The association of six autoimmune bullous diseases with thyroid disorders: a population-based study.

BACKGROUND: The association of autoimmune bullous diseases (AIBDs) with thyroid disorders remains to be profoundly investigated. OBJECTIVE: To evaluate the epidemiological association between six AIBDs and thyroid disorders. METHODS: A population-based cross-sectional study enrolled patients with bullous pemphigoid (BP), mucous membrane pemphigoid (MMP), epidermolysis bullosa acquisita (EBA), pemphigoid gestationis (PG), pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Patients with these six AIBDs were compared with six age- and sex-matched control groups regarding the prevalence of thyroiditis and hyperthyroidism. Logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI) for thyroid disorders. RESULTS: The study population included 1,743, 251, 106, 126, 860 and 103 patients with BP, MMP, EBA, PG, PV and PF respectively. The corresponding control groups consisted of 10,141, 1,386, 606, 933, 5,142 and 588 matched controls respectively. A significant association was found between thyroiditis and BP (OR, 1.98; 95% CI, 1.18-3.35; P = 0.010), MMP (OR, 7.02; 95% CI, 1.87-26.33; P = 0.004) and PV (OR, 2.73; 95% CI, 1.45-5.15; P = 0.002). With regards to hyperthyroidism, PF was the only AIBD to demonstrate significant comorbidity (OR, 2.42; 95% CI, 1.13-5.21; P = 0.024). EBA and PG were not found to cluster with any of the investigated thyroid conditions. CONCLUSION: Patients with BP, MMP, PV and PF experience an elevated burden of thyroid disorders. Patients with these AIBDs presenting with suggestive symptoms may be carefully screened for comorbid thyroid disorders.

Updated S2 K guidelines for the management of bullous pemphigoid initiated by the European Academy of Dermatology and Venereology (EADV).

BACKGROUND: Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease of the skin and mucous membranes. This disease typically affects the elderly and presents with itch and localized or, most frequently, generalized bullous lesions. A subset of patients only develops excoriations, prurigo-like lesions, and eczematous and/or urticarial erythematous lesions. The disease, which is significantly associated with neurological disorders, has high morbidity and severely impacts the quality of life. OBJECTIVES AND METHODOLOGY: The Autoimmune blistering diseases Task Force of the European Academy of Dermatology and Venereology sought to update the guidelines for the management of BP based on new clinical information, and new evidence on diagnostic tools and interventions. The recommendations are either evidence-based or rely on expert opinion. The degree of consent among all task force members was included. RESULTS: Treatment depends on the severity of BP and patients' comorbidities. High-potency topical corticosteroids are recommended as the mainstay of treatment whenever possible. Oral prednisone at a dose of 0.5 mg/kg/day is a recommended alternative. In case of contraindications or resistance to corticosteroids, immunosuppressive therapies, such as methotrexate, azathioprine, mycophenolate mofetil or mycophenolate acid, may be recommended. The use of doxycycline and dapsone is controversial. They may be recommended, in particular, in patients with contraindications to oral corticosteroids. B-cell-depleting therapy and intravenous immunoglobulins may be considered in treatment-resistant cases. Omalizumab and dupilumab have recently shown promising results. The final version of the guideline was consented to by several patient organizations. CONCLUSIONS: The guidelines for the management of BP were updated. They summarize evidence- and expert-based recommendations useful in clinical practice.

The burden of neurological comorbidities in six autoimmune bullous diseases: a population-based study.

BACKGROUND: Apart from bullous pemphigoid (BP), the association of other autoimmune bullous diseases (AIBDs) with neurological conditions is poorly understood. OBJECTIVE: To estimate the association between a wide array of AIBDs and neurological conditions. METHODS: A retrospective cross-sectional study recruited patients with BP, mucous membrane pemphigoid (MMP), epidermolysis bullosa acquisita (EBA), pemphigoid gestationis (PG), pemphigus vulgaris (PV) and pemphigus foliaceus (PF). These patients were compared with their age- and sex-matched control subjects with regard to the lifetime prevalence of Parkinson's disease (PD), Alzheimer's disease (AD), stroke, epilepsy and multiple sclerosis (MS). Logistic regression was used to calculate OR for specified neurological disorders. RESULTS: The current study included 1743, 251, 106, 126, 860 and 103 patients diagnosed with BP, MMP, EBA, PG, PV and PF, respectively. These patients were compared with 10 141, 1386, 606, 933, 5142 and 588 matched controls, respectively. Out of the investigated neurological conditions, PD associated with BP (OR, 2.71; 95% CI, 2.19-3.35); AD with BP (OR, 2.11; 95% CI, 1.73-2.57), MMP (OR, 2.37; 95% CI, 1.03-5.47), EBA (OR, 6.00; 95% CI, 1.90-18.97) and PV (OR, 2.24; 95% CI, 1.40-3.60); stroke with BP (OR, 1.84; 95% CI, 1.55-2.19) and EBA (OR, 2.79; 95% CI, 1.11-7.01); and epilepsy with BP (OR, 2.18; 95% CI, 1.72-2.77) and PV (OR, 1.80; 95% CI, 1.19-2.73). MS did not significantly cluster with any of the six AIBDs. CONCLUSION: In addition to BP, EBA and PV were found to cluster with neurological comorbidities. Patients with these AIBDs with compatible symptoms may be carefully assessed for comorbid neurological disorders.

