Chambers, RC

Ciurtin, C

Giles, IP

Isaacs, JD

Lendrem, DW

Longley, N

Mehta, P

Moraitis, E

Sanchez, E

English

UCL Discovery

1  Influenza vaccination and interruption of methotrexate in adult patients with 1 rheumatoid arthritis in the COVID-19 era: an ongoing dilemma  2 Puja Mehta†, Emilie Sanchez, Elena Moraitis, Nicky Longley, Dennis  W. Lendrem, Ian P. 3 Giles, Rachel C. Chambers, Coziana Ciurtin*, John D. Isaacs* 4 *authors contributed equally 5 †corresponding author: Dr Puja Mehta, Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne 6 Building, 5 University Street, WC1E 6JF and Department of Rheumatology, University College London 7 Hospital NHS Trust, U.K, puja.mehta@ucl.ac.uk 8  9 Centre for Inflammation and Tissue Repair, UCL Respiratory, Division of Medicine, University College 10 London, London, U.K. Puja Mehta (MD); Professor Rachel Chambers (PhD);  11 Department of Clinical Virology, University College London Hospital (UCLH), U.K. Emilie Sanchez (MD) 12 Hospital for Tropical Diseases, UCLH and London School of Hygiene and Tropical Medicine Nicky 13 Longley (MD Res); 14 Rheumatology Department, Great Ormond Street Hospital for Children, London, UK. Elena Moraitis 15 (PhD); 16 Translational and Clinical Research Institute, Newcastle University; and Musculoskeletal Unit, Newcastle 17 upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, U.K. Dennis W. Lendrem (DPhil) 18 Department of  Rheumatology, University College London Hospital (UCLH), U.K.  Puja Mehta (MD), 19 Professor Ian. P. Giles (PhD);  20 Centre for Rheumatology Research, Division of Medicine, UCL, London, UK. Professor Ian Giles (PhD);  21 Centre for Adolescent Rheumatology, Division of Medicine, UCL, London, UK U.K. Coziana  Ciurtin 22 (PhD);  23 Translational and Clinical Research Institute, Newcastle University; and Musculoskeletal Unit, Newcastle 24 upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, U.K. Professor John D. Isaacs (PhD) 25  26 Article Type: Commentary 27 Total: 869/800 words 28 References: 10/10 29 Supplementary Appendix: 1 Table 30 2  Keywords:  influenza, vaccination, COVID-19, MTX, immunogenicity, rheumatoid arthritis  31  32 With the COVID-19 pandemic continuing unabated and the advent of the influenza season, 33 public health authorities have emphasised that influenza vaccination is of paramount 34 importance1. Vaccination can reduce the severity of influenza infection and prevent 35 hospitalisations1, which may help to conserve already strained healthcare resources. EULAR 36 recommend that annual influenza vaccination should be strongly considered for most patients 37 with chronic autoimmune inflammatory rheumatic diseases (AIIRD), as these patients are at 38 increased risk of infection, due to inherent and/or iatrogenic immunocompromise2. There is no 39 optimal formulation (valency or dose) of the inactivated influenza vaccine for patients with 40 AIIRD. Patients with AIIRD require potentially life-long immunosuppression. Short-term 41 interruption of treatment may sometimes be necessary to restore immune responses, e.g. with 42 severe infection or major surgery. Anecdotally, some clinicians temporarily discontinue 43 methotrexate (MTX) (e.g. one week before/after immunisation) in patients with rheumatoid 44 arthritis (RA) to optimise the efficacy of influenza vaccination, although this approach is not 45 supported by guidelines. Here we consider the evidence-base for and implications of this 46 strategy in the COVID-19 pandemic. 47  48 Seasonal influenza is a major global cause of morbidity, mortality and burden on healthcare 49 services. Influenza may be clinically confused with COVID-19 and co-infection carries a worse 50 prognosis3. Influenza vaccination reduces the incidence, complications, hospital admissions 51 and mortality from influenza and pneumonia in AIIRD2. The host immune system (including 52 immunosenescence with ageing) may influence vaccine effectiveness. MTX is the most 53 commonly prescribed first-line disease modifying anti-rheumatic drug (DMARD) for RA alone 54 or in combination with biologic therapy. The immunosuppressive effect of MTX is beneficial 55 in RA to reduce biologic-associated immunogenicity (anti-drug antibodies)4, but may 56 compromise vaccine responses5. 