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Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease, associated with impaired skin barrier function and an atopic background. Various complicating factors, such as irritants, aeroallergens, food, microbial organisms, contact allergens, sweat, and scratching can induce the development of AD symptoms. Irritants, including soap/shampoo and clothes, can cause itching and eczematous lesions. In addition, young children with AD tend to become sensitized to eggs, milk, or peanuts, while older children and adults more often become sensitized to environmental allergens, such as house dust mites (HDM), animal dander, or pollen. Serum-specific IgE levels and skin prick test reactions to food tend to show high negative predictive values and low specificity and positive predictive values for diagnosing food allergy. On the other hand, AD adult patients tend to have severe skin symptoms and exhibit high HDM-specific IgE levels. Microbial organisms, e.g., Staphylococcus aureus and Malassezia furfur, might contribute to the pathogenetic mechanisms of AD. While sweat plays a major role in maintaining skin homeostasis, it can become an aggravating factor in patients with AD. Furthermore, scratching often exacerbates eczematous lesions. Several patient-specific complicating factors are seen in most cases. The identification and management of complicating factors are important for controlling AD.

Although melanoma is the most aggressive skin cancer, recent advances in BRAF and/or MEK inhibitors against BRAF-mutated melanoma have improved survival rates. Despite these advances, a treatment strategy targeting NRAS-mutated melanoma has not yet been elucidated. We discovered CH5126766/RO5126766 as a potent and selective dual RAF/MEK inhibitor currently under early clinical trials. We examined the activity of CH5126766/RO5126766 in a panel of malignant tumor cell lines including melanoma with a BRAF or NRAS mutation. Eight cell lines including melanoma were assessed for their sensitivity to the BRAF, MEK, or RAF/MEK inhibitor using in vitro growth assays. CH5126766/RO5126766 induced G1 cell cycle arrest in two melanoma cell lines with the BRAF V600E or NRAS mutation. In these cells, the G1 cell cycle arrest was accompanied by up-regulation of the cyclin-dependent kinase inhibitor p27 and down-regulation of cyclinD1. CH5126766/RO5126766 was more effective at reducing colony formation than a MEK inhibitor in NRAS- or KRAS-mutated cells. In the RAS-mutated cells, CH5126766/RO5126766 suppressed the MEK reactivation caused by a MEK inhibitor. In addition, CH5126766/RO5126766 suppressed the tumor growth in SK-MEL-2 xenograft model. The present study indicates that CH5126766/RO5126766 is an attractive RAF/MEK inhibitor in RAS-mutated malignant tumor cells including melanoma.

Monocytes play a critical role in chronic atopic dermatitis (AD) and are the primary leukocytes that interact with activated platelets. Although activated platelets release a variety of mediators, the role of platelets in cutaneous allergic inflammation remains unclear. Serotonin (5-hydroxytryptamine, 5-HT) is one of the prototypic mediators produced by activated platelets. We examined the effect of 5-HT on the function and lifespan of human monocytes. Normal human monocytes treated with 5-HT exhibited upregulated expression of costimulatory molecules, enhanced capacity to produce cytokines following lipopolysaccharide treatment, and to stimulate allogeneic CD4+ T cells. 5-HT also attenuated the apoptosis in normal human monocytes in a dose-dependent manner. The plasma levels of 5-HT were increased in patients with AD compared with controls and correlated with the SCORAD index. 5-HT also inhibited monocyte apoptosis in these patients. 5-HT upregulated Bcl-2 and Mcl-1, and inhibited the activation of caspase-3. The effects of 5-HT on monocyte apoptosis were mediated by the 5-HT1 and/or 5-HT7 receptors. 5-HT and a 5-HT1/6/7-receptor agonist induced phosphorylation of extracellular signal-regulated kinase1/2 and activation of nuclear transcription factor-κB. These findings support that 5-HT activates monocytes and inhibits apoptosis, allowing them to remain in the tissue and contribute to chronic inflammation.