Patients with bullous pemphigoid and comorbid psoriasis present with less blisters and lower serum levels of anti-BP180 autoantibodies.

BACKGROUND: Although the association of bullous pemphigoid (BP) and psoriasis is well-established, the clinical and immunological features of patients with coexisting BP and psoriasis are yet to be investigated. OBJECTIVE: We aimed to estimate the prevalence of psoriasis amongst patients with BP and to elucidate the clinical and immunological characteristics of BP patients with comorbid psoriasis. METHODS: A retrospective cohort study including all consecutive patients diagnosed with BP throughout the years 2009-2019 in a tertiary referral centre. RESULTS: The study encompassed 273 patients with BP, of whom 11 (4.0%; 95% CI, 2.3-7.1%) had comorbid psoriasis. The onset of psoriasis preceded that of BP in 81.8% of patients by a median (range) latency of 26.5 (5.0-34.0) years. Compared to BP patients without psoriasis, those with BP and comorbid psoriasis were significantly younger at the onset of BP [71.8 (9.3) vs. 79.4 (9.8) years; P = 0.023], had a milder erosive phenotype [erosion/blister BPDAI mean (SD)score; 5 (4.1) vs. 22.3 (15.2); P = 0.025], lower levels of anti-BP180 NC16A serum autoantibodies [236.6 (266.3) vs. 556.2 (1323.6) U/mL; P = 0.008] and a higher prevalence of isolated linear C3 deposits (36.4% vs. 14.1%; P = 0.043) and a lower prevalence of linear immunoglobulin G deposits (36.4% vs. 68.7%; P = 0.025) along the dermal-epidermal junction by direct immunofluorescence microscopy. CONCLUSIONS: Patients with BP and comorbid psoriasis present at a younger age with milder erosive phenotype and lower levels of pathogenic autoantibodies.

The impact of lesional inflammatory cellular infiltrate on the phenotype of bullous pemphigoid.

BACKGROUND: The influence of cutaneous cellular infiltration on the phenotype of bullous pemphigoid (BP) remains to be established. OBJECTIVES: To evaluate the main histopathological characteristics of patients with BP and to assess the association between the composition of lesional inflammatory infiltrate and the various clinical, immunological and immunopathological aspects of the disease. METHODS: Retrospective study encompassing patients diagnosed with BP throughout the years 2009-2020 in a specialized tertiary referral centre. RESULTS: The study encompassed 136 patients with BP, of whom 27 (19.9%) demonstrated a cell-poor inflammatory infiltrate in lesional skin specimens. Overall, 78 (57.4%), 71 (52.2%) and 5 (3.7%) specimens were found to include eosinophil-predominant, lymphocyte-predominant and neutrophil-predominant inflammatory infiltrates, respectively. Relative to the remaining patients with BP, those with an eosinophil-predominant inflammatory infiltrate had higher (90.8% vs. 77.2%; P = 0.030) whilst those with a cell-poor inflammatory infiltrate lower (70.3% vs. 88.7%; P = 0.017) seropositivity of anti-BP180 NC16A IgG. The latter subgroup presented with higher prevalence of mucosal involvement (25.9% vs. 8.3%; P = 0.011) and a non-inflammatory clinical phenotype (50.0% vs. 17.1%; P = 0.041). Patients with lymphocyte-predominant inflammatory infiltrate manifested with higher severity BPDAI scores and a lower frequency of the non-inflammatory subtype (11.1% vs. 36.4%; P = 0.035), whilst those with a neutrophilic infiltrate presented with lower mean (SD) levels of anti-BP180 NC16A IgG [269.3 (227.6) vs. 722.7 (1499.6) U/mL; P = 0.003]. CONCLUSIONS: Eosinophil-predominance and high cellularity in the lesional inflammatory infiltrate of BP skin are associated with increased seropositivity of anti-BP180 NC16A IgG. Lymphocyte-predominant infiltrates predict a more severe phenotype, pointing towards a pathogenic role of autoreactive lymphocytes.

