Costello syndrome is a rare RASopathy caused by pathogenic variants in HRAS and is characterized by distinctive craniofacial features, growth failure, cardiac abnormalities, tumor predisposition, and various cutaneous manifestations. Although eczema has been reported in patients with Costello syndrome, reports of severe AD-like eczema accompanied by clinically significant allergic manifestations, including food allergy, remain limited. We report a female patient with Costello syndrome caused by a heterozygous HRAS variant, NM_005343.4:c.37G>T, p.(Gly13Cys), who developed severe atopic dermatitis-like eczema and hen’s egg and cow’s milk allergies from infancy. Despite treatment with topical anti-inflammatory agents and emollients, her AD-like eczema remained refractory. Add-on dupilumab therapy was initiated in adolescence, resulting in marked improvement in her skin manifestations within 1 month, and clinical improvement was maintained during subsequent follow-up. This case suggests that dupilumab may be an effective therapeutic option for refractory atopic dermatitis-like eczema associated with Costello syndrome. The clinical course also supports the possible contribution of epithelial-driven type 2 inflammation to severe allergic manifestations in Costello syndrome, although direct mechanistic evidence was not obtained.
BackgroundPrurigo chronica multiformis is a refractory chronic pruritic dermatosis that predominantly affects older adults, but the frequency and significance of antinuclear antibody (ANA) positivity remain unclear.MethodsThis retrospective single-center study included 26 patients with prurigo chronica multiformis treated between March 2016 and April 2025. Patients were divided into two groups according to ANA status, and baseline characteristics, allergic background, laboratory investigations, extent of skin involvement, and responsiveness to topical corticosteroids were compared.ResultsFive of 26 patients (19.2%) were positive for ANA. Among evaluable patients, all patients in the positive group showed sensitization to at least one allergen, which was more frequent than in the negative group (100% vs. 37.5%, p = 0.035). The median peripheral blood eosinophil percentage was significantly lower in the positive group (4.0% vs. 8.0%, p = 0.031). No significant differences were observed in the eosinophil count, total IgE levels, extent of skin involvement, or responsiveness to topical corticosteroids.ConclusionApproximately one-fifth of patients with prurigo chronica multiformis were positive for ANA. ANA-positive patients showed a high rate of allergen sensitization and a lower peripheral blood eosinophil percentage. These findings suggest that prurigo chronica multiformis may include an immunologic subtype in which autoimmunity and allergic inflammation intersect.
Pruritus is the most burdensome and persistent symptom of atopic dermatitis (AD), often impairing quality of life more profoundly than visible skin inflammation. Emerging evidence indicates that itch in AD is not merely a downstream consequence of inflammation but an active disease driver that reshapes epidermal barrier integrity and neural plasticity. At the center of AD itch lies a dynamic, bidirectional network linking keratinocytes and sensory neurons. Barrier disruption triggers the release of keratinocyte-derived pruritogens and stress signals that directly activate or sensitize cutaneous nerve fibers, amplifying itch transmission. These epithelial–neuronal interactions are further integrated by intracellular signaling pathways that coordinate environmental and neural inputs. This review synthesizes current mechanistic insights across epidermal and neural compartments and proposes a conceptual framework in which AD itch progresses from peripherally driven signaling to centrally amplified and neurally entrenched states.
