Hospitalization and mortality in Asian autoimmune bullous dermatosis patients: A 17-year retrospective study.

Limited data exist on the factors associated with hospitalization and mortality in Asian inpatients with autoimmune bullous dermatoses (AIBDs). This study aimed to elucidate the risk factors affecting hospitalization and mortality rates in Asian patients with AIBDs. A retrospective analysis of patients with AIBDs treated at Siriraj Hospital during a 17-year period was performed using the International Classification of Diseases 10th revision codes. The characteristics of inpatients and outpatients were compared, and mortality rates and associated factors were identified. The study included 360 AIBD patients (180 inpatients, 180 outpatients). Inpatients were significantly younger than outpatients. The identified risk factors for hospitalization were malignancy (odds ratio [OR] 2.83, 95% confidence interval [CI] 1.13-8.04; p = 0.034), moderate to severe disease (OR 2.52, 95% CI 1.49-4.34; p < 0.001), systemic corticosteroid use ≥15 mg/day (OR 2.27, 95% CI 1.21-4.41; p = 0.013) and oral cyclophosphamide treatment (OR 9.88, 95% CI 3.82-33.7; p < 0.001). Kaplan-Meier analysis revealed mortality rates of 26%, 36% and 39% for inpatients with pemphigus at 1, 3 and 5 years, respectively. For inpatients with pemphigoid, the corresponding rates were 28%, 38% and 47%. Infections, particularly pneumonia, were the predominant cause of death in both conditions. This study confirmed that both Asian ethnicity and healthcare disparities may be correlated with adverse outcomes in patients with AIBDs. Pemphigus mortality rates were substantially greater in Asian patients than in Caucasian patients. Continuous monitoring of factors contributing to hospitalization and mortality is imperative to improve treatment outcomes.

Influence of pharmacogenomic polymorphisms on allopurinol-induced cutaneous adverse drug reactions in Thai patients.

BACKGROUND: Allopurinol has been causing substantial morbidity and mortality particularly in Asian population by producing cutaneous adverse drug reactions (cADRs). Nonetheless, there are no data describing whether other genetics are a valid marker for prediction of allopurinol-induced cADRs patients in addition to HLA-B*58:01 allele. The goal of this study was to identify suitable single nucleotide polymorphisms (SNPs) for allopurinol induced cADRs among Thai patients. METHODS: We conducted a case-control association study after enrolling 57 Thai patients with allopurinol induced cADRs and 101 allopurinol-tolerant controls. The genetic biomarkers and associated SNPs located on chromosome 6p21 were examined by TaqMan® SNP genotyping assays in both the cases and the controls. RESULTS: Out of fifteen SNPs in nine genes, we found four combined SNPs (rs3099844 of HCP5, rs9263726 of PSORS1C1, rs9263733 of POLR2LP, and rs9263745 of CCHCR1) were significantly associated with allopurinol-induced cADRs compared to the tolerant controls (OR 73.2; 95% CI 24.2-266.8; P = 1.9 × 10- 24). The overall sensitivity, specificity, positive predictive value and negative predictive value of these combinations were 84%, 94%, 9%, and 100%, respectively. However, the variant alleles of these SNP combinations were detected in 89.5% (51/57) of the cases. Moreover, the HLA-B*58:01 allele was observed in 86.0% of patients with allopurinol-induced cADRs, but only in 4.0% of tolerant controls (OR: 137.2; 95% CI: 38.3-670.5 and p-value = 1.7 × 10- 27). CONCLUSIONS: Thus, this research confirms the association between the specific HLA-B*58:01 allele and all phenotypes of allopurinol-induced cADRs in Thais. Furthermore, there was found the combined four SNPs (rs3099844, rs9263726, rs9263733, and rs9263745) could be used as alternative novel biomarkers for predicting cADRs in patients taking allopurinol.

Unveiling the role of neutrophils in chronic spontaneous urticaria: Beyond mast cells.

