Pathophysiology of systemic sclerosis (scleroderma)

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.

Abbreviations

ECM

extracellular matrix

SSc

systemic sclerosis

TGF

transforming growth factor

1. INTRODUCTION

Fibrosing skin diseases represent a large heterogeneous group of diseases ranging from the occurrence of a few small fibrotic plaques in localized scleroderma to wide spread disease with involvement of many internal organs in systemic sclerosis. ¹ There is still no comprehensive understanding of the underlying pathogenesis; however, whereas the initial triggers differ between the diseases, the development of fibrosis follows similar pathophysiological events. This is probably best studied in systemic sclerosis (SSc), an autoimmune driven, chronic fibrosing disease that involves the skin but also various internal organs. ² , ³ , ⁴ , ⁵ , ⁶

Systemic sclerosis is a rare disease; the clinical picture of advanced disease is highly characteristic and easy to diagnose. However, patients with an early stage of the disease are often overlooked, hence the disease might be considerably more frequent. It is a severe disease that still has a high mortality compared to other connective tissue diseases. The clinical features include the severe hardening of the skin at the extremities but also in the face. Raynaud's syndrome usually precedes the disease. Later, digital ulcerations develop, sometimes leading to necrosis and loss of fingertips (Figure 1). The patients can suffer from extensive calcifications, severe pruritus and extensive telangiectasias.

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. 2 with permission from The New England Journal of Medicine

Systemic sclerosis is also a complex, multifaceted disease that not only involves the skin but in addition many other organs, frequently associated with severe pulmonary and renal disease. GI manifestations are found in most patients and many also have musculoskeletal involvement. Some suffer from cardiac disease, which is probably more common than anticipated and often overlooked. ⁴ , ⁷

Unfortunately, still no causal therapy is available, and antifibrotic treatment options are very limited. This stands in contrast to the considerable progress made in symptomatic management of the organ complications, which has led to a clear improvement in the quality of life of many patients. However, further development of disease modifying therapies requires a better understanding of the pathophysiological events leading to the fibrotic reaction and the resulting tissue damage. ⁸

The main pathophysiological events of SSc can be visualized using routine histology (Figure 2): there is an early swelling of the endothelial cells, which is followed by a lympho‐histiocytic inflammatory infiltrate around affected blood vessels. Later, a dense deposition of extracellular matrix develops with activated myofibroblasts and homogenized collagen bundles. There have been many investigations aimed at understanding the cellular and molecular alterations during these three steps in the pathophysiology of the disease, and these have enabled the identification of novel therapeutic targets. In the following we will summarize the current knowledge in the disease pathogenesis and discuss in particular how novel techniques in biomedicine have led to a better understanding of the fibrotic reaction.

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. 2 with permission from The New England Journal of Medicine

2. GENETIC AND ENVIRONMENTAL FACTORS

The involvement of genetic factors in the pathogenesis of SSc has been studied first in twin studies, in analyzing human leucocyte antigen genes and more recently also in large multicenter genome‐wide association studies. These have identified many genes that are involved in the control of inflammation and autoimmunity and probably are related to susceptibility to the disease development. ⁹ , ¹⁰

In addition, several environmental factors were identified that lead to scleroderma or scleroderma like conditions. Examples include silica dust, drugs, food contaminants and others. Although the exact mode of action of most compounds is still not understood, the data suggest that a genetic susceptibility together with external factors are crucial for the initial disease induction. ¹¹

3. ALTERATIONS OF THE VASCULAR SYSTEM IN SSC

In almost all scleroderma patients, the Raynaud's phenomenon is a characteristic feature. Depending on the subset, it may precede the disease by several years (limited SSc) or by only a short time (diffuse SSc). Later, clinical features include digital ulcerations, critical digital ischemia and kidney and heart damage due to vascular alterations. ¹²

