Clinical Profiles of Japanese Patients with Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Collected by a Nationwide System from 2006 to 2023.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are potentially life-threatening severe cutaneous adverse drug reactions. These diseases are rare, and their onset is difficult to predict because of their idiosyncratic reactivity. The Japan Severe Adverse Reactions Research Group, led by the National Institute of Health Sciences, has operated a nationwide to collect clinical information and genomic samples from patients with SJS/TEN since 2006. This study evaluated the associations of clinical symptoms with sequelae and specific causative drugs/drug groups in Japanese patients with SJS/TEN to identify clinical clues for SJS/TEN treatment and prognosis. Acetaminophen, antibiotics, and carbocisteine were linked to high frequencies of severe ocular symptoms and ocular sequelae (p < 0.05). For erythema and erosion areas, antipyretic analgesics had higher rates of skin symptom affecting <10% of the skin than the other drugs, suggesting narrower lesions (p < 0.004). Hepatic dysfunction, was common in both SJS and TEN, and antiepileptic drugs carried higher risks of hepatic dysfunction than the other drug groups (p = 0.0032). This study revealed that the clinical manifestations of SJS/TEN vary according to the causative drugs.

Bexarotene-induced hypothyroidism and dyslipidemia; a nation-wide study.

Central hypothyroidism and dyslipidemia are well-known adverse events (AEs) of bexarotene therapy. Although hypothyroidism is known to cause dyslipidemia, no study has examined the association between hypothyroidism and dyslipidemia in patients undergoing bexarotene therapy. The aim of this study is to examine this association. A retrospective observational study was performed among 294 patients who initiated bexarotene therapy in Japan (nation-wide postmarketing complete surveillance). Jonckheere-Terpstra (one sided) test was performed to evaluate the effect of the bexarotene dose on lipid metabolisms, and regression analyses were performed to evaluate associations of bexarotene dose, free thyroxine (FT4), body mass index (BMI), and lipid metabolisms. Most patients developed hypothyroidism. Two-third of patients showed FT4 values below the lower limit at 1 week. Triglycerides (TG) increased in a bexarotene dose-dependent manner, and grade ≥3 AEs on hypertriglyceridemia was observed in 39% of the patients. Additionally, one-third of grade ≥3 AEs on hypertriglyceridemia occurred within 1 week. The delta_FT4 (difference in FT4 from baseline) negatively correlated with TG increase at 1 week (p = 0.012) but not with low density lipoprotein cholesterol (LDL-C) increase at any week. Bexarotene-induced hypothyroidism is almost inevitable and occurred quickly. Bexarotene-induced hypertriglyceridemia showed positive bexarotene dose dependency and negative delta_FT4 dependency. Prophylactic and appropriate thyroid hormone compensation therapy and starting bexarotene at low doses with subsequent titration while managing dyslipidemia may have a beneficial effect for the successful continuation of bexarotene therapy without severe endocrine and metabolic AEs.

Interleukin-18 as a severity marker and novel potential therapeutic target for epidermolytic ichthyosis.

BACKGROUND: Epidermolytic ichthyosis (EI) is a major form of nonsyndromic inherited ichthyosis, characterized by erythroderma, marked hyperkeratosis and scale, bulla and erosion at birth, associated with KRT1/KRT10 mutations. The cytokine and chemokine profiles in EI are poorly understood, and specific treatment options have not been established. AIM: To explore novel biomarkers and therapeutic targets in patients with EI. METHODS: We analysed cytokine levels in serum and skin samples from 10 patients with inherited ichthyosis, including seven patients with EI. Wild-type and mutant KRT1 constructs were established and transfected into HaCaT cells, an immortalized keratinocyte cell line, for in vitro immunoblotting and immunocytochemistry analyses. RESULTS: Multiplex cytokine/chemokine analysis revealed that 10 cytokines/chemokines [interleukin (IL)-1ß, IL-4, IL-17A, IL-16, IL-18, IL-1 receptor-α, macrophage colony-stimulating factor, interferon-α2, basic fibroblast growth factor and monocyte chemotactic protein-3] were significantly increased in patients with EI. Furthermore, IL-18 levels were significantly higher in patients with EI [n = 7; 2714.1 (1438.0) pg mL-1] than in healthy controls [n = 11; 218.4 (28.4) pg mL-1, P < 0.01]. Immunohistochemical analyses showed that IL-18 expression was elevated in skin samples from patients with EI. Serum IL-18 levels correlated with the severity of ichthyosis, as measured by the Ichthyosis Scoring System. Immunoblotting analysis revealed that mature IL-18 levels were increased in the supernatant of mutant KRT1 expressing HaCaT cells. Additionally, these cells showed NLRP3 aggregation in the cytoplasm and ASC clustered around mutant keratin aggregations. These findings suggest that mutant keratin might promote the activation of the NLRP3 inflammasome and its downstream caspase-1-mediated IL-18 release in keratinocytes from patients with EI. CONCLUSIONS: Our results suggest that serum IL-18 is a severity marker released from the skin of patients with EI. Blockade of IL-18 may be a useful novel therapeutic option for patients with EI.

