Pathogenesis of systemic sclerosis associated interstitial lung disease

Abstract

Systemic sclerosis is an autoimmune disease leading to vasculopathy and fibrosis of skin and internal organs. Despite likely shared pathogenic mechanisms, the patterns of skin and lung fibrosis differ. Pathogenesis of interstitial lung disease, a major cause of death in systemic sclerosis, reflects the intrinsic disease pathobiology and is associated with distinct clinical phenotypes and laboratory characteristics. The commonest histological pattern of systemic sclerosis-interstitial lung disease is non-specific interstitial pneumonia. Systemic sclerosis-interstitial lung disease pathogenesis involves multiple components, including susceptibility and triggering factors, which could be genetic or environmental. The process is amplified likely through ongoing inflammation and the link between inflammatory activity and fibrosis with IL6 emerging as a key mediator. The disease is driven by epithelial injury, reflected by markers in the serum, such as surfactant proteins and KL-6. In addition, mediators that are produced by epithelial cells and that regulate inflammatory cell trafficking may be important, especially CCL2. Other factors, such as CXCL4 and CCL18, point towards immune-mediated damage or injury response. Monocytes and alternatively activated macrophages appear to be important. Transforming growth factor beta appears central to pathogenesis and regulates epithelial repair and fibroblast activation. Understanding pathogenesis may help to unravel the stages of systemic sclerosis-interstitial lung disease, risks of progression and determinants of outcome. With this article, we set out to review the multiple factors, including genetic, environmental, cellular and molecular, that may be involved in the pathogenesis of systemic sclerosis-interstitial lung disease and the mechanisms leading to sustained fibrosis. We propose a model for the pathogenesis of systemic sclerosis-interstitial lung disease, based on the available literature.

Keywords: Fibroblast; autoantibodies; cytokine; lung fibrosis; pathogenesis.

Figure 1.

Development and progression of SSc–ILD suggests contrasting drivers in disease subsets: (a) Time to clinically significant pulmonary fibrosis and (b) average FVC change over time in subgroups by antibodies and subset. Autoantibody and skin subset appear to determine the development and progression of SSc–ILD. Thus, some antibodies are associated with early development of extensive disease, with ATA having the highest risk. (a) Time to development of clinically significant ILD in 403 SSc patients, positive for the three most common scleroderma-specific autoantibodies, anti-centromere (ACA), anti-topoisomerase I (ATA) and anti-RNA polymerase antibody (ARA). While in their great majority, ACA+ patients develop limited cutaneous and ARA+ diffuse cutaneous subset of SSc (97% and 92% in this cohort), ATA+ subjects can present with either subset (35% limited and 65% diffuse in this cohort), which does affect their overall survival, but not their risk of significant ILD. (b) Modelling FVC changes over time in 297 SSc–ILD patients, who were positive for either ACA, ATA or ARA. Disease progression, based on modelled FVC trajectory, show relevant ANA associated differences. Thus, ARA and ATA overall have similar later-stage rate of progression, but at different levels of impairment, reflecting higher risk of early severe ILD in ATA. This later stage progression likely depends on factors outlined in Figure 1 and may also reflect systemic fibrotic activity, as the slope of decline for ATA+ cases is greater in those with diffuse compared with limited skin involvement.

Figure 2.

Phases of development and progression of lung fibrosis in systemic sclerosis (SSc–ILD). Schematic illustrating the three independent phases in pathogenesis of SSc–ILD that reflect different susceptibility within the SSc subgroups based upon skin extent and ANA reactivity. In a susceptible patient, triggering events that may reflect lung injury or intrinsic disease-related immune mechanisms lead to interstitial inflammation and fibrosis. This may then extend and become clinically meaningful through similar mechanisms. Outcome of progression, stability or regression will be affected by systemic disease features, including SSc subset, ANA and intrinsic lung fibrotic mechanisms such as tissue stiffness and structural changes to lung architecture.