Limited Cutaneous and Diffuse Cutaneous Scleroderma: Circulating Biomarkers Differentiate Lung Involvement (original) (raw)

Evaluation and management approaches for scleroderma lung disease

Therapeutic Advances in Respiratory Disease, 2017

Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are leading causes of morbidity and mortality in systemic sclerosis (SSc). As symptoms are often under-reported in SSc, early screening of ILD and PAH is of paramount importance, and early treatment may be associated with better clinical outcomes. Serologies are particularly helpful in identifying patients at risk for pulmonary involvement. Pulmonary function testing, high-resolution computed tomography of the chest and echocardiography are important tools in the initial screening of these patients. Extensive research has also led to an improved understanding of the mediators involved in the pathogenesis of ILD and PAH. As a result, there have been significant advances in the development of novel targeted therapeutics and an increase in the number of early-phase clinical trials in SSc.

Clinical and laboratory features of scleroderma patients with pulmonary hypertension

Rheumatology, 2000

Objective. Pulmonary hypertension (PH) is a frequent cause of death in patients with systemic sclerosis (SSc). In this study, we examined the occurrence of PH and investigated the clinical and laboratory features of SSc patients with PH. Methods. A cross-sectional study of 125 Japanese patients with SSc was conducted using Doppler echocardiography, other multiple cardiopulmonary tests, and laboratory examination. Results. PH (systolic pressure >40 mmHg) was diagnosed in 20 patients (16%) by Doppler echocardiography. In the six patients who had secondary pulmonary hypertension (SPH), PH was due to severe pulmonary fibrosis; 14 patients had isolated pulmonary hypertension (IPH). An elevated erythrocyte sedimentation rate (ESR) and increased immunoglobulin G (IgG) were found in a significantly greater proportion of the patients with PH than in those without PH. The incidence of pitting scars/ulcers was significantly greater in the patients with SPH than in those without PH. Conclusion. Elevated ESR and increased IgG were common features of scleroderma patients with PH, and scleroderma patients with SPH were inclined to have pitting scars/ulcers.

Cross-sectional study of soluble selectins, fractions of circulating microparticles and their relationship to lung and skin involvement in systemic sclerosis

BMC Musculoskeletal Disorders, 2015

Background: Endothelial damage and activation may play central roles in the pathogenesis of systemic sclerosis (SSc) and are reflected by microparticles (MPs) and soluble selectins. The objective of this study was to determine if these potential biomarkers are associated with specific organ involvements or cutaneous subgroups of SSc patients. Method: MPs in platelet-poor plasma from 121 patients with SSc, 79 and 42 with limited and diffuse cutaneous disease, respectively, were characterized by flow cytometry for their capacity to bind annexin V in combination with surface markers of either platelets (PMPs), leukocytes (LMPs) or endothelial cells (EMPs). Soluble E-and P-selectin levels were determined in plasma. By correlation analyses, this was held against involvement of skin, lung function, lung fibrosis, pulmonary artery hypertension, and serology. Results: None of the markers were associated with cutaneous subgroups of SSc. Concentrations of annexin V non-binding EMPs and annexin V non-binding LMPs were negatively correlated to pulmonary diffusing capacity (DL CO) (r =-0.28; p = 0.003; r =-0.26; p = 0.005) and forced vital capacity (FVC) (r =-0.24; p = 0.009; r =-0.29; p = 0.002), driven by patients with limited and diffuse cutaneous disease, respectively. Soluble E-selectin levels correlated negatively to DL CO (r =-0.21, p = 0.03) and FVC (r =-0.25; p = 0.007); and soluble P-selectin correlated negatively to DL CO (r =-0.23, p = 0.01). Conclusion: Negative correlations between annexin V non-binding EMP and LMP concentrations with lung function parameters (DL CO and FVC) differed between limited and diffuse cutaneous subsets of SSc, indicative of various pathogeneses of lung involvement in SSc, possibly with a differential role of MPs.

Clinically Significant Interstitial Lung Disease in Limited Scleroderma

CHEST Journal, 2008

Methods: Retrospective cohort study of all SSc patients who had been referred for further evaluation of ILD and had undergone surgical lung biopsy. Clinical data were abstracted by review of the medical record, and lung biopsy specimens were reviewed and classified according to current pathologic criteria. Results: All patients presented with significant respiratory symptoms. Twenty-two of 27 subjects had surgical lung biopsy-proven ILD, and 5 subjects had miscellaneous non-ILD patterns. Of those subjects with ILD, 64% (14 of 22 subjects) had a nonspecific interstitial pneumonia (NSIP) pathologic pattern (fibrotic NSIP, 13 subjects; cellular NSIP, 1 subject), and 36% (8 of 22 subjects) had the usual interstitial pneumonia (UIP) pattern. Subjects with NSIP were younger (median age, 42 vs 58 years, respectively; p ‫؍‬ 0.003), but no differences were noted in pulmonary physiology (FVC: NSIP group, 52% predicted; UIP group, 65% predicted; p ‫؍‬ 0.22; diffusing capacity of the lung for carbon monoxide: NSIP group, 40% predicted; UIP group, 42% predicted; p ‫؍‬ 1.0). All patients had limited skin involvement. The Scl-70 antibody was absent among those assessed (NSIP group, 0 of 10 subjects; UIP group, 0 of 7 subjects). All patients were treated with cytotoxic therapy. The median survival time for those with NSIP was 15.3 years (5,596 days) compared with 3 years (1,084 days) for those with UIP (p ‫؍‬ 0.07 [log-rank test]). Conclusions: In SSc patients with limited cutaneous disease and clinically significant ILD, fibrotic NSIP and UIP are the predominant pathologic patterns. Those with the UIP pattern of disease had a trend toward shorter survival time.

