Comorbidities of bullous pemphigoid: A single-center retrospective case-control study from Turkey.

Although significant associations between bullous pemphigoid (BP) and certain comorbidities, primarily subtypes of neurological disorders, have been reported in several populations, it has yet to be demonstrated whether a correlation exists between pre-existing comorbidities and serum titers of anti-BP180 and 230 immunoglobulin G (IgG) antibodies among BP patients. The aim of the current study is to investigate the demographic and clinical features of BP patients in a large series from Turkey, determine the prevalence of pre-existing neurological and systemic disorders, and assess the correlation between the existence of certain comorbidities and basal serum titers of anti-BP180 and 230 IgG autoantibodies. Thus, data from 145 BP patients diagnosed in the study's center between 1987 and 2017 were retrospectively analyzed and compared with 310 age- and sex-matched control subjects. The serum titers of anti-BP 180 and 230 IgG autoantibodies were compared between the patients with and without comorbidities and its subtypes among 55 patients with available serum basal anti-BP levels. Twenty-eight of the BP patients (19.3%) had already been diagnosed with at least one neurological disorder at the onset of BP. According to regression analysis, preexisting neurological disorders (p = 0.017), stroke (p = 0.017), and malignancies (p = 0.005) were found to be higher among the study's BP patients than the controls. The serum titers of anti-BP180 and 230 that were measured at the time of diagnosis were significantly higher in patients with neurological disorders than in patients without neurological disorders (p = 0.042; p = 0.018). Among the pre-existing comorbidities, neurological disorders, particularly stroke, and malignancies were found to be significantly connected to the occurrence of BP in the selected Turkish population. The high titers of serum anti-BP180 and 230 IgG antibodies at the time of BP diagnoses may highlight undiagnosed pre-existing neurological disorders by provoking suspicion.

Dupilumab as a novel therapy for bullous pemphigoid: A multicenter case series.

BACKGROUND: Bullous pemphigoid (BP) is an autoimmune blistering disorder occurring mostly in the elderly that lacks adequate treatments. OBJECTIVE: To describe our experience using dupilumab in a series of patients with BP. METHODS: This is a case series of patients from 5 academic centers receiving dupilumab for BP. Patients were eligible if they had a clinical diagnosis of BP confirmed by lesional skin biopsy evaluated by one of more of the following: hematoxylin and eosin staining, direct immunofluorescence, or enzyme-linked immunosorbent assay for BP180 or BP230, or both. RESULTS: We identified 13 patients. Patients were an average age of 76.8 years, and the average duration of BP before dupilumab initiation was 28.8 months (range, 1-60 months). Disease clearance or satisfactory response was achieved in 92.3% (12 of 13) of the patients. Satisfactory response was defined as clinician documentation of disease improvement and patient desire to stay on the medication without documentation of disease clearance. Total clearance of the BP was achieved in 53.8% (7of 13) of patients No adverse events were reported. LIMITATIONS: Include small sample size, lack of a control group, lack of a standardized assessment tool, and lack of standardized safety monitoring. CONCLUSION: Dupilumab may be an additional treatment for BP, leading to disease clearance or satisfactory response in 92.3% of patients, including in those in whom previous conventional therapy had failed.

Psychiatric comorbidity in individuals with bullous pemphigoid and all bullous disorders in the Danish national registers.