A case of cutaneous syncytial myoepithelioma with extensive adipocytic metaplasia: Usefulness of EWSR1-PBX3 gene fusion analysis.

Cutaneous syncytial myoepithelioma (CSM) is a recently recognized variant of myoepithelioma characterized by an intradermal syncytial proliferation of spindled, ovoid, and histiocytoid cells. Immunohistochemically, tumor cells usually show strong expression of S-100 protein and epithelial membrane antigen (EMA). Here we report a case of CSM in the thigh of a 51-year-old Japanese woman. Histopathological findings showed a sheet-like growth of ovoid cells and histiocytoid cells with an eosinophilic syncytial cytoplasm, and adipocytic metaplasia was widely observed in the tumor. Immunohistochemical staining revealed a diffuse, strong pattern for EMA, smooth muscle actin (SMA), and HHF35, and variable expression of S-100 protein and p63 in ovoid and histiocytoid cells without significant mitotic figures or pleomorphism. In addition, EWSR1-PBX3 gene fusion, which is characteristic of CSM, was observed in the tumor. Based on these findings, we diagnosed the patient as having CSM. Our case shows that CSM can exhibit extensive adipocytic metaplasia, which could make its histopathological diagnosis challenging.

Risk factors for lymph node metastasis in cutaneous squamous cell carcinoma: a long-term retrospective study of Japanese patients.

BACKGROUND: Cutaneous squamous cell carcinoma (CSCC) is one of the most common skin cancers. Prognosis is favorable following surgical resection of early-stage disease, but the management of the metastatic disease is challenging. Several prognostic risk factors have been described in the American Joint Committee on Cancer/the Union for International Cancer Control (UICC) 8th edition staging and the Brigham and Women's Hospital T classification system. However, their clinical validity in Asian populations is unclear because of racial differences in the clinical characteristics of CSCC. This study aimed to identify factors that could predict lymph node metastasis in Asian patients. METHODS: This retrospective single-center study evaluated 540 patients with primary CSCC between 1989 and 2013. Five factors were evaluated for their ability to predict lymph node metastasis: maximum tumor diameter, tumor thickness, depth of invasion, degree of differentiation, and infiltrative growth pattern (INF). RESULTS: Tumor diameter > 2 cm (p < 0.0001), tumor thickness > 6 mm (p < 0.0001), invasion beyond the subcutaneous fat (p < 0.0001), poor differentiation (p = 0.042), and INFc infiltration (p < 0.0001) were associated with lymph node metastasis in the univariate analyses. In the multivariate analysis, lymph node metastasis was independently associated with tumor size > 2 cm [hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.4-6.2; p = 0.006], tumor thickness > 6.0 mm (HR 2.9, 95% CI 1.3-6.4; p = 0.007), and invasion beyond the subcutaneous fat (HR 2.3, 95% CI 1.0-5.1; p = 0.045). CONCLUSION: Larger tumor diameter, greater tumor thickness, and deeper invasion included in the UICC T classification system are associated with increased risks of lymph node metastasis from CSCC in Japanese patients.

