THE VASCULITIC SYNDROMES

Vasculitis is a clinicopathologic process characterized by inflammation of the blood vessel itself. Associated with this inflammation may be compromise of the vessel lumen with resulting ischemic changes in the tissues supplied by the vessel. Any size, location, and type of blood vessel may be involved, including large muscular arteries, medium-sized and small arteries, arterioles, capillaries, postcapillary venules, and veins. This heterogeneous category of diseases comprises unique syndromes as well as diseases with overlapping clinical and pathologic features. The vasculitis may be the primary process, or it may be a component of another underlying disease. Furthermore, vasculitis varies considerably in its clinicopathologic manifestations. Certain of the vasculitic disorders are rarely life threatening (e.g., the hypersensitivity vasculitic syndromes in which cutaneous involvement usually predominates). Other vasculitic syndrome's may be fulminant and, if untreated, rapidly fatal diseases (e.g., Wegener's granulomatosis and polyarteritis nodosa). The vasculitic syndromes are generally thought to result from immunopathogenic mechanisms; however, the evidence for this varies among the different syndromes. Among these mechanisms, the deposition of circulating immune complexes with subsequent vessel damage has emerged as the major immunopathologic event associated with most of the vasculitic syndromes. The presence of circulating immune complexes does not prove that the associated vasculitis is caused by them, since many nonvasculitic diseases are also associated with circulating immune complexes, and complexes per se need not result in vasculitis, even in diseases in which vasculitis is present. In only a few diseases has the actual antigen involved in the immune complex been identified. The most noted of these is the hepatitis B surface antigen that has been demonstrated in the circulating immune complexes, cryoprecipitable serum components, and involved tissues of certain patients with hepatitis B antigenemia-associated vasculitis.

The mechanism of tissue damage from immune complexes is thought to be similar to serum sickness. In this model, soluble immune complexes are formed in antigen excess and deposited in blood vessel walls in areas of increased vascular permeability. The increased permeability is attributed to release of vasoactive amines from platelets or mast cells under the influence of specific IgE. Following deposition of complexes, various components of complement are activated, particularly C5a, which is strongly chernotactic for neutrophils. The neutrophils infiltrate the vessel wall at the site of immune complex deposition and release intracytoplasmic enzymes such as collagenase and elastase that directly damage the vessel wall. Compromise of the lumen occurs with resulting ischernic changes.

Certain of the vasculitides are characterized by granulomatous inflammation in and around the blood vessels. Although granulornatous responses are generally of the delayed hypersensitivity type, immune complexes themselves can trigger granuloma formation and thereby produce granulornatous vasculitis.

Why certain persons develop vasculitis and others do not is an extraordinarily complex issue and likely involves a number of host factors such as genetic predisposition, immunoregulatory mechanisms, and the integrity of the reticuloendothelial system, which clears the complexes from the circulation. In addition, the reasons that certain complexes cause vasculitis and that certain types of vessels and not others are involved probably relate to the size and physicochemical properties of the immune complex and to other physical factors such as turbulence of blood flow, hydrostatic pressure within vessels, and previously damaged vessel endothelium.

