Vasculitis in primary vasculitides, granulomatoses, and connective tissue diseases

Vasculitis in Primary Vasculitides, Granulomatoses, and Connective Tissue Diseases ROBERT T. MCCLUSKEY, MD, AND ROBERT FIENBERG, MD Problems with the classification and diagnosis of vasculitides are discussed. The evidence related to the pathogenelic importance of immune complexes in vasculitis, both in experimental models and human disease, is reviewed. The finding, by immunofluoreseence, of immunoglobulins and complement components in vessel walls has provided indirect evidence of a role of immune complexes in certain forms of h u m a n vasculitis. However, specific antigens have been demonstrated in very few instances, notably in some patients with hepatitis B infection. In most forms of h u m a n vasculitis there is no information about causative factors. The widely held belief that therapeutic drugs cause an appreciable proportion of cases of h u m a n vasculitis appears unfounded. H u m Pathol 14:305-315, 1983.

Vasculitis is seen in a variety o f conditions, including "connective tissue" diseases. We will discuss salient feattn'es o f tile major forms o f vasculitis and what we believe to be important unresolved tlttestit)ns, analyzing the subject from the point o f view o f classification and pathologic features, primary patltogenetic ntechanistns, and causative factors. CLASSIFICATION AND PATHOLOGIC FEATURES OF VASCULITIS AND RELATED GRANULOMATOSIS T h e r e is no satisfactory classification o f vasculitis. T h e reasons are several: There are wide variation in tire distribution of lesions and type o f vessels involved in a given condition and overlapping distribution among various forms o f vasculitis; there is insufficient knowledge of etiologic agents and pathogenetic ntechanisms; anti tire clinical, laboratory, and pathologic features in m a n y forms o f vasculitis are not distinctive. T h e subject is f u r t h e r confused by the fact tttat different names are often used to describe a given condition; conversely, tire same term is sometimes used to refer to apparently diverse conditions. Nevertheless, certain classifications are useful, especially with respect to prediction o f outcome and response to tlterapy. We will use the classification shown in table 1, fi'eely admitting that is incomplete and imperfect. T h e demonstration in histologic preparations o f inflammation o f vessel walls, often with necrosis, is the definitive way o f establishing the diagnosis o f vasculitis. T h e diagnosis o f associated granulomas also d e p e n d s on histologic findings. Nevertheless, other types o f information are usefnl in diagnosis and classification, including clinical features, laboratory and immunofluorescence findings, and identification Received from the Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. Address corresIxmdence and reprint requests to Dr. McCluskey.

305

of underlying diseases, especially the connective tissue diseases anti ltepatitis B infection.

Periarteritis Nodosa [Polyarteritis Nodosa] Periarteritis nodosa is generally defined as a condition in which medium-sized arteries show leukocyte infihration, necrosis, and fibrosis, in various stages o f development or repair. Granuloma formation is not a feature of this condition. Small aneurysms are frequently Fresent. In m a n y patients glomerulonephritis is seen, generally with focal necrosis and crescent formation. Tlie distribution of arterial lesions differs from one patient to another, and the clinical manifestations vary accordingly. Ho~(ever, the extent o f arterial lesions cannot be d e t e r m i n e d with certainty on clinical grounds. T h e r e are no diagnostic laboratory findings. Although the histologic findings are characteristic, periarteritis nodosa is clearly not a disease entity, as shown by the occurrence o f the same type o f vasculitis in some patients with hepatitis B infection, r h e u m a t o i d arthritis, or systemic lupus erythematosus (SLE).

Small Vessel Vasculitis (Hypersensitivity Vasculitis) Small vessel vasculitis comprises a group o f vasculitides in which vennles, capillaries, and ill some cases arterioles are affected. Lesions are commonly seen in the skin, where they usually appear as purpura or urticaria. ~ Because tltey are easily biopsied, cutaneous lesions ltave been studied more t h o r o u g h l y than tltose in other sites, and mnch o f current thinking about small vessel vasculitis is based on cutaneous vasculitis. Although in early studies tlte affected cutaneous vessels were t h o u g h t to be arterioles, more recent evidence based on electron microscopy or 1-ttm sections shows that venules are principally or exclusively involved." T h e venular walls are infiltrated by neutrophils and mononuclear'cells in varying proportions and often show necrosis with deposits o f fibrin (fibrinoid necrosis). Some require necrosis for the diagnosis." T h e c o m m o n presence o f nuclear debris tins led to the use o f the term leukocytoclastic vasculitis. Extravasation of erythrocytes is common. C u t a n e o u s vasculitis clearly comprises a very heterogeneous group, as it can be seen in idiopathic form, apparently in d r u g reactions, and in HenochSch6nlein p u r p u r a , essential mixed cryoglobulinemia, hepatitis B infection, Sj6gren's syndrome, SLE, rheumatoid arthritis, and Wegener's (pathergic) granulomatosis, as well as other conditions. ~An important

HUMAN PAIHOLOGY

TABLE 1. I.

11.

III.

