Summary
Background
Patients on therapeutic immunosuppressants for immune-mediated inflammatory diseases were excluded from COVID-19 vaccine trials. We therefore aimed to evaluate humoral and cellular immune responses to COVID-19 vaccine BNT162b2 (Pfizer-BioNTech) in patients taking methotrexate and commonly used targeted biological therapies, compared with healthy controls. Given the roll-out of extended interval vaccination programmes to maximise population coverage, we present findings after the first dose.
Methods
In this cohort study, we recruited consecutive patients with a dermatologist-confirmed diagnosis of psoriasis who were receiving methotrexate or targeted biological monotherapy (tumour necrosis factor [TNF] inhibitors, interleukin [IL]-17 inhibitors, or IL-23 inhibitors) from a specialist psoriasis centre serving London and South East England. Consecutive volunteers without psoriasis and not receiving systemic immunosuppression who presented for vaccination at Guy’s and St Thomas’ NHS Foundation Trust (London, UK) were included as the healthy control cohort. All participants had to be eligible to receive the BNT162b2 vaccine. Immunogenicity was evaluated immediately before and on day 28 (±2 days) after vaccination. The primary outcomes were humoral immunity to the SARS-CoV-2 spike glycoprotein, defined as neutralising antibody responses to wild-type SARS-CoV-2, and spike-specific T-cell responses (including interferon-γ, IL-2, and IL-21) 28 days after vaccination.
Findings
Between Jan 14 and April 4, 2021, 84 patients with psoriasis (17 on methotrexate, 27 on TNF inhibitors, 15 on IL-17 inhibitors, and 25 on IL-23 inhibitors) and 17 healthy controls were included. The study population had a median age of 43 years (IQR 31–52), with 56 (55%) males, 45 (45%) females, and 85 (84%) participants of White ethnicity. Seroconversion rates were lower in patients receiving immunosuppressants (60 [78%; 95% CI 67–87] of 77) than in controls (17 [100%; 80–100] of 17), with the lowest rate in those receiving methotrexate (seven [47%; 21–73] of 15). Neutralising activity against wild-type SARS-CoV-2 was significantly lower in patients receiving methotrexate (median 50% inhibitory dilution 129 [IQR 40–236]) than in controls (317 [213–487], p=0·0032), but was preserved in those receiving targeted biologics (269 [141–418]). Neutralising titres against the B.1.1.7 variant were similarly low in all participants. Cellular immune responses were induced in all groups, and were not attenuated in patients receiving methotrexate or targeted biologics compared with controls.
Interpretation
Functional humoral immunity to a single dose of BNT162b2 is impaired by methotrexate but not by targeted biologics, whereas cellular responses are preserved. Seroconversion alone might not adequately reflect vaccine immunogenicity in individuals with immune-mediated inflammatory diseases receiving therapeutic immunosuppression. Real-world pharmacovigilance studies will determine how these findings reflect clinical effectiveness.
Funding
UK National Institute for Health Research.
Introduction
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Drugs such as methotrexate, and biologics targeting the cytokines tumour necrosis factor (TNF), interleukin (IL)-17, and IL-23, are highly effective at attenuating the shared pathogenic immune pathways across immune-mediated inflammatory diseases, but they also increase the risk of serious infections, particularly with respiratory pathogens.
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Notably, in many countries, including the UK, individuals with immune-mediated inflammatory diseases receiving therapeutic immunosuppressants were advised to undertake stringent public health risk-mitigating measures (shielding) early in the pandemic due to concerns over drug-related risks of severe illness from COVID-19.
Shielding has led to reduced natural acquisition of protective immunity to SARS-CoV-2, and substantial psychological, social, and economic costs.
