Advancing Treatment in Bullous Pemphigoid: A Comprehensive Review of Novel Therapeutic Targets and Approaches.

Bullous pemphigoid is one of the most common autoimmune bullous diseases occurring primarily in the elderly. Pathogenic autoantibodies against BP180 and BP230 at the dermal-epidermal junction cause subepidermal blisters, erosions, and intense pruritus, all of which adversely affect the patients' quality of life and may increase their morbidity and mortality. Current systemic treatment options for bullous pemphigoid are limited to corticosteroids and immunosuppressants, which can have substantial side effects on these vulnerable patients that even exceed their therapeutic benefits. Therefore, more precisely, targeting therapies to the pathogenic cells and molecules in bullous pemphigoid is an urgent issue. In this review, we describe the pathophysiology of bullous pemphigoid, focusing on autoantibodies, complements, eosinophils, neutrophils, proteases, and the T helper 2 and 17 axes since they are crucial in promoting proinflammatory environments. We also highlight the emerging therapeutic targets for bullous pemphigoid and their latest discoveries in clinical trials or experimental studies. Further well-designed studies are required to establish the efficacy and safety of these prospective therapeutic options.

Targeting type 2 inflammation in bullous pemphigoid: current and emerging therapeutic approaches.

Bullous pemphigoid (BP) is one of the most common autoimmune bullous diseases and mainly affects an elderly population with multi-morbidity. Due to the frailty of many BP patients, existing treatment options are limited. The blisters associated with BP result from IgG and IgE autoantibodies binding to the central components of hemidesmosome, BP180, and BP230, stimulating a destructive inflammatory process. The known characteristic features of BP, such as intense pruritus, urticarial prodrome, peripheral eosinophilia, elevated IgE, as well as recent expanding evidence from in vitro and in vivo studies implicate type 2 inflammation as an important driver of BP pathogenesis. Type 2 inflammation is an inflammatory pathway involving a subset of CD4+ T cells that secrete IL-4, IL-5, and IL-13, IgE-secreting B cells, and granulocytes, such as eosinophils, mast cells, and basophils. It is believed that effectors in type 2 inflammation may serve as novel and effective treatment targets for BP. This review focuses on recent understandings of BP pathogenesis with a particular emphasis on the role of type 2 inflammation. We summarize current clinical evidence of using rituximab (B-cell depletion), omalizumab (anti-IgE antibody), and dupilumab (anti-IL-4/13 antibody) in the treatment of BP. The latest advances in emerging targeted therapeutic approaches for BP treatment are also discussed.

Taiwanese dermatological association (TDA) consensus for the management of pemphigus.

Pemphigus is an uncommon but life-threatening autoimmune blistering disease characterized by the presence of antibodies against desmogleins. Without effective treatment, pemphigus can result in significant morbidity and mortality. Existing consensus statements on pemphigus management from international medical groups provide varying guidelines, especially on treatment. Thus, on January 4, 2020, a panel of seven dermatology experts from the Taiwanese Dermatological Association (TDA) and one rheumatology expert convened to develop a consensus for the management of pemphigus. These experts with extensive experience in pemphigus management were recommended by their respective teaching hospitals and primary care clinics in Taiwan and by the TDA. The meeting reviewed the available consensus statements from international dermatology groups, including the European Dermatology Forum (EDF), the European Academy of Dermatology and Venereology (EADV), and the International Bullous Diseases Consensus Group. Using these guidelines as a basis for discussion and consensus formulation, these experts formulated their consensus statement that provides practical, concise but comprehensive recommendations as to the diagnosis, treatment, and monitoring of pemphigus patients in Taiwan. This consensus serves as a clinical reference for physicians for the management of pemphigus in Taiwan or wherever it may be applicable.

Efficacy of Dupilumab on Different Phenotypes of Adult with Moderate-to-Severe Atopic Dermatitis in Taiwan: A Real-World Study.

