A Randomized Clinical Trial of 2-Week Methotrexate Discontinuation in Rheumatoid Arthritis Patients Vaccinated With Inactivated Sars-Cov-2 Vaccine

Abstract

ObjectivesTo 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.MethodsThis 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).ResultsRandomization 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).ConclusionWe 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.FundingFAPESP/CNPq/B3-Bolsa de Valores-Brasil.

Increment of immunogenicity after third dose of a homologous inactivated SARS-CoV-2 vaccine in a large population of patients with autoimmune rheumatic diseases

“…This finding is superior to the 47%–68% rate of positive antibodies reported for transplant recipients after mRNA additional dose25 28 29 45 and may be explained in part by the distinct intensity of immunosuppression, with a high frequency of multiple drug therapy in transplanted population. In addition, the temporary discontinuation of MTX and MMF in more than half of patients under these therapies might also have contributed to improved immune response, as reported recently by our group in rheumatoid arthritis population 46. The higher rates of anti-SARS-CoV-2 seropositivity in patients who withheld MMF herein were statistically not significant, probably due to a limited power for this analysis.…”

“…In addition, the temporary discontinuation of MTX and MMF in more than half of patients under these therapies might also have contributed to improved immune response, as reported recently by our group in rheumatoid arthritis population. 46 The higher rates of anti-SARS-CoV-2 seropositivity in patients who withheld MMF herein were statistically not significant, probably due to a limited power for this analysis.…”

“…The large number of patients with ARD and the inclusion of an age-balanced and sex-balanced CG are relevant strengths of the present study and provided a sizeable sample to evaluate humoral response to additional vaccine dose and the impact of the drugs. In fact, the few studies focusing on the third dose for immunocompromised individuals were small-sized17 50 or did not have a control group 24 25 28–30 44 46…”

Antibody response to SARS-CoV-2 mRNA vaccines in patients with rheumatic diseases in Japan: Interim analysis of a multicentre cohort study

“…Aroujo et al. reported that stopping MTX for 2 weeks after COVID-19 inactivated vaccination increased antibody titres, seroconversion rates, and RA flares [ 20 ]. It is theoretically uncontroversial that the temporary cessation of drugs that reduce antibody titres can improve antibody titres to some extent.…”

Immunogenicity, breakthrough infection, and underlying disease flare after SARS-CoV-2 vaccination among individuals with systemic autoimmune rheumatic diseases

“…A study performed in Hong Kong using administrative data among 5493 RA patients showed no association between vaccine receipt and RA flare as well as no difference in RA drug prescriptions after vaccination 44 . However, a randomized trial of holding vs. continuing methotrexate in RA patients after COVID-19 vaccine did show higher disease activity in those who held methotrexate 45 . This suggests that immunosuppressive medication changes around vaccination, rather than vaccine-specific effects, could explain at least some RMD flares after vaccination.…”