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      Methotrexate and TNF inhibitors affect long-term immunogenicity to COVID-19 vaccination in patients with immune-mediated inflammatory disease

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          Abstract

          Studies have revealed that patients with immune-mediated inflammatory diseases, especially those on immunomodulatory medication, have attenuated immunogenicity to COVID-19 vaccination.1, 2 These findings have informed American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) recommendations regarding use of immunomodulatory therapies peri-vaccination. Recent longitudinal studies in immunocompetent adults have found waning humoral immunity by 6-months post-vaccination.3, 4 However, despite an already diminished initial response to immunisation in patients with immune-mediated inflammatory diseases, there are scarce data regarding their longer-term humoral response. We hypothesised that patients with immune-mediated inflammatory diseases who are treated chronically with certain disease-modifying rheumatic drugs (ie, methotrexate) or anti-cytokine therapies (ie, TNF inhibitors), would have lower rates of adequate humoral response over time compared with patients without these diseases or those receiving other immunomodulatory medications. Using the New York University SAGA cohort, we obtained post-vaccination blood samples from participants with immune-mediated inflammatory diseases (n=245) and healthy controls (n=27) and analysed SARS-CoV-2-spike-specific antibody titres and neutralisation capacity at 4-week, 3-month, and 6-month timepoints after vaccination. This study was approved by the NYU institutional review board (20–01078) and all patients provided informed consent for participation. Full methods can be found in the appendix (p 2). Healthy individuals and those with immune-mediated inflammatory diseases were similar in age, sex, and history of previous SARS-CoV-2 infection (appendix pp 3–4). Diagnoses included predominantly psoriatic disease, rheumatoid arthritis, and inflammatory bowel disease. The proportion of participants who achieved an adequate humoral response (ie, anti-spike IgG titre ≥5000 RU/mL) among healthy individuals and participants with immune-mediated inflammatory diseases remained stable between 4 weeks and 3 months after vaccination: 26 (96%) of 27 healthy controls were seropositive at 4 weeks versus 25 (100%) of 25 at 3 months, as were 216 (88%) of 245 participants with immune-mediated inflammatory diseases versus 193 (89%) of 217 (appendix p 5). Adequate humoral response rates decreased significantly in both groups by the 6-month timepoint (17 [65%] of 26 controls [p=0·0017] and 96 [56%] of 170 participants with IMIDs [p<0·0001]), as did IgG titres, percentage of antibodies with neutralising capacity, and rates of adequate neutralising response (ie, ≥35%) (figure ). Neutralising capacity correlated strongly with IgG antibody response (r=0·812, appendix p 14). No singular diagnosis demonstrated significant differences in adequate humoral response compared with healthy controls (appendix p 5). Previous COVID-19 infection was associated with increased antibody titres and neutralisation capacity at all timepoints and an increased adequate humoral response rate at 6 months (appendix p 6). Figure Longitudinal humoral response to COVID-19 vaccination in healthy controls and patients with IMID Humoral response represented by the spike IgG titres (A), the proportion of patients achieving an adequate spike IgG response as defined by greater than or equal to 5000 RU/mL (B), percentage neutralising capacity (C), and proportion of patients achieving an adequate neutralising capacity as defined by greater than or equal to 35% (D). (E) Proportion of patients achieving an adequate spike IgG response, by immunomodulatory use, as defined by spike IgG titres greater than or equal to 5000 RU/ml. The 4-week timepoint is defined at 4 weeks after the first dose of Janssen Ad26.COV2.S (Johnson & Johnson) and BNT162b2 (Pfizer–BioNTech) and 5 weeks after the first dose of mRNA-1273 (Moderna). IMID=immune-mediated inflammatory disease. RU=relative units. At week 4, when compared with healthy controls, patients with immune-mediated inflammatory diseases who were not receiving methotrexate achieved a similar rate of adequate humoral response (150 [93%] of 161; appendix p 7), whereas those on methotrexate had a lower rate of adequate humoral response (66 [79%] of 84; p=0·002). Patients on methotrexate tended to be older, female, and have rheumatoid arthritis, and had a mean weekly dose of 14·5 mg. Mean IgG titres and neutralising antibodies were similarly lower in patients on methotrexate than in healthy controls and those not