The etiology of cutaneous necrotizing vasculitis

Vasculitis is a multisystem disorder with frequent involvement of the skin. Understanding of the vasculitides has been difficult, owing to their many manifestations and the multitude of classifications that have been proposed. Part of the problem relates to descriptions by subspecialists, each with his or her own bias. In 1952, Zeek offered a classification of vasculitis that, with modifications, is still the one mainly used today. Nevertheless, it is important to subclassify patients because of possible differences in etiopathogenesis, prognosis, associations with specific diseases, involvement in a certain organ, or therapeutic approach. Most of these differences are not actually acknowledged by these classification systems.1 A method of subclassifying these disorders separates the diseases by vessel size. Capillaries are involved in capillaritis. Small vessels, usually the postcapillary venule, are involved in what is traditionally known as leukocytoclastic vasculitis (LCV). Small arteries or arterioles can be involved in the panniculitides or polyarteritis nodosa (PAN). Medium-sized arteries are involved, particularly, near their bifurcations, in PAN, and in the granulomatous vasculitides. Large vessels are involved in giant-cell arteritis and its variants. It is absolutely necessary to perform a thorough systematic evaluation in patients with cutaneous disease as a manifestation of vasculitis to offer reliable prognostic advice to the patient. The pitfalls of viewing a multisystem disorder through a specialist’s eye are self-evident. Also, the problems of meaningful labeling and classification arise. Usually, the label polyarteritis nodosa (PAN) implies a poorer prognosis than does that of cutaneous LCV; however, as stated earlier and illustrated in the following discussions, these subclassifications are less than perfect. Our proposed variation of these classification2–4 may simplify and offer meaningful prognostication. We would divide these entities into those characterized by small-vessel and large-vessel vasculitides. The traditional LCV, which can be caused by unknown factors (idiopathic), infections, drugs, abnormal proteins, or an associated systemic disease, is within the small-vessel vasculitis category. To prognosticate within this group of patients, it is important to define the presence and type of systemic involvement. Large-vessel vasculitis includes PAN, granulomatous vasculitides, and giantcell arteritis. Affected patients generally have systemic disease, but they can also have cutaneous diseases. The cutaneous lesions can consist of those typical LCV, but ulceration, ischemic changes, necrosis, and livedo reticularis may be common. Strong experimental and clinical evidence suggests that cutaneous LCV is an immune complex disease (type III hypersensitivity reaction). Although multiple causes or associated conditions are possible and there are many clinical expressions, the linkage between the injury (cause) and the manifestation is probably an immune complex disease that leads to the inflammatory reaction.2–4 Figure 1 is a schematic representation of the pathogenesis of LCV. After antigenic exposure, soluble antigen-antibody complexes (circulating immune complexes, CIC) are formed. In the presence of antigen excess, these complexes can precipitate in the vessel wall. Following the deposition of the CIC, a complex series of events is initiated, ultimately leading to vessel wall damage, leakage of fluid (urticarial lesions), leakage of red blood cells (purpura), and ischemia (necrosis or ulceration).2–4 In addition to the immunologic events, several nonimmunologic factors may play a role in disease expression. Vasoactive amines, in particular endogenous histamine, can precipitate the deposition of CIC. This can be exploited clinically as a test for studying immune reactant deposits in lesional skin. Endothelial cells also appear to be primarily involved. These cells may produce and release cytokines that enhance the inflammatory response. Finally, local factors, such as anatomic location and viscosity, may help explain the clinical manifestations of a given vasculitic syndrome. Multiple etiologic agents have been implicated in the various vasculitic syndromes. Etiologic factors or associated conditions are similar for all the syndromes and From the Department of Dermatology, University of Florence, Florence, Italy. Address correspondence to Grazia Campanile, M.D., Department of Dermatology, University of Florence, Via degli Alfani, 37, 50121, Florence, Italy.