Showing papers in "Journal of Dermatology in 2021"

Vitiligo: A focus on pathogenesis and its therapeutic implications

Abstract: Vitiligo is the most common depigmenting disorder affecting 0.1%-2% of the population worldwide. The characteristic white patches result from the selective loss of melanocytes. Sustained recent efforts have resulted in a detailed understanding of the genetic architecture of vitiligo. About 80% of vitiligo risk is attributable to genetic factors; and the rest (20%) is attributable to the environment. Over the past decade, substantial progress has been made in our understanding of the pathogenesis of vitiligo which is now clearly classified as an autoimmune disease. Melanocytes from patients with vitiligo are more susceptible to oxidative stress which begets the release of exosomes and inflammatory cytokines that will lead to activation of the innate immune response and subsequently to adaptive immune response through activation of autoreactive cytotoxic CD8+ T cells. These produce interferon-γ (IFN-γ) which promotes disease progression through IFN-γ-induced chemokine secretion from surrounding keratinocytes to further recruit T cells to the skin through a positive feedback loop. CD8 tissue-resident memory T cells are in turn responsible for long-term maintenance and potential relapse of vitiligo in human patients through cytokine-mediated recruitment of T cells from the circulation. This review summarizes the current knowledge on vitiligo and attempt to give an overview of the future in vitiligo treatment.

Basics and recent advances in the pathophysiology of atopic dermatitis.

Abstract: Atopic dermatitis is a common, chronic inflammatory skin disease that is characterized by skin barrier dysfunction, inflammation and intense itch. Although the exact mechanisms behind its pathogenesis remain unclear, it is evident that the complex interplay among barrier dysfunction, inflammation and itch are critical in its development, progression and chronicity. Abnormalities in filaggrin, intercellular lipids and tight junctions induce barrier-disrupted skin, which produces thymic stromal lymphopoietin, interleukin (IL)-25 and IL-33; these in turn promote skin inflammation characterized by type 2 immune deviation. This inflammation then downregulates the expression of filaggrin in keratinocytes and exacerbates epidermal barrier dysfunction. Furthermore, various itch mediators/pruritogens produced during this inflammatory process can act directly on sensory nerves and cause itch. In this review, we summarize the basics and recent advances in our understanding of the pathophysiology of atopic dermatitis focusing on three aspects: barrier dysfunction, skin inflammation and itch.

Pathophysiology of psoriasis: A review

Abstract: Psoriasis is a complex chronic inflammatory skin disease caused by the dynamic interplay between multiple genetic risk foci, environmental risk factors, and excessive immunological abnormalities. Psoriasis affects approximately 2% of the population worldwide, and dramatic advances have been achieved in the understanding and treatment options for psoriasis. Recent progress in biological therapies has revealed the fundamental roles of tumor necrosis factor-α, interleukin (IL)-23p19, and the IL-17A axis together with skin-resident immune cells and major signal transduction pathways in the pathogenesis of psoriasis. In addition to IL-17-producing T helper17 cells, innate lymphoid cell (ILC)3 induces psoriasis rashes directly without T-cell/antigen interaction in response to the released antimicrobial peptides from activated keratinocytes and inflammatory cytokines. ILC3 typically expresses retinoic acid receptor-related orphan receptor gamma t in the nucleus, matures in the presence of IL-7 and IL-23, and produces IL-17 and IL-22. The number of ILC3s is increased in the blood, psoriasis rash, and even in nonrash areas of psoriatic skin. Psoriasis is significantly associated with cardiovascular disease, metabolic syndrome, and inflammatory disorders, particularly the severe type. The similarity of enterobacteria in the psoriasis gut to that in diabetic patients may be related to its pathogenesis. In the current review, we focus on the pathophysiology of psoriasis in the accelerated immunological inflammatory loop, danger signal from keratinocytes, and cytokines, particularly IL-17 and IL-23p19. In addition, pathophysiological speculation with regard to morphology has been supplemented. Finally, the differences and similarities between psoriasis and atopic dermatitis are discussed.

Development of a light-weight deep learning model for cloud applications and remote diagnosis of skin cancers

