A case of anti-SAE1/2 antibody-positive dermatomyositis with extensive panniculitis: A possible cutaneous manifestation of treatment resistance.

Dermatomyositis constitutes a heterogeneous group of autoimmune inflammatory conditions with a wide variety of clinical outcomes. The symptomatic heterogeneity carries skin, muscle, and joint manifestations; pulmonary and cardiac involvements; and concomitant malignancy. Any of these symptoms often appear at different combinations and time courses, thus posing difficulty in early diagnosis and appropriate treatment choice. Recent progress in laboratory investigations explored the identification of several myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies, allowing precise characterization for a clinical perspective of the disease. MSAs can be detectable in approximately 80% of patients with whole dermatomyositis, some of which closely reflect unique clinical features in the particular disease subset(s), including the distribution and severity of organ involvement, treatment response, and prognosis. However, only limited evidence has been available in dermatomyositis-associated panniculitis, mostly that in anti- melanoma differentiation-associated protein 5 antibody-positive disease. We present a rare case of a patients with dermatomyositis with extensive panniculitis on the trunk whose serum IgG autoantibodies reacted with both subunits of small ubiquitin-like modifier activating enzymes (SAEs), SAE1 and SAE2. The onset of panniculitis coincided with increased disease activity, including disease-related skin manifestations, fever, dysphagia, and muscle weakness in the extremities. These symptoms responded well to a high dose of systemic steroid, but even upon receiving a high-dose intravenous immunoglobulin, the panniculitic lesions and pruritic erythema flared with tapering of steroid dose, further requiring tacrolimus and mycophenolate mofetil to achieve disease remission. To our knowledge, this is the third reported case of anti-SAE autoantibody-positive dermatomyositis with panniculitis. We aim to extend the understanding of the current limitation and further perspective in the clinical management of the extremely rare skin manifestation associated with dermatomyositis.

A cysteine proteinase inhibitor ALLN alleviates bleomycin-induced skin and lung fibrosis.

BACKGROUND: Systemic sclerosis (SSc) is a connective tissue disease that is characterized by fibrosis in the skin and internal organs, such as the lungs. Activated differentiation of progenitor cells, which are mainly resident fibroblasts, into myofibroblasts is considered a key mechanism underlying the overproduction of extracellular matrix and the resultant tissue fibrosis in SSc. Calpains are members of the Ca2+-dependent cysteine protease family, whose enzymatic activities participate in signal transduction and tissue remodeling, potentially contributing to fibrosis in various organs. However, the roles of calpain in the pathogenesis of SSc remain unknown. This study aimed to examine the anti-fibrotic properties of N-acetyl-Leu-Leu-norleucinal (ALLN), one of the cysteine proteinase inhibitors that primarily inhibit calpain, in vitro and in vivo, to optimally translate into the therapeutic utility in human SSc. METHODS: Normal human dermal and lung fibroblasts pretreated with ALLN were stimulated with recombinant transforming growth factor beta 1 (TGF-ß1), followed by assessment of TGF-ß1/Smad signaling and fibrogenic molecules. RESULTS: ALLN treatment significantly inhibited TGF-ß1-induced phosphorylation and nuclear transport of Smad2/3 in skin and lung fibroblasts. TGF-ß1-dependent increases in α-smooth muscle actin (αSMA), collagen type I, fibronectin 1, and some mesenchymal transcription markers were attenuated by ALLN. Moreover, our findings suggest that ALLN inhibits TGF-ß1-induced mesenchymal transition in human lung epithelial cells. Consistent with these in vitro findings, administering ALLN (3 mg/kg/day) three times a week intraperitoneally remarkably suppressed the development of skin and lung fibrosis in a SSc mouse model induced by daily subcutaneous bleomycin injection. The number of skin- and lung-infiltrating CD3+ T cells decreased in ALLN-treated mice compared with that in control-treated mice. Phosphorylation of Smad3 and/or an increase in αSMA-positive myofibroblasts was significantly inhibited by ALLN treatment on the skin and lungs. However, no adverse effects were observed. CONCLUSIONS: Our results prove that calpains can be a novel therapeutic target for skin and lung fibrosis in SSc, considering its inhibitor ALLN.

Evaluation of prognostic prediction ability of the novel Japanese risk factor scoring system in a Japanese cohort of resectable cutaneous squamous cell carcinoma: A retrospective cross-sectional study.

