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Keywords:

  • Fibrosis;
  • connective tissue;
  • hypoxia;
  • growth factor

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. The vascular system in SSc
  5. The connective tissue in SSc
  6. Growth factors and their inhibition
  7. The emerging role of tyrosine kinase inhibitors in fibrotic diseases
  8. Is there a role for phototherapy to treat fibrotic processes?
  9. The immune system in the pathogenesis of systemic sclerosis: a potential role for B cells and for B-cell depleting strategies?
  10. Key challenges for future scleroderma research
  11. Acknowledgements
  12. References

Please cite this paper as: Scleroderma: from pathophysiology to novel therapeutic approaches. Experimental Dermatology 2010; 19: 393–400.

Abstract:  Systemic scleroderma may serve as a paradigm for orphan diseases where the rarity, different subsets and fluctuating disease activity constitute major obstacles of research into mechanisms and therapeutic development. Recently, significant advances in the detailed understanding of the functioning of growth factors, their receptors and of the physiology of the connective tissue have been achieved. In particular, an improved concept was developed for the pathophysiology of scleroderma, highlighting the role of hypoxia, cellular stress and a concert of interacting cytokines. Tyrosine kinases have been shown to regulate the activity of a number of cytokines and growth factors, e.g. transforming growth factor-β and platelet-derived growth factor, which play a central role in the pathophysiology of SSc. Novel pharmacological compounds interacting with signalling cascades induced by hypoxia and intracellular signal transduction pathways of mesenchymal cells, e.g. tyrosine kinase inhibitors, are currently being investigated for the treatment of this life-threatening disease.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. The vascular system in SSc
  5. The connective tissue in SSc
  6. Growth factors and their inhibition
  7. The emerging role of tyrosine kinase inhibitors in fibrotic diseases
  8. Is there a role for phototherapy to treat fibrotic processes?
  9. The immune system in the pathogenesis of systemic sclerosis: a potential role for B cells and for B-cell depleting strategies?
  10. Key challenges for future scleroderma research
  11. Acknowledgements
  12. References

Systemic sclerosis (SSc, scleroderma) is a rare, severe disease involving the connective tissue of affected organs including in particular the skin, gastrointestinal tract, lung, heart and kidney. The disease hallmark is an overproduction and accumulation of collagen and other extracellular matrix (ECM) proteins resulting in fibrosis and tissue dysfunction. The aetiology of SSc is still not well elucidated, but the dominant phenomena are immunologic mechanisms, vascular endothelial cell injury and an activation of fibroblasts (Table 1). The rarity of SSc, several disease subsets and a highly variable course of the disease are major obstacles to perform adequately designed studies with a sufficient number of patients (1,2). Since several years, at the national and international level, epidemiological approaches have been taken, which will allow to better define disease subsets. Furthermore, these endeavours prepare the ground for the recruitment of appropriate numbers of well-defined patients for multi-centre clinical studies (3,4).

Table 1.   Important factors in the pathogenesis of scleroderma
1) Genetic background
 a Regulation of the immune response
 b Control of cytokine activity
 c Regulation of fibroblast differentiation
2) Vascular injury
 a Molecular mimicry/EC autoantibodies
 b Infection/environmental toxicity
 c Hypoxia/radical formation/inflammation
3) Induction of the autoimmune response
 a Production of antinuclear autoantibodies
 b Production of cell surface receptor antibodies
 c Dysregulation of the cellular immune response
4) Excessive deposition of extracellular matrix (ECM) proteins
 a Dysregulation of fibrogenic cytokine activities
 b Activation of fibroblasts/myofibroblasts
 c Induction of ECM protein synthesis
 d Alteration of the turnover of the ECM
 e Development of autocrine loops for persistent activation of fibroblasts

Significant advances have been made during recent years in symptomatic organ-specific therapy in particular with regard to the prevention of renal crisis, pulmonary hypertension and oesophageal involvement (5–8). However, despite widespread use of corticosteroids and immunosuppressive agents in these patients (9), no immunosuppressive or antifibrotic therapy is available with clearly proven efficacy that targets the underlying disease process with the exception of cyclophosphamide (10). Nevertheless, recent studies indicate that survival rates for patients with SSc have improved significantly with 10-year survival rates approaching 80% (11–13), in subgroups of the disease even approaching the rate of the respective control group (14).