Abstract: Skin cancer is among the 10 most common cancers. Recent research revealed the superiority of artificial intelligence (AI) over dermatologists to diagnose skin cancer from predesignated and cropped images. However, there remain several uncertainties for AI in diagnosing skin cancers, including lack of testing for consistency, lack of pathological proof or ambiguous comparisons. Hence, to develop a reliable, feasible and user-friendly platform to facilitate the automatic diagnostic algorithm is important. The aim of this study was to build a light-weight skin cancer classification model based on deep learning methods for aiding first-line medical care. The developed model can be deployed on cloud platforms as well as mobile devices for remote diagnostic applications. We reviewed the medical records and clinical images of patients who received a histological diagnosis of basal cell carcinoma, squamous cell carcinoma, melanoma, seborrheic keratosis and melanocytic nevus in 2006-2017 in the Department of Dermatology in Kaohsiung Chang Gung Memorial Hospital (KCGMH). We used the deep learning models to identify skin cancers and benign skin tumors in the manner of binary classification and multi-class classification in the KCGMH and HAM10000 datasets to construct a skin cancer classification model. The accuracy reached 89.5% for the binary classifications (benign vs malignant) in the KCGMH dataset; the accuracy was 85.8% in the HAM10000 dataset in seven-class classification and 72.1% in the KCGMH dataset in five-class classification. Our results demonstrate that our skin cancer classification model based on deep learning methods is a highly promising aid for the clinical diagnosis and early identification of skin cancers and benign tumors.

Psoriasis: Recent progress in molecular‐targeted therapies

Abstract: Psoriasis is a multifactorial recalcitrant inflammatory skin disease characterized by bothersome scaly reddish plaques especially on frequently chafed body parts, such as the extensor sites of the extremities and scalp. Nonetheless, through recent advance in molecular-targeted therapies including biologics and small-molecule inhibitors, even the severest symptoms of psoriasis and its comorbidities, such as psoriatic arthritis, can be excellently treated. The superb clinical effects lead to not only remarkable alleviation of symptoms but also a deep understanding of patients' impaired "quality of life" caused by this disease. Along with the development of novel treatment options targeting various specific molecules, such as proinflammatory cytokines and signal transduction-associated molecules, clinicians have thoroughly understood the molecular mechanism of psoriasis, and discovered that the IL-23/IL-17 axis mainly depending on Th17 cell function is a crucial pathogenesis of this disease. Accumulation of knowledge about the working mechanism and clinical effect of molecular-targeted therapies is indispensable for clinicians to establish a more refined therapeutic strategy for treating psoriasis.

Patient characteristics and burden of disease in Japanese patients with generalized pustular psoriasis: Results from the Medical Data Vision claims database.

Abstract: Generalized pustular psoriasis (GPP) is a rare and severe systemic, neutrophilic skin disease. To date, accurate clinical profiling of patients with GPP remains poorly understood. In this study, we present the characteristics and estimate the burden of disease in patients with GPP compared with those with plaque psoriasis, in Japan. This retrospective study was conducted using the Medical Data Vision database between January 1, 2015, and December 31, 2019. Patients with at least one confirmed inpatient or outpatient diagnostic code for GPP (L40.1) or psoriasis vulgaris (L40.0) were included for analysis. The main outcome measures included comparisons of the prevalence of comorbidities, medication use, and healthcare resource utilization between patients with GPP, patients with plaque psoriasis, and a general population-matched cohort. In total, 718 patients with GPP and 27,773 patients with plaque psoriasis were identified. Patients with GPP were more likely to be female than those with plaque psoriasis (51.6% vs. 38.7%). During the 12-month follow-up period, patients with GPP were more likely to experience comorbidities than those with plaque psoriasis, including psoriatic arthritis, other forms of psoriasis, osteoporosis, interstitial pneumonia, and peptic ulcer disease. Medication use also differed between those with GPP and those with plaque psoriasis: patients with GPP were more likely to be prescribed antibiotics and psychiatric medication. Patients with GPP were also more likely to require more healthcare resource utilization with longer hospitalizations than those with plaque psoriasis. Overall, in Japan, patients with GPP have a higher burden of illness than those with plaque psoriasis.

Alopecia areata: Current understanding of the pathophysiology and update on therapeutic approaches, featuring the Japanese Dermatological Association guidelines

Abstract: Alopecia areata (AA) is a relatively common nonscarring hairloss disease characterized by an autoimmune response to anagen hair follicles (HFs). Accumulated evidence suggests that collapse of the HF immune privilege subsequent to triggering events, represented by viral infection, leads to autoimmune response in which autoreactive cytotoxic CD8+NKG2D+ T cells mainly target exposed HF autoantigens. AA had been recognized as type 1 inflammatory disease, but recent investigations have suggested some roles of type 2- and Th17-associated mediators in AA pathogenesis. The significance of psychological stress in AA pathogenesis is less emphasized nowadays, but psychological comorbidities, such as depression and anxiety, attract greater interest in AA management. In this regard, the disease severity may not solely be evaluated by the extent of hair loss. Use of trichoscopy markedly improved the resolution of the diagnosis and evaluation of the phase of AA, which is indispensable for the optimization of treatment. For the standardization of AA management, the establishment of guidelines/expert consensus is pivotal. Indeed, the Japanese Dermatological Association (JDA) and other societies and expert groups have published guidelines/expert consensus reports, which mostly recommend intralesional/topical corticosteroid administration and contact immunotherapy as first-line treatments, depending on the age, disease severity, and activity of AA. The uniqueness of the JDA guidelines can be found in their descriptions of intravenous corticosteroid pulse therapy, antihistamines, and other miscellaneous domestically conducted treatments. Considering the relatively high incidence of spontaneous regression in mild AA and its intractability in severe subsets, the importance of course observation is also noted. Evidenced-based medicine for AA is currently limited, however, novel therapeutic approaches, represented by JAK inhibitors, are on their way for clinical application. In this review, the latest understanding of the etiopathogenesis and pathophysiology, and update on therapeutic approaches with future perspectives are summarized for AA, following the current version of the JDA AA management guidelines.

