Lung Disease In Systemic Sclerosis Research Articles

THU0412 Reactive hyperemia index (RHI) is associated with macrovascular disease and lung disease in systemic sclerosis

BackgroundVasomotor endothelial function is an emerging data in functional exploration. Its meaning is well established in cardiology, where it independently predicted the occurrence of cardiovascular events. It interest has been...

Increased circulating soluble vascular adhesion protein-1 levels in systemic sclerosis: association with lower frequency and severity of interstitial lung disease

To determine circulating soluble vascular adhesion protein-1 (sVAP-1) levels and their clinical associations in patients with systemic sclerosis (SSc). Serum VAP-1 levels were examined by enzyme-linked immunosorbent assay in 71 SSc patients, 13 systemic lupus erythematosus patients and 50 healthy individuals. Serum sVAP-1 levels were significantly elevated in SSc patients (617.2±338.7ng/mL) compared with healthy individuals (320.2±144.2ng/mL; P<0.001) and patients with systemic lupus erythematosus (329.0±176.1ng/mL; P<0.001). Among SSc patients, there were no differences in serum sVAP-1 levels between those with limited cutaneous SSc and those with diffuse cutaneous SSc. SSc patients with raised sVAP-1 levels had interstitial lung disease and decreased percent vital capacity less often than those with normal sVAP-1 levels. sVAP-1 levels were positively correlated with percent vital capacity in patients with SSc. Serum sVAP-1 levels were increased in patients with SSc, and associated with a lower frequency and severity of interstitial lung disease in SSc, suggesting that sVAP-1 plays a role in the pathogenesis of interstitial lung disease in SSc.

Systemic sclerosis and the gut

Gastrointestinal involvement (GI) is increasingly recognized as a major cause of both morbidity and mortality in systemic sclerosis (SSc). GI complications are common, second only to skin involvement, and affect up to 90% of patients. Although treatment modalities have changed little for upper gut symptoms such as GI reflux, there are emerging treatment modalities for the common lower gut symptoms (constipation and fecal incontinence), which will be reviewed. The important link between reflux and interstitial lung disease in SSc is also addressed. The aim of this review is to help the clinician understand and manage GI symptoms in SSc.

Clinical and Radiographic Heterogeneity of Interstitial Lung Disease in Systemic Sclerosis Based on Disease-Specific Autoantibodies

Patients with SSc have the presence of several autoantibodies, some of which are SSc-specific antibodies associated with the clinical features of SSc (9-13). The presence of anti-topoisomerase I (topo-I) antibody is associated with the development of skin fibrosis and progressive ILD in SSc. Anti-centromere antibody (ACA) is seen in patients with limited skin disease and is a minor risk factor for the development of ILD. However, it remains unclear whether SSc-specific antibodies are associated with pulmonary function and radiological findings of HRCT. We divided SSc patients into 5 clusters on the basis of SSc-specific autoantibodies present and retrospectively evaluated the clinical and radiological features of ILD among these 5 SSc patient clusters. Abstract Background: Patients with systemic sclerosis have the presence of several autoantibodies, some of which are systemic sclerosis-specific autoantibodies that are related to the clinical features of this disease. We retrospectively evaluated the clinical and radiological features of systemic sclerosis in patients with interstitial lung disease on the basis of these autoantibodies. Method: This study comprised 226 patients with systemic sclerosis. We divided patients with systemic sclerosis into 5 clusters based on the systemic sclerosis-specific autoantibodies present and compared the clinical and radiological features of interstitial lung disease among these 5 systemic sclerosis clusters. Results: Of 226 patients, interstitial lung disease was present in 73 (32.3%) patients. Clustering by Ward cluster analysis subsequently identified 5 major clusters of patients. Clusters of patients with anti-topoisomerase I antibody and without systemic sclerosis-specific autoantibodies had a higher incidence of interstitial lung disease compared to the other clusters (75.0% and 51.9%, respectively). Patients in these two clusters had higher percentages of cough and dyspnea, higher incidence of traction bronchiectasis and honeycomb-like cysts in computed tomography, and a decrease in percentage predicted of vital capacity. In contrast, patients with anti-centromere antibody had few clinical and laboratory findings and the lowest incidence of interstitial lung disease (16.8%). Patients with anti- ribonucleic antibody or nucleolar pattern in anti-nuclear antibody had moderate findings among the 5 clusters. Conclusion: The results showed that there were differences in clinical and radiological findings among patients with systemic sclerosis-specific autoantibodies.

