Interstitial lung disease associated with systemic sclerosis (SSc-ILD)

Abstract

Background: Systemic sclerosis (SSc) is a rare connective tissue disease with a heterogeneous clinical course. Interstitial lung disease (ILD) is a common manifestation of SSc and a leading cause of death.

Main body: All patients newly diagnosed with SSc should receive a comprehensive clinical evaluation, including assessment of respiratory symptoms, a high-resolution computed tomography (HRCT) scan of the chest, and pulmonary function tests. ILD can develop in any patient with SSc, including those with pulmonary hypertension, but the risk is increased in those with diffuse (rather than limited) cutaneous SSc, those with anti-Scl-70/anti-topoisomerase I antibody, and in the absence of anti-centromere antibody. While it can occur at any time, the risk of developing ILD is greatest early in the course of SSc, so patients should be monitored closely in the first few years after diagnosis. An increased extent of lung fibrosis on HRCT and a low forced vital capacity (FVC) are predictors of early mortality. While not all patients will require treatment, current approaches to the treatment of progressive SSc-ILD focus on immunosuppressant therapies, including cyclophosphamide and mycophenolate mofetil. In patients with severe and/or rapidly progressive disease, both haematopoietic stem cell transplantation (HSCT) and lung transplantation have been successfully used. A number of medications, including the two drugs approved for the treatment of idiopathic pulmonary fibrosis (IPF), are under active investigation as potential new therapies for SSc-ILD.

Conclusions: Physicians managing patients with SSc should maintain a high level of suspicion and regularly monitor for ILD, particularly in the first few years after diagnosis.

Fig. 1

The pathogenesis of SSc (Adapted from [2]). SSc is initiated by microvascular injury, inducing inflammation, an autoimmune response, and fibroblast activation and differentiation. Activated myofibroblasts perform a series of functions, culminating in excess deposition of extracellular matrix and the development of fibrosis. Republished with permission of The Journal of Clinical Investigation, from Systemic sclerosis: a prototypic multisystem fibrotic disorder, Varga J and Abraham D, Volume No. 117, Edition No. 3, 2007; permission conveyed through Copyright Clearance Center, Inc.

Fig. 2

Causes of SSc-related deaths between 1972 and 2001 (Adapted from [21]). Reproduced from Ann Rheum Dis, Steen VD and Medsger TA, Volume 66, Pages 940–44, 2007, with permission from BMJ Publishing Group Ltd.

Fig. 3

A simple staging system for prediction of survival in patients with SSc-ILD. a Patients with SSc may be classified as having limited disease or extensive disease based on the extent of fibrosis seen on HRCT of the lungs, plus FVC per cent predicted in patients with 10–30% fibrosis on HRCT. b Extensive lung disease is a significant predictor of mortality with a hazard ratio of 3.46 compared to limited disease [30]. Reprinted with permission of the American Thoracic Society. Copyright© 2018 American Thoracic Society. Goh NS et al. 2008. Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care Med 2008;177:1248–54. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society

Fig. 4

FVC % predicted in patients who received CYC or placebo for 1 year followed by an additional year of monitoring in SLS I (adapted from [39]). The vertical lines represent the standard error. FVC = forced vital capacity; CYC = cyclophosphamide. Reprinted with permission of the American Thoracic Society. Copyright© 2018 American Thoracic Society. Tashkin DP, et al. 2007. Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease. Am J Respir Crit Care Med. 2007;176:1026–34. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society

Fig. 5

Effect of MMF for 2 years vs CYC for 1 year followed by placebo for 1 year on FVC % predicted in SLS II (adapted from [35]). The vertical lines represent the 95% CI. Reprinted from The Lancet Respir Med, Volume 4, Tashkin DP, et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial, Pages 708–19, Copyright (2016), with permission from Elsevier