Perspective to precision medicine in scleroderma.

Systemic sclerosis (SSc) is a rare and heterogeneous disease with no relevant environmental trigger or significant responsible gene. It has been and will continue to be difficult to identify large enough patients to conduct classic population-based epidemiologic exposure/non-exposure studies with adequate power to ascertain environmental and genetic risk factors for these entities. The complexity of pathogenesis and heterogeneity are likely to require personalized/precision medicine for SSc. Since several potential drugs are currently available for specific patients if not whole SSc, classification of SSc seems to form the foundation for a better therapeutic strategy. To date, SSc has been classified based on the extent/severity of the affected area as well as some disease markers, including the autoantibody profile. However, such an analysis should also lead to improvements in the design of appropriately stratified clinical trials to determine the effects and prediction of targeted therapies. An approach based on drug response preclinically conducted using patients' own fibroblasts in vitro, can provide a precise disease marker/therapeutic selection for clinical practice. Because scleroderma dermal fibroblasts have a persistent hyper-productive phenotype occurring not only in person, but also in cell culture conditions. Thus, an accumulating approach based on disease markers ensures progression and de-escalation to re-establish a better life with a personally optimized drug environment after the onset of SSc.

Inhibitory role of interleukin-10 in the cutaneous reverse Arthus reaction.

The formation and deposition of immune complexes (IC) containing immunoglobulin (Ig)G antibodies induces an acute inflammatory response with tissue injury. One of the experimental models of IC-related vasculitis is the cutaneous reverse passive Arthus reaction, in which IgG antibodies are injected i.d., followed immediately by the i.v. application of the corresponding antigen. This reaction is characterized by edema, hemorrhage and neutrophil infiltration. To assess the role of the anti-inflammatory cytokine interleukin (IL)-10 in IC-related vasculitis, we investigated the cutaneous Arthus reaction using IL-10 knockout (IL-10KO) mice. Edema, which was quantified macroscopically by measuring the vascular leakage of Evans blue dye at 4 h after IC challenge, was significantly increased in IL-10KO mice compared with wild-type mice. In addition, hemorrhage, which was assessed by the average diameter of purpuric spots at 8 h after IC challenge, was enhanced significantly in IL-10KO mice compared with wild-type mice. Histological examination showed that the number of extravascular neutrophils was significantly increased in IL-10KO mice compared with wild-type mice at 4 and 8 h after IC challenge. Analysis of pro-inflammatory cytokine mRNA expression showed that IL-6 mRNA levels were significantly increased in IL-10KO mice compared with wild-type mice at 4 and 8 h after IC challenge. These results showed that IC-induced inflammation and vascular damage were significantly enhanced in the absence of IL-10. Thus, IL-10 may limit tissue disruption by suppressing the excessive infiltration of neutrophils and cytokine expression in a mouse model of type III vasculitis.

Relationship between the Degrees of Itch and Serum Lipocalin-2 Levels in Patients with Psoriasis.

BACKGROUND: Lipocalin-2 (LCN2), a protein secreted mainly by activated neutrophils, has been associated with neurodegeneration, obesity, and inflammatory responses. Serum LCN2 concentration has been reported elevated in patients with psoriasis, but lower in patients with atopic dermatitis (AD). Spinal astrocyte-derived LCN2 was found to be involved in enhancement of itch in a mouse model of AD. However, the relationship between LCN2 and itch in patients with psoriasis has not been determined. Objective. This study examined the correlation between serum LCN2 levels and the degrees of itch in patients with psoriasis. METHODS: Serum LCN2 concentrations were measured by enzyme-linked immunosorbent assays (ELISA) in patients with psoriasis and AD and in healthy controls. The degree of itch was assessed using a visual analog scale (VAS), and disease severity was determined by measuring psoriasis area and severity index (PASI) and scoring atopic dermatitis (SCORAD). Correlations among serum LCN2 level, VAS, PASI, and SCORAD were analyzed statistically. We further examined the serum LCN levels in psoriasis patients before and after biological treatment. RESULTS: Serum LCN2 concentrations were significantly higher in patients with psoriasis and AD than those in healthy controls. In patients with psoriasis, serum LCN2 concentrations were significantly correlated with VAS, but not with PASI. In contrast, serum LCN2 concentrations did not correlate with VAS or SCORAD in patients with AD. Serum LCN2 levels in psoriasis patients significantly decreased after the biological treatment along with improvement of VAS. CONCLUSION: Serum LCN2 concentration is associated with the degree of itch in patients with psoriasis, suggesting that serum LCN2 may be a useful clinical marker for itch in psoriasis.

