From the Guidelines
Sclerosis during inflammatory mechanisms occurs through a complex interplay of vasculopathy, inflammation, and fibrosis, characterized by collagen deposition in skin and internal organs, as highlighted in the 2023 EULAR recommendations for the treatment of systemic sclerosis 1. The process involves immune activation, where tissue injury triggers an inflammatory response with the release of pro-inflammatory cytokines by immune cells like macrophages, T cells, and neutrophils.
- Key factors in this process include:
- The activation of resident fibroblasts and the recruitment of circulating fibrocytes to the site of inflammation
- The transformation of activated fibroblasts into myofibroblasts, which produce excessive amounts of collagen, fibronectin, and other extracellular matrix proteins
- The dysregulation of matrix metalloproteinases (MMPs), leading to an imbalance favoring matrix accumulation over degradation
- The stimulation of myofibroblast activity and matrix production by growth factors like TGF-β and PDGF As noted in the study published in the Annals of the Rheumatic Diseases 1, this complex process ultimately leads to tissue hardening and scarring, replacing normal tissue architecture with dense, fibrotic tissue, and is a major contributor to the high mortality rate associated with systemic sclerosis.
- The main causes of death in SSc are SSc-interstitial lung disease (SSc-ILD) and SSc-related heart involvement, emphasizing the need for early intervention to limit the onset and/or progression of life-threatening manifestations 1.
From the Research
Cellular Mechanisms of Sclerosis
The cellular mechanisms by which sclerosis occurs during inflammatory processes are complex and involve multiple signaling pathways.
- Inflammation plays a key role in the development of sclerosis, with various immune cells and cytokines contributing to the disease process 2.
- The NLRP3 inflammasome pathway and its regulated inflammatory cytokine interleukin-1β have been implicated in the development of atherosclerosis, a condition characterized by sclerosis of the arterial walls 2.
- In the context of systemic sclerosis-associated interstitial lung disease (SSc-ILD), the use of antifibrotic agents such as nintedanib has been shown to delay disease progression 3, 4, 5.
- Nintedanib targets profibrotic pathways, including those involved in the regulation of fibroblast activity and the deposition of extracellular matrix proteins 5.
Signaling Pathways
Several signaling pathways have been implicated in the development of sclerosis, including:
- The NLRP3 inflammasome pathway 2
- Toll-like receptors 2
- Proprotein convertase subtilisin/kexin type 9 2
- Notch and Wnt signaling pathways 2
- These pathways are involved in the regulation of immune responses and the deposition of extracellular matrix proteins, and their dysregulation can contribute to the development of sclerosis.
Therapeutic Interventions
Therapeutic interventions targeting these signaling pathways may be effective in the treatment of sclerosis.
- Nintedanib, an antifibrotic agent, has been shown to delay disease progression in patients with SSc-ILD 3, 4, 5.
- Pirfenidone, another antifibrotic agent, has been approved for the treatment of idiopathic pulmonary fibrosis, a condition characterized by sclerosis of the lung tissue 6.
- Targeting the NLRP3 inflammasome pathway and its regulated inflammatory cytokine interleukin-1β may represent a new route for the treatment of atherosclerotic diseases 2.