CLASSIFICATION OF THE VASCULITIC SYNDROMES

The heterogeneity and the obvious overlap among the vasculitis syndromes have led to difficulties in classification of this group of diseases. The first report of a vasculitic syndrome was in 1866 by Kussmaul and Maier, who described the clinicopathologic features in a patient with what is now recognized as classic polyarteritis nodosa. It became evident that there were numerous vasculitic syndromes with diverse clinical and pathologic manifestations, but diagnostic criteria were controversial. More precise and accurate classification schemes now have emerged, based upon reexamination of clinical, pathologic, and immunologic features as well as responses to certain therapeutic regimens. Table 439-1 illustrates one such classification scheme. The first group of vasculitides is the polyarteritis nodosa group. This syndrome is described in detail in Ch. 440. It is the prototype of the serious systemic necrotizing vasculitides and manifests certain features such as small and mediumsized muscular artery involvement, hypertension, visceral vessel involvement, and a noticeable lack of lung involvement. Eventually physicians recognized a systemic vasculitis that resembled classic polyarteritis nodosa except that lung involvement was a prominent feature and the patients generally manifested eosinophilia, granulornatous reactions, and a strong allergic diathesis, usually severe asthma. Most of these patients had what is now referred to as allergic angiitis and granulornatosis of the Churg-Strauss type. This disease is quite similar to classic polyarteritis nodosa except for the divergent features mentioned above. Many systemic necrotizing vasculitides manifest clinicopathologic characteristics that overlap these two syndromes as well as the hypersensitivity group of vasculitides (discussed below). This subgroup has been referred to as the "polyangiitis overlap syndrome" of systemic necrotizing vasculitis.

In addition to the polyarteritis nodosa group of systemic necrotizing vasculitides, certain other vasculitides are systemic and involve multiple organ systems. However, they are referred to by different names, since they possess characteristic clinical and/or pathologic features. This is true of diseases such as Wegener's granulomatosis (see Ch. 441) and the giant cell arteritides. In the latter group, the two major subcategories-cranial or temporal arteritis (see Ch. 442) and Takayasu's arteritis (see Ch. 56)-are systemic diseases involving large muscular arteries with mononuclear cell and often giant cell infiltration within the walls of the involved arteries. Despite the predisposition for certain vessels in these diseases (tem poral artery in cranial arteritis and subclavian artery in Takayasu's arteritis), these are systemic diseases which involve multiple arteries. Lymphomatoid granulomatosis (see Ch. 441) is generally considered in the differential diagnosis of systemic necrotizing vasculitis with lung involvement such as Wegener's granulomatosis. However, it is not strictly speaking an inflammatory response in vessels but an infiltration of blood vessel walls with atypical and often neoplastic-looking lymphoid cells.

The hypersensitivity vasculitides include a broad and heterogeneous group of disorders which have often caused confusion in categorization. These are discussed in detail in this chapter.

Other vasculitic syndromes can be considered under the category of "miscellaneous" for want of a better term. These include Behqet's disease, the major pathologic feature of which is a true vasculitis (see Ch. 453), and thromboangiitis obliterans, which is an inflammatory and occlusive disease of arteries and veins, although its true vasculitic character has been questioned. In addition to the granulomatous vasculitis of the central nervous system, which is seen in association with certain lymphoproliferative malignancies, there is also a rare syndrome of isolated vasculitis of the central nervous system that occurs in the apparent absence of systemic vasculitis or other systemic disease.

HYPERSENSITIVITY VASCULITIS

Hypersensitivity vasculitis is a term applied to a heterogeneous group of disorders that are thought to represent a hypersensitivity reaction to an antigenic stimulus such as a drug or an infectious agent; hence the word "hypersensitivity. " Although the antigenic stimuli associated with this group are heterogeneous, these disorders generally share the characteristic of involvement of small vessels. They can be subdivided into two basic groups. The vast majority of the patients manifest involvement of the postcapillary venules, and hence have a venulitis. A smaller group of patients falls into the second category, in which arterioles are predominantly involved (arteriolitis). Most importantly, there is a predominant and often exclusive involvement of the vessels of the skin. Confusion in the literature generally resulted from grouping this category of vasculitis with the more serious systemic varieties such as classic polyarteritis nodosa and related diseases. It is true that the hypersensitivity vasculitides may have variable degrees of organ system involvement other than of the skin. However, this is usually less severe than that of typical systemic vasculitis of polyarteritis nodosa and Wegener's granulomatosis. Most frequently, the skin is exclusively involved or, if other organ systems are involved, the cutaneous disease still dominates the clinical picture.