Epidemiological study of terbinafine-resistant dermatophytes isolated from Japanese patients.

Abstract: Terbinafine (TRF) has been used in the treatment of fungal infections for more than 20 years. Recently, TRF-resistant Trichophyton interdigitale and T. rubrum strains have been isolated from human patients worldwide. However, an epidemiological study of TRF-resistant strains in Japanese patients has not been investigated. In the present study, antifungal susceptibility testing was performed on clinical isolates from Japanese patients to assess TRF-resistance patterns of T. interdigitale and T. rubrum strains. We also sequenced the squalene epoxidase (SQLE) encoding gene of TRF-resistant T. rubrum strains. Two hundred and ten T. interdigitale and T. rubrum clinical isolates were obtained from 210 human cases of tinea pedis, tinea corporis, tinea unguium, tinea cruris, tinea manuum, tinea faciei and tinea capitis in Tokyo, Saitama, Chiba, Hyogo and Kumamoto, Japan, in 2020. Five T. rubrum isolates (N74, N79, N99, H30 and K2) grew on Sabouraud's dextrose agar (SDA) containing 1 mg/L of TRF. All five strains exhibited TRF minimum inhibitory concentrations (MICs) ≥32 mg/L but remained susceptible to azoles. We determined SQLE sequences in these TRF-resistant T. rubrum strains and found that all strains harbored missense mutations (L393F) in the SQLE-encoding gene.

Clinical characteristics and health-care resource utilization in patients with generalized pustular psoriasis using real-world evidence from the Japanese Medical Data Center database.

Abstract: Little is known about the disease burden, health-care resource utilization (HCRU), or treatment of patients with generalized pustular psoriasis (GPP) in Japan. This retrospective cohort study used data from the Japanese Medical Data Center database to compare the demographics, comorbidities, and medication use of patients with GPP and plaque psoriasis and estimate their all-cause HCRU. The patient selection period was from January 1, 2015 to December 31, 2019, and patients must have had at least one confirmed inpatient claim or outpatient claim for GPP or plaque psoriasis. During the 12-month follow-up period, 110 patients with GPP and 20,254 patients with plaque psoriasis were identified. An age- and sex-matched (4:1) comparator control cohort, including members of the general population without a diagnosis of psoriasis (but allowing for a diagnosis of psoriatic arthritis), GPP, or palmoplantar pustulosis, was used. The most prevalent comorbidities in patients with GPP included allergic rhinoconjunctivitis, hypertension, and peptic ulcer disease. Patients with GPP were more likely to experience more comorbidities than those with plaque psoriasis, including asthma, chronic obstructive pulmonary disease, interstitial pneumonia, hyperuricemia and gout, tonsillitis, psoriatic arthritis, other psoriasis, and osteoporosis. Patients with GPP were more likely to be treated with a combination therapy than those with plaque psoriasis (65.5% vs 21.7%, respectively) and less likely to be treated with a topical medication alone (20.9% vs 50.8%). Patients with GPP had more outpatient visits than patients in the plaque psoriasis or matched control cohorts (mean [standard deviation], 14.8 [8.3] vs 11.0 [7.6] and 7.8 [7.2], respectively). They were also more likely to require inpatient hospitalization (24.5% vs 6.4% and 5.0%, respectively). Despite study limitations, patients with GPP in Japan were found to have a higher disease burden, including presence of comorbidities and medication use, than those with plaque psoriasis.

Real-world effectiveness of guselkumab in patients with psoriasis: Health-related quality of life and efficacy data from the noninterventional, prospective, German multicenter PERSIST trial.