The mRNA‐1273 vaccine for coronavirus disease (COVID‐19) authorised as one of the first COVID‐19 vaccines was released by Moderna in December 2020. A recent study indicates that messenger RNA (mRNA) vaccines appear to be effective in preventing aggravation, hospitalisation and death against COVID‐19 infection. However several adverse effects have been reported. Of these, the dermatological adverse effects are relatively rare entities Herein, we present a case of inflammatory disseminated superficial porokeratosis exacerbated after administration of the fourth dose of the mRNA‐1273 vaccine.

There is increasing recognition of the role of Toll-like receptor 3 (TLR3) in noninfectious inflammatory diseases, but the function of TLR3 in inflammatory skin diseases is unclear. We investigated the functions of TLR3 in allergic and irritant contact dermatitis (ICD). The contact hypersensitivity (CHS) response was lower in Toll-like receptor 3 knockout (Tlr3 KO) mice, and was greater in TLR3 transgenic (Tg) mice than in wild-type (WT) mice after challenge with 2,4,6-trinitro-1-chlorobenzene. Adoptive transfer of immunized lymph node cells from Tlr3 KO mice induced CHS in WT recipients. In contrast, adoptive transfer of those from WT mice did not fully induce CHS in Tlr3 KO recipients. The ICD reaction following croton oil application was lower in Tlr3 KO mice, and was greater in TLR3 Tg mice than in WT mice. Maturation, migration, and antigen presentation of dendritic cells and proliferation of lymphocytes between WT mice and Tlr3 KO mice were comparable. These results show that TLR3 enhances antigen-independent skin inflammation in the elicitation phase of allergic contact dermatitis and in ICD.

Lichen planopilaris (LPP) is a type of lymphocytic cicatricial alopecia, which can occur at unusual sites. It can be difficult to diagnose at an early stage and may be misdiagnosed as seborrheic dermatitis or psoriasis in early stages before alopecia occurs. We report a rare case in which alopecia occurred between two long surgical scars on the scalp several years after surgery. Dermoscopy and biopsy led to a diagnosis of LPP. The localization of the lesions in our case suggests that oxidative stress from the failure of lymph flow might have induced LPP. Oral roxithromycin, a macrolide antibiotic, with anti-oxidative and anti-inflammatory was effective at stopping its progression.

Background The incidence of melanoma among those of an Asian ethnicity is lower than in Caucasians; few large‐scale Asian studies that include follow‐up data have been reported. Objectives To investigate the clinical characteristics of Japanese patients with melanoma and to evaluate the prognostic factors. Methods Detailed patient information was collected from the database of Japanese Melanoma Study Group of the Japanese Skin Cancer Society. The American Joint Committee on Cancer seventh Edition system was used for TNM classification. The Kaplan‐Meier method and Cox proportional hazards model were used to estimate the impact of clinical and histological parameters on disease‐specific survival in patients with invasive melanoma. Results In total, 4594 patients were included in this analysis. The most common clinical type was acral lentiginous melanoma (40.4%) followed by superficial spreading melanoma (20.5%), nodular melanoma (10.0%), mucosal melanoma (9.5%), and lentigo maligna melanoma (8.1%). The 5‐year disease‐specific survival for each stage was as follows: IA = 98.0%, IB = 93.9%, IIA = 94.8%, IIB = 82.4%, IIC = 71.8%, IIIA = 75.0%, IIIB = 61.3%, IIIC = 41.7%, and IV = 17.7%. Although multivariate analysis showed that clinical classifications were not associated with survival across all stages, acral type was an independent poor prognostic factor in stage IIIA. Conclusions Our study revealed the characteristics of melanoma in the Japanese population. The 5‐year disease‐specific survival of each stage showed a similar trend to that of Caucasians. While clinical classification was not associated with survival in any stages, acral type was associated with poor survival in stage IIIA. Our result might indicate the aggressiveness of acral type in certain populations.