Pulmonary hypertension: a correct diagnosis for a suitable therapy in scleroderma patients

Clinical and experimental rheumatology

Systemic sclerosis (SSc) is a heterogeneous disorder characterised by dysfunction of the endothelium and dysregulation of fibroblasts, resulting in excessive production of collagen, and abnormalities of the immune system. Progressive fibrosis of the skin and internal organs is a pathologic hallmark of the disease, resulting in major organ damage and failure. Pulmonary hypertension (PH) is frequent in patients with SSc and, pulmonary arterial hypertension (PAH) represents one of the main causes of death. PH is not a specific disease, but a haemodynamic condition characterized by a mean pulmonary pressure ≥25mmHg. In SSc, because of the great variability in clinical manifestation, it is possible to identify pulmonary hypertension due to left heart disease, PH due to respiratory disease or pulmonary arterial hypertension. The knowledge of PH and the right diagnosis are crucial to assess the most appropriate therapeutic strategy. In this article, the new classification criteria of PH ha...

Predictive value of serum III procollagen for diagnosis of pulmonary involvement in patients with scleroderma

The European respiratory journal, 1995

High resolution computed tomography (HRCT) was recently demonstrated to be as good as open lung biopsy for the diagnosis of pulmonary involvement in patients with scleroderma. Nevertheless, in view of its price and related irradiation, HRCT cannot be recommended as a screening test. Serum III procollagen (sPIIINP) is an aminopropeptide of type III collagen, which is released during conversion into collagen by specific proteases. Increased levels of sPIIINP have been observed in patients with scleroderma. The aim of the present study was to assess the relationship between sPIIINP measurement and pulmonary involvement defined according to HRCT and pulmonary function tests (PFT) with single-breath carbon monoxide transfer capacity (TL,CO) in 28 patients suffering from scleroderma. Patients were divided into two groups for analysis, Group A comprising 16 patients without pulmonary scleroderma and Group B comprising 12 patients with pulmonary scleroderma. All patients had stable cutaneou...

Scleroderma lung study (SLS): differences in the presentation and course of patients with limited versus diffuse systemic sclerosis

Annals of the Rheumatic Diseases, 2007

Objectives: Pulmonary fibrosis is a leading cause of death in systemic sclerosis (SSc). This report examines the differences at baseline and over 12 months between patients with limited versus diffuse cutaneous SSc who participated in the Scleroderma Lung Study. Methods: SSc patients (64 limited; 94 diffuse) exhibiting dyspnoea on exertion, restrictive pulmonary function and evidence of alveolitis on bronchoalveolar lavage and/or high-resolution computed tomography (HRCT) were randomised to receive cyclophosphamide (CYC) or placebo and serially evaluated over 12 months. Results: Baseline measures of alveolitis, dyspnoea and pulmonary function were similar in limited and diffuse SSc. However, differences were noted with respect to HRCT-scored fibrosis (worse in limited SSc), and to functional activity, quality of life, skin and musculoskeletal manifestations (worse in diffuse SSc) (p,0.05). When adjusted for the baseline level of fibrosis, both groups responded similarly to CYC with regard to lung function and dyspnoea (p,0.05). Cyclophosphamide was also associated with more improvement in skin score in the diffuse disease group more than in the limited disease group (p,0.05). Conclusions: After adjusting for the severity of fibrosis at baseline, CYC slowed the decline of lung volumes and improved dyspnoea equally in the limited and the diffuse SSc groups. On the other hand, diffuse SSc patients responded better than limited patients with respect to improvements in skin thickening. D iffuse and limited cutaneous systemic sclerosis (SSc) are differentiated not only by the extent and degree of skin thickening, but also by different propensities to visceral involvement. 1-3 Patients with diffuse cutaneous SSc (dcSSc) are at a much higher risk for the development of severe heart and kidney involvement than are those with limited cutaneous SSc (lcSSc). 2 3 However, data from Steen et al 4 suggest that patients with lcSSc are at only a slightly lower risk for the development of severe interstitial lung involvement than are patients with dcSSc. While several studies, 5-9 including a recent large randomised placebo-controlled trial, 10 have shown a beneficial effect of cyclophosphamide (CYC) on the course of SSc-related interstitial lung disease, no study has examined patients with limited versus diffuse SSc for differences in the presentation of their interstitial lung disease or how their pulmonary and systemic manifestations respond to CYC.