IV. V.

Volume t4, No. 4 [April '1983}

glomeruli. Lately, however, the term hypersensitivity vasctditis has been used to refer to conditions in which skin involvement dominates the clinical picture and in which evidence o f serious visceral invoiventent is rare. 5 It thus appears that the condition described by Zeek as hypersensitivity vasculitis (insofar as it is possible to determine what was included in this group) probably corresponds to what Davson et al. 6 called the microscopic form o f periarteritis nodosa, and is largely unrelated to what is today usually called hypersensitivity vasculitis. Another important and unanswered question concerning small vessel (hypersensitivity) vascnlitis is whether, when visceral involvement occurs, venules are predominantly involved. It is not clear that the same type of carefifl structural studies that led to the recognition that venules and not arterioles are affected in cutaneous vasculitis have been performed in studies of visceral vascular lesions.

Classification of Conditions with Vasculilis

Primary vasculitides* of unknown cause A. Periarteritis nodosa (polyarteritis nodosa; classical polyarteritis nodosa; systemic necrotizing vasculitis) B. Small vessel vasculitis (hypersensitivity or allergic vasculitis; leukocytoclastic vasculitis; allergic vasculitis) 1. Cutaneous vasculitls (cutaneous necrotizing vasculitis, cutaneous venulitis; involvement apparently confined to skin) 2. Small vessel vasculitis with Ctltaneous and visceral involvement 3. ltypocomplementemic (urtic,lrial) vasculitis C. Unclassified vasculitis (or overlap) with features of periarteritis nodosa and small vessel vasculitis D. tlenoch-Sch6nlein purpura (anaphylactoid purpura) E. Essential mixed cryoglobulinemia F. Giant cell arteritis and aortitis G, Localized forms of periarteritis nodosa Connective tissue diseases in which vasculitis sometimes occurs A. Rheumatoid arthritis B. Systemic lupus erythematosus (SLE) C, Derumtomyositis D. Rheumatic fever E. Sj6gren's syudrome Diseases with known causative agents in which vasculitis sometimes occurs A. Hepatitis B infection (various forms of vasculitis including periarteritis nodosa) B. Bacterial infections (Pseudomonas, Streptococcns, endocarditic bacteria) C. Drug addiction (amphetamine) D. Rickettsial infections E. Drug reactions--small vessel vasculitis Wegener's granulomatosis (pathergic grantdotnatosis) Allergic granulomatosis (Churg-Strauss syndrome)

Hypocomplementemic Small Vessel (Urticarial] Vasculitis

* In the primary vasculitides, lesions appear to be restricted to blood vessels (aside from ischemic changes); in the other categories primary extravascular lesions occur and may be of major importance. Lymphomatuid granulomatosis is not included here, since it appears to be a I)'mphoproliferative disorder or lymphoma, raiher than a true vasculitis.

and unanswered question concerning idiopathic or drug-induced cutaneous vasculitis is, How widespread are the vascular lesions? In most patients clinical signs of visceral involvement are rare. However, small vessel vasculitis has bcen documented in a number of organs in cases tlaought to be drug-related? The lesions were described as involving small arteries, arterioles, capillaries, and venules; the vessels were infiltrated by mononnclear cells and eosinophiis; and no necrotizing lesions were found. Moreover, in some patients extracutaneous vasculitis is suspected clinically because o f arthralgia or abdominal pain. The extent to which the kidney is involved in cases of cutaneous vasculitis of special interest, since glomeruli or vessels, or both, are commonly affected in certain forms of vasculitis. It appears that if one excludes Henoch-Sch6nlein purpura, SLE, mixed cryoglobulinemia, and h)'pocomplementemic (urticarial) vasculitis, g l o m e r u l o n e p h r i t i s or renal vasculitis rarely if ever occurs. A factor" contributing to the confusion about the frequency o f renal involvement in cutaneous vasculitis stems from the uncertainty as to what constitutes the group usually designated as hypersensitivity vasculitis. Zeek 4 originally used this term to refer to patients with disseminated necrotizing lesions a f f e c t i n g small a r t e r i e s a n d o f t e n 306

Chronic idiopathic c u t a n e o u s vasculitis and hypocomplementemia appear to constitute a separate syndrome. 7-1~ Systemic involvement is rather common and is manifested by arthritis, abdominal pain, uveitis, ntyositis, and glomerulonephritis. However, the glomerular disease is, apparently, usually relatively mild and in one case studied hy biopsy was characterized by diffuse hypercellularity without necrosis or crescent formation. ~ Using improved histologic t e c h n i q u e s (1-/zm sections f r o m Eponembedded tissue) Soter et al. z have sltown that tbe cutaneous vasculitis in patients with hypocomplementcmia is clmracterized by a predominantly neutrophilic infiltrate, whereas in patients with normal contplement levels lymphocytes are more numerous titan neutrophils. These authors presented evidence that the histologic differences between the two groups are characteristic throughout various stages o f development of the lesions, although this conclusion has been questioned? ~ Hypocomplementemic vasculitis has some features of SLE, or mixed cryoglobulinemia, but appears to be a separate syndrome.