The involvement of the vascular system in SSc affects mainly arterioles and the microvascular system, however, a direct or indirect involvement of larger vessels has also been reported. Initially, swelling of endothelial cells is noted with endothelial cell apoptosis. This is accompanied by an altered expression of adhesion proteins and cytokines. Chronic hypoxia and reactive oxygen species result in continuous damage and complete loss of capillaries. Ensuing pathophysiological events include smooth muscle cell proliferation, intima thickening, duplications of the basement membrane and probably also endothelial‐mesenchymal transition. There are many studies reporting alterations of circulating levels of angiogenic and angiostatic factors and the generation of reactive oxygen species, however, the early pathogenic factors are still poorly understood. ¹³ More recently, circulating functional autoantibodies directed against the vascular angiotensin II receptor type 1 and the endothelin 1 type A receptor were reported and they are thought to play a pathogenic role. ¹⁴ , ¹⁵ However, their exact involvement in the pathogenesis remains to be established and it is also not yet clear, whether they might be used as biomarkers or even represent therapeutic targets.

4. THE ACTIVATION OF THE ADAPTIVE AND INNATE IMMUNE SYSTEM IN SSC

Vasculopathy is also considered to be one of the major triggers for the overshooting immune response that is seen in SSc patients. It is postulated that damaged and apoptotic endothelial cells release damage‐associated molecular patterns (DAMPs) that activate and recruit immune cells. ¹⁶ In addition, an altered expression of cell adhesion molecules facilitates immune cell infiltration for instance of T cells, monocytes and macrophages during early SSc, even before endothelial cell damage is observed. ¹⁷ The proinflammatory cytokine interleukin (IL)‐6 is more abundant during the early disease stages and is linked to SSc severity. ¹⁸ Vascular damage and the immune response are closely interlinked and may even be mutually dependent.

Immune cells are responsible for the secretion of several “fibrogenic” factors such as IL‐4, IL‐13 and transforming growth factor (TGF)‐β. ¹⁹ SSc patients exhibit a characteristic overabundance of these factors in their serum. ²⁰ , ²¹ The inhibition or depletion of these factors was shown to prevent or ameliorate fibrosis in different model systems. ²² , ²³ , ²⁴ , ²⁵ IL‐4 and IL‐13 are predominantly secreted by type 2 helper T (Th2) cells. ²⁶ Both factors can influence the immune response by stimulating B cell proliferation and synthesis of immunoglobulin and adhesion molecules. ²⁶ , ²⁷ They stimulate TGFβ production, fibroblast proliferation and differentiation, ²³ , ²⁸ promote ECM production by increasing collagen synthesis ²⁹ , ³⁰ while simultaneously inhibiting the synthesis of collagenases like metalloproteinase (MMP)1 and MMP3 and enhancing tissue inhibitor of metalloproteinase (TIMP)‐1. ³¹ TGFβ is involved in several signaling cascades that promote inflammatory and “fibrogenic” effects in SSc patients. It induces the phosphorylation of SMAD proteins leading to SMAD4‐mediated gene expression ³² and it can activate mitogen‐activated protein kinase (MAPK)‐mediated signaling via c‐Jun N‐terminal kinase (JNK), p38 and extracellular signal‐regulated kinases (ERK) 1 and 2. As inducer of IL‐13 synthesis via the transcription factor GATA‐3, TGFβ may participate in a vicious cycle of signaling events that propagate immune cell and fibroblast activation.

The immune cells involved in SSc development and progression include members of the innate and adaptive immune response. However, it still remains unclear, which cells are crucial in the onset of the disease and may therefore be promising targets for therapeutic intervention.

