Arm heating to relieve Raynaud's phenomenon in systemic sclerosis: A single-arm multicentre prospective clinical trial.

OBJECTIVES: Raynaud's phenomenon, one of the major symptoms of systemic sclerosis (SSc), is difficult to treat. Although it is empirically considered that warming is a beneficial technique, there is no supportive evidence. We conducted a multicentre study to evaluate whether continuous heating of the arm alleviates Raynaud's phenomenon in SSc. METHODS: A pair of disposable warmers was applied to the upper arm near the elbow of patients with SSc. Two weeks of non-warmer application were followed by 2 weeks of warmer application, which was repeated twice. The Raynaud Condition Score (RCS), number of episodes, and duration of Raynaud's phenomenon were recorded. The differences in the mean RCS, frequency, and duration of Raynaud's phenomenon between the warmer application and non-application periods were analysed. RESULTS: Twenty-eight patients were included in the analysis. The average RCS was 1.98 and 2.66 during the warmer application and non-application periods, respectively. The change between the two periods was statistically significant by paired t-test. In addition, the frequency and total duration of Raynaud's phenomenon in the warmer application period were significantly lower than those in the non-application period. CONCLUSIONS: Heating of the upper arm near the elbow is effective in alleviating Raynaud's phenomenon in SSc.

Branched chain amino acids in the treatment of polymyositis and dermatomyositis: a phase II/III, multi-centre, randomized controlled trial.

OBJECTIVES: To assess the efficacy and safety of branched chain amino acids (BCAAs) in the treatment of PM/DM prior to official approval of their use in Japan. METHODS: Treatment naïve adults with PM/DM were enrolled in a randomized, double-blind trial to receive either TK-98 (drug name of BCAAs) or placebo in addition to conventional treatment. After 12 weeks, patients with an average manual muscle test (MMT) score <9.5 were enrolled in an open label extension study for a further 12 weeks. The primary endpoint was the change of the MMT score at 12 weeks. The secondary endpoints were the clinical response and the change of functional index (FI). RESULTS: Forty-seven patients were randomized either to the TK-98 (n = 24) or placebo (n = 23) group. The changes of MMT scores at 12 weeks were 0.70 (0.19) [mean (s.e.m.)] and 0.69 (0.18), respectively (P = 0.98). Thirteen patients from the TK-98 group and 12 from the placebo group were enrolled in the extension study. The MMT scores in both groups improved similarly. The increase of the FI scores of the shoulder flexion at 12 weeks was significantly greater in the TK-98 group [27.9 (5.67) vs 12.8 (5.67) for the right shoulder flexion, and 27.0 (5.44) vs 13.4 (5.95) for the left shoulder; P < 0.05]. Frequencies of adverse events up to 12 weeks were similar. CONCLUSION: BCAAs showed no effect on the improvement of the muscle strength evaluated by MMT and the clinical response. However, they were partly effective for improving dynamic repetitive muscle functions. TRIAL REGISTRATION: UMIN-CTR Clinical Trial, https://center6.umin.ac.jp/, UMIN000016233.

ISSVA Classification of Vascular Anomalies and Molecular Biology.

Vascular anomalies include various diseases, which are classified into two types according to the International Society for the Study of Vascular Anomalies (ISSVA) classification: vascular tumors with proliferative changes of endothelial cells, and vascular malformations primarily consisting of structural vascular abnormalities. The most recent ISSVA classifications, published in 2018, detail the causative genes involved in many lesions. Here, we summarize the latest findings on genetic abnormalities, with the presentation of the molecular pathology of vascular anomalies.

Elevated Alpha 1(I) to Alpha 2(I) Collagen Ratio in Dermal Fibroblasts Possibly Contributes to Fibrosis in Systemic Sclerosis.