Introduction Upadacitinib, an oral, selective Janus kinase inhibitor, is approved in Japan for the treatment of moderate-to-severe atopic dermatitis (AD), a chronic inflammatory skin disease characterized by eczematous morphology and intense itch. Methods Rising Up is an ongoing phase 3, randomized, multicenter study evaluating the long-term safety and efficacy of upadacitinib in Japan. Patients with moderate-to-severe AD were randomized 1:1:1 to topical corticosteroids plus upadacitinib 15 mg (UPA15), upadacitinib 30 mg (UPA30), or placebo at baseline; at week 16, placebo patients were rerandomized 1:1 to UPA15 or UPA30 (plus topical corticosteroids per investigator discretion). This 2-year interim analysis evaluated safety and efficacy through 112 weeks (data cutoff date: 11 August 2021). Adverse events (AEs), AEs of special interest (AESIs), and laboratory data were assessed. Efficacy assessments included ≥ 75% and ≥ 90% improvement from baseline in Eczema Area and Severity Index (EASI 75/90), achievement of clear or almost clear on the validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD 0/1), and ≥ 4-point improvement in the Worst Pruritus Numerical Rating Scale (WP-NRS). Results A total of 272 patients were enrolled and 242 were ongoing at data cutoff (UPA15, n  = 120; UPA30, n  = 122). After 112 weeks of treatment, serious AEs, AEs leading to discontinuation, and most AESIs were generally infrequent, and rates were similar between the two upadacitinib groups. One event each of rectal cancer and cerebellar hemorrhage was reported in the UPA15 group; no thrombosis events were observed. The most common AEs included acne, nasopharyngitis, and herpes zoster. EASI 75, EASI 90, vIGA-AD 0/1, and WP-NRS response rates were maintained through week 112. Conclusion UPA15 and UPA30 were well tolerated through 112 weeks of treatment with similar safety profiles to short-term studies and demonstrated durable long-term efficacy for the treatment of moderate-to-severe AD in adults and adolescents. Trial Registration ClinicalTrials.gov identifier, NCT03661138.

Background IgA nephropathy is the most common glomerulonephritis. Secondary IgA nephropathy complicated with systemic diseases, including psoriasis, is also often reported. Generalized pustular psoriasis is a form of psoriasis characterized by sterile pustules on reddened skin and fever. Infliximab, one of the first-line therapies for severe psoriasis, has also been reported to cause systemic vasculitis and IgA nephropathy. We herein report a case of IgA nephropathy activated during infliximab treatment for generalized pustular psoriasis. Case presentation A 28-year-old woman presented with episodic gross hematuria, increasing proteinuria, and renal dysfunction. She had been receiving anti-TNFα therapy with infliximab because of generalized pustular psoriasis for 3 years, but her skin symptoms worsened following withdrawal during pregnancy. After delivery, her skin symptoms improved with the resumption of infliximab, but clinical signs suggested glomerulonephritis, and renal biopsy showed active IgA nephropathy. Infliximab was discontinued, and the combination of corticosteroids, tonsillectomy, and secukinumab, an IL-17A inhibitor, improved both the skin symptoms and the glomerulonephritis. Conclusions In our case, the activity of IgA nephropathy was exacerbated by anti-TNFα therapy but was improved by the combination of corticosteroids, tonsillectomy, and an IL-17A inhibitor against the original disease. Autoimmune diseases may underlie the development of secondary IgA nephropathy associated with anti-TNFα therapy, and so further studies are needed to better understand the association between molecular-targeted drugs and IgA nephropathy.

Background GA2LEN‐ADCARE is a branch of the largest multidisciplinary network of research centres and clinical care in allergy and asthma, GA2LEN, focussing on the field of atopic dermatitis (AD). AD is a chronic inflammatory skin disease with high burden and many comorbidities requiring different levels of treatment. The need for aligned information from all involved healthcare providers led to the discussion of an integrated care pathway (ICP) plan for AD patient care involving all stakeholders and considering the complexity and variability of the disease, with a particular focus placed on the large number of patients with milder forms of AD. Methods The GA2LEN ADCARE network and all stakeholders, abbreviated the AD‐ICPs working group, were involved in the discussion and preparation of the AD‐ICPs during a series of subgroup workshops and meetings in years 2020 and 2021. Results Here we discuss the unmet needs in AD, the methodology for devising an AD‐ICP and the ICP action plan. Conclusion The GA2LEN ADCARE network has outlined the unmet needs in AD and provided an action plan for devising AD‐ICPs, considering the complexity and variability of the disease.