Bullous pemphigoid (BP) is a chronic autoimmune blistering dermatosis that predominantly affects the elderly, characterized by subepidermal blister formation and systemic inflammation.1,2 Although primarily a dermatologic condition, emerging evidence suggests an association between BP and increased cardiovascular comorbidities, including heart failure and arrhythmias.3,4 These associations may be mediated by chronic inflammation, immune dysregulation, and shared risk factors such as advanced age and comorbid conditions.5,6

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is strongly associated with systemic inflammatory states.7,8 Inflammatory processes contribute to both structural and electrical remodeling of the atria, thereby increasing susceptibility to arrhythmogenesis.9,10 Given the chronic systemic inflammation inherent in BP, a plausible pathophysiological link to AF exists. However, the association between BP and incident AF remains insufficiently investigated.

This nationwide cohort study aimed to evaluate the risk of incident AF in patients with BP by using a large-scale database and applying robust epidemiological methods to clarify this potential relationship.

The authors initially included 61,569 subjects from the database. After applying stabilized IPW, the exposed cohort comprised 9,554 patients with BP, and the unexposed cohort included 52,015 controls without BP. Most baseline characteristics were appropriately balanced between the study cohorts after stabilized IPW (Table 1). The demographic data of study cohorts before stabilized IPW are provided in Table S3 in the Supplementary materials.

Overall, new-onset AF was identified in 510 of the 9,554 patients with BP, compared to 1,902 of the 52,015 controls, with incidence rates of 15.03 and 7.99 per 1,000 person-years, respectively (Table 2). The mean follow-up duration was 3.03-years. Patients with BP had a significantly increased risk of incident AF compared to controls (HR 1.83; 95% CI 1.66–2.02; p < 0.001), as shown in Table 2. Fig. 1 illustrates the cumulative incidence curves, with the BP cohort showing a higher cumulative incidence of developing AF (P < 0.001, log-rank test).

Fig. 1.

Cumulative incidence curve for incident atrial fibrillation.

BP, Bullous Pemphigoid.

Table 3 presents the results of the age- and sex-stratified analyses. The increased risk of incident AF associated with BP remained significant in those aged ≥ 65-years (HR 1.98; 95% CI 1.79–2.19; P < 0.001) but not in those aged < 65-years (HR 1.61; 95% CI 1.01–2.58; P = 0.0467). When stratified by sex, the association between BP and increased AF risk also remained significant for both male (HR 2.46; 95% CI 2.14–2.83; P < 0.001) and female participants (HR 1.55; 95% CI 1.35–1.78; P < 0.001).

As demonstrated in Table 2, sensitivity analyses consistently supported the primary findings. The sensitivity analysis, which included additional adjustment for covariates imbalanced after IPW, showed a similarly increased risk of AF among BP patients (HR = 1.88; 95% CI 1.70–2.08; P < 0.001). The analysis accounting for mortality as a competing risk, using Fine-Gray sub-distribution hazards models, also revealed a comparable result (HR = 1.47; 95% CI 1.33–1.62; P < 0.001). Furthermore, the sensitivity analysis that applied a truncation of weights exceeding 5 similarly yielded a consistent finding (HR = 1.99; 95% CI 1.80–2.21; P < 0.001).

The nationwide cohort study demonstrated that patients with BP had a 1.83-fold increased risk of developing AF compared with individuals without BP. A similar pattern of elevated AF risk was observed across age- and sex-stratified analyses, although the association in individuals aged < 65-years was not statistically significant under the applied threshold. Furthermore, multiple sensitivity analyses consistently supported the robustness of the association between BP and incident AF.

