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Review
. 2022 Mar;38(3):187-195.
doi: 10.1002/kjm2.12505. Epub 2022 Mar 2.

Pathophysiology of systemic sclerosis (scleroderma)

Ann-Helen Rosendahl  1 , Katrin Schönborn  1   2 , Thomas Krieg  1   2   3   4
Affiliations
Review

Pathophysiology of systemic sclerosis (scleroderma)

Ann-Helen Rosendahl et al. Kaohsiung J Med Sci. 2022 Mar.

Abstract

Systemic sclerosis (scleroderma) is an autoimmune-triggered chronic fibrosing disease that affects the skin and many other organs. Its pathophysiology is complex and involves an early endothelial damage, an inflammatory infiltrate and a resulting fibrotic reaction. Based on a predisposing genetic background, an altered balance of the acquired and the innate immune system leads to the release of many cytokines and chemokines as well as autoantibodies, which induce the activation of fibroblasts with the formation of myofibroblasts and the deposition of a stiff and rigid connective tissue. A curative treatment is still not available but remarkable progress has been made in the management of organ complications. In addition, several breakthroughs in the pathophysiology have led to new therapeutic concepts. Based on these, many new compounds have been developed during the last years, which target these different pathways and offer specific therapeutic approaches.

Keywords: extracellular matrix; fibroblast; fibrosis; inflammation.

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Conflict of interest statement

All authors declare no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Representative photographs of SSc symptoms. (A) Edema of the fingers and hyperkeratosis of the nail folds and (B) digital ulceration. Source: Images reprinted from Ref. with permission from The New England Journal of Medicine
FIGURE 2
FIGURE 2
Hematoxylin and eosin staining of SSc skin, showing excess extracellular matrix (ECM), vascular alterations, and in the smaller image, lymphohistiocytic inflammation around the blood vessels. Source: Images reprinted from Ref. with permission from The New England Journal of Medicine
FIGURE 3
FIGURE 3
SSc development and pathogenesis is induced and reinforced by an intricate interplay between vasculature, immune cells and fibroblasts, which subsequently leads to vasculopathy, inflammation, autoimmunity and excessive accumulation of an altered extracellular matrix (ECM). Early damage in the vasculature causes endothelial cell apoptosis, immune cell infiltration and loss of small blood vessels. These processes release cytokines, DAMPs and ROS that activate cells of the innate and adaptive immune system. These release a variety of proinflammatory and fibrogenic cytokines. B cells secrete autoantibodies directed against the nuclear and several other antigens and may be involved in tissue damage. Activation of resident fibroblasts is caused by several fibrogenic cytokines. These can also lead to the transdifferentiation of (pre‐)adipocytes, endothelial cells and mesenchymal stem cells into myofibroblasts. Myofibroblasts secrete high levels of ECM components into the affected tissue leading to severe stiffening and rigidity of the involved tissue. The increased stiffness is perceived by integrins expressed at the surface of (myo)fibroblasts, which induce signaling that contributes to further activation in a vicious cycle, culminating in excessive ECM deposition and evasion from apoptosis
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