on methotrexate. At 3 months and 6 months after vaccination, patients on methotrexate had numerically lower rates of adequate response and titres than did healthy controls and patients not on methotrexate (66 [86%] of 77 vs 25 [100%] of 25 and 127 [91%] of 140, respectively, p=0·10 at 3 months; and 28 [46%] of 61 vs 17 [65%] of 26 and 68 [62%] of 109, respectively, p=0·08 at 6 months) with similar trends seen in antibody titre and neutralising antibodies. The overall adequate humoral response rate of patients receiving methotrexate differed significantly from healthy controls at 4 weeks (p=0·039), and was numerically lower, but did not differ significantly at 3 and 6 months (figure; appendix p 8). The unadjusted odds ratio (OR) of achieving an adequate response to COVID-19 vaccination at week 4 for all methotrexate use (ie, alone or in combination with other medications) was 0·27 (95% CI 0·12–0·60, p=0·001), when compared with those not on methotrexate (appendix p 9). This effect remained significant when adjusting for age and sex and when restricting analysis to methotrexate monotherapy. The unadjusted OR for methotrexate use at 3 months was 0·61 (95% CI 0·26–1·45, p=0·26) and at 6 months was 0·51 (95% CI 0·27–0·97, p=0·039; appendix pp 10–11). The results at 3 and 6 months remain similar after adjusting for age and sex (appendix pp 10–11). At 4 weeks, 37 (44%) of 84 patients on methotrexate held at least one dose immediately before or after vaccination (appendix p 7). Among patients receiving methotrexate, those who held their medication during the peri-vaccination period had an unadjusted OR of 3·50 (95% CI 1·04–11·75, p=0·043) achieving an adequate response compared with those who did not hold any doses (appendix p 9). This difference remained true at 3 months (unadjusted OR 8·33, 1·01–68·87, p=0·049) and 6 months (5·60, 1·68–18·70, p=0·005; appendix pp 10–11). There was no difference in adequate humoral response rates between the use of high-dose methotrexate (≥15 mg) and low-dose methotrexate (≤12·5 mg) in any combination of use (appendix p 12). Patients with immune-mediated inflammatory diseases on TNF inhibitors had similar rates of adequate humoral response compared with those not on TNF inhibitors at 4 weeks (88 [88%] of 100 vs 128 [88%] of 145) and 3 months (74 [87%] of 85 vs 119 [90%] of 132), and compared with healthy controls. However, by 6 months the proportion of adequate antibody response was lower, although not statistically significant, in patients on TNF inhibitors compared with patients receiving other medications (30 [45%] of 66 vs 66 [63%] of 104, p=0·053; appendix p 13). Although adequate neutralising response was only significantly lower in the TNF group at 6 months, neutralising antibody concentration was significantly decreased at all timepoints, as were antibody titres at 3 and 6 months. Compared with those not receiving TNF inhibitors, the unadjusted OR of having an adequate humoral response following vaccination while receiving a TNF inhibitor was 0·48 (95% CI 0·26–0·90, p=0·022; appendix p 11) at 6 months post-vaccination, no such difference was seen at the 4-week and 3-month timepoints (appendix pp 9-10). The overall adequate humoral response rate for patients on TNF inhibitors declined significantly from 88 (88%) of 100 at 4 weeks and 74 (87%) of 85 at 3 months, to 30 (45%) of 66 at 6 months (p<0·0001 for both 4 weeks vs 6 months and 3 months vs 6 months; appendix pp 8–9). Concomitant TNF inhibitor use attenuated the early suppressive effect of methotrexate (appendix p 8). However, at 6 months, combined TNF inhibitor–methotrexate use had the lowest adequate humoral response rate of any medication (9 [35%] of 26), even when compared with all methotrexate use (figure, appendix p 8). This combination had an unadjusted OR of 0·35 (95% CI 0·14–0·83, p=0·018; appendix p 11) of achieving adequate humoral response at 6 months compared with those not on this combination. This effect remained significant when adjusting for age and sex. In the New York University SAGA cohort, participants with immune-mediated inflammatory diseases had a decline to 56% in adequate humoral response at 6 months. Importantly, healthy controls had a lower humoral response rate at 6 months (65%) than reported in previous studies (81–84%).4, 5 We continue to observe that methotrexate hampers the humoral immune response to COVID-19 vaccination. This effect is somewhat attenuated at the 3-month and 6-month timepoints, which might reflect the fact that methotrexate slows, rather than prevents, antibody production. In particular, the 3-month timepoint might reflect the peak immunogenicity of the vaccination captured in our study, thereby overcoming any observable effect on humoral response. Although dose of