Mast cells and eosinophils are considered pivotal contributors to the pathogenesis of chronic spontaneous urticaria (CSU). However, emerging evidence suggests that neutrophils also play a central role. Cutaneous mast cells and macrophages orchestrate the recruitment of neutrophils through the regulation and activation of diverse processes, including heightened local vascular permeability and chemokine release. Studies have demonstrated increased activation and elevated levels of neutrophil-related cytokines in CSU patients. Moreover, neutrophils have been proposed as antigen-presenting cells during the late-phase reaction of immunoglobulin E-mediated allergy and have been associated with the expression of calcitonin gene-related protein and vascular endothelial growth factor in CSU. Histopathological analysis of lesional skin in CSU patients revealed significantly higher eosinophil and neutrophil counts than unaffected skin. However, the extent of neutrophil infiltration in the skin does not appear to correlate with the number of neutrophils in peripheral blood. The utility of the neutrophil-lymphocyte ratio as a marker for disease activity or remission in CSU remains inconclusive. Neutrophil-targeted therapy may confer benefits for CSU patients who exhibit resistance to antihistamines. Omalizumab has demonstrated its ability to reduce neutrophil counts, the neutrophil-lymphocyte ratio, and the neutrophil-monocyte ratio in peripheral blood. While dapsone and colchicine are recommended as alternative treatment options for CSU, their evidential support from published studies remains limited. Inhibitors targeting interleukin-1 and neutrophil-related cytokines have been proposed as potential therapeutic interventions for patients exhibiting neutrophil predominance. Further research is warranted to gain deeper insights into the involvement of neutrophils in CSU and to explore potential therapeutic interventions.

Disease activity of patients with chronic urticaria receiving COVID-19 vaccines.

BACKGROUND: Cutaneous adverse events after receiving a COVID-19 vaccine were identified. The disease activity of urticaria after a COVID-19 vaccine has never been explored in chronic urticaria patients. OBJECTIVE: To evaluate disease activity of chronic urticaria after receiving a COVID-19 vaccine. METHODS: A prospective cross-sectional study was conducted in chronic urticaria patients aged 18 or above who visited Siriraj Hospital between July and September 2021, and received the first and second dose of COVID-19 vaccine. The status prior to vaccination, including disease activity, disease control and disease severity was assessed by a urticaria activity score over seven days, urticaria control test, and modified medication score. The disease activity after vaccination was recorded. RESULTS: A total of 130 patients with a mean age of 45.9 ± 14.7 were enrolled in this study. Adenoviral and inactivated vaccines were administered to 85 (65.4%) and 45 patients (34.6%), respectively. Exacerbation was reported in 20 cases (15.4%) after the first dose and 17 cases (13.1%) after the second dose. Nine patients (45%) reported exacerbation after both the first and second dose. The majority of patients only had wheal, while three patients reported wheal with angioedema. No anaphylaxis was reported. Factor predicting exacerbation was concurrent thyroid disease (aRR 2.78, p < 0.01). CONCLUSIONS: Approximately 15% of chronic urticaria patients reported exacerbation after receiving a COVID-19 vaccination. No serious events were observed. Chronic urticaria patients should be vaccinated against COVID-19 after a discussion of the risk of disease flare-up.

Adult female acne: Clinical characteristics and factors significantly associated with polycystic ovary syndrome.