Immunosuppression for interstitial lung disease in systemic sclerosis – novel insights and opportunities for translational research

Systemic sclerosis (SSc) is a chronic inflammatory disorder characterized by a disturbance in fibroblast function culminating in the telltale skin thickening and fibrosis of visceral organs. Interstitial lung disease (ILD) is common (Steele et al. 2011) and is the leading cause of death in this disease (Steen and Medsger 2007). The immunohistopathogenesis of SSc-ILD is characterized by immune dysfunction and inflammation. Thus, immunosuppression has been hypothesized as a useful treatment for SSc-ILD. However, randomized clinical trials (RCTs) have thus far only revealed a modest effect of immunosuppression (Hoyles et al. 2006; Tashkin et al. 2006). We believe that these small observed effects are due, at least in part, to the actual design of the RCTs, in particular subject selection, which did not properly identify patients likely to respond to treatment.

Treatment for pulmonary manifestations of juvenile systemic sclerosis

Purpose Children with systemic sclerosis (SSc) may develop severe alveolitis with progressive, potentially fatal interstitial fibrosis. There have been no controlled trials for treatment of juvenile SSc. Adult trials suggest benefit from cyclophosphamide (CY) therapy, though with significant risk for adverse events. As part of a larger study to develop objective clinical and radiological measures for outcomes in juvenile SSc, we reviewed the courses of seven patients with SSc lung disease who were treated with extensive courses of CY or methotrexate.

Interstitial Lung Disease in Systemic Sclerosis: Pathophysiology, Current and New Advances in Therapy

Systemic sclerosis is an autoimmune connective tissue disorder characterized by fibrosis of the skin and visceral organs. Interstitial lung disease (ILD) is a major complication of this disease and along with pulmonary arterial hypertension is the leading cause of mortality in scleroderma patients. The pathogenesis of pulmonary fibrosis is characterized by epithelial cell injury, activation of the coagulation pathway and inflammation, which create a profibrogenic environment in the lung in the setting of autoimmunity. The current standard of treatment for ILD in systemic sclerosis is cyclophosphamide. In view of the modest benefits in pulmonary function seen with cyclophosphamide in two recent trials and its significant toxicity, the search for alternative treatments is ongoing. With the advances in our understanding of the pathogenic mechanisms of pulmonary fibrosis, many promising therapeutic agents have come into view, but their efficacy needs to be evaluated before they can be recommended clinically. This review discusses the pathogenesis of pulmonary fibrosis with a focus on the potential target pathways, the current treatment options and recent advances in the treatment of ILD in systemic sclerosis.

Clinical decision rule to predict the presence of interstitial lung disease in systemic sclerosis

To develop a clinical decision rule to predict the presence of interstitial lung disease (ILD) in systemic sclerosis (SSc; scleroderma) and to estimate the prevalence of SSc-ILD. Patient data were extracted from the Canadian Scleroderma Research Group registry. Three algorithms for the clinical decision rule were considered based on lung auscultation, chest radiography (CXR), and % predicted forced vital capacity (FVC). High-resolution computed tomography (HRCT) scans were used as the gold standard to determine the diagnostic properties of the 3 algorithms. Multiple imputation was used to impute HRCT data when missing, thereby avoiding bias due to differential referral for HRCT. This study included 1,168 patients. Of the patients with HRCT scans, 65% had evidence of ILD, compared to 26% by physical examination and 22% by CXR. The FVC of those who did not have HRCT was 8.8% greater than those who did (95% confidence interval [95% CI] 6.0-11.6%). Algorithm A, which identified the presence of ILD based on crackles on lung auscultation and/or findings on CXR, had a likelihood ratio of 3.9, compared to 3.2 for Algorithm B (which included patients with FVC <70%) and 2.2 for Algorithm C (which included patients with FVC <80%). The prevalence of ILD in the cohort was estimated to be 52% (95% CI 46-59%). We developed a simple clinical decision rule to predict SSc-ILD with good test characteristics. The prevalence of ILD in a large, unselected SSc cohort was estimated to be 52%.