Activation of circulating monocytes and M2 macrophages and their infiltration into the affected skin are both hallmarks of SSc. ³³ The alternatively activated M2 macrophages drive—in contrast to inflammatory M1 macrophages—the reconstitution of injured tissue and can also cause excessive ECM deposition. Both, M1 and the M2 macrophages are capable of producing large amounts of “fibrogenic” factors like TGFβ, IL‐4, and IL‐13 or proinflammatory mediators like IL‐6. ¹⁹ A recent study showed that M2 macrophages also influence crosslinking of collagen by modulating fibroblast activities. ³⁴

Also neutrophils produce “fibrogenic” cytokines like TGFβ, IL‐6, and VEGF ³⁵ and release reactive oxygen species (ROS) ³⁶ that activate fibroblasts by triggering the release of TGFβ from its latent ECM‐bound state. Polymorphonuclear neutrophils (PMN) from SSc patients were more prone to the release of neutrophil extracellular traps (NETs), which are chromatin‐based structures involved in the capturing and killing of pathogens. ³⁷ At the same time, DNA and remnants of nuclear proteins were detected in the serum and lesions of SSc patients. They were thought to cause further immune activation through plasmacytoid dendritic cell (pDC) activation and interferon‐α production. ³⁸ , ³⁹

Dendritic cells (DCs) contribute to the pathophysiology of SSc by activating naive T cells to present antigens, which influences the immune responses. ⁴⁰ DCs are involved in many autoimmune diseases where their dysregulation leads to increased cytokine secretion and presentation of autoantigens from apoptotic cells. ⁴¹ In SSc patients, an increased number of Toll‐like receptor‐8 (TLR8) on the cell surface of plasmacytoid (p) DCs enhances signaling and causes secretion of high amounts of interferon (IFN)‐α and chemokine (C‐X‐C motif) ligand 4 (CXCL4) into the skin. CXCL4 potentiates TLR8‐mediated signaling leading to a positive feedback loop. ⁴⁰

Mast cells are attracted into fibrotic lesions by local PAI (plasminogen activator inhibitor) signaling stemming from epidermal keratinocytes. ⁴² Their infiltration can precede the first pathological skin changes, which makes them an interesting target during early disease development. Apart from histamine release which induces lung fibroblast proliferation, mast cells can secrete many fibrogenic mediators. They release platelet‐activating factor that causes platelets to aggregate and release profibrotic factors like TGFβ, PDGF, and fibronectin. Similar to macrophages, they produce high amounts of TGFβ and other profibrotic signaling molecules such as IL‐4, IL‐6, IL‐13 TNF‐α, and PDGF. ⁴³ , ⁴⁴ In addition, mast cells can promote fibrosis by directly interacting with skin fibroblasts in a serpine1‐dependent manner. Serpine1, a downstream target of TGFβ, functions as chemotactic mediator for mast cells and induces intercellular adhesion molecule 1 (ICAM1) expression in fibroblasts, which is needed for mast cells to adhere to fibroblasts. ⁴² However, also mice lacking mast cells can develop fibrotic lesions. ⁴⁵ , ⁴⁶

High expression of ICAM1 is seen in SSc lesions; ICAM1 can facilitate invasion of T cells that are attracted by a local increase in TGFβ levels. ⁴⁷ , ⁴⁸ Type 2 T helper (Th2) cells are considered to play a key role in SSc. They secrete high levels of IL‐4 and IL‐13 and induce TGFβ release from macrophages and fibroblasts. The function of other T cell subtypes like Th17 cells is still under investigation. Some findings point to a profibrotic role via IL‐35 secretion but others observed an antifibrotic function. ⁴⁹ , ⁵⁰

SSc patients exhibit an abnormal B cell homeostasis in the blood with higher numbers of activated naive and lower numbers of memory B cells. ⁵¹ The B cell activating factor (BAFF) was shown to correlate with disease severity. ⁵² Activated B cells hold multiple roles in the development of SSc: they secrete IL‐6 that induces differentiation of M2 macrophage and Th2 cells, they promote a profibrotic phenotype in skin fibroblasts by direct cell–cell contact ⁵³ or TGFβ secretion. In addition, autoantibodies are found in 95% of patients with SSc. Specific autoantibodies are characteristic for different scleroderma subtypes and allow early diagnosis, prognosis and prediction of organ involvement. ⁵⁴ , ⁵⁵ While the majority of autoantibodies are directed against nuclear, nucleolar and intracellular proteins and are probably not involved in the pathophysiology, circulating autoantibodies to cell surface receptors such as PDGF and endothelin1 were shown in some cases to trigger profibrotic responses by receptor binding ⁵⁶ , ⁵⁷ (see above).

