Prevalence and clinical markers of herpes simplex virus infection in oral lesions of bullous pemphigoid.

Background: The manifestations of bullous pemphigoid (BP) and herpes simplex virus (HSV) infection are similar in oral mucosa, and the laboratory detection of HSV has some limitations, making it difficult to identify the HSV infection in oral lesions of BP. In addition, the treatments for BP and HSV infection have contradictory aspects. Thus, it is important to identify the HSV infection in BP patients in time. Objective: To identify the prevalence and clinical markers of HSV infection in oral lesions of BP. Methods: This prospective cross-sectional descriptive analytical study was conducted on 42 BP patients with oral lesions. A total of 32 BP patients without oral lesions and 41 healthy individuals were enrolled as control groups. Polymerase chain reaction was used to detect HSV. Clinical and laboratory characteristics of patients with HSV infection were compared with those without infection. Results: A total of 19 (45.2%) BP patients with oral lesions, none (0.0%) BP patients without oral lesions, and four (9.8%) healthy individuals were positive for HSV on oral mucosa. Among BP patients with oral lesions, the inconsistent activity between oral and skin lesions (p=0.001), absence of blister/blood blister in oral lesions (p=0.020), and pain for oral lesions (p=0.014) were more often seen in HSV-positive than HSV-negative BP patients; the dosage of glucocorticoid (p=0.023) and the accumulated glucocorticoid dosage in the last 2 weeks (2-week AGC dosage) (p=0.018) were higher in HSV-positive BP patients. Combining the above five variables as test variable, the AUC was 0.898 (p<0.001) with HSV infection as state variable in ROC analysis. The absence of blister/blood blister in oral lesions (p=0.030) and pain for oral lesions (p=0.038) were found to be independent predictors of HSV infection in multivariable analysis. A total of 14 (73.7%) HSV-positive BP patients were treated with 2-week famciclovir and the oral mucosa BPDAI scores significantly decreased (p<0.001). Conclusion: HSV infection is common in BP oral lesions. The inconsistent activity between oral and skin lesions, absence of blister in oral lesions, pain for oral lesions, higher currently used glucocorticoid dosage, and higher 2-week AGC dosage in BP patients should alert physicians to HSV infection in oral lesions and treat them with 2-week famciclovir in time.

Identification of Risk Factors for Gliptin-associated Bullous Pemphigoid among Diabetic Patients.

Drug-associated bullous pemphigoid has been shown to follow long-term gliptin (dipeptidyl-peptidase 4 inhibitors) intake. This study aimed at identifying risk factors for gliptin-associated bullous pemphigoid among patients with type 2 diabetes. A retrospective study was conducted in a tertiary centre among diabetic patients exposed to gliptins between the years 2008-2021. Data including demographics, comorbidities, medications, and laboratory results were collected using the MDClone platform. Seventy-six patients with type 2 diabetes treated with dipeptidyl-peptidase 4 inhibitors who subsequently developed bullous pemphigoid were compared with a cohort of 8,060 diabetic patients exposed to dipeptidyl-peptidase 4 inhibitors who did not develop bullous pemphigoid. Based on a multivariable analysis adjusted for age and other covariates, Alzheimer's disease and other dementias were significantly more prevalent in patients with bullous pemphigoid (p = 0.0013). Concomitant use of either thiazide or loop diuretics and gliptin therapy was associated with drug-associated bullous pemphigoid (p < 0.0001 for both). While compared with sitagliptin, exposure to linagliptin and vildagliptin were associated with bullous pemphigoid with an odds ratio of 5.68 and 6.61 (p < 0.0001 for both), respectively. These results suggest gliptins should be prescribed with caution to patients with type 2 diabetes with coexisting Alzheimer's and other dementias, or patients receiving long-term use of thiazides and loop diuretics. The use of sitagliptin over linagliptin and vildagliptin should be preferred in these patients.

Bullous pemphigoid and diabetes mellitus: a systematic review and meta-analysis.

