The association between COVID-19 vaccines and bullous pemphigoid risk: A UK population-based study

Bullous pemphigoid (BP) is a rare autoimmune blistering disease mostly affecting older people.¹ Previous studies reported varied BP risk following COVID-19 vaccines, but were either hospital-based or sampled from ethnically homogeneous populations not representative of the United Kingdom.^2–4 Accurate BP risk estimates following COVID-19 vaccination could help GPs and patients consider routine vaccinations. Earlier BP recognition may result in less severe symptoms and a need for aggressive treatments. We conducted a population-based nested case–control study (2021–2023) using the Clinical Practice Research Datalink (CPRD) GOLD and Aurum and linked hospital data. People (cases ≥18 years old) with the earliest BP record (validated Read/ICD-10 code)⁵ were matched up to four controls by age, sex and general practice. COVID-19 vaccine exposure (general, product: AstraZeneca®/Pfizer®/Spikevax®; technology: vector/mRNA) was the latest vaccination within 3 months prior to the index date. The period was chosen based on previous studies on BP onset⁶ and because it is likely that after 3 months, vaccine efficacy drops, potentially decreasing the risk of a dysregulated immune response.⁷ Doses (0/1/2/≥3) were the number of vaccinations prior to the index date. To estimate BP risk (odds ratio [OR]) following vaccine exposures, we used conditional logistic regression. We adjusted a priori for confounders: stroke, dementia and Parkinson’s disease, previously associated with BP¹, which qualified people for more vaccine doses per the UK vaccination policy.⁸ Analogically, we tested if diabetes, multiple sclerosis, epilepsy, rheumatoid arthritis, severe mental illness (schizophrenia, affective and other disorders) and SARS-CoV-2 infection were cofounders (Figure 1a).^{1, 3, 9, 10} Multivariable analysis adjusted for the latest prescription of drugs previously associated with BP, namely DPP-4 inhibitors and antiepileptics, issued within 1 year before BP diagnosis and anti-inflammatory drugs within 3 months, as this exposure window qualified for additional vaccine doses.^6, 8 We performed Charlson Comorbidity Index (CCI: 0–2 vs. ≥3) subgroup analysis to inform risk–benefit assessment of vaccinations. Sensitivity analyses included: (i) adjusting for ethnicity and deprivation to examine sociodemographic inequalities, (ii) a reduced 2-month exposure window to assess temporal delay between vaccination and BP onset. Post hoc mediation analysis proposed SARS-CoV-2 infection could mediate the vaccine–BP association, as additional doses may reduce infection and, indirectly, BP risk. We included 2828 cases (median age 80 [IQR: 72–86], 50.5% women) and 11,067 controls (Table 1). There was no evidence of increased BP risk after COVID-19 vaccines. Individuals after ≥3 doses had an observed lower odds of BP (adjusted OR: 0.48; 95% CI: 0.29–0.79; p < 0.005, Figure 1b). Sensitivity, subgroup and mediation analyses had similar results. The results were consistent with previous studies, which found no association between COVID-19 vaccines and BP and a lower risk following a third dose.^2–4 However, these results should not be interpreted as evidence of a causal relationship. Our study’s strengths include a large sample drawn from >2000 UK practices. We adjusted for confounders with reliable data, and our design aligns with UK vaccination policy and BP research.^{1, 3, 6, 8–10} However, residual confounding may persist, as SARS-CoV-2 infections were likely under-ascertained in CPRD. Despite using validated codes,⁵ misclassification is possible due to coding delays, mild/atypical cases and no BP severity data. Missing ethnicity and deprivation data limited the interpretation of vaccine uptake inequalities. Surveillance bias may have affected estimates for ≥3 doses, as conditions that often require regular consultations qualified for additional doses.⁸ Furthermore, as BP is a condition of older people, our results are also not generalisable to younger people. Our study found no association between COVID-19 vaccines and BP, which may reassure healthcare professionals and patients about vaccine safety. However, any skin manifestations in people at high risk of BP, that is, the elderly and/or with neurological comorbidities, should be addressed promptly.

Information

Type

Journal article

Issue

Journal of the European Academy of Dermatology and Venereology

Publisher

 John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.

Addresses
This work was supported by the National Institute for Health and Care Research (NIHR) grant via the School for Primary Care Research Funding Round 8 (award ID to Dr S Gran: Project No: 684)