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Dysphagia develops with low frequency in patients with dermatomyositis. Our objective was to determine the clinical and laboratory features that can estimate the development of dysphagia in dermatomyositis. This study included 92 Japanese patients with adult-onset dermatomyositis. The associations between dysphagia and clinical and laboratory features including disease-specific autoantibodies determined by immunoprecipitation assays were analyzed. Videofluoroscopy swallow study (VFSS) was performed for all patients with clinical dysphagia (n = 13, 14.1%) but not for patients without clinical dysphagia. Typical findings of dysphagia (pharyngeal pooling, n = 11 and/or nasal regurgitation, n = 4) was detected by VFSS in all patients with clinical dysphagia. Eleven patients with dysphagia (84.6%) had anti-transcription intermediary factor 1γ (TIF-1γ) antibody. By univariate analysis, the average age and the male to female ratio, internal malignancy, and anti-TIF-1γ antibody were significantly higher and the frequency of interstitial lung diseases and manual muscle testing (MMT) scores of sternomastoid and dertoid muscles were significantly lower in patients with dysphagia than in patients without dysphagia. Among patients with anti-TIF-1γ antibody, the mean age, the ratios of male to female and internal malignancy were significantly higher and mean MMT scores of sternomastoid muscle were significantly lower in patients with dysphagia compared with patients without dysphagia. By multivariable analysis, the risk of dysphagia was strongly associated with the existence of internal malignancy and ant-TIF-1γ antibody and was also associated with reduced scores of manual muscle test of sternomastoid muscle. Dysphagia was markedly improved after the treatment against myositis in all 13 patients. These findings indicate that dysphagia can develop frequently in patients with internal malignancy, anti-TIF-1γ antibody, or severe muscle weakness of sternomastoid muscle.

To identify similarities and differences in the clinical features of adult Japanese patients with individual anti-aminoacyl-tRNA synthetase antibodies (anti-ARS Abs). This was a retrospective analysis of 166 adult Japanese patients with anti-ARS Abs detected by immunoprecipitation assays. These patients had visited Kanazawa University Hospital or collaborating medical centers from 2003 to 2009. Anti-ARS Ab specificity included anti-Jo-1 (36%), anti-EJ (23%), anti-PL-7 (18%), anti-PL-12 (11%), anti-KS (8%), and anti-OJ (5%). These anti-ARS Abs were mutually exclusive, except for one serum Ab that had both anti-PL-7 and PL-12 reactivity. Myositis was closely associated with anti-Jo-1, anti-EJ, and anti-PL-7, while interstitial lung disease (ILD) was correlated with all 6 anti-ARS Abs. Dermatomyositis (DM)-specific skin manifestations (heliotrope rash and Gottron's sign) were frequently observed in patients with anti-Jo-1, anti-EJ, anti-PL-7, and anti-PL-12. Therefore, most clinical diagnoses were polymyositis or DM for anti-Jo-1, anti-EJ, and anti-PL-7; clinically amyopathic DM or ILD for anti-PL-12; and ILD for anti-KS and anti-OJ. Patients with anti-Jo-1, anti-EJ, and anti-PL-7 developed myositis later if they had ILD alone at the time of disease onset, and most patients with anti-ARS Abs eventually developed ILD if they did not have ILD at disease onset. Patients with anti-ARS Abs are relatively homogeneous. However, the distribution and timing of myositis, ILD, and rashes differ among patients with individual anti-ARS Abs. Thus, identification of individual anti-ARS Abs is beneficial to define this rather homogeneous subset and to predict clinical outcomes within the \"anti-synthetase syndrome.\"

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.