Systemic sclerosis (SSc) is characterized by excessive collagen deposition in the skin and internal organs. Activated fibroblasts are the key effector cells for the overproduction of type I collagen, which comprises the α1(I) and α2(I) chains encoded by COL1A1 and COL1A2, respectively. In this study, we examined the expression patterns of α1(I) and α2(I) collagen in SSc fibroblasts, as well as their co-regulation with each other. The relative expression ratio of COL1A1 to COL1A2 in SSc fibroblasts was significantly higher than that in control fibroblasts. The same result was observed for type I collagen protein levels, indicating that α2(I) collagen is more elevated than α2(I) collagen. Inhibition or overexpression of α1(I) collagen in control fibroblasts affected the α2(I) collagen levels, suggesting that α1(I) collagen might act as an upstream regulator of α2(I) collagen. The local injection of COL1A1 small interfering RNA in a bleomycin-induced SSc mouse model was found to attenuate skin fibrosis. Overall, our data indicate that α2(I) collagen is a potent regulator of type I collagen in SSc; further investigations of the overall regulatory mechanisms of type I collagen may help understand the aberrant collagen metabolism in SSc.

Up-regulation of IGF-1, RANTES and VEGF in patients with anti-centromere antibody-positive early/mild systemic sclerosis.

OBJECTIVE: Multiple cytokine network may control the pathogenesis of vasculopathy in patients with systemic sclerosis (SSc). We aimed at comparing angiogenic cytokine profile among SSc patients at various clinical stage. METHODS: We divided nine patients with anti-centromere antibody (ACA) who were suspected of SSc and diagnosed as having SSc into three groups (group1: pre-clinical stage of SSc, group2: mild/early SSc and group3: typical lcSSc) according to the ACR/EULAR2013 classification criteria or ACR1980 preliminary classification, and serum sample were obtained from them. We evaluated the expression levels of 20 cytokines by membrane array. RESULTS: Average values of EGF, ENA-78, bFGF, IGF-I, IL-8, MCP-1, TGF-ß1, thrombopoietin, VEGF and VEGF-D in group2 were increased compared as those of group1 more than twofold. Statistically significant difference was found in serum levels of IGF-1, RANTES and VEGF between group1 and group2. There was also significant difference in the value of VEGF between group1 and group3. There were mild and significant correlations between serum IGF-1 and RANTES levels (r = 0.721, p = .028). CONCLUSION: IGF-1, RANTES and VEGF are thought to be involved in the disease development from pre-clinical stage of SSc to early/mild SSc. Thus, these cytokines may be utilized as a biomarker for early diagnosis.

Adipophilin expression in cutaneous malignant melanoma is associated with high proliferation and poor clinical prognosis.

Adipophilin (ADP) is a primary protein component of lipid droplets (LDs). For more than half a century, certain types of cancer cells have been known to contain LDs in their cytoplasm. However, the pathological significance of ADP or LDs in cancer remains unclear. In the present study, we investigated the association between ADP and other pathological characteristics in cutaneous malignant melanomas to clarify the role of ADP in melanoma cells. We immunostained whole paraffin sections of primary cutaneous melanomas obtained from 90 cases for ADP, after which we analyzed the correlation between ADP immunohistochemistry (IHC) and patient survival data. We also studied the relationship between the ADP IHC score and in situ hybridization (ISH) score of ADP mRNA, and the Ki67-labeling index (Ki67-LI) by using tissue microarrays consisting of 74 primary cutaneous malignant melanomas, 19 metastasizing melanomas, and 29 melanocytic nevi. Finally, we analyzed the relationship between ADP expression and cell proliferation in cutaneous melanoma cell lines. We found that high ADP expression was associated with poor metastasis-free survival, disease-specific survival, and overall survival rates of patients with cutaneous melanomas (P < 0.05). By linear regression analysis, ADP IHC was correlated with increasing ADP mRNA ISH H-scores and Ki67-LI scores in melanocytic lesions (P < 0.01). ADP IHC and ADP ISH H-scores and Ki67-LI scores were greater in pT3-4 melanomas than in pT1-2 melanomas. In cell-based assays, cells with increased ADP expression showed higher proliferation rates compared with those of low-ADP cells. Thus, ADP expression in malignant melanoma was significantly associated with high cell proliferation and poor clinical prognosis. Our results thus indicate a significant association between ADP and melanoma progression, and we propose that ADP may be a novel marker of aggressive cutaneous melanoma with a lipogenic phenotype.