57  58 The effects of temporary discontinuation of MTX on antibody titres to the trivalent influenza 59 vaccine, were investigated in a prospective, randomised parallel-group, single-blind, single-60 centre pilot study of patients with RA (n=199) taking stable MTX doses6.  Patients were 61 randomised to continue MTX (group 1; n=54); suspend MTX four weeks before vaccination 62 3  (group 2; n=44); suspend MTX two weeks before and after vaccination (group 3; n=49); or 63 four weeks after vaccination (group 4; n=52)6. All groups demonstrated similar frequency of 64 satisfactory vaccine responses (≥four-fold increase in antibody titre), however group 3 65 achieved significantly higher vaccine responses compared with group 1. Withholding MTX 66 four weeks prior (group 2) was not associated with significantly different antibody titres, 67 whereas discontinuing MTX for four weeks after vaccination (group 4) resulted in 68 improvement compared with group 1. To reduce the risk of RA flares, whilst achieving 69 adequate vaccine response, a shorter MTX discontinuation period was investigated in a 70 prospective, multicentre study, where patients with RA on stable MTX doses, were randomised 71 to continue MTX (n=156) or withhold MTX for two weeks (n=160) after the quadrivalent 72 influenza vaccine7. Significantly more patients in the MTX-hold group, achieved satisfactory 73 vaccine responses ( ≥fourfold increase in antibody titre in ≥2/4 influenza antigens) compared 74 with the MTX-continue group (75.5% vs 54.5%, p<0.001; difference 21.0%, 95% CI 10.6-75 31.7%). Neither of these studies demonstrated a significant increase in RA flares following 76 discontinuation of MTX6,7. A recent post-hoc analysis of these studies compared disease 77 activity between the MTX-hold groups (for four weeks before6 [n=44] or two weeks after7 78 [n=161] vaccination) with a pooled MTX-continue group (n=210)8. The analysis concluded 79 that short-term discontinuation of MTX for 2 weeks was safe, whereas discontinuation for 4 80 weeks was associated with a transient increase in disease flares although adjusted flare rates 81 were 2.90 (2-week hold) and 3.94 (4-week hold) 8. However, only one arm (group 2) from the 82 first study was included and, furthermore, flare rate was based on disease activity measured at 83 a single fixed time-point, four weeks after methotrexate interruption.  This corresponded to the 84 end of the four week interruption period in the first study and two weeks after MTX resumption 85 in the second. The original studies did not demonstrate significantly increased flare rates with 86 methotrexate interruption, and transient disease activity increases were readily controlled; 87 vaccine responses were >70% higher in the second study, even with MTX continuation (Table).  88  89 It is unclear whether antibody titres to influenza vaccines (often used sole surrogate outcomes 90 for efficacy) translate into protection from infection, or if there are better correlates in 91 immunocompromised patients e.g. T-cell responses9. Whilst the risks of RA flare and need for 92 glucocorticoids appears small, both can increase infection risk. Patients with AIIRD receiving 93 ≥10mg prednisolone had significantly poorer outcomes with COVID-1910. Furthermore, the 94 generalisability of these studies (both from Korea) with low baseline MTX doses (10-15mg 95 4  weekly) is unknown6,7. The influence of patient age, MTX dose and administration route, 96 duration and degree of RA disease activity and other confounders (including smoking/alcohol) 97 is unclear. A large multi-centre, international study would be required to confirm whether 98 transient MTX interruption peri-vaccination reduces incidence/severity of influenza, as well as 99 the optimal strategy to achieve this.  100  101 Whilst a two-week discontinuation of MTX post-vaccination in patients with quiescent disease 102 may improve influenza vaccine responses, without a significant impact on RA disease activity6-103 8, currently there is insufficient evidence to alter clinical practice or guidelines.  