Expression of T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain on CD4+ T cells in patients with atopic dermatitis.

The T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is a co-inhibitory receptor mainly expressed on T cells. Although TIGIT plays an important role in various autoimmune diseases, its role in atopic dermatitis (AD) remains unclear. In this study, we examined the expression levels of TIGIT and their association with clinical features in patients with AD. TIGIT expression on CD4+ T cells, central memory T cells, effector memory T cells and regulatory T cells was determined by flow cytometry. CD4+ T cells exhibited enhanced TIGIT expression in patients with AD compared with healthy individuals. In particular, effector memory T cells and regulatory T cells, but not central memory T cells, exhibited higher TIGIT expression in patients with AD than in healthy individuals. The frequency of TIGIT+ cells among CD4+ T cells was significantly increased in patients with mild AD compared with healthy individuals, while decreased in patients with severe AD. Consistently, the frequency of TIGIT+ cells among CD4+ T cells was negatively correlated with both serum thymus and activation-regulated chemokine levels and immunoglobulin E levels in patients with AD. Furthermore, TIGIT expression on CD4+ T cells inhibited cell proliferation in patients with AD. These results suggest that TIGIT expression on CD4+ T cells in patients with AD may be increased to suppress chronic cutaneous inflammation. Moreover, TIGIT expression may be impaired in a subset of patients with AD, leading to a deterioration of skin inflammation. Our study may provide new insight into a TIGIT pathway-based therapeutic approach for AD.

Prediction of therapeutic response before and during i.v. cyclophosphamide pulse therapy for interstitial lung disease in systemic sclerosis: A longitudinal observational study.

There have been no established parameters to predict responsiveness to i.v. cyclophosphamide (IVCY) pulse therapy in combination with corticosteroids in patients with interstitial lung disease (ILD) related to systemic sclerosis (SSc). This retrospective study was conducted to determine predictive factors for efficacy of IVCY at the time of before and during the treatment. Thirty-two Japanese SSc patients, ever treated for ILD with IVCY in combination with prednisolone, were analyzed retrospectively. We performed detailed time-course analyses of parameters derived from blood samples and pulmonary function tests. With the exclusion of eight unclassified patients, 24 patients were classified into 14 good responders (GR) or 10 poor responders (PR) on the basis of changes in percent predicted diffusing capacity for carbon monoxide (DLco). Pretreatment percent predicted DLco was significantly reduced in PR compared with GR. In addition, serum parameters such as Krebs von den Lungen-6 (KL-6), surfactant protein D (SP-D) and C-reactive protein were significantly higher in PR than in GR. Furthermore, our time-course analyses revealed a transient increase in serum KL-6 levels with a peak at 3 months after the first infusion of cyclophosphamide, which showed no relation to therapeutic efficacy. Moreover, continuously high serum KL-6 levels (>2000 U/mL) and rapid decrease in SP-D levels (<200 ng/mL) during IVCY were remarkably characteristic of PR and GR, respectively. ILD severity/activity before treatment and variability of serum KL-6 and SP-D levels during treatment may be useful to predict therapeutic effects of IVCY on SSc-ILD.

Strong correlation between cancer progression and anti-transcription intermediary factor 1γ antibodies in dermatomyositis patients.

OBJECTIVES: Transcription intermediary factor 1γ (ΤΙF1γ) protein is known as a tumour suppressor that promotes cellular differentiation. Autoantibodies to ΤΙF1γ have a strong clinical association with cancers associated with dermatomyositis (DM). This study aims to identify the clinical characteristics of cancers in anti-ΤΙF1γ antibody-positive adult patients with DM. METHODS: This retrospective analysis covered 160 adult DM patients who visited Nagoya University Hospital or collaborating medical centres between 2003 and 2016. Anti-TIF1γ antibody and other myositis-specific autoantibodies were detected by ELISA. Based on a review of medical charts, the cancers were staged according to the TNM Classification of Malignant Tumours of the Union for International Cancer Control and were divided into the two groups of "advanced" or "non-advanced" according to the stage classification. RESULTS: Forty-one of the 160 (26%) patients had cancer. The incidence was significantly higher in the anti-TIF1γ-positive patients than in the anti-TIF1γ-negative patients (23/34=68% vs. 18/126=14%, p<1x10-6). Anti-TIF1γ-positive patients with cancer were found more frequently in the "advanced" group than in the "non-advanced" group (21/23=91% vs. 9/18=50%, p<0.0046). The intervals between DM diagnosis and cancer diagnosis were significantly shorter in the anti-TIF1γ-positive patients than in the anti-TIF1γ-negative patients (p=0.047). CONCLUSIONS: Not only did anti-TIF1γ antibodies correlate strongly with malignancy in DM patients, but cancers were also significantly more advanced in anti-TIF1γ-positive DM patients than in anti-TIF1γ-negative patients. Cancers in such cases were very frequently found close to the time of the DM diagnosis.