BACKGROUND: Bullous pemphigoid (BP) is an autoimmune blistering skin disease that takes a profound physical and mental toll on those affected. The aim of the study was to investigate the bidirectional association between BP and all bullous disorders (ABD) with a broad array of psychiatric disorders, exploring the influence of prescribed medications. METHODS: This nationwide, register-based cohort study encompassed 6,470,450 individuals born in Denmark and alive from 1994 to 2016. The hazard ratios (HRs) of a subsequent psychiatric disorder in patients with BP/ABD and the reverse exposure and outcome were evaluated. RESULTS: Several psychiatric disorders were associated with increased risk of subsequent BP (4.18-fold for intellectual disorders, 2.32-fold for substance use disorders, 2.01-fold for schizophrenia and personality disorders, 1.92-1.85-1.49-fold increased risk for organic disorders, neurotic and mood disorders), independent of psychiatric medications. The association between BP and subsequent psychiatric disorders was not significant after adjusting for BP medications, except for organic disorders (HR 1.27, CI 1.04-1.54). Similar results emerged with ABD. CONCLUSION: Psychiatric disorders increase the risk of a subsequent diagnosis of BP/ABD independent of medications, whereas medications used for the treatment of BP/ABD appear to account for the subsequent onset of psychiatric disorders. Clinically, an integrated approach attending to both dermatological and psychiatric symptoms is recommended, and dermatologists should remain vigilant for early symptoms of psychiatric disorders to decrease mental health comorbidity.

A review and guide to drug-associated oral adverse effects-Oral mucosal and lichenoid reactions. Part 2.

Dental practitioners and other health professionals commonly encounter and manage adverse medicine effects that manifest in the orofacial region. Numerous medicines are associated with a variety of oral adverse effects. However, due to lack of awareness and training, these side effects are not always associated with medicine use and are underreported to pharmacovigilance agencies by dentists and other health professionals. This article aims to inform health professionals about the various oral adverse effects that can occur and the most commonly implicated drugs to improve the management, recognition and reporting of adverse drug effects. This article follows on from Part 1; however, the focus here is on lichenoid reactions and oral mucosal disorders including oral aphthous-like ulceration, mucositis and bullous disorders such as drug-induced pemphigus, pemphigoid, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Mucous membrane pemphigoid-associated paronychia with onychomadesis.

BACKGROUND: Mucous membrane pemphigoid (MMP) is an autoimmune blistering disease that is notoriously difficult to treat. Nail involvement in MMP is rare. CASE PRESENTATION: We report on a 58 years old man with severe MMP who presented with onychomadesis. CONCLUSION: To our knowledge, mucous membrane pemphigoid associated paronychia and onychomadesis have not been reported before. We believe it is important for dermatologists to be aware of this entity.

Localized pemphigus foliaceus with unilateral facial involvement.

Pemphigus foliaceus is a superficial vesiculobullous disease that typically presents with widespread lesions. Localized presentations are less frequent, and they typically occur in middle-aged patients, following exposure to topical medications, and later on, become more disseminated. We present a case of a 19-year-old female with a localized presentation of pemphigus foliaceus unrelated to previous topical medications, that was a diagnostic and therapeutically challenging case. We also discuss the literature on localized cases, differences in presentations and responses to various treatment modalities.

Concordance of Clinical, Histologic and Direct Immunofluorescence Findings in Patients with Autoimmune Bullous Dermatoses in Vietnam.