Due to 104 restricted access to healthcare during the initial COVID-19 pandemic some patients 105 experienced RA flares, and interrupting MTX may risk destabilising disease control. 106 Nonetheless, we feel available evidence merits individualised discussions with patients with 107 well-controlled disease, regarding the potential benefits and risks of omission of 1-2 doses of 108 MTX, regarding influenza vaccine efficacy, and perhaps COVID-19 vaccination when 109 available. 110  111  112 Author Contributions: PM, CC and JI drafted manuscript. DWL provided statistical input. All authors 113 contributed to discussions, revised and approved the manuscript. 114 Funding: No funding was received for this study.  115 Disclosures: PM is an MRC-GSK EMINENT clinical training fellow with project funding outside the submitted 116 work. PM receives co-funding by the NIHR University College London Hospitals Biomedical Research Centre 117 (UCLH BRC). PM has served on an advisory board for SOBI, outside the submitted work. RCC reports grants 118 from UKRI MRC, grants from GlaxoSmithKline, grants from NIHR ULCH BRC,  during the conduct of the 119 study. CC receives co-funding from the UCLH BRC (525, 773) and Versus Arthritis (21593). JDI is a NIHR 120 Senior Investigator and is supported by the Newcastle NIHR Biomedical Research Centre in Ageing and Long-121 Term Conditions. All other authors have nothing to disclose. 122  123 References 124  125 1. Jaklevic MC. Flu Vaccination Urged During COVID-19 Pandemic. Jama 2020; 324(10): 926-7. 126 2. Furer V, Rondaan C, Heijstek MW, et al. 2019 update of EULAR recommendations for 127 vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Annals of the 128 rheumatic diseases 2020; 79(1): 39. 129 3. Iacobucci G. Covid-19: Risk of death more than doubled in people who also had flu, English 130 data show. BMJ 2020; 370: m3720. 131 5  4. Mehta P, Manson JJ. What Is the Clinical Relevance of TNF Inhibitor Immunogenicity in the 132 Management of Patients With Rheumatoid Arthritis? Front Immunol 2020; 11(589). 133 5. Hua C, Barnetche T, Combe B, Morel J. Effect of methotrexate, anti-tumor necrosis factor α, 134 and rituximab on the immune response to influenza and pneumococcal vaccines in patients with 135 rheumatoid arthritis: a systematic review and meta-analysis. Arthritis care & research 2014; 66(7): 136 1016-26. 137 6. Park JK, Lee MA, Lee EY, et al. Effect of methotrexate discontinuation on efficacy of seasonal 138 influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial. Annals of the 139 rheumatic diseases 2017; 76(9): 1559-65. 140 7. Park JK, Lee YJ, Shin K, et al. Impact of temporary methotrexate discontinuation for 2 weeks 141 on immunogenicity of seasonal influenza vaccination in patients with rheumatoid arthritis: a 142 randomised clinical trial. Annals of the rheumatic diseases 2018; 77(6): 898-904. 143 8. Park JK, Kim MJ, Choi Y, Winthrop K, Song YW, Lee EB. Effect of short-term methotrexate 144 discontinuation on rheumatoid arthritis disease activity: post-hoc analysis of two randomized trials. 145 Clin Rheumatol 2020; 39(2): 375-9. 146 9. McElhaney JE, Xie D, Hager WD, et al. T cell responses are better correlates of vaccine 147 protection in the elderly. Journal of immunology (Baltimore, Md : 1950) 2006; 176(10): 6333-9. 148 10. Gianfrancesco M, Hyrich KL, Al-Adely S, et al. Characteristics associated with hospitalisation 149 for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology 150 Alliance physician-reported registry. Annals of the rheumatic diseases 2020; 79(7): 859-66. 151  152  153  154  155  156  157  158  159  160  161  162  163  164  165  166  167  168 

Influenza vaccination and interruption of methotrexate in adult patients in the COVID-19 era: an ongoing dilemma

https://discovery.ucl.ac.uk/id/eprint/10114746/3/Mehta_Flu%20Vacc%20and%20MTX%20revisions%20-%20CLEAN.pdf

Influenza vaccination and interruption of methotrexate in adult patients in the COVID-19 era: an ongoing dilemma

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