Abstract: Psoriasis is a common, chronic inflammatory skin disorder negatively impacting health-related quality of life (HRQoL). Guselkumab, targeting interleukin-23 (IL-23), is an approved biologic therapy for psoriasis. PERSIST is an ongoing prospective, noninterventional, long-term, German multicenter study evaluating the effect of guselkumab on HRQoL, and its efficacy and safety in patients with moderate-to-severe psoriasis in a real-world setting. The primary endpoint is the proportion of patients with a Dermatology Life Quality Index (DLQI) score ≤ 1 at week 28. Of 303 patients enrolled and treated with guselkumab, mean age and disease duration were 49.7 and 21.0 years, respectively, and 51.2% (n = 155) of patients had received ≥1 prior biologic therapy. Mean baseline DLQI score was 13.7, and mean symptom and sign scores in the Psoriasis Symptoms and Signs Diary (PSSD) were 51.9 and 60.8, respectively. Baseline Psoriasis Area Severity Index (PASI) and body surface area (%) scores were 16.4 and 27.5. Following 28 weeks of guselkumab treatment, the mean DLQI score decreased to 2.8, and 56.8% of patients (n = 150) achieved DLQI ≤ 1. Mean PSSD symptom and sign scores also improved, decreasing to 12.5 and 15.9, respectively. At week 28, PASI 90 response was 55.3%; significant improvement was observed in patients with psoriasis in difficult-to-treat areas. Overall, analyses demonstrated that guselkumab was effective in the real-world setting, as measured by HRQoL and skin improvements, even in patients with a high burden of disease and those who have received multiple biologic therapies. No new safety signals were observed.

Clinical characteristics of Japanese pustular psoriasis: A multicenter observational study.

Abstract: Generalized pustular psoriasis (GPP) is a rare and severe subtype of psoriasis. Because of its rarity, GPP studies with a large sample size have been scarce. We studied the characteristics of GPP and pustular psoriasis using data from the West Japan Psoriasis Registry that had been registered until the end of December 2020. The dataset included 104 patients with pustular psoriasis and 1290 patients with other subtypes of psoriasis. Multivariate analysis revealed a significantly greater number of female patients, a significantly lower mean body mass index, and a significantly lower ratio of habitual drinkers in pustular psoriasis, compared to other subtypes of psoriasis. Of the 104 patients, 102 had GPP, including 88 von Zumbusch, 10 juvenile-onset, and four annular pustular psoriasis. Although the male : female ratio of GPP with psoriasis vulgaris (GPP+PsV) (47/20) was similar to that of psoriasis in Japan, the GPP without PsV (GPP-PsV) group highlighted a female predominance (13/22). The mean age at GPP onset was 45.3 years, and the mean interval from PsV onset to GPP onset was 12.5 years. Four of nine patients with GPP had an IL36RN gene mutation. Infection, medicine, and pregnancy were the precipitating factors for GPP. A family history of psoriasis was present in eight (7.8%) patients with GPP. Twenty-four patients with GPP had psoriatic arthritis. Biologics were used in 76.5% of patients with GPP, followed by etretinate (37.3%), cyclosporine (24.5%), methotrexate (13.7%), apremilast (8.8%), and granulocyte and monocyte adsorption apheresis (6.9%). Etretinate was used in 17 (51.5%) of 33 patients with GPP with less than 10-year history. Thus, etretinate remains a good treatment option for GPP even in the era of biologics. Hypertension was the most commonly identified comorbidity, followed by diabetes. We believe that the characteristics revealed in this study can further contribute to effective GPP management.

Epidemiological survey of the psoriasis patients in the Japanese Society for Psoriasis Research from 2013 to 2018.

Abstract: In Japan, the Japanese Society for Psoriasis Research (JSPR) has been conducting annual epidemiological surveys of patients with psoriasis since 1982 The aim of this study was to conduct a recent epidemiological analysis of the psoriasis patients who were enrolled in the JSPR from 2013 to 2018 A total of 15 287 cases were enrolled from 132 medical institutions, out of which 653% (9989 cases) were male and 347% (5298 cases) were female Approximately 500% of the cases had past history and comorbidities, such as hypertension (420%), dyslipidemia (300%), diabetes mellitus (237%), hyperuricemia (151%), cardiovascular disease (60%), and cerebral vascular disorders (60%) There was a yearly increase in the use of corticosteroid/vitamin D3 combinations and apremilast for treating psoriasis In contrast, the use of phototherapy gradually decreased From 2013 to 2018, approximately 186% of the cases were treated with biologics, such as infliximab (176%), adalimumab (233%), ustekinumab (214%), secukinumab (116%), ixekizumab (76%), brodalumab (63%), and guselkumab (43%) In the past decade, the biologics have changed the treatment and management of psoriasis This survey includes significant information regarding the recent perspective of psoriasis in the Japanese Society, especially focusing on the treatment trends after the introduction of biologics

Coronavirus disease 2019-associated immunoglobulin A vasculitis/Henoch-Schönlein purpura: A case report and review.