The hippocampal gamma oscillation is important for cognitive function, and its deficit is related to cognitive impairment in Alzheimer’s disease (AD). Recently, it has been recognized that post-translational modification via histone acetylation is a fundamental molecular mechanism for regulating synaptic plasticity and cognitive function. However, little is known regarding the regulation of hippocampal gamma oscillation by histone acetylation. We investigated whether histone acetylation regulated kainate-induced gamma oscillations and their important regulator, fast-spiking interneurons, using acute hippocampal slices of AD model mice (PSAPP transgenic mice). We found a decrease in kainate-induced gamma oscillations in slices from PSAPP mice, accompanied with the increased activity of fast spiking interneurons in basal state and the decreased activity in activated state. The histone deacetylase (HDAC) inhibitor (SAHA, named vorinostat) restored deficits of gamma oscillation in PSAPP mice, accompanied with rescue of activity of fast spiking interneurons in basal and activated state. The effect of SAHA was different from that of the clinical AD drug donepezil, which rescued only function of fast spiking interneurons in basal state. Besides, activator of nuclear receptor family 4a (NR4a) receptor (cytosporone B), as one of the epigenetic modification related to HDAC inhibition, rescued the deficits in gamma oscillations in PSAPP mice. These results suggested a novel mechanism in which HDAC inhibition improved impairment of gamma oscillations in PSAPP mice by restoring the activity of fast spiking interneurons both in basal and activated state. The reversal of gamma oscillation deficits by HDAC inhibition and/or NR4a activation appears to be a potential therapeutic target for treating cognitive impairment in AD patients.

Background Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular injury and inflammation, followed by excessive fibrosis of the skin and other internal organs, including the lungs. CX3CL1 (fractalkine), a chemokine expressed on endothelial cells, supports the migration of macrophages and T cells that express its specific receptor CX3CR1 into targeted tissues. We previously reported that anti-CX3CL1 monoclonal antibody (mAb) treatment significantly inhibited transforming growth factor (TGF)-β1-induced expression of type I collagen and fibronectin 1 in human dermal fibroblasts. Additionally, anti-mouse CX3CL1 mAb efficiently suppressed skin inflammation and fibrosis in bleomycin- and growth factor-induced SSc mouse models. However, further studies using different mouse models of the complex immunopathology of SSc are required before the initiation of a clinical trial of CX3CL1 inhibitors for human SSc. Methods To assess the preclinical utility and functional mechanism of anti-CX3CL1 mAb therapy in skin and lung fibrosis, a sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) mouse model was analyzed with immunohistochemical staining for characteristic infiltrating cells and RNA sequencing assays. Results On day 42 after bone marrow transplantation, Scl-cGVHD mice showed increased serum CX3CL1 level. Intraperitoneal administration of anti-CX3CL1 mAb inhibited the development of fibrosis in the skin and lungs of Scl-cGVHD model, and did not result in any apparent adverse events. The therapeutic effects were correlated with the number of tissue-infiltrating inflammatory cells and α-smooth muscle actin (α-SMA)-positive myofibroblasts. RNA sequencing analysis of the fibrotic skin demonstrated that cGVHD-dependent induction of gene sets associated with macrophage-related inflammation and fibrosis was significantly downregulated by mAb treatment. In the process of fibrosis, mAb treatment reduced cGVHD-induced infiltration of macrophages and T cells in the skin and lungs, especially those expressing CX3CR1. Conclusions Together with our previous findings in other SSc mouse models, the current results indicated that anti-CX3CL1 mAb therapy could be a rational therapeutic approach for fibrotic disorders, such as human SSc and Scl-cGVHD.

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 Ca 2+ -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-β1), followed by assessment of TGF-β1/Smad signaling and fibrogenic molecules. Results ALLN treatment significantly inhibited TGF-β1-induced phosphorylation and nuclear transport of Smad2/3 in skin and lung fibroblasts. TGF-β1-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-β1-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.

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by dysregulation of the immune system, vascular damage, and fibrosis of the skin and internal organs. Patients with SSc show a heterogeneous phenotype and a range of clinical courses. Therefore, biomarkers that are helpful for precise diagnosis, prediction of clinical course, and evaluation of the therapeutic responsiveness of disease are required in clinical practice. SSc-specific autoantibodies are currently used for diagnosis and prediction of clinical features, as other biomarkers have not yet been fully vetted. Krebs von den Lungen-6 (KL-6), surfactant protein-D (SP-D), and CCL18 have been considered as serum biomarkers of SSc-related interstitial lung disease. Moreover, levels of circulating brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) can provide diagnostic information and indicate the severity of pulmonary arterial hypertension. Assessment of several serum/plasma cytokines, chemokines, growth factors, adhesion molecules, and other molecules may also reflect the activity or progression of fibrosis and vascular involvement in affected organs. Recently, microRNAs have also been implicated as possible circulating indicators of SSc. In this review, we focus on several potential SSc biomarkers and discuss their clinical utility.