BACKGROUND: Adult female acne (AFA) may be different from adolescent acne, and may be a sign of polycystic ovary syndrome (PCOS). The objective of the study was to investigate the clinical characteristics of AFA, and the factors significantly associated with PCOS in AFA. METHODS: AFA patients aged 25 years or older were enrolled. History taking and dermatologic examinations were performed by dermatologists. PCOS was diagnosed by gynaecologists. Perimenopausal acne (aged 45 years or older) and the Dermatology Life Quality Index (DLQI) were also evaluated. RESULTS: Among 208 patients, mean age was 31.8 ± 7.1 years and 47.1%, 26.9%, and 26% had persistent, late-onset, and recurrent acne, respectively. The common aggravating factors included pre-menstruation (72.6%) and stress (53.8%). Recurrent acne was significantly aggravated by cosmetic products. Higher body mass index (BMI) was positively correlated with acne severity. Acne lesions were predominately located on both cheeks (87.0%) and at the perioral area (81.7%). PCOS was identified in 48.1%. Younger age (≥25 to <33 years), premenstrual flare, and irregular menstruation, but not hirsutism or androgenetic alopecia, were associated with PCOS in univariate and multivariate analysis. Perimenopausal acne was identified in 6.7%. The total mean DLQI score was 8.0 ± 5.4 (range from 0 to 23). CONCLUSIONS: Persistent acne with moderate severity was common in AFA patients and higher BMI was associated with acne severity. PCOS should be screened in AFA patients with younger age, premenstrual flare, and irregular menstruation.

Factors Predicting the Response to Cyclosporin Treatment in Patients With Chronic Spontaneous Urticaria: A Systematic Review.

PURPOSE: This study aimed to systemically review literature relating to factors that could potentially predict a favorable response to cyclosporine A (CsA) treatment for chronic spontaneous urticaria (CSU). METHODS: A systematic literature review was done according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis recommendations. RESULTS: A total of 13 studies (404 patients with CSU and 200 healthy patients) were included. There were only 1 randomized controlled trial (RCT) and 12 non-RCTs. Our systematic review showed that positive autologous serum skin test results, positive baseline basophil histamine release assays, positive baseline basophil activation test responses, elevated baseline plasma D-dimer levels, elevated baseline serum interleukin (IL)-2, IL-5, and tumor necrosis factor-alpha (TNF-α) levels, and low baseline serum IgE levels might assist in predicting favorable CsA responses in CSU patients. Decreased plasma D-dimer levels; and decreased serum IL-2, IL-5, and TNF-α levels were reported to be correlated with clinical improvement after CsA treatment. CONCLUSIONS: Since most positive results were from non-RCT articles and some data were still inconsistent, this systematic review identified no reliable practical biomarker for predicting CsA treatment response in patients with CSU. There were no positive predictors with good consistency and mechanical plausibility.

Cutaneous toxicities of epidermal growth factor receptor inhibitors: A prospective study in 60 Asian patients.

BACKGROUND: Several prospective studies have been conducted in epidermal growth factor receptor (EGFR) inhibitor-related cutaneous reactions in Caucasian patients, but prospective studies in Asian populations are scarce. OBJECTIVE: To investigate the cutaneous side effects of EGFR inhibitors in Asian cancer patients and to assess tumor response to dermatologic manifestations. METHODS: Sixty patients with lung or colorectal cancer who were receiving EGFR inhibitors were prospectively followed for at least one year by oncologists and dermatologists. RESULTS: Of 60 patients (33 males, 27 females), 46 lung cancer patients received erlotinib (n=29) and gefitinib (n=17). Cetuximab was prescribed in 14 colorectal cancer patients. Fifty-eight patients (58/60, 96.7%) developed cutaneous reactions. The most common reactions were xerosis (82.8%), acne (79.3%), and skin desquamation (62.1%). Most reactions were mild and well-tolerated. Of 14 patients who had severe reactions, temporary treatment interruption was necessary in 3 patients and a decreasing dose was required in another 3 patients. There were no statistically significant differences in type, severity, or number of cutaneous reactions between responders (29/58) and non-responders (29/58) to EGFR inhibitors. At median follow-up time of 11.92±1.08 months, no patient died from cutaneous toxicities. Nine patients died from cancer and 11 patients lost to follow-up. CONCLUSION: In this Asian population, almost all patients (96.7%) developed cutaneous toxicities of EGFR inhibitors. Xerosis, acne, and desquamation were common in Asian cancer patients. Most reactions were mild and well tolerated. Due to limited number of patients, this study did not show significant associations between cutaneous toxicities and tumor response.

Analysis of HLA-B Allelic Variation and IFN-γ ELISpot Responses in Patients with Severe Cutaneous Adverse Reactions Associated with Drugs.

