The Effects of Eculizumab on the Pathology of Degos Disease
Xuan Wang, Cynthia M Magro. Weill Medical College of Cornell University, New York, NY
Background: Degos disease is a frequently fatal and largely incurable occlusive vasculopathy most commonly affecting the skin, the gastrointestinal tract and brain. We have previously published an article in your journal describing that vascular C5b-9 deposition and an interferon alpha (INF-α) rich microenvironment are found to be pathogenetically important to the evolution of the vascular changes. We recently described the use of Eculizumab as a salvage drug in the treatment of near fatal Degos disease. The effects of Eculizumab on the pathology of Degos disease are explored in this manuscript.
Design: Archival skin and gastrointestinal biopsy material was procured over a period of 2.5 years before and after the initiation of Eculizumab therapy in our index case. Routine light microscopy and immunohistochemical assessment for C3d, C4d, C5b-9, MxA and caspase 3 were examined. Direct immunofluorescent studies were also conducted on select biopsy material.
Results: We found that pre-Eculizumab biopsies showed an active thrombotic microangiopathy associated with a high INF-α signature and extensive vascular deposits of C5b-9 in skin and gastrointestinal biopsy material. Endothelial cell apoptosis as revealed by Caspase 3 expression was noted. Inflammation comprising lymphocytes and macrophages along with mesenchymal mucin was observed as well. Post-Eculizumab biopsies did not show active luminal thrombosis but only chronic sequelae of prior episodes of vascular injury. There was no discernible caspase 3 expression. After 12 months of therapy, C5b-9 was no longer detectable in tissue. The high INF-α signature and inflammation along with mucin deposition was not altered by the drug. In addition, there was little effect of the drug on the occlusive fibrointimal ateriopathy.
Conclusions: We concluded that complement activation and enhanced endothelial cell apoptosis plays an important role in the thrombotic microvascular complications of Degos disease. However, the larger vessel atherosclerotic-like changes appear to be independent of complement activation and may be on the basis of other upstream mechanisms which in this case was in the context of high levels of INF-α. A more integrated approach addressing upstream and downstream pathways such as those attributable to complement deposition are critical for the successful treatment of Degos disease. It does have a role as a salvage drug in acutely ill patients in whom a thrombotic diathesis may be pathogenetically significant to a precipitous decline in their clinical state.
Wednesday, March 6, 2013 9:30 AM
Poster Session V # 80, Wednesday Morning