Cause and Mechanism

 
The etiology and pathogenesis of Degos' disease have not been elucidated, despite extensive histochemical, ultrastructural, immunological, and coagulation studies having been performed in the past 20 years.41 Application of methods for detection of deposits of antibodies in tissue by immunofluorescence, circulating immune complexes, anti-nuclear and anti-DNA antibodies, and lymphocyte transformation tests have been unrevealing of an immunological basis.1,5,7,18,19,20,29,30,33 What seems to be a denominator in common histopathologically in the various organs and systems involved is what has been called an "obliterating arteriolitis" or "endovasculitis with secondary thrombosis and slow tissue necrosis."18 Vascular damage surely is present in lesions of Degos' disease, but no agreement obtains about the nature of that injury. The three most reasonable theories proposed for the abnormality fundamental to Degos' disease are coagulopathy, vasculitis, and primary disorder of endothelial cells.13
 

1. Degos's Disease As A Coagulopathy

 
A thrombus in a vessel situated in the deep reticular dermis is claimed to be the primary event, the resulting curtailment of blood and of damage to endo-thelial cells leading to deposits of mucin in the dermis and the calling forth of a scant infiltrate of mononuclear cells.13
 

Evidence in favor

 
  • An increase in fibrinogen was discerned by Roenigk and Farmer in two of three patients with Degos' disease. They also found an increase in level of fibrinogen in patients with renal lesions of lupus erythematosus.33
  • Stahl42 and Drucker43 each told of one patient in whom aggregation of platelets in vitro was exaggerated. Both patients responded to therapy with aspirin and dipirydamol directed against aggregation of platelets.
  • Black et al. observed complete loss of fibrinolysis around small blood vessels in the center of both early and fully established papules. Because the zone in which fibrinolysis was absent was wedge-shaped and extended to the level of the deep dermis, the authors inferred that slow occlusion of arterioles there was responsible. They suggested further that disturbance of endothelial function leads to impairment of normal fibrinolytic activity.44
  • Páramo et al. wrote about decrease in levels of plasminogen and increase in activity of plaminogen activator inhibitor in a patient with Degos' disease.45 The transformation of plasminogen into plasmin permits degradation of fibrin in the circulation and lysis of a clot, whereas inhibitors of plasminogen activators prevent fibrinolytic activity.
  • Vasquez-Doval et al. shared their experience with two patients with Degos' disease in whom fibrinolytic activity and alterations in platelet function were impaired. In one patient there was increase in the activity of plasminogen activator inhibitor-1. In a second patient there were alterations in aggregation of platelets and poor fibrinolytic response with a decrease in tissue plasminogen activator.46 Tissue plasminogen activator (tPA) is derived from endothelial cells and converts plasminogen to plasmin with subsequent lysis of a clot. Defects of fibrinolysis that result from alterations in tPA may occur for several reasons, among them congenital deficiency, defective release of tPA, and increase in plasminogen inhibitors, the consequence of this being thrombotic complications.
  • Englert et al.,47 Mauad et al.,27 and Farrell et al.12 each recorded one patient with Degos' disease, each of whom exhibited lupus anticoagulant and anticardiolipin antibodies that are associated with a tendency to thrombosis in patients with lupus erythematosus and other connective tissue disorders. Moreover, the patient described originally by Degos had a positive Wassermann reaction, which he attributed to previous exposure to Treponema pallidum.1 An alternative explanation might be that it was a false-positive reaction caused by anticardiolipin antibody.41
  • Yoshikawa et al. detailed findings in a patient with Degos' disease who had persistent elevations of the thrombin-antithrombin III complex and plasmin-alfa-2 plasmin inhibitor complex.22 These alterations indicate abnormalities both in the coagulation cascade and of fibrinolytic activity.
 