We aimed to systematically review and meta-analyze the association between diabetes mellitus (DM) and bullous pemphigoid (BP). Bullous pemphigoid (BP) is a prevalent autoimmune subepidermal blistering disease. Comorbid health conditions like neurological diseases and malignancies have been associated with BP. Growing evidence suggests that type 2 diabetes mellitus (T2DM) may increase the risk of developing BP. This review aims to synthesize this evidence. A systematic literature review was performed using Medline, PubMed, and Scopus in March 2022. Studies exploring the association between BP and DM were included. Data were extracted, and quality was assessed using the Newcastle-Ottawa scale. Meta-analysis was conducted to identify the odds ratio (OR) and 95% confidence intervals (CI) of the association. Seventeen studies were included, most being case-control studies from Europe and Asia. The pooled OR was 2.06 (95% CI: 1.61-2.62), suggesting a significant association between DM and BP. However, strong heterogeneity (I2 = 88%) was observed. Evidence consolidates a significant relationship between DM and BP, potentially due to alterations in the immune system and skin properties caused by diabetes. Strengths of this review include a comprehensive search, rigorous methodology, large sample size, and heterogeneity evaluation. However, varying study quality, potential publication bias, and unaccounted confounding factors present limitations. There is a potential link between T2DM and an increased risk of BP. Further studies are required to understand this association and the underlying mechanisms.

Relationship between bullous pemphigoid and malignancy: A Mendelian randomization study.

Bullous pemphigoid (BP) is the most common autoimmune blistering disease, which primarily affects the elderly. However, the relationship between BP and malignancy remains controversial in traditional observational studies. The aim of this study, which included only European populations, was to assess the potential causative link between BP and 13 types of malignant tumors in a two-sample Mendelian randomization (MR) study. BP was not associated with an increased risk of developing 13 types of malignant tumors. This study did not find a causal relationship between BP and malignant tumors. However, further research is warranted to examine the generalizability of this conclusion in non-European populations.

Accurate diagnosis of bullous pemphigoid requires multiple health care visits.

Introduction: Accurate use of diagnostic codes is crucial for epidemiological and genetic research based on electronic health record (EHR) data. Methods: This retrospective study validated the International Classification of Diseases (ICD)-10 diagnostic code L12.0 for bullous pemphigoid (BP) using EHR data from two Finnish university hospitals. We found 1225 subjects with at least one EHR entry of L12.0 between 2009 and 2019. BP diagnosis was based on clinical findings characteristic of BP and positive findings on direct immunofluorescence (DIF), BP180-NC16A enzyme-linked immunosorbent assay (ELISA) or indirect immunofluorescence (IIF) assay. Results: True BP was found in 901 patients; the positive predictive value (PPV) for L12.0 was 73.6% (95% CI 71.0-76.0). L12.0 was more accurately registered in dermatology units than any specialized health care units (p<0.001). Including patients with multiple L12.0 registrations (≥3), increased the accuracy of the L12.0 code in both dermatology units and other settings. Discussion: One diagnostic code of L12.0 is not enough to recognize BP in a large epidemiological data set; including only L12.0 registered in dermatology units and excluding cases with <3 L12.0 record entries markedly increases the PPV of BP diagnosis.

Pemphigus and pemphigoid are associated with Alzheimer's disease in older adults: evidence from the US Nationwide inpatient sample 2016-2018.