Coexistence of bullous pemphigoid with neuropsychiatric comorbidities is associated with anti-BP230 seropositivity.

BACKGROUND: While clustering of bullous pemphigoid (BP) with neuropsychiatric diseases is well-established, the clinical and immunological profile of BP patients with this comorbidity remains to be decisively determined. OBJECTIVES: To evaluate the burden of neurological and psychiatric comorbidities among patients with BP and to elucidate the clinical, immunological and immunopathological features of patients with BP and comorbid neuropsychiatric conditions. METHODS: We performed a retrospective study encompassing patients diagnosed with BP throughout the years 2009-2020 in a specialized tertiary referral centre. Multivariate logistic regression model was used to identify predictors of neuropsychiatric conditions among patients with BP. RESULTS: The study included 273 patients with BP, of whom 123 (45.1%) presented with comorbid neuropsychiatric disease. Compared to the remaining patients with BP (n = 150), those with pre-existing neuropsychiatric diseases demonstrated older mean [standard deviation (SD)] age [81.7 (9.1) vs. 76.9 (10.1); P < 0.001], female preponderance (65.0% vs. 49.3%; P = 0.009), higher seropositivity rate of anti-BP230 (67.7% vs. 36.5%; P = 0.006) and higher levels of anti-BP180 NC16A IgG [651.3 (1279.6) vs. 370.4 (818.6) U/mL; P = 0.039]. In multivariate analysis, anti-BP230 seropositivity was independently associated with coexistence of BP with neuropsychiatric conditions [adjusted odds ratio (OR), 3.43; 95% CI, 1.24-9.52; P = 0.018]. In a sensitivity analysis confined to patients with neurological diseases (n = 103), older age [82.1 (8.4) vs. 77.2 (10.3); P < 0.001] and increased anti-BP230 seropositivity (68.0% vs. 39.7%; P = 0.018) were identified. CONCLUSIONS: The coexistence of BP with neuropsychiatric diseases is independently associated with the generation of anti-BP230 antibodies.

Amyloidosis in hidradenitis suppurativa: a cross-sectional study and review of the literature.

BACKGROUND: Coexistence of hidradenitis suppurativa (HS) and amyloidosis has been anecdotally described, but the association between these conditions is yet to be firmly established. AIM: To study the association between HS and amyloidosis using a large-scale computerized database, and to perform a literature review to characterize all reported patients with coexistent HS and amyloidosis. METHODS: A cross-sectional study was conducted comparing the prevalence of amyloidosis among patients with HS and age-, sex- and ethnicity-matched healthy controls (HCs). Additionally, a review of literature was performed to summarize all reported cases with a dual diagnosis of both conditions. RESULTS: In total, 4417 patients with HS and 22 085 controls were included in the study. The prevalence of amyloidosis was increased in patients with HS compared with the HC group [n = 7 (0.2%) vs. n = 2 (0.0%), respectively; OR = 17.5; 95% CI 3.6-84.4; P < 0.001]. In a multivariate analysis, HS was still associated with amyloidosis (OR = 11.2; 95% CI 1.3-94.5; P = 0.03). The literature review identified nine patients who developed amyloidosis during the course of HS, with 44.4% eventually having renal failure. ‬Favourable outcomes were reported in patients managed by tumour necrosis factor (TNF)-α inhibitors. CONCLUSION: This study establishes the association between HS and amyloidosis. Screening for amyloidosis may be considered in patients with HS with a relevant clinical picture, mainly proteinuria. TNF-α inhibitors may be preferred in patients with a dual diagnosis of these conditions.

Treatment and clinical outcomes in anti-p200 pemphigoid: a systematic review.

