Abstract

Systemic sclerosis (SSc) is an orphan and incurable connective tissue disease that affects particularly the skin. The characteristic features of SSc include extensive fibrosis, fibroproliferative vasculopathy, systemic autoimmunity and inflammation. Skin involvement is crucial in the disease process and skin thickening provides a surrogate measure of disease severity and has prognostic value.

In patients with SSc, an abnormal accumulation of extracellular matrix constituents is the most prominent pathological manifestation of the disease in skin. Two stages can be described based on histopathology of the lesional skin: an early cellular stage and a later fibrotic stage. Early skin lesions are characterized by the presence of i) thickened collagen bundles within the reticular dermis that run parallel to the skin surface, and ii) inflammatory cell infiltrates composed mainly of activated T cells. Later stages are characterized by an excessive accumulation of extracellular matrix components leading to increased skin thickness. In contrast to early lesions, late skin lesions have few if any inflammatory cells. Increased myofibroblast counts are also observed in the dermis of SSc patients throughout the different disease stages, which participate to the upregulated synthesis of collagen and other extracellular matrix proteins.

Skin biopsies taken from patients with SSc have shown nearly indistinguishable patterns of gene expression in clinically affected and clinically unaffected tissue, even though these were clearly distinguishable from the patterns found in similar tissue from healthy controls. Thus, histopathology changes observed in the skin occur relatively early in the disease course and can be measured in what is considered, healthy clinically unaffected skin.

Histopathology of the skin is not requested for the diagnosis of SSc. Skin biopsy is recommended for the diagnosis of SSc by French health authorities only in the case of diagnostic doubt with other scleroderma like disorders (nephrogenic systemic fibrosis, eosinophilic fasciitis, scleromyxedema…). Conversely, skin biopsy is usually performed during the evaluation process of new drugs, in parallel of the evaluation of the modified Rodnan skin score (mRSS). Indeed, a large number of biomarkers reflecting the different aspects of the disease are differentially expressed in the skin of patients with SSc and thus may be modulated by new therapies. These biomarkers can reflect SSc-related vasculopathy (in particular increased levels of vascular endothelial growth factor), inflammatory processes (increased levels of IL-6, TNF-a…) or fibrosis (transforming growth factor-b, thrombospondin-1, cartilage oligomeric matrix protein…). Some of these markers have been shown to correlate with the mRSS.

Skin biopsy is also often performed for research purposes. Indeed, the first step analysis of new candidates or pathways that may contribute to the disease pathogenesis requires the evaluation of their dermal expression or activation in the skin of SSc patients compared to healthy controls.

Finally, skin biopsy may also have a prognostic value: patterns of gene expression that readily distinguish normal from scleroderma skin, and possibly specific overexpression or underexpression of specific molecular markers may correlate with disease progression and prognosis. However, this aspect is not considered yet in clinical practice.

Histological analysis of lung, heart and kidney is not performed in routine because of the limited access of these tissues. In addition the cell analysis of bronchoalveolar lavage fluid is not performed anymore for decision-making, which is based on the results of high-resolution chest CT scan and pulmonary function tests.