Japanese patients with very high-risk cutaneous squamous cell carcinomas (cSCCs), based on the National Comprehensive Cancer Network guidelines, have been reported to display a higher cumulative incidence of relapse and disease-specific death (DSD) than those with high-risk cSCC. Therefore, prognosis prediction is crucial for Japanese patients with very high-risk cSCCs. Herein, we aimed to evaluate the prognostic prediction ability of our novel Japanese Risk Factor Scoring Systems (JARF scoring) in a Japanese cohort of cSSC patients. Data of 424 Japanese patients with resectable very high-risk cSCCs were analysed. We compared the prognostic ability of the following three staging systems: Brigham and Women's Hospital (BWH) tumour staging, number of NCCN very high-risk factors, and JARF scoring, including recurrent tumour, high-risk histological features, deep tumour invasion and lymphatic or vascular involvement as risk factors. The prognostic ability of these staging systems was evaluated according to the cumulative incidence of local recurrence (LR), regional lymph node metastasis (RLNM), DSD, and overall survival (OS). When BWH staging was used, high T stage led to significantly poor outcomes only in the cumulative incidence of RLNM (p = 0.01). The presence of very high-risk NCCN factors led to significantly poor outcomes in terms of RLNM (p = 0.03) and OS (p = 0.02). Meanwhile, a high number of risk factors in the JARF scoring system clearly led to poor outcomes in terms of LR (p = 0.01), RLNM (p < 0.01), DSD (p = 0.03), and OS (p < 0.01). The JARF scoring system may accurately predict the risk of recurrence and death in very high-risk cSCC patients in Japan.

Lichen Sclerosus: A Current Landscape of Autoimmune and Genetic Interplay.

Lichen sclerosus (LS) is an acquired chronic inflammatory dermatosis predominantly affecting the anogenital area with recalcitrant itching and soreness. Progressive or persistent LS may cause urinary and sexual disturbances and an increased risk of local skin malignancy with a prevalence of up to 11%. Investigations on lipoid proteinosis, an autosomal recessive genodermatosis caused by loss-of-function mutations in the extracellular matrix protein 1 (ECM1) gene, led to the discovery of a humoral autoimmune response to the identical molecule in LS, providing evidence for an autoimmune and genetic counterpart targeting ECM1. This paper provides an overview of the fundamental importance and current issue of better understanding the immunopathology attributed to ECM1 in LS. Furthermore, we highlight the pleiotropic action of ECM1 in homeostatic and structural maintenance of skin biology as well as in a variety of human disorders possibly associated with impaired or gained ECM1 function, including the inflammatory bowel disease ulcerative colitis, Th2 cell-dependent airway allergies, T-cell and B-cell activation, and the demyelinating central nervous system disease multiple sclerosis, to facilitate sharing the concept as a plausible therapeutic target of this attractive molecule.

Retrospective evaluation of the utility of two-step surgery for facial basal cell carcinoma and squamous cell carcinoma.

In older patients with facial basal cell carcinoma (BCC) or squamous cell carcinoma (SCC), surgery should be aimed to reduce treatment-related sequelae and burden with achieving local tumor care. Therefore, we adopted a two-step surgery (TSS) involving the application of a dermal regeneration template onto the skin defect after tumor resection and subsequent reconstruction by full-thickness skin grafting. We performed a detailed comparison of conventional one-step surgery (OSS) and TSS, including evaluation of local tumor curability, postoperative cosmetic and/or functional impairments, and patient burden. Forty-six patients who underwent TSS and 104 patients treated with OSS were retrospectively investigated. The cohort consisted of 77 men and 73 women (median age, 83 years). The BCC: SCC ratio was 56.7%: 43.3%. The tumor size and excision margin were significantly larger in the TSS group than in the OSS group (p = 0.03). The histopathological margin was positive after the first surgery in six cases, but was negative after additional resection in all cases, regardless of OSS or TSS. Local recurrence was not observed in this study. The frequency of postoperative sequelae (POS) in TSS was slightly lower than in OSS (17.4% vs. 27.9%, p = 0.16). A shorter average operation time per session was significantly associated with the location of the vertical defect [below adipose tissue vs. within adipose tissue, estimate: -0.28 (hour), p < 0.001] and surgical procedure [OSS vs. TSS, estimate: -0.13 (hour), p = 0.03] by multiple regression models. The ratio of general anesthesia was relatively lower in TSS than in OSS (9.8% vs. 17.3%, p = 0.12). Thus, TSS showed a good local curability and POS statistically equivalent to OSS, reducing the surgical burden, particularly shortening each operation time without any adverse events, despite the TSS group having significantly larger tumors than the OSS group. Since TSS is a simple procedure, it can be an outstanding option for facial BCC and SCC.

A rare case of eosinophilic gastritis induced by nivolumab therapy for metastatic melanoma.