Are High Doses of Prednisone Necessary for Treatment of Interstitial Lung Disease in Systemic Sclerosis?

IntroductionInterstitial lung disease (ILD) as part of systemic sclerosis (SS) is a leading cause of morbidity and mortality. ObjectivesTo evaluate the use of intravenous pulse cyclophosphamide combined with low and high doses of prednisone in the treatment of ILD in SS is equally effective. MethodAn experimental, exploratory and randomized single-blind clinical trial was conducted at Hermanos Ameijeiras Clinical Surgical Hospital from September 2006 to December 2009, including 23 patients with SS and ILD. Two treatment schedules were evaluated and randomly assigned. Group A was composed of 13 patients with a monthly dose of cyclophosphamide (ev) for 6 months and a twice-monthly dose for the remaining 6 months, prednisone (1mg×kg×day) 4 weeks and then the dose was lowered to 5mg every 2 weeks up to 10mg. Group B: 10 patients with cyclophosphamide (ev), oral prednisone 10mg daily. ResultsThere are significant differences at onset of CVF and the honeycomb pattern between both groups, where the high dose group was at a disadvantage. At the end of treatment the low dose group achieved improvement of radiologic lesions and the Warrick index, unlike the high dose group. The remaining variables experienced improvement in both groups without marked inequality. Similarly, slight adverse reactions were present in both groups. Two patients dropped out of the study. ConclusionsA combination of low dose steroids with cyclophosphamide is effective in interstitial lung disease treatment especially in active disease, and results did not show differences regarding the high dose group but the sample size and the evolutionary severity of high dose patients oblige other studies to verify these data.

Detection of Interstitial Lung Disease in Systemic Sclerosis through Partitioning of Lung Transfer for Carbon Monoxide

Background: Interstitial lung disease (ILD) is a leading cause of death in systemic sclerosis (SSc). Sensitivities and specificities of the current pulmonary function tests (PFTs) for the detection of ILD in SSc are poor. Objective: To determine whether diffusion capacity of the lungs for carbon monoxide (DLCO) partitioned into membrane conductance for CO (DmCO) and alveolar capillary blood volume (Vcap) could provide more sensitive clues to ILD than current PFTs. Methods: DmCO and Vcap were determined in 35 consecutive SSc patients in whom a cardiac and/or pulmonary vascular abnormality had been rejected according to the recommended screening algorithm. ILD was diagnosed with high-resolution computed tomography. Results: Among 35 patients [6 men; median age (first–third quartile) 61.9 years (49.5–67.7)], 22 had no ILD and 13 did. Total lung capacity (TLC), vital capacity and DLCO [percentage of predicted value (%pred)] were lower in patients with ILD [86 (82–103) vs. 106 (98–112), p = 0.01, 96 (88–112) vs. 114 (104–121), p = 0.04, and 67 (59–81) vs. 80 (71–94), p = 0.02, respectively]. DmCO (%pred) and the ratio of DmCO to Vcap were much lower in patients with ILD [54 (48–72) vs. 83 (66–92), p < 0.001, and 0.22 (0.21–0.27) vs. 0.40 (0.35–0.53), p < 0.0001, respectively]. According to receiver operating characteristic analysis, the DmCO:Vcap ratio displayed higher sensitivity and specificity than TLC, vital capacity and DLCO in identifying ILD in our study group (p < 0.01). Conclusions: These results suggest that the partitioning of DLCO might be of interest for identifying ILD in SSc patients.