methotrexate did not affect humoral response; importantly, participants who held at least one dose of methotrexate during the peri-vaccination period had much higher odds of achieving an adequate humoral response than those who did not. These findings support the notion that this drug can substantially affect the biological response to vaccination and support the rationale behind current guidelines from ACR and EULAR for methotrexate use during this time. Crucially, by 6 months, TNF inhibitors (especially in combination with methotrexate) led to further decreased rates of immunogenicity compared with earlier timepoints. Most initial studies did not demonstrate any effect of TNF inhibitors on adequate humoral response.1, 2, 6 However, Chen and colleagues 7 observed reduced antibody activity against the SARS-CoV-2 delta (B.1.617.2) variant in patients receiving TNF inhibitors, especially at 3-month and 5 or 6-month timepoints. Like methotrexate, 8 TNF inhibitors have previously been shown to impair the immune response to vaccines against other viral infections.9, 10 Mechanistic studies are needed to evaluate the seemingly synergistic effect of these drugs on weakening the antibody response of COVID-19 and other vaccines. Although the relevance of our findings are constrained by the small sample size and scarcity of established correlates of levels of immunogenicity to efficacy, they show that both methotrexate and TNF inhibitors might lead to a dampened humoral response to COVID-19 vaccinations. Although TNF inhibitors do not demonstrate an initial effect on immunogenicity, persistence of adequate humoral response is significantly decreased by month 6 (appendix p 11). Taken together, these findings support the use of supplemental booster dosing in patients with immune-mediated inflammatory diseases, and specifically for those being treated with TNF inhibitors or TNF inhibitor–methotrexate combination therapy. Larger studies are needed to validate these results and to assess the effects of other immunomodulatory therapies, which will help to identify optimal timing and strategy of COVID-19 (and potentially other) vaccines. For more on New York University SAGA see https://clinicaltrials.med.nyu.edu/clinicaltrial/1360/serologic-testing-genomic-analysis/ JUS reports consultancy fees from Janssen, Novartis, Pfizer, Sanofi, UCB, AbbVie, and Amgen, and funding for investigator-initiated studies from Pfizer, Sanofi, and Janssen. MJM reports laboratory research and clinical trials contracts with Lilly, Pfizer, and Sanofi, and personal fees for scientific advisory board service from Merck, Meissa Vaccines, and Pfizer. PMI reports consulting fees from GlaxoSmithKline and Momenta/Janssen. RHH reports consulting fees from Janssen. SA reports grant support from Johnson & Johnson. GS reports consulting fees from AbbVie. DPH reports consultancy fees from AbbVie, Bristol Myers Squibb, Janssen, Takeda, UCB, and Pfizer, and reports research support from Janssen and Pfizer. JEA reports consultancy fees from BioFire Diagnostics and Janssen; research grant support from BioFire Diagnostic; and holds US patent 2012/0052124A1. SCh reports consulting fees from AbbVie, Pfizer, and Bristol Myers Squibb. AS reports consulting fees from Lilly, GlaxoSmithKline, AstraZeneca, and Kezar. ALN reports consultancy fees from Janssen, UCB, AbbVie, and Bristol Myers Squibb, and her immediate family member owns shares of stock in Johnson & Johnson, Eli Lilly, AbbVie, and Pfizer. All other authors declare no competing interests. RHH, SU, and JEA contributed equally to this paper. DPH and JUS contributed equally to this paper. All data relevant to the study are included in the article or uploaded as supplementary information. Further de-identified data can be made available upon request via email to the corresponding author. This study was funded by US National Institutes of Health (NIH)–National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR074500 to Scher, T32-AR-069515 to RHH and JUS), NIH–National Institute of Diabetes and Digestive and Kidney Diseases (K23DK124570 to JEA), NIH–National Institute of Allergy and Infectious Diseases (AI082630 and AI158617 to SH), Rheumatology Research Foundation (Scientist Development Award to RHH), Bloomberg Philanthropies, Pfizer COVID-19 Competitive Grant Program, The Beatrice Snyder Foundation, The Riley Family Foundation, Crohn's and Colitis Foundation (to JEA), and the Judith and Stewart Colton Center for Autoimmunity (to JEA). No authors are employed by the NIH. We are grateful to our patients and their families for participating in this study and to our colleagues who referred patients to use. We thank Luz Alvarado, Rhina Medina, Parvathi Girija, and Jyoti Patel for coordinating and for data entry efforts.