Introduction: Autoimmune bullous dermatoses (ABD) represent a heterogeneous group of blistering disorders that may be debilitating with high morbidity. Clinical, histological, and direct immunofluorescence (DIF) studies are essential in establishing an accurate diagnosis of ABD, which is essential for its clinical management. Our study objective was to perform a systematic evaluation of ABD cases in a patient population at an academic medical center in Ho Chi Minh City, Vietnam, and determine the degree of concordance of clinical, histological, and DIF findings in ABD. Methodology: A systematic retrospective cross-sectional study was performed on 92 patients diagnosed with ABD by clinical, histological, and DIF studies at the University of Medicine and Pharmacy in Ho Chi Minh City, Vietnam, between September 2019 and September 2021. The clinical histories, H and E stained tissue sections, and DIF stains were evaluated by pathologists at the University of Medicine and Pharmacy. Results: ABD was evaluated as a whole and subdivided into an intraepidermal blister subgroup and a subepidermal blister subgroup. The analysis of paired diagnostic methods (clinical, histological, and DIF) for concordance with the final diagnosis was performed and showed that there were no statistically significant differences between the paired methods (McNemar's test, p > 0.05). There was moderate concordance between the clinical, histological, and DIF diagnoses among all ABD cases (Brennan-Prediger coefficient Kappa test, κBP = 0.522, CI = 0.95). In the intraepidermal blister subgroup, the diagnostic accuracies of the histology and DIF stains were comparable to each other, and both were more accurate than a clinical diagnosis alone. In the subepidermal blister subgroup, there was no statistically significant difference in each pair of the three diagnostic methods (clinical, histological, and DIF) (McNemar's test, p > 0.05). The concordance between the clinical, histological, and DIF diagnoses was high for the intraepidermal blister subgroup (Kappa test, κBP = 0.758, CI = 0.95). However, the concordance between the clinical, histological, and DIF diagnoses was slight for the subepidermal blister subgroup (Kappa test, κBP = 0.171, CI = 0.95). Conclusion: Histological evaluation is highly accurate in the diagnosis of the intraepidermal blister subgroup, but it is not as accurate in the diagnosis of the subepidermal blister subgroup in the Vietnamese patient cohort in which clinical, histological, and DIF studies were performed. DIF stains are a crucial diagnostic tool for ABD in this patient population.

Drug Adherence and its Association with Health Literacy Among Patients with Autoimmune Bullous Diseases.

Background: Despite the emergence of novel medications, poor drug adherence is an obstacle toward disease management in patients with autoimmune bullous dermatoses (AIBDs). Objectives: We sought to evaluate medication adherence among patients with AIBDs and determine the impact of health literacy on adherence. Methods: We performed a cross-sectional survey of patients with AIBDs who attended Razi Hospital from May to October 2021. Drug adherence and health literacy were assessed using the Morisky Medication Adherence Scale-8 (MMAS-8; scored 0-8) and Health Literacy for Iranian Adults (HELIA; scored 0-100) questionnaires, respectively. Multivariable ordinal regression, including the covariates age, sex, education level, and annual income, were employed for analyses. Results: Two hundred participants with a mean±standard deviation (SD) age of 50.3±13.5 years were recruited. The female:male ratio was 1.2. About half (53%) of the patients reported good adherence (MMAS-8 score of 8) to their AIBD medications. Moreover, limited health literacy, with a mean±SD score of 57.8±25.8, was noted. Multivariable ordinal regression indicated that literacy score was significantly associated with good drug adherence (odds ratio [OR]: 0.11 per 1 score of health literacy increase, 95% confidence interval [CI]: 0.09-0.14). Conclusion: These findings showed suboptimal drug adherence and health literacy of patients with AIBDs. Improving patient health literacy might be a way to increase drug adherence.

Claudin-4 Upregulation in Acantholytic and Autoimmune-Mediated Bullous Disorders.

Claudin-4 is a key component of tight junctions, which play an important role in the formation of the epidermal barrier by forming a circumferential network in the granular layer that serves as a gatekeeper of the paracellular pathway. The aim of this study is to illustrate claudin-4 immunohistochemical staining patterns of different blistering disorders. We collected 35 cases, including two Hailey-Hailey disease, one Darier disease, three Grover disease, one acantholytic acanthoma, two warty dyskeratoma, 11 pemphigus vulgaris (PV) including six mucosal PV, and two pemphigus foliaceus. For comparison, we included five cases of normal skin, five eczema, and three bullous pemphigoid cases. Claudin-4 demonstrated weak-to-moderate expression in keratinocytes located in the stratum granulosum, keratinocytes surrounding hair follicles, and adnexal glands. Further, claudin-4 exhibited moderate-to-strong membranous staining in disrupted keratinocytes surrounding and within the acantholytic and bullous areas in 16/22 of the acantholytic cases (not seen in the six cases of mucosal PV) and all three bullous pemphigoids. This finding suggests that claudin-4 is upregulated in these conditions, which may be a compensatory response to the disrupted barrier function. This finding could shed light on the molecular mechanisms underlying disrupted barrier function in blistering disorders, independent of the specific underlying disease mechanism.