The challenge for the development of new effective therapeutic modalities for SSc targeting the disease process is therefore twofold (i) to identify the relevant pathophysiological pathways underlying the disease process and (ii) to perform clinical studies in the appropriate clinical subset of the disease to target the identified pathways (1,2,15).

The vascular system in SSc

  1. Top of page
  2. Abstract
  3. Introduction
  4. The vascular system in SSc
  5. The connective tissue in SSc
  6. Growth factors and their inhibition
  7. The emerging role of tyrosine kinase inhibitors in fibrotic diseases
  8. Is there a role for phototherapy to treat fibrotic processes?
  9. The immune system in the pathogenesis of systemic sclerosis: a potential role for B cells and for B-cell depleting strategies?
  10. Key challenges for future scleroderma research
  11. Acknowledgements
  12. References

Raynauds phenomenon, reflecting involvement of the vascular system in SSc, is usually the earliest clinical sign of the disease. Later in the disease course, complications of vascular involvement can be observed in all major organs leading to different clinical presentations as diverse, pulmonary arterial hypertension (PAH), digital ulcers, renal crisis or watermelon stomach. The morphological changes that can be observed in small vessels at the ultrastructural level have been interpreted as a sign that microvascular injury is a primary event in this disease (16). The loss of capillaries as a typical disease manifestation (17) has been related to an increase in angiostatic factors and programmed endothelial cell death (apoptosis) (18–20). Also, it has been suggested that latent cytomegalovirus infection contributes to the known phenomenon of endothelial cell cytotoxicity of scleroderma serum by identifying IgG autoantibodies that bind a cytomegalovirus protein and induce apoptosis in human endothelial cells (21,22). Interestingly, a very recent study on patients with SSc followed up after stem cell therapy indicates for the first time that the observed loss of capillaries, a well-known (usually interpreted as end stage) hallmark of the disease, may be reversible (23). The putative mechanism involves reversal of the enhanced expression of antiangiogenic interferon-α and loss of vascular endothelial (VE) cadherin expression in SSc after autologous haematopoietic cell transplant.

The molecular pathways induced by short-term or long-term hypoxia in cellular components of the vessel wall such as endothelial and smooth muscle cells have only recently been characterized in more detail (24). An increasing number of studies have been performed, reporting partly conflicting results on the presence of circulating endothelial progenitor cells (25–28) and their behaviour under hypoxic conditions (29). Also, diverging results have been reported for the presence of pro-angiogenic and antiangiogenic factors (26,30,31). These differences may be related to different disease phases and the heterogeneity of patients with SSc (32) as well as technical aspects regarding, e.g., the isolation and cultivation of the rare endothelial progenitor cells.

Hypoxia also has profound effects on fibroblasts, where it induces the synthesis of a number of proteins involved in ECM remodelling, e.g. thrombospondin 1, fibronectin, lysylhydroxylase-2, transforming growth factor-β (TGF-β)-induced protein (33,34), as well as the synthesis of connective tissue growth factor (CTGF) (35). The induction of epithelial–mesenchymal transition, a newly evolving concept for the pathogenesis of fibrosis in the lung and kidney, has recently been linked directly to hypoxia, (36) as well as to the activity of TGF-β (37). Thus, hypoxia plays a central role in altering the composition of the ECM and maintaining the vicious circle of the fibrotic process (84).

Thus, early treatment of the vascular component of SSc pathophysiology may be considered as a major step to prevent the damage and activation of vascular and mesenchymal cells, finally leading to fibrosis and failure of the affected organs (38,39). New drugs targeting different aspects of vascular pathology have recently become available, e.g. endothelin receptor antagonists and phosphodiesterase-5 (PDE-5) inhibitors. Endothelin receptor antagonists (Bosentan, Sitaxsentan) and PDE-5 inhibitors (Sildenafil) have been approved for the treatment of PAH, whereas the endothelin receptor antagonist bosentan has been approved for the prevention of digital ulcers. Unfortunately, a study investigating the effect of bosentan on fibrotic lung involvement has not resulted in significant improvement (40). Nevertheless, clinical studies using these new compounds are urgently needed to investigate the role of a hypoxia-targeting strategy for the development of organ fibrosis (e.g. gastrointestinal involvement, lung involvement).