Seronegative Oligoarthritis Preceding Psoriasis by 9.5 Years.

We report a case of psoriatic arthritis where oligoarthritis preceded the skin lesions. A 57-year-old man complained of left third-finger pain. Laboratory examinations were negative for anti-cyclic citrullinated peptide antibodies and rheumatoid factor; he was treated for suspected rheumatoid arthritis. Six years later, X-ray revealed enthesitis of his fingers and wrist joint. At 9.5 years after the initial visit, skin lesions appeared in the left auricular region and buttock and dermatopathology findings indicated psoriasis vulgaris. The final diagnosis was psoriatic arthritis. In cases of seronegative oligoarthritis, psoriatic arthritis must be considered because some patients demonstrate osteoarticular lesions preceding skin lesions.

Blockade of TNF receptor superfamily 1 (TNFR1)-dependent and TNFR1-independent cell death is crucial for normal epidermal differentiation.

BACKGROUND: A delicate balance between cell death and keratinocyte proliferation is crucial for normal skin development. Previous studies have reported that cellular FLICE (FADD-like ICE)-inhibitory protein plays a crucial role in prevention of keratinocytes from TNF-α-dependent apoptosis and blocking of dermatitis. However, a role for cellular FLICE-inhibitory protein in TNF-α-independent cell death remains unclear. OBJECTIVE: We investigated contribution of TNF-α-dependent and TNF-α-independent signals to the development of dermatitis in epidermis-specific Cflar-deficient (CflarE-KO) mice. METHODS: We examined the histology and expression of epidermal differentiation markers and inflammatory cytokines in the skin of CflarE-KO;Tnfrsf1a+/- and CflarE-KO;Tnfrsf1a-/- mice. Mice were treated with neutralizing antibodies against Fas ligand and TNF-related apoptosis-inducing ligand to block TNF-α-independent cell death of CflarE-KO;Tnfrsf1a-/- mice. RESULTS: CflarE-KO;Tnfrsf1a-/- mice were born but experienced severe dermatitis and succumbed soon after birth. CflarE-KO;Tnfrsf1a+/- mice exhibited embryonic lethality caused by massive keratinocyte apoptosis. Although keratinocytes from CflarE-KO;Tnfrsf1a-/- mice still died of apoptosis, neutralizing antibodies against Fas ligand and TNF-related apoptosis-inducing ligand substantially prolonged survival of CflarE-KO;Tnfrsf1a-/- mice. Expression of inflammatory cytokines, such as Il6 and Il17a was increased; conversely, expression of epidermal differentiation markers was severely downregulated in the skin of CflarE-KO;Tnfrsf1a-/- mice. Treatment of primary keratinocytes with IL-6 and, to a lesser extent, IL-17A suppressed expression of epidermal differentiation markers. CONCLUSION: TNF receptor superfamily 1 (TNFR1)-dependent or TNFR1-independent apoptosis of keratinocytes promotes inflammatory cytokine production, which subsequently blocks epidermal differentiation. Thus blockade of both TNFR1-dependent and TNFR1-independent cell death might be an alternative strategy to treat skin diseases when treatment with anti-TNF-α antibody alone is not sufficient.

Electron Microscopic and Immunohistochemical Findings of the Epidermal Basement Membrane in Two Families with Nail-patella Syndrome.

Nail-patella syndrome is an autosomal dominant disorder characterized by nail dysplasia and skeletal anomaly. Some patients have been shown to have ultrastructural abnormalities of the glomerular basement membrane that result in nephrosis. However, little has been reported on the epidermal basement membrane in this condition. This paper reports 2 families with nail-patella syndrome. Direct sequencing analysis of LMX1B revealed that family 1 and family 2 were heterozygous for the mutations c.140-1G>C and c.326+1G>C, respectively. To evaluate the epidermal basement membrane zone, ultrastructural and immunohistochemical analyses were performed using skin specimens obtained from the dorsal thumb. Electron microscopy showed intact hemidesmosomes, lamina lucida, lamina densa, and anchoring fibrils. Immunofluorescence studies with antibodies against components of the epidermal basement membrane zone revealed a normal expression pattern among the components, including type IV collagen. These data suggest that nail dysplasia in patients with nail-patella syndrome is not caused by structural abnormalities of the epidermal basement membrane.

