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Objectives: Methotrexate (MTX) is one of the most commonly used medications to treat rheumatoid arthritis (RA). However, the effect of MTX treatment on cellular immune responses remains incompletely understood. This raises concerns about the vulnerability of these patients to emerging infections and following vaccination., Methods: In the current study, we investigated the impact of MTX treatment in patients with immune-mediated inflammatory disease on B and CD4 T cell SARS-CoV-2 vaccination responses. Eighteen patients with RA and two patients with psoriatic arthritis on MTX monotherapy were included, as well as 10 patients with RA without immunosuppressive treatment, and 29 healthy controls. CD4 T and B cell responses were analysed 7 days and 3-6 months after two SARS-CoV-2 messenger RNA vaccinations. High-dimensional flow cytometry analysis was used to analyse fresh whole blood, an activation-induced marker assay to measure antigen-specific CD4 T cells, and spike probes to study antigen-specific B cells., Results: Seven days following two SARS-CoV-2 vaccinations, total B and T cell counts were similar between MTX-treated patients and controls. In addition, spike-specific B cell frequencies were unaffected. Remarkably, the frequency of antigen-specific CD4 T cells was reduced in patients using MTX and correlated strongly with anti-RBD IgG antibodies. These results suggest that decreased CD4 T cell activity may result in slower vaccination antibody responses in MTX-treated patients., Conclusion: Taken together, MTX treatment reduces vaccine-induced CD4 T cell activation, which correlates with lower antibody responses., Trial Registration Number: NL8900., Competing Interests: Competing interests: FE, GW, SMvH and TWK report (governmental) grants from ZonMw to study immune response after SARS-Cov-2 vaccination in auto-immune diseases. FE also reports grants from Prinses Beatrix Spierfonds, CSL Behring, Kedrion, Terumo BCT, Grifols, Takeda Pharmaceutical and GBS-CIDP Foundation; consulting fees from UCB Pharma and CSl Behring; honoraria from Grifols. All other authors report no disclosures relevant to the manuscript., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Messenger RNA (mRNA) vaccines provide robust protection against SARS-CoV-2 in healthy individuals. However, immunity after vaccination of patients with multiple sclerosis (MS) treated with ocrelizumab (OCR), a B cell-depleting anti-CD20 monoclonal antibody, is not yet fully understood., Methods: In this study, deep immune profiling techniques were employed to investigate the immune response induced by SARS-CoV-2 mRNA vaccines in untreated patients with MS (n=21), OCR-treated patients with MS (n=57) and healthy individuals (n=30)., Results: Among OCR-treated patients with MS, 63% did not produce detectable levels of antibodies (non-seroconverted), and those who did have lower spike receptor-binding domain-specific IgG responses compared with healthy individuals and untreated patients with MS. Before vaccination, no discernible immunological differences were observed between non-seroconverted and seroconverted OCR-treated patients with MS. However, non-seroconverted patients received overall more OCR infusions, had shorter intervals since their last OCR infusion and displayed higher OCR serum concentrations at the time of their initial vaccination. Following two vaccinations, non-seroconverted patients displayed smaller B cell compartments but instead exhibited more robust activation of general CD4 + and CD8 + T cell compartments, as indicated by upregulation of CD38 and HLA-DR surface expression, when compared with seroconverted patients., Conclusion: These findings highlight the importance of optimising treatment regimens when scheduling SARS-CoV-2 vaccination for OCR-treated patients with MS to maximise their humoral and cellular immune responses. This study provides valuable insights for optimising vaccination strategies in OCR-treated patients with MS, including the identification of CD38 and HLA-DR as potential markers to explore vaccine efficacy in non-seroconverting OCR-treated patients with MS., Competing Interests: Competing interests: JK received research grants for multicentre investigator-initiated trials (DOT-MS trial, ClinicalTrials.gov Identifier: NCT04260711 (ZonMw) and BLOOMS trial (ZonMw and Treatmeds), ClinicalTrials.gov Identifier: NCT05296161); received consulting fees from F Hoffmann-La Roche, Biogen, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); reports speaker relationships with F Hoffmann-La Roche, Biogen, Immunic, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); and adjudication committee of MS clinical trial of Immunic (payments to institution only)., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

For patients with immune-mediated inflammatory diseases (IMIDs), concerns exist about increased disease activity after vaccination. We aimed to assess changes in disease activity after SARS-CoV-2 vaccination in patients with IMIDs, and determine risk factors for increased disease activity. In this substudy of a prospective observational cohort study (Target-to-B!), we included patients with IMIDs who received a SARS-CoV-2 vaccine. Patients reported changes in disease activity on a five-point Likert scale every 60 days for up to twelve months after first vaccination. In case of self-reported increased activity, hospital records were screened whether the treating physician reported increased activity, and for potential intensification of immunosuppressive (ISP) treatment. Mixed models were used to study determinants for self-reported increased disease activity. In total, 2111 patients were included for analysis after primary immunization (mean age 49.7 years [SD 13.7], 1329/2111 (63.0%) female), from which 1266 patients for analysis after first additional vaccination. Increased disease activity at 60 days after start of primary immunization was reported by 223/2111 (10.6%). In 96/223 (43.0%) the