BackgroundReal-world data on the long-term effectiveness of tildrakizumab in Japanese patients with psoriasis remain limited, particularly in cohorts with relatively low baseline disease severity.ObjectivesTo evaluate the 52-week effectiveness and safety of tildrakizumab in a real-world Japanese clinical setting, including exploratory subgroup analyses.MethodsThis retrospective, single-center observational study included 30 consecutive patients with psoriasis treated with tildrakizumab 100 mg in accordance with the approved Japanese dosing regimen. Disease severity was assessed using the Psoriasis Area and Severity Index (PASI) at weeks 0, 4, 16, 28, 40, and 52 (visit window ±1 week). Mean PASI scores were analyzed using observed values. For responder analyses, non-responder imputation (NRI) was applied; patients who discontinued treatment or had missing PASI data were classified as non-responders. Responder endpoints included PASI75 and absolute PASI ≤3. Exploratory subgroup analyses were conducted according to baseline characteristics. Statistical analyses were performed using GraphPad Prism.ResultsThe mean PASI score improved from 11.45 at baseline (median 9.2) to 2.90 at week 52. Using NRI, PASI75 and PASI ≤3 achievement rates reached 56.7% and 60.0% at week 52, respectively. Four patients discontinued treatment because of insufficient efficacy, with final PASI scores of 7.5 (week 4), 1.6 (week 16), 3.7 (week 28), and 3.2 (week 40). Twenty-six patients (86.7%) continued treatment through week 52. Seven adverse events were documented during the study period, and no treatment discontinuations related to adverse events occurred.ConclusionTildrakizumab demonstrated sustained real-world effectiveness in Japanese patients with psoriasis, with no treatment discontinuations related to adverse events. Interpretation of the safety and subgroup findings should take into account the retrospective single-center design and exploratory nature of the analyses.
Interleukin-33 (IL-33) is a nuclear alarmin expressed in epidermal keratinocytes and plays an important role in atopic dermatitis. Environmental stimulation induces extracellular release of IL-33 from the skin. The molecular mechanisms regulating IL-33 release in vivo are not well understood. Previous studies using non-cutaneous tissues or in vitro systems have suggested that IL-33 release is independent of caspase-1. In this study, we examined the role of caspase-1 in IL-33 release from keratinocytes in vivo. Caspase-1 was detected in the nuclei of murine epidermal keratinocytes. After topical stimulation with the hapten 2,4-dinitrofluorobenzene (DNFB), nuclear IL-33 staining in keratinocytes was rapidly lost in wild-type mice. This change was markedly reduced in caspase-1/11–deficient mice. Genetic deletion of caspase-1/11 reduced IL-33–mediated skin inflammation in mice overexpressing IL-33 in keratinocytes, and reduced expression of type 2 cytokines was also observed in the skin. These findings suggest that caspase-1 may play a role in pathogenic IL-33 release in the skin and may control alarmin activity differently across tissues.
Xeroderma pigmentosum (XP) is a disorder that causes sun sensitivity, pigmented spots in sun-exposed areas, and neurological symptoms due to an inborn error in the DNA repair process for damage caused by sun exposure. We report a case with XP type F (XPF) diagnosed in a patient in her 70s. We identified that she was homozygous for a deep intronic variant of ERCC4, NC_000016.10(NM_005236.3): c.207+196T>A. This variant causes aberrant mRNA splicing, which confirmed the diagnosis of XP. Seven cases with the same intronic variant have been reported in Japan. In our case, we independently analyzed the qualitative and quantitative aspects of abnormal mRNA splicing, which had not been reported previously, and found approximately 7.7% of the mRNA retained normal splicing. Furthermore, immunostaining of patient’s skin with anti-ERCC4/XP antibody confirmed that the ERCC4 protein was partially expressed rather than being completely absent. This partial expression was predicted to be associated with the relatively mild phenotype observed in our patient.
Hyperhidrosis, defined as excessive sweating beyond physiological needs. It impairs the quality of life (QOL) of patients. While there are many studies on the relationship between sweating and skin diseases, however few studies have been conducted from epidemiological perspective of hyperhidrosis on coexisting skin diseases. This study aimed to investigate the prevalence, severity, affected areas, and treatment history of hyperhidrosis among patients with skin diseases. An anonymous, self-report questionnaire was administered to 1,000 patients at the department of dermatology, Gunma University Hospital between June and August 2022, yielding 885 responses (88.5%). Hyperhidrosis was defined using the Hornberger’s diagnostic criteria, and severity was assessed by the Hyperhidrosis Disease Severity Scale (HDSS). The overall prevalence of hyperhidrosis among this skin disease patient cohort was 22.4% (n = 198), which was higher than the rate previously reported in Japan (10%–12.8%). Patients with hyperhidrosis were significantly younger (mean age 51.3 years) than those without (mean age 57.2 years; p < 0.01). Over half (54.3%) of affected patients reported severe or very severe symptoms (HDSS 3 or 4). The most common affected sites were the head/face (15.1%), followed by the axillary (8.7%). The prevalence was high in inflammatory skin diseases, with 29.2% of Atopic Dermatitis (AD) patients, 17.7% of psoriasis patients, and 7.1% of Alopecia Areata (AA) patients also having hyperhidrosis. Despite the high prevalence and severity, only a small fraction of hyperhidrosis patients (7.9%) reported a history of treatment. These findings suggest that hyperhidrosis is a common complication in skin disease. This high prevalence may be attributable to compensatory sweating caused by primary skin diseases. To improve patient’s QOL, dermatologists should actively screen for hyperhidrosis and combine sweat management with skin disease treatment.
