Impact of methotrexate on first-dose COVID-19 mRNA vaccination
Authors: Caoilfhionn M Connolly, Julie J Paik
Journal: The Lancet Rheumatology (2021)

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,1Ribeiro ACM Guedes LKN Moraes JCB et al.Reduced seroprotection after pandemic H1N1 influenza adjuvant-free vaccination in patients with rheumatoid arthritis: implications for clinical practice.Ann Rheum Dis. 2011; 70: 2144-2147Crossref PubMed Scopus (77) Google Scholar, 2Kapetanovic MC Roseman C Jönsson G et al.Antibody response is reduced following vaccination with 7-valent conjugate pneumococcal vaccine in adult methotrexate-treated patients with established arthritis, but not those treated with tumor necrosis factor inhibitors.Arthritis Rheum. 2011; 63: 3723-3732Crossref PubMed Scopus (121) Google Scholar and a temporary discontinuation of therapy for 2 weeks enhances influenza vaccine immunogenicity in patients with rheumatoid arthritis.3Park JK Lee YJ Shin K et al.Impact of temporary methotrexate discontinuation for 2 weeks on immunogenicity of seasonal influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial.Ann Rheum Dis. 2018; 77: 898-904PubMed Google Scholar 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.4Curtis JR Johnson SR Anthony DD Arasaratnam RJ et al.American College of Rheumatology Guidance for COVID-19 Vaccination in Patients With Rheumatic and Musculoskeletal Diseases: Version 2.Arthritis Rheumatol. 2021; (published online June 15.)https://doi.org/10.1002/art.41877Crossref Scopus (142) Google Scholar The degree to which this pause will translate to enhanced COVID-19 vaccine responses is unclear, but data are rapidly accumulating. In The Lancet Rheumatology, Satveer Mahil and colleagues report on both the humoral and cellular immune responses to the first dose of the COVID-19 vaccine BNT162b2 (Pfizer-BioNTech) in a prospective longitudinal cohort of patients with dermatologist-confirmed psoriasis.5Mahil SK Bechman K Raharja A et al.The effect of methotrexate and targeted immunosuppression on humoral and cellular immune responses to the COVID-19 vaccine BNT162b2: a cohort study.Lancet Rheumatol. 2021; (published online July 8.)https://doi.org/10.1016/S2665-9913(21)00212-5Summary Full Text Full Text PDF PubMed Scopus (126) Google Scholar The patients from this cohort were unique in that they were largely in remission and were treated with methotrexate or other targeted biological monotherapy without concurrent use of glucocorticoids. In addition to assessing serological conversion, Mahil and colleagues addressed the key components of the adaptive immune response to vaccination, including T-cell responses and neutralising antibody responses. The humoral response to vaccination is well represented in the literature due to convenience and accessibility of antibody measurement. Seroconversion, or presence of IgG antibody specific to the SARS-CoV-2 spike protein, has been the main outcome measure used to assess COVID-19 vaccine responses in clinical trials and major studies so far. However, it is increasingly recognised that deeper immunophenotyping with rigorous assessment of humoral and cellular immunity will be needed to accurately evaluate COVID-19 vaccine immunogenicity. The main finding of the study by Mahil and colleagues was a disparity between humoral and cellular immunogenicity of the BNT162b2 vaccine in patients treated with methotrexate. They report that cellular immunity, including T helper 1 and follicular T-cell responses, were similar in healthy controls and patients taking all classes of immunosuppression. Notably, however, they reported only a 47% (95% CI 21–73; seven of 15 patients) seroconversion rate in patients receiving methotrexate, along with correlating lower levels of antibody neutralisation (median 50% inhibitory dilution 129 [IQR 40–236]) compared with healthy controls (317 [213–487], p=0·0032). The rate of serological conversion was quite low, contrasting with a previous study in which most patients taking methotrexate showed adequate humoral responses after the first dose of BNT162b2 vaccine.6Boyarsky BJ Ruddy JA Connolly CM et al.Antibody response to a single dose of SARS-CoV-2 mRNA vaccine in patients with rheumatic and musculoskeletal diseases.Ann Rheum Dis. 2021; (published online March 23.)https://doi.org/10.1136/annrheumdis-2021-220289Crossref Scopus (154) Google Scholar Larger prospective studies have recently shown considerable immunogenicity induced by two doses of BNT162b2 vaccine in patients treated with methotrexate,7Furer V Eviatar T Zisman D et al.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.Ann Rheum Dis. 2021; (published online June 14.)https://doi.org/10.1136/annrheumdis-2021-220647Crossref Google Scholar, 8Ruddy JA Connolly CM Boyarsky BJ et al.High antibody response to two-dose SARS-CoV-2 messenger RNA vaccination in patients with rheumatic and musculoskeletal diseases.Ann Rheum Dis. 2021; (published online May 24)DOI: 10.1136/annrheumdis-2021-220656Crossref Scopus (107) Google Scholar although data on cellular responses were not included. Notably, adherence to methotrexate was confirmed in all patients in the study by Mahil and colleagues, without any pause in the vaccination period, which could account for some of the disparities in the seroconversion rate. Consistent with existing data, Mahil and colleagues showed that targeted biological therapies, including tumour necrosis factor inhibitors, anti-interleukin (IL)-23 or anti-IL-17 agents, did not affect vaccine responses.6Boyarsky BJ Ruddy JA Connolly CM et al.Antibody response to a single dose of SARS-CoV-2 mRNA vaccine in patients with rheumatic and musculoskeletal diseases.Ann Rheum Dis. 2021; (published online March 23.)https://doi.org/10.1136/annrheumdis-2021-220289Crossref Scopus (154) Google Scholar, 7Furer V Eviatar T Zisman D et al.