Association of Comorbid Trauma and Stressor‐Related Disorders in Pemphigus and Pemphigoid: A Case‐Control Study

Autoimmune blistering diseases (AIBDs) such as pemphigus and bullous pemphigoid (BP) are chronic, debilitating disorders characterized by loss of keratinocyte adhesion. Pemphigus affects 0.5–3 per million annually, while BP, the most common AIBD, occurs in up to 50 per million, particularly in older adults [1]. The unpredictable relapses, prolonged immunosuppression, and disfiguring lesions contribute to substantial psychosocial burden. We evaluated the association between trauma- and stressor-related disorders and AIBDs using the All of Us (AoU) database. A nested case–control study was conducted utilizing the AoU controlled tier data set version 8, and all cases of pemphigus and pemphigoid were included (concept IDs 135338 and 139899 respectively). Cases were matched to controls by age, race, and sex at birth (approximately 1:5 ratio) using nearest-neighbor propensity matching. Comorbid acute stress disorder (ASD; < 1 month), post-traumatic stress disorder (PTSD; ≥ 1 month), and generalized anxiety disorder (GAD; ≥ 6 months) were assessed. For each patient, GAD, PTSD, and ASD were evaluated once, based on the presence of a diagnosis code recorded after the initial AIBD diagnosis; multiple visits or repeated codes were not used to assess longitudinal changes. Group characteristics were compared using χ2 (or Fisher's) tests, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. The cohort included 165 pemphigus vulgaris and 250 BP patients matched to 823 and 1248 controls, respectively. Among pemphigoid patients, 144 had BP, 66 mucous membrane pemphigoid, and 40 unspecified pemphigoid. The majority of pemphigus patients were > 65 years of age (61.21%), White (61.82%), and female (58.79%). Similarly, most BP patients were > 65 years of age (67.60%), White (65.20%), and female (58.00%) (Table S1). In this cohort, comorbid GAD was not significantly increased in pemphigus (OR 1.03, 95% CI 0.56–1.88, p = 0.928) or pemphigoid (OR 0.52, 95% CI 0.26–1.01, p = 0.052) compared with matched controls. By contrast, both pemphigus and pemphigoid were associated with higher odds of comorbid ASD (pemphigus: OR 2.09, 95% CI 1.02–4.30, p = 0.045; pemphigoid: OR 2.57, 95% CI 1.30–5.08, p < 0.0065). Odds of comorbid PTSD were not increased in either pemphigus (OR 0.49, 95% CI 0.17–1.38, p = 0.176) or pemphigoid (OR 0.73, 95% CI 0.33–1.64, p = 0.453) (Table 1). In a subgroup analysis controlling for H02-class immunosuppressants, including systemic corticosteroids (Table S2), the association with comorbid ASD was not statistically significant, while comorbid GAD was lower in pemphigoid patients compared with controls (OR 0.38, 95% CI 0.20–0.73, p = 0.004), suggesting that immunosuppressant use, including systemic corticosteroids, may attenuate the observed association with psychiatric comorbidities. Psychiatric comorbidities, particularly depression and anxiety, are well documented in AIBDs and correlate with decreased quality of life, treatment adherence, and disease activity [2]. However, trauma-related disorders remain underexplored. Stress may promote immune dysregulation through hypothalamic–pituitary–adrenal axis activation, Th1/Th2 imbalance, and cytokines (IL-6, TNF-α), implicated in AIBD pathogenesis [3, 4]. Chronic inflammatory disease may also act as a psychological stressor, reinforcing a bidirectional loop. We found no increase in GAD or PTSD, but significantly higher odds of ASD in both conditions. This acute stress signal, particularly in BP, suggests a limited window around diagnosis or flares where early intervention may alter disease trajectory. These findings extend prior work on psychiatric burden in AIBDs and suggest trauma-related psychopathology may be underrecognized. Neuroendocrine and cytokine shifts may amplify autoantibody-driven inflammation, while disease burden can perpetuate stress [4]. The absence of increased PTSD suggests these responses may be transient rather than chronic. Clinicians should also remain aware that systemic corticosteroids can be associated with neuropsychiatric adverse effects, including anxiety, mood changes, insomnia, and affective symptoms, which may influence observed psychiatric comorbidity in AIBDs. Limitations include the retrospective cross-sectional design, potential diagnostic misclassification, and reliance on coded data. Importantly, psychiatric diagnoses were not assessed longitudinally; although defined relative to the AIBD diagnosis date, repeated healthcare encounters may generate multiple entries without clear temporal resolution, limiting the ability to determine onset, chronicity, or causal direction. Dermatologists should screen for acute stress and anxiety in AIBDs, facilitate early mental health referral, and coordinate multidisciplinary care to improve outcomes. Recognition of trauma-related psychopathology may help mitigate both short- and long-term disease burden. We gratefully acknowledge All of Us participants for their contributions, without whom this research would not have been possible. We also thank the National Institutes of Health's All of Us Research Program for making available the participant data examined in this study. The authors declare no conflicts of interest. Data and code used in this study are available as a featured workspace to registered researchers of the All of Us Researcher Workbench. For information about access, please visit https://www.researchallofus.org/. Table S1: Summarizes demographic characteristics of pemphigus and pemphigoid patients and their matched controls. Table S2: Presents the subgroup case–control analysis controlling for H02-class immunosuppressant use, including systemic corticosteroids. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.