Yukari Mizukami

Successful treatment with ustekinumab of psoriasis vulgaris in a patient undergoing hemodialysis.

Psoriasis is a common chronic inflammatory skin disease but psoriasis patients with renal impairment undergoing dialysis are not frequently seen. Furthermore, the published work contains little information on the treatment with biologic drugs of patients with end‐stage renal disease. We describe a 57‐year‐old man with refractory plaque‐type psoriasis and end‐stage renal disease due to polycystic kidney disease undergoing hemodialysis. He had tried topical medications and ultraviolet therapy for many years and was then treated with ustekinumab (an interleukin‐12 and interleukin‐23 blocker), which resulted in good clinical response along with stable renal function. After a few years of therapy, no side‐effects have been observed. Our experience with this patient expands the spectrum of ustekinumab to include psoriasis patients with renal failure undergoing hemodialysis.

Sorafenib stimulates human skin type mast cell degranulation and maturation

BACKGROUND Sorafenib is a multi-kinase inhibitor for treating advanced hepatocellular and renal cell carcinomas by targeting various types of receptors and signaling molecules, including vascular endothelial growth factor receptors, platelet-derived growth factor receptor, and Raf-1. Sorafenib may cause diverse cutaneous adverse reactions, including hand-foot reaction, facial and scalp eruptions, alopecia and pruritus. However, the mechanism of these adverse effects has not been well-investigated. OBJECTIVE Mast cells (MCs) are reported to be associated with various types of skin diseases. To investigate the mechanism of sorafenib-induced cutaneous adverse effects, we focused on MCs in situ. METHODS We evaluated skin samples of organ cultured normal human skin treated with sorafenib using c-Kit, tryptase, and stem cell factor (SCF), Ki-67, and TUNEL immunohistochemistry as well as quantitative real-time polymerase chain reaction to evaluate MC number, degranulation, proliferation, and apoptosis in situ. RESULTS Sorafenib significantly increased the number and degranulation of skin-type MCs compared with the vehicle-treated control group in situ. However, sorafenib did not affect MC proliferation and apoptosis, suggesting that it stimulated MC maturation from resident precursors. Furthermore, sorafenib increased SCF expression in situ. The increase in MC number by sorafenib was abrogated by co-administration of SCF neutralizing antibody or the phosphoinositide 3-kinase (PI3K) inhibitor, wortmannin, but not the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor, PD98059. This suggests that SCF is involved in sorafenib-induced MC maturation. In addition, the compensatory upregulation of PI3K-signaling from inhibition of MAPK signaling by sorafenib might stimulate MC maturation in situ. We also evaluated MCs within the skin samples from patients with drug eruptions by sorafenib administration. The total and degranuated MCs number as well as SCF expression was significantly increased compared to healthy individuals. CONCLUSION Our results contribute to a better understanding of the mechanism by which sorafenib induces adverse cutaneous reactions via activation of skin-type MC degranulation and maturation. This activation appears to be related to PI3K signaling and SCF production, which could be a new targets for treating sorafenib-induced adverse reactions.

Re-investigating the Basement Membrane Zone of Psoriatic Epidermal Lesions: Is Laminin-511 a New Player in Psoriasis Pathogenesis?:

Psoriasis is a complex chronic inflammatory skin disease characterized by epidermal thickening on the basis of increased keratinocyte proliferation and insufficient apoptosis. Laminins are important components of the basement membrane (BM) and impact on epidermal keratinocyte growth/apoptosis. Although several laminins are involved in the pathogenesis of psoriasis, it is still controversial about the expression patterns of laminin isoforms and which laminins are important in the development of psoriasis. Because laminin-511 and -332 are key BM components in human skin, and laminin-511 stimulates human hair follicle growth, we asked whether the BM zone in psoriasis shows any laminin-related abnormalities. This showed that the BM expression of laminin-511 and -332 was significantly increased within the skin lesion of psoriasis. Immunofluorescence microscopy revealed that laminin-511, -332, and collagen type IV proteins were also significantly increased in psoriasis-like skin lesions of Imiquimod-treated mice. Transmission electron microscopy showed a few gaps of lamina densa, and its thickness was significantly increased. Finally, laminin-511 treatment significantly stimulated the proliferation and inhibited apoptosis of HaCaT cells, while laminin-α5 chain gene knockdown decreased proliferation and induced apoptosis. These phenomenological observations raise the question of whether laminin-511-controlled keratinocyte growth/death may be a previously overlooked player in the pathogenesis of psoriatic epidermal lesions.

Case of alopecia induced by sorafenib, possible mechanism similar to alopecia areata