BACKGROUND: Pemphigus and pemphigoid are rare autoimmune skin disorders caused by autoantibodies against structural proteins and characterized by blistering of the skin and/or mucous membranes. Associations have been noted between skin diseases and Alzheimer's dementia (AD). Dementia is a neurological disorder of progressive cognitive impairment with increasing incidence among older adults. This study aimed to assess the potential associations between pemphigus, pemphigoid and AD in a large, nationally representative US cohort. METHODS: All data of hospitalized patients aged 60 years or older were extracted from the US Nationwide Inpatient Sample (NIS) database 2016-2018. Patients with a history of head trauma, diagnosis of vascular dementia, history of cerebrovascular disease, or malformation of cerebral vessels were excluded. The study population was divided into those with and without pemphigus (cohort 1) and with and without pemphigoid (cohort 2). RESULTS: Pemphigus was independently associated with a 69% increased risk of AD. Adults ≥80 years old with pemphigus were 72% more likely to develop AD than adults without pemphigus. Women with pemphigus were 78% more likely to develop AD than women without pemphigus. On the other hand, pemphigoid was independently associated with a 39% increased risk for AD and subjects ≥80 years with pemphigoid were 40% more likely to have AD than those without pemphigoid. Females with pemphigoid were 63% more likely to have AD than those without pemphigoid. Moreover, Hispanic older adults with pemphigus were 3-times more likely to have AD than those without pemphigoid. CONCLUSIONS: Pemphigus and pemphigoid were both independently associated with AD in older adults, especially among females and octogenarians. Further studies addressing the etiology and mechanisms underlying these associations are highly warranted.

The association between bullous pemphigoid and cognitive outcomes in middle-aged and older adults: A systematic review and meta-analysis.

BACKGROUND: Bullous pemphigoid (BP) is a rare autoimmune skin condition that causes large fluid-filled blisters on the skin, especially in older adults. BP has been linked to various diseases and medications, but its association with cognitive outcomes is unclear. METHODS: We conducted a systematic review and meta-analysis of studies investigating the association between BP and cognitive outcomes, such as all-cause dementia, Alzheimer's disease, and vascular dementia in middle-aged and older adults. We searched PubMed, Embase, and Web of Science databases for relevant studies published up to March 2023. We included studies that reported odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs) for the association between BP and cognitive outcomes. We pooled the ORs, or HRs using random-effects models and performed subgroup and sensitivity analyses to explore potential sources of heterogeneity. RESULTS: The study selection process identified 13 studies for inclusion in the analysis, 11 studied arms of which used a case-control design and 7 studied arms of which used a cohort design. The studies were conducted primarily in Europe, with a few from Asia and the United States. The meta-analysis found that BP was associated with higher odds of all-cause dementia in middle-aged and older participants in both cohort studies(HR = 1.41,95% CI: 1.20-1.66, P = 0.000) and case-control (OR = 4.25, 95% CI, 2.73-6.61; P = 0.000). The study found no significant publication bias in the included studies. The meta-regression analyses identified some subgroups associated with significantly reported odds ratios in case-control association analysis, including Europe, BP diagnosed based on clinical, histology, immunofluorescence, and both adjustment status of NO and YES. CONCLUSIONS: Our meta-analysis suggests that BP is associated with an increased risk of all-cause dementia in middle-aged and older adults. Further studies are needed to elucidate the underlying mechanisms and causal relationship between BP and cognitive outcomes.

Retrospective analysis of autoimmune bullous diseases in Middle Franconia.

Introduction: Autoimmune bullous diseases (AIBDs) are a group of rare cutaneous disorders affecting cornified skin and mucous membranes. They are characterized by tense or flaccid blistering and erosions due to autoantibodies against desmosomal and hemidesmosomal structural proteins of the skin. This group of disorders can be divided into those of pemphigoid and those of pemphigus diseases. If left untreated, these autoimmune diseases can cause serious or even life-threatening complications such as loss of fluid, superinfections or impaired food intake. Due to modern standardized serological assays, the diagnosis of AIBDs can usually be confirmed in combination with their clinical appearance. Whereas for a long time corticosteroids were the major players in the treatment of these diseases, with the approval of rituximab and other immunosuppressive agents, the therapy has increasingly improved. Methods: In this study, we aimed to investigate epidemiologic and clinical features as well as diagnostics and therapy of bullous autoimmune diseases in Middle Franconia, a governorate within the German federal state of Bavaria. Patients diagnosed or treated because of a AIBDs between 01.04.2013 and 31.03.2019 at the dermatological department of the university hospital Erlangen were included in this retrospective study (n = 242). Patients were either diagnosed for the first time (n=176) or the diagnosis has been confirmed (n=66) at the department. The respective incidence was calculated among the 176 subjects who had been diagnosed at the center in this period. Data was taken from patient records and analyzed with Microsoft® Excel. The evaluation included the diagnoses of pemphigus vulgaris (PV), pemphigus foliaceus (PF), bullous pemphigoid (BP), mucous membrane pemphigoid (MMP), linear IgA dermatosis (LAD), epidermolysis bullosa acquisita (EBA), and dermatitis herpetiformis (DH). Results: This study shows that the incidence of each AIBDs in Middle Franconia is low and comparable (PV, PF, LAD, EBA) or lower (BP, MMP, DH) than in other studies and regions. BP is the most common newly diagnosed AIBD in Middle Franconia. Discussion: Due to the chronic and sometimes severe course of AIBDs, repeated in-house treatments are often necessary. To date, mainly topically and systemically applied corticosteroids in combination with immunomodulators are used as first-line therapy.