Evidence before this study
Individuals with immune-mediated inflammatory diseases receiving therapeutic immunosuppression were excluded from COVID-19 vaccine trials; therefore, characterisation of vaccine efficacy in this vulnerable population is important. Given the roll-out of extended interval vaccination programmes, the effect of immunosuppression on the immunogenicity of a single dose of vaccine is of major public, and personal, health importance. Methotrexate, but not targeted biological therapies, can impair serological responses to influenza and pneumococcal vaccines, but whether these drug-specific effects can be generalised to COVID-19 vaccines is not known. We searched PubMed for peer-reviewed studies published up to April 16, 2021, using the terms “immunosuppression”, “COVID-19”, “vaccination immune response”, and “vaccine immunogenicity”, with no language restrictions. Studies on both humoral and cellular immunogenicity of the COVID-19 vaccine in patients with immune-mediated inflammatory diseases receiving immunosuppression had not been done. Early evidence relating to a range of cancer therapies suggests that both humoral and cellular responses to the first dose of the COVID-19 vaccine BNT162b2 (Pfizer-BioNTech) are severely attenuated.
Added value of this study
We evaluated the effect of methotrexate and biologics targeting tumour necrosis factor, interleukin (IL)-17, and IL-23 on humoral and cellular immune responses to the first dose of the COVID-19 vaccine BNT162b2 in patients with psoriasis. Seroconversion rates were lower in patients receiving immunosuppressants than in healthy controls, with the lowest rate identified in those receiving methotrexate. Neutralising titres against wild-type SARS-CoV-2 were also attenuated in patients receiving methotrexate compared with healthy controls but were preserved in those receiving targeted biologics. Neutralising activity against the B.1.1.7 variant was uniformly low among all participants, including healthy controls. By contrast, spike-specific T-cell responses (including interferon-γ, IL-2, and IL-21 production) were induced in patients receiving methotrexate and all classes of biologics, and were detectable at similar levels to those in healthy controls.
Implications of all the available evidence
These findings indicate that seroconversion alone might not adequately reflect vaccine immunogenicity in individuals with immune-mediated inflammatory diseases receiving therapeutic immunosuppression, and caution against routine use of seroconversion data in isolation in clinical practice. When taking into account functional humoral immunity and T-cell responses, our data suggest that targeted biologics do not impair vaccine responses and provide some reassurance to this vulnerable population. Notably, although methotrexate attenuated humoral immunity, cellular responses were preserved. Real-world pharmacovigilance studies will determine how these data reflect clinical effectiveness. Findings in relation to the B.1.1.7 variant indicate that those on immunosuppression, in common with the general population, might remain vulnerable after the first dose of BNT162b2, and therefore risk mitigation (in addition to vaccination) remains a key strategy in the pandemic.
Studies evaluating immunogenicity to influenza and pneumococcal vaccines indicate that methotrexate, but not targeted therapies such as TNF inhibitors, impairs humoral responses, based on lower antibody titres in patients receiving this drug than in healthy controls.
Successful host protection induced by vaccinations is mediated by a complex interplay between innate, humoral, and cellular immunity, all of which are likely to be required for effective and enduring defence against SARS-CoV-2.
Thus, there is an urgent need to determine both functional antibody and antigen-specific cell-mediated immunogenicity to COVID-19 vaccines in individuals receiving different types of therapeutic immunosuppression to inform and, if necessary, revisit public health policy decisions. Assessment of immune responses to a single dose of vaccine is particularly pertinent given the roll-out of extended-interval vaccination programmes in countries such as the UK to maximise population coverage.
We aimed to investigate the effect of monotherapy with methotrexate, and biologics targeting TNF, IL-17, and IL-23, on immunogenicity after the first dose of BNT162b2. We sought to characterise both humoral and cellular immune responses.
Methods
Study design and participants
and the reported variation in intensity of cellular responses observed with different COVID-19 vaccines,
individuals with past SARS-CoV-2 infection or those who received the ChAdOx1 nCoV-19 vaccine were excluded from the main analysis.
This study was approved by the London Bridge Research Ethics Committee (REC reference 06/Q0704/18). All participants provided written informed consent before enrolment.
Procedures
Clinical and safety data and blood samples were collected at three study visits: baseline (same day of and immediately before vaccination), 28 days (±2 days) after the first dose of BNT162b2, and 14 days (±2 days) after the second dose (which was planned to be administered 12 weeks after the first dose as per UK Government guidelines). Data on immune responses after the second vaccine dose will be reported elsewhere.
), and local or systemic adverse events after vaccination. C-reactive protein was not assessed in any participants at the study visits. Plasma and peripheral blood mononuclear cells were isolated from blood samples as previously described.