Abstract: Immunoglobulin A (IgA) vasculitis or Henoch-Schonlein purpura is a predominantly pediatric disease occurring after a triggering viral or bacterial infection. Conversely, drug exposure is the most common inciting event in adult cases of IgA vasculitis. Recently, data has suggested a temporal association between coronavirus disease 2019 (COVID-19) and the development of IgA vasculitis in children and adults. Here, we describe a case of IgA vasculitis with nephritis in a 70-year-old man with COVID-19 and perform a comprehensive review of eight reported cases of suspected COVID-19-associated IgA vasculitis. When compared to classical IgA vasculitis, COVID-19-associated IgA vasculitis exclusively affects males (p < 0.00002) and is more common in adults (p < 0.005). Among cases of COVID-19-associated IgA vasculitis, adult cases were associated with significantly more arthralgia than pediatric cases (p = 0.04). In cases where skin biopsy was obtained, direct immunofluorescence (DIF) was negative for IgA in 50% of cases; thereafter, kidney biopsy DIF was positive for IgA in all cases. With this study, we provide support for an association between IgA vasculitis and severe acute respiratory syndrome coronavirus 2 infection and provide clinical information differentiating its manifestations from classical IgA vasculitis.

Skin microbiome in acral melanoma: Corynebacterium is associated with advanced melanoma.

Abstract: Dear Editor, The gut microbiome has attracted significant attention as a disease modifier of melanoma. A recent study has shown that the microbial diversity in the skin microbiome was lower in patients with melanoma than in patients with nevi. However, no study has reported the association, if any, between the skin microbiome and clinical findings in melanoma. Therefore, we investigated the clinical significance of the skin microbiome in patients with acral melanoma. This study was performed in accordance with the Declaration of Helsinki principles and was approved by the institutional review board of Kumamoto University Hospital. Written informed consent was obtained from all patients included in this study. We retrospectively investigated 27 patients with acral melanoma who presented to Kumamoto University Hospital between April 2013 and April 2020. Cancer staging was performed based on the 8th edition of the American Joint Committee on Cancer/Union for International Cancer Control melanoma staging system. Immunohistochemistry was performed using a primary antibody against interleukin (IL)-17 (Abcam, Cambridge, UK) as described previously. Before initiation of surgical treatment, we performed microbiome analysis based on bacterial culture studies using swab sampling. All statistical analyses were performed using Fisher’s exact test or the Mann–Whitney U-test; we used GraphPad Prism version 7.0 software (GraphPad Software, La Jolla, CA, USA) in this study. P < 0.05 was considered statistically significant. We investigated the association between bacterial culture results and melanoma staging (Tables 1, Fig. S1). With regard to the genus, only Corynebacterium was significantly associated with melanoma in patients with stage III/IV (76.9%) disease compared with those with stage I/II (28.6%) lesions. Corynebacterium was either the most or the second most detected genus among the stage III/IV melanoma patients. With regard to the species, we observed no association between cutaneous bacterial flora and melanoma staging. Also, detection of Corynebacterium was significantly increased in patients with T3/T4 melanoma compared with T1/T2 melanoma. In addition, more IL-17-positive cells were detected in Corynebacterium-positive patients compared with Corynebacterium-negative patients. There was no significant difference

Similarity and difference between palmoplantar pustulosis and pustular psoriasis.

Abstract: Palmoplantar pustulosis is a chronic inflammatory disorder characterized by sterile pustules predominantly involving the palms and soles. Palmoplantar pustulosis has many similar aspects to psoriasis, either plaque and pustular type, namely familial occurrence between palmoplantar pustulosis and psoriasis, the appearance of the Kobner phenomenon, joint involvement, and nail involvement. Pustular psoriasis is classified into generalized and localized types, and there are a number of papers regarding palmoplantar pustulosis as an acral variant of localized pustular psoriasis. Many Japanese dermatologists consider palmoplantar pustulosis to be a distinct entity from pustular psoriasis, and the coexistence of palmoplantar pustulosis and psoriasis is rare. However, outside Japan, palmoplantar pustulosis is often considered to be palmoplantar psoriasis or palmoplantar pustular psoriasis, and extra-palmoplantar lesions are also considered to be psoriasis. The purpose of the current review is to compare the similarities and differences between palmoplantar pustulosis and generalized/localized pustular psoriasis. Japanese patients with palmoplantar pustulosis have a close relationship with focal infection, and the associated bone-joint manifestation exclusively involves the anterior chest wall. Furthermore, pediatric occurrence of palmoplantar pustulosis is extremely rare, and difference of genetic background between palmoplantar pustulosis and psoriasis has also been reported. Treatment of focal infection often results in dramatic effects on both cutaneous lesions and joint pain of palmoplantar pustulosis. Those findings suggest that palmoplantar pustulosis should be separately considered from either palmoplantar psoriasis or palmoplantar pustular psoriasis. The clinicopathological features and therapeutic approach of both diseases are discussed.