Predictive and sensitive biomarkers for thyroid dysfunctions during treatment with immune-checkpoint inhibitors.

Immune-related adverse events (irAEs) are often seen during immune-checkpoint inhibitor (ICI) treatment of various malignancies. Endocrine irAEs including thyroid dysfunctions are the most common irAEs, but their biomarkers remain unclear. In order to identify individuals who are susceptible to thyroid irAE for earlier diagnosis and appropriate follow-up, the current study is aimed to investigate biomarkers of thyroid irAE. Herein, patients with advanced malignant diseases who received ICIs treatment were prospectively studied. Clinical and laboratory examination, thyroid function, and autoantibodies were evaluated at baseline, and every 4 wk after first treatment with ICIs. Cytokines/chemokines were measured at baseline and at 4 wk. In vivo effects of ICIs on experimental autoimmune thyroiditis were evaluated. Twenty-six patients with malignant diseases who received ICIs treatment were enrolled in the study. Patients were divided into two groups: those who developed thyroid irAE, and those without irAEs. Comparing the two groups, early increase (≤4 wk) in serum thyroglobulin (Tg) levels and thyroid autoantibodies was seen in thyroid irAE (P < .05). Notably, higher levels of serum IL-1ß, IL-2, and GM-CSF at baseline, and early decrease of IL-8, G-CSF, and MCP-1 were significantly associated in the development of thyroid irAE (P < .05). In vivo effects of anti-PD-1 antibody on deterioration of mice experimental thyroiditis were seen. In conclusion, early change in Tg, thyroid autoimmunity, and cytokine levels might indicate development of thyroid irAE. Pre-existing thyroid autoimmunity might be involved with the development of thyroid irAE. Potential application of these factors as surrogate biomarkers for tumor therapy was indicated.

First external validation of sensitivity and specificity of the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for idiopathic inflammatory myopathies with a Japanese cohort.

OBJECTIVE: To externally validate the performance of the new European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria set for idiopathic inflammatory myopathies (IIM) with a Japanese cohort. METHODS: This study included 420 IIM and 402 non-IIM cases. Probability of having IIM in each patient was calculated using the collected data set. The cut-off probability was set at 55%, as recommended by EULAR/ACR. Patients classified as IIM by the criteria were further subclassified with classification trees. RESULTS: When the probability cut-off was set at 55%, the sensitivity/specificity of the new criteria to diagnose IIM were 89.3%/91.0% in the total cohort, 88.1%/95.1% without muscle biopsy data and 90.4%/65.5% with biopsy data. The cohort included 12 overlap syndrome patients with biopsy data, who were included as non-IIM cases in accordance with traditional Japanese methods. When they were included in the IIM cases, the specificity in patients with biopsy increased to 74.4%. The sensitivity/specificity of the new criteria to diagnose polymyositis/dermatomyositis (PM/DM) plus juvenile and amyopathic DM in the Japanese cohort was 87.4%/92.4%, which were greater than those of the Tanimoto's criteria revised to enable classification of amyopathic DM (ADM) (71.2%/87.8%) and were comparable with those of Bohan & Peter's criteria to diagnose those diseases except for ADM (88.4%/88.3%). CONCLUSIONS: Our study externally validated high specificity of the new criteria for the first time, although with several limitations, including low percentage of child patients. The new criteria have higher sensitivity and/or specificity in classification of PM/DM than the previously reported criteria, demonstrating its usefulness for interethnic patients.

Japanese clinical practice guidelines for vascular anomalies 2017.