The connective tissue in SSc

  1. Top of page
  2. Abstract
  3. Introduction
  4. The vascular system in SSc
  5. The connective tissue in SSc
  6. Growth factors and their inhibition
  7. The emerging role of tyrosine kinase inhibitors in fibrotic diseases
  8. Is there a role for phototherapy to treat fibrotic processes?
  9. The immune system in the pathogenesis of systemic sclerosis: a potential role for B cells and for B-cell depleting strategies?
  10. Key challenges for future scleroderma research
  11. Acknowledgements
  12. References

The amount of ECM in the connective tissue is tightly controlled by continuously ongoing synthetic and degradative processes. It is widely assumed that fibrosis results primarily from an increased synthesis and deposition of ECM components accompanied by unchanged or decreased proteolytic activity. The regulation of the mechanisms inhibiting or restricting this fibrotic process is not yet well understood (41,42). Surprisingly, a number of recent studies demonstrate that fibrosis may also be accompanied by increased proteolytic activity which could indicate major remodelling as a reflection of counter-regulatory mechanisms (41,43). This view is supported by the remarkable clinical remission of organ fibrosis which can be observed in some patients surviving a severe disease episode, e.g. spontaneously or after stem cell transplantation.

Recently, a marked induction of the formation of bone type cross-links was shown in SSc skin (33,44). Thus, sclerotic tissue of skin and lung of the patients is a major source of the increased bone type degradation products that were reported in the serum of patients (45,46). The relevance of this finding and the potential use of collagen telopeptides as a surrogate marker for disease severity were demonstrated by the near-normalization of telopeptide levels after autologous peripheral blood stem cell transplantation that correlated with a marked reduction of the skin score and improvement of lung function parameters (47). Microarray analysis of involved SSc skin also demonstrated the induction of a number of genes reflecting a bone/cartilage phenotype and indicated that hypoxia may be one factor that is involved in the process of transdifferentiation of fibroblasts to an altered bone-like phenotype (48,49). Similar findings have been reported in lung fibrosis (54,55). In lung, cardiac and kidney fibrosis, several studies suggest that a differentiation of epithelial cells in lung to mesenchymal cells with a bone/cartilage phenotype can occur (37,55,56). The complexity of the fibrotic process is further enhanced by circulating mesenchymal stem cells originating in the bone marrow, which are accumulated in the connective tissue of affected organs (57).

Growth factors and their inhibition

  1. Top of page
  2. Abstract
  3. Introduction
  4. The vascular system in SSc
  5. The connective tissue in SSc
  6. Growth factors and their inhibition
  7. The emerging role of tyrosine kinase inhibitors in fibrotic diseases
  8. Is there a role for phototherapy to treat fibrotic processes?
  9. The immune system in the pathogenesis of systemic sclerosis: a potential role for B cells and for B-cell depleting strategies?
  10. Key challenges for future scleroderma research
  11. Acknowledgements
  12. References

Several factors released during inflammation have been ascribed a prominent role in the regulation of fibrotic processes. These include a number of growth factors but also other mediators like endothelin (50–52) and hormones (53). The growth factors, which are the target of several ongoing clinical trials (see Table 2, and for up to date information ‘http://www.clinicaltrials.gov’), are described in detail later.

Table 2.   Novel therapeutic approaches
Pharmaceutical agentActionFibrosing disease studied
  1. Novel therapeutic approaches that are presently being studied in human studies (http://www.clinicaltrials.gov).