To determine phenotype-related dupilumab response in adult patients with atopic dermatitis (AD), this multicenter, retrospective study included 111 adults with moderate-to-severe AD in Taiwan, with median age of 31.5 years (18-87) and 71 (64.0%) males. Patients received dupilumab 300 mg per two to three weeks up to 12 months. We found a significant improvement after 4 and 16 weeks of treatment in all patients for all the assessed scores, including eczema area and severity index (EASI) improvement ≥50% (EASI-50) and 75% (EASI-75), EASI reaching minimal clinically important difference (MCID), and Investigator's Global Assessment (IGA) improvement ≥2. Importantly, prior to asthma, early AD onset and 3-week drug intervals were significantly associated with a high proportion of EASI-75 at month 12, while prurigo and lichenoid phenotypes were associated with a lower proportion of EASI-75 at month 12. However, the majority of adverse events were mild in severity. In conclusion, our study results identify phenotype-related dupilumab response at month 12 in adults with moderate-to-severe AD, and we suggest that treatment should not be discontinued until reaching a satisfactory clinical response.

Detecting Lesional Granulysin Levels for Rapid Diagnosis of Cytotoxic T lymphocyte-Mediated Bullous Skin Disorders.

BACKGROUND: Bullous skin disorders are induced by different pathomechanisms and several are emergent, including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Rapid diagnostic methods for SJS/TEN or cytotoxic T-lymphocyte (CTL)-mediated bullous disorders are crucial for early treatment. Granulysin, primarily expressed by CTLs, is a specific cytotoxic protein responsible for SJS/TEN and similar skin reactions. OBJECTIVE: To assess granulysin levels in blister fluids to differentiate SJS/TEN and similar CTL-mediated bullous reactions from other autoimmune bullous disorders. METHODS: Using ELISA, we measured granulysin in blister fluids from patients with bullous skin disorders, including SJS/TEN, erythema multiforme major, bullous fixed-drug eruption, bullous lupus erythematosus, paraneoplastic pemphigus, pemphigus vulgaris, bullous pemphigoid, purpura fulminans-related bullae, and hand-foot syndrome/hand-foot-skin reactions. We compared serum and blister granulysin levels in patients with SJS/TEN presenting varying severity, monitoring serial granulysin levels from acute to late stages. RESULTS: Overall, 144 patients presenting with bullous skin disorders were enrolled. Blister granulysin levels (mean ± SD) in CTL-mediated disorders, including TEN (n = 28; 3938.7 ± 3475.7), SJS-TEN overlapping (n = 22; 1440.4 ± 1179.6), SJS (n = 14; 542.0 ± 503.2), erythema multiforme major (n = 7; 766.3 ± 1073.7), generalized bullous fixed-drug eruption (n = 10; 720.4 ± 858.3), and localized bullous fixed-drug eruption (n = 16; 69.0 ± 56.4), were significantly higher than in non-CTL-mediated bullous disorders (P < .0001), including bullous lupus erythematosus (n = 3; 22.7 ± 20.1), paraneoplastic pemphigus (n = 3; 20.3 ± 8.6), pemphigus vulgaris (n = 3; 4.4 ± 2.8), bullous pemphigoid (n = 18; 4.0 ± 2.7), purpura fulminans (n = 4; 5.9 ± 5.5), and hand-foot syndrome/hand-foot-skin reactions (n = 6; 4.6 ± 3.5). Blister granulysin levels correlated with clinical severity of SJS/TEN (P < .0001). CONCLUSIONS: Determination of blister granulysin levels is a noninvasive and useful tool for rapid differential diagnosis of SJS/TEN and other similar CTL-mediated bullous skin disorders for treatment selection.

The Function of HLA-B*13:01 Involved in the Pathomechanism of Dapsone-Induced Severe Cutaneous Adverse Reactions.