Background Systemic sclerosis (SSc) is a collagen disease that exhibits intractable fibrosis and vascular injury of the skin and internal organs. Transforming growth factor-β (TGF-β)/Smad signaling plays a central role in extracellular matrix (ECM) production by α-SMA-positive myofibroblasts. Myofibroblasts may be partially derived from various precursor cells in addition to resident fibroblasts. Recently, our high-throughput in vitro screening discovered a small compound, LG283, that may disrupt the differentiation of epithelial cells into myofibroblasts. This compound was originally generated as a curcumin derivative. Methods In this study, we investigated the effect of LG283 on inhibiting fibrosis and its mechanism. The action of LG283 on TGF-β-dependent fibrogenic activity and epithelial-mesenchymal transition (EMT) was analyzed in vitro. The effects of LG283 were also examined in a bleomycin-induced skin fibrosis mouse model. Results LG283 suppressed TGF-β-induced expression of ECM, α-SMA, and transcription factors Snail 1 and 2, and Smad3 phosphorylation in cultured human dermal fibroblasts. LG283 was also found to block EMT induction in cultured human epithelial cells. During these processes, Smad3 phosphorylation and/or expression of Snail 1 and 2 were inhibited by LG283 treatment. In the bleomycin-induced skin fibrosis model, oral administration of LG283 efficiently protected against the development of fibrosis and decrease of capillary vessels without significantly affecting cell infiltration or cytokine concentrations in the skin. No apparent adverse effects of LG283 were found. LG283 treatment remarkably inhibited the enhanced expression of α-SMA and phosphorylated Smad3, as well as those of Snail 1 and 2, in the bleomycin-injected skin. Conclusions The LG283 compound exhibits antagonistic activity on fibrosis and vascular injury through inhibition of TGF-β/Smad/Snail mesenchymal transition pathways and thus, may be a candidate therapeutic for the treatment of SSc. Although the involvement of EMT in the pathogenesis of SSc remains unclear, the screening of EMT regulatory compounds may be an attractive approach for SSc therapy.

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.

Plasma cell balanitis (PCB), also known as Zoon's balanitis, is a chronic, benign inflammatory dermatosis affecting the glans penis, mainly occurring in uncircumcised middle-aged men. Currently, there has been no recommended and standardized treatment. Topical corticosteroids are the most common first-line therapy in clinical practice but often account for the primary inefficacy relapse and adverse events, particularly in cases requiring long-term use due to the high transcutaneous absorption in the penile skin. A series of recent case reports may suggest topical calcineurin inhibitors as a promising alternative, offering significant improvement in corticosteroid-resistant cases. In this paper, we describe a 61-year-old uncircumcised male patient with a one-year history of asymptomatic erosive erythema on the penis, which was initially unresponsive to topical corticosteroids. Lesional skin biopsy histologically confirmed a diagnosis of plasma cell balanitis. Combined treatment of a preceding topical corticosteroid with 0.1% tacrolimus ointment led to a dramatic clinical response within two weeks of treatment, followed by almost complete resolution after six weeks. This approach enabled the maintenance of the treatment efficacy with a weak-potency corticosteroid throughout the clinical course. Recurrence occurred with reduced application frequency, but the daily use of the same regimen rapidly restored favorable disease control. We discuss the potential difficulty in managing PCB, with particular interest in the relatively high frequency of corticosteroid resistance in nearly half of the cases reported to date. This paper also updates the possible mechanisms of action and clinical benefits of topical calcineurin inhibitors in plasma cell biology.