Interstitial Lung Disease in Systemic Sclerosis: Diagnosis and Management

In 460 B.C., Hippocrates described a syndrome of thickened skin. It wasn’t until 1752 that this condition was described in more detail by Carlo Curzio. The term “scleroderma” was first used by Giovambattista Fantonetti in 1836. There was little interest in this disease again until the mid-late 1900’s and now it is a clearly defined disease with ongoing research into pathophysiology and treatment options. Scleroderma is broken down into three main categories: localized, systemic and sine. The first, localized sclerosis is limited to the skin. It has deep and extensive involvement of the skin but spares any internal organ involvement. Systemic Scleroderma (SSc) is divided into limited and diffuse based on the extent of skin involvement. Limited cutaneous (lcSSc) can involve the forearms, hands, legs, feet and face. Diffuse cutaneous (dcSSc) can involve any body area. Both will involve internal organs, differentiating them from the localized form. The last major category, Sine (ssSSc), is rare and involves only internal organs, sparing the skin.

Circulating Biomarkers of Interstitial Lung Disease in Systemic Sclerosis

Interstitial lung disease (ILD) is a major cause of morbidity and mortality in patients with systemic sclerosis (SSc). Although a large proportion of SSc patients have only limited interstitial involvement with an indolent course, in a significant minority ILD is progressive, requiring prompt treatment and careful monitoring. One of the main challenges for the clinician treating this highly variable disease is the early identification of patients at risk of progressive ILD, while avoiding potentially toxic treatments in those whose disease is inherently stable. Easily available and repeatable biomarkers that allow estimation of the risk of ILD progression and early response to treatment are highly desirable. In this paper, we review the evidence for circulating biomarkers with potential roles in diagnosis, monitoring of disease activity, or determining prognosis. Peripheral blood biomarkers offer the advantages of being readily obtained, non-invasive, and serially monitored. Several possible candidates have emerged from studies performed so far, including SP-D, KL-6, and CCL18. Presently however, there are few prospective studies evaluating the predictive ability of prospective biomarkers after adjustment for disease severity. Future carefully designed, prospective studies of well characterised patients with ILD, with optimal definition of disease severity and outcome measures are needed.

Screening for interstitial lung disease in systemic sclerosis: the diagnostic accuracy of HRCT image series with high increment and reduced number of slices

ObjectivesThe objective of this study is to assess diagnostic accuracy for the detection of interstitial lung disease (ILD) in image series with high increment and reduced number of slices in...

Management of interstitial lung disease in systemic sclerosis

Interstitial lung disease (ILD) is very common in systemic sclerosis (SSc) and the leading cause of death. High-resolution computed tomography is a sensitive tool for the diagnosis of ILD in SSc and is abnormal in up to 90% of patients. The most common radiographic and histopathologic pattern seen in these patients is one of nonspecific interstitial pneumonia. Despite the high incidence of disease, the prognosis for most patients is good and those who progress tend to do so early in the course of disease. Treatment options are limited by a paucity of placebo-controlled trials. Data for use of cyclophosphamide and mycophenolate mofetil exist and there is an ongoing trial comparing these two treatments. Although there are limited data to guide us on how to care for these patients, this article proposes a management algorithm. There is ongoing research on new biological treatments as well as the use of biomarkers to predict the course of disease and response to treatment and these may shape the future manage...

Serum CC chemokine ligand-18 predicts lung disease worsening in systemic sclerosis

Elevated serum CC chemokine ligand (CCL)18 reflects lung fibrosis activity in systemic sclerosis (SSc) and could be an early marker of lung function worsening. Therefore, we sought to evaluate whether serum CCL18 levels at baseline could predict worsening of lung disease in SSc. In this prospective study, 83 SSc patients were analysed longitudinally over a 4-yr observation period for the risk of occurrence of combined deleterious events, defined as a 10% decrease from baseline of total lung capacity or forced vital capacity % predicted, or death, according to serum CCL18 at inclusion. Receiver operating characteristic (ROC) curve analysis was performed for prediction of events during the first year after inclusion. The best cut-off level of serum CCL18 for prediction of a combined event within the follow-up period was 187 ng · mL(-1), with 53% sensitivity and 96% specificity (area under the ROC curve 0.86; p < 0.001). After a mean ± SD follow-up of 33.7 ± 10.8 months, a higher rate of disease progression occurred in the group with serum CCL18 levels >187 ng · mL(-1). The adjusted hazard ratio was 5.36 (95% CI 2.44-11.75; p < 0.001). In summary, serum CCL18 is an accurate predictive biomarker for the identification of patients with a higher risk of subsequent scleroderma lung disease worsening.