Henoch-SchOnlein Purpura Henoch-Sch6nlein purpura is a distinctive form of small vessel vasculitis of unknown cause, characterized by purpura, abdominal pain, gastrointestinal hemorrhage, and renal involvement. The vascular lesions involve venules and glomerular capillaries. In typical cases the glomeruli show only slight diffuse mesangial hypercellularity. However, in some cases severe glomerular disease occurs, usually with extensive crescent formation. A distinctive feature o f HenOch-Sch6nlein purpura is tile predominance o f IgA in the glomerulnr and vascular deposits, t2

Idiopathic Mixed Cryoglobulinemia Idiopathic mixed cryoglobulinemia is characterized by the presence of appreciable quantities of

VASCULITIDES,GRANULOMATOSES,AND CONNECTIVETISSUEDISEASES(McCluskey & Flenberg)

cryoprecipitable complexes in the circulation, usually containing IgM and IgG, in the absence of recognized lymphoproliferative or connective tissue disease? 3 Clinically the disease is manifested by purpura and, frequently, polyarthralgia and renal disease. A variety of vascular lesions occur, including cutaneous and visceral venulitis and necrotizing arteritis, which in some cases closely resembles periarteritis nodosa. The glomerular lesions are usually characterized by diffuse hypercellularity and intraluminal eosinophilic masses. There is abundant evidence that the renal and vascular lesions are due to accumulation o f I g M - IgG complexes. Vasculitis in Connective Tissue Diseases

The two connective tissue diseases in which vasculitis occurs most frequently are SLE and rheumatoid arthritis? 4 Although many patients with SLE probably have immune complex deposits in small vessels, ~sobvious signs of vasculitis are present in only a minority. The type of vasculitis ~;aries. Substantial numbers of patients develop cutaneous venulitis?~'~r Venulitis in the small intestine and other sites in a few patients also has been described. ~s Vascular lesions in tile central nervous system have been described: ~9 The involved vessels are, principally, small arteries, which show necrosis or proliferation but usually little or no inflammatory infiltrate. Necrotizing lesions of arteries and arterioles have been observed in the kidney in association with severe proliferative lupus nephritis; patients with such lesions generally have severe hypertension, and the vascular lesions resemble those of malignant hypertension. 2~ Widespread necrotizing arteritis, resulting in a condition resembling periarteritis nodosa, has been described in a few patients with SLE. z~ A number of extra-articular manifestations occur in rheumatoid arthritis, but in most cases they are of limited clinical significance. A variety of forms o f vasculitis have been described. 22 In some cases necrotizing venulitis occurs, and is noted most often in :he skin or in association with rheumatoid nodules? 4 ~,lononuclear cell infiltrates have been observed l r o u n d small arteries in r a n d o m muscle biopsy ;pecimens. 23 Bywaters 24 described obliterative entoarteritis in digital artery biopsy specimens; this may "epresent the end stage of necrotizing arteritis. ~5 2Jncommonly, patients with rhematoid arthritis delelop w i d e s p r e a d n e c r o t i z i n g lesions involving nedium-sized arteritis in a variety of sites, producing t condition similar to periarteritis nodosaY 6 tVegener's (Pathergic] Granulomatosis

Wegener's (pathergic) granulomatosis is a disinctive clinico pathologic condition o f u n k n o w n ause. It was first recognized as a disseminated dis9ase 27 characterized by necrotizing granulomas in the tpper and lower respiratory tract, vasculitis, and focal lecrotizing glomerulonephritis. In 1955 Fienberg ~s [escribed a localized form of the disease, particularly 307

