Title: The association between medicines/vaccines commonly prescribed to older people and bullous pemphigoid: a UK population-based study.
Funder: Department of Health and Social Care

Abstract: Background Bullous pemphigoid (BP) is a serious skin disease that results in large painful blisters developing over the body and occurs most commonly in older people (over 70 years). Despite several comorbidities such as stroke and a threefold increase in mortality, BP remains under-researched. The cause of BP is unclear. The auto-immune process may be triggered by medicines such as diuretics but current evidence mainly comprises case-reports and small hospital-based studies. Electronic healthcare records from the Clinical Practice Research Datalink (CPRD) provide an opportunity to conduct a large population-based study, representative of people with BP in the UK, to assess exposure to prescribed medicines. Early identification of BP and prompt withdrawal of suspect medicine may lead to BP remission and improve long-term patient outcomes, including quality of life. We aim to determine whether medicines/vaccines, prescribed for common conditions in older people, are associated with BP in the UK population. The objectives are: To determine the adjusted odds ratio of developing BP per therapeutic group and class, and for multiple exposure (i.e. the use of more than one therapeutic group of medicine/vaccine during the observation period), for medicines/vaccines commonly prescribed to older people in the UK. To identify which of the above are less associated with risk of BP, giving clinicians/prescribers alternative treatment options. To identify additional medicines associated with BP using machine learning. To identify associations between combinations of medicines prescribed to BP patients using machine learning. To describe patient characteristics of those at risk of BP, following medicine use, using machine learning. Methods A UK population-based nested case-control study using the CPRD to determine associations between identified medicines/vaccines and BP. BP cases will be matched to up to 4 controls (age, sex, GP practice) using incidence density sampling. Exposure: medicines/vaccines commonly prescribed for older people; antibacterial, medicine for the cardiovascular system, stroke, diabetes, dementia and influenza vaccination in the year leading up to diagnosis. Outcome measures: the odds of BP per therapeutic group, per class, and individual medicine; and for multiple exposure (i.e. drug-drug interactions); (reference=no exposure). Analysis: multivariable conditional logistic regression adjusted for a priori confounders. Confounding by indication will be considered and different exposure criteria assessed. We will undertake exploratory association rule mining to identify individual and combinations of medicines prescribed prior to BP. We will conduct unsupervised machine learning cluster analysis to identify groups of patients with particular demographic and clinical characteristics and their associations with prescribed medicines linked to BP. Timelines for delivery 1st November 2021-30th November 2022 Dissemination and Anticipated Impact Patient partners to review and disseminate key findings to patient support groups. Publication in peer-reviewed journals. We will target national prescribing committees and other relevant organisations, the Royal College of General Practitioners, and the British Association of Dermatologists. This study will (i) provide greater awareness of the risk of drug-associated BP amongst specialist and non-specialist healthcare professionals and therefore may facilitate earlier diagnosis of BP; (ii) support withdrawal of suspect medicines and switching to alternatives, where available, to achieve earlier remission of BP.

Lay abstract: Background to the research Bullous pemphigoid (BP) is a blistering skin condition that occurs mostly in older people (over 70 years). It causes painful, itching blisters, and open sores. These symptoms are usually treated with oral steroids. BP can lead to death. The cause of BP is unclear. Studies show some commonly prescribed medicines and vaccines such as antibiotics, medicines for the heart and blood circulation, diabetes and dementia, and the influenza vaccine may lead to BP, but the findings are from small specialist hospitals. Stopping suspect medicines has been shown to help recovery from BP. Therefore, better research is needed to identify which medicines and vaccines are linked with BP, and to find alternatives that are less associated with BP. Greater awareness of the risk of BP following the use of certain medicines or vaccines will offer the potential for earlier diagnosis of BP. Earlier diagnosis may mean disease control is possible with less aggressive treatment and improved wellbeing, for example by reducing discomfort from blisters. Withdrawal of suspect medicines and switching to alternatives, where available, may lead to recovery from BP. NHS costs may subsequently be reduced as fewer people may require advanced treatment (which have severe side-effects), or medical care for their BP. Design and methods We will use patient data which is routinely collected from over 1700 GP surgeries across the UK to calculate the risk of developing BP for patients taking certain medicines and vaccines compared to those not taking them. This is an efficient way to undertake research on uncommon conditions like BP and it will reveal what happens in healthcare settings across the whole country, not just in specialist hospitals. We will consider medicines or vaccines which are commonly prescribed for older people. We will also use a novel computer science technique, which handles large amounts of data well and will allow us to confirm our findings as well as identify additional medicines associated with BP. Patient and public involvement Patients with blistering skin conditions, including BP, have helped to develop this study. They will help us make sure the results are presented in a format that is easy for patients to understand and will publicise these results to the patient community. We are supported by the only UK based patient support group for BP PEM Friends (www.pemfriendsuk.co.uk). In the words of one patient, &ldquo;So little is known about BP &hellip;the more awareness of what could trigger BP the better&hellip;&rdquo; Dissemination We will publish our work and specifically target national prescribing committees and other relevant organisations, the Royal College of General Practitioners, the British Association of Dermatologists, and PEM Friends to share details with healthcare professionals and patients.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: SKIN