Exacerbation of atopic dermatitis symptoms by ustekinumab in psoriatic patients with elevated serum immunoglobulin E levels: Report of two cases.

Psoriasis is a chronic inflammatory skin disease mainly mediated by a T-helper cell subset, Th17 cells. Recently, increased levels of total serum immunoglobulin (Ig)E have been reported in a subset of psoriatic patients. Ustekinumab (UST) is one of the most commonly used biologic agents for the treatment of moderate to severe plaque psoriasis, and a previous report also documented effectiveness of UST for psoriatic patients with high serum IgE levels. We experienced two psoriatic patients with high serum IgE levels, in whom UST completely improved psoriasis but paradoxically provoked or exacerbated atopic dermatitis (AD)-like symptoms. This reciprocal phenomenon suggests the shift of Th balance toward Th2, along with altered profiles of inflammatory cytokines. It appears prudent to consider the possibility of such adverse effects when treating psoriatic patients with UST with concomitant AD symptoms, a history of AD or high serum IgE levels.

Clinical Significance of Serum Galectin-9 and Soluble CD155 Levels in Patients with Systemic Sclerosis.

Signaling through coinhibitory receptors downregulates the immune response to prevent excessive immune activation and maintain optimal immunity and tolerance. The aim of this study was to examine the levels of the soluble forms of coinhibitory receptors and their ligands, namely, galectin-9 (the ligand of T-cell immunoglobulin and mucin domain 3) and CD155 (the ligand of T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain), and their association with clinical features in patients with systemic sclerosis (SSc). The serum levels of galectin-9 and soluble sCD155 were examined by enzyme-linked immunosorbent assays in patients with SSc, and the results were evaluated with respect to clinical features. Patients with SSc exhibited raised serum levels of galectin-9, but not sCD155. Serum galectin-9 levels were raised not only in patients with diffuse cutaneous SSc but also in patients with limited cutaneous SSc. Furthermore, serum galectin-9 levels correlated positively with the erythrocyte sedimentation rate. In addition, increased serum galectin-9 levels tended to be associated with higher mortality and serious organ involvement. These results suggest that galectin-9, but not CD155, may be involved in the pathogenesis of SSc. In addition, the measurement of serum galectin-9 levels could be used to predict serious organ involvement and high mortality in patients with SSc.

New onset or transition of disease state of psoriatic arthritis during treatment with ustekinumab: A single-center retrospective study.

Ustekinumab (UST) is a treatment option for psoriatic arthritis (PsA), but recent observations indicate that some psoriatic patients may experience new onset of PsA or worsening of pre-existent PsA. We retrospectively analyzed all cases of psoriasis vulgaris (PsV) and PsA treated with UST in our facility between 2011 and 2015. PsA developed in eight out of 179 PsV patients, mostly later than 8 months after initiation of UST. It was generally not severe, and none had received tumor necrosis factor (TNF)-α inhibitors previously, indicating that the possibility of unmasking pre-existing subclinical arthritis is minimal. The eruptions were well controlled at the time of the onset of arthritis in most cases. Interestingly, those who developed arthritis showed a significantly lower body mass index. Regarding pre-existing PsA, nine PsA patients received UST, and at least partial improvement of PsA could be achieved in two out of three bio-naive and three out of six bio-switched patients from TNF-α inhibitors. PsA was largely more refractory to UST than the eruptions. Altogether, our present study is in agreement with the notion that UST may be less efficient than TNF-α inhibitors for PsA. While UST cannot fully prevent new development of PsA, it is unlikely that UST increases the risk of new onset of PsA as a paradoxical adverse reaction.