in tile hmg, and proposed tile name pathergic granulomatosis for the entire spectrum. Wegener's granulomatosis is not a form of primary vasculitis2a; i n d e p e n d e n t extravascular necrotizing granulomatous lesions are invariably present and account for much of the tissue destruction often seen in this disease, especially in the respiratory tract. In its earliest recognizable stage, the extravascular lesion appears to consist of a form of fibrinoid or g r a n u l a r necrosis without invading leukocytes? ~ Later, tile necrotic zone becomes s u r r o u n d e d by palisading histocytes, producing a lesion that resembles the rheumatoid nodule. Diffuse granulomatous tissue with multinucleated giant cells is often a feature. Discrete extravascular tubercle-like granulomas, typical of sarcoidosis and tuberculosis, are not seen, although involved vessels with granulomatous vasculitis may resemble them. The recognition of extravascular granulomas is of more than academic interest; in many cases the diagnosis can be made with certainty on tile basis of biopsy specimens that fail to show vasculitis. If vasculitis is found, however, the diagnosis is, of course, strengthened. Unfortunately, some biopsy specimens o f necrotizing lesions show only nondiagnostic granulation tissue. In such cases, repeated biopsies are indicated. Clearly, early diagnosis is essential, so that cyclophosphamide therapy can be instituted in an attempt to prevent further tissue destruction or renal involvement? ~ Diagnosis depends on interpretation o f histologic findings, since there are no other pathognomonic laboratory findings?2 Several types o f vascular lesions are seen in Wegener's granulomatosis, including phlebitis, necrotizing arteritis similar to that seen in periarteritis nodosa, and granulomatous vasculitis. In some organs, especially the kidney and organs of the gastrointestinal tract, vasculitis is often seen without extravascular granulomas. 33 Vasculitis may lead to ischemic injury. However, the ischemic injury does not cause the granulomas, as indicated by the fact that granulomas are not seen in periarteritis nodosa. The glomerular lesions in Wegener's granulomatosis are typically focal and necrotizing. Crescent formation is common and may be extensive. Irreversible sclerosis of glomeruli can develop quickly, and renal failure is the major cause o f death. Granulomatous lesions and vasculitis are rarely encountered in biopsy specimens of the kidneys. Immunofluorescence findings are generally not distinctive. However, even though they are not pathognomonic, if glomerular lesions are found in a patient with upper or lower respiratory lesions compatible with Wegener's granulomatosis, the diagnosis is virtually unassailable. The distribution of lesions varies among patients with Wegener's granulomatosis; so too does the rate at which the lesions progress. In a recent study of 12 untreated patients, lesions involving the skin or upper respiratory mucosa persisted for periods ranging from 9 months to 18 years (average, 6.5 years) before diagnosis, z~ The clinical course in these patients differed markedly from that of the classical disseminated form, which Walton 34estimated to be 5 months.

HUMANPATHOLOGY Volumet4, No. 4 (April '1983)

tion o f circulating immune complexes in vessels. Tile evidence of this mechanism has been provided principally by studies on experimental acute serum sickness in rabbits, a9 In this model, some rabbits given a single intravenous injection o f a large amount of a foreign serum protein, commonly bovine serum albumin, develop, at about 10 to 14 days, necrotizing arteritis and acute giomerulonephritis. The lesions appear during the period when circulating immune complexes are being formed, in antigen excess (tile immune phase o f antigen elimination), and regress quickly after disappearance of antigen from the circulation. Immunoflnorescence studies have revealed tile presence of immunoglobulins, bovine serum albumin, and c o m p l e m e n t in vascular lesions and g l o m e r u l i : ~ albeit often only in small amounts. However, bovine serum albumin is reported 4~ not to be detectable in vessels or glomeruli before tile immune phase of antigen elimination, which has provided a major but not conclusive argument against the possibility that free antigens fix in tissues and subsequently combine with antibodies. T h e most common type of arterial lesion is characterized by segmental infiltration o f vessel walls with neutrophils and mononuclear cells and by necrosis and disruption of the internal elastic membrane. T h e lesions resemble those of periarteritis nodosa. Depletion of complement or neutrophils largely prevents the arteritis, as does tile administration of antihistamine agents, a9 Curiously, necrotizing arteritis is not generally a feature of experimental chronic serum sickness, even thougb in this model immune complexes are present in the circulation for prolonged periods. The model is induced in rabbits by daily intravenous injections of foreign protein for periods o f several weeks or longer? ~ Although necrotizing arteritis is not usually seen, many rabbits develop severe chronic immune complex glomerulonephritis 41 and immune complex deposits in small vessels and extravascular sites in various tissues/z Christian and Sergent 43 have proposed the following explanation for the difference between tile two models with respect to tile development of arteritis. In acute serum sickness, large amounts o f antigen equilibrate outside tile circulation, including in arterial walls, before the formation of antibodies; when antibodies are produced and released into tile circulation, they react with antigens within tissues to form complexes locally. In contradistinction, in chronic serum sickness, in which smaller doses o f antigen are given daily, for the most part after circulating antibodies have appeared, the formation of complexes occurs largely within the circulation. Although tbis hypothesis is plausible, other mechanisms may be involved; for example, rabbits with chronic serum sickness may fail to release mediators or bec o m e refractory to mediators that promote vascular localization of complexes. There is evidence that release of vasoactive amines from platelets is reqtfired for vascular localization o f immune complexes in acute serum sickness. 44 O f interest here also are the experiments o f G e r m u t h and Heptinstall, 45 who showed that rabbits given repeated, intermittent injec-

Allergic Granutomatosis [Churg- Strauss Syndrome]