The elevated risk of AF observed among patients with BP may be attributed to the intricate interplay between chronic systemic inflammation and autoimmune-mediated pathophysiological mechanisms. BP is characterized by sustained immune activation and elevated circulating levels of proinflammatory cytokines such as interleukin-6, tumor necrosis factor-α, and interleukin-1β.32,33 These cytokines promote atrial structural remodeling by stimulating fibroblast proliferation and extracellular matrix deposition, leading to atrial fibrosis and disruption of normal myocardial conduction pathways.34,35 Concurrently, systemic inflammation induces oxidative stress and endothelial dysfunction, compromising the electrophysiological integrity of atrial myocytes and facilitating abnormal impulse generation and reentry.36 Moreover, autoimmune mechanisms, including molecular mimicry and potential cross-reactivity with cardiac antigens, may contribute to myocardial injury and electrical remodeling.37 Collectively, these processes establish a proarrhythmic substrate that predisposes individuals with BP to AF. These findings underscore the importance of proactive cardiovascular surveillance in this vulnerable patient population.

Previous studies have looked into the association of BP with comorbidities related to AF. A cohort study conducted by Yang et al. showed that BP have an increased risk of stroke (HR 2.37; 95% CI 1.78–3.15) and particularly ischemic stroke.38 One population-based cohort study from Denmark demonstrated that patients with autoimmune bullous disease have an elevated risk of arrhythmia (HR 1.16; 95% CI 1.02–1.32).39 In patients with pemphigus, one study by Namazi et al. indicated that the maximum P-wave duration and P-wave dispersion were significantly higher than those of the control group.40

To the best of our knowledge, this study is the first study to investigate the association between BP and AF. The main strength of the present research is the large-scale cohort study using nationwide data from real-world practice. Multiple sensitivity analyses were performed and confirmed our robust analyses with consistent results. However, our study has several limitations. First, as is inherent to registry-based studies, the NHIRD utilized for our analysis was limited by the lack of data on certain potential unmeasured confounders. Specifically, the authors were unable to adjust for lifestyle factors (e.g., smoking status, alcohol intake, obesity/body mass index) and granular clinical characteristics, such as the specific severity of BP or the amount of corticosteroid use. Furthermore, data on racial disparities were not captured, preventing an analysis of outcomes across different racial groups. Even though IPW was applied to minimize potential confounding effects, there is still a possibility of residual confounders. Second, the diagnoses of BP and HF relied primarily on ICD codes. While these codes have been shown to have high positive predictive value, potential misclassification might still have existed. Third, as the cohort was drawn from a single national database, the generalizability of these findings to other ethnic groups or geographic regions remains undetermined. Future studies involving diverse populations and varying healthcare settings are warranted to validate these results.

In conclusion, BP is associated with an increased risk for AF, as evidenced by this real-world cohort study. Cardiological evaluation should be considered for BP patients who present with symptoms such as palpitations, dyspnea, or lightheadedness. Electrocardiograms or echocardiography may be valuable tools for diagnosis and risk stratification in patients with BP. Recognizing BP as a potential condition necessitating heightened AF surveillance provides an opportunity for targeted interventions aimed at reducing the stroke burden.

Tai-Li Chen: The study concept and design; data collection, or analysis and interpretation of data; statistical analysis; writing of the manuscript of critical review of important intellectual content; final approval of the final version of the manuscript.

Wan-Ting Huang: Data collection, or analysis and interpretation of data; statistical analysis; writing of the manuscript or critical review of important intellectual content; final approval of the final version of the manuscript.

Chen-Yi Wu: Data collection, or analysis and interpretation of data; writing of the manuscript or critical review of important intellectual content; final approval of the final version of the manuscript.

Ching-Hui Loh: Data collection, or analysis and interpretation of data; writing of the manuscript or critical review of important intellectual content; final approval of the final version of the manuscript.

Huei-Kai Huang: The study concept and design; data collection, or analysis and interpretation of data; statistical analysis; writing of the manuscript or critical review of important intellectual content; effective participation in the research guidance; final approval of the final version of the manuscript.

Ching-Chi Chi: The study concept and design; data collection, or analysis and interpretation of data; writing of the manuscript or critical review of important intellectual content; effective participation in the research guidance; final approval of the final version of the manuscript.

Tai-Li Chen, Huei-Kai Huang, and Ching-Chi Chi had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

This work was supported by the Hualien Tzu Chi Hospital (TCRD112-024).

The entire dataset supporting the results of this study was published in this article.