Imatinib mesylateTyrosine kinase inhibitorSSc, IPF, SSc-ILD, GVHD-(sclerodermatous)
DasatinibTyrosine kinase inhibitorSSc-ILD
AbataceptBinds B-7 molecule of T-cell receptor (prevents activation of the T cell)Diffuse SSc
Medi-551Monoclonal antibody to CD19SSc
Medi-546Antibody to interferon-α/β receptor-2 (blocks type I IFN)SSc
UVA 1Induction of connective tissue–degrading proteases, apoptosis of inflammatory cellsSSc (skin)
BosentanInhibits endothelin-1IPF, SSc-ILD, SSc (skin)
P144Inhibits TGF-βSSc (skin cream)
RituximabAntibody to CD-20Fibrosing skin disorders (i.e. localized scleroderma; eosinophilic faciitis; severe SSc)
QAX576Inhibits IL-13SSc-ILD, IPF
GB 0998 (IV-Ig)ImmunomodulatorSSc

TGF-β

The pluripotent growth factor TGF-β has a myriad of inhibiting and stimulating activities on proliferation, apoptosis as well as protein synthesis of epithelial cells, mesenchymal cells and cells of the immune system (58). TGF-β is the most potent inducer of collagen synthesis, suppresses the production of matrix-degrading metalloproteinases and is regarded as a master regulator of the fibrotic process in the pathogenesis of systemic sclerosis (59,60). TGF-β supports the transdifferentiation of fibroblasts to myofibroblasts characterized by the expression of α-smooth muscle actin. These myofibroblasts are recognized as indicator cells of fibrotic processes in lung or kidney. Nearly all cells involved in the pathophysiology of SSc, i.e. endothelial cells, fibroblasts, platelets and a variety of immune cells, synthesize TGF-β. Furthermore, fibroblasts of patients with SSc express increased numbers of TGF-β receptors, thereby enhancing the potential cellular response to TGF-β (61,62).

Thus, a number of different strategies to inhibit the TGF-β pathway have been investigated (see Fig. 1). These include (i) extracellular approaches, (ii) cell surface receptor–oriented approaches, (iii) interference with intracellular signalling and (iv) interference with secondary messengers such as CTGF. As an extracellular approach, enhanced storage of TGF-β by overexpressing decorin as a binding partner for latent TGF-β was shown to be beneficial (63) as well as neutralizing antibodies to TGF-β (64). In analogy to the successful use of soluble TNF-α receptors in rheumatoid arthritis, soluble TGF-β receptors have been developed with the aim to inhibit TGF-β activity (65,66). Use of antisense oligonucleotides (61) and inactivation of a master transcription factor of TGF-β, Smad 3, also efficiently inhibited induction of fibrosis (67).

image

Figure 1.  Approaches to interrupt the activity of TGF-β in the pathophysiology of scleroderma.

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The pleiotropic effects of TGF-β in a multitude of cellular systems should nevertheless caution against an injudicious use of TGF-β-blocking strategies as this could be associated with autoimmunity, cellular dysplasias and progression to cancer, which may only become apparent over time. The topical use of inhibitory TGF-β antibodies appeared to be well tolerated (68,69). There are also preliminary clinical studies employing systemic application of inhibitory TGF-β antibodies; however, the experience is still limited. In one study, increased morbidity and mortality were observed without any measurable clinical effect (70).

Platelet-derived growth factor (PDGF)

PDGF is a dimeric peptide growth factor that is secreted by several cell types such as platelets, fibroblasts and smooth muscle cells. PDGF is a potent mitogen for cells of mesenchymal and neuroectodermal origin (71). In addition, PDGF induces migration, differentiation and transformation of various cell types. PDGF takes part in the complex regulation of apoptosis and the generation of O2 radicals (72,73). Thereby PDGF is increasingly recognized as an important player in wound healing, PAH and inflammatory diseases (74,75). PDGF signal transduction involves two specific transmembrane receptor tyrosine kinases, α- and β-PDGFR, which differ in their signal transduction cascades and biological effects (71,72). For instance, activation of the PDGFR-α results in phosphorylation of MAP-kinases (Erk 1/2, p38, JNK), activation of Ras and induction of ‘immediate early genes’ such as Egr-1, c-fos, c-jun, etc. (73).