In 1951 Cburg and Strauss 35 described 13 patients with a history o f asthma, who d e v e l o p e d eosinophilia, widespread vascular lesions of the type seen in periarteritis nodosa, phlebitis, and granulomatous lesions involving both vessels and extravascular tissue. Some patients had focal necrotizing glomerulitis. Among a group of patients described a few years later by Rose and Spencerfl 6 some had features similar to those of the Churg-Strauss group. However, it is difficult to be certain how many of tile cases were similar, since the correlation o f the clinical data and the histologic findings in individual patients was not clearly presented? GLately, relatively few patients with features o f tile C h u r g - S t r a u s s syndrome have been describedY Despite its obvious similarities to Wegener's granulomatosis in terms of pathologic features (vascular and extravascular granulomas, necrotizing arteritis, glomerulitis and phlebitis), allergic granulomatosis has generally been considered a separate syndrome or a syndrome closely linked to periarteritis nodosa, as in the "overlap syndrome", as The justification for distinguishing C h u r g - S t r a u s s syndrome from Wegener's granulomatosis is that patients with Chnrg-Strauss syndrome have a history of asthma and exhibit eosinophilia and eosinophilic infiltrations of lesions. However, eosinophils are" sometimes seen in lesions of patients with "typical" Wegener's granulomatosis, and t h e r e is no a priori reason that Wegener's grantdomatosis cannot develop in a patient with asthma. There does not appear to be sufficient information concerning tile response of patients with Churg-Strauss syndrome to cyclopbospbamide therapy, which might provide evidence concerning its relationship to Wegener's granulomatosis. For the moment, it seems appropriate to consider allergic granulomatosis as a separate syndrome. Whether it differs ftmdamentally from Wegener's granulomatosis or is basicallytlle same--with, perhaps, certain added pathogenetic mechanisms, such as an IgE component--will not be certain until more is known o f basic pathogenetic mechanisms and causative agents. PRIMARY PATHOGENETIC MECHANISMS IN VASCULITIS

Primary pathogenetic mechanisms are those factors that initiate the vascular damage, such as tile trapping of circulating immune (antigen-antibody) complexes in vessel walls. We will not discuss in detail secondary pathogenetic mechanisms, such as complement activation and release of lysosomal enzymes from leukocytes. Immune Complex Accumulation Experimental Evidence

Tile primary pathogenetic mechanism most widely noted in the literature on vasculitis is deposi308

VASCULITIDES,GRANULOMATOSES,AND CONNECTIVETISSUEDISEASES{McCluskey & Fienberg)

tions of antigens at intervals of several weeks generally develop severe arteritis without glomerulonephritis. The hypothesis of Christian and Sergent 43 implies that the primary pathogenetic mechanism in the vascular lesions of acute serum sickness is in sitn formation o f immune complexes within vessels (as occurs in the Arthus reaction) rather titan trapping of circulating immune complexes as proposed by Dixon et al. 4~ (Considerable recent evidence indicates that in situ formation is responsible for glomerular deposits in certain forms of immune complex glomerulonephritis? ~) The relative importance of these two mechanisms of immune complex accumulation in tissues is of more than theoretical interest, since it bears on the value of assays for circulating immune complexes. Experiments in which preformed ixnmune complexes are injected intravenously (usually either once or several times during a period of a few days) should provide information about the potential o f circulating complexes to become trapped in vessels and to cause vascular damage (if one assumes that in vivo dissociation does not occur to an appreciable extent). Although arteritis is occasionally seen in such experiments, 47 in most instances the vascular deposits that develop are predominantly in venules a4 a n d pathologic signs of vasculitis are meager. Such experiments, as well as the model of chronic serum sickness, indicate that the mere presence of large amounts of circulating complexes is not sufficient to produce vasculitis. In addition, tile fact that different lesions are seen in acnte serum sickness, "intermittent" serum sickness, and chronic serum sickness show that distinctive (and generally unknown) mechanisms are responsible for accumulation of immtme complexes in glomeruli 4s and blood vessels as well as in different types of blood vessels. 39 Furthermore, the occasional finding o f immune complex deposits in small vessels without the usual pathologic features of vasculitis 44 indicates that secondary pathogenetic mechanisms must be brought into play to induce inflammation. Evidence In Human Vasculltls

IMMUNOGLOBULIN DEPOSITS IN VASCULAR LESIONS. Evidence of a pathogenetic role of immune complexes in human vasculitis can be obtained by demonstrating immunoglobulins and complement components in lesions by use of immunofiuorescence or immunoperoxidase techniques. However, since these proteins, as well as other plasma proteins, can be secondarily trapped in damaged vessels (especially necrotic vessels)4a the findings cannot be considered definitive; proof of the presence of immune complexes requires the demonstration o f specific antibodies and antigens in the deposits. Evidence of specific antibodies is best obtained through studies of immunoglobulins eluted from lesions by procedures that dissociate immune complexes. High concentrations o f specific antibodies have been demonstrated in eluates obtained from experimental immune complex glomerulonephritis and in human lupus nephritis. 5~ However, it is not generally possible to elute sufficient 309