Details of immunogenicity assays are presented in the appendix (pp 2–3). Humoral immunogenicity was based on seroconversion, assessed using ELISAs for IgG specific for the SARS-CoV-2 spike glycoprotein, and the functional capacity of participants’ plasma to neutralise both the prototypic (wild-type) strain of SARS-CoV-2 and the B.1.1.7 variant (VOC 202012/01 lineage), which has become highly prevalent in the UK following its emergence in late 2020. We first identified and excluded individuals with evidence of previous COVID-19 based on baseline IgG reactivity to both the SARS-CoV-2 nucleoprotein and spike protein.
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we also analysed IL-17A and IL-22 responses to total spike peptide pools. Direct FluoroSpot assays were used to detect interferon-γ and IL-2, and IL-17A and IL-22 (Th17 cytokine profile), and direct ELISpot assays were used to detect IL-21.
Outcomes
The primary outcomes were humoral and cellular immunity to the SARS-CoV-2 spike glycoprotein 28 days (±2 days) after the first dose of BNT162b2. Specifically, humoral immunity was defined as the presence of antibodies with neutralising capacity against the spike glycoprotein of wild-type SARS-CoV-2, and cellular immunity was defined as the presence of T cells secreting interferon-γ, IL-2, or IL-21 in response to stimulation with two peptide pools spanning the entire length of the SARS-CoV-2 spike glycoprotein.
Secondary outcomes (all of which were measured 28 days (±2 days) after the first dose of BNT162b2) were antibody seroconversion rates (presence of IgG antibodies specific for the spike glycoprotein, without assessment of neutralising capacity); the presence of antibodies with neutralising capacity against the spike glycoprotein of the SARS-CoV-2 pseudotype expressing the spike B.1.1.7 variant; the presence of T cells secreting IL-17A and IL-22 in response to stimulation with two peptide pools spanning the entire length of the spike glycoprotein; safety (adverse events); and patient-reported worsening of psoriasis.
Adverse events were classified as local or systemic, and graded as mild (no or minimal interference with activity and no or minimal medical intervention required), moderate (limitation in activity and medical intervention required), severe (marked limitation in activity and medical intervention required).
Results following the second dose will be presented elsewhere, and the primary and secondary outcomes will remain the same as the current study (but related to the second dose).
Statistical analysis
Demographic and clinical characteristics, adverse events, and humoral and cellular immunogenicity were summarised using descriptive statistics. Statistical imbalance across the treatment groups was calculated with the Kruskal-Wallis or χ2 test. The key exposure measure was immunosuppressive treatment type, comprising five mutually exclusive groups: patients receiving methotrexate, TNF inhibitors, IL-17 inhibitors, or IL-23 inhibitors, and healthy controls (individuals not receiving immunosuppressive drugs).
We tested two pre-determined hypotheses: that patients taking methotrexate would have lower humoral, cellular, or both humoral and cellular immunogenicity to the first dose of BNT162b2 compared with healthy controls; and that patients taking methotrexate would have lower humoral, cellular, or both humoral and cellular immunogenicity to the first dose of BNT162b2 compared with patients taking targeted biological therapy (TNF inhibitors, IL-17 inhibitors, or IL-23 inhibitors).
Comparisons were made using linear regression of log-transformed immunogenicity measures, with robust estimates of variance to derive 95% CIs and p values. A 5% α level was used for significance testing. No correction for multiple hypothesis testing was made. Correlations were derived using Pearson’s method. Data were analysed in Stata (version 16).
Role of the funding source
The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the manuscript.
Results
Table 1Baseline characteristics of study participants
Data are median (IQR), n (%), or n/N (%) unless otherwise specified. Statistical imbalance of the baseline characteristics across the treatment groups is presented by either the Kruskal-Wallis or χ2 test. IL=interleukin. TNF=tumour necrosis factor.