BACKGROUND: The prevention and confirmation of drug-induced severe cutaneous adverse reactions (SCARs) are difficult. OBJECTIVE: To determine the benefit of HLA-B allele prescreening and the measurement of drug-specific IFN-γ-releasing cells in the prevention and identification of the culprit drug in patients with SCARs. METHODS: A total of 160 patients with SCARs were recruited from 6 university hospitals in Thailand over a 3-year period. HLA-B alleles were genotypically analyzed. The frequencies of drug-specific IFN-γ-releasing cells in patients with SCARs were also measured. RESULTS: The drugs commonly responsible for SCARs were anticonvulsants, allopurinol, beta-lactams, antituberculosis agents, and sulfonamides. If culprit drugs had been withheld in patients carrying known HLA-B alleles at risk, it would have prevented 21.2% of SCAR cases, mainly allopurinol- and carbamazepine-related SCARs. Culprit drug-specific IFN-γ-releasing cells could be identified in 45.7% (53 of 116) of patients with SCARs caused by 5 major drug groups, particularly in patients diagnosed with drug reactions with eosinophilia and systemic symptoms (DRESS) (50.0%), followed by Stevens-Johnson syndrome/toxic epidermal necrolysis (46.0%), and acute generalized exanthematous pustulosis (31.3%). According to our study, high frequencies of drug-specific IFN-γ-releasing cells were significantly demonstrated in patients who suffered from DRESS phenotype, having anticonvulsants or the drugs belonging to the "probable" category based on the Naranjo algorithm scale, as the culprit drugs. CONCLUSIONS: HLA-B prescreening would succeed in preventing only a minority of SCAR victims. Drug-specific IFN-γ-releasing cells are detectable in almost half of patients. Better strategies are required for better SCAR prevention and culprit drug confirmation.

Immunologic Studies of Progesterone-Induced Neutrophilic Urticaria.

A 33-year-old woman presented with recurring pruritic, erythematous papules around the mouth and on the hands, of 1.5 years' duration. These flares typically began several days before her menstrual cycle and persisted for approximately 1 week. Physical examination revealed urticarial plaques on the neck. Due to the nature of the eruption, which corresponded with her menstrual cycle, a diagnosis of autoimmune progesterone urticaria was considered and workup pursued.

Clinicopathological Significance among Patients with In vivo Epidermal Nuclear Staining by Direct Immunofluorescence Study.

CONTEXT: In vivo epidermal nuclear staining (ENS) can be found in patients with autoimmune connective tissue diseases (CNTDs) and other diseases. AIMS: The aim of this study was to reveal the underlying diseases and direct immunofluorescence (DIF) characters of patients with in vivo ENS and association of in vivo ENS with circulating autoantibodies. SETTINGS AND DESIGN: A retrospective analysis was conducted involving skin biopsy specimens submitted for DIF study at the Dermatoimmunology Laboratory at Siriraj Hospital between 2002 and 2012. SUBJECTS AND METHODS: The findings of DIF study, clinical manifestations, and diagnosis of patients who had positive ENS were investigated. STATISTICAL ANALYSIS USED: The SPSS software version 18.0. Descriptive statistics were used to report demographic data, clinical characteristics, and laboratory investigation results. Moreover, Chi-squared test or Fisher's exact test were used to compare the categorical variables. RESULTS: One hundred and thirty-eight out of 3735 submitted specimens (3.7%) showed positive ENS. The most common diagnosis was CNTD (79%) followed by vasculitis (10.1%). Lupus erythematosus was the most common diagnosis among CNTD (78%). No association between levels of serum antinuclear antibodies (ANA) titer and intensity of ENS (P = 0.660). However, we found that patients with positive in vivo ANA had lower prevalence of systemic involvement. CONCLUSIONS: Although lupus erythematosus was the most common diagnosis among patients with in vivo ENS, the presence of ENS does not indicate any specific diagnosis. However, patients with ENS tend to have less systemic involvement.