The objective was to prepare guidelines to perform the current optimum treatment by organizing effective and efficient treatments of hemangiomas and vascular malformations, confirming the safety, and systematizing treatment, employing evidence-based medicine (EBM) techniques and aimed at improvement of the outcomes. Clinical questions (CQs) were decided based on the important clinical issues. For document retrieval, key words for literature searches were set for each CQ and literature published from 1980 to the end of September 2014 was searched in Pubmed, Cochrane Library, and Japana Centra Revuo Medicina (JCRM). The strengths of evidence and recommendations acquired by systematic reviews were determined following the Medical Information Network Distribution System (MINDS) technique. A total of 33 CQs were used to compile recommendations and the subjects included efficacy of resection, sclerotherapy/embolization, drug therapy, laser therapy, radiotherapy, and other conservative treatment, differences in appropriate treatment due to the location of lesions and among symptoms, appropriate timing of treatment and tests, and pathological diagnosis deciding the diagnosis. Thus, the Japanese Clinical Practice Guidelines for Vascular Anomalies 2017 have been prepared as the evidence-based guidelines for the management of vascular anomalies.

Effect of topical immunotherapy with squaric acid dibutylester for alopecia areata in Japanese patients.

BACKGROUND: The Japanese guidelines for the treatment of alopecia areata list topical immunotherapies as a drug therapy for this condition. However, there is insufficient evidence of its efficacy to support this recommendation. Thus, we sought to clarify the effect of topical immunotherapy on the progression and severity of alopecia areata in Japanese patients. METHODS: To evaluate the effect of topical immunotherapy with squaric acid dibutylester (SADBE) in alopecia areata patients, we performed a retrospective cohort study on 49 alopecia patients who had received topical immunotherapy with SADBE. Patients were evaluated by the change in alopecia severity at 6 and 12 months after the initiation of topical immunotherapy. The improvement rate was calculated by determination of the complete and partial responses rate to treatment with topical immunotherapy by application of SADBE. RESULTS: The improvement rate in all alopecia patients treated with SADBE topical immunotherapy was 57.8% (complete response; 11.1% and partial response; 46.7%). CONCLUSIONS: Topical immunotherapy with SADBE is an effective treatment for alopecia areata. Therefore, the current treatment recommendations for alopecia areata with topical immunotherapies are appropriate.

Clinical and histological evaluation of a single high energy microwave treatment for primary axillary hyperhidrosis in Asians: A prospective, randomized, controlled, split-area comparative trial.

BACKGROUND AND OBJECTIVES: Microwave treatment is an effective non-invasive treatment option for primary axillary hyperhidrosis (PAH), but the treatment parameters vary and no histopathological studies have been performed to validate clinical outcomes. This study investigated its efficacy and safety and histopathological changes after a single microwave treatment at the maximum energy level for PAH in Asians. MATERIALS AND METHODS: A prospective, clinical, and histological split-area randomized controlled trial (RCT) was performed in Japan. Twenty-six subjects underwent a single microwave treatment at the maximum energy level 5 (5.8 GHz/axilla) on the randomized side of axillae. The primary outcome was the mean difference between both sides in the improvement of modified single-underarm Hyperhidrosis Disease Severity Scale (msHDSS) scores over the course of the 12-month study period from baseline. The secondary outcomes were; the percentage of responders with at least a 2-point drop in the msHDSS score of 3 or 4 group or with a 1-point drop in the msHDSS score of 2 group; the percentage of responders with at least a 75% reduction in sweat weight over 12 months; recurrence rate; and adverse effects. We also performed a histological assessment for 13 selected subjects. RESULTS: Twenty-four subjects completed the study. There were statistically significant differences in improvement of msHDSS scores between the microwave-treated and control sides (P < 0.05) from baseline at 0.5, 1, 3, 6, and 12 months. In the msHDSS score of 3 or 4 group, the percentage of responders with at least a 2-point drop on the microwave-treated side versus control side was 72.2 versus 11.1% (P < 0.05) at 1 month, 83.3 versus 5.6% (P < 0.05) at 3 months, 61.1 versus 38.9% (P = 0.317) at 6 months and 38.9 versus 16.7% (P = 0.264) at 12 months. The percentage of responders with at least a 75% reduction in sweat weight on the microwave-treated side versus control side was 75.0 versus 37.5% at 1 month, 75.0 versus 29.2% at 3 months, 83.3 versus 50.0% at 6 months and 70.8 versus 33.3% at 12 months (all P < 0.05). Recurrence on the microwave-treated side was observed in 4.2% and 12.5% of 24 subjects at 3 and 12 months, respectively. No serious side-effects were noted. Histology showed the diameter and density of secretory eccrine glands and nerve fiber lengths around eccrine glands were significantly decreased after treatment compared to baseline (P = 0.002, 0.027, 0.003, respectively). CONCLUSIONS: A single-session microwave treatment at the maximum energy level significantly improved the PAH of Japanese patients and had minimal side effects. This technique demonstrates that diminished size of secretory eccrine glands and nerve fiber degeneration could be useful markers for predicting the efficacy of the treatment. Lasers Surg. Med. 9999:1-8, 2019. © 2019 Wiley Periodicals, Inc.