Table 2Immunogenicity of the first dose of the COVID-19 vaccine BNT162b2
A threshold EC50 value of 25 was used for anti-SARS-CoV-2 IgG titres, at which serological responses were classified as positive. A threshold value of 30 cytokine-secreting cells per million peripheral blood mononuclear cells was established for total T-cell responses (interferon-γ, IL-2, or IL-21), at which the T-cell response was classified as positive. EC50=half maximal effective concentration. Humoral and cellular data were missing for two patients on methotrexate, three patients on TNF inhibitors, and two patients on IL-23 inhibitors. No cellular data were available for one healthy control. IL=interleukin. TNF=tumour necrosis factor.
Figure 2Serological immune responses to COVID-19 vaccine BNT162b2
Spike-specific IgG titres (EC50) in plasma samples on day 28 after vaccination in healthy controls and patients with psoriasis receiving methotrexate or targeted biological monotherapy. The circles represent individual values. The red diamonds and range lines indicate the median and IQR. In the IL-23 inhibitor group, filled circles represent participants receiving IL-23p19 inhibitors and hollow circles represent participants receiving an IL-12/23p40 inhibitor. The horizontal dashed line indicates the seroconversion threshold. EC50=half maximal effective concentration. IL=interleukin. TNF=tumour necrosis factor.
Figure 3Functional humoral immunogenicity of the COVID-19 vaccine BNT162b2
(A) Neutralisation titres against wild-type SARS-CoV-2 on day 28 after the first dose of BNT162b2. (B) Neutralisation titres against B.1.1.7 SARS-CoV-2 variant on day 28 after the first dose of BNT162b2. The circles represent individual values. The red diamonds and range lines indicate the median and IQR. In the IL-23 inhibitor group, filled circles represent participants receiving IL-23p19 inhibitors and hollow circles represent participants receiving an IL-12/23p40 inhibitor. The horizontal dashed line indicates neutralisation activity threshold. (C) Correlation between spike-specific IgG and neutralisation titres against wild-type or the B.1.1.7 variant. Blue diamonds show individual patients, shading indicates the 95% CI. EC50=half maximal effective concentration. ID50=50% inhibitory dilution. IL=interleukin. TNF=tumour necrosis factor.
and T follicular helper (Tfh)-derived IL-21 is crucial for memory B-cell responses.
Receiver operator characteristic curve analysis established threshold values to determine a positive response for the total T-cell response (Th1 or Tfh; a combination of interferon-γ, IL-2, and IL-21) and for each individual cytokine (appendix p 11). All study groups showed a wide range of cytokine responses to peptides derived from commonly encountered viruses and fungal antigens, with no major differences in the magnitude or polarisation of response in any group (appendix p 12).
Figure 4Cellular immunogenicity of the COVID-19 vaccine BNT162b2
(A) Total T-cell response, as determined by combined interferon-γ, IL-2, and IL-21 responses to stimulation with peptides from total spike peptide pools, reported as number of cytokine-secreting cells per 106 cells in PBMC samples on day 28 after the first dose of BNT162b2. The horizontal line indicates the T-cell response threshold. (B) IL-17A and IL-22 responses to stimulation with peptides from total spike peptide pools, reported as number of cytokine-secreting cells per 106 cells in PBMC samples on day 28 after the first dose of COVID-19 vaccine BNT162b2. The horizontal line indicates the T helper 17 response threshold. The circles represent individual values. The red diamonds and range lines indicate the median and IQR. In the IL-23 inhibitor group, filled circles represent participants receiving IL-23p19 inhibitors and hollow circles represent participants receiving an IL-12/23p40 inhibitor. (C) Spearman correlation between T-cell responses (cytokine-secreting cells per 106 PBMCs) and humoral immune responses as determined by ELISA and neutralisation assays. The colour scale indicates the Spearman R values; all p values are less than 0·01. EC50=half maximal effective concentration. ID50=50% inhibitory dilution. IL=interleukin. PBMCs=peripheral blood mononuclear cells. TNF=tumour necrosis factor.