Tinea capitis caused by Trichophyton tonsurans presenting as an obscure patchy hair loss due to daily antifungal shampoo use.

Tinea capitis is unusual and often misdiagnosed in healthy adults. We report a case of a healthy woman with a several-year history of asymptomatic, bizarre-shaped, non-scarring alopecia. She had used over-the-counter ketoconazole shampoo regularly for a long time. An initial potassium hydroxide preparation showed negative result for fungal organism. The scalp biopsy revealed endothrix infection, and dermoscopic examination demonstrated the comma hair and corkscrew hair signs. The fungal culture showed Trichophyton tonsurans. The daily use of antifungal shampoo could be the important factor to conceal clinical and laboratory findings for diagnosis of T. tonsurans tinea capitis in our case, which required high clinical suspicion and histopathology and dermoscopic examinations.

Human in vitro skin organ culture as a model system for evaluating DNA repair.

BACKGROUND: UV-exposures result in accumulation of genetic lesions that facilitate the development of skin cancer. Numerous pharmacologic agents are currently under development to both inhibit formation of DNA lesions and enhance repair. Drugs must be evaluated in vitro, currently performed in cell culture systems, before being tested on humans. Current systems do not account for the architecture and diverse cellularity of intact human skin. OBJECTIVE: To establish a novel, functionally viable, and reproducible in vitro skin organ culture system for studying the effects of various pharmacologic agents on DNA repair. METHODS: Human skin was obtained from neonatal foreskins. Intact skin punches derived from foreskins were cultured in vitro prior to exposure to UV-irradiation, and evaluated for DNA-damage using a DNA dot blot. Serial skin biopsies were obtained from patients with actinic keratoses treated with topical imiquimod. Expression of immune-stimulating and DNA repair genes was evaluated in ex vivo and in vitro samples. RESULTS: DNA dot blots revealed active repair of UV induced lesions in our in vitro skin organ culture. The photo-protective effect of sunscreen was detected, while imiquimod treatment did not enhance DNA repair in vitro. The DNA repair molecules XPA and XPF were up-regulated in the skin of imiquimod treated patients with actinic keratoses and imiquimod treated bone marrow-derived cell lines, but not keratinocytes. CONCLUSION: Our in vitro human skin organ culture model detected repair of UV-induced DNA lesions, and may be easily adapted to investigate various photo-protective drugs intended to prevent or treat skin cancer.

A case series of refractory cutaneous sarcoidosis successfully treated with infliximab.

INTRODUCTION: Sarcoidosis is a systemic granulomatous disease of unknown cause. The management of sarcoidosis remains problematic. Systemic and topical corticosteroids are the mainstay of therapy but may cause unacceptable side effects. Biologic therapies, such as infliximab, have recently been proposed as another treatment option for cutaneous sarcoidosis. CASE REPORT: The authors describe three patients who were diagnosed with cutaneous sarcoidosis with systemic involvement. All of the patients were refractory to conventional therapies but responded to infliximab therapy. CONCLUSION: Infliximab is an alternative medication for refractory sarcoidosis that has a relatively benign side-effect profile. However, definite indications, dosage, interval, and duration of treatment for cutaneous sarcoidosis are not firmly established.

Imiquimod-induced TLR7 signaling enhances repair of DNA damage induced by ultraviolet light in bone marrow-derived cells.

