WITHDRAWING METHOTREXATE AFTER BOTH VERSUS ONLY SECOND DOSE OF THE CHADOX1 NCOV-19 VACCINE IN PATIENTS WITH AUTOIMMUNE INFLAMMATORY ARTHRITIS: TWO INDEPENDENT RANDOMIZED CONTROLLED TRIALS (MIVAC I AND II)

BackgroundPausing methotrexate (MTX) for two to four weeks, improved immunogenicity of influenza vaccination in patients with rheumatoid arthritis (RA), albeit a risk of disease flare (1). This guided the framing of guidelines on MTX withdrawal for COVID-19 vaccination (2). However, evidence for MTX withdrawal for COVID-19 vaccination is limited to observational studies only.ObjectivesTo compare the efficacy and safety of holding MTX after each (MIVAC 1) and only after the second dose (MIVAC II) of the ChAdOx1 vaccine versus continuation of MTX in two randomized controlled trials (RCTs).MethodsTwo single centre, investigator-blinded, RCTs were conducted in patients with RA or Psoriatic arthritis (PsA) on stable doses of MTX without prior COVID-19 (CTRI reg. no. MIVAC I: CTRI/2021/07/03463 & MIVAC II: CTRI/2021/07/035307). In MIVAC I, unvaccinated patients were randomised (1:1) to hold or continue MTX for two weeks after each dose of the vaccine. MIVAC II included patients who had continued MTX during the first dose of ChAdOx1 and were randomised (1:1) to hold or continue MTX for 2 weeks after the second vaccine dose. The primary outcome for both the trials was the anti-Receptor Binding Domain (RBD) antibody titres measured four weeks after the second vaccine dose (per protocol analysis). Secondary outcome was the flare rate, defined as an increase in disease activity scores (DAS28/cDAPSA) or physician intent to hike DMARDs.Results250 patients were randomized for MIVAC 1 and 178 for MIVAC II and after due exclusions, 158 and 157 were eligible for analysis respectively (Figure 1). In MIVAC I, median anti-RBD titres were significantly high in the MTX hold group [2484 (1050-4388) versus 1147(433-2360), p=0.001] but the flare rate was higher in the hold group [20 (25%) versus 6(8%) p=0.005] compared to continue group. In MIVAC II median anti-RBD titres were significantly high for the MTX hold group [2553 (1792-4823) versus 990 (356-2252), p=0.001] when compared to continue group but there was no difference in the flare rate between the groups [9(11.8%) and 4(7.9%), p=0.15] (Table 1). Since both were parallel studies in similar population, MTX hold arms across both the trials were compared for anti-RBD titres and flare. There was no difference in the anti-RBD titres [p=0.2] between the groups. In MIVAC I, 29(36.25%) patients had reported flare (19 in either first or second dose, 10 for both doses) when compared to MIVAC II where only 9(11.84%) patients had reported flare after the second dose (P <0.001).Table 1.Baseline demographics and key resultsVariableMIVAC IMIVAC IIMTX HoldMTX ContinuePMTX HoldMTX ContinueP valueN=80N=78valueN=76N=81Age†48 (38-53.3)49 (39-59)0.1953 (42.3-59)53(50-62)0.14Female (%) ‡73 (91.3)75 (96.2)0.3365 (85.5)70 (86.4)>0.99RA (%) ‡69(86.3)69 (93.2)70 (85.6)80 (87.7)PsA (%) ‡11(13.8)6 (8.1)0.316 (7.9)1 (1.2)0.057DAS28†2.7 (2.4-3.2)2.6 (2-3.3)0.62.7(2.3-3.4)2.8 (2.1-3.5)0.78cDAPSA †2(3-4.5)2.5(1.3-3.8)0.463(2.8-3)30.15Prednisolone (%) ‡29 (36.3)23(31.1)0.424(31.6)26 (32.1)>0.99MTX mg/week†17.5 (10-25)15 (10-20)0.05715 (9.4-25)17.5(7.5-25)0.92Anti- RBD antibody titres post second dose (IU/mL) †2484 (1050-4388.8)1147.5 (433.5-2360.3)<0.0012553.5 (1792.5-4823.8)990.5 (356.1-2252.5)<0.001Flare (N%) ‡Post first dose20 (25)6 (8)0.005NANAPost second dose19 (23.8)10(13.3)0.19 (11.8)4 (7.9)0.15All analysis as per protocol population.†Median (interquartile range): Mann Whitney U test.‡ N (%): Fisher Exact test. Bolded if p<0.05.ConclusionHolding MTX after both the doses or only after the second dose of ChAdOx1 yields higher anti-RBD antibody titres as compared to continuing MTX. Comparing across the trials, holding MTX only after the second dose appears to be non-inferior to holding MTX after both doses of the vaccine with a lesser risk of flare.References[1]Park JK et al. Clin Rheumatol. 2020 Feb; 39(2):375-379.[2]Curtis JR, et al. Arthritis & Rheumatology. 2021 Oct;73(10): e60-75.AcknowledgementsAcknowledgments to all participating investigators, patients and their familiesDisclosure of InterestsAnu Sreekanth: None declared, Teny Skaria: None declared, Sneha Joseph: None declared, Rashwith Umesh: None declared, Manju Mohanan: None declared, Aby Paul: None declared, Sakir Ahmed Speakers bureau: Sakir Ahmed had received honorarium as speaker from Pfizer, Dr Reddy’s, Cipla, and Novartis unrelated to this Comment, Pankti Mehta: None declared, Seena Oomen: None declared, Janet Benny: None declared, Justin George: None declared, Anagha Paulose: None declared, K Narayanan: None declared, Sanjana Joseph: None declared, Anuroopa Vijayan: None declared, Kaveri Nalianda: None declared, Padmanabha Shenoy: None declared