Dapsone-induced hypersensitivity reactions may cause severe cutaneous adverse reactions, such as drug reaction with eosinophilia and systemic symptoms (DRESS). It has been reported that HLA-B*13:01 is strongly associated with dapsone-induced hypersensitivity reactions among leprosy patients. However, the phenotype specificity and detailed immune mechanism of HLA-B*13:01 remain unclear. We investigated the genetic predisposition, HLA-B*13:01 function, and cytotoxic T cells involved in the pathogenesis of dapsone-induced severe cutaneous adverse reactions. We enrolled patients from Taiwan and Malaysia with DRESS and maculopapular eruption with chronic inflammatory dermatoses. Our results showed that the HLA-B*13:01 allele was present in 85.7% (6/7) of patients with dapsone DRESS (odds ratio = 49.64, 95% confidence interval = 5.89-418.13; corrected P = 2.92 × 10-4) but in only 10.8% (73/677) of general population control individuals in Taiwan. The level of granulysin, the severe cutaneous adverse reaction-specific cytotoxic protein released from cytotoxic T cells, was increased in both the plasma of DRESS patients (36.14 ± 9.02 ng/ml, P < 0.05) and in vitro lymphocyte activation test (71.4%, 5/7 patients) compared with healthy control individuals. Furthermore, dapsone-specific cytotoxic T cells were significantly activated when co-cultured with HLA-B*13:01-expressing antigen presenting cells in the presence of dapsone (3.9-fold increase, compared with cells with no HLA-B*13:01 expression; P < 0.01). This study indicates that HLA-B*13:01 is strongly associated with dapsone DRESS and describes a functional role for the HLA-restricted immune mechanism induced by dapsone.

Chromoblastomycosis in Taiwan: A report of 30 cases and a review of the literature.

Chromoblastomycosis (CBM) is an implantation mycosis characterized by the presence of pigmented muriform cells in tissue. CBM is endemic in Taiwan, but only three formal cases have been reported to date because of underreporting. To describe and update its epidemiologic features, we report a series of 30 cases between 2003 and 2016 at a single medical center. Patients were predominately male (2.75:1). The mean age of onset was 65.9 years, and disease duration ranged from 2 months to 20 years. Diabetes was the most common comorbidity, and extremities were the most frequent sites of involvement. The lesions presented as papuloplaque, verrucous, cicatricial, targetoid, or mixed types. The dermoscopic features were variable, including red dots, white vague areas, black globules, and sand-like patterns. Among 10 Fonsecaea isolates further identified by sequencing the ITS regions of ribosomal DNA, nine were F. monophora and one was F. nubica. All but one patient received either systemic antifungal agents, surgical excision, or both. Surgical excision achieved a higher complete remission rate than the other forms of treatment did.

Risk and association of HLA with oxcarbazepine-induced cutaneous adverse reactions in Asians.

OBJECTIVE: To investigate the risk and genetic association of oxcarbazepine-induced cutaneous adverse reactions (OXC-cADRs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), in Asian populations (Chinese and Thai). METHODS: We prospectively enrolled patients with OXC-cADRs in Taiwan and Thailand from 2006 to 2014, and analyzed the clinical course, latent period, drug dosage, organ involvement, complications, and mortality. We also investigated the carrier rate of HLA-B*15:02 and HLA-A*31:01 of patients with OXC-cADRs and compared to OXC-tolerant controls. The incidence of OXC-SJS/TEN was compared with carbamazepine (CBZ)-induced SJS/TEN according to the nationwide population dataset from the Taiwan National Health Insurance Research Database. RESULTS: We enrolled 50 patients with OXC-cADRs, including 20 OXC-SJS/TEN and 6 drug reaction with eosinophilia and systemic symptoms, of Chinese patients from Taiwan and Thai patients from Thailand. OXC-cADRs presented with less clinical severity including limited skin detachment (all ≦5%) and no mortality. There was a significant association between HLA-B*15:02 and OXC-SJS (p = 1.87 × 10-10; odds ratio 27.90; 95% confidence interval [CI] 7.84-99.23) in Chinese and this significant association was also observed in Thai patients. The positive and negative predictive values of HLA-B*15:02 for OXC-SJS/TEN were 0.73% and 99.97%, respectively. HLA-A*31:01 was not associated with OXC-cADRs. The incidence and mortality of OXC-SJS/TEN was lower than CBZ-STS/TEN in new users (p = 0.003; relative risk 0.212; 95% CI 0.077-0.584). CONCLUSIONS: Our findings suggest that HLA-B*15:02 is significantly associated with OXC-SJS in Asian populations (Chinese and Thai). However, the severity and incidence of OXC-SJS/TEN are less than that of CBZ-SJS/TEN. The need for preemptive HLA-B*15:02 screening should be evaluated further.

p38MAPK signaling and desmoglein-3 internalization are linked events in pemphigus acantholysis.