Suppressive Effects of Mesenchymal Stem Cells in Adipose Tissue on Allergic Contact Dermatitis.

BACKGROUND: Allergic contact dermatitis (ACD), which is accelerated by interferon (IFN)-γ and suppressed by interleukin (IL)-10 as regulators, is generally self-limited after removal of the contact allergen. Adipose tissue-derived multipotent mesenchymal stem cells (ASCs) potentially exert immunomodulatory effects. Considering that subcutaneous adipose tissue is located close to the site of ACD and includes mesenchymal stem cells (MSCs), the MSCs in adipose tissue could contribute to the self-limiting course of ACD. OBJECTIVE: The aims of the present study were to elucidate the effects of MSCs in adipose tissue on ACD and to examine any cytokine-mediated mechanisms involved. METHODS: Ear thickness in a C57BL/6 mouse model of ACD using contact hypersensitivity (CHS) elicited by 2,4,6-trinitro-1-chlorobenzene was evaluated as a marker of inflammation level. Five and nine mice were injected with ASCs and phosphate-buffered saline (PBS), respectively. After ASC or PBS injection, real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay were performed. RESULTS: Histology showed that CHS was self-limited and ear thickness was suppressed by ASCs in a dose-dependent manner. IFN-γ expression in the elicited skin site and regional lymph nodes was significantly lower in ASC-treated mice than in control mice. IL-10 expression did not differ between treated and control mice. The suppressive effects of ASCs on CHS response did not differ between IL-10 knock-out C57BL/6 mice and wild-type mice. CONCLUSION: The present findings suggest that MSCs in adipose tissue may contribute to the self-limiting course of ACD through decreased expression of IFN-γ, but not through increased expression of IL-10.

Switching of biologics in psoriasis: Reasons and results.

Efficacy and safety profiles of biologics have been established for moderate to severe psoriasis. However, inefficacy or adverse events sometimes require changing the treatment to other biologics. Here, we examine the effectiveness of this strategy. We retrospectively investigated cases requiring switching biologics. We enrolled 275 psoriatic patients treated with biologics between January 2010 and December 2014 in our hospital. Of these, 51 required a switch to another biologic. First-line therapies were infliximab (IFX, n = 26), adalimumab (ADA, n = 18) and ustekinumab (UST, n = 7), and second-line therapies were IFX (n = 5), ADA (n = 21) and UST (n = 25). Reasons for switching were inefficacy (n = 38), adverse events (n = 11) and others (n = 2). The details were primary failure (n = 15), secondary failure (n = 23) and infusion reactions (n = 8). In 49 patients who switched biologics due to inefficacy and adverse events, the mean Psoriasis Area and Severity Index (PASI) score at week 16 was 4.3 for first-line therapies and 2.9 for second-line therapies (P < 0.05). Switching to a second biologic therapy to address the first's inefficacy or adverse events often results in significant improvement in moderate to severe psoriasis.

Neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and mean platelet volume in Japanese patients with psoriasis and psoriatic arthritis: Response to therapy with biologics.

Recent studies indicate the presence of systemic inflammation in psoriatic patients, and this inflammatory status is significantly associated with a range of comorbidities. The aim of this study was to evaluate the clinical significance of novel inflammatory biomarkers, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and mean platelet volume (MPV) in Japanese patients with plaque-type psoriasis (PsV) and psoriatic arthritis (PsA). One hundred and eighty-six patients with PsV and 50 patients with PsA treated with biologics, including infliximab, adalimumab and ustekinumab, were retrospectively analyzed before and after treatment. At baseline, NLR and PLR, as well as C-reactive protein (CRP), were significantly higher in PsA patients than those in PsV patients, and a significant correlation was found between NLR and PLR. In PsV patients, the NLR-high and PLR-high subgroups exhibited significantly higher Psoriasis Area and Severity Index scores compared with the NLR-low and PLR-low subgroups, respectively, and the NLR-high subgroup also showed higher CRP levels. MPV value was negatively associated with the presence of arthritis, but its association with inflammation was less clear than that of NLR or PLR. After treatment of the patients with biologics for up to 12 months, NLR and PLR decreased promptly in parallel with a decrease of CRP, irrespective of the type of biologics used. Altogether, these results indicate that both NLR and PLR may be useful markers to evaluate systemic inflammation in psoriatic patients. They may serve as simple, convenient and cost-effective biomarkers to monitor the disease course after systemic therapy.