Dietary habits in Japanese patients with bullous pemphigoid: low intake of retinol.

BACKGROUND: Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease. Dietary habits may modulate the pathogenesis of BP. OBJECTIVES: We evaluated dietary habits in Japanese patients with BP and compared their results to those of age- and sex-matched healthy controls. We also examined the relationship between dietary habits versus IgG anti-BP180NC16A antibody or parameters of BP disease area index (BPDAI); cutaneous blisters/erosions, cutaneous urticaria/erythema, and mucosal blisters/erosions. MATERIALS & METHODS: Dietary habits were assessed by the validated, Brief-type self-administered Diet History Questionnaire. Severity of disease was assessed with BPDAI. RESULTS: Patients with BP showed a lower intake of retinol (vitamin A1) and beverages, and a higher intake of seasoning/spices, compared to controls. The bivariate and multivariable logistic regression analysis showed that BP was associated with a low intake of retinol and beverages. There were no significant correlations between IgG anti-BP180NC16A antibody levels and intake of nutrients/foods. The BPDAI score for cutaneous blisters/erosions significantly positively correlated with intake of carbohydrate and negatively with intake of retinol, vitamin A, animal fat, cholesterol, phosphorus, and vitamin B2. The BPDAI score for cutaneous urticaria/erythema significantly negatively correlated with intake of vitamin A. BP patients with mucosal blisters/erosions had a higher intake of cholesterol, n-6 polyunsaturated fatty acid, and eggs, and lower intake of seasoning/spices, compared to patients without BP. CONCLUSION: The supplementation of vitamin A might have prophylactic and/or therapeutic effects on BP.

Association between chronic kidney disease and risk of bullous pemphigoid: a nationwide population-based cohort study.

BACKGROUND: Studies have shown that bullous pemphigoid (BP) occurs in patients with chronic kidney disease (CKD). However, the risk of developing BP in patients with CKD remains inconclusive. OBJECTIVE: To investigate whether CKD increases the risk of BP. METHODS: Participants were recruited from the National Health Insurance Database of Taiwan between 2007 and 2018. Overall, 637,664 newly diagnosed patients with CKD and 637,664 age-, sex-, and comorbidity-matched non-CKD participants were selected. A competing risk model was used to evaluate the risk of development of BP. RESULTS: After adjusting for age, sex, and comorbid diseases in the multivariate model, CKD was a significant risk factor for BP (adjusted hazard ratio [aHR]: 1.29; 95% confidence interval [CI]: 1.17-1.42; p < 0.001). CKD patients were classified into the dialytic or non-dialytic groups and compared to non-CKD participants, and this revealed that patients with dialysis-dependent CKD had the highest risk of BP (aHR 1.75; 95% CI 1.51-2.03), followed by patients with non-dialysis-dependent CKD (aHR 1.20; 95% CI 1.08-1.32). LIMITATIONS: We lacked detailed laboratory data on the severity of CKD. CONCLUSIONS: Compared with individuals without CKD, those with CKD had a 1.3-fold increased risk of BP. Patients with dialysis-dependent CKD had an even higher BP risk (1.8-fold).

The relationship between bullous pemphigoid and renal disease and related treatments: a review of the current literature.

