Calcinosis cutis is the deposition of insoluble calcium in the skin and subcutaneous tissues. It represents a major clinical problem in patients with SSc affecting at least one quarter of patients. It is associated with longer disease duration, digital ulcers, acro-osteolysis, positive anticentromere antibody, and positive anti-PM/Scl antibody. Although pathogenesis is unknown, there is evidence supporting local trauma, chronic inflammation, vascular hypoxia, and dysregulation of bone matrix proteins as potential mechanisms. Diagnosis can be made clinically or with plain radiography. Several pharmacologic therapies have been tried for calcinosis with variable and modest results, but surgical excision of calcium deposits remains the mainstay of treatment.

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A recent study demonstrated a significant role for leukotriene B4 (LTB4) causing pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). LTB4 was found to directly injure luminal endothelial cells and promote growth of the smooth muscle cell layer of pulmonary arterioles. The purpose of the current study was to determine the effects of LTB4 on the pulmonary adventitial layer, largely composed of fibroblasts. Here, we demonstrate that LTB4 enhanced human pulmonary artery adventitial fibroblast (HPAAF) proliferation, migration and differentiation in a dose-dependent manner through its cognate G-protein coupled receptor, BLT1. LTB4 activated HPAAF by up-regulating p38 MAPK as well as Nox4 signaling pathways. In an autoimmune model of PH, inhibition of these pathways blocked perivascular inflammation, decreased Nox4 expression, reduced reactive oxygen species production, reversed arteriolar adventitial fibroblast activation and attenuated PH development. This study uncovers a novel mechanism by which LTB4 further promotes PAH pathogenesis, beyond its established effects on endothelial and smooth muscle cells, by activating adventitial fibroblasts.

IMPORTANCE Prior studies have estimated that up to 20% of adults with dermatomyositis (DM) have calcinosis, which can lead to significant morbidity. Identification of risk factors may provide a better understanding of the pathogenesis and ultimately therapy for this difficult clinical problem. Risk factors for calcinosis in adults with DM have not been extensively studied. OBJECTIVES To determine the prevalence of calcinosis and to identify associated clinical features in a cohort of extensively phenotyped adults with DM. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional study of 126 patients diagnosed as having DM from January 1, 2006, through January 1, 2013, was performed. Patients were adults (≥18 years of age) attending the Stanford University Medical Center clinic. MAIN OUTCOMES AND MEASURES Calcinosis, defined as the presence of calcium deposition in the skin and subcutaneous tissues on physical examination. RESULTS Fourteen patients (11.1%) had calcinosis, with the extremities most commonly involved. Patients with vs those without calcinosis had a longer disease duration (median, 6.9 years; range, 2.4–18.1; vs median, 3.9 years; range, 0.2-19.2 years; P = .003) and more fingertip ulcers (50.0% vs 9.3%, P < .001). An association between calcinosis and both interstitial lung disease and anti–MDA-5 autoantibodies was identified, but this association did not persist in multivariate models that adjusted for fingertip ulcers. Fingertip ulcers and disease duration were strongly associated with calcinosis in all multivariate models, independent of the underlying autoantibody present. Autoantibodies to NXP-2 were associated with calcinosis (odds ratio, 15.52; 95% CI, 2.01-119.90), whereas anti–transcriptional intermediary factor 1-γ antibodies were protective (odds ratio, 0.2; 95% CI, 0.01-0.99) in multivariate analyses that adjusted for fingertip ulcers and other covariates. CONCLUSIONS AND RELEVANCE Calcinosis was a relatively uncommon clinical feature in our cohort of adults with DM. Our data suggest that calcinosis is positively associated with longer disease duration, fingertip ulcers, and NXP-2 autoantibodies and negatively associated with transcriptional intermediary factor 1-γ antibodies. A common vascular mechanism may underlie the development of both calcinosis and fingertip ulcers in patients with DM.