Dermatomyositis (DM) is a rare idiopathic inflammatory myopathy characterized by muscle weakness and cutaneous manifestations in adults and children. Calcinosis, a complication of DM, is the abnormal ...deposition of insoluble calcium salts in tissues, including skin, subcutaneous tissue, tendons, fascia, and muscle. Calcinosis is more commonly seen in juvenile DM (JDM), but also develops in adult DM. Although the mechanism of calcinosis remains unclear, several pathogenic hypotheses have been proposed, including intracellular accumulation of calcium secondary to an alteration of the cellular membrane by trauma and inflammation, local vascular ischemia, dysregulation of mechanisms controlling the deposition and solubility of calcium and phosphate, and mitochondrial damage of muscle cells. Identifying calcinosis biomarkers is important for early disease detection and risk assessment, and may lead to novel therapeutic targets for the prevention and treatment of DM-associated calcinosis. In this review, we summarize myositis autoantibodies associated with calcinosis in DM, histopathology and chemical composition of calcinosis, genetic and inflammatory markers that have been studied in adult DM and JDM-associated calcinosis, as well as potential novel biomarkers.
•Anti-NXP2 autoantibodies have been associated with calcinosis in both adult and juvenile dermatomyositis (DM).•The structure and composition of calcinosis differ from normal trabecular bone, with a mineral content of carbonate apatite.•Inflammation plays a central role in the calcinosis process in DM, with calcium as a chemoattractant for inflammatory cells.•Further research is needed to identify serum biomarkers for calcinosis in DM.
Abstract Objective A patulous esophagus on high-resolution computed tomography (HRCT) of the thorax is frequently observed in patients with systemic sclerosis (SSc). Microaspiration has been ...purported to play a role in the development and progression of SSc interstitial lung disease (ILD), but studies examining the role of microaspiration in SSc-ILD have yielded conflicting results. This study was conducted to determine the association between esophageal diameter and SSc-ILD. Methods A cross-sectional study of Northwestern Scleroderma Registry patients with available HRCT exams was conducted. The predictor variable was the widest esophageal diameter (WED) on HRCT, and the primary and secondary outcome variables were radiographic ILD and pulmonary function tests respectively. The degree of radiographic ILD was assessed using a semi-quantitative score adapted from published methods. Estimated regression coefficients adjusted for age, sex, race, body mass index, smoking; SSc disease subtype, serum autoantibodies and disease duration; modified Rodnan skin score, proton pump inhibitor and immune suppressant medication use and erythrocyte sedimentation rate were calculated. Results 270 subjects were studied. In the adjusted analyses, there were positive associations between WED and total ILD score (β=0.27; 95% CI, 0.09 to 0.41), fibrosis (β=0.15; 95% CI, 0.07 to 0.23), and ground glass opacities (β=0.12; 95% CI, 0.04 to 0.20); there were negative associations between WED and FVC % predicted (β=-0.42; 95% CI, -0.69 to -0.13), and adjusted DLCO % predicted (β=-0.45; 95% CI, -0.80 to -0.09) after adjusting for potential confounders. Conclusions Increasing esophageal diameter on HRCT in patients with SSc is associated with more severe radiographic ILD, lower lung volumes, and lower DLCO % predicted. Longitudinal studies are needed to determine if esophageal dilatation is associated with the incidence and/or progression of ILD in patients with SSc.
The in vivo preclinical pharmacodynamic profile of TD-1211, a selective opioid receptor antagonist currently under development for the treatment of opioid-induced constipation, was compared to that ...of the clinically studied opioid antagonists, naltrexone, alvimopan, and ADL 08-0011 (the primary active metabolite of alvimopan). The oral activity of TD-1211 was evaluated in models of gastrointestinal (GI) and central nervous system (CNS) function in the rat and dog. Oral administration of TD-1211, naltrexone, and ADL 08-0011 reversed loperamide-induced inhibition of gastric emptying and castor oil-induced diarrhea in rats and nonproductive GI circular smooth muscle contractility in dogs. Alvimopan was only efficacious in the castor oil model. Oral administration of naltrexone and ADL 08-0011, but not TD-1211 or alvimopan, was associated with a CNS withdrawal response in morphine-dependent mice, inhibition of morphine-induced anti-nociception in rat and dog hot plate tests, and hypothermia and sedation in dogs. It is concluded that TD-1211 has potent in vivo GI activity, consistent with opioid receptor antagonism, but has no significant CNS activity. The data from these studies support the clinical development of TD-1211 as a novel treatment for opioid-induced GI dysfunction.