material from vascular lesions, since they are focal and segmental. Additional evidence of immune complexes in vessel walls can be obtained by demonstrating, in association with immunoglobulin containing deposits, a particular antigen suspected of being involved in the disease under consideration, such as hepatitis antigens in patients with vasculitis and hepatitis B infection. This approach is limited, since in most cases there is no clue to tile offending antigen. Moreover, it is possible that certain free circulating antigens become secondarily trapped in damaged vessels. F u r t h e r m o r e , false-positive findings are common in immunofluorescence studies. Despite these considerations, tile demonstration of immunoglobulin and complement components in damaged vessels provides evidence of immune complexes, and ira suspected antigen can also be shown, the evidence is strengthened. Conversely, tile absence of immunoglobulins a r g u e s against an i m m u n e c o m p l e x pathogenesis; however, this evidence is compelling only if it is possible to examine lesions in early stages, since immune complexes can be rapidly degraded within vessel walls. Most of the literature concerning the demonstration of immunoglobulins and complement components in vasculitis other than cutaneous vasculitis consists of reports on small nnmbers of cases studied by immnnofluorescence, and tile overall incidence of positive results is impossible to determine. To our knowledge, relatively few cases of periarteritis nodosa have been studied; immunoglobulins have been found in some cases 51-53 but in others they have been lacking. 54-z6 Furthermore, in one study in which immunoglobulins were demonstrated in vessels (together with albumin and fibrinogen), incubation of the sections in acid buffers, which causes dissociation of immune complexes, failed to result in the loss of staining. 53 We could find only a few reports of immunofluorescence studies in Wegener's granulomatosis. Hu et alY described IgM, C3, and fibrin in one of four cases of Wegener's grannlomatosis with cutaneous necrotizing vasculitis; the vessels studied were small and may have been venules. Shasby et al. 5s described granular staining for IgG and C3 in medium-size blood vessel walls in the lung in two cases (as well as in apparently histologically normal alveolar walls). Although immunoglobulins and complement components have been r e p o r t e d to be p r e s e n t in tile glomeruli in some cases of Wegener's granulomatosis, they have generally been described as sparse or scattered. 59 In our experience only faint, focal staining for IgG, IgM, or C3 is found in glomeruli. Negative findings have been described by Mclntosh et al. 56 I m m u n o f l u o r e s c e n c e studies o f g r a n u l o m a s in Wegener's granulomatosis have apparently not been reported. Immunoglobulins and complement components have been detected in blood vessel walls in a few cases of vasculitis associated with rheumatoid arthritisY 5 Moreover, Nowoslawksi 6~ was able to demonstrate rheumatoid factor activity in vessel walls, through the reaction o f fluorescein labeled aggregated gamma

HUMAN PATHOLOGY

Volume t4, No. 4 (April -1983)

globulins with the deposits; this observation provides evidence for I g M - I g G complexes. Some reports dealing with vascular deposits in SLE have dealt with cutaneous vessels. 61'G2 Immunoglobulins and complement components, including C3, Clq, and the terminal attack component, C5-9, 62 have been demonstrated in the walls of small vessels, probably venules. Cases with necrotizing arteriolitis or arteritis in the kidney have shown either granular or homogeneous deposits of immunoglobulins and C3. 2~ A specimen of jejunum with venulitis showed C3 in vessel walls, but not IgG? s In two patients with SLE studied at autopsy, widespread granular deposits of IgG, IgM, and C3 were found in small blood vessels, apparently capillaries, venules, and arterioles, in all tissues examined. Is Although one o f those patients was described as having "necrotizing vascular inflammatory lesions" in several organs, it appears that the immune deposits were much more extensive than vasculitic lesions. Cutaneous small vessels in patients with mixed cryoglobulinemia have been shown to contain immunoglobulins o f the same classes as those present in the circulating cryoglobulins. ~3 Furthermore, rheumatoid factor activity has been demonstrated in glomerular deposits through reactivity of aggreated IgG. In addition, IgM eluted from a renal specimen showed rheumatoid factor activity. 6~ Specimens with cutaneous vasculitis have been much more widely studied by immunofluorescence than have other tissues. Early lesions from various forms of cutaneous vasculitis have generally been shown to contain immunoglobulins, c o m p l e m e n t components, and often fibrin. 65-6~ Lesions apparently older than 24 hours may show only fibrin. 6s In many cases IgM has been the only immunoglobulin class detected. 66 Immunoglobulin G has also been described, but in some series has been found in only a small percentage o f cases. 67 In Henoch-Sch6nlein purpura, IgA is the predominant or only immunoglobulin. ~2 It has also been described in some cases o f cutan e o u s vasculitis a p p a r e n t l y not associated with Henoch-Sch6nlein purpura, 6~ but in these instances other immunoglobulins are generally more conspicuous. It is not known whether there are differences in the immunofluorescence findings between the patients with neutrophil-rich infiltrates and those with lymphocyte-rich infiltrates, z Two lines of evidence indicate that the positive findings in cutaneous vasculitis are not simply the result of trapping o f circulating immune complexes in damaged vessels. First, studies on uninvolved skin have shown immunoglobulins and complement in apparently normal vessels. 66.6s Second, the selective accumulation o f certain immunoglobulin classes in many specimens, especially IgA in cases of HenochSch6nlein purpura, is difficult to explain on the basis of nonspecific trapping. The relative infrequency of the finding of IgG in many forms of cutaneous vasculitis is surprising and unexplained. Apparently, hepatitis B antigens are the only

