Interstitial lung disease in Systemic sclerosis: insights into pathogenesis and evolving therapies

Abstract

Interstitial lung disease (ILD) is a leading cause of mortality in systemic sclerosis (SSc). However, mortality is improving as pathogenesis is being better understood and new therapies emerge. The roles of the inflammasome and NETosis in fibrosis are being elucidated. Epigenetic targets like DNA methylation and microRNA show promise as new targets for anti-fibrotic agents. The IL17-23 pathway has been shown to be active in SSc-ILD. Newer biomarkers are being described like CCL18 and the anti-eIF2B antibody. Hypothesis-free approaches are identifying newer genes like the ALOX5AP and XRCC4 genes. Computer-aided interpretations of CT scans, screening with ultrasonography and magnetic resonance imaging (MRI) are gradually emerging into practice. Imaging can also predict prognosis. A plethora of studies has shown the benefit of immunosuppression in halting ILD progression. Extent of lung involvement and PFT parameters are used to initiate therapy. The best evidence is for cyclophosphamide and mycophenolate. Besides these, corticosteroids and rituximab are being used in cases refractory to the first line drugs. Stem cell transplant is also backed by evidence in SSc. Longer studies on maintenance therapy are awaited. The inflammation in SSc is mostly subclinical and there is great interest in developing anti-fibrotic drugs for SSc-ILD. Perfinidone and nintedanib are under trial. The last resort is lung transplantation.

Keywords: Interstitial lung disease; progression; systemic sclerosis.

Figure 1.

In a background of genetic susceptibility, various environmental insults (A) lead to (B) endothelial injury and (C) Inflammation. (B) Endothelial activation leads to conversion of endothelial cells into mesenchymal progenitors (D). Also (C) inflammation causes NETosis and inflammasome activation that initiate a repair process that is imprinted on the fibroblasts (E). All these lead to conversion of fibroblasts into myofibroblasts and extracellular matrix deposition in the lung interstitium (F) and thus fibrotic lung disease. (NIMA: Non-inherited maternal antigens; TGF-β: Transforming growth factor-β; PDGF: Platelet derived growth factor; CTGF: Connective Tissue Growth Factor; α-SMA : α- Smooth muscle actin; PADI: Peptidyl arginine deiminase)