Influenza vaccination and interruption of methotrexate in adult patients in the COVID-19 era: an ongoing dilemma
Authors: Puja Mehta, Emilie Sanchez, Elena Moraitis, Nicky Longley, Dennis W Lendrem, Ian P Giles, Rachel C Chambers, Coziana Ciurtin, John D Isaacs
Journal: The Lancet Rheumatology (2020)

With the COVID-19 pandemic continuing unabated and the advent of the influenza season, public health authorities have emphasised that influenza vaccination is of paramount importance.1Jaklevic MC Flu vaccination urged during COVID-19 pandemic.JAMA. 2020; 324: 926-927Crossref PubMed Scopus (28) Google Scholar Vaccination can reduce the severity of influenza infection and prevent hospitalisations,1Jaklevic MC Flu vaccination urged during COVID-19 pandemic.JAMA. 2020; 324: 926-927Crossref PubMed Scopus (28) Google Scholar which might help to conserve already strained health-care resources. The European League Against Rheumatism recommends that annual influenza vaccination should be strongly considered for most patients with chronic autoimmune inflammatory rheumatic diseases, as these patients are at increased risk of infection due to inherent or iatrogenic immunocompromise.2Furer V Rondaan C Heijstek MW et al.2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases.Ann Rheum Dis. 2020; 79: 39-52Crossref PubMed Scopus (499) Google Scholar There is no optimal formulation (valency or dose) of inactivated influenza vaccine for patients with autoimmune inflammatory rheumatic diseases. These patients require potentially life-long immunosuppression, and short-term interruption of immunomodulation might sometimes be necessary to restore immune responses (eg, with severe infection or major surgery). Anecdotally, some clinicians temporarily discontinue methotrexate (eg, one week before or after immunisation) in patients with rheumatoid arthritis to optimise the efficacy of influenza vaccination, although this approach is not supported by guidelines. In this Comment, we consider the evidence base for and implications of this strategy during the COVID-19 pandemic. Seasonal influenza is a major global cause of morbidity, mortality, and burden on health-care services. Influenza might be clinically confused with COVID-19, and co-infection carries a poor prognosis.3Iacobucci G Covid-19: Risk of death more than doubled in people who also had flu, English data show.BMJ. 2020; 370m3720Crossref PubMed Scopus (36) Google Scholar Influenza vaccination reduces the incidence of and complications, hospital admissions, and mortality from influenza and pneumonia in patients with autoimmune inflammatory rheumatic diseases.2Furer V Rondaan C Heijstek MW et al.2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases.Ann Rheum Dis. 2020; 79: 39-52Crossref PubMed Scopus (499) Google Scholar The host immune system (including immunosenescence with ageing) might influence vaccine efficacy. Methotrexate is the most commonly prescribed first-line disease modifying anti-rheumatic drug (DMARD) for patients with rheumatoid arthritis, either alone or in combination with biological therapy. The immunosuppressive effect of methotrexate is beneficial in patients with rheumatoid arthritis to reduce biologic-associated immunogenicity (anti-drug antibodies),4Mehta P Manson JJ What is the clinical relevance of TNF inhibitor immunogenicity in the management of patients with rheumatoid arthritis?.Front Immunol. 2020; 11: 589Crossref PubMed Scopus (16) Google Scholar but might compromise vaccine responses.5Hua C Barnetche T Combe B Morel J 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.Arthritis Care Res (Hoboken). 2014; 66: 1016-1026Crossref PubMed Scopus (233) Google Scholar The effects of temporary discontinuation of methotrexate on antibody titres to the trivalent influenza vaccine were investigated in a prospective, randomised, parallel-group, single-blind, single-centre pilot study of 199 patients with rheumatoid arthritis who were taking stable methotrexate doses (appendix).6Park JK Lee MA Lee EY et al.Effect of methotrexate discontinuation on efficacy of seasonal influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial.Ann Rheum Dis. 2017; 76: 1559-1565Crossref PubMed Scopus (93) Google Scholar Patients were randomly assigned to continue methotrexate (group 1; 54 patients), suspend methotrexate 4 weeks before vaccination (group 2; 44 patients), suspend methotrexate 2 weeks before and 2 weeks after vaccination (group 3; 49 patients); or suspend methotrexate 4 weeks after vaccination (group 4; 52 patients).6Park JK Lee MA Lee EY et al.Effect of methotrexate discontinuation on efficacy of seasonal influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial.Ann Rheum Dis. 2017; 76: 1559-1565Crossref PubMed Scopus (93) Google Scholar All groups showed a similar frequency of satisfactory vaccine responses (≥4-times increase in antibody titre); however, group 3 achieved significantly higher vaccine responses compared with group 1. Withholding methotrexate 4 weeks before influenza vaccination (group 2) was not associated with significantly different antibody titres, whereas discontinuing methotrexate for 4 weeks after vaccination (group 4) resulted in improvement compared with group 1. To reduce the risk of rheumatoid arthritis flares while achieving an adequate vaccine response, a shorter methotrexate discontinuation period was investigated in a prospective, multicentre study, in which patients with rheumatoid arthritis on stable methotrexate doses were randomly assigned to continue methotrexate (156 patients) or withhold methotrexate for 2 weeks (160 patients) after the quadrivalent influenza vaccine.7Park 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 Significantly more patients in the methotrexate-hold group achieved satisfactory vaccine responses (≥4-times increase in antibody titre to at least two of four influenza antigens) compared with the methotrexate-continue group (75·5% vs 54·5%; p<0.001; difference 21·0%, 95% CI 10·6–31·7%). Neither of these studies showed a significant increase in rheumatoid arthritis flares after discontinuation of