Cancer immunotherapy using immune checkpoint inhibitors can cause immune reactions at various sites as a side effect called immune-related adverse events (irAEs). The gastrointestinal tract is susceptible to irAEs, however, the degree and presentation vary considerably from case to case. A 76-year-old woman was diagnosed with anal mucosal melanoma. She underwent radical surgery and received postoperative adjuvant therapy. However, because new metastases were also found in bilateral inguinal lymph nodes, immunotherapy with nivolumab was performed. Approximately 10 months after the initiation of nivolumab administration, she presented with epigastric discomfort and nausea, and her laboratory data showed severe eosinophilia (1938/mm3). Computed tomography demonstrated a diffuse thickening of the gastric wall. Esophagogastroduodenoscopy and endoscopic ultrasonography showed mucosal thickening due to edema, and histologic examination revealed severe invasion of eosinophils in the lamina propria. Subsequently, she was diagnosed with eosinophilic gastritis due to irAEs induced by nivolumab. Oral administration of prednisolone rapidly normalized her endoscopic and histologic findings, dramatically reducing her symptoms. This is a very rare and important case report of nivolumab-induced severe eosinophilic gastritis. Although gastric lesions as IrAEs is rare, it is necessary to differentiate eosinophilic gastritis if unexplained nausea occurred during the administration of immune checkpoint inhibitors.

Knapperer Resektionsrand bei Plattenepithelkarzinomen mit hohem oder sehr hohem Risiko: eine retrospektive multizentrische Studie mit 1000 Patienten.

HINTERGRUND UND ZIELE: Bei kutanen Plattenepithelkarzinomen (PEK) ist die Einhaltung der in Leitlinien empfohlenen festen Resektionsränder oft schwierig und knappere Ränder sind wünschenswert. Ziel dieser Studie war die Bewertung des Auftretens von Rezidiven und krankheitsspezifischen Todesfällen bei knapperen Resektionsrändern für PEK mit hohem oder sehr hohem Risiko. PATIENTEN/METHODEN: PEK-Patienten mit hohem oder sehr hohem Risiko, bei denen eine Tumorexzision durchgeführt wurde, wurden retrospektiv untersucht. Die Patienten wurden in eine Gruppe mit Standardrand gemäß Leitlinienempfehlung (standard margin group, SMG) und eine Gruppe mit knapperen Rändern (narrower-margin group, NMG) eingeteilt. Gemeinsame primäre Endpunkte waren lokales Rezidiv, PEK-Rezidiv und PEK-bedingter Tod. Die Wahrscheinlichkeit eines PEK-bedingten Tods und konkurrierender Mortalitätsrisiken wurde mittels kumulativer Inzidenzfunktion (CIF) beschrieben. Unterschiede bei der CIF zwischen den Gruppen wurden mit dem Test nach Gray verglichen. ERGEBNISSE: Insgesamt wurden 1.000 Patienten mit PEK (hohes Risiko, 570; sehr hohes Risiko, 430) eingeschlossen. In der Kohorte mit hohem Risiko gab es keine signifikanten Unterschiede bei der unvollständigen Exzisionsrate (IER) zwischen SMG und NMG (2,6 % vs. 3,0 %, P > 0,99). In der Kohorte mit sehr hohem Risiko war die IER in der SMG jedoch signifikant geringer als in der NMG (8.9 % vs. 16.2 %, P = 0,03). Keine signifikanten Unterschiede zwischen SMG und NMG wurden für Lokalrezidiv (hohes Risiko, P = 0.56; sehr hohes Risiko, P = 0,70), PEK-Rezidiv (hohes Risiko, P = 0,30; sehr hohes Risiko, P = 0,47) und PEK-bedingtem Tod (hohes Risiko, P = 0,23; sehr hohes Risiko, P = 0,83) beobachtet. SCHLUSSFOLGERUNGEN: Die Größe des Resektionsrands hat einen begrenzten Einfluss auf Randkontrolle, Rezidive und krankheitsspezifischen Tod bei PEK mit hohem Risiko.

Narrower clinical margin in high or very high-risk squamous cell carcinoma: a retrospective, multicenter study of 1,000 patients.