T-cell reactivities were also evident in serological non-responders (individuals without evidence of seroconversion) who were receiving methotrexate (seven of eight), TNF inhibitors (three of five), and IL-23 inhibitors (one of four). Thus, T-cell responses were successfully induced following vaccination in patients receiving either methotrexate or targeted biologics, with similar levels of response across treatment groups, independently of detectable humoral immunogenicity.
and the association between Th17 cell activation and severe COVID-19,
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we next analysed IL-17A and IL-22 cytokine responses to total spike peptide pools across the study groups. IL-17A and IL-22 responses were low across all four immunosuppressant groups, and similar to responses seen in controls (figure 4B). Collectively, interferon-γ, IL-2, and IL-21 T cell responses (in particular, interferon-γ) broadly correlated with serological and functional humoral immune responses (figure 4C). By contrast, no correlation was observed between Th17 type responses and humoral immunity. However, there was variation in the strength of correlation across cytokines and drug categories (appendix p 15).
Discussion
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Consistent with our data indicating lower levels of spike-specific IgG in patients receiving TNF inhibitors versus controls, a study of 1293 patients with inflammatory bowel disease showed lower antibody titres and seroconversion rates following a single dose of vaccine in those receiving TNF blockade (infliximab) than in a reference cohort of patients receiving vedolizumab (gut-selective integrin inhibitor).
Multivariable models highlighted an association of age of 60 years or older and co-therapy (azathioprine, mercaptopurine, or methotrexate) with lower SARS-CoV-2 antibody titres; however, neutralising titres or cellular immunity (which were similar in our TNF inhibitor cohort versus controls) were not explored. Serological responses to a single dose of vaccine were also lower in recipients of solid organ transplants receiving anti-metabolite immunosuppression (mycophenolate mofetil, mycophenolic acid, or azathioprine) than in those not receiving such immunosuppression.
Finally, both cellular and humoral immunogenicity of a single dose of vaccine was low in immunocompromised individuals with solid and haematological cancers.
This finding contrasts with our data showing intact cellular responses in immunosuppressed individuals with immune-mediated inflammatory diseases and might be attributable to the effect of the underlying malignancy and type or burden of therapeutic immunosuppression.
In our dataset, the first dose of BNT162b2 induced favourable T-cell responses (interferon-γ, IL-2, and IL-21) to total spike peptide pools in the majority of controls and patients receiving immunosuppressants, with no attenuation in cellular immunity found in those receiving methotrexate or targeted biological monotherapy compared with controls. Furthermore, T cells from patients receiving methotrexate or targeted biologics who were serological non-responders demonstrated T-cell reactivities following the vaccine, thus highlighting a disparity between humoral and cellular responses.
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Cellular immunity has been shown to be crucial for clearance of SARS-CoV-2 and recovery from COVID-19.
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SARS-CoV-2-specific CD4 and CD8 T-cell responses were observed in patients with COVID-19,
and memory B cells and Tfh cells were identified following recovery. T cells recognising peptides derived from the spike glycoprotein, nucleoprotein, and matrix of SARS-CoV-2 were found in the convalescent phase, and low numbers of T cells, T-cell exhaustion, and increased levels of pro-inflammatory cytokines are hallmarks of severe COVID-19. Thus, cellular responses after vaccination might affect overall vaccine efficacy against SARS-CoV-2. Given the known effect of methotrexate and biological therapies on T-cell proliferation, activation, and cytokine production, our data on cell-mediated responses after vaccination are encouraging.
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Trial data in rheumatoid arthritis indicate that temporary methotrexate discontinuation for 2 weeks after influenza vaccination might increase seroprotection rates compared with continuing methotrexate.
However, only humoral immunogenicity was assessed, and the clinical significance of higher antibody responses on the incidence of influenza infections is unknown. Registry data suggest that methotrexate or biological monotherapy for immune-mediated inflammatory diseases is not associated with adverse COVID-19 outcomes,
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so it is unclear whether the reduced humoral responses to BNT162b2 in the context of methotrexate translate to an increased SARS-CoV-2 infection risk.
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While assessing responses following the second vaccine dose is vital, we identified low neutralisation titres against B.1.1.7 after vaccination in both controls and patients with psoriasis receiving immunosuppressants, which underlines the need for ongoing risk mitigating measures following the first dose of vaccine. Emerging evidence indicates that neutralising antibody titres against B.1.1.7 generated by vaccination might not correlate with clinical vaccine effectiveness against symptomatic COVID-19,
so the contribution of cellular immunity (T-cell and natural killer cell responses and antibody-dependent cellular cytotoxicity or phagocytosis) in vaccine-induced protection against new lineages of SARS-CoV-2 warrants investigation.