methotrexate.6Park JK Lee MA Lee EY et al.Effect of methotrexate discontinuation on efficacy of seasonal influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial.Ann Rheum Dis. 2017; 76: 1559-1565Crossref PubMed Scopus (93) Google Scholar, 7Park 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 A post-hoc analysis of these studies compared disease activity between the methotrexate-hold groups (for 4 weeks before6Park JK Lee MA Lee EY et al.Effect of methotrexate discontinuation on efficacy of seasonal influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial.Ann Rheum Dis. 2017; 76: 1559-1565Crossref PubMed Scopus (93) Google Scholar [44 patients] or two weeks after7Park 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 [160 patients] vaccination) with a pooled methotrexate-continue group (210 patients).8Park JK Kim MJ Choi Y Winthrop K Song YW Lee EB Effect of short-term methotrexate discontinuation on rheumatoid arthritis disease activity: post-hoc analysis of two randomized trials.Clin Rheumatol. 2020; 39: 375-379Crossref PubMed Scopus (17) Google Scholar The analysis concluded that short-term discontinuation of methotrexate for 2 weeks was safe, whereas discontinuation for 4 weeks was associated with a transient increase in disease flares, although adjusted flare rates were 2·90 (2-week hold) and 3·94 (4-week hold).8Park JK Kim MJ Choi Y Winthrop K Song YW Lee EB Effect of short-term methotrexate discontinuation on rheumatoid arthritis disease activity: post-hoc analysis of two randomized trials.Clin Rheumatol. 2020; 39: 375-379Crossref PubMed Scopus (17) Google Scholar However, only one group (group 2) from the first study was included and flare rate was based on disease activity measured at a single fixed timepoint, 4 weeks after methotrexate interruption. This timepoint corresponded to the end of the 4 week interruption period in the first study and 2 weeks after methotrexate resumption in the second study. The original studies did not show significantly increased rheumatoid arthritis flare rates with methotrexate interruption, and transient disease activity increases were readily controlled. Vaccine responses were more than 70% higher in the second study, even with methotrexate continuation (appendix). It is unclear whether antibody titres to influenza vaccines (often used as the sole surrogate outcomes for efficacy) translate into protection from infection, or if there are better correlates in immunocompromised patients (eg, T-cell responses).9McElhaney JE Xie D Hager WD et al.T cell responses are better correlates of vaccine protection in the elderly.J Immunol. 2006; 176: 6333-6339Crossref PubMed Scopus (462) Google Scholar Although the risks of rheumatoid arthritis flare and need for glucocorticoids appear small, both can increase infection risk. Patients with autoimmune inflammatory rheumatic diseases receiving prednisolone at 10 mg or more had significantly poorer COVID-19 outcomes.10Gianfrancesco M Hyrich KL Al-Adely S et al.Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry.Ann Rheum Dis. 2020; 79: 859-866Crossref PubMed Scopus (904) Google Scholar Furthermore, the generalisability of these studies (both from Korea) with low baseline methotrexate doses (10–15 mg weekly) is unclear.6Park JK Lee MA Lee EY et al.Effect of methotrexate discontinuation on efficacy of seasonal influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial.Ann Rheum Dis. 2017; 76: 1559-1565Crossref PubMed Scopus (93) Google Scholar, 7Park 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 The influence of patient age, methotrexate dose and administration route, duration and degree of rheumatoid disease activity, and other confounders (including smoking, alcohol consumption, and obesity) is also unclear. A large multicentre, international study would be required to confirm whether transient methotrexate interruption around the time of vaccination reduces incidence or severity of influenza, as well as the optimal strategy to achieve this. Although a 2-week discontinuation of methotrexate after vaccination in patients with quiescent disease might improve influenza vaccine responses without a substantial impact on rheumatoid arthritis disease activity,6Park JK Lee MA Lee EY et al.Effect of methotrexate discontinuation on efficacy of seasonal influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial.Ann Rheum Dis. 2017; 76: 1559-1565Crossref PubMed Scopus (93) Google Scholar, 7Park 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, 8Park JK Kim MJ Choi Y Winthrop K Song YW Lee EB Effect of short-term methotrexate discontinuation on rheumatoid arthritis disease activity: post-hoc analysis of two randomized trials.Clin Rheumatol. 2020; 39: 375-379Crossref PubMed Scopus (17) Google Scholar there is insufficient evidence to alter clinical practice or guidelines. Some patients had rheumatoid arthritis flares due to restricted access to health care during the initial COVID-19 pandemic, and interrupting methotrexate treatment might risk destabilising disease control. Nonetheless, we feel that the available evidence merits individualised discussions with patients with well-controlled disease regarding the potential benefits and risks of omission of 1–2 doses of methotrexate, influenza vaccine efficacy, and perhaps COVID-19 vaccination when available. PM is a Medical Research Council (MRC)-GSK EMINENT clinical training fellow with project funding outside the submitted work. PM receives co-funding from the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre (UCLH BRC). PM has served on an advisory board for SOBI, outside the submitted work. RCC reports grants from UK Research and Innovation MRC, grants from GSK, and grants from NIHR ULCH BRC. CC receives co-funding from the UCLH BRC (525, 773) and Versus Arthritis (21593). JDI is a NIHR Senior Investigator and is supported by the Newcastle NIHR Biomedical Research Centre in Ageing and Long-Term Conditions. All other authors declare no competing interests. CC and JDI contributed equally to this Comment. Download .pdf (.24 MB) Help with pdf files Supplementary appendix