Systemic sclerosis (SSc) is a multisystemic fibrotic disorder that affects the skin and internal organs. Despite an improved outcome probably reflecting a better management of disease complications, morbidity and mortality remain higher than those of patients with other connective tissue diseases. SSc is still considered incurable; however, during recent years, intensive research activities have deepened the understanding of pathogenic mechanisms and have led to the identification of cellular and molecular anti-fibrotic targets. This review article will discuss potential future targeted therapeutic options based on data from in vitro studies, experimental models of fibrosis and first human trials with focus on scleroderma skin and lung fibrosis.
Systemic sclerosis (SSc) is a multisystemic fibrotic disorder that affects the skin and internal organs. Current pathogenic concepts suggest that based on a genetic susceptibility, exogenous stimuli such as infections trigger the onset of the disease. Microvascular injury is supposed to be the initial event which together with inflammatory and autoimmune reactions leads to the activation and transdifferentiation of fibroblasts to myofibroblasts finally resulting in tissue fibrosis .
SSc has a worldwide distribution with a prevalence of approximately 0.07% and a female preponderance. The health-related quality of life of scleroderma patients is remarkably decreased compared to the general population. Besides fatigue, which is often among the leading complaints of patients, approximately 80% of patients suffer from gastrointestinal disturbances. Skin fibrosis may lead to joint contractures and impaired mobility, and may affect the facial appearance with hypomimic features and microstomia. Physical activity may be further impaired due to lung and cardiac involvement with approximately 50% of patients experiencing dyspnoea. Despite a slightly improved outcome, which probably reflects a better management of disease complications, the mortality remains high with a 10-year survival rate of approximately 55–66%. Whereas in the 1970s scleroderma renal crisis was the main cause of SSc-associated deaths, to date, interstitial lung disease (ILD) and pulmonary arterial hypertension account for >60% of SSc-related mortality .
SSc is still considered incurable, but during the last decade basic science and translational studies have provided substantial novel insights into pathogenic mechanisms leading to the identification of numerous cellular and molecular pro-fibrotic key players of which some may qualify as therapeutic targets.
In the present review we will discuss currently available and emerging future therapeutic options with emphasis on molecular or cell-based targeted therapies for skin and lung fibrosis as two of the most devastating complications of the disease. An overview of the discussed targets and currently available drugs will be provided in Table 1 . Additionally, challenges for clinical study design and evaluation will be addressed.
| Targets | Available drugs | References |
|---|---|---|
| Epigenetic targets | ||
| DNA methyl transferases | Inhibitors such as 2-deoxy-5-acacytidine (5-aza) | |
| Histone deacetylases | 2nd generation HDAC inhibitors such as SAHA | www.clinicaltrials.gov |
| microRNAs such as miR-29a | ||
| Transcription factors | ||
| STAT4 | HMG-CoA reductase inhibitors (=statins) such as lovastatin | |
| T-bet | ||
| Fra-2 (AP-1 family) | T5224, small-molecule inhibitor of AP-1 | |
| Intracellular molecules | ||
| PPARγ | Agonists such as rosiglitazone | |
| S100A4 | ||
| Notch | Inhibitors of Notch signalling such as DAPT and others | www.clinicaltrials.gov |
| Cytokines, growth factors, chemokines, bioactive lipids, peptides | ||
| TGFβ | Several inhibitors, e.g. monoclonal anti-TGFβ antibodies such as CAT-192, fresolimumab, GC1008 etc. | www.clinicaltrials.gov |
| Tyrosine kinases | Inhibitors such as imatinib, nilotinib, dasatinib, SU6656 | www.clinicaltrials.gov |
| CTGF | Monoclonal anti-CTGF antibodies such as FG3019 | www.clinicaltrials.gov |
| ET-1 | Endothelin receptor blockers such as bosentan, ambrisentan, sitaxentan | www.clinicaltrials.gov |
| IL-13 | Monoclonal antibodies against IL-13 such as QAX576 | www.clinicaltrials.gov |
| IL-6 | Monoclonal antibodies against IL-6 such as Tocilizumab | |
| CXCL12/CRCR4 signalling | CXCR4 inhibitors such as AMD3100 and others | www.clinicaltrials.gov |
| MCP-1/CCR2 signalling | CCR2 inhibitors such as PF-04136309, BMS-741672, MLN1202 | www.clinicaltrials.gov |
| LPA1 | LPA1/3 inhibitor (SAR100842) | www.en.sanofi.com |
| Wnt signalling | Several inhibitors, e.g. PRI-724, CWP232291, resveratrol | www.clinicaltrials.gov |
| T cell-targeted therapies | ||
| mTOR (abrogation of T-cell responses to cytokines) | Inhibition by rapamycin | www.clinicaltrials.gov |
| Th17 cell differentiation | Inhibition by halofuginone | |
| IL-2 receptor | Basiliximab, chimeric monoclonal antibody against the α-chain of the IL-2 receptor | |
| T-cell costimulation | Inhibition by abatacept, a recombinant fusion protein (CTLA4-IgG) | |
| B cell-targeted therapies | ||
| CD20-positive B cells | Monoclonal anti-CD20 antibody, rituximab | (unpublished data) |
| BAFF(BLyS) | Belimumab, human monoclonal antibody against soluble BAFF | |
| Activation of the coagulation system | ||
| Thrombin | Inhibitors such as dabigatran etexilate | |
| 5-HT (serotonin) receptors | 5-HT 2A/B inhibitors such as terguride, cyproheptadine or the selective 5-HT 2B inhibitor SB 204741 | (unpublished data) |
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