There are also several reports describing a dysregulation of regulatory immune cells. The levels and activity of regulatory T cells (Treg) and regulatory B cells (Breg) are both reduced in SSc patients; this directly correlates with SSc severity possibly due to reduced secretion of IL‐10 by these cell types. ⁵⁸ , ⁵⁹ , ⁶⁰ Natural killer (NK) cells were shown to reduce the fibrotic response by stimulating myofibroblast apoptosis as seen in liver fibrosis or by secretion of IFNγ that inhibits myofibroblast activation and differentiation. ⁶¹ However, a reduction in CD56hi NK cells and reduced killing activity were observed in SSc patients, which may further propagate the development of fibrosis. ⁶²

Taken together, while the intricate interplay between the immune cells involved in SSc development still needs further investigation, there are already many processes uncovered that explain the dysregulation of the immune response and link it to vasculopathy and fibrosis.

5. THE DEVELOPMENT OF FIBROSIS WITH DEPOSITION OF AN ALTERED ECM IN SSC

The inflammatory profibrogenic cytokines and growth factors discussed above lead to the activation of fibroblasts. The origin of these fibroblasts is still unclear; they have been discussed to derive from the circulation to some extent, and also from the subcutaneous layer, from transdifferentiation or from resident cells in the tissue. These activated fibroblasts have the characteristics of myofibroblasts, which have initially been described in tissue repair. ⁶³ , ⁶⁴ During wound healing or tissue repair, these myofibroblasts function as professional repair or scar‐forming cells. ⁶⁵ These scars consist of a stiff, collagen‐rich ECM, resulting in a tissue with reduced mechanical stability. Myofibroblasts in SSc are thought to persist in an activated state, causing an uncontrolled synthesis, deposition and remodeling of ECM proteins. This will result in a disturbed ECM deposition, a fibrotic tissue structure and ultimately additional organ failure beyond repair.

Myofibroblasts are generally considered to be plastic cells that have alpha‐smooth muscle actin (α‐SMA) positive stress fibers and contractile properties that aid in wound closure. They secrete pro‐fibrotic mediators, such as TGFβ, and ECM components, such as collagens, elastin, glycoproteins (e.g., fibronectin, laminins, and tenascin) and proteoglycans. Myofibroblasts have long been regarded as the key culprit in SSc fibrosis. The presence of myofibroblasts in normal tissue is rare, in contrast, the number of myofibroblasts in SSc is increased because of decreased apoptosis and increased transdifferentiation. ⁶⁵ , ⁶⁶ , ⁶⁷ , ⁶⁸

Whether or not a cell undergoes apoptosis is determined by the balance between pro‐apoptotic (e.g., BAX and BIM) and anti‐apoptotic proteins (e.g., BCL2 protein family). During normal tissue healing, when the myofibroblasts have completed their repair task in the tissue, the apoptotic threshold is lowered in the cell and the cells are more susceptible to undergo apoptosis. ⁶⁹ This is, in short, because the anti‐apoptotic BCL‐2‐signaling decreases once the ECM becomes softer in the later stages of wound remodeling, which, in turn, results in a BIM‐mediated apoptosis of the myofibroblasts. ⁷⁰ Similarly, in SSc myofibroblasts, the mechanotransduction pathway causes mitochondrial priming (a lowered threshold for apoptosis) by increased amounts of the pro‐apoptotic protein BIM. ⁷⁰ As a result, the SSc myofibroblasts depend on the upregulation of anti‐apoptotic BCL‐X_L (that inhibits BIM activation) to survive. Lagares et al. also showed that by inhibiting BCL‐X_L with a BH3‐mimetic called ABT‐263 (Navitoclax), BIM was released and myofibroblast apoptosis was increased in both a bleomycin mouse model in vivo and in SSc fibroblasts in vitro.

