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We describe a patient with extracutaneous pyoderma gangrenosum (PG), who presented with chest pain. Histological examination showed extracutaneous neutrophilic infiltration of the spleen and lung, with later findings of PG.

Introduction Our previous clinical studies have demonstrated the short-term efficacy and safety of the sirolimus gel for patients with tuberous sclerosis complex (TSC). However, long-term clinical evidence is lacking. Our objective was to assess the safety and efficacy of long-term treatment with the sirolimus gel for the skin lesions of TSC patients. Methods We conducted a multicenter, open-label, uncontrolled clinical trial in 94 Japanese patients with TSC. Patients applied the 0.2% sirolimus gel on their face or head twice daily for > 52 weeks (maximum 136 weeks for safety). The safety endpoints were the rate of adverse event (AE)-caused discontinuation (primary endpoint) and the incidence of AEs. The efficacy endpoint was the response rate of angiofibromas, cephalic plaques, and hypomelanotic macules. Results Among 94 enrolled patients (mean age, 21 years; range 3–53 years), the rate of AE-caused discontinuation was 2.1% (2/94 patients). Although application site irritation and dry skin occurred relatively frequently, none of the drug-related AEs were serious; most of the drug-related AEs resolved rapidly. The major drug-related AEs (≥ 5% in incidence) were application site irritation (30.9%), dry skin (27.7%), acne (20.2%), eye irritation (8.5%), pruritus (8.5%), erythema (7.4%), dermatitis acneiform (6.4%), and dermatitis contact (5.3%). The response rates of angiofibromas, cephalic plaques, and hypomelanotic macules were 78.2% [95% confidence interval (CI) 68.0–86.3%], 66.7% (95% CI 51.1–80.0%), and 72.2% (95% CI 46.5–90.3%), respectively. Conclusions The gel was well tolerated for a long time by patients with TSC involving facial skin lesions and continued to be effective. Trial Registration ClinicalTrials.gov identifier: NCT02634931.

Oculocutaneous albinism (OCA) is an autosomal recessive disease characterized by the reduction or complete lack of melanin pigment in the skin, hair, and eyes. No effective treatment for OCA is available at present. OCA type 1 is caused by mutations that disrupt the function of tyrosinase (TYR), the rate-limiting enzyme of melanin synthesis. Recently, it was shown that tyrosinase in some patients with OCA type 1 mutation is retained in the endoplasmic reticulum and that its catalytic activity is lost, a phenomenon known as endoplasmic reticulum retention. However, to our knowledge, the intracellular localization of tyrosinase in Japanese patients with OCA type 1 missense mutations has not been reported. In this study, we first investigated the intracellular localization of Japanese OCA type 1A missense mutant tyrosinases using Western blotting and immunohistochemical staining. R77Q, R239W, D383N, and P431L mutant tyrosinases were retained in the endoplasmic reticulum, and H211Y mutant tyrosinase was partially transported to the Golgi apparatus. Second, we explored the possibility of chemical chaperone therapy for Japanese patients with OCA type 1A missense mutations and found that HeLa cells expressing P431L mutant tyrosinase have restored tyrosinase activity after treatment with a low-dose tyrosinase inhibitor, as a chemical chaperone, in a dose-dependent manner. These results provide the basis for a possible chemical chaperone therapy to recover tyrosinase activities in patients with OCA type 1A patients.

A 28-year-old man was transferred to our emergency room for dyspnea and wheals on the entire body. He had eaten landlocked ayu fish (Plecoglossus altivelis) the so-called "koayu fish", from Lake Biwa, and had immediately experienced a stomachache. Wheals and dyspnea developed one hour later and were successfully treated with intravenous corticosteroids. The patient was examined for koayu fish and related allergens by skin prick and allergen-specific immunoglobulin E (IgE) (ImmunoCAP

Racemic RS-4-(4-hydroxyphenyl)-2-butanol (rhododendrol; trade name: Rhododenol [RD]), which is used in topical skin-lightening cosmetics, was unexpectedly reported in Japan to induce leukoderma or vitiligo called RD-induced leukoderma (RIL) after repeated application. To our knowledge, no studies have investigated chemical-induced vitiligo pathogenesis on a genome-wide scale. Here, we conducted a genome-wide association study (GWAS) for 147 cases and 112 controls. CDH13, encoding a glycosylphosphatidylinositol-anchored protein called T-cadherin (T-cad), was identified as the strongest RIL susceptibility gene. RD sensitivity was remarkably increased by T-cad knockdown in cultured normal human melanocytes. Furthermore, we confirmed tyrosinase upregulation and downregulation of the anti-apoptotic molecules (BCL-2 and BCL-XL), suggesting that T-cad is associated with RD via tyrosinase or apoptotic pathway regulation. Finally, monobenzyl ether of hydroquinone sensitivity also tended to increase with T-cad knockdown, suggesting that the T-cad could be a candidate susceptibility gene for RIL and other chemical-induced vitiligo forms. This is the first GWAS for chemical-induced vitiligo, and it could be a useful model for studying the disease's genetic aspects.