INTRODUCTION: Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disorder in older adults. There is increasing evidence that BP has connections with renal diseases, such as glomerulopathy and neoplasm; it is also linked to the receipt of renal replacement therapy. AREAS COVERED: In this review, we summarize the current evidence that BP is a comorbidity of common renal diseases. Furthermore, our exploration of the characteristics and possible mechanisms underlying these connections provides insights that may facilitate the prevention, diagnosis, and management of BP. EXPERT OPINION: There is mounting proof that BP is not just a skin immunological disorder but rather a systemic immune-mediated illness. Quantities of case reports focused on BP as a renal disease comorbidity and the coexistence of them is not accidental. However, the underlying mechanisms are still needed to be investigated. Clinicians should be alert to the comorbidities in order to facilitate effective treatment and improve patient prognosis.

Risk of bullous pemphigoid and pemphigus in patients on chronic dialysis: A nationwide population-based cohort study.

Bullous pemphigoid has a high incidence among dialysis patients. However, whether or not chronic dialysis is an independent risk factor of bullous pemphigoid remains unclear. We aimed to investigate the effect of chronic dialysis on the development of bullous pemphigoid and pemphigus. We performed a retrospective cohort study using records from Taiwan's National Health Insurance Research Database between 2008 and 2019. We identified a dialysis cohort that included patients on chronic hemodialysis and peritoneal dialysis, and the hazard ratios (HRs) for bullous pemphigoid and pemphigus were compared with those of a sex-, age-, and index-matched cohort, then the results were adjusted for various confounding factors. Among 93 538 patients on chronic dialysis and 93 538 patients in the control group, 287 and 139 developed incident bullous pemphigoid, and 45 and 35 developed incident pemphigus after a median follow-up of 3.7 and 5.6 years, respectively. The incidence rates of bullous pemphigoid in the dialysis patients and the control group were 74.2 and 25.2 per 100 000 person-years, respectively (difference between groups, P < 0.0001). The incidence rates of pemphigus in the dialysis patients and the control group were 11.6 and 6.3 per 100 000 person-years, respectively (difference between groups, P < 0.01). Cox proportional hazard adjustment showed the HR for bullous pemphigoid in dialysis patients was 2.12 (95% confidence interval [CI] 1.64-2.74, P < 0.0001) compared with the control group. Dialysis patients aged <75 years had an even higher risk of bullous pemphigoid development (5- to 8-fold) than the control group. The adjusted HR for pemphigus was not elevated in dialysis patients (adjusted HR 1.52, 95% CI 0.87-2.67, P = 0.14). Chronic dialysis is an independent risk factor for developing bullous pemphigoid, but not a risk factor for pemphigus. Physicians should be aware of the predisposition of chronic dialysis patients to bullous pemphigoid.

Risk of Incident Venous Thromboembolism Among Patients With Bullous Pemphigoid or Pemphigus Vulgaris: A Nationwide Cohort Study With Meta-Analysis.

Background Bullous pemphigoid (BP) and pemphigus vulgaris (PV) share similar pathophysiology with venous thromboembolism (VTE) involving platelet activation, immune dysregulation, and systemic inflammation. Nevertheless, their associations have not been well established. Methods and Results To examine the risk of incident VTE among patients with BP or PV, we performed a nationwide cohort study using Taiwan's National Health Insurance Research Database and enrolled 12 162 adults with BP or PV and 12 162 controls. A Cox regression model considering stabilized inverse probability weighting was used to calculate the hazard ratios (HRs) for incident VTE associated with BP or PV. To consolidate the findings, a meta-analysis that incorporated results from the present cohort study with previous literature was also conducted. Compared with controls, patients with BP or PV had an increased risk for incident VTE (HR, 1.87 [95% CI, 1.55-2.26]; P<0.001). The incidence of VTE was 6.47 and 2.20 per 1000 person-years in the BP and PV cohorts, respectively. The risk for incident VTE significantly increased among patients with BP (HR, 1.85 [95% CI, 1.52-2.24]; P<0.001) and PV (HR, 1.99 [95% CI, 1.02-3.91]; P=0.04). In the meta-analysis of 8 studies including ours, BP and PV were associated with an increased risk for incident VTE (pooled relative risk, 2.17 [95% CI, 1.82-2.62]; P<0.001). Conclusions BP and PV are associated with an increased risk for VTE. Preventive approaches and cardiovascular evaluation should be considered particularly for patients with BP or PV with concomitant risk factors such as hospitalization or immobilization.

