key: cord-0687323-9a7jmwfe
authors: Mehta, Puja; Sanchez, Emilie; Moraitis, Elena; Longley, Nicky; Lendrem, Dennis W; Giles, Ian P; Chambers, Rachel C; Ciurtin, Coziana; Isaacs, John D
title: Influenza vaccination and interruption of methotrexate in adult patients in the COVID-19 era: an ongoing dilemma
date: 2020-11-10
journal: Lancet Rheumatol
DOI: 10.1016/s2665-9913(20)30392-1
sha: bf43470408a6f1aeac5ac4b7819340292b92e6b4
doc_id: 687323
cord_uid: 9a7jmwfe

nan

With the COVID-19 pandemic continuing unabated and the advent of the influenza season, public health authorities have emphasised that influenza vaccina tion is of paramount importance. 1 Vaccination can reduce the severity of influenza infection and prevent hos pi tal isa tions, 1 which might help to conserve already strained health-care resources. The European League Against Rheumatism recommends that annual influ enza vaccination should be strongly considered for most patients with chronic autoimmune inflamma tory rheu matic diseases, as these patients are at increased risk of infection due to inherent or iatrogenic immuno com promise. 2 There is no optimal formulation (valency or dose) of inactivated influenza vaccine for patients with autoimmune inflammatory rheumatic diseases. These patients require potentially lifelong immunos uppression, 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 influ enza 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. 3 Influ enza vaccination reduces the incidence of and complications, hos pital admissions, and mortality from influenza and pneu monia in patients with autoimmune inflammatory rheu matic diseases. 2 The host immune system (includ ing immuno senescence 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 biologicassociated immunogenicity (anti-drug antibodies), 4 but might compromise vaccine responses. 5 The effects of temporary discontinuation of methotrexate on antibody titres to the trivalent influ enza 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). 6 Patients were randomly assigned to continue methotrex ate (group 1; 54 patients), suspend methotrexate 4 weeks before vaccina tion (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). 6 All groups showed a similar frequency of satisfactory vaccine responses (≥4-times increase in antibody titre); however, group 3 achieved significantly higher vaccine responses com pared 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 vaccina tion (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 metho trexate doses were randomly assigned to continue methotrexate (156 patients) or withhold methotrexate for 2 weeks (160 patients) after the quadrivalent influenza vaccine. 7 Significantly more patients in the methotrexatehold group achieved satisfactory vaccine responses (≥4-times increase in antibody titre to at least two of four influenza antigens) compared with the methotrexatecontinue 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. 6,7 A posthoc analysis of these studies compared disease activity between the methotrexate-hold groups (for 4 weeks before 6 [44 patients] or two weeks after 7 [160 patients] vaccination) with a pooled methotrexate-continue group (210 patients). 8 The analysis concluded that short-term discontinuation of methotrexate for 2 weeks was safe, whereas discontinuation for 4 weeks was associated Comment e10

www.thelancet.com/rheumatology Vol 3 January 2021 with a transient increase in disease flares, although adjusted flare rates were 2·90 (2-week hold) and 3·94 (4-week hold). 8 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). 9 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. 10 Furthermore, the generalisability of these studies (both from Korea) with low baseline metho trexate doses (10-15 mg weekly) is unclear. 6, 7 The influence of patient age, methotrexate dose and administration route, duration and degree of rheumatoid disease acti vity, and other confounders (includ ing smok ing, alcohol consumption, and obesity) is also unclear. A large multi centre, 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 sub stantial impact on rheumatoid arthritis disease acti vity, [6] [7] [8] 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 wellcontrolled 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.

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