Interstitial Lung Disease in Connective Tissue Disease: A Common Lesion With Heterogeneous Mechanisms and Treatment Considerations

Abstract

Connective tissue disease (CTD) related interstitial lung disease (CTD-ILD) is one of the leading causes of morbidity and mortality of CTD. Clinically, CTD-ILD is highly heterogenous and involves rheumatic immunity and multiple manifestations of respiratory complications affecting the airways, vessels, lung parenchyma, pleura, and respiratory muscles. The major pathological features of CTD are chronic inflammation of blood vessels and connective tissues, which can affect any organ leading to multi-system damage. The human lung is particularly vulnerable to such damage because anatomically it is abundant with collagen and blood vessels. The complex etiology of CTD-ILD includes genetic risks, epigenetic changes, and dysregulated immunity, which interact leading to disease under various ill-defined environmental triggers. CTD-ILD exhibits a broad spectra of clinical manifestations: from asymptomatic to severe dyspnea; from single-organ respiratory system involvement to multi-organ involvement. The disease course is also featured by remissions and relapses. It can range from stability or slow progression over several years to rapid deterioration. It can also present clinically as highly progressive from the initial onset of disease. Currently, the diagnosis of CTD-ILD is primarily based on distinct pathology subtype(s), imaging, as well as related CTD and autoantibodies profiles. Meticulous comprehensive clinical and laboratory assessment to improve the diagnostic process and management strategies are much needed. In this review, we focus on examining the pathogenesis of CTD-ILD with respect to genetics, environmental factors, and immunological factors. We also discuss the current state of knowledge and elaborate on the clinical characteristics of CTD-ILD, distinct pathohistological subtypes, imaging features, and related autoantibodies. Furthermore, we comment on the identification of high-risk patients and address how to stratify patients for precision medicine management approaches.

Keywords: autoantibodies; connective tissue disease; environmental exposure; genetics; interstitial lung disease; risk assessment; signs and symptoms; therapeutics.

Figure 1

Pathogenesis and development of ILD. In genetically susceptible individuals, external factors such as smoking, environmental chemicals, infections and gastroesophageal reflux disease (GERD) can lead to epithelial cell injury and aberrant repair, alveolar macrophage activation, neutrophil recruitment, and oxidative stress. Over time, increased ECM turnover will result in the development of fibrosis. With these exposures the host's immune tolerance is broken leading to chronic inflammation from cellular and humoral autoimmunity, endothelial cell dysfunction, granuloma formation, and alveolar macrophage activation thus further aggravating inflammation. As the disease progresses, interstitial pneumonia changes from an early alveolitis (increased alveolar space content of inflammatory products, reflecting inflammatory ILD pattern) to a transition period (thickened alveolar septum and the deposition of collagen fibers, significantly reduced capillary beds), and eventually ending in alveolar structural destruction and fibrosis. This figure is created with MedPeer.

Figure 2

Radiological imaging pattern of CTD-ILD. (A) “anterior upper lobe” sign. (B) “exuberant honeycombing” sign. (C) “straight-edge” sign. All these signs are indicated by arrows.