High-Risk Human Papillomavirus E6/E7 mRNA Is Rarely Detected in Nonanogenital Cutaneous Squamous Cell Carcinoma: An RNA In Situ Hybridization-Based Tissue Microarray Study.

High-risk human papillomavirus (HR-HPV) is known to play an oncogenic role in squamous cell carcinoma (SCC) at certain anatomical sites, namely the uterine cervix, oropharynx, and anogenital skin. However, the association between HR-HPV and nonanogenital cutaneous SCC (CSCC) remains controversial. In this study, we addressed this controversy by performing HR-HPV E6/E7 mRNA in situ hybridization (ISH) on 243 CSCC samples. A cocktail of E6/E7 mRNA ISH probes, recognizing 18 HR-HPV genotypes, was applied to a tissue microarray of paraffin-embedded sections of 154 invasive and 89 in situ CSCC specimens. The anatomical sites of CSCC included the head and neck (n = 100), extremities (n = 100), trunk (n = 25), and anogenitalia (n = 18). We also investigated the correlation between the p16 expression and HR-HPV status by immunohistochemistry. The results of HR-HPV E6/E7 mRNA ISH showed that 5.8% (14/243) of all CSCC samples were positive for HR-HPV, including 66.7% (12/18) of the anogenital and only 0.9% (2/225) of the nonanogenital CSCC samples (P < 0.01). For the detection of diffuse p16 expression by immunohistochemistry, the sensitivity was 100% (14/14 HR-HPV-positive CSCC samples), and the specificity was 72.1% (165/229 HR-HPV-negative specimens). Thus, HR-HPV E6/E7 mRNA was rarely detected in nonanogenital CSCC, making it unlikely that the virus contributes to the pathogenesis of this malignancy. In addition, p16 immunoreactivity has a limited value as a surrogate marker for transcriptionally active HR-HPV in nonanogenital CSCC.

Treatment consensus for management of polymyositis and dermatomyositis among rheumatologists, neurologists and dermatologists.

Although rheumatologists, neurologists and dermatologists see patients with polymyositis (PM) and dermatomyositis (DM), their management appears to vary depending on the physician's specialty. The aim of the present study was to establish the treatment consensus among specialists of the three fields to standardize the patient care. We formed a research team supported by a grant from the Ministry of Health, Labor and Welfare, Japan. Clinical questions (CQ) on the management of PM and DM were raised. A published work search on CQ was performed primarily using PubMed. Using the nominal group technique, qualified studies and results in the published work were evaluated and discussed to reach consensus recommendations. They were sent out to the Japan College of Rheumatology, Japanese Society of Neurology and Japanese Dermatological Association for their approval. We reached a consensus in 23 CQ and made recommendations and a decision tree for management was proposed. They were officially approved by the three scientific societies. In conclusion, a multidisciplinary treatment consensus for the management of PM and DM was established for the first time.