Role of neutrophil-to-lymphocyte, neutrophil-to-eosinophil and platelet-to-lymphocyte ratios in the diagnosis of bullous pemphigoid and Pemphigus disease.

Context: Bullous pemphigoid (BP) and "Pemphigus diseases" (PD) can have overlapping clinical manifestations and accurate distinction is crucial for appropriate management. Aims: The study aimed at analyzing the utility of simple hematological markers of systemic inflammation like neutrophil-to-lymphocyte ratio (NLR), neutrophil-to-eosinophil ratio (NER), and platelet-to-lymphocyte ratio (PLR) in clinical decision making in the setting of clinical differentials of BP and PD in a particular case. Methods: This single-centre based retrospective observational analytical study included adult subjects newly diagnosed to have BP (n=66) or PD (n=53), confirmed with direct immune-fluorescence testing, over a period of six years. Blood counts performed using Coulter™ hematology analyser, at the time of their initial presentation, were retrieved from the hospital medical records, and the leucocyte ratios were calculated. Statistical Analysis: The data were compared between the two groups, using Mann-Whitney U test and chi-square test /Fisher's exact test. ROC curve analysis was performed to estimate cut-off values. Results: The BP group had a significantly higher NLR, total leukocyte counts (TLC), absolute eosinophil counts (AEC), and absolute lymphocyte counts (ALC), and lower NER values compared to the PD group (P < 0.05). Areas under ROC for NLR, NER, TLC, AEC, and ALC were between 0.5 and 0.7. NLR ≥ 7, AEC ≥ 2055/cumm, and TLC ≥ 15,000/cumm had a specificity of 90.6, 100, and 100% respectively for identifying BP patients out of the two groups, but with a low sensitivity of 22.7, 21, and 22.7%, respectively. Conclusions: NLR can be a valuable diagnostic adjunct in subtyping autoimmune bullous disorders, albeit in a small proportion of cases.

Dermoscopic Differentiation of Blister Beetle Dermatitis and Herpes Zoster: an Observational Study.

Introduction: Blister beetle dermatitis (BBD) and herpes zoster (HZ) manifest suddenly with vesicular lesions mimicking each other and progress rapidly. But a lack of definite differentiating criteria yearns the need for better investigating modality. Though histopathology persuades the need, is an invasive procedure, commonly deferred. Thus, dermoscopy, a non-invasive rapid diagnostic tool, can help in differentiating. Objectives: To evaluate different dermoscopic patterns of BBD and HZ to differentiate both and to study dermoscopic features in early and late stages of lesions. Methods: An observational cross-section study conducted in southern India. Nine patients with clinical features suggestive of BBD and HZ were recruited. Lesions were divided arbitrarily into early and late. Dermoscopic examination was performed with handheld dermoscope. Diagnosis was confirmed by skin biopsy and Tzanck smear wherever necessary. Statistical analysis performed using data in terms of frequencies and percentages. Results: Dermoscopy of early BBD lesions showed multiple discrete and confluent yellowish-white structures, brown dots, roundish white globules, gray structures, 'targetoid pattern', brown areas over intense reddish pink background. Late BBD lesions revealed pinkish-white area, reduced gray structures and, dotted and globular vessels. Early HZ lesions showed poly-lobular gray and brown globules, bright pink background, gray globules covered by grayish veil-like structure with gray rim. Late HZ lesions revealed 'solar eclipse' pattern and 'crumpled fabric' patterns. The dermoscopic findings correlated with histopathology. Conclusions: Dermoscopic patterns show peculiar features consistently pertaining to BBD and HZ, thus help in early diagnosis assisting in accurate treatment in both conditions.

