Scleroderma (Systemic Sclerosis)

Biomarkers for scleroderma (systemic sclerosis)

Scleroderma (Systemic Sclerosis) is a chronic autoimmune connective tissue disease characterized by immune dysregulation, vasculopathy, and progressive fibrosis of the skin and internal organs. The disease shows significant heterogeneity in clinical presentation, organ involvement, and disease progression. Biomarker-driven approaches provide insights into immune activity, fibrotic processes, and underlying disease mechanisms.

Despite recent advances, several unmet needs remain in systemic sclerosis. Biomarkers may help improve assessment of disease activity and progression, identify patients at risk of organ involvement, and support patient stratification and treatment selection. In addition, biomarkers could facilitate the development of more targeted therapeutic approaches.

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Figure 1. Type III and VI collagen biomarker levels of fibrosis and fibrolysis are higher in early diffuse patients compared to asymptomatic controls.

Biomarkers associated with early diffuse systemic sclerosis

The distribution of skin involvement is a key factor in classifying SSc patients into limited or diffuse cutaneous subtypes. Diffuse cutaneous SSc is characterized by widespread skin involvement, affecting the torso, face, and both the upper and lower limbs. Compared to limited cutaneous SSc, diffuse SSc is more aggressive, with greater organ involvement and higher mortality rates. In a study published in PLoS One, in 2018 , biomarkers of type III and VI collagen formation PRO-C3 and PRO-C6, as well as type III and VI collagen degradation C3M and C6M, were generally elevated in both early (<2Y) and late stages (>10Y) of diffuse SSc compared to asymptomatic controls (Figure 1). Additionally, early diffuse SSc patients tend to present upregulated ECM biomarker levels compared to late diffuse SSc patients. This study suggests that ECM biomarkers are valuable tools both for investigating disease pathogenesis and serving as diagnostic tools.

ECM biomarkers enable monitoring of therapeutic response in systemic sclerosis

Understanding the relationship between systemic sclerosis (SSc) and circulating biomarkers is important for drug development, as biomarkers can support patient stratification and assessment of therapeutic responses.

A recent analysis from the focuSSced trial, published in Clinical Immunology showed that 48 weeks of tocilizumab treatment reduced the ECM biomarkers C3M and C4M, likely reflecting reduced MMP-9 activity following IL-6 inhibition. In contrast, the fibrosis biomarker PRO-C3, which correlated with mRSS (ρ = 0.3), remained unchanged, consistent with the limited effect of tocilizumab on fibrosis. These findings highlight the potential of ECM biomarkers to monitor distinct disease processes, mode of action, and treatment effects in SSc.

Figure 2. Degradation of ECM biomarkers shows a pharmacodynamic effect with Tocilizumab treatment.

In the NOVESA trial, published in Arthritis & Rheumatology, 24 weeks of Ziritaxestat treatment resulted in reductions in the ECM biomarkers C3M, C4M, C6M, and C7M, likely reflecting reduced MMP activity following autotaxin inhibition (Figure 3). These biomarker changes were accompanied by a significant reduction in mRSS at week 24 compared with placebo, indicating improved skin involvement and supporting the potential of ECM biomarkers for monitoring treatment effects in systemic sclerosis.

Figure 3. Degradation of ECM biomarkers shows a pharmacodynamic effect with Ziritaxestat treatment.

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About systemic sclerosis (SSc)

  • Systemic sclerosis (SSc) is a chronic rheumatic disease with one of the highest mortalities within rheumatology.

     

    It is an autoimmune, fibro-inflammatory skin disease characterized by a distinctive triad of microvascular damage (vasculopathy), immune activation with autoimmunity, and generalized fibrosis of multiple organs, including the skin and lungs.

     

    The great heterogeneity of disease cause and presentation creates considerable challenges in developing treatment and treating patients.

     

    The prevalence of SSc varies considerably around the world. Northern Europe and parts of Asia have a prevalence of >150 per million, whereas southern Europe, North America, and Australia have a higher prevalence of up to 443 per million.

     

    As with other autoimmune diseases, women are about six times more likely to get SSc than men.

  • Skin fibrosis is assessed by the modified Rodnan Skin Score (mRSS) and the presence of vascular damage, including Raynaud’s Phenomenon, is included in the diagnostic assessment.

     

    Furthermore, the presence of auto-antibodies and pulmonary involvement (either presented as interstitial lung disease or pulmonary arterial hypertension) is included in the diagnosis.

     

    There is no cure or disease-modifying drug for SSc, but symptoms and inflammation can be treated using NSAIDs, steroids, or biologics.

     

    The type of treatment depends on the symptoms and organs involved. Several novel drugs are in development targeting either the inflammatory and/or the fibrotic axis.

  • Systemic Sclerosis is characterized by microvascular damage (vasculopathy), immune activation with autoimmunity, and generalized fibrosis of multiple organs, including the skin and lungs.

     

    The different organs that may be affected by SSc have tissues consisting mainly of collagens.

     

    The collagens are remodeled as part of normal homeostasis of the organ– that is, collagens are broken down and rebuilt as part of normal repair and maintenance of the tissue.

     

    In SSc, the balance of tissue remodeling, i.e. formation and degradation of ECM proteins, is interrupted resulting in fibrosis of the organs.

     

    Similarly, vascular remodeling leads to increased or disrupted vascularization, which may be detected by increased turnover of the ECM proteins of the vasculature.

     

    Nordic Bioscience’s biomarkers can directly quantify this fibrosis and microvascular damage in a serum sample.

  • Yes, studies have shown that biomarkers such as PRO-C3 and PRO-C4 are associated with clinical deterioration, such as FVC decline or skin score increase. These markers provide a molecular readout of fibrotic activity and can identify patients with progressive disease.

    ECM biomarkers respond to treatments like tocilizumab, making them useful for evaluating pharmacodynamic effects. Reductions in degradation markers (e.g., C3M and C4M) indicate therapeutic impact on tissue breakdown processes, helping guide treatment decisions and clinical trial design.

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