As mentioned above there is increasing evidence that the major profibrotic cytokine TGFβ is a crucial mediator of the fibrotic process in SSc. ⁷¹ TGFβ1 was identified as biomarker in SSc skin and lung fibrosis. ⁷² TGFβ signaling has been described to lower the Acid Sphingomyelinase (ASMase) amount in normal fibroblasts. ⁷³ This is interesting because ASMase is a major sphingolipid enzyme that is downregulated in SSc fibroblasts and plays a significant role in Fas‐mediated apoptosis (i.e., extrinsic apoptotic pathway). Consequently, a decreased amount of ASMase results in apoptosis resistance in the SSc fibroblasts and promotes fibrotic signaling. It has also been described that micro RNAs (miRNA) are involved in the pro‐and anti‐apoptotic balance in myofibroblasts. miRNAs are able to bind to messenger RNAs (mRNA) and induce their degradation. In SSc cells, miRNA21 expression is increased and binds to the mRNA of the pro‐apoptotic BAX. ⁷⁴ This is supported by an earlier study, which stated that SSc myofibroblasts have reduced levels of the pro‐apoptotic BAX compared to control myofibroblasts. ⁶⁸ This could increase the apoptotic threshold in SSc myofibroblasts and act as a pro‐survival mechanism.

All this reduces the sensitivity of SSc fibroblasts towards apoptosis and ultimately keeps the already existing ECM producing myofibroblasts in an active state.

In addition to the decreased apoptosis of SSc myofibroblasts, both the transdifferentiation to and the activation of SSc myofibroblasts are increased. TGFβ is the main growth factor that induces the transdifferentiation of other cells to myofibroblasts and as a result causes ECM build‐up. ⁷⁵ As a consequence of the initial injury in SSc, the cells produce TGFβ and platelet derived growth factor (PDGF), which further promotes myofibroblast transdifferentiation. ⁷⁵ , ⁷⁶ A prolonged exposure to connective tissue growth factor (CTGF) is also able to cause tissue fibrosis in humans and mice. ⁷⁷

Many cell types contribute to the increase in myofibroblasts in fibrosis. Amongst these are tissue‐resident fibroblasts, circulating monocyte‐derived mesenchymal progenitor cells (fibrocytes), epithelial‐mesenchymal transition (EMT), ⁷⁸ endothelial‐to‐mesenchymal transition (EndoMT), ⁷⁹ and pericytes. ⁸⁰ TGFβ induces EndoMT in SSc cells and may also contribute to pericytes transdifferentiating to myofibroblasts via ADAM12 upregulation.

Another curious feature of SSc is the loss of the subcutaneous adipose tissue. In vitro TGFβ stimulation of mouse adipocytes causes adipocyte‐myofibroblast transition (AMT), a loss of adipogenesis, and an upregulation of profibrotic genes in the cells. ⁸¹ Subcutaneous adipose mesenchymal stem cells ⁸² and mature adipocytes are both involved in the transdifferentiation into fibroblast‐like cells. ⁸³ It has also been shown that the adipocytes from fibrotic locations in SSc are phenotypically different from normal adipocytes. ⁸³ Taken together, these results could explain the loss of subcutaneous adipose tissue in SSc patients.

Myofibroblast transdifferentiation is also highly dependent on mechanical tension, which is significantly increased in the ECM of SSc tissues. ⁸⁴ Mechanical tension is mediated to the fibroblasts via integrins and key components in focal adhesions. ⁸⁵ , ⁸⁶ Interestingly, depletion of α11β1 integrin has been shown to suppress fibrosis and impair the fibroblast‐myofibroblast transdifferentiation. ⁸⁷ , ⁸⁸ The integrins transduce mechanical and biochemical signal across the cell membrane, resulting in profound adaptation of the cell to its environmental demands including the control of TGFβ secretion. ⁸⁹ Integrin‐mediated tension also promotes the release of active TGFβ from the ECM where it is stored in a latent, inactive form. ⁹⁰