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          Most cited references10

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          Waning Immune Humoral Response to BNT162b2 Covid-19 Vaccine over 6 Months

          Background Despite high vaccine coverage and effectiveness, the incidence of symptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been increasing in Israel. Whether the increasing incidence of infection is due to waning immunity after the receipt of two doses of the BNT162b2 vaccine is unclear. Methods We conducted a 6-month longitudinal prospective study involving vaccinated health care workers who were tested monthly for the presence of anti-spike IgG and neutralizing antibodies. Linear mixed models were used to assess the dynamics of antibody levels and to determine predictors of antibody levels at 6 months. Results The study included 4868 participants, with 3808 being included in the linear mixed-model analyses. The level of IgG antibodies decreased at a consistent rate, whereas the neutralizing antibody level decreased rapidly for the first 3 months with a relatively slow decrease thereafter. Although IgG antibody levels were highly correlated with neutralizing antibody titers (Spearman’s rank correlation between 0.68 and 0.75), the regression relationship between the IgG and neutralizing antibody levels depended on the time since receipt of the second vaccine dose. Six months after receipt of the second dose, neutralizing antibody titers were substantially lower among men than among women (ratio of means, 0.64; 95% confidence interval [CI], 0.55 to 0.75), lower among persons 65 years of age or older than among those 18 to less than 45 years of age (ratio of means, 0.58; 95% CI, 0.48 to 0.70), and lower among participants with immunosuppression than among those without immunosuppression (ratio of means, 0.30; 95% CI, 0.20 to 0.46). Conclusions Six months after receipt of the second dose of the BNT162b2 vaccine, humoral response was substantially decreased, especially among men, among persons 65 years of age or older, and among persons with immunosuppression.
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            Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine in adult patients with autoimmune inflammatory rheumatic diseases and in the general population: a multicentre study

            Introduction Vaccination represents a cornerstone in mastering the COVID-19 pandemic. Data on immunogenicity and safety of messenger RNA (mRNA) vaccines in patients with autoimmune inflammatory rheumatic diseases (AIIRD) are limited. Methods A multicentre observational study evaluated the immunogenicity and safety of the two-dose regimen BNT162b2 mRNA vaccine in adult patients with AIIRD (n=686) compared with the general population (n=121). Serum IgG antibody levels against SARS-CoV-2 spike S1/S2 proteins were measured 2–6 weeks after the second vaccine dose. Seropositivity was defined as IgG ≥15 binding antibody units (BAU)/mL. Vaccination efficacy, safety, and disease activity were assessed within 6 weeks after the second vaccine dose. Results Following vaccination, the seropositivity rate and S1/S2 IgG levels were significantly lower among patients with AIIRD versus controls (86% (n=590) vs 100%, p<0.0001 and 132.9±91.7 vs 218.6±82.06 BAU/mL, p<0.0001, respectively). Risk factors for reduced immunogenicity included older age and treatment with glucocorticoids, rituximab, mycophenolate mofetil (MMF), and abatacept. Rituximab was the main cause of a seronegative response (39% seropositivity). There were no postvaccination symptomatic cases of COVID-19 among patients with AIIRD and one mild case in the control group. Major adverse events in patients with AIIRD included death (n=2) several weeks after the second vaccine dose, non-disseminated herpes zoster (n=6), uveitis (n=2), and pericarditis (n=1). Postvaccination disease activity remained stable in the majority of patients. Conclusion mRNA BNTb262 vaccine was immunogenic in the majority of patients with AIIRD, with an acceptable safety profile. Treatment with glucocorticoids, rituximab, MMF, and abatacept was associated with a significantly reduced BNT162b2-induced immunogenicity.
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              Effect of methotrexate, anti-tumor necrosis factor α, and rituximab on the immune response to influenza and pneumococcal vaccines in patients with rheumatoid arthritis: a systematic review and meta-analysis.