Severe acute respiratory syndrome coronavirus 2 infection in patients with autoimmune bullous diseases in China.

Patients with autoimmune bullous diseases (AIBDs) are considered to be immunocompromised and, consequently, they may be more susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and have poorer outcomes. However, the risk and repercussions of SARS-CoV-2 infection in patients with AIBDs have not been fully understood. Therefore, we aimed to investigate the risk factors of SARS-CoV-2 infection and the impact of SARS-CoV-2 on patients with AIBDs. From December 2022 to January 2023, all patients with AIBDs who visited our clinic were enrolled in this study. Meanwhile, web-based questionnaires and telesurveys were used as supplements. Information about patients' demographics, comorbidities, SARS-CoV-2 infection, and vaccination, as well as AIBD status and treatments were collected and analyzed. The diagnosis of SARS-CoV-2 infection was based on a positive polymerase chain reaction test, and/or an antigen test, or the presence of typical symptoms in conjunction with an epidemiological history. Finally, 95 patients with AIBDs were enrolled, including 47 cases of pemphigus and 48 cases of pemphigoid cases, and 73 had symptoms consistent with coronavirus disease 2019. Common symptoms after SARS-CoV-2 infection were fever (80.8%), fatigue (75.0%), cough (71.2%), muscle/joint pain (49.3%), and sore throat (45.2%). No significant differences were found between SARS-CoV-2-infected and asymptomatic patients. Patients who had hypertension (p = 0.034), hyperlipidemia (p = 0.017), or more than two comorbidities (p = 0.011) were more likely to develop pneumonia after infection. Patients with pemphigus who did not achieve disease control (p = 0.045) or had an oral corticosteroid dose ≥15 mg/day (p = 0.024) and patients with pemphigoid with a disease duration ≥2 years (p = 0.037) were more prone to AIBDs aggravation. In conclusion, patients with AIBDs are generally susceptible to SARS-CoV-2 infection. Individuals with newly diagnosed AIBDs, uncontrolled disease, and a higher corticosteroid dose are more susceptible to disease exacerbation.

Venous Thromboembolism in Patients With Bullous Pemphigoid.

Importance: Studies have linked bullous pemphigoid (BP) with venous thromboembolism (VTE) across several data sources finding 6-fold to 15-fold increased incidence rates. Objective: To determine the incidence of VTE in patients with BP compared with similar controls. Design, Setting, and Participants: This cohort study used insurance claims data from a nationwide US health care database from January 1, 2004, through January 1, 2020. Patients with dermatologist-recorded BP were identified (≥2 diagnoses of BP [International Classification of Diseases, Ninth Revision (ICD-9) 694.5 and ICD-10 L12.0] recorded by dermatologists within 1 year). Risk-set sampling identified comparator patients without BP and free of other chronic inflammatory skin diseases. Patients were followed-up until the first of the following events occurred: VTE, death, disenrollment, or end of data stream. Exposures: Patients with BP compared with those without BP and free of other chronic inflammatory skin diseases (CISD). Main outcome: Venous thromboembolism events were identified and incidence rates were computed before and after propensity-score (PS) matching to account for VTE risk factors. Hazard ratios (HRs) compared the incidence of VTE in BP vs non-CISD. Results: Overall, 2654 patients with BP and 26 814 comparator patients without BP or another CISD were identified. The mean (SD) age in the BP group was 73.0 (12.6) years and 55.0 (18.9) years in the non-CSID group. With a median follow-up time was 2 years, the unadjusted incidence rate (per 1000 person-years) of outpatient or inpatient VTE was 8.5 in the BP group compared with 1.8 in patients without a CISD. Adjusted rates were 6.7 in the BP group compared with 3.0 in the non-CISD group. Age-specific adjusted incidence rates (per 1000 person-years) in patients aged 50 to 74 years was 6.0 (vs 2.9 in the non-CISD group) and in those aged 75 years or older was 7.1 (vs 4.53 in the non-CISD group). After 1:1 propensity-score matching including 60 VTE risk factors and severity markers, BP was associated with a 2-fold increased risk of VTE (2.24 [1.26-3.98]) vs those in the non-CISD group. When restricting to patients aged 50 years or older, the adjusted relative risk of VTE was 1.82 (1.05-3.16) for the BP vs non-CISD groups. Conclusions: In this nationwide US cohort study, BP was associated with a 2-fold increased incidence of VTE after controlling for VTE risk factors in a dermatology patient population.