BACKGROUND: Current treatment paradigms in anti-p200 pemphigoid rely on low levels of evidence, primarily originating from case reports and case series. OBJECTIVE: To systematically review the utilized treatment modalities for anti-p200 pemphigoid and to synthesize the available clinical outcomes of treated patients. METHODS: We conducted a systematic review of the literature using Ovid-Medline (1946-2018), Embase (1947-2018) and Web of Science (1900-2018) databases with a broad and inclusive search strategy along with a subsequent search of retrieved articles. All case reports and case series of patients with anti-p200 pemphigoid were included. RESULTS: Sixty-eight eligible studies comprising 113 anti-p200 pemphigoid patients with a mean age of 65.5 years were included in the qualitative synthesis. The clinical outcome of patients following treatment was reported for 91 (80.5%) patients, of whom 83 (91.2%) had achieved complete remission at least once. Complete remission on-therapy was observed in 51 (56.0%) and complete remission off-therapy in 12 (13.2%) patients. Thirty-six (39.6%) patients had experienced at least one flare during the duration of follow-up. A combination of systemic corticosteroids and adjuvant immunomodulatory agents was the leading therapeutic approach (63.0%) required for disease control. Systemic and topical corticosteroids as monotherapy were sufficient to control the disease in 19.6% and 13.0% of cases, respectively. Dapsone was the most commonly used (41.3%) adjuvant agent. The highest rates of complete remission were achieved in patients managed by systemic corticosteroids as monotherapy (100%) and in those managed by systemic corticosteroids with adjuvant agents (90.7%). Conversely, 45.5% of patients treated only by topical corticosteroids experienced at least one relapse during follow-up. CONCLUSION: The vast majority of patients had reached a complete remission during the course of the disease, whereas a considerable proportion of patients experienced at least one relapse. A combination of systemic corticosteroids and adjuvant immunomodulatory agents was the most frequently utilized therapeutic approach.

Chronic urticaria and osteoporosis: a longitudinal, community-based cohort study of 11 944 patients.

BACKGROUND: Chronic urticaria (CU) carries many risk factors for osteoporosis, but data on the relationships between CU and osteoporosis are lacking. OBJECTIVES: To evaluate the association between CU and osteoporosis in a large community-based study. METHODS: A nationwide observational longitudinal cohort study was conducted. CU was defined as four pairs of urticaria diagnoses; each pair was recorded within a period of 6 weeks and was registered by physicians in a primary-care setting. Patients with CU and their age- and sex- matched controls were followed for the incidence of osteoporosis and other laboratory data between 2002 and 2017. Data regarding systemic steroid exposure and other relevant risk factors for osteoporosis were obtained. Analyses of risk for osteoporosis were performed in Cox regression models adjusted for age, sex, exposure to systemic corticosteroids, obesity, smoking and hyper- and hypothyroid disease. RESULTS: The study included 11 944 patients with CU and 59 829 controls. During the study's observation period, 1035 (8·7%) patients with CU were diagnosed with osteoporosis, compared with 4046 (6·8%) controls. The adjusted multivariate analysis demonstrated that CU was significantly associated with a higher risk for osteoporosis (hazard ratio 1·23, 95% confidence interval 1·10-1·37, P < 0·001). CONCLUSIONS: CU may impose a risk for osteoporosis. Appropriate targeted screening should be considered.

From bench to bedside: evolving therapeutic targets in autoimmune blistering disease.

Autoimmune blistering diseases comprise a group of heterogenous conditions characterized by the loss of tolerance and subsequent development of autoantibodies targeting epidermal and subepidermal adhesion proteins. Blisters and erosions form on the skin and mucous membranes leading to significant morbidity and mortality. Traditional therapies rely on systemic immunosuppression. Advancements in our understanding of the pathophysiology of pemphigus and pemphigoid have led to the development of molecules which target specific pathways involved in induction and perpetuation of disease. In this review, we outline the novel therapeutic strategies including B-cell depletion, T-regulatory cell repletion, cell signalling inhibitors and small molecular inhibitors, inhibitory monoclonal antibodies, as well as complement inhibition. We additionally review their current level of clinical evidence. We lastly review therapeutics targets gleaned from the experimental epidermolysis bullosa acquisita mouse model. These emerging treatments offer an exciting progression from basic science discoveries that have the potential to transform the treatment paradigm in autoimmune blistering diseases.

Gastrointestinal symptoms, gastrointestinal bleeding and the role of diet in patients with autoimmune blistering disease: a survey of the International Pemphigus and Pemphigoid Foundation.