Splicing variant of WDFY4 augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis.

OBJECTIVES: Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases in which both genetic and environmental factors play important roles. To identify genetic factors of IIM including polymyositis, dermatomyositis (DM) and clinically amyopathic DM (CADM), we performed the first genome-wide association study for IIM in an Asian population. METHODS: We genotyped and tested 496 819 single nucleotide polymorphism for association using 576 patients with IIM and 6270 control subjects. We also examined the causal mechanism of disease-associated variants by in silico analyses using publicly available data sets as well as by in in vitro analyses using reporter assays and apoptosis assays. RESULTS: We identified a variant in WDFY4 that was significantly associated with CADM (rs7919656; OR=3.87; P=1.5×10-8). This variant had a cis-splicing quantitative trait locus (QTL) effect for a truncated WDFY4isoform (tr-WDFY4), with higher expression in the risk allele. Transexpression QTL analysis of this variant showed a positive correlation with the expression of NF-κB associated genes. Furthermore, we demonstrated that both WDFY4 and tr-WDFY4 interacted with pattern recognition receptors such as TLR3, TLR4, TLR9 and MDA5 and augmented the NF-κB activation by these receptors. WDFY4 isoforms also enhanced MDA5-induced apoptosis to a greater extent in the tr-WDFY4-transfected cells. CONCLUSIONS: As CADM is characterised by the appearance of anti-MDA5 autoantibodies and severe lung inflammation, the WDFY4 variant may play a critical role in the pathogenesis of CADM.

Transethnic meta-analysis identifies GSDMA and PRDM1 as susceptibility genes to systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune disease characterised by skin and systemic fibrosis culminating in organ damage. Previous genetic studies including genome-wide association studies (GWAS) have identified 12 susceptibility loci satisfying genome-wide significance. Transethnic meta-analyses have successfully expanded the list of susceptibility genes and deepened biological insights for other autoimmune diseases. METHODS: We performed transethnic meta-analysis of GWAS in the Japanese and European populations, followed by a two-staged replication study comprising a total of 4436 cases and 14 751 controls. Associations between significant single nuclear polymorphisms (SNPs) and neighbouring genes were evaluated. Enrichment analysis of H3K4Me3, a representative histone mark for active promoter was conducted with an expanded list of SSc susceptibility genes. RESULTS: We identified two significant SNP in two loci, GSDMA and PRDM1, both of which are related to immune functions and associated with other autoimmune diseases (p=1.4×10-10 and 6.6×10-10, respectively). GSDMA also showed a significant association with limited cutaneous SSc. We also replicated the associations of previously reported loci including a non-GWAS locus, TNFAIP3. PRDM1 encodes BLIMP1, a transcription factor regulating T-cell proliferation and plasma cell differentiation. The top SNP in GSDMA was a missense variant and correlated with gene expression of neighbouring genes, and this could explain the association in this locus. We found different human leukocyte antigen (HLA) association patterns between the two populations. Enrichment analysis suggested the importance of CD4-naïve primary T cell. CONCLUSIONS: GSDMA and PRDM1 are associated with SSc. These findings provide enhanced insight into the genetic and biological basis of SSc.

Dysregulated interleukin-23 signalling contributes to the increased collagen production in scleroderma fibroblasts via balancing microRNA expression.