Recently, stimulatory autoantibodies against the PDGF receptor were detected in the serum of patients with SSc, which could have a causal role in the pathogenesis of this disease. These antibodies bind to the receptors, stimulate signalling pathways and lead to increased type I collagen gene expression in fibroblasts (76,84). Such stimulatory autoantibodies are not specific for SSc and have also been detected in graft versus host patients (77). The role of these growth factor receptor antibodies in the pathophysiology of SSc, however, is not completely clear, and there are conflicting data in the literature (78).

CTGF

CTGF is a member of the CCN family of proteins including CTGF, Cyr 61 and Nov (79) and was first identified as a PDGF-like factor. CTGF has biological activities similar to TGF-β and leads to increased fibroblast proliferation, migration and connective tissue synthesis. There is also evidence that injection of CTGF into a mouse leads to a strong fibrotic response (80). This is in good agreement with the finding that CTGF mRNA is overexpressed in scleroderma (81) and that it is induced by hypoxic conditions (35). Interestingly, CTGF can be induced by TGF-β, which closely links the activity of both cytokines (82,83).

The emerging role of tyrosine kinase inhibitors in fibrotic diseases

  1. Top of page
  2. Abstract
  3. Introduction
  4. The vascular system in SSc
  5. The connective tissue in SSc
  6. Growth factors and their inhibition
  7. The emerging role of tyrosine kinase inhibitors in fibrotic diseases
  8. Is there a role for phototherapy to treat fibrotic processes?
  9. The immune system in the pathogenesis of systemic sclerosis: a potential role for B cells and for B-cell depleting strategies?
  10. Key challenges for future scleroderma research
  11. Acknowledgements
  12. References

Signal transduction of several cytokines and growth factors relevant for the development of fibrosis involves tyrosine kinases. Their activity can be inhibited by ‘small molecules’ so-called tyrosine kinase inhibitors. Among these substances are axitinib, sunitinib imatinib, dasatinib, sorafenib und nilotinib (see Table 3). These molecules were originally developed for the treatment of oncologic diseases such as chronic myeloid leukaemia and gastrointestinal tumors to inhibit proliferative signals via blockade of the tyrosine kinases bcr/abl and c-kit. However, because of their structural properties, these substances are not entirely specific but show variable ‘cross-reactivity’ with other tyrosine kinases.

Table 3.   Tyrosine kinase inhibitors and their targets
ImatinibPDGFR, bcr/abl, c-kit
Sunitinibc-KIT, PDGFRA/B VEGFRs-1, -2 and 3, FLT3, CSF-1R, RET
AxitinibVEGFR-1, VEGFR-2 and VEGFR-3, PDGFR-α, PDGFR-β, c-kit
DasatinibPDGFR, bcr/abl, c-kit, Src
SorafenibPDGFR, VEGFR, c-kit, Flt-3, B-Raf, b-Raf-V600E
NilotinibPDGFR, bcr/abl, c-kit

Because of the effective inhibition of pathways involving PDGF signalling, the TRK-inhibitor imatinib was tested in a mouse model of pulmonary hypertension (74) demonstrating remarkable effects. This has already led to successful use in some patients (85) and to the initiation of a controlled study which is currently under way.

An initial clinical observation reported on the beneficial effect of imatinib treatment of bone marrow fibrosis during imatinib treatment of chronic myeloid leukaemia (86). Along the same line, Distler et al. (87) demonstrated that imatinib, which blocks the activity of c-abl, an important downstream signalling molecule of TGF-β, can reduce the synthesis of ECM proteins. This result could also be extended into the in vivo situation of the bleomycin fibrosis model (88,89) and positive clinical observations on its use in SSc and graft versus host disease (GVHD) begin to appear (90–92).

By virtue of at least partially targeting key molecular pathways operative in the fibrotic process of SSc, tyrosine kinase inhibitors thus appear as attractive therapeutic tools. The risk of adverse effects of these agents can be controlled and in general is Iower than for other compounds such as immunosuppressive agents like d-penicillamine, methotrexate and cyclophosphamide that have been used widely in patients with SSc for several decades without or modest proven clinical benefit (9,10,93,94). Given that several tyrosine kinase inhibitors are already approved for oncologic indications and given that this drug class is usually well tolerated with favourable pharmacokinetics, randomized controlled trials in well-defined groups of patients with SSc are clearly needed.

