Systemic Sclerosis and Associated Pulmonary Manifestations

Systemic sclerosis is a complex autoimmune connective‐tissue disorder characterised by microvascular injury, immune dysregulation and progressive fibrosis of the skin and internal organs. A triad of endothelial dysfunction, autoreactive inflammation and aberrant activation of fibroblasts drives excessive deposition of extracellular matrix, leading to tissue stiffening and organ impairment. The lungs are among the most frequently affected organs, with interstitial lung disease manifested by alveolar wall thickening and distortion of pulmonary architecture, and pulmonary arterial hypertension resulting from vasculopathy and vascular remodelling. These pulmonary complications are the principal drivers of morbidity and mortality, exhibiting a highly variable course that often progresses insidiously in the first years after diagnosis. Improved understanding of the cellular sources of fibrosis, molecular pathways of matrix production and immune‐fibroblast cross‐talk has opened new avenues for early detection, risk stratification and targeted intervention.

Research from Nature Portfolio

Recent studies employing single‐cell analyses of affected skin in systemic sclerosis have identified two principal cellular contributors to extracellular matrix deposition: myofibroblasts and endothelial‐to‐mesenchymal‐transitioning cells (EndoMT). This work uncovered a central role for effectors of the Hippo signalling pathway in modulating the differentiation and profibrotic function of both cell types, and demonstrated in vitro that pharmacological alteration of Hippo pathway activity can reverse fibrotic phenotypes. In parallel, investigations into intracellular profibrotic signalling have revealed that the transcription factor STAT3 integrates multiple upstream cues—including TGF-β and non-receptor tyrosine kinases—to orchestrate fibroblast activation. Genetic deletion or pharmacological inhibition of STAT3 in experimental models attenuates skin fibrosis, highlighting STAT3 as a promising molecular checkpoint for antifibrotic therapy.

Systemic Sclerosis and Associated Pulmonary Manifestations publication trend

The graph below shows the total number of articles in systemic sclerosis and associated pulmonary manifestations across all publications each year (not limited to Nature Index journals).

Technical terms

Systemic sclerosis (SSc): An autoimmune disease with widespread microvascular injury and progressive fibrosis of skin and internal organs.

Interstitial lung disease (ILD): A group of disorders characterised by inflammation and fibrosis of the pulmonary interstitium leading to impaired gas exchange.

Myofibroblast: A differentiated fibroblast expressing contractile proteins that produces excessive extracellular matrix in fibrosis.

Endothelial-to-mesenchymal transition (EndoMT): A process by which endothelial cells acquire mesenchymal, fibroblast-like properties, contributing to fibrosis.

Hippo pathway: A kinase cascade that regulates cell proliferation and differentiation, here implicated in controlling profibrotic cell fate.

STAT3: A transcription factor activated by cytokines and growth factors that integrates profibrotic signalling in fibroblasts.

References

1. Pathogenesis of Systemic Sclerosis. Frontiers in Immunology (2015).
2. Systems-based identification of the Hippo pathway for promoting fibrotic mesenchymal differentiation in systemic sclerosis. Nature Communications (2024).
3. Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis. Nature Communications (2017).
4. Progressive interstitial lung disease in patients with systemic sclerosis-associated interstitial lung disease in the EUSTAR database. Annals of the Rheumatic Diseases (2020).
5. Interstitial lung disease associated with systemic sclerosis (SSc-ILD). Respiratory Research (2019).
6. A circulating cell population showing both M1 and M2 monocyte/macrophage surface markers characterizes systemic sclerosis patients with lung involvement. Respiratory Research (2018).