Vascular Leak Is a Central Feature in the Pathogenesis of Systemic Sclerosis
Tracy M Frech, Monica P Revelo, Stavros G Drakos, Maureen A Murtaugh, Boaz Markewitz, Allen D Sawitzke, Dean Y Li. University of Utah, Salt Lake City
Background: Systemic Sclerosis (SSc) is a multi-organ system disease characterized by activation of immune cells, production of auto-antibodies, microvascular changes, and fibrosis. Clinical studies suggest that there are three classic stages of SSc: edematous, fibrotic, and atrophic. Definition of microvascular changes occurring during this early edematous phase prior to the development of fibrosis is of utmost importance. Whole-field digital microscopy offers a means of rapidly carrying out quantitative, reproducible measurements of micro-anatomical features in high-resolution pathology images and in large image datasets with control for intra-observer and inter-observer variability. As such, its use for systematic examination of subtle differences exhibited by diseased tissue has potential to improve the characterization of the histologic stage, prognosis, and treatment responses.
Design: Twenty consecutive SSc patients were biopsied on the left or right medial forearm with a 6 mm punch biopsy. Biopsy specimens in the same location were obtained from 4 healthy controls. These specimens were processed with hematoxylin and eosin, histochemical and immunohistochemical stains. Wholefield digital microscopy was used to grade vascular abnormalities.
Results: Whole-field digital microscopy of SSc skin biopsies revealed that endothelial abnormalities are a universal feature regardless of clinical features and/or duration of disease. These features were not seen in the healthy control specimens and did not vary with disease characteristics. Wholefield digital microscopy identified interstitial edema (29.3 ± 9.7%, p = 0.03) and fibrosis (75.4 ± 5.4%, p =0.01) in all SSc patients. The presence of hand/finger edema significantly correlated with less fibrosis on skin biopsy specimens (Spearman correlation -0.50; p=0.02). Perivascular and interstitial infiltrate of mast cells were present in all SSc specimens.
Conclusions: Whole-field digital microscopy offers a means of rapidly carrying out quantitative, reproducible measurements of microscopic features of SSc microvascular change and should be integrated into SSc research and clinical care. The universal morphologically abnormal endothelial cells and interstitial edema in all SSc patients who were biopsied regardless of their clinical characteristics suggests that SSc may be an intrinsic disease of the endothelium with fibrosis as the result of antecedent vascular leak.
Monday, March 19, 2012 1:00 PM
Poster Session II # 315, Monday Afternoon