Is there a role for phototherapy to treat fibrotic processes?

  1. Top of page
  2. Abstract
  3. Introduction
  4. The vascular system in SSc
  5. The connective tissue in SSc
  6. Growth factors and their inhibition
  7. The emerging role of tyrosine kinase inhibitors in fibrotic diseases
  8. Is there a role for phototherapy to treat fibrotic processes?
  9. The immune system in the pathogenesis of systemic sclerosis: a potential role for B cells and for B-cell depleting strategies?
  10. Key challenges for future scleroderma research
  11. Acknowledgements
  12. References

Because of its biophysical properties resulting in clinically relevant penetration into deeper layers of the dermis, UVA irradiation (320–400 nm) has been regarded as a potential therapeutic option for fibrotic disorders of the skin. UVA irradiation alone, and more so in conjunction with photosensitizing agents, was shown to increase the expression, synthesis and activation of matrix metalloproteinases, whereas it decreases collagen synthesis in human dermal fibroblasts. Recently, we could demonstrate that repetitive UVA irradiation of fibroblasts leads to the release of another potent proteinase group (i.e. cathepsins) (95).

UVA irradiation also destroys collagen cross-links which are increased in lesional fibrotic skin (96) and induces a variety of cytokines and soluble factors in vitro which can affect the inflammatory process. In addition, UVA phototherapy has major immunosuppressive effects via the induction of apoptosis of T cells, impairment of cell proliferation and the induction of inhibitory cytokines like IL-10.

Several studies have been initiated during the last years using systemic and bath psoralene and UVA (PUVA) therapy, as well as low- and high-dose UVA1 therapy [for review Sunderkötter et al., 2006 (97)]. In these studies, patients suffering to varying degrees from localized scleroderma, systemic sclerosis and GVHD skin fibrosis improved substantially as monitored by skin score, cutaneous elastometry or evaluation of skin thickness by ultrasound analysis. Despite these positive results reported by several groups, double blind, controlled, prospective, randomized studies of well-defined patient groups will have to be performed.

The immune system in the pathogenesis of systemic sclerosis: a potential role for B cells and for B-cell depleting strategies?

  1. Top of page
  2. Abstract
  3. Introduction
  4. The vascular system in SSc
  5. The connective tissue in SSc
  6. Growth factors and their inhibition
  7. The emerging role of tyrosine kinase inhibitors in fibrotic diseases
  8. Is there a role for phototherapy to treat fibrotic processes?
  9. The immune system in the pathogenesis of systemic sclerosis: a potential role for B cells and for B-cell depleting strategies?
  10. Key challenges for future scleroderma research
  11. Acknowledgements
  12. References

During recent years, the appraisal of the role of B cells in the pathogenesis of autoimmune diseases has undergone a remarkable change. This is largely because of therapeutic effects observed after the use of depleting CD20 antibodies in autoimmune diseases as e.g. rheumatoid arthritis, pemphigus vulgaris, etc. (98). The clinical observations have enlivened the research on the role of B cells in both antibody-mediated diseases and generally considered T-cell-mediated diseases, e.g. multiple sclerosis. These studies strongly support the view that in vivo B cells should be regarded not only as the source for the generation of antibody-secreting plasma cells but also as potent antigen-presenting cells.

Presence of characteristic autoantibodies targeting nuclear antigens is one of the hallmarks of the disease in about two-thirds of patients with SSc. These antibodies have been shown to constitute a prognostic factor indicating disease course and organ involvement with Scl-70 and centromere as most prominent antigens (4). Very recently, one study reported on the induction of interferon-α by scleroderma sera containing autoantibodies to Scl-70 (99). In this study, however, a direct causal relation to the Scl-70 antibodies could not be demonstrated. To date, the pathogenic role of antinuclear antibodies characteristic for SSc still remains elusive.

