Systemic Sclerosis Associated Interstitial Lung Disease: New Directions in Disease Management

Abstract

A subgroup of patients with systemic sclerosis (SSc) develop interstitial lung disease (ILD), characterized by inflammation and progressive scarring of the lungs that can lead to respiratory failure. Although ILD remains the major cause of death in these individuals, there is no consensus statement regarding the classification and characterization of SSc-related ILD (SSc-ILD). Recent clinical trials address the treatment of SSc-ILD and the results may lead to new disease-altering therapies. In this review, we provide an update to the diagnosis, management and treatment of SSc-ILD.

Keywords: cyclophosphamide; interstitial lung disease; nintedanib; pirfenidone; scleroderma; systemic sclerosis.

Figure 1

The pathogenesis of SSc-ILD involves vascular, immunological, and fibrotic processes. The initial injury begins with endothelial and alveolar cell injury, which upregulates adhesion molecules and chemokines to attract leukocytes, which enable both innate and adaptive immune responses. Anti-topoisomerase 1 antibodies form immune complexes, and are taken up via Fc receptors, and activate endosomal Toll-like receptors in immune cells, which leads to type I interferon production. IFN release can induce TLR 3 expression on the surface of fibroblasts, causing pro-collagen production. Ligands for Toll-like receptors (TLRs) stimulate dendritic cells to produce IFN-α and interleukin (IL)-6, which in turn activate Th2 cells, produce IL-4 and IL-13, and stimulate pro-fibrotic macrophages. Macrophages produce multiple profibrotic factors including: TGFβ, connective tissue growth factor (CTGF), and PDGF, which promote fibroblast recruitment, invasion and proliferation. Fibroblast activation then occurs, and differentiation to a contractile myofibroblast phenotype result in overproduction and accumulation of extracellular matrix, resulting in progressive fibrosis. ^*Immunosuppression agents: mycophenolate mofetil, cyclophosphamide, tacrolimus, cyclosporine, tocilizumab, rituximab.

Figure 2

HRCT of a usual interstitial pneumonia (UIP) pattern, characterized by honeycombing (red arrows), and traction bronchiectasis (blue arrow). Normal lung tissue is signaled with green arrows.

Figure 3

Fibrotic nonspecific interstitial pneumonia (NSIP).