Clinical analysis of generalized pustular psoriasis in Chinese patients: A retrospective study of 110 patients.

Abstract: Generalized pustular psoriasis is an immune-mediated dermatologic condition characterized by widespread, sterile, subcorneal pustules. However, limited information exists regarding the clinical course of generalized pustular psoriasis. This study aimed to examine the precipitating factors, clinical manifestations, laboratory data, relapse patterns, and prognosis of generalized pustular psoriasis at our hospital and to improve the diagnosis and treatment. A retrospective analysis was conducted for generalized pustular psoriasis in our department from 2014 to 2019. In total, 110 patients were included in our study (mean age 46.5 years). The female:male ratio was 1:2.7. Ninety-four (85.5%) had a psoriasis vulgaris history, 12 (10.9%) had a psoriatic arthritis history, five (4.5%) had an erythrodermic psoriasis history, and 16 (14.5%) had a family history of psoriasis. Eleven (10.0%) cases were triggered by infections and 17 (15.5%) were caused by the sudden discontinuation of systemic drugs. During hospitalization, the proportion of patients with hyperlipidemia was higher after acitretin treatment than before acitretin treatment (P 0.05). The onset age of generalized pustular psoriasis was younger in patients without prior psoriasis (P 0.05). Moreover, among patients with fever, skin lesion clearance rates were highest in the biological agent group (81.8%). However, among patients without fever, skin lesion clearance rates were highest in the acitretin group (86.7%). No patients presented serious complications or died. Our study presents the detailed clinical course of generalized pustular psoriasis in Chinese patients. These results will help to better understand and treat generalized pustular psoriasis.

Safety and effectiveness of secukinumab in psoriasis vulgaris and psoriatic arthritis: Real-world evidence in Japan.

Abstract: Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin-17A, has been available for the treatment of moderate to severe psoriasis and psoriatic arthritis since February 2015 in Japan. Because there was a time gap after the previous approval of biologics for psoriatic disease indication, it was suggested that patients to be treated with secukinumab at its launch might have refractory disease symptoms. In order to assess the safety and effectiveness of secukinumab in those patients, a 52-week, open-label, multicenter, observational cohort study was conducted. In total, 306 and 250 patients were included in the safety and effectiveness analysis sets, respectively. Over half of patients had previously received biologics (56.9%). Adverse events, serious adverse events and adverse reactions were reported in 41.2%, 7.2% and 24.2% of patients, respectively. The most commonly reported adverse reactions were oral candidiasis (2.9%), consistent with those reported in clinical studies. In addition, none of the patient characteristics assessed for the effect on safety of secukinumab increased the occurrence of adverse reactions. Psoriasis Area and Severity Index score (mean ± standard deviation) improved from baseline (14.7 ± 12.3) to week 12 (1.78 ± 3.3), which was maintained up to week 24 (1.59 ± 3.0). The proportion of patients with a Dermatology Life Quality Index score of 0/1 improved from baseline (2.2%) to week 12 (64.7%) and sustained up to week 24 (71.4%). In addition to the skin symptoms, improvement was observed in all psoriatic arthritis disease-related assessments. The current study reaffirmed the safety and effectiveness of secukinumab with broader patients than those in the clinical studies.

Treatment options for DOCK8 deficiency-related severe dermatitis.

Abstract: Background Cutaneous manifestations of dedicator of cytokinesis 8 gene (DOCK8) deficiency, a combined type of T and B cell immunodeficiency, previously designated as autosomal recessive hyper IgE syndrome, includes dermatitis and skin infections. There are limited treatment options for dermatitis related to the syndrome. Objective To describe a cohort of patients with DOCK8 deficiency with a focus on the treatment of their cutaneous manifestations. Methods A retrospective study on all children with the genetic diagnosis of DOCK8 deficiency treated at the Sheba Medical Center between 1/1/2003 and 1/1/2021 was preformed. Collected data included: demographic features, family history, laboratory, genetic testing, skin manifestations, treatment, and disease course. Description of two cases of severe recalcitrant dermatitis treated with dupilumab is detailed. Results Nine children with a genetic diagnosis of DOCK8 deficiency were included, of whom six were girls (66%) with a median age of 8.5 (±2.2 SD) years. The median age at diagnosis was 2.8 (±2.6 SD) years. Six patients were born to consanguineous parents. Five out of six patients who received hematopoietic stem cell transplantation (HSCT) had a complete response, and one was recently transplanted. Of note, two patients, while awaiting HSCT, were treated with dupilumab for their severe dermatitis resulting in a marked improvement of the cutaneous manifestations and pruritus. Conclusions Hematopoietic stem cell transplantation is the gold standard and most effective therapy for patients with DOCK8 deficiency. Dupilumab, a biological therapy indicated for atopic dermatitis and other Th2 derived dermatoses, is an excellent option for dermatitis in patients with DOCK8 deficiency and can be used as a bridge before HSCT. Larger studies are needed to confirm this observation.