              To assess the current literature on the impact of rheumatoid arthritis (RA) treatments on the humoral response to pneumococcal and influenza vaccines. We systematically searched the literature for studies evaluating the immune response to vaccines in RA patients receiving methotrexate (MTX) and/or biologic agents. The efficacy of vaccination, assessed by the response rate based on increased antibody titers before and 3-6 weeks after vaccination, was extracted by one investigator and verified by another. In total, 12 studies were included. RA patients mainly received MTX, anti-tumor necrosis factor α (anti-TNFα), or rituximab (RTX). Influenza vaccination response was reduced for RTX (43 patients; pooled odds ratio [OR] 0.44 [95% confidence interval (95% CI) 0.17-1.12] for H1N1, OR 0.11 [95% CI 0.04-0.31] for H3N2, and OR 0.29 [95% CI 0.10-0.81] for B) but not for anti-TNFα (308 patients; OR 0.93 [95% CI 0.36-2.37] for H1N1, OR 0.79 [95% CI 0.34-1.83] for H3N2, and OR 0.79 [95% CI 0.37-1.70] for B). For MTX, results differed depending on the method of analysis (222 patients; OR 0.35 [95% CI 0.18-0.66] for at least 2 strains, ORs were close to 1.0 in the single strain analysis). Pneumococcal vaccination response was reduced for 139 patients receiving MTX compared with controls (OR 0.33 [95% CI 0.20-0.54] for serotype 6B and OR 0.58 [95% CI 0.36-0.94] for 23F) but not for anti-TNFα (258 patients; OR 0.96 [95% CI 0.57-1.59] for 6B and OR 1.20 [95% CI 0.57-2.54] for 23F). For RTX, the response was reduced (88 patients; OR 0.25 [95% CI 0.11-0.58] for 6B and OR 0.21 [95% CI 0.04-1.05] for 23F). MTX decreases humoral response to pneumococcal vaccination and may impair response to influenza vaccination. The immune response to both vaccines is reduced with RTX but not with anti-TNFα therapy in RA patients. Copyright © 2014 by the American College of Rheumatology.
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                Author and article information

                Journal
                Lancet Rheumatol
                Lancet Rheumatol
                The Lancet. Rheumatology
                Elsevier Ltd.
                2665-9913
                1 April 2022
                1 April 2022
                Affiliations
                [a ]Division of Rheumatology, Department of Medicine, NYU Grossman School of Medicine, New York, NY 10016, USA
                [b ]Division of Gastroenterology, Department of Medicine, NYU Grossman School of Medicine, New York, NY 10016, USA
                [c ]Division of Infectious Disease, Department of Medicine, NYU Grossman School of Medicine, New York, NY 10016, USA
                [d ]Vaccine Center, Department of Medicine, NYU Grossman School of Medicine, New York, NY 10016, USA
                [e ]Department of Dermatology, New York University Langone Health, New York, NY, USA
                [f ]Department of Population Health, New York University Langone Health, New York, NY, USA
                Author notes
                [†]

                New York University SAGA Investigators: Alan Chen, Marie Samanovic, Ariela K Holmer, Adam S Faye, Lilly Drohan, Gitanjali Reddy, Rochelle L Castillo, Sicy Lee, Pamela Rosenthal, Soumya M Reddy, and Gary Zagon

                Article
                S2665-9913(22)00069-8
                10.1016/S2665-9913(22)00069-8
                8975261
                5fe832ee-577c-4a42-b574-be18d7bd02f9
                © 2022 Elsevier Ltd. All rights reserved.

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