BACKGROUND AND OBJECTIVES: In cutaneous squamous cell carcinoma (cSCC), adherence to guideline-recommended fixed surgical margins is often difficult, and narrower margins are preferable. This study aimed to evaluate relapse and disease-specific death with narrower margins for high or very high-risk cSCC. PATIENTS/METHODS: We retrospectively investigated high or very high-risk cSCC patients who underwent tumor excision. Patients were divided into guideline-recommended standard margin group (SMG) and narrower-margin group (NMG). Co-primary outcomes were local relapse, SCC relapse, and SCC death. Cumulative incidence function (CIF) was used to describe SCC death probability and competing risk mortality. Gray's test was used to compare differences in CIF between the groups. RESULTS: In total, 1,000 patients with cSCC (high-risk, 570; very high-risk, 430) were included. In the high-risk cohort, there were no significant differences in incomplete excision rate (IER) between SMG and NMG (2.6 % vs. 3.0 %, P > 0.99). However, in the very high-risk cohort, IER in SMG was significantly lower than in NMG (8.9 % vs. 16.2 %, P = 0.03). No significant differences were observed between SMG and NMG for local relapse (high-risk, P = 0.56; very high-risk, P = 0.70), SCC relapse (high-risk, P = 0.30; very high-risk, P = 0.47), and SCC death (high-risk, P = 0.23; very high-risk, P = 0.83). CONCLUSIONS: Surgical margin size has limited impact on margin control, relapse, and disease-specific death in high-risk cSCC.

Involvement of the Peripheral µ-Opioid Receptor in Tramadol-Induced Constipation in Rodents.

Tramadol is a weak opioid that produces analgesic effect via both the µ-opioid receptor (MOR) and non-opioid targets. Constipation is the most common opioid-related side effect in patients with cancer and non-cancer pain. However, the contribution of MOR to tramadol-induced constipation is unclear. Therefore, we used naldemedine, a peripherally acting MOR antagonist, and MOR-knockout mice to investigate the involvement of peripheral MOR in tramadol-induced constipation using a small intestinal transit model. A single dose of tramadol (3-100 mg/kg, per os (p.o.)) inhibited small intestinal transit dose-dependently in rats. Naldemedine (0.01-10 mg/kg, p.o.) blocked the inhibition of small intestinal transit induced by tramadol (30 mg/kg, p.o.) in rats. The transition rate increased dose-dependently over the range of naldemedine 0.01-0.3 mg/kg, and complete recovery was observed at 0.3-10 m/kg. Additionally, tramadol (30 and 100 mg/kg, subcutaneously (s.c.)) inhibited small intestinal transit in wild-type mice but not in MOR-knockout mice. These results suggest that peripheral MOR participates in tramadol-induced constipation.

Long-standing refractory hidradenitis suppurativa responded to a brodalumab monotherapy in a patient with psoriasis: A possible involvement of Th17 across the spectrum of both diseases.

Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic inflammatory skin disease mainly affecting apocrine gland-rich areas of the body with painful nodules, persisted abscess, sinus tracts, and scarring. The etiopathology of HS remains unclearly understood, but the disease is considered as a polygenic autoinflammation condition originating from follicular hyperkeratosis and occlusion. Recent advances concerning the substantial roles of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-17, and IL-23 have accelerated in developing a repertoire of therapeutic biologics in HS. Currently five biologics antagonistic for these different cytokines, adalimumab, anakinra, etanercept, infliximab, and ustekinumab, have been explored in the treatment setting of HS; however, only limited evidence is available for the therapeutic advantage of IL-17 pathway blockade. We present a 47-year-old Japanese man who had a long-standing, debilitating HS complicated with psoriasis, both of which were refractory to a series of the standard treatment. Not only psoriatic skin but also HS lesions responded dramatically to brodalumab, an IL-17 receptor antagonist, accompanied with decrease of validated assessments, namely the Hurley's staging classification and modified Sartorius score. Brodalumab was well tolerated with rapid improvement and no adverse reaction, and finally gave a satisfactory maintenance of disease remission. To our best knowledge, this is the first successful use of anti-IL-17 receptor antibody in a Japanese case with coexistence of HS and psoriasis. We also discuss extending understanding of the potential benefit and current limitation of brodalumab in the treatment of HS.

Fatal case of pancreatic panniculitis caused by occult neuroendocrine tumor in the corresponding organ: A case report and review of the published work.