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.Ann Rheum Dis. 2021; (published online June 14.)https://doi.org/10.1136/annrheumdis-2021-220647Crossref Google Scholar, 8Ruddy JA Connolly CM Boyarsky BJ et al.High antibody response to two-dose SARS-CoV-2 messenger RNA vaccination in patients with rheumatic and musculoskeletal diseases.Ann Rheum Dis. 2021; (published online May 24)DOI: 10.1136/annrheumdis-2021-220656Crossref Scopus (107) Google Scholar Data on cellular responses to COVID-19 vaccination in patients with immune-mediated inflammatory diseases are scarce, and Mahil and colleagues are to be commended for their robust study design. However, their finding of preserved cellular response in most patients taking methotrexate contradicts that of Haberman and colleagues,9Haberman RH Herati R Simon D et al.Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease.Ann Rheum Dis. 2021; (published online May 25.)https://doi.org/10.1136/annrheumdis-2021-220597Crossref PubMed Scopus (212) Google Scholar who showed ameliorated humoral and cellular response to two doses of BNT162b2 in patients treated with methotrexate. The cause for this disparity is unclear and warrants additional investigation in larger samples of patients. In addition, the effect of peri-vaccination modification of therapy remains to be defined. Last, methotrexate is a widely used therapy across many immune-mediated inflammatory diseases, and this study focused on patients with psoriasis; patients with other diseases were not included, and the authors did not examine the effect of other immunosuppressant regimens on the response to the first dose of the BNT162b2 vaccine. There is a growing body of evidence to suggest that lymphocyte-depleting agents such as mycophenolate, rituximab, and glucocorticoids, and the B-cell incompetence that results, are the primary factors associated with an attenuated humoral response to COVID-19 vaccines.6Boyarsky BJ Ruddy JA Connolly CM et al.Antibody response to a single dose of SARS-CoV-2 mRNA vaccine in patients with rheumatic and musculoskeletal diseases.Ann Rheum Dis. 2021; (published online March 23.)https://doi.org/10.1136/annrheumdis-2021-220289Crossref Scopus (154) Google Scholar, 7Furer V Eviatar T Zisman D et al.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.Ann Rheum Dis. 2021; (published online June 14.)https://doi.org/10.1136/annrheumdis-2021-220647Crossref Google Scholar, 9Haberman RH Herati R Simon D et al.Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease.Ann Rheum Dis. 2021; (published online May 25.)https://doi.org/10.1136/annrheumdis-2021-220597Crossref PubMed Scopus (212) Google Scholar Further studies are required to assess both cellular and humoral response to COVID-19 vaccines across a heterogeneous population of patients with immune-mediated inflammatory diseases. In immunocompetent patients, mRNA vaccines have elicited a strong antibody response, even after a single dose.10Sahin U Muik A Derhovanessian E et al.COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses.Nature. 2020; 586: 594-599Crossref PubMed Scopus (1368) Google Scholar Previous studies have suggested that patients taking methotrexate have robust humoral responses; however, Mahil and colleagues report low rates of seroconversion in their sample of 17 patients. Although it is encouraging that cellular responses appear to be preserved even in patients with poor humoral responses, these findings are not consistent across study groups. During this period of clinical uncertainty, patients might remain vulnerable, especially after the first dose, and should engage in risk mitigation strategies. Furthermore, given the promising findings after two-dose vaccination, we believe that both doses of the BNT162b2 vaccine should be administered per the approved schedule to reduce the burden of COVID-19 in this vulnerable population. Patients receiving immunosuppressive therapies should be prioritised for the regular schedule of vaccination (ie, not a prolonged interval between doses) and should be aware of the potential for suboptimal vaccine responses, even after completion of the vaccine series. With the spectre of variants looming, vaccination will allow patients to achieve maximum protection and reduce the burden of COVID-19. In the interim, there is a need for ongoing vigilance in observing non-pharmacological preventive measures in these patients. We declare no competing interests. The effect of methotrexate and targeted immunosuppression on humoral and cellular immune responses to the COVID-19 vaccine BNT162b2: a cohort study