Imiquimod is a TLR7/8 agonist that has anticancer therapeutic efficacy in the treatment of precancerous skin lesions and certain nonmelanoma skin cancers. To test our hypothesis that imiquimod enhances DNA repair as a mechanism for its anticancer activity, the nucleotide excision repair genes were studied in bone marrow-derived cells. Imiquimod enhanced the expression of xeroderma pigmentosum (XP) A and other DNA repair genes (quantitative real-time PCR analysis) and resulted in an increased nuclear localization of the DNA repair enzyme XPA. This was dependent on MyD88, as bone marrow-derived cells from MyD88(-/-) mice did not increase XPA gene expression and did not enhance the survival of MyD88(-/-)-derived bone marrow-derived cells after UV B exposure as was observed in bone marrow-derived cells from MyD88(+/+) mice. Imiquimod also enhanced DNA repair of UV light (UVL)-irradiated gene expression constructs and accelerated the resolution of cyclobutane pyrimidine dimers after UVL exposures in P388 and XS52. Lastly, topical treatment of mouse skin with 5% imiquimod cream prior to UVL irradiation resulted in a decrease in the number of cyclobutane pyridimine dimer-positive APC that were found in local lymph nodes 24 h after UVL irradiation in both wild-type and IL-12 gene-targeted mice. In total, these data support the idea that TLR7 agonists such as imiquimod enhance DNA repair in bone marrow-derived cells. This property is likely to be an important mechanism for its anticancer effects because it protects cutaneous APC from the deleterious effects of UVL.

Prevalence and clinical features of Thai patients with bullous pemphigoid.

BACKGROUND: Bullous pemphigoid (BP) is a rare, subepidermal autoimmune blistering disease. Studies from different regions show discrepancies in clinical features and courses. OBJECTIVES: To reveal clinical characteristics, investigations and clinical outcomes of Thai patients with BP and to evaluate the association of BP with malignancy, diabetes mellitus and neurologic diseases. METHODS: Patients diagnosed as BP who had visited the autoimmune skin clinic at Siriraj Hospital between 1991 and 2009 were retrospectively studied. RESULTS: Fifty-eight patients were enrolled. Mean age of onset was 69.3 years. The female to male ratio was 2.7:1. Fifteen percent of the patients had mucosal involvement and 38.9% showed peripheral blood eosinophilia. The sensitivity of the direct and indirect immunofluorescence test in the diagnosis of BP was 95.7% and 73.5%, respectively. The frequency of diabetes mellitus in BP patients was significantly higher than that in the general population (p < 0.001). BP patients had a significantly higher chance of having neurologic diseases compared with other autoimmune vesiculobullous disease patients (adjusted odd ratios 4, 95% confidence interval 1.2-13.3). Disease control was achieved in 89.7% of the patients. One-year and three-year 6.4% remission rate was and 66.3%, respectively. CONCLUSIONS: BP usually occurred in the seventh and eighth decade of life and affected females more than males. BP is associated with diabetes mellitus and neurologic diseases. Corticosteroids are the mainstay of the treatment. Two-thirds of patients are likely to be in remission within three years.

Diagnostic significance of colloid body deposition in direct immunofluorescence.

BACKGROUND: Colloid bodies (CB) in direct immunofluorescence (DIF) studies are usually found in interface dermatitis. Furthermore, CB can be found in various skin diseases and even in normal skin. AIM: To evaluate the diagnostic value of CB deposits in DIF studies. METHODS: From 1996-2007, data from 502 patients where DIF studies showed immunoreactants at CB were enrolled. The definite diagnoses of these patients were based on clinical, histopathological and immunofluorescent findings. The results of DIF studies were analyzed. RESULTS: Immunoreactants at CB were detected in 44.4%, 43.8%, 4.2%, 3.8%, and 2.2% of interface dermatitis, vasculitis, autoimmune vesiculobullous disease, panniculitis, and scleroderma/morphea, respectively. The most common immunoreactant deposit of all diseases was Immunoglobulin M (IgM). Brighter intensity and higher quantity of CB was detected frequently in the group with interface dermatitis. CONCLUSIONS: Immunoreactant deposits at CB alone can be found in various diseases but a strong intensity and high quantity favor the diagnosis of interface dermatitis. CB plus dermoepidermal junction (DEJ) deposits are more common in interface dermatitis than any other disease. Between lichen planus (LP) and discoid lupus erythematosus (DLE), CB alone is more common in LP; whereas, CB plus DEJ and superficial blood vessel (SBV) is more common in DLE. The most common pattern in both diseases is CB plus DEJ. The quantity and intensity of CB in LP is higher than in DLE.