Fibrosis results from an accumulation of collagens, elastin, glycosaminoglycans, tenascin and fibronectin in the ECM of the affected tissues. ² , ⁵ , ⁶ , ⁹¹ The ECM of SSc patients contains increased amounts of collagen type I, III, V, and VI, as well as fibronectin and proteoglycans when compared to healthy controls. Additionally, there is an increased amount of “damage‐associated molecular patterns” (DAMPs) in SSc ECM, for example, fibronectin‐EDA, tenascin‐C. ⁹² , ⁹³ These DAMPs are able to activate profibrotic gene expression, myofibroblast differentiation and enhance the effects of TGFβ on the fibroblasts via the TLR4 pathway. ⁹⁴

Cartilage oligomeric matrix protein (COMP) was found to be highly expressed in all fibrotic conditions including SSc. ⁹⁵ COMP is a large glycoprotein that interacts with many other ECM proteins and plays an important role in regulating collagen fibrillogenesis. In addition, COMP has been shown to be required for the secretion of different collagen types and is therefore closely linked to the excessive accumulation and altered macromolecular arrangement of ECM in stiff fibrotic tissues. ⁹⁶

In conclusion, SSc fibrosis is caused by chronic fibroblast activation, decreased myofibroblast apoptosis, enhanced deposition of an ultrastructurally altered ECM and decreased ECM degradation, causing irreversible damage to the tissues (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

6. NEW THERAPEUTIC APPROACHES BASED ON THE BETTER UNDERSTANDING OF THE PATHOPHYSIOLOGICAL EVENTS

Technological breakthroughs and the understanding of disease mechanisms at the cellular and molecular level have led to a better stratification of the patients and to the development of several new therapeutic approaches.

A prerequisite for successful clinical trials is the selection of a specific patient cohort. For SSc, this was based on clinical classification only for a long time. Now a molecular classification is available that is based on gene expression profiles in skin biopsies. This differentiates (a) an inflammatory phenotype, (b) a fibro‐proliferative pattern, (c) a normal like pattern, and (d) a limited cutaneous phenotype. ⁹⁷

This molecular stratification has already been used in clinical trials. ⁹⁸ , ⁹⁹ Although its predictive value still needs to be determined, it adds another dimension for the selection of patients and might—together with other serum biomarkers and improved clinical criteria—contribute to a better classification. This would then allow to select patients who will most likely respond to specific therapies.

Therapeutic development has been rapidly progressing during the last years, and considerable progress has been made to treat the organ complications associated with SSc. Some are already since long in clinical routine use, whereas others were developed more recently but are already approved for specific indications. These include for example the tyrosine kinase inhibitor Nintedanib for SSc‐ILD and the IL‐6 signaling inhibitor Tocilizumab. Others (e.g., Abatacept) revealed positive results in first preliminary trials, but still need to be studied in more detail. ⁶

These novel compounds target the microvascular alterations, the immune response (e.g., JAK inhibitors, IL‐4/IL‐13 inhibitors, Belinumab) and also the different steps in the activation of myofibroblasts (e.g., TGFβ inhibitors, ROCK inhibitors, LPA inhibitors). Of particular interest is the regulation of macrophage differentiation by IL‐4 and IL‐13. ¹⁰⁰ Basic research work in mice has demonstrated that IL‐4 receptor α signaling controls the metabolic pathways in macrophages and, through these, regulates the assembly of collagen fibrils in the ECM. ³⁴ Modulation of this pathway would therefore not only regulate the cytokine release in macrophages and the activation of myofibroblasts but also the macromolecular arrangement of the fibrotic ECM. Another promising approach might be the modulation of those specific fibroblast subpopulations that are crucial for the fibrotic response. Overall, however, different combinations of compounds may need to be selected for specific disease stages to allow a disease modifying approach.

CONFLICT OF INTEREST

All authors declare no conflict of interest.

Rosendahl A‐H, Schönborn K, Krieg T. Pathophysiology of systemic sclerosis (scleroderma). Kaohsiung J Med Sci. 2022;38:187–195. 10.1002/kjm2.12505