ETIOLOGY. As indicated by the terminology, the etiology is usually a recognizable antigenic stimulus such as a drug, microbe, toxin, or foreign or endogenous protein. From an etiologic standpoint the hypersensitivity vasculitides segregate into two distinct groups, depending on the source of the sensitizing antigen. In the classic original group, the antigen is foreign to the host. In the second group the antigen is enclogenous. For example, certain connective tissue diseases may manifest a typical hypersensitivity small vessel vasculitis. These diseases are generally characterized by circulating immune complexes in which one of the components is an endogenous protein to which antibody is directed. This is true of patients with systemic lupus erythematosus who develop immune complexes composed of endogenous DNA and anti-DNA antibodies; in addition, patients with rheumatoid arthritis may develop immune complexes of rheumatoid factor with antibody activity against endogenous immunoglobulin. Thus, in most of the hypersensitivity vasculitides, the identity of the etiologic agent which triggers the formation of immune complexes is at least strongly suspected.

INCIDENCE AND PREVALENCE. It is difficult to determine an accurate incidence for the hypersensitivity group of vasculitides owing to the marked heterogeneity among these diverse syndromes. However, the hypersensitivity group of vasculitides is much more common than the polyarteritis group and other syndromes such as Wegener's granulomatosis and Takayasu's arteritis. The disease can be seen at any age and in both sexes; however, this varies considerably with the particular subgroup in question.

PATHOLOGY AND PATHOGENESIS. The histopathologic hallmark of the hypersensitivity vasculitides is a leukocytoclastic venulitis. The term leukocytoclasis refers to nuclear debris derived from the neutrophils that have infiltrated in and around the involved vessels. In skin biopsies, this type of involvement is most common in the postcapillary venules just beneath the epidermis. When biopsies are obtained in the acute phase of active disease, the typical pattern of neutrophil infiltration is readily observed. In the subacute or chronic stages, biopsies often reveal mononuclear cell infiltration. In the second and smaller category of hypersensitivity vasculitis, arterioles and capillaries are predominantly involved. In the typical case of hypersensitivity vasculitis with a predominance of cutaneous involvement, the lesions are usually found in the lower extremities or in the dependent areas such as the sacrum in supine patients. This is most likely due to the increase in hydrostatic pressure within the postcapillary venules in these areas.

Although immune complex deposition is widely considered to be the pathogenic mechanism of this group of vasculitis, not every case of hypersensitivity vasculitis has had immune complexes demonstrated, even when carefully sought, as mentioned above.

CLINICAL MANIFESTATIONS. just as the broad group is etiologically heterogeneous, so too are the clinical manifestations. However, the hallmark of the group is the predominance of cutaneous involvement. The skin lesions may appear as the classic palpable purpura which results from the extrav asation Of erythrocytes into the tissue Surrounding the involved venules. In addition, one may see macules, papules, vesicles, bullae, subcutaneous nodules, ulcers, and even recurrent or chronic urticaria.

Even though skin lesions generally dominate, various organ system involvements can be seen. Certain constellations of clinicopathologic findings define relatively distinct syndromes. For example, in Henoch-Schonlein purpura the typical syndrome consists of palpable purpura (usually over the buttocks), arthralgias, gastrointestinal symptoms, and glomerulonephritis. Henoch-Schonlein purpura is usually seen in children; however, adults of any age may be affected. The disease usually remits spontaneously after one week. However, the disease is remarkable for its tendency to recur a number of times over weeks to months before remission is complete. The characteristic skin lesions are present in virtually all patients. The majority of patients also have arthralgias involving multiple joints, but frank arthritis is rare. The gastrointestinal involvement is usually manifested as colicky abdominal pain which may mimic an acute surgical abdomen. Patients may experience nausea, vomiting, diarrhea, constipation, and occasionally the passage of blood and mucus per rectum. In the more severe and rare case, bowel intussusception may occur. Renal disease is a glomerulitis (see Ch. 81), which is usually expressed as microscopic hematuria without significant renal functional impairment. However, in rare cases renal failure can occur. Most frequently, patients recovery spontaneously and completely. Other groups within the hypersensitivity category include serum sickness and serum sickness-like reactions. The classic manifestations are fever, urticaria, arthralgias, and lymphadenopathy occurring seven to ten days after primary exposure to the antigen in question, which for serum sickness is usually a heterologous serum protein and for serum sickness-like reactions is usually a drug such as penicillin. Most of the manifestations of this disorder are not the result of vasculitis. However, in rare cases cutaneous vasculitis typical of the hypersensitivity group is documented. In addition, patients may rarely progress to a typical systemic necrotizing vasculitis involving multiple organ systems