Pancreatic panniculitis (PP) is a rare clinical variant of subcutaneous fat necrosis, developing in patients with a variety of pancreatic diseases such as acute or chronic pancreatitis, tumors and cysts. The tumor-associated PP represents a noteworthy skin manifestation of underlying internal malignancies, also known as dermadrome. Among causative pancreatic tumors, acinar cell carcinoma is the most frequent malignancy; however, little is known about how the origin of tumor cells and progression stage of pancreatic tumors potentially contribute to the establishment of panniculitis. Here, we present a 69-year-old Japanese male case of clinically aggressive PP on the bilateral legs, whose skin lesions developed prior to the diagnosis of occult pancreatic tumor and liver metastasis. Moreover, the immunopathology of the pancreatic lesion revealed neuroendocrine tumor (NET), a rare pathological variant. Skin lesions immediately spread to the upper limbs with extensive ulcerations and necrosis, accompanied by high levels of serum lipase and elastase, but not with other pancreatic enzymes. He died 2 months after the initial development of the skin lesion due to rapid deterioration of general condition. We reviewed 14 cases, including ours, of PP with NET in the pancreas thus far reported, to identify the clinicopathological characteristics regarding to what extent this rare complication could reflect the clinical course of pancreatic tumors and overall prognosis. Our published work review found that the disease has a significant male predominance (male : female, 13:1) and cases with occult pancreatic tumors died within 4 months after the development of their skin lesions. Our case was the poorest prognostic outcome. This report emphasizes that dermatologists should recognize PP with NET, reflecting a fatal prognosis, and to make a prompt diagnosis.

Gene silencing of extracellular matrix protein 1 (ECM1) results in phenotypic alterations of dermal fibroblasts reminiscent of clinical features of lichen sclerosus.

BACKGROUND: Lichen sclerosus (LS) is an acquired inflammatory mucocutaneous disease affecting the anogenital area, characterized histologically by hyalinosis and thickened vessel walls in the dermis. The presence of serum autoantibodies against extracellular matrix protein 1 (ECM1) in LS patients may suggest its involvement in disease pathogenesis. OBJECTIVE: To examine if reduced ECM1 production by dermal fibroblasts contributes to the pathogenic features of LS. METHODS: Gene expression in ECM1 knockdown human dermal fibroblasts was analyzed by cDNA microarray. Functional enrichment for genes involved in cellular functions was conducted. Protein expression was analyzed by ELISA and confocal laser scanning microscopy using LS skin. RESULTS: Microarray analysis identified 3035 differentially expressed genes in ECM1 knockdown cells, wherein 1471 were upregulated genes related exclusively to cell adhesion, proliferation, apoptosis, intracellular signaling, and extracellular matrix organization. Further narrowing with criteria specific for localization and function of ECM1 identified 48 upregulated genes identified to have structural, fibrogenic, and carcinogenic properties. Of these, laminin-332 and collagen-IV displayed altered immunolabeling within the basement membrane zone (BMZ) and dermal vessels in LS skin, similar to that of collagen-VII, which exhibited unchanged transcription levels in ECM1-knockdown fibroblasts. Collagen-VII bound to recombinant ECM1 in a solid-phase immunoassay and colocalized with ECM1 in the skin BMZ. Further, ECM1-knockdown fibroblasts exhibited a marked delay in cell migration and gel contraction. CONCLUSION: In the absence of ECM1 expression in fibroblasts there is selective dysregulation and disassembly of structural and extracellular matrix molecules, which may result in microstructural abnormalities reminiscent of LS.

Association of functional (GA)n microsatellite polymorphism in the FLI1 gene with susceptibility to human systemic sclerosis.

OBJECTIVE: Susceptibility genes that can account for characteristic features of SSc such as fibrosis, vasculopathy and autoimmunity remain to be determined. In mice, deficiency of Friend leukaemia integration 1 transcription factor (Fli1) causes SSc-like disease with these features. The human FLI1 gene contains (GA)n microsatellite, which has been shown to be associated with expression level. Because microsatellite polymorphisms are difficult to capture by genome-wide association studies, we directly genotyped FLI1 (GA)n microsatellite and examined its association with SSc. METHODS: Genomic DNA from 639 Japanese SSc patients and 851 healthy controls was genotyped for (GA)n microsatellite using the fragment assay. The cut-off repeat number for susceptibility to SSc was determined by receiver operating characteristics (ROC) analysis. Association with susceptibility and clinical characteristics was examined using logistic regression analysis. FLI1 mRNA levels were determined using quantitative RT-PCR. RESULTS: Based on the ROC analysis, (GA)n alleles with ≥22 repeats were collectively defined as L alleles and alleles with ≤21 repeats as S alleles. (GA)n L alleles were significantly associated with susceptibility to SSc (P = 5.0e-04, odds ratio 1.34, additive model). Significant association was observed both in diffuse cutaneous and limited cutaneous SSc. Among the SSc, (GA)n L alleles were significantly enriched in the patients with a modified Rodnan total skin thickness score ≥10 compared with those with a score <10. FLI1 mRNA levels were significantly decreased in healthy controls carrying (GA)n L alleles as compared with non-carriers. CONCLUSION: Extended repeat alleles of FLI1 (GA)n microsatellite may be associated with lower FLI1 mRNA levels and susceptibility to human SSc.