Imaging of interstitial lung disease in systemic sclerosis: computed tomography versus ultrasound

Interstitial lung disease related to systemic sclerosis (SSc-ILD) is a main prognostic determinant of the disease. High-resolution computed tomography is the reference tool to detect SSc-ILD in the clinical arena. It enables the diagnosis, quantification and monitoring of lung involvement, providing robust information for the management of the disease; yet its cost and especially radiological burden can make it unappealing to SSc patients, who are often young women in their reproductive age, who require serial testing to assess the natural history of the disease. Recently, lung ultrasound has been proposed as a nonionizing technique to detect and semiquantifiy SSc-ILD. This new application of ultrasound seems interesting, as it is fast, inexpensive and can easily be performed at the patient’s bedside with a handheld device. Magnetic resonance is the current gold standard for noninvasive virtual histological discrimination of different tissues. Despite still being underused for the evaluation of the lungs,...

Coagulation and Autoimmunity in Scleroderma Interstitial Lung Disease

Interstitial lung disease in systemic sclerosis (SSc-ILD) is often an irreversible and progressive fibrosing process that now is the leading cause of scleroderma-related deaths. In this review we present our current understanding of the role played by coagulation and particularly by thrombin in autoimmune-mediated tissue injury and fibrosis, mainly as it relates to SSc-ILD. We used PubMed to search for articles published up to October 2010 for keywords referring to autoimmunity, coagulation, pulmonary fibrosis, and scleroderma. SSc-ILD is an autoimmune disease associated with lymphocyte activation and release of various cytokines and growth factors. The production of autoantibodies is a central feature in SSc. Activation of the coagulation cascade with release of thrombin is 1 of the earliest events following tissue injury. Thrombin contributes to autoimmune responses by activating of pathogenic Th2 lymphocyte profile in SSc. Thrombin also modulates tissue repair responses, stimulates transformation of epithelial cells, endothelial cells, and fibroblasts into myofibroblast phenotype, and induces secretion of several pro-immune and profibrotic factors, which serve as antigens for pathogenic autoantibodies production in SSc-ILD. The identification of links between autoimmunity and coagulation would provide new insights into the pathogenesis of pulmonary fibrosis associated with autoimmune diseases and further acknowledge the importance of thrombin in the development of SSc-ILD.

Scleroderma and Related Disorders [202-212]: 202. Multi-Centre Audit of Treatment of Interstitial Lung Disease in Systemic Sclerosis with IV Cyclophosphamide

Scleroderma and Related Disorders [202-212]: 202. Multi-Centre Audit of Treatment of Interstitial Lung Disease in Systemic Sclerosis with IV Cyclophosphamide

Imaging Lung Disease in Systemic Sclerosis

Interstitial lung disease and pulmonary hypertension (PH) are the most common cardiopulmonary findings in patients with systemic sclerosis (SSc). About two thirds of patients suffering from SSc develop scleroderma interstitial lung disease. PH is present in about 20% of SSc patients and is typically associated with severe lung disease, although it may be an isolated manifestation of SSc. High-resolution CT scanning is a key method for evaluating chest involvement. There are four roles of imaging in scleroderma interstitial lung disease: 1) detection of lung involvement, 2) identification of patients likely to respond to treatment, 3) assessment of treatment efficacy, and 4) exclusion of other significant diseases to include PH and cardiac and esophageal abnormalities.

Gastroesophageal Reflux and Lung Disease in Systemic Sclerosis

Gastroesophageal Reflux and Lung Disease in Systemic Sclerosis