increase was confirmed by the treating physician and in 36/223 (16.1%) ISP treatment was intensified. Increased disease activity at seven to 60 days after additional vaccination, was reported by 139/1266 (11.0%). Vaccinations were not temporally associated with self-reported increased disease activity. Conversely, increased disease activity before first vaccination, neuromuscular disease, and multiple sclerosis were associated. Altogether, self-reported increased disease activity after vaccination against SARS-CoV-2 was recorded in a minority of patients and was generally mild. Moreover, multivariate analyses suggest that disease related factors, but not vaccinations are the major determinants for self-reported increased disease activity., Competing Interests: Declaration of competing interest F Eftimov and T Kuijpers report (governmental) grants from ZonMw to study immune response after SARS-Cov-2 vaccination in auto-immune diseases. F Eftimov also reports grants from Prinses Beatrix Spierfonds, CSL Behring, Kedrion, Terumo BCT, Grifols, Takeda Pharmaceutical Company, and GBS-CIDP Foundation; consulting fees from UCB Pharma and CSL Behring; honoraria from Grifols. AJ van der Kooi reports grants from CSL Behring and participation on an advisory board for Argen-X. M Löwenberg reports a grant from Galapagos not related to this study, and honoraria from Bristol Myers Squibb, Pfizer, Takeda, and Tillotts. Ph I Spuls is involved in performing clinical trials with many pharmaceutical industries that manufacture drugs used for the treatment of e.g. psoriasis and atopic dermatitis, for which financial compensation is paid to the department/hospital and is a chief investigator of the TREAT NL registry taskforce and SECURE-AD registry. M.W. Bekkenk is a secretary for Dutch Experimental Dermatology Board and head of the pigmentary disorders group within the Dutch Dermatology Board, and reports honoraria from Pfizer, Sanofi, Novartis and Fondation René Touraine. J Killestein has speaking relationships with Merck Serono, Biogen Idec, TEVA, Sanofi, Genzyme, Roche and Novartis; Amsterdam UMC, location VUmc, MS Center Amsterdam has received financial support for research activities from Merck Serono, Bayer Shcering Pharma, Biogen Idec, GlaxoSmithKline, Roche, Teva, Sanofi, Genzyme, GlaxoSmithKline, and Novartis. B Horváth reports unpaid positions as medical advisor for several patient groups, a board position for ERN-SKIN, and associate editor for The British Journal of Dermatology; reports grants from Abbvie, Akari Therapeutics, Celgene, and Novartis; consulting fees from UCB Pharma, Novartis and Janssen-Cilag; honoraria from Abbvie. J.J.G.M. Verschuuren reports consulting fees from Argenx, Alexion and NMD Pharma; is coinventor on patent applications based on MuSK-related research. DJ Hijnen reports grants from Abbvie, AstraZeneca, Janssen, LEO Pharma and UCB Pharma, and honoraria from Abbvie, Galderma, Janssen, Lilly, Pfizer, Sanofi and UCB Pharma, and a paid position in an advisory board for BIOMAP IMI. P.A. van Doorn participated on an advisory board for Octapharma. P. van Paassen reports grants from Alexion Pharma and GSK; and participation on GSK and Vifor Pharma advisory boards. G.R.A.M. D'Haens reports consulting fees from Abbvie, Agomab, AstraZeneca, AM Pharma, AMT, Arena Pharmaceuticals, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Exo Biologics, Galapagos, Index Pharmaceuticals, Kaleido, Roche, Gilead, Glaxo Smith Kline, Gossamerbio, Pfizer, Immunic, Johnson and Johnson, Origo, Polpharma, Procise Diagnostics, Prometheus laboratories, Prometheus Biosciences, Progenity, and Protagonist; honoraria from Abbvie, Arena, Galapagos, Gilead, Pfizer, BMS, Takeda; participation on advisory boards for Abbvie, Seres Health, Galapagos, and AstraZeneca. R.B. Takkenberg reports honoraria from Sobi and Norgine and participation in an advisory board for Norgine. SH Goedee is a board member of the Dutch Society of Clinical Neurophysiology (unpaid), reports grants from Prinses Beatrix Spierfonds, and received speaker fees from Shire/Takeda. AH Zwinderman reports paid data safety monitoring board positions for Torrent Ltd and Foresee Pharmaceuticals Co. No other disclosures were reported. Bar plot showing proportions of self-reported increased disease activity (with corresponding 95% CI's), physician confirmed increased disease activity, and treatment intensification, within each IMID group at 60 days after start of primary immunization. IBD: inflammatory bowel disease; IMID: immune-mediated inflammatory disease; ISP: immunosuppressant; MS: multiple sclerosis; NMO: neuromyelitis optica; SLE: systemic lupus erythematosus. Bar plot showing incidence of self-reported increased disease activity at different timepoints. A) self-reported increased disease activity within 60 days after vaccination: at 60 days after start of primary immunization (prim. imm.), seven to 60 days after first additional vaccination (add. vacc.), and at other follow-up moments within seven to 60 days after a vaccination other than the moments mentioned before (e.g. second vaccination of primary immunization or second additional vaccination). B) self-reported increased disease activity not within 60 days after vaccination, in the two-monthly follow-up surveys starting at first vaccination. Figure showing the results of the multivariate mixed model on determinants of self-reported increased disease activity. RR's with corresponding 95% CI for age, female sex, BMI, IMID group (with gastro-intestinal disease as reference group), recent increased disease activity (self-reported increased disease activity in the three months preceding enrollment), ISP use, and any SARS-CoV-2 vaccination in 60 days before the survey. BMI: body mass index; CI: confidence interval; IMID: immune-mediated inflammatory disease; ISP: immunosuppressant; MS: multiple sclerosis; NMO: neuromyelitis optica; RR: relative risk; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2., (Copyright © 2022. Published by Elsevier Ltd.)

