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Abstract
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.
- methotrexate
- COVID-19
- vaccination
- arthritis
- rheumatoid
Data availability statement
All data relevant to the study are included in the article.
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Data availability statement
All data relevant to the study are included in the article.
Footnotes
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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