Risk of Serious Infections in Patients with Bullous Pemphigoid: A Population-based Cohort Study.

Patients with bullous pemphigoid are susceptible to serious infections, which are the leading cause of death in these patients. The aims of this population-based cohort study were to investigate the incidence and spectrum of serious infections in patients with bullous pemphigoid and to identify associated risk factors. The outcome measure was any infection requiring hospitalization. Hazard ratios with 95% confidence intervals were estimated using subdistribution hazard models. In total, 12,300 patients with bullous pemphigoid and 49,200 matched controls were identified through the National Health Insurance Research Database in Taiwan. Within 2 years of bullous pemphigoid diagnosis, 5,006 (40.7%) patients developed serious infections, with an incidence of 385.5/1,000 person-years. Patients with bullous pemphigoid were twice as likely to develop serious infections as controls (adjusted hazard ratio, 2.01; 95% confidence interval 1.92-2.10). Systemic corticosteroid use was the strongest risk factor, resulting in a 2-fold increase in the risk for serious infections. Other independent risk factors were advanced age, female sex, low income, and certain comorbidities. In conclusion, this study demonstrated an increased risk of serious infections following a diagnosis of bullous pemphigoid. Prophylaxis of serious infections through active intervention with the risk factors may be essential in reducing the morbidity and mortality associated with bullous pemphigoid.

Worldwide epidemiologic factors in pemphigus vulgaris and bullous pemphigoid.

Autoimmune blistering diseases such as bullous pemphigoid (BP) and pemphigus vulgaris (PV) are complex, multifactorial, and polygenic diseases, whose exact pathogenesis is difficult to pinpoint. Research aimed at elucidating the associated epidemiologic risk factors of these two diseases has been hampered by their rare disease status. Further, a lack of centralization and standardization of available data makes the practical application of this information challenging. In order to collate and clarify the available literature we comprehensively reviewed 61 PV articles from 37 different countries and 35 BP articles from 16 different countries addressing a range of disease relevant clinical parameters including age of onset, sex, incidence, prevalence, and HLA allele association. The reported incidence of PV ranged from 0.098 to 5 patients per 100,000 people, while BP ranged from 0.21 to 7.63 patients per 100,000. Prevalence of PV ranged from 0.38 to 30 per 100,000 people and BP ranged from 1.46 to 47.99 per 100,000. The mean age of onset in patients ranged from 36.5 to 71 years for PV and 64 to 82.6 years for BP. Female-to-male ratios ranged from 0.46 to 4.4 in PV and 1.01 to 5.1 in BP. Our analysis provides support for the reported linkage disequilibrium of HLA DRB1*0402 (an allele previously shown to be associated with PV) and DQB1*0302 alleles in Europe, North America, and South America. Our data also highlight that HLA DQB1*0503 (also known to be associated with PV) appears in linkage disequilibrium with DRB1*1404 and DRB1*1401, mainly in Europe, the Middle East, and Asian countries. The HLA DRB1*0804 allele was only associated with PV in patients of Brazilian and Egyptian descent. Only two HLA alleles were reported as associated with BP more than twice in our review, DQB1*0301 and DQA1*0505. Collectively, our findings provide detailed insights into the variation of disease parameters relevant to PV and BP that can be expected to inform future work aimed at unraveling the complex pathogenesis of these conditions across the globe.