BackgroundCalcium and magnesium are essential ions that regulate multiple functions of keratinocytes. However, their precise effects on keratinocyte behavior remain incompletely understood.ObjectivesTo investigate the effects of varying calcium and magnesium concentrations on cell proliferation, migration, and the expression of genes related to differentiation and skin hydration in keratinocytes.MethodsHaCaT cells were stimulated by culture media with various calcium (0.32–18.0 mM) and magnesium concentrations (0.28–8.11 mM). MTT Assay was performed for proliferation. Cell migration ability was observed for 24 h using culture-Insert 2 well. mRNA levels of differentiation-associated gene expression was examined by qPCR assay.ResultsCompared to standard DMEM, lower calcium concentrations and higher magnesium concentrations promoted keratinocyte proliferation. The combination of low calcium and high magnesium additively enhanced cell migration. However, both conditions tended to suppress the expression of genes related to differentiation and moisture retention.ConclusionKeratinocyte functions related to proliferation, migration, and differentiation are intricately regulated by the concentrations of calcium and magnesium, as well as their interactions. Lower calcium and higher magnesium medium might have potential to enhance proliferation and migration in keratinocytes. However, further investigations under in vivo conditions are required to evaluate their effects and to translate these findings into clinical applications.
We report a rare case of dermatomyositis in a woman in her 60s, presenting with chronic pruritic erythema and symmetrical subcutaneous indurations in both axillae. Physical examination revealed Gottron’s papules and erythematous plaques on the hands and upper extremities. Laboratory tests showed mildly elevated serum CK, aldolase, and CRP levels. CT revealed increased fat density in both axillae, suggestive of panniculitis. Skin and subcutaneous biopsies confirmed interface dermatitis and panniculitis with membranocystic changes. After that, bilateral inguinal panniculitis developed. Autoantibody screening identified strong positivity for anti-NXP-2 and anti-Ki antibodies. Anti-NXP-2 antibody was further confirmed by immunoprecipitation-Western blotting. The diagnosis of dermatomyositis was made, and oral prednisolone (10 mg, 0.2 mg/kg/day) led to marked improvement. These findings may suggest a potential association between anti-NXP-2 antibodies and panniculitis.
BackgroundPatch tests (PT) and/or lymphocyte transformation tests (LTT) are typically performed, when diagnosed with cutaneous adverse drug reactions (CADR). However, their positivity rates can vary depending on the rash type. Additionally, these tests do not always produce positive results, even when the causative drug is used. Conversely, non-specific reactions can occasionally occur.ObjectivesThis study aimed to evaluate the positive rates of PT and LTT for different rash types and to analyze the false-positive and false-negative results of these tests in relation to drug provocation outcomes.MethodsThis was a retrospective descriptive study. The results of PT, LTT, and drug provocation tests for patients diagnosed with CADR at Department of Dermatology, Kyoto Prefectural University of Medicine, from January 2008 to May 2018, were assessed.ResultsA total of 234 patients were diagnosed with CADR, with 43 showing positive reactions to one or more drugs. The highest positivity rate was found in cases of fixed drug eruption. Among the 138 patients who underwent LTT, 44 tested positive for one or more drugs. Drug provocation tests were performed on 31 patients, with 5 exhibiting positive reactions to five drugs. It was observed that three antibiotics produced false-negative results in both PT and LTT. Additionally, antipyretic analgesics yielded false positive results in LTT for 4 patients.ConclusionIt was suggested that the reactivity of PT and LTT could differ based on the rash type. False negatives and false positives might also happen. These factors should be considered when interpreting the test results.
