The effects of Eculizumab on the pathology of malignant atrophic papulosis

Abstract

BackgroundDegos disease is a frequently fatal and incurable occlusive vasculopathy most commonly affecting the skin, gastrointestinal tract and brain. Vascular C5b-9 deposition and a type I interferon (IFN) rich microenvironment are held to be pathogenetically important in the evolution of the vascular changes. We recently discovered the use of eculizumab as a salvage drug in the treatment of near fatal Malignant atrophic papulosis (MAP). The effects of eculizumab on the pathology of MAP are explored.MethodsArchival skin and gastrointestinal biopsy material was procured over a 2.5-year period before and after 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.ResultsThe patient had received eculizumab as a emergent life saving measure and following rapid improvement he continued with biweekly infusions for 4 years. Although improved he continues to have signs and symptoms of persistent abdominal disease. Pre-Eculizumab biopsies showed an active thrombotic microangiopathy associated with a high type I interferon signature and extensive vascular deposits of C5b-9 in skin and gastrointestinal biopsies. 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 type I IFN 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 arteriopathy which appears to be one characterized by extensive myofibroblastic expansion of the intima potentially as revealed by staining for smooth muscle actin without immunoreactivity for desmin and myogenin.ConclusionsComplement activation and enhanced endothelial cell apoptosis play an important role in the thrombotic complications of MAP. However, the larger vessel proliferative intimal changes appear to be independent of complement activation and may be on the basis of other upstream mechanisms. Monitoring C5b-9 deposition in tissue is likely not of great value in assessing treatment response to eculizumab given the persistence of C5b-9 in tissue for several months despite clinically effective C5 blocking therapy. A more integrated approach addressing upstream and downstream pathways in addition to those attributable to complement activation are critical for the successful treatment of MAP. Eculizumab may be used as salvage therapy in critically ill patients with thrombotic microangiopathy.

Malignant atrophic papulosis with motor aphasia and intestinal perforation: A case report and review of published works

“…The mortality in all patients with the systemic type was 65.3% (34/52), whereas no patient death was observed among the 28 patients with pure cutaneous involvement ( P < 0.05). In patients with extracutaneous involvement ( n = 43, excluding six patients whose information was not available and three patients with cutaneous involvement after systemic manifestations) . Moreover, we found that in patients in the systemic category, the first systemic manifestation occurred at a median of 2.0 years (95% CI, 0–7.8) after disease onset.…”

Benign atrophic papulosis (Köhlmeier–Degos disease): the wedge‐shaped dermal necrosis can resolve with time

“…The age at disease onset is 36.5 years (range 5-60), not differing between BAP and MAP. 9 Harvell et al 10 examined histological specimens of the lesions according to the duration of their existence. 5,6 Confocal microscopy could detect additionally densified collagen fibres and a decrease in dermal capillaries inside the connective tissue necrosis but presence of capillary hyperplasia in the periphery of the lesion.…”

Diffuse atrophic papules and plaques, intermittent abdominal pain, paresthesias, and cardiac abnormalities in a 55-year-old woman

“…2,3,16 Eculizumab, a monoclonal antibody which binds C5 complement, has led to dramatic responses in a small number of patients, possibly due to antiapoptotic endothelial effects. 4,17,18 Results of recent use of eculizumab in combination with treprostinil, a prostacyclin analog that may enhance endothelial progenitor cells, are also encouraging. 17 Early success with eculizumab supports complement activation as a potential driving mechanism of MAP, although reports of disease progression after initial response to the drug indicate additional factors at work in disease pathogenesis.…”

“…17 Early success with eculizumab supports complement activation as a potential driving mechanism of MAP, although reports of disease progression after initial response to the drug indicate additional factors at work in disease pathogenesis. 17,18 …”