Mutations in SDR9C7 gene encoding an enzyme for vitamin A metabolism underlie autosomal recessive congenital ichthyosis.

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of hereditary skin disorder characterized by an aberrant cornification of the epidermis. ARCI is classified into a total of 11 subtypes (ARCI1-ARCI11) based on their causative genes or loci. Of these, the causative gene for only ARCI7 has not been identified, while it was previously mapped on chromosome 12p11.2-q13.1. In this study, we performed genetic analyses for three Lebanese families with ARCI, and successfully determined the linkage interval to 9.47 Mb region on chromosome 12q13.13-q14.1, which was unexpectedly outside of the ARCI7 locus. Whole-exome sequencing and the subsequent Sanger sequencing led to the identification of missense mutations in short chain dehydrogenase/reductase family 9C, member 7 (SDR9C7) gene on chromosome 12q13.3, i.e. two families shared an identical homozygous mutation c.599T > C (p.Ile200Thr) and one family had another homozygous mutation c.214C > T (p.Arg72Trp). In cultured cells, expression of both the mutant SDR9C7 proteins was markedly reduced as compared to wild-type protein, suggesting that the mutations severely affected a stability of the protein. In normal human skin, the SDR9C7 was abundantly expressed in granular and cornified layers of the epidermis. By contrast, in a patient's skin, its expression in the cornified layer was significantly decreased. It has previously been reported that SDR9C7 is an enzyme to convert retinal into retinol. Therefore, our study not only adds a new gene responsible for ARCI, but also further suggests a potential role of vitamin A metabolism in terminal differentiation of the epidermis in humans.

CADM1 is a diagnostic marker in early-stage mycosis fungoides: Multicenter study of 58 cases.

BACKGROUND: Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma. Early-stage MF patches or plaques often resemble inflammatory skin disorders (ISDs), including psoriasis and atopic dermatitis. Cell adhesion molecule 1 gene (CADM1), which was initially identified as a tumor suppressor gene in human non-small cell lung cancer, has been reported as a diagnostic marker for adult T-cell leukemia/lymphoma. OBJECTIVE: We investigated CADM1 expression in MF neoplastic cells, especially during early stages, and evaluated its usefulness as a diagnostic marker for MF. METHODS: We conducted a retrospective study by using immunohistochemical staining and confirmed the expression of CADM1 in MF. In addition, we compared CADM1 messenger RNA expression in microdissected MF samples and ISD samples. RESULTS: In the overall study period, 55 of 58 MF samples (94.8 %) stained positive for CADM1. None of the 50 ISD samples showed positive reactivity (P < .0001). We found CADM1 messenger RNA expression in the intradermal lymphocytes of patients with MF but not in those of patients with an ISD. LIMITATIONS: We did not conduct a validation study for MF cases in other institutions. CONCLUSIONS: CADM1-positive cells can be identified in early stages with fewer infiltrating cells and may be useful as a diagnostic marker for early-stage MF.

Allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning for mycosis fungoides and Sezary syndrome.

Advanced-stage mycosis fungoides and Sezary syndrome (MF/SS) have a poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT), particularly using a reduced-intensity conditioning (RIC) regimen, is a promising treatment for advanced-stage MF/SS. We performed RIC-HSCT in nine patients with advanced MF/SS. With a median follow-up period of 954 days after HSCT, the estimated 3-year overall survival was 85.7% (95% confidence interval, 33.4-97.9%) with no non-relapse mortality. Five patients relapsed after RIC-HSCT; however, in four patients whose relapse was detected only from the skin, persistent complete response was achieved in one patient, and the disease was manageable in other three patients by the tapering of immunosuppressants and donor lymphocyte infusion, suggesting that graft-versus-lymphoma effect and 'down-staging' effect from advanced stage to early stage by HSCT improve the prognosis of advanced-stage MF/SS. These results suggest that RIC-HSCT is an effective treatment for advanced MF/SS.