Background Choroidal melanoma with metastasis is known to have a poor prognosis with no established standard therapy. Recently there are some case reports that combination therapy of IPI and NIVO is effective, but with high incidence of immune-related adverse events (irAE). Case presentation A 53-year-old man presented with choroidal melanoma of the right eye and underwent stereotactic radio surgery but eighteen months later developed diffuse hepatic metastases. He was treated with combination therapy of IPI and NIVO, but he developed hyposalivation from the next day of first administration, and grade 3 hepatic disorder after 2 cycles. After 3 days administration of mPSL 125mg followed by PSL 0.5mg/kg, his hepatic enzymes normalized, then we started steroid tapering. At the dose of 30mg, he developed grade 4 Stevens-Johnson syndrome, for which 3 days pulse therapy of mPSL 1mg was effective. We re-escalated PSL to 1mg/kg and tapered carefully. At the dose of 15mg, MRI showed progression of liver metastasis. We decided to resume nivolumab monotherapy three months after termination of IPI+NIVO therapy, but it resulted in grade 3 diarrhea. Lower gastrointestinal endoscopy found seemingly normal mucosa, but histological examination showed inflammatory cell infiltration with hemorrhage, which means irAE. Now he is continuing steroid therapy at 15mg of PSL. Conclusion Our patient developed various irAEs after IPI+NIVO therapy for metastatic choroidal melanoma. Each irAEs responded to corticosteroid therapy, but unexpected severe irAEs occurred even with high dose steroid. As a result, prolonged steroid therapy is often needed to control various irAEs, and in those cases, we have to take extra attention to adverse events of steroids such as opportunistic infections.

Because some users develop depigmentation after the use of melanogenesis-inhibiting products containing the quasi-drug ingredient Rhododenol, Japanese Dermatological Association (JDA) established a Special Committee on the Safety of Cosmetics Containing Rhododenol on July 17, 2013 and management guide for dermatologists has been updated on the website in order to delineate the diagnostic criteria for Rhododenol-induced leukoderma and provides a broad guide for standard treatment based on current knowledge. This guide is produced on the basis of the guide (version 7) updated on June 20, 2014 in the website. Rhododenol-induced leukoderma refers to depigmentation of varying severity that develops after the use of cosmetics containing Rhododenol, mainly at the site of use. In most cases, repigmentation of part or all the affected area is evident after discontinuation. Histopathologically cellular infiltration around the hair follicles and melanophages are present in most cases. The number of melanocytes in the lesion is declined but not totally absent in most cases. Rhododenol itself is a good substrate for tyrosinase, resulting in the formation of Rhododenol metabolites (e.g., Rhododenol quinone). Melanocytes are damaged by Rhododenol metabolites during the subsequent metabolic process. The continued use of cosmetics containing Rhododenol thus induces tyrosinase activity-dependent cytotoxicity in melanocytes in the epidermis at application sites, resulting in decreasing the amount of melanin produced by melanocytes; the addition of some other factor to this process is believed to subsequently cause the decrease or disappearance of melanocytes themselves from the epidermis.

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by the triad of tyrosinase-positive oculocutaneous albinism, bleeding diathesis due to storage-pool deficiency of platelets, and a lysosomal ceroid storage disease. The disorder is particularly frequent in Puerto Rico and in an isolated village in the Swiss Alps. We have used a linkage disequilibrium mapping approach to localize the HPS gene in both of these groups to a 0.6 centiMorgan interval in chromosome segment 10q23.1-q23.3. These results indicate that the Puerto Rican and Swiss forms of HPS are either allelic or that they result from mutations in very closely linked genes in this region. This region of distal chromosome 10q is syntenic to the region of mouse chromosome 19 that includes 'pale ear' (ep) and 'ruby-eye' (ru), which must be considered as potential murine homologues to human HPS.

Human skin color is known to be associated with the risk of cutaneous cancer. Some reports indicated that pigmentation-related gene variants were associated with cutaneous cancer risk in Caucasian populations, but there are no similar reports in East Asian populations. This study aimed to evaluate the association between pigmentation-related genes and the risk of skin cancer in Japanese populations. We studied the associations between 12 variants of four pigmentation-related genes and melanin index variations in 198 Japanese patients with skin cancer and compared these findings to those of 500 Japanese controls by using multiple logistic regression analysis. Furthermore, we analyzed an independent sample of 107 Japanese patients with skin cancer. A non-synonymous variant, H615R in the oculocutaneous albinism 2 gene (OCA2), was associated with the risk of malignant melanoma in the Yamagata group (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.17-0.86; P = 0.020). Another non-synonymous variant, A481T in OCA2, was associated with the risk of squamous cell carcinoma and actinic keratosis in the Osaka group (OR, 3.16; 95% CI, 1.41-7.04; P = 0.005). In malignant melanoma cases, the minor allele in OCA2 H615R might have induced the development of lesions in sun-exposed skin (OR, 26.32; 95% CI, 1.96-333; P = 0.014). Our results suggest that some OCA2 variants are definite risk factors for the onset of cutaneous cancer in Japanese populations.