BACKGROUND: Autoimmune blistering diseases are a group of severe mucocutaneous conditions that typically require the use of prolonged corticosteroids and immunosuppression. Properly managing associated comorbidities is an integral part of these patients' care. The frequency of gastrointestinal symptoms, particularly gastrointestinal bleeding in these patients, is not known. Likewise, the effect of diet on disease is unknown. OBJECTIVE: To determine the incidence of gastrointestinal comorbidities and the role of diet in patients with autoimmune blistering disease. METHODS: We distributed an e-survey to patients with autoimmune blistering disease utilizing the International Pemphigus and Pemphigoid Foundation's listserv. The incidence of gastrointestinal symptoms and gastrointestinal bleeding were recorded, as were foods avoided and those noted to be beneficial in patients' disease. Historical incidences in the general population were used as controls. RESULTS: A total of 200 responses were collected. 30.3% of patients experienced gastroesophageal reflux following treatment of their autoimmune blistering disease, with 51.7% utilizing some form of gastrointestinal symptomatic treatment. The incidence of gastrointestinal bleeding following an autoimmune blistering diagnosis was 2.1%, which remained significant despite correction for non-steroidal anti-inflammatory use (NSAID), but not corticosteroid use. 65.2% of patients reported dietary limitations because of their autoimmune blistering disease. Significant intolerances after correction for multiple comparisons included alcohol, citrus and spicy foods. Greater than 10% of patients reported improvements in their disease with vegetables and dairy. CONCLUSIONS: Gastrointestinal comorbidities are common in patients with autoimmune blistering diseases, with gastrointestinal bleeding occurring in 2.1% of patients following a diagnosis of autoimmune blistering disease. While further work is needed to determine the relative risk of routine gastrointestinal prophylaxis in this population, gastrointestinal bleeding prophylaxis should be considered in patients receiving corticosteroids, particularly those taking NSAIDs. Dietary limitations are additionally frequent in this population. Patients should be cautious of alcohol, citrus and spicy foods.

Atopic dermatitis and the metabolic syndrome: a cross-sectional study of 116 816 patients.

BACKGROUND: Data regarding the association between atopic dermatitis (AD) and the metabolic syndrome are controversial. OBJECTIVE: To evaluate the prevalence of the metabolic syndrome and its components in a large group of patients with AD compared to a matched reference group. METHODS: A cross-sectional study of AD patients diagnosed by a dermatologist between 1998 and 2016, and a matched comparison group was performed. We analysed the association between AD and metabolic syndrome, its components and possible complications for the entire study population, adults (age > 18) and adults with moderate-to-severe AD. RESULTS: The study included 116 816 patients with AD and 116 812 comparison enrollees. AD in the entire group of patients and in the adult patients was associated with a higher prevalence of dyslipidaemia and a lower prevalence of diabetes and metabolic syndrome. Moderate and severe AD were associated, respectively, with higher prevalence rates of the metabolic syndrome (17.0% vs. 9.4%), its components (obesity: 22.2% vs. 18.6%; diabetes: 15.9% vs. 9.2%; hypertension 27.9% vs. 15.3%; dyslipidaemia 47.1% vs. 28.5%, all P values < 0.001) and cardiovascular morbidity (all P values < 0.001). Multivariate analysis demonstrated a significant overrepresentation of the metabolic syndrome in moderate-to-severe AD (P = 0.04). CONCLUSIONS: Severely affected patients with AD may have one or more undiagnosed components of metabolic syndrome.

Peripheral eosinophilia in bullous pemphigoid: prevalence and influence on the clinical manifestation.

BACKGROUND: Peripheral eosinophilia has been reported in 50-60% of patients with bullous pemphigoid (BP) and correlated positively with disease severity. OBJECTIVES: To establish an association of peripheral eosinophilia with the different morphological characteristics of BP. METHODS: The study was designed as a case-control study. Diagnosis of BP was grounded on well-established immunopathological criteria. Five age-, sex- and ethnicity-matched controls were randomly selected for each patient with BP. RESULTS: Overall, 225 patients with BP and 1125 control participants were enrolled. A total of 113 (50·2%) patients with BP and 49 (4·4%) controls had pathological peripheral eosinophilia (P < 0·001). An independent association between eosinophil count and the diagnosis of BP was observed [odds ratio 59·9 (per 1000 eosinophil µL-1 increase); P < 0·001]. Patients with BP with eosinophilia were significantly older at presentation (P = 0·003) and had increased palmoplantar involvement (P = 0·005), whereas patients with normal eosinophil counts had greater involvement of mucosal surfaces (P = 0·002) and the head and neck (P = 0·047). Patients with BP with extensive disease had significantly higher eosinophil counts than patients with mild-to-moderate disease (996·5 ± 1052·5 vs. 696·1 ± 962·6 cells µL-1 ; P < 0·001). CONCLUSIONS: Patients with BP with serum eosinophilia were significantly older and had higher palmoplantar involvement. Patients with BP with a normal eosinophil count were younger and presented more frequently with atypical clinical manifestations.