OBJECTIVES: The overexpression of IL-12 family cytokines is implicated in the pathogenesis of SSc, but their exact role is still unclear. The aim of this study was to investigate the regulation of extracellular matrix expression by IL-23 and its contribution to the phenotype of SSc. METHODS: The mRNA expression was determined by PCR array and real-time PCR. The expression levels of proteins were determined by immunoblotting and immunohistochemical staining. The effect of IL-23 on dermal fibrosis in vivo was examined in a mouse model of SSc induced by bleomycin injection. RESULTS: Among the IL-12 family members, IL-23 decreased expression of type I collagen protein in cultured normal dermal fibroblasts. We found that miR-4458 and miR-18a mediated the reduction of collagen expression by IL-23. On the contrary, IL-23 up-regulated type I collagen expression in SSc fibroblasts. The paradoxical effects of IL-23 in SSc fibroblasts were also mediated by the balance between miR-4458 and miR-18a expression. Moreover, we revealed that injection of IL-23 into the mouse skin accelerated skin fibrosis. CONCLUSION: This is the first study to report that the balance of two miRNAs is involved in the collagen dysregulation in SSc fibroblasts. Clarification of the regulatory mechanism of tissue fibrosis by IL-23 in SSc skin may lead to a better understanding of this disease and new therapeutic approaches.

Transforming growth factor ß-inhibitor Repsox downregulates collagen expression of scleroderma dermal fibroblasts and prevents bleomycin-induced mice skin fibrosis.

Inhibition of transforming growth factor (TGF)-ß1 signalling may be one of the most reliable approaches to treat skin fibrosis of scleroderma. Although there have been many basic researches of TGF-ß blockade reagents, few of them were proved to have inhibitory effects on fibrosis both in vitro and in vivo. In this study, we randomly chose four commercially available low molecular weight compounds (Repsox, LY2109761, LY364947 and K02288) from TGF-ß1 inhibitor library, and compared their antifibrotic effects in vitro and in vivo. We demonstrated that Repsox has the most potent inhibitory effects on TGF-ß-induced expression of CTGF and collagen of cultured normal dermal fibroblasts in vitro and their constitutive overexpression of scleroderma fibroblast in vitro. In addition, Repsox could attenuate skin fibrosis by bleomycin in vivo, via the downregulation of CTGF or collagen. Our results may facilitate clinical trial of Repsox against fibrotic diseases in future.

Treatment of psoriasis with ustekinumab improved skin tightening in systemic sclerosis.

Systemic sclerosis (SSc) is a chronic autoimmune disease characterised by fibrosis, inflammation and vasculopathy in the skin and internal organs. Recently, several articles described that Th17 cells, IL-23 and IL-17 levels were significantly elevated in the peripheral blood or fibrotic sites of SSc. We report a case of SSc and psoriasis administered ustekinumab, IL-12/IL-23 inhibitor. In this case, the skin tightening was successfully improved and ustekinumab was more effective, even though oral prednisolone (9-12 mg/day) had some effect on skin tightening and arthralgia. We consider that inhibition of Th17 cytokines may lead to therapeutic efficacy against SSc. Ustekinumab has the potential for a treatment option of SSc.

EBI3 Downregulation Contributes to Type I Collagen Overexpression in Scleroderma Skin.

IL-12 family cytokines are implicated in the pathogenesis of various autoimmune diseases, but their role in the regulation of extracellular matrix expression and its contribution to the phenotype of systemic sclerosis (SSc) remain to be elucidated. Among the IL-12 family members, IL-35 decreases type I collagen expression in cultured dermal fibroblasts. IL-35 consists of p35 and EBI3 subunits, and EBI3 alone could downregulate the protein and mRNA expression of type I or type III collagen in the presence or absence of TGF-ß costimulation. We found that collagen mRNA stability was reduced by EBI3 via the induction of miR-4500. The IL-35 levels in the sera or on the surface of T cells were not altered in SSc patients, while EBI3 expression was decreased in the keratinocytes of the epidermis and regulatory T cells of the dermis in SSc skin compared with normal skin, which may induce collagen synthesis in SSc dermal fibroblasts. We also found that gp130, the EBI3 receptor, was expressed in both normal and SSc fibroblasts. Moreover, we revealed that EBI3 supplementation by injection into the skin improves mice skin fibrosis. Decreased EBI3 in SSc skin may contribute to an increase in collagen accumulation and skin fibrosis. Clarifying the mechanism regulating the extracellular matrix expression by EBI3 in SSc skin may lead to better understanding of this disease and new therapeutic strategies using ointment or microinjection of the subunit.