Antibodies targeting endothelial cells as pathogenic factors displaying the cytotoxic effects of scleroderma sera have been repeatedly described. The target antigens of these antibodies could not be well defined, although molecular mimicry has been described as a potential mechanism for cytotoxic antibodies targeting a CMV protein (21,22).

In 2007, for the first time, a pathogenetic role of cell surface–specific antibodies recognizing the PDGF receptor expressed e.g. on fibroblasts has been described (76,84). This report is in line with a number of publications describing the concept of antibodies directed to cell surface molecules, thereby inducing signal transduction pathways in several unrelated diseases, e.g. rejection of renal allografts, preeclampsia, and hypertrophic cardiomyopathy (100–102).

Signs of B-cell activation were reported in patients with systemic sclerosis, e.g. elevated B-cell activating factor (BAFF) and April serum levels (103). Whereas in scleroderma skin only rarely B cells can be detected, B-cell infiltration of the lung has been described in SSc-associated interstitial lung disease (104). Also, a number of animal studies have addressed the potential role of B cells in the pathogenesis of fibrosis (105). Hasegawa et al. (106) investigated the effect of B lymphocyte depletion in the tight skin mouse model and described substantial improvement of the inflammatory reaction and the ensuing fibrosis. The potential pathogenic role of autoantibodies in the pathogenesis of SSc is summarized in Fig. 2, for current studies see Table 2.

image

Figure 2.  Potential pathogenic role of autoantibodies in the pathogenesis of systemic sclerosis.

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The aforementioned experimental data are discordant to the failure of rituximab to induce a clinical therapeutic response in systemic sclerosis in most of the treated patients (107–109). The results are also in contrast to the impressive clinical effects observed in other inflammatory autoimmune diseases such as pemphigus or rheumatoid arthritis. This clinical observation may have several explanations. The inflammatory mouse models can obviously not be transferred directly to the human. In addition, it suggests an uncoupling of the fibrotic response from the inflammatory B-cell dependent part. Recent studies clearly indicate that long-lived plasma cells, which are not carrying the CD20 antigen anymore, survive the treatment and continue to synthesize pathogenic antibodies (110).

Because of the high mortality of patients with rapidly progressive disease equalling the mortality rate of aggressive cancer, in the second half of the 1990s, high-dose immunosuppressive therapy and stem cell transplantation were increasingly considered (111). Since 2001, a number of publications report profound effects of these treatment modalities on disease activity as well as rapid and impressive resolution of skin fibrosis (112–115). Here, two studies in Europe (http://www.astistrial.com) and North America (http://www.sclerodermatrial.org) are currently under way.

Although in the near future these treatments will be reserved for patients with progressive life-threatening disease forms, the gratifying results observed in some patients strongly support the general concept that fibrosis is reversible.

Key challenges for future scleroderma research

  1. Top of page
  2. Abstract
  3. Introduction
  4. The vascular system in SSc
  5. The connective tissue in SSc
  6. Growth factors and their inhibition
  7. The emerging role of tyrosine kinase inhibitors in fibrotic diseases
  8. Is there a role for phototherapy to treat fibrotic processes?
  9. The immune system in the pathogenesis of systemic sclerosis: a potential role for B cells and for B-cell depleting strategies?
  10. Key challenges for future scleroderma research
  11. Acknowledgements
  12. References

Based on the current understanding of the pathophysiology of scleroderma as described in this review, key challenges of scleroderma research are as follows: (i) an improved understanding of the components driving connective tissue remodelling as it takes place in the different stages of SSc and (ii) to understand the particular role of the immune system in SSc, as this disease can be so clearly discriminated from other inflammatory autoimmune diseases by its poor response to currently available anti-inflammatory and disease-modifying therapy.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. The vascular system in SSc
  5. The connective tissue in SSc
  6. Growth factors and their inhibition
  7. The emerging role of tyrosine kinase inhibitors in fibrotic diseases
  8. Is there a role for phototherapy to treat fibrotic processes?
  9. The immune system in the pathogenesis of systemic sclerosis: a potential role for B cells and for B-cell depleting strategies?
  10. Key challenges for future scleroderma research
  11. Acknowledgements
  12. References