Pemphigus vulgaris (PV) is an autoimmune blistering disease in which antibodies against the desmosomal cadherin, DSG3 (desmoglein-3), cause acantholysis. It has become increasingly clear that loss of cell-cell adhesion in PV is a complex and active process involving multiple signaling events such as activation of p38MAPK. It has also been demonstrated that incubating keratinocytes with PV IgG causes a redistribution of DSG3 from the cell surface to endosomes, which target these proteins for degradation. This study was undertaken to determine the relationship between p38MAPK and DSG3 endocytosis in pemphigus. In this work, we confirm that PV IgG causes internalization of cell-surface DSG3 into endosomes (as early as 4 h), which are then depleted from both detergent-soluble and detergent-insoluble pools. Cell-surface DSG3 internalization and depletion from both the detergent-soluble and detergent-insoluble fractions were blocked by the p38MAPK inhibitor SB202190. These data suggest that p38MAPK is capable of regulating PV IgG-mediated DSG3 internalization and that previously isolated mechanistic observations may be linked to a common pathway by which pemphigus autoantibodies lead to acantholysis.

Biphasic activation of p38MAPK suggests that apoptosis is a downstream event in pemphigus acantholysis.

In pemphigus vulgaris and pemphigus foliaceus (PF), autoantibodies against desmoglein-3 and desmoglein-1 induce epidermal cell detachment (acantholysis) and blistering. Activation of keratinocyte intracellular signaling pathways is emerging as an important component of pemphigus IgG-mediated acantholysis. We previously reported activation of p38 mitogen-activated protein kinase (MAPK) in response to pathogenic pemphigus vulgaris and PF IgG. Inhibition of p38MAPK blocked pemphigus IgG-induced cytoskeletal reorganization in tissue culture and blistering in pemphigus mouse models. We now extend these observations by demonstrating two peaks of p38MAPK activation in pemphigus tissue culture and mouse models. Administration of the p38MAPK inhibitor SB202190 before PF IgG injection blocked both peaks of p38MAPK phosphorylation and blister formation, consistent with our previous findings; however, administration of the inhibitor 4 h after PF IgG injection blocked only the later peak of p38MAPK activation but failed to block blistering. Examination of the temporal relationship of p38MAPK phosphorylation and apoptosis showed that apoptosis occurs at or after the second peak of p38MAPK activation. The time course of p38MAPK activation and apoptotic markers, as well as the ability of inhibitors of p38MAPK to block activation of the proapoptotic proteinase caspase-3, suggest that activation of apoptosis is downstream to, and a consequence of, p38MAPK activation in pemphigus acantholysis. Furthermore, these observations suggest that the earlier peak of p38MAPK activation is part of the mechanism leading to acantholysis, whereas the later peak of p38MAPK and apoptosis may not be essential for acantholysis.

Comparison of the surgical outcomes of punch incision and elliptical excision in treating epidermal inclusion cysts: a prospective, randomized study.

BACKGROUND: Punch incision has been introduced as an alternative method to surgical excision for troublesome epidermal inclusion cysts. To date, there is no randomized study directly comparing the long-term results of these two methods. OBJECTIVE: To compare the surgical outcomes of these two procedures and to identify the characteristics of a lesion most suitable for the punch incision technique. METHODS: In a 16-month period, 60 patients with noninfected epidermal inclusion cysts were randomly treated with either punch incision or elliptical excision. Demographic data, size, and location of lesion, length of wound, operative time, complications, recurrence, and patient satisfaction were compared statistically. RESULTS: The mean lengths of the wounds in the punch incision and elliptical excision groups were 0.73 and 2.34 cm, respectively (p<.001). Mean operative time was significantly shorter in the punch group (12.7 minutes) as compared with the surgical group (21.6 minutes) (p<.001). No complication occurred in the punch incision group. There was no significant difference in the recurrence rate. CONCLUSION: Punch incision produces a superior cosmetic result while keeping a low recurrence rate of cysts. Epidermal inclusion cysts measuring 1 to 2 cm that are located on the face or in an area of cosmetic concern are best treated with punch incision.