Hemidesmosomal Reactivity and Treatment Recommendations in Immune Checkpoint Inhibitor-Induced Bullous Pemphigoid-A Retrospective, Monocentric Study.

Immune checkpoint inhibitors (ICI) induce T-cell-mediated antitumour responses. While ICI were initially successfully applied in metastasized melanoma, they are now approved for several tumour entities. Numerous autoimmune disorders have been reported to occur as adverse events of the treatment, among them bullous pemphigoid (BP), with less than 1% of the patients experiencing ICI-induced BP. This number is higher than the estimated prevalence of autoimmune bullous diseases in the general population of Germany, which lies around 0.05%. We here describe our cohort of eight patients, who developed a bullous pemphigoid under or shortly after ICI treatment. Half of them had a severe subtype (as shown by BPDAI >57) and showed a median onset of ICI-BP after 10 months of ICI initiation. Six patients had a palmar and/or plantar involvement, while oral involvement occurred in one case. All patients had linear epidermal IgG depositions in split skin in the indirect immunofluorescence. In four out of five biopsies available for direct immunofluorescence, linear IgG and C3 depositions were detected at the basement membrane, while one patient showed linear IgM staining. Moderate to high levels of FLBP180 autoantibodies were found in seven of eight cases. The disease can still be active after ICI discontinuation, while rituximab might be required for remission. Finally, four tumour samples were stained histochemically for collagen XVII (BP180), but no enhanced expression was found.

Targeting heat shock proteins 90 and 70: A promising remedy for both autoimmune bullous diseases and COVID-19.

Heat shock proteins (Hsps), including Hsp90 and Hsp70, are intra- and extracellular molecules implicated in cellular homeostasis and immune processes and are induced by cell stress such as inflammation and infection. Autoimmune bullous disorders (AIBDs) and COVID-19 represent potentially life-threatening inflammatory and infectious diseases, respectively. A significant portion of AIBDs remain refractory to currently available immunosuppressive therapies, which may represent a risk factor for COVID-19, and suffer from treatment side-effects. Despite advances in vaccination, there is still a need to develop new therapeutic approaches targeting SARS-CoV-2, especially considering vaccine hesitancy, logistical distribution challenges, and breakthrough infections. In this mini review, we briefly summarize the role of targeting Hsp90/70 as a promising double-edged sword in the therapy of AIBDs and COVID-19.

Utility of Direct Immunofluorescence in Cutaneous Autoimmune Bullous Disorders.

Background Autoimmune bullous disorders (AIBD) are a heterogeneous group of disorders with substantial clinical overlap associated with blistering of skin or mucosa. Aims The present study aimed to study the histopathological spectrum and evaluate the utility of direct immunofluorescence (DIF) on snap-frozen and paraffin-embedded sections in resolving the differential diagnosis of AIBD and connective tissue disorders of the skin. We also compared the efficacy of DIF on paraffin versus the snap-frozen sections in diagnosing AIBD. Methods The present study was conducted for three years (2017-2019) and included 27 biopsies. We also included a retrospective analysis that included 25 biopsies collected over three years (2014-2017). Histopathological examination and DIF were conducted on all samples. Results Pemphigus vulgaris was the most common autoimmune cutaneous disorder constituting 37% (n = 10) in prospective and 36% (n = 9) in the retrospective study. DIF showed a specificity of 81.25% in our prospective study. While on the paraffin-embedded sections, it showed a specificity of 66.6% in our retrospective study. In the prospective study, DIF on paraffin-embedded sections had a positivity rate of 43.75% as compared to 81.25% in DIF done on snap-frozen sections. Conclusion DIF is a sensitive tool for the diagnosis as well as distinguishing immune-mediated bullous disorders from other lesions primarily when performed on snap-frozen sections. The diagnostic yield is enhanced by DIF in cases that pose a diagnostic dilemma both clinically and histologically. The final diagnosis depends on all clinical, histopathological and immunofluorescence findings.

