key: cord-0824995-pl7qav6w
authors: Haberman, Rebecca H; Um, Seungha; Axelrad, Jordan E; Blank, Rebecca B; Uddin, Zakwan; Catron, Sydney; Neimann, Andrea L; Mulligan, Mark J; Herat, Ramin Sedaghat; Hong, Simon J; Chang, Shannon; Myrtaj, Arnold; Ghiasian, Ghoncheh; Izmirly, Peter M; Saxena, Amit; Solomon, Gary; Azar, Natalie; Samuels, Jonathan; Golden, Brian D; Rackoff, Paula; Adhikari, Samrachana; Hudesman, David P; Scher, Jose U
title: Methotrexate and TNF inhibitors affect long-term immunogenicity to COVID-19 vaccination in patients with immune-mediated inflammatory disease
date: 2022-04-01
journal: Lancet Rheumatol
DOI: 10.1016/s2665-9913(22)00069-8
sha: 7cb7a97114a6ca149d2f966c1714ab340da9024e
doc_id: 824995
cord_uid: pl7qav6w

nan

Studies have revealed that patients with immunemediated 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 ther apies 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 immunemediated 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 postvaccination blood samples from participants with immune-mediated inflammatory diseases (n=245) and healthy controls (n=27) and analysed SARS-CoV-2-spikespecific 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 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 . 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 . 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 inhibitormethotrexate 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.

SU and SA designed the data collection tools, analysed and curated the data, and revised the paper. JEA and DPH designed the study, acquired data, and revised the draft. All authors approved the final version to be published and agree to be accountable for all aspects of the work. RHH and JUS verified the underlying data and had final responsibility for the decision to submit for publication

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

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Large-scale study of antibody titer decay following BNT162b2 mRNA vaccine or SARS-CoV-2 infection

Significant reduction in humoral immunity among healthcare workers and nursing home residents 6 months after COVID-19 BNT162b2 mRNA vaccination. medRxiv

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