Diversity analysis of gut microbiota between healthy controls and those with atopic dermatitis in a Chinese population

Abstract: An increasing body of evidence suggests that gut microbiota is involved in atopic dermatitis (AD). We aimed to use high-throughput sequencing to characterize the differences in the composition of the gut microbiota between healthy controls and patients with AD. Fecal samples from 93 volunteers were analyzed using 16S rRNA sequencing, including 44 patients with AD and 49 healthy control subjects, aged 6-22 years. Our data show that the operational taxonomic unit composition in patients with AD had greater component similarity than the healthy controls. Patients with AD had a lower alpha diversity than healthy control subjects. The relative abundance of Porphyromonadaceae, Blautia, Parabacteroides, Bacteroides ovatus, Bacteroides uniformis and Prevotella stercorea was significantly higher (P < 0.05) in patients with AD than healthy control subjects. Clostridium and P. stercorea were higher (P < 0.05) in healthy control subjects compared with patients with AD. The results of linear discriminant analysis effect size show that Bacteroidaceae and Porphyromonadaceae can act as possible biomarkers associated with diagnosis of AD. However, this needs further experimental verification. Taken together, these results demonstrate the changes in microbiota composition in AD compared with a healthy control group, opening the way to future diagnosis or intervention studies.

Role of necroptosis in infection-related, immune-mediated, and autoimmune skin diseases.

Abstract: Regulated necrosis, also termed necroptosis, is another programmed cell death depending on a unique molecular pathway that does not overlap with apoptosis. Tumor necrosis factor and Toll-like receptor family members, interferon, and other mediators are the factors that mainly cause necroptosis. Activating necroptosis by ligands of death receptors requires the kinase activity of receptor-interacting proteins 1 and 3, and a mixed lineage kinase domain-like protein, which is a critical downstream mediator of necroptosis. Increasing evidence has revealed that necroptosis does not only involve physiological regulation but also the occurrence, development, and prognosis of certain diseases, such as septicemia, neurodegenerative diseases, and ischemic-reperfusion injury. Many excellent documented systematic discussions of necroptosis and its role in various skin diseases. In this review, we summarize the molecular mechanism of necroptosis, as well as the current knowledge on the contribution of necroptosis, in infection-related, immune-mediated, autoimmune skin diseases, and malignant skin tumors.

Early add-on administration of mepolizumab and intravenous immunoglobulin effective in treating eosinophilic granulomatosis with polyangiitis.

Abstract: Treatment of eosinophilic granulomatosis with polyangiitis (EGPA) remains a challenge because currently available therapies, corticosteroids and immunomodulators, do not always control symptoms and are often associated with significant morbidity and relapse. Mepolizumab has been demonstrated to be an effective add-on therapy with steroid-sparing effect in cases of relapsing or refractory EGPA. Intravenous immunoglobulin (IVIG) therapy is effective against mononeuritis multiplex or heart failure in patients with EGPA who do not respond to corticosteroid-cyclophosphamide treatment. We present two cases of EGPA in which earlier add-on administration of adjunct mepolizumab and IVIG led to significant improvement in EGPA symptoms and prevention of flare-up of the disease. We suggested that earlier add-on combination administration of IVIG and mepolizumab might be a useful adjunct treatment to induce clinical remission of EGPA and improve the rate of remission, decrease relapse rate, and allow for reduced glucocorticoid use without any serious adverse drug effects.

Safety considerations of systemic Janus kinase inhibitors in atopic dermatitis applications.

Abstract: Janus kinase (JAK) inhibitors are emerging treatments for atopic dermatitis (AD). Due to this novel role as a therapeutic option for patients with AD, we aimed to review current evidence on the pathophysiology and the safety and adverse effects (AEs) of oral JAK inhibitors for the treatment of AD utilizing the key terms atopic dermatitis, JAK inhibitors, and adverse effect or event. Our study indicated that oral JAK inhibitors have a moderate safety profile for use in AD in several reviews and phase II or III clinical trials. Headaches, nausea, and nasopharyngitis are the most commonly reported systemic AEs. Furthermore, acne, herpes simplex, herpes zoster, and eczema herpeticum are the most commonly recorded dermatological AEs. Current evidence indicates JAK inhibitors may also have less association with some of the serious AEs, although there is potential for increased risk of asthma, acute pancreatitis, neutropenia, and thrombocytopenia. Whereas data remain limited for the long-term safety of JAK inhibitor use in patients with AD, many ongoing clinical trials have promising preliminary results.