A number of disorders have vasculitis as a manifestation of an underlying primary disease. Included in these diseases are systemic lupus erythematosus, rheumatoid arthritis, mixed cryoglobulinemia, and other connective tissue diseases. In these disorders, the manifestations of the underlying disease usually predominate. When vasculitis is observed, it is generally of the small vessel cutaneous type, which is virtually indistinguishable from the vasculitis seen in the hypersensitivity group with recognized exogenous antigens. However, patients with these disorders, particularly systemic lupus erythematosus and rheumatoid arthritis, may also develop a systemic necrotizing vasculitis which closely resembles the polyarteritis nodosa group in manifestations and severity. Nevertheless, in the typical case, the cutaneous vasculitis usually dominates the clinical picture with respect to the vasculitic process.

Other diseases which may fall into this category of small vessel hypersensitivity vasculitis are the vasculitis associated with congenital deficiencies of various complement components such as Clr, Cis, and C2, erythema elevatum diutinum; hypocompicmentemic vasculitis; the vasculitis associated with certain neoplasms, particularly of the lymphoid type; and the vasculitis associated with other primary disorders such as ulcerative colitis, Crohn's disease, biliary cirrhosis, and retroperitoneal fibrosis.

DIAGNOSIS. The diagnosis of hypersensitivity vasculitis rests on the demonstration of vasculitis on biopsy. Since the predominant organ involved is the skin, histopathologic material is usually readily available. Because cutaneous involvement is often present in severe systemic vasculitides, one should undertake a systematic workup of other organ systems in patients who present with apparently isolated cutaneous vasculitis.

TREATMENT AND PROGNOSIS. Therapy of the hypersensitivity group of vasculitides has in general been unsatisfactory. Since most cases resolve spontaneously, the lack of response to therapeutic regimens is of less importance. However, in those patients who go on to develop persistent cutaneous disease or serious organ system involvement, several regimens have been tried with variable results. In cases in which a recognized antigenic stimulus is present, the first order of therapy is to remove the antigen; e.g., to remove sensitizing drugs or responsible organisms by appropriate antibiotic therapy when possible. In situations in which disease appears to be self-limited, no specific therapy is indicated. However, when disease persists or results in organ system dysfunction, a glucocorticosteroid is the drug of choice. Prednisone is usually administered in doses of 1 mg per kilogram per day with rapid tapering when possible, in some instances directly to discontinuation or initially to an alternate-day regimen followed by ultimate discontinuation (see Ch. 30). In cases that prove refractory to corticosteroid therapy, cytotoxic agents such as cyclophosphamide have been used. The efficacy of these regimens has not yet been fully evaluated in hypersensitivity vasculitis. Thus, one should be reluctant to institute cytotoxic agents in persons with disease limited to the skin, particularly since the response of the cutaneous variety of hypersensitivity vasculitis to cytotoxic agents has not been as dramatic as the response of the systemic vasculitides such as Wegener's granulomatosis (see Ch. 441) and the polyarteritis nodosa group

The prognosis of most of the diseases in this category is generally excellent, with spontaneous and complete remissions in most patients. However, certain patients may develop persistent and debilitating cutaneous disease, and others may evolve a typical systemic vasculitis with a serious prognosis.