Objective 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.
Data availability statement
All data relevant to the study are included in the article.
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Handling editor Josef S Smolen
CSRA and ACM-R contributed equally.
Contributors CSRA, ACM-R, CGSS, EFNY, NEA and EB conceived and designed the study. EB is responsible for the overall content as the guarantor. CSRA, ACM-R, CGSS, KRB, DSD, AYS, CAS, EFNY, TP, LdVKK, GZ, RMRP, CAS and NEA reviewed the charts and selected and invited potential patients for the study. CSRA and MSRS were the two non-blinded researchers and were responsible for randomisation, enrolment, explanation of the procedures, informed consent, safety surveillance and patient follow-up by telephone for adherence purposes. ACM-R, CGSS, KRB, DSD and AYS were the blinded investigators responsible for disease activity measures. LdVKK, TP and EB organised and supervised blood collection and vaccination protocol. SGP supervised serum processing, SARS-CoV-2-specific antibody ELISA/neutralisation assays and SARS-CoV-2 RT-PCR. ACM-R, CGSS, KRB, DSD, AYS, EFNY, SGP, CAS, TP, LdVKK, GZ, RMRP, NEA and EB participated in data collection and analysis and clinical data management. CSRA, ACM-R, CGSS, EFNY, SGP, CAS, LdVKK, NEA and EB were responsible for writing and revision of the manuscript. All authors helped edit the manuscript.
Funding This study was sponsored by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (no 2015/03756-4 to NEA, SGP, CAS and EB; no 2017/14352-7 to TP; no 2019/17272-0 to LdvKK; no 2021/06616-0 to GZ); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (no 305242/2019-9 to EB; no 304984/2020-5 to CAS; no 305556/2017-7 to RMRP); and B3 - Bolsa de Valores do Brasil.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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