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The aim of this study was to utilise the Quality Enhancement Research Initiative in Systemic Sclerosis (QuERI-SSc) to measure and reduce a perceived gap in the diagnosis of pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc).Rheumatologists enrolled patients with SSc (aged ≥ 18 years) and provided data on a panel of diagnostic tests over 3 years. Pulmonary function testing, echocardiography, 6-minute walk distance, N-terminal pro-brain natriuretic peptide assays, high-resolution computed tomography of the lungs, and ventilation/perfusion scan plus right heart catheterisation (RHC; when appropriate) were emphasised. Exclusion criteria included previously documented PAH, interstitial lung disease, and SSc overlapping with other connective tissue disease.Participating rheumatologists enrolled 207 patients with SSc (90% female; 80% white), with a median age of 57 years and median disease duration of 5 years. A total of 82% of patients were classified as New York Heart Association functional class I and II; of these patients, 177 had an echocardiogram at enrolment and 191 at any time during the study. Of those who met study-specified criteria for RHC at enrolment, only 3 of 7 patients underwent RHC.The screening algorithm was successful in identifying patients with mild impairment. Although specific tools were recommended for screening PAH in patients with SSc, results indicate that significant diagnostic care gaps still exist in the general rheumatology community. Better understanding and adherence to guidelines could improve the care and, ideally, outcomes of these high-risk patients.

Scleroderma (SSc) is an autoimmune connective tissue disorder characterized by progressive fibrosis of the skin and internal organs. The leading cause of death in SSc patients is pulmonary dysfunction as a result of interstitial fibrosis and pulmonary vasculopathy. Our objective was to evaluate histopathological abnormalities associated with the development of pulmonary fibrosis in SSc.Postmortem SSc lung tissue from various stages of fibrosis and tissue from normal lung were analyzed by Masson's trichrome staining and immunohistochemistry. Monoclonal antibodies against smooth muscle-alpha actin (myofibroblast marker), von Willebrand Factor, platelet endothelial cell adhesion molecule-1 (endothelial cell markers), or caldesmon (smooth muscle cell marker) were employed.We found that in the early active stages of SSc lung fibrosis two major types of cellular abnormalities occur. One is the induction of a large number of smooth muscle alpha-actin-positive myofibroblasts in interstitia. The other is the excessive formation of alveolar capillaries (hypervascularity) accompanied by an increase in the number of microvascular endothelial cells. The vascular abnormality also involves the development of microvessels that are irregular in size and shape. However, the population of myofibroblasts and capillary endothelial cells decline as the fibrosis progresses to its most marked, later stages.We conclude that the induction of myofibroblasts and the overdevelopment of capillary microvessels characterize the progression of lung fibrosis in SSc. Using these histological alterations as criteria, therefore we have divided the fibrosis formed in the SSc lungs into four pathological stages. These results suggest that both fibroblast overproliferation and vascular abnormality play an important role in the pathogenesis of lung fibrosis in SSc.

The vascular hypothesis for the pathogenesis of systemic sclerosis was perhaps Professor LeRoy's most important scientific contribution. One early and important consequence of vascular injury is the release of activated thrombin. In this manuscript we present our data and review the current understanding of the role played by thrombin in the process of fibrosis, particularly as it relates to scleroderma lung disease. Thrombin's cellular effects are intimately involved in promoting myofibroblast differentiation, endothelial cell activation, extracellular matrix protein deposition, and the induction of important profibrotic factors. Such studies confirm that thrombin is one of the major mediators in the development and progression of pulmonary fibrosis. Therefore, targeting the major receptor of thrombin, PAR-I, and its downstream signaling molecules may lead to novel therapeutic approaches for the management of scleroderma lung fibrosis. We are indebted to Dr LeRoy for his many contributions to the field of scleroderma, and for all that he did to stimulate our interest in these studies.

Lymphokine activated killer (LAK) cells, which arise from interleukin-2 (IL-2) activation of natural killer (NK) cells, are capable of lysing NK-resistant cell targets, including endothelial cells (EC). Since EC cytotoxicity is postulated to play a role in the pathogenesis of systemic sclerosis (SSc), experiments were performed to measure LAK activity in the peripheral blood lymphocytes (PBL) of 10 SSc patients and 10 normal controls. SSc patients had no significant spontaneous cytotoxicity against NK-resistant cell targets, including EC. After IL-2 stimulation in vitro, SSc patients and normal controls demonstrated cytotoxicity toward NK-resistant cell targets, including EC. This LAK-mediated EC cytotoxicity was actually lower for SSc patients than for normal controls. These studies do not preclude a role for LAK-mediated EC cytotoxicity in the pathogenesis of SSc, but demonstrate that LAK cells are not spontaneously present in circulating PBL.

Immunofluorescence (IF) data from three different biopsy sites (nailfold, forearm, buttock) were studied in 18 patients with scleroderma (SD, systemic sclerosis) and the results compared with those obtained from 10 normal controls (NC) and 7 patients with systemic lupus erythematosus (SLE). Immunoglobulin (Ig) deposits were detected by direct IF technique at the dermo-epidermal junction (DEJ) in 8/14 nailfolds, 6/15 forearms and in none of the buttock specimens of SD patients. Epidermal nuclear staining was present in 6/14 nailfolds, and in 6/15 forearms and buttocks. The most prominent finding was the observation of multiple Ig deposits in the cuticle of 9/14 patients with SD. NC group was negative in all sites for epidermal nuclear staining and the only DEJ deposit occurred in the forearm of one subject. In conclusion, this study demonstrates that Ig deposits in SD, both at the DEJ and in the epidermal nuclei, occur more often than previously reported and are especially frequent in the nailfoldcuticle area.