Vitiligo is an acquired pigment disorder in which depigmented macules result from the loss of melanocytes from the involved regions of skin and hair. The color dissimilarity on the cosmetically sensitive regions frequently induces quality of life impairment and high willingness to pay for treatment in patients with vitiligo. The Vitiligo Japanese Task Force was organized to overcome this situation and to cooperate with the Vitiligo Global Issues Consensus Conference. This guideline for the diagnosis and treatment of vitiligo in Japan is proposed to improve the circumstances of Japanese individuals with vitiligo. Its contents include information regarding the diagnosis, pathogenesis, evaluation of disease severity and effectiveness of treatment, and evidence-based recommendations for the treatment of vitiligo. The therapeutic algorithm based on the proposed recommendation is designed to cure and improve the affected lesions and quality of life of individuals with vitiligo.

Background Generalized vitiligo is an acquired disorder in which depigmented macules result from the autoimmune loss of melanocytes from the involved regions of skin. Generalized vitiligo is frequently associated with other autoimmune diseases, particularly autoimmune thyroid diseases (Hashimoto's thyroiditis and Graves' disease), rheumatoid arthritis, adult-onset type 1 diabetes mellitus, psoriasis, pernicious anemia, systemic lupus erythematosus, and Addison's disease. Methods One hundred and thirty-three Japanese patients with generalized vitiligo were enrolled in this study to investigate the occurrence of autoimmune diseases in Japanese patients with generalized vitiligo and their families. Results Twenty-seven of the patients with generalized vitiligo (20.3%) had autoimmune diseases, particularly autoimmune thyroid disease (sixteen patients, 12%) and alopecia areata (seven patients, 5.3%). Thirty-five patients (26.3%) had a family history of generalized vitiligo and/or other autoimmune diseases. Familial generalized vitiligo was present in fifteen (11.3%), including four families with members affected by autoimmune disorders. Twenty (15.0%) had one or more family members with only autoimmune disorders. Conclusions Among Japanese vitiligo patients, there is a subgroup with strong evidence of genetically determined susceptibility to not only vitiligo, but also to autoimmune thyroid disease and other autoimmune disorders.

Superficial thrombophlebitis is known as a frequent complication of Behcet’s disease. Infliximab may promote healing of superficial thrombophlebitis in patients with Behcet’s disease. However, thrombophlebitis as a complication of rheumatoid arthritis (RA) is rare and treatments have not been reported. We describe the case of a 47-year-old man with RA with complications of superficial thrombophlebitis who was treated using methotrexate and infliximab. Erythema nodosum and cord-like induration with pain in the extremities completely disappeared following a single infusion of infliximab and oral acetylsalicylic acid was not needed. This case suggests that infliximab might offer effective treatment for patients showing superficial thrombophlebitis with RA.

Most patients with tuberous sclerosis complex (TSC), an autosomal-dominant disorder that is caused by the constitutive activation of mammalian target of rapamycin, experience disfigurement caused by skin lesions involving facial angiofibromas. Many have been left untreated because of a lack of therapeutic options that are less invasive than surgery or laser treatment.To confirm the efficacy and safety of sirolimus gel, 0.2%, for treatment of patients with angiofibromas and/or skin lesions.Multicenter, randomized clinical trial at 9 centers in Japan from December 2015 to October 2016 including 62 children and adults with TSC.Patients who developed angiofibromas were randomly assigned, in a 1:1 ratio, to receive sirolimus gel, 0.2%, or placebo, each applied topically twice daily for 12 weeks.The primary end point was composite improvement in the size and color of angiofibromas in photographs at week 12 of treatment. It was assessed by an independent review committee comprising 3 blinded dermatologists who categorized patient results into the following 6 categories: "markedly improved," "improved," "slightly improved," "unchanged," "slightly aggravated," and "aggravated."Sixty-two patients (27 pediatric and 35 adult; 34 [55%] female; mean [SD] age, 22.5 [11.9] years) were enrolled and randomly assigned to receive sirolimus gel, 0.2% (30 patients), or placebo (32 patients). The response rates of angiofibromas at weeks 4, 8, and 12 of treatment were 0 each in the placebo group in contrast to 20% (95% CI, 8%-39%; P = .01), 43% (95% CI, 26%-63%; P .001), and 60% (95% CI, 41%-77%; P .001), respectively, in the sirolimus group. None of the 31 assessable patients in the placebo group were rated improved or better, and 26 of them (84%) were rated unchanged. In contrast, 5 (17%) and 13 (43%) patients in the sirolimus group were rated markedly improved and improved, respectively. Adverse events were mild to moderate and were observed in 27 (90%) and 22 (69%) patients in the sirolimus and placebo groups, respectively; however, none of the trial participants discontinued treatment. Acute pancreatitis developed as a serious adverse event in 1 patient in the sirolimus group, and the patient recovered soon after hospitalization without discontinuing treatment.Sirolimus gel, 0.2%, demonstrated a significant clinical benefit for patients with TSC involving angiofibromas, thus providing a promising therapeutic modality.ClinicalTrials.gov Identifier: NCT02635789.