Purpose of Review
Calcinosis is a common complication of systemic sclerosis with no known effective pharmacologic therapy. We reviewed the literature regarding systemic sclerosis-related calcinosis ...as well as other disorders of biomineralization in order to identify targets of future study for calcinosis.
Recent Findings
Patients with systemic sclerosis-related calcinosis demonstrate systemic abnormalities in mineralization pathways, including decreased levels of the mineralization inhibitor inorganic pyrophosphate. Insights from other mineralization disorders suggest that local and systemic phosphate metabolism pathways involving the ABCC6, ENPP1, and NT5E genes play a critical role in regulation of ectopic calcification. Knockout models of these genes may lead to an appropriate murine model for study of calcinosis. Poly(ADP-ribose) polymerase (PARP) enzymes may also play a critical role in hydroxyapatite nucleation and warrant future study in systemic sclerosis.
Summary
Study of local and systemic mineralization pathways, particularly phosphate metabolism pathways and PARP enzymes, should provide greater insight into the pathogenesis of systemic sclerosis-related calcinosis.
Objective To investigate the regulation of early growth response-2 (Egr-2) by transforming growth factor β3 (TGF-β3) and its functions in cultured human uterine leiomyoma smooth muscle cells. Design ...Laboratory research. Setting Academic medical center. Patient(s) Primary leiomyoma cells from patients with symptomatic leiomyomata. Intervention(s) Tissue culture followed by RNA and protein analysis. Main Outcome Measure(s) Cell proliferation, alteration in extracellular matrix component expression. Result(s) In vivo mRNA levels of Egr-2 were statistically significantly higher in leiomyoma tissues compared with matched myometrial tissues, and showed a statistically significant correlation with TGF-β3 messenger RNA (mRNA) levels in leiomyoma tissues. In primary leiomyoma smooth muscle cells, TGF-β3 statistically significantly induced Egr-2 gene expression in a dose-dependent and time-dependent manner. Small interfering RNA (siRNA) knockdown of Egr-2 markedly increased the level of the proliferation marker proliferating cell nuclear antigen and the expression of proto-oncogene c-myc. On the other hand, ablation of Egr-2 stimulated collagen-1A1 and collagen-3A1 transcription and inhibited dermatopontin gene expression. However, the mRNA levels of α-smooth muscle actin and fibronectin were not affected by Egr-2 knockdown. Conclusion(s) We demonstrated that TGF-β3 regulated Egr-2 gene expression and presented evidence that Egr-2 decreases collagen production and stimulates dermatopontin gene expression.
A 50 year-old man presented with five months of progressive cough and dyspnea, followed by the acute onset of fever and hypoxemic respiratory failure. Open lung biopsy was notable for pulmonary ...capillaritis with bronchiolitis obliterans organizing pneumonia. Creatine kinase was normal, and aldolase was mildly elevated. There was no history of muscle weakness or rashes. Testing for anti-PL-7 antibodies was positive, and a diagnosis of the antisynthetase syndrome was made. This is the first reported case of pulmonary capillaritis in association with the PL-7 antisynthetase syndrome. Our case highlights the importance of testing for antisynthetase antibodies in patients presenting with pulmonary capillaritis, even in the absence of characteristic skin rashes or overt muscle weakness.
Intra-articular hyaluronan therapy (IAHA) is a common but controversial nonsurgical treatment of symptomatic knee osteoarthritis. The overall treatment effect of IAHA for osteoarthritis pain is ...substantial, but the majority of this benefit is mediated by the placebo effect. Despite the large overall benefit of IAHA when the effect of the hyaluronan is combined with the placebo effect, there is only a small benefit of questionable clinical significance of IAHA compared with intra-articular placebo. Compared with intra-articular corticosteroids, however, IAHA most likely is comparable for long-term pain relief and possibly slightly inferior for short-term pain relief.
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