Objectives: To evaluate whether a third vaccination shows an added effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) T-cell responses in patients with multiple sclerosis treated with ocrelizumab or fingolimod., Methods: This is a substudy of a prospective multicenter study on SARS-CoV-2 vaccination in patients with immune-mediated diseases. Patients with MS treated with ocrelizumab, fingolimod, and no disease-modifying therapies and healthy controls were included. The number of interferon (IFN)-γ secreting SARS-CoV-2-specific T cells at multiple time points before and after 3 SARS-CoV-2 vaccinations were evaluated., Results: In ocrelizumab-treated patients (N = 24), IFN-γ-producing SARS-CoV-2-specific T-cell responses were induced after 2 vaccinations with median levels comparable to healthy controls (N = 12) and patients with MS without disease-modifying therapies (N = 10). A third vaccination in ocrelizumab-treated patients (N = 8) boosted T-cell responses that had declined after the second vaccination, but did not lead to higher overall T-cell responses as compared to immediately after a second vaccination. In fingolimod-treated patients, no SARS-CoV-2-specific T cells were detected after second (N = 12) and third (N = 9) vaccinations., Discussion: In ocrelizumab-treated patients with MS, a third SARS-CoV-2 vaccination had no additive effect on the maximal T-cell response but did induce a boost response. In fingolimod-treated patients, no T-cell responses could be detected following both a second and third SARS-CoV-2 vaccination., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Studies have suggested incremental short-term adverse events (AE) after repeated vaccination. In this report, we assessed occurrence and risk factors for short-term AEs following repeated SARS-CoV-2 vaccination in patients with various immune-mediated inflammatory diseases (IMIDs)., Methods: Self-reported daily questionnaires on AEs during the first 7 days after vaccination were obtained of 2259 individuals (2081 patients and 178 controls) participating in an ongoing prospective multicenter cohort study on SARS-CoV-2 vaccination in patients with various IMIDs in the Netherlands (T2B-COVID). Relative risks were calculated for potential risk factors associated with clinically relevant AE (rAE), defined as AE lasting longer than 2 days or impacting daily life., Results: In total, 5454 vaccinations were recorded (1737 first, 1992 second and 1478 third vaccinations). Multiple sclerosis, Crohn's disease and rheumatoid arthritis were the largest disease groups. rAEs were reported by 57.3% (95% CI 54.8-59.8) of patients after the first vaccination, 61.5% (95% CI 59.2-63.7) after the second vaccination and 58% (95% CI 55.3-60.6) after the third vaccination. At day 7 after the first, second and third vaccination, respectively, 7.6% (95% CI 6.3-9.1), 7.4% (95% CI 6.2-8.7) and 6.8% (95% CI 5.4-8.3) of patients still reported AEs impacting daily life. Hospital admissions and allergic reactions were uncommon (<0.7%). Female sex (aRR 1.43, 95% CI 1.32-1.56), age below 50 (aRR 1.14, 95% CI 1.06-1.23), a preceding SARS-CoV-2 infection (aRR 1.14, 95% CI 1.01-1.29) and having an IMID (aRR 1.16, 95% CI 1.01-1.34) were associated with increased risk of rAEs following a vaccination. Compared to the second vaccination, the first vaccination was associated with a lower risk of rAEs (aRR 0.92, 95% CI 0.84-0.99) while a third vaccination was not associated with increased risk on rAEs (aRR 0.93, 95% CI 0.84-1.02). BNT162b2 vaccines were associated with lower risk on rAEs compared to CX-024414 (aRR 0.86, 95% CI 0.80-0.93)., Conclusions: A third SARS-CoV-2 vaccination was not associated with increased risk of rAEs in IMID patients compared to the second vaccination. Patients with an IMID have a modestly increased risk of rAEs after vaccination when compared to controls. Most AEs are resolved within 7 days; hospital admissions and allergic reactions were uncommon., Trial Registration: NL74974.018.20 , Trial ID: NL8900. Registered on 9 September 2020., (© 2022. The Author(s).)