Dear Editor, Sorafenib is a multikinase inhibitor for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma. Sorafenib has been reported to cause many cutaneous sideeffects including hand–foot skin reaction, xerosis and alopecia. However, the mechanism by which sorafenib induces alopecia has not been well investigated. Here, we report a case of alopecia induced by sorafenib, which is histopathologically similar to alopecia areata (AA). A 21-year-old Japanese woman had been treated with sorafenib for hepatitis B virus-related hepatocellular carcinoma and multiple lung metastasis. Five days after the treatment, she noticed erythemas on her neck and back. There was no eruption on her scalp. Although she stopped taking sorafenib at day 9, the skin rash got worse. From histopathological findings of vacuolar dermatitis and clinical presentation, we diagnosed erythema multiforme induced by sorafenib. We started to treat her with oral prednisolone (PSL) at 30 mg/day in combination with topical glucocorticosteroid cream. Skin rash then gradually disappeared and we reduced the amount of PSL in accordance with the skin symptoms. Approximately 3 months after the beginning of sorafenib treatment, she felt sudden scalp hair loss without apparent bald patches (Fig. 1a). More than 10% of (dystrophic anagen) hairs in each bundle were pulled out. There were yellow dots on her scalp by trichoscopy which is a typical feature of AA. Histopathological examination of scalp skin specimens demonstrated an increased percentage of telogen hair follicles and the infiltration of inflammatory cells composed of lymphocytes, but not eosinophils around hair bulbs (Fig. 1b–d). Scanning electron microscopy revealed a sign of tapering hair (Fig. 1e) which is consistent with previously reported findings. Although there were no obvious bald patches, we suspected that similar mechanism to AA could also be induced in this case. To test this hypothesis, we further performed interferon (IFN)-c and major histocompatibility complex (MHC) class I immunohistochemistry. An increased number of IFN-c-positive cells and upregulated MHC class I expression around hair bulbs are reported to be deeply associated in the development of AA. In fact, the number of IFN-cpositive cells and MHC class I expression were increased around hair bulbs (Fig. 1f,g,i). Therefore, we treated her with topical glucocorticosteroid. Her hair loss gradually improved. As far as we know, there are no reports of alopecia induced by sorafenib whose mechanism is similar to that of AA. There is a possibility that the collapse of immune privilege (IP) characterized by IFN-c-positive cell migration/proliferation as well as increased MHC class I expression around the hair bulb was induced by sorafenib. In addition to the post-active phase of AA, there is another possibility of other hair diseases including telogen effluvium induced by a large amount of IFN-c. Therefore, the diagnosis must be considered very carefully. However, the observations by scanning electron microscopy and trichoscopy are not in line with telogen effluvium. Although further investigations for dissecting the effect of sorafenib on the collapse of IP are still needed, our case may contribute to unveiling the mechanism of alopecia induced by sorafenib.

Novel splice site mutation in the LIPH gene in a patient with autosomal recessive woolly hair/hypotrichosis: Case report and published work review

Autosomal recessive woolly hair is a relatively rare hereditary hair disorder characterized by sparse, short, curly hair. This condition is known to be caused by mutations in the LIPH gene, LPAR6 gene or KRT25 gene. In the Japanese population, most patients with autosomal recessive woolly hair carry one of two founder mutations in the LIPH gene, c.736T>A (p.Cys246Ser) or c.742C>A (p.His248Asn). However, occasionally, individuals with this condition carry compound heterozygous mutations, typically one founder mutation and another mutation. In this study, we describe a patient with a compound heterozygous mutation in the LIPH gene at c.736T>A and c.1095‐3C>G. The latter mutation created a novel splice site. This was the fourth splice site mutation to be described in the LIPH gene. Furthermore, we performed an in vitro transcription assay in cultured cells, and demonstrated that the c.1095‐3C>G mutation led to a frame‐shift, which created a premature termination codon at the protein level (p.Glu366Ilefs*7). Finally, we summarized the mutations previously reported for the LIPH gene. Our findings provide further clues as to the molecular basis of autosomal recessive woolly hair.

Case of alopecia similar to alopecia areata multilocularis accompanied with neurofibromatosis type 1.

autonomic function tests revealed that they had no specific disorders except for anhidrosis. However, some abnormalities existed in their serum biochemistry data, such as the elevation of aspartate aminotransferase, alanine aminotransferase, c-glutamyltransferase and alkaline phosphatase. Although we could not detect the specific autoantibody in these patients, some circumstantial evidences, especially in multiple organ dysfunction, pointed to these clinical manifestations as autoimmune diseases. Treatment involved IVIG infusions (400 mg/kg) during 3–4 h for 5 days. From 1 week after the beginning of the treatment, the skin of both patients tended to be wet, and approximately 3 weeks after the start of treatment, generalized sweating was confirmed (Fig. 1b). Moreover, these patients have had no recurrence for a long period. As an interesting finding, both patients also manifested improved liver function at least 3 weeks after IVIG treatment. Onaka et al. described a 43-year-old woman who had acute idiopathic pandysautonomia complicated by acute pancreatitis or liver injury. It is also possible that our two patients had an autoimmune hepatitis affected by AIGA. Although the association of these two disease entities has never been reported before, the clinical association between multiple sclerosis and autoimmune hepatitis is known. Recent data indicate that the presence of anti-PGAM1 autoantibody is a common finding in both autoimmune hepatitis and immune-mediated neurological diseases such as multiple sclerosis and neuromyelitis optica. Novel autoantibodies may occur in both autoimmune hepatitis and AIGA, which may suggest a common immunological background. In conclusion, IVIG may be an effective therapeutic agent for patients with AIGA, especially those with liver injury and repeated recurrences. ACKNOWLEDGMENTS: This work was supported in part by JSPS KAKENHI, Grant-in-Aid for Young Scientists (B) 15K19184, and Grant-in-Aid for Scientific Research (C) 15K08620.

A case of scarring alopecia with Kikuchi-Fujimoto disease.

A case of scarring alopecia with Kikuchi–Fujimoto disease Editor, Irreversible damage to the hair follicle (HF) resulting in permanent hair loss characterizes the cicatricial alopecias, which are associated with several diseases (e.g. lupus erythematosus), infection, and tumors. Kikuchi–Fujimoto disease (KFD) is a rare, benign, autoimmune condition characterized by lymphadenopathy, fever, and neutropenia. However, no case reports of cicatricial alopecia accompanying KFD have been published. Here, we report for the first time a case of cicatricial alopecia associated with KFD. A 25-year-old man initially presented with fever and tender cervical lymph nodes on the right side 1 year prior