A Case of Severe Bullous Dermatitis With Mixed Bullous Pemphigoid and Pemphigus Vulgaris Cutaneous Manifestations.

Bullous dermatoses include the rare, chronic autoimmune diseases pemphigus vulgaris and bullous pemphigoid. These diseases are traditionally taught to be differentiated by the presence of mucosal lesions (pemphigus vulgaris) and bullae without mucosal involvement (bullous pemphigoid). In the clinical setting, however, these diseases often contain overlapping features that present challenges to care teams without access to dermatologic care and leave patients without a clear treatment pathway. The ability to differentiate these two diseases clinically is imperative as it determines treatment regimens which when applied can mitigate unnecessary morbidity and mortality. Identifying these conditions clinically for the correct treatment also allows providers to rely less on laboratory assessments which are often unavailable or may take considerable time to result. This report details the clinical course of a patient who presented with an undifferentiated bullous dermatitis with features of both pemphigus vulgaris and bullous pemphigoid and aims to highlight the features of presentation which overlap between pemphigus vulgaris and bullous pemphigoid and those which are more characteristic for one over the other.

Ultra-low dose rituximab for refractory pemghigus vulgaris: a pilot study.

Background: Pemphigus vulgaris is an autoimmune blistering disease affecting the skin and mucous membranes. Current treatments for pemphigus vulgaris include anti-inflammatory and immunosuppressive agents. Rituximab, an anti-CD20 monoclonal antibody, has been shown to be effective for the treatment of pemphigus vulgaris. However, the optimal dosage of rituximab for the treatment of this autoimmune bullous disease has not been clearly defined.The aim of this study was to investigate the clinical efficacy and adverse effects of an ultra-low dosage regimen of rituximab for pemphigus vulgaris.Methods: We performed a prospective non-randomized open case series including eight patients affected by pemphigus vulgaris. Patients were treated with an ultra-low dosage of rituximab (a single infusion of 200 mg).Results: All patients had a positive response after infusion. At the end of the follow-up period, 5 patients achieved a complete remission and 3 a partial remission. Except for one case of sepsis due to Citrobacer freundii and a pneumonia due to Haemophilus influenzae, no adverse events were documented in our patients.Conclusions: Data from our study suggest that an ultra-low dosage of rituximab could be an effective treatment for pemphigus vulgaris. Consequently, there is a need for a larger, confirmatory, randomized, multicenter trial.

An array of unusual clinical features in a woman with amlodipine-induced linear immunoglobulin A disease.

Linear immunoglobulin A disease (LAD) is a rare, autoimmune, vesicular-bullous disease that is either idiopathic or drug-induced, most commonly by vancomycin and in rare instances by amlodipine. In drug-induced LAD, certain uncommon and atypical clinical features can occur. In our patient, a 49-year-old woman with amlodipine-induced LAD, atypical features such as koebnerization and palmo-plantar involvement occurred. She presented with tense, clear fluid-filled vesicles, bullae, and erosions all over her body, especially on the palms and soles, with some lesions showing a string-of-pearls appearance. The lesions were preceded by pruritus, and the patient had changed her anti-hypertensive medication from telmisartan to telmisartan-amlodipine for previous 10 days. Skin biopsy and direct immunofluorescence testing confirmed LAD. During the hospital stay, along with new crops of lesions, a few vesicles were present along the lines where she had scratched and the band of tight elastic sleeves of the sterile gown she wore, which is suggestive of koebnerization. Knowing the atypical manifestations of drug-induced LAD may aid clinicians in determining an early diagnosis, and LAD should be an important consideration in the differential diagnosis of vesiculobullous disease with palmar-plantar involvement. Amlodipine is a commonly used anti-hypertensive drug, so knowledge of its potential to cause this disease is important. Furthermore, knowing the potential for koebnerization, avoidance of trauma and the gentle handling of these patients can lead to early recovery from this self-limiting disease.