Lichen planus‐like lesion preceding bullous pemphigoid development after programmed cell death protein‐1 inhibitor treatment

Abstract: Immune checkpoint inhibitors including programmed cell death protein 1 (PD-1) antibody are used in major breakthrough therapies in cancer, however they cause unique adverse events, termed immune-related adverse events (irAEs). Among the various dermatological irAEs, an autoimmune bullous disease, bullous pemphigoid (BP), the hallmarks of which are circulating autoantibodies to epidermal basement membrane zone (BMZ) including BP180, have been noted. However, the mechanism and timing of autoantibody production in PD-1 inhibition remains unclear. Herein we report the case of a lichen planus (LP)-like lesion in presence of anti-BMZ antibodies, preceding BP in a patient treated with pembrolizumab, a PD-1 antibody. A 72-year-old Japanese woman with a 3-month history (6 cycles) of pembrolizumab was referred to our department for pruritic purple-red papules or plaques. Histological finding revealed LP-like dermatitis. Although pembrolizumab was stopped because of disease progression, she developed edematous erythematous lesions and tense blisters seven weeks later. Based on histopathological findings, direct immunofluorescence (DIF) assay and positive findings on chemiluminescent enzyme immunoassay (CLEIA) for BP180, she was diagnosed with BP and administered oral prednisolone. The blisters and erythemas improved, whereas her respiratory condition worsened and she died 29 days after the development of BP. We performed DIF of formalin-fixed, paraffin-embedded specimens biopsied from the LP-like lesion and revealed IgG deposition at the epidermal BMZ. This finding showed anti-BMZ antibodies had already existed at LP-like lesion preceding development of BP; this suggests that the preceding LP-like lesion induced anti-BMZ antibody production, resulting in the development of BP.

Outlines of the Japanese guidelines for the management of primary cutaneous lymphomas 2020.

Abstract: Since the publication of the Japanese "Guidelines for the management of cutaneous lymphomas" in 2011, the World Health Organization (WHO) classification of hematolymphoid neoplasms and the WHO-European Organisation for Research and Treatment of Cancer classification for primary cutaneous lymphomas were updated and a number of novel systemic drugs for cutaneous T-cell lymphoma had been approved in Japan. In 2020, we revised the Japanese guidelines for the management of cutaneous lymphomas with consideration of the recent advances in the understanding of the pathophysiology and classification of cutaneous lymphomas together with the update of treatment strategies reflecting the advent of novel drugs. In addition to a brief explanation of epidemiology, diagnosis, staging system, prognosis and management of each subtype of cutaneous lymphomas, the recommendations for nine clinical questions regarding treatment options that can vary even among experts are also described. A systematic review process and determination of recommendations in answer to each clinical question have been performed in accordance with the Grading of Recommendations, Assessment, Development and Evaluation scheme by a multidisciplinary expert panel consisting of dermatologists, a hematologist and a radiation oncologist. In this article, we present the outlines of the revised Japanese "Guidelines for the management of cutaneous lymphomas".

Care for children with atopic dermatitis in the Netherlands during the COVID-19 pandemic: Lessons from the first wave and implications for the future.

Abstract: The first wave of the coronavirus disease 2019 (COVID-19) pandemic had an enormous impact on health-care services, including on care provision for children with atopic dermatitis (AD). We investigated the impact of COVID-19 on the care for children with moderate to severe AD at our tertiary outpatient clinic and examined satisfaction with care. We reviewed outpatient records, comparing total number and types of consultations during the first COVID-19 wave (March until July 2020) with the corresponding months of 2019 and 2018. In addition, we conducted a questionnaire-based study investigating the impact of COVID-19 on clinical and psychological symptoms, and satisfaction with care. A total number of 913 consultations (466 individual children) were conducted during the first COVID-19 wave in 2020, while 698 (391 individual children) and 591 consultations (356 individual children) were conducted in 2019 and 2018. The proportion of remote consultations was higher (56.2%) compared to 14.0% in 2019 and 12.7% in 2018. Worsening of AD was reported by 9.7% of caretakers. Overall satisfaction with provided care was high (8.6; interquartile range [IQR] = 7.3-10.0). Caretakers receiving face-to-face consultation were significantly (p = 0.026) more satisfied (9.0; IQR = 8.0-10.0) than caretakers receiving remote consultation (7.9; IQR = 7.0-9.5). The COVID-19 pandemic had an unprecedented impact on care provision for children with AD, particularly on the number of remote consultations. Overall satisfaction with care was high. The impact of COVID-19 on disease severity remained limited. Remote consultations seem to be a useful tool that can be put into practice during the COVID-19 pandemic.