Araujo
  2. Ana Cristina Medeiros-Ribeiro
  3. Carla G S Saad
  4. Karina Rossi Bonfiglioli
  5. Diogo Souza Domiciano
  6. Andrea Yukie Shimabuco
  7. Matheus Santos Rodrigues Silva
  8. Emily Figueiredo Neves Yuki
  9. Sandra Gofinet Pasoto
  10. Tatiana Pedrosa
  11. Leonard de Vinci Kanda Kupa
  12. Gioanna Zou
  13. Rosa M R Pereira
  14. Clóvis Artur Silva
  15. Nádia Emi Aikawa
  16. Eloisa Bonfa

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Abstract

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 patients with rheumatoid arthritis (RA).

Methods

This was a single-centre, prospective, randomised, investigator-blinded, intervention study ( NCT04754698 , CoronavRheum) including adult patients with RA (stable Clinical Disease Activity Index (CDAI) ≤10, prednisone ≤7.5 mg/day) randomised (1:1) to withdraw MTX (MTX-hold) for 2 weeks after each vaccine dose or maintain MTX (MTX-maintain), evaluated at day 0 (D0), D28 and D69. Coprimary outcomes were anti-SARS-CoV-2 S1/S2 IgG seroconversion (SC) and neutralising antibody (NAb) positivity at D69. Secondary outcomes were geometric mean titres (GMT) and flare rates. For immunogenicity analyses, we excluded patients with baseline positive IgG/NAb, and for safety reasons those who flared at D28 (CDAI >10) and did not withdraw MTX twice.

Results

Randomisation included 138 patients with 9 exclusions (5 COVID-19, 4 protocol violations). Safety evaluation included 60 patients in the MTX-hold and 69 patients in the MTX-maintain group. Further exclusions included 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, the MTX-hold group (n=37) had a higher rate of SC than the MTX-maintain group (n=55) (29 (78.4%) vs 30 (54.5%), p=0.019), 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). At D28 flare, the rates were comparable in both groups (CDAI, p=0.122; Disease Activity Score in 28 joints with C reactive protein, p=0.576), whereas CDAI >10 was more frequent in MTX-hold at D69 (p=0.024).

Conclusion

We provided novel data that 2-week MTX withdrawal after each dose of the Sinovac-CoronaVac vaccine improves anti-SARS-CoV-2 IgG response. The increased flare rates after the second MTX withdrawal may be attributed to the short-term interval between vaccine doses. This strategy requires close surveillance and shared decision making due to the possibility of flares.

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  1. Version published to 10.1136/annrheumdis-2021-221916
  2. 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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  3. Version published to 10.1101/2021.11.23.21266785v1 on medRxiv