Evidence Against

 
  • Not all patients with Degos' disease have abnormalities in the coagulation cascade or in platelet or fibrinolytic activity. Fibrinogen levels have been found to be normal in most patients with Degos' disease.13 Fibrinogen also is an acute-phase reactant, which might explain why it is elevated in some patients with the disease.
  • Normal aggregation of platelets has been observed in many patients with Degos' disease.13 Moreover, many patients do not respond to therapy directed against aggregation of platelets.
  • No significant abnormalities in plasminogen, anti-thrombin III, protein C, and levels of coagulation factors have been detected in most patients.
  • The fibrinolytic defect in the center of early and late lesions of the disease has been confirmed in many patients, but the significance of this finding is in dispute; it is well established that avascular tissue has little detectable activity of plasminogen activator.13
  • Most patients with Degos' disease do not have lupus anticoagulant and/or anticardiolipin antibodies. In a series of 15 patients, none had detectable levels of antiphospholipid and antiendothelial-cell antibodies.41
  • No thrombus can be demonstrated in many skin lesions that are typical of Degos' disease clinically.
 

2. Degos' Disease As A Vasculitis

 

Evidence in Favor

 
  • Soter et al. proposed that the inflammatory phase is early and transient. That being the case, the findings at that stage will not be evident in sections of tissue of biopsy specimens taken from lesions that are mature clinically. They suggested that the early event could be an injury mediated by lymphocytes to small vessels of the superficial and deep plexuses. Thrombosis could be secondary to injury to endothelial cells.28
  • Su et al. proposed that a "lymphocyte-mediated necrotizing vasculitis represents the prominent cutaneous change of Degos' disease." They saw an analogy between the widespread vasculitic process of Degos' disease and that observed in patients with lupus erythematosus in whom skin lesions are similar to those of Degos' disease.14
 

Evidence Against

 
  • The elastic lamina of affected small arteries remains intact in Degos' disease, unlike the situation in vasculitides such as those of allergic vasculitis or of poly-arteritis nodosa.
  • An autoimmune mechanism has been deemed by several authors to be responsible for lesions of Degos' disease, but no immunological abnormalities have been encountered consistently in these patients. Immunofluorescence techniques, direct and indirect, have shown, episodically, deposits of IgA, IgG and C3 in the dermis and the perivascular tissue.19,28,29,30,44 Antinuclear antibodies are either present in low amount or are not present at all, and latex fixation test, complement level, serum immunoglobulins, and circulating immune complexes usually are negative or within normal limits.
  • The lack of response of patients with Degos' disease to therapy with corticosteroids administered systemically supports the theory that the process is not basically a vasculitis.
 

3. Degos' Disease As A Primary Disorder Of Endothelial Cells

 

Evidence in Favor

 
  • Tribble proposed that the primary defect in Degos' disease resides in endothelial cells. Endothelial swelling and proliferation could lead to an abnormality of coagulation with thrombosis and necrosis of skin, gut, and central nervous system.30
  • Molenaar et al. thought that an abnormality of endothelial cells might be the primary event in Degos' disease. These authors observed that the vascular lesions resembled closely those in a murine model of lupus erythematosus. This model involves male mice only and is characterized by widespread non-inflammatory and degenerative vascular changes with secondary thrombosis. The murine model is associated with low levels of circulating immune complexes that seem to be deposited in the wall of a vessel in a manner that prevents a certain threshold necessary to elicit an inflammatory response from being exeeded. A similar phenomenon is thought by them to occur in patients with Degos' disease.29
  • The endothelial changes of Degos' disease have been postulated to be induced by a virus. Howard and Nishida showed tubulo-reticular aggregates, 250–300 Å, within swollen degenerating endothelial cells, similar to those found in endothelial cells of lupus erythematosus.48
  • Studies of lesions of Degos' disease by electron microscopy have shown both necrosis of endothelial cells and occlusion of the lumen of vessels by hypertrophied endothelial cells.14,28 Swelling and proliferation of endothelial cells are a common response to injury of vessels and could represent the primary change in Degos' disease.
 

Evidence Against

 
  • Olmos and Laugier considered the tubular-reticular inclusions within endothelial cell to be non-specific particles that result from degeneration of cells.35 The structures have been seen rarely in normal tissue, but they have been noted especially in patients with lupus erythematosus and other connective tissue disorders,11 in neoplastic cells, in immunodeficiency states, and in cells from wounds induced experimentally.13 Rich and Owens demonstrated that these structures occur in cells secondary to the effects of native or recombinant interferon alfa and beta.49
  • The precise nature of the endothelial defect that leads to thrombosis in Degos' disease has not been elucidated.