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Tumour necrosis factor (TNF) plays a pivotal role in the control of bacterial intracellular infection.1 The introduction of anti-TNF therapy to treat rheumatoid arthritis (RA) prompted the investigation of infection rates within these patients.2 Following an early signal of an increased risk of tuberculosis in anti-TNF treated patients,3 there have been many reports suggesting an increased risk of other intracellular bacterial infections, including listeria and salmonella.4 ,5 Indeed, the BSR Biologics Register (BSRBR) has reported an increase of such infections within anti-TNF treated patients compared with patients treated with non-biologic disease-modifying antirheumatic drugs.6 In response to these findings, patient information leaflets for anti-TNF agents (etanercept (ETN), infliximab (INF), adalimumab (ADA)) were modified in the UK in January 2006 advising patients to avoid high risk foods, such as raw eggs and poultry, which are associated with an increased risk of these infections.7–9 Given the addition of this advice, we investigated the rate of bacterial intracellular infection, before and after these guidelines were introduced, in RA patients treated with anti-TNF therapy within the BSRBR.10
A total of 11 723 patients with RA starting their first anti-TNF on enrolment in the BSRBR were included. This comprised 9376 patients starting therapy pre 2006 and 2347 post 01 January 2006. Participants were followed until death, last received follow-up or 31 March 2011, whichever came first. Intracellular infections were identified through regular consultant follow-up reports. We included all infections due to listeria and salmonella. Person years of follow-up were divided into periods before or after 01 January 2006, with patients able to contribute to both periods. Rates of intracellular infection were compared among the two periods in patients ever on anti-TNF, on anti-TNF at the time of infection or having had anti-TNF within a 90-day window from the first missed dose.
Nine patients who had ever received anti-TNF therapy had an infection with salmonella or listeria before 01 January 2006 (four ETN, three INF, two ADA) with six occurring post 01 January 2006 (two ETN, two INF, two ADA) (table 1). Crude incidence rates (IR) per 10 000 person years of follow-up were 5.1 (95% CI 2.3 to 9.6) pre 01 January 2006 and 1.4 (95% CI 0.5 to 3.1) post 01 January 2006. This equates to a rate ratio of 0.27 (95% CI 0.15 to 0.50), or a 73% reduction. When the analysis was confined to infections which occurred while the patient was on therapy, a similar reduction was seen from 2006 onwards: pre 01 January 2006 IR=4.6 (95% CI 1.8 to 9.4), post 01 January 2006 IR=1.2 (0.3, 3.0); rate ratio 0.26 (95% CI 0.20 to 0.34). This reduction was also found when allowing for a 90-day ‘lag window’ following treatment, accounting for any residual effect of the drug (table 2).
In summary, in this large national cohort of anti-TNF treated RA patients, intracellular infection rates dropped dramatically following inclusion of dietary advice in anti-TNF patient information leaflets. Although it may not be possible to eliminate this infection risk entirely, this study shows the positive impact of informing patients of how to modify their risk of adverse events.
The authors acknowledge the enthusiastic support of the rheumatology patients and healthcare teams in the UK in providing the data. In addition, we acknowledge the support of the BSRBR management and steering committees.
Contributors RD, WGD, KLH: Study concept and design; BSRBR Control Centre Consortium: acquisition of data; RD, WGD, ML, KDW, DPMS, KLH: analysis and interpretation of data; RD, WGD, KLH: drafting of manuscript. All authors contributed to critical revision of the manuscript for important intellectual content and approved the article for publication.
Collaborators *BSRBR Control Centre Consortium. The BSRBR Control Centre Consortium consists of the following institutions (all in the UK): Antrim Area Hospital, Antrim (Dr Nicola Maiden), Cannock Chase Hospital, Cannock Chase (Dr Tom Price), Christchurch Hospital, Christchurch (Dr Neil Hopkinson), Royal Derby Hospital, Derby (Dr Sheila O'Reilly), Dewsbury and District Hospital, Dewsbury (Dr Lesley Hordon), Freeman Hospital, Newcastle-upon-Tyne (Dr Ian Griffiths), Gartnavel General Hospital, Glasgow (Dr Duncan Porter), Glasgow Royal Infirmary, Glasgow (Prof Hilary Capell), Haywood Hospital, Stoke-on-Trent (Dr Andy Hassell), Hope Hospital, Salford (Dr Romela Benitha), King's College Hospital, London (Dr Ernest Choy), Kings Mill Centre, Sutton-In Ashfield (Dr David Walsh), Leeds General Infirmary, Leeds (Prof Paul Emery), Macclesfield District General Hospital, Macclesfield (Dr Susan Knight), Manchester Royal Infirmary, Manchester (Prof Ian Bruce), Musgrave Park Hospital, Belfast (Dr Allister Taggart), Norfolk and Norwich University Hospital, Norwich (Prof David Scott), Poole General Hospital, Poole (Dr Paul Thompson), Queen Alexandra Hospital, Portsmouth (Dr Fiona McCrae), Royal Glamorgan Hospital, Glamorgan (Dr Rhian Goodfellow), Russells Hall Hospital, Dudley (Prof George Kitas), Selly Oak Hospital, Selly Oak (Dr Ronald Jubb), St Helens Hospital, St Helens (Dr Rikki Abernethy), Weston General Hospital, Weston-super-Mare (Dr Shane Clarke/Dr Sandra Green), Withington Hospital, Manchester (Dr Paul Sanders), Withybush General Hospital, Haverfordwest (Dr Amanda Coulson), North Manchester General Hospital (Dr Bev Harrison), Royal Lancaster Infirmary (Dr Marwan Bukhari) and The Royal Oldham Hospital (Dr Peter Klimiuk).
Funding This study was funded by the British Society for Rheumatology (BSR). The BSR commissioned the Biologics Register (BSRBR) as a UK wide national project to investigate the safety of biologic agents in routine medical practice. DPMS and KH are principal investigators on the BSRBR. BSR receives restricted income from UK pharmaceutical companies, presently Abbott Laboratories, Swedish Orphan Biovitrum, Merck, Pfizer, UCB and Roche. This income finances a wholly separate contract between the BSR and the University of Manchester. The principal investigators and their team have full academic freedom and are able to work independently of pharmaceutical industry influence. All decisions concerning analyses, interpretation and publication are made autonomously of any industrial contribution. Members of the Manchester team, BSR trustees, committee members and staff complete an annual declaration in relation to conflicts of interest.
Competing interests None.
Patient consent Obtained.
Data sharing statement Information on data is available at www.rheumatology.org.uk.
Ethics approval The study was approved by the North-West Multicentre Research Ethics Committee. Patient consent was obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
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