Important follow-up immunogenicity data following the (extended 12 week interval) booster dose of vaccine in our infection-naive participants receiving immunsuppression are anticipated.
Contributors
SKM, CHS, TIMT, KJD, MAB, JBG, and JNB contributed to study design. SKM, CHS, TIMT, and KJD developed the study protocol. DB, AR, CD-V, CG, TL, EP, JS, KS, KJD, and TIMT contributed to sample preparation and performed the assays. SKM, CHS, AC, TIMT, MHM, KJD, MAB, JBG, and JNB contributed to clinical interpretation of study findings. KB, SN, and JG proposed statistical analysis methods and undertook the analysis. FM, SKM, AR, and TD contributed to all aspects of governance and study delivery. TD and AR contributed to data capture methods. SKM, CHS, TIMT, KJD, JBG, KB, JNB, MAB, MM, CD-V, AC, and SN contributed to drafting and editing the final report. TIMT, KJD, JBG, and KB were responsible for verifying the underlying data. CHS and JBG secured the funding for the study. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Data sharing
The authors are happy to share data on request to the corresponding author.
Declaration of interests
CHS reports grants from AbbVie, Sanofi, Novartis, and Pfizer, outside the submitted work. JBG reports personal fees from AbbVie, Sanofi, Novartis, Pfizer, Janssen, and UCB, and grants from Eli Lilly, outside the submitted work. SKM reports departmental income from AbbVie, Celgene, Eli Lilly, Janssen-Cilag, Novartis, Sanofi, and UCB, outside the submitted work. MAB reports departmental income from Clementia, Eli Lilly, Ipsen, Novartis, Pathios Therapeutics, Regeneron, and UCB, outside the submitted work. JNB reports grants and personal fees from AbbVie, Novartis, Lilly, and J&J, outside the submitted work. SN reports personal fees from Pfizer and Janssen, outside of the submitted work. APC reports grants from Bristol Myers Squibb and Janssen, and speaker bureau and consultancy fees from AbbVie, Bristol Myers Squibb, and UCB. TIMT reports grants from GlaxoSmithKline, Sanofi, and Imcyse, and consultancy fees from GlaxoSmithKline, Novartis, UCB, and Quell Therapeutics, outside the submitted work. All other authors declare no competing interests.
Acknowledgments
This research was funded by the UK National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London and the NIHR Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the UK National Health Service, the NIHR, or the UK Department of Health. This work was supported by a grant from the Psoriasis Association to CHS; a King’s Together Rapid COVID-19 Call award to MHM and KJD; Fondation Dormeur, Vaduz for funding equipment to KJD; a Huo Family Foundation Award to MHM and KJD; a grant from the Chronic Disease Research Foundation (CDRF-22/2020) to MAB, MHM, and KJD; part of the EDCTP2 programme supported by the European Union (RIA2020EF-3008 COVAB); UK Medical Research Council (MRC) through the Genotype-to-Phenotype UK National Virology Consortium (MR/W005611/1) to MHM and KJD; and a grant from Isaac Schapera Research Trust to AR. CG was supported by the MRC-KCL Doctoral Training Partnership in Biomedical Sciences (MR/N013700/1). SKM is funded by an MRC Clinical Academic Research Partnership award (MR/T02383X/1).
Supplementary Material
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- Impact of methotrexate on first-dose COVID-19 mRNA vaccination
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The current approach to COVID-19 vaccination of patients with immune-mediated inflammatory diseases is largely extrapolated from existing data relating to other vaccines. It is well recognised that methotrexate impairs humoral responses to both influenza and pneumococcal vaccines,1,2 and a temporary discontinuation of therapy for 2 weeks enhances influenza vaccine immunogenicity in patients with rheumatoid arthritis.3 These data were used as a surrogate for COVID-19 vaccination responses, prompting the American College of Rheumatology (ACR) to recommend temporary interruption of methotrexate for 1 week after each vaccine dose.
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