3t0

antigens that have been convincingly demonstrated in lesions of vasculitis. However, in cases of rheumatoid arthritis or mixed cryoglobulinemia, the IgG that is sometimes detected may represent antigen combined with rheumatoid factor or anti-idiotypes. ~9 CIRCULATING IMMUNE COMPLEXES. T h e demonstration of immune complexes in the circulation has also been used as evidence of their pathogenetic importance in certain diseases. In the past decade, numerous assays have been developed for the detection of small amounts o f immune complexes in serum or other fluids (see V. Agnello, "The Use o f Immune Complex Assays in Rheumatic Diseases," on p. 343 of this issue). T h e various assays depend on different properties o f immune c o m p l e x e s , and no single assay detects all types o f immune complexes. Since aggregated Y globuIins produce positive results with virtually all the assays, the tests do not provide conclusive evidence of the presence o f immune complexes. Circulating immune complexes have been sought in a variety of diseases in which these substances are thought to play a key pathogenetic role, in particular in various forms of presumed immune complex glomerulonephritis. The results have been variable. T~ Circulating complexes have been found in most cases of active lupus nephritis and in many cases o f glomerulonephritis associated with bacterial endocarditis~ in contradistinction, in many forms o f chronic glomerulonephritis circulating complexes are frequently, even usually, absent. 4a Circulating immune complexes might be responsible for tissue deposits and yet escape detection if they are present only intermittently or if the methods used are inadequate to detect the relevant type of complex; in addition, immune complexes may be present in tissues but not found in the circulation if they rapidly deposit in tissues or if they form in situ. Conversely, the demonstration o f circulating immune complexes does not prove pathogenetic significance, since they have been found in numerous conditions without signs of vasculitis or glomerulonephritis. Even when circulating complexes are found in association with tissue deposits, the relationship may be uncertain; for example, DNA-containing complexes are of major importance in g l o m e r u l a r d e p o s i t s o f l u p u s nephritis, yet D N A - a n t i - D N A complexes apparently account for only a small percentage o f the circulating complexes. ~ In some cases, evidence of the relevance of the circulating complexes can be obtained by showing that certain properties o f circulating complexes are shared by those in the deposits; for example, in Henoch-Sch6nlein p u r p u r a both circulating complexes ~2 and deposits have been shown to contain IgA. F u r t h e r evidence o f this type is n e e d e d to strengthen the evidence for a pathogenetic role o f circulating immune complexes. Circulating immune complexes have-been reported to be present in some patients with vasculitis, but there are insufficient data concerning how often they are found in most categories. T3T h e r e appears to

VASCULIIIDES, GRANULOMATOSES, AND CONNECTIVETISSUEDISEASES(McCluskey & Fienberg}

be a high incidence of circulating immune complexes in patients with cutaneous vasculitisY "r4 Apparently only a few patients with periarteritis nodosa or Wegener's granulomatosis have been studied. (Among 400 references cited in a recent review, z~ neither disease was mentioned in the titles.) In some studies, immune complexes apparently have not been found in periarteritis nodosa, ~ whereas positive results lmve been recorded in a few cases in others, rS"r6 Circulating complexes are found in most patients with active SLE, but apparently their presence and levels have not been directly correlated with the development of vasculitisr~ it is clear that many patients lmve high levels of complexes without obvious evidence o f vasculitis (ahhougll deposits in glomeruli and small vessels may be abundant). There is evidence tlmt among patients with rheumatoid arthritis those with the highest levels o f I g M - I g G complexes are most likely to develop arteritis, rr By definition, all patients with mixed cryoglobulinemia lmve evidence of circulating immune complexes (since cryoimmunoglobulins are thought frequently to represent immune complexes). In most mixed cryoglobulins, IgM fimctions as the antibody, directed largely against determinants in the Fc portion of polyclonal lgG. The IgM reacts best with IgG ttmt has combined with antigen; therefore, "essential" mixed cryoglobulinemia may represent a condition in which IgM rheumatoid factor combines with immune complexes containing an antigen other than IgG. In some cases, hepatitis B products appear to represent such antigens. 7s Recently, evidence tlmt some of the IgM antibodies in mixed cryoglobulins may represent anti-idiotypes has been pl-esented. G9 Patients with vasculitis and hepatitis B infection lmve frequently been found to lmve circulating immune complexes (not only by detection o f cryoglobufins), and in some cases hepatitis antigens have been detected in the complexes/9 HVPOCOMPLE~IrNTE~nA. Hypocomplementemia, which is observed in patients with hypocomplementemic (urticarial) vasculitis, SLE, mixed cryoglobulinemia, and rheumatoid arthritis with vasculitis as well as in some patients with what is classified as periarteritis nodosa, provides indirect evidence of excessive consumption of complement components following activation by immune complexes. However, in some cases hereditary deficiencies of components may be responsible and may act as a predisposing factor in the development of vasculitis. 8~Furthermore, in some diseases o f unknown pathogenesis and diseases presumed to be mediated by immune complexes, impaired synthesis of complement develops. Other Mechanisms

Although there is abundant evidence that immune complexes can initiate vascular injury, other immunologic mechanisms (operating alone or in combination with immune complexes) can probably also contribute to or cause vasculitis. The IgE an_

311

tibodies may facilitate deposition o f circulating immune complexes in blood vessels through release of mediators from basophils and platelets, sl It has been proposed that T cells may trigger vasculitis by interaction o f sensitized lymphocytes with antigens localized in vessel walls, leading to a delayed-type hypersensitivity reaction, s2 Direct p r o o f o f this mechanism has apparently not been obtained in experimental models. However, some of the arterial lesions of acute serum sickness in rabbits are characterized by subendothelial collections of mononuclear cells, which suggests, but certainly does not prove, cell-mediated mechanisms. 39 Moreover, in certain rabbits with serum sickness granulomatous vascular lesions develop. 83 One mechanism o f granuloma formation is a delayed-type hypersensitivity reaction elicited by insoluble antigensS4; it is possible that the formation of immune complexes, especially in antibody excess, might serve to make antigens to which a person has cell-mediated reactivity insoluble, thereby triggering a granulomatous response. Whether immune complexes can evoke a granulomatous response without an associated delayed-type hypersensitivity c o m p o n e n t is not clear. Nonimmunologic meclmnisms can also lead to granuloma formation. As noted earlier, certain forms o f cutaneous vasculitis in man are characterized by a predominantly l y m p h o c y t i c i n f i h r a t e , z and it has been suggested this reflects cell-mediated mechanisms. However, histologic findings are not reliable guides to pathogenetic meclmnisms. It is hoped that the use of monoclonal antibodies with immunoperoxidase techniques, which permit the identification in frozen sections of surface antigens of T and B cell subsets as well as other mononuclear cells, will lead to fllrther insight into cellular mechanisms in vasculitis. By use of these techniques, it tins been found in human renal allografts that mononuclear cells invading blood vessels contain numerous T5/8 + cells, which supports a role o f cytotoxic T cells in the vascular injury, s5 Theoretically, cytolytic T cells might attack the host's own vascular cells if their surfaces were altered by viral infection or drugs. Nonimmunologic mechanisms apparently can also cause vasculitis, including necrotizing arteritis. T h u s , rats with experimental hypertension develop necrotizing arteritis; moreover, the vascular lesions have been shown to contain immunoglobulins 49 (as have human vascular lesions in malignant hypertensionSa). Hypertension may contribute to the vascular damage seen in some patients with SLE or periarteritis nodosa. Turkeys injected with Mycoplasma gallisepticisms6 develop severe cerebral arteritis, which appears to mediated by myoplasma toxins. Because o f the tmcertainties concerning pathogenetic mechanisms in vasculitis, it is not possible at present to construct a comprehensive classification based on such mechanisms. In cases in which immunoglobulins are detected in vessel walls (presumed immune complex), there are no distinctive patterns that lead to subclassifications such as those established

HUMAN PATHOLOGY

for glomerular diseases. Nevertheless, in certain conditions, findings relevant to pathogenesis may also be useful in classification and diagnosis, such as the finding of IgA in vascular deposits in l-lenoch-Sch6nlein purpura. CAUSATIVE FACTORS IN HUMAN VASCULITIS Causative factors in disease include predisposing conditions of the host, some of which are at least partly under genetic control, and etiologic agents, such as microorganisms or drugs. In most cases o f vasculitis, neither type of causative factor can be identified. There is evidence of the importance of genetic factors in SLE, rheumatoid arthritis, and other connective tissue diseases, obtained in part through association o f these diseases with certain HLA antigens. Evidence of similar associations in patients with idiopathic vasculitis apparently has not b e e n o b t a i n e d . H o w e v e r , s o m e patients with hereditary defects o f complement components, most often C2, develop "immune complex disorders" including vasculitis. 8~ Among etiologic agents, therapeutic drugs have been cited frequently as causes of vasculitis--~-in particular, periarteritis nodosa. In fact, in some reviews drugs are listed as a major cause o f periarteritis nodosa. This concept was apparently launched in a paper by Rich, s7 in which he reported that seven patients who had received sulfonamides were found at autopsy to have necrotizing arterial lesions. However, six of these patients had also received foreign serum, and on the basis o f the nature of the autopsy findings and the clinical features it seems likely that these patients died of the infectious process for which they were given serum and that in six patients, at least, the arterial lesions resulted from true serum sickness. Since then, a number of sporadic reports have linked certain drugs with periarteritis nodosa, but it is not clear that the drugs were causative. However, Citron et al. ss have reported convincing evidence that certain drug addicts develop necrotizing arteritis indistinguishable from periarteritis nodosa. Because the patients they studied had taken a number of drugs, the etiologic agent could not be identified with certainty; however, methamphetamine was considered a likely cause. The pathogenetic mechanisms were not elucidated. As far as we are aware, there is no experimental evidence that a drug can initiate necrotizing arteritis or necrotizing glomerulonephritis through an immune complex mechanisna, although it is theoretically possible that drug h a p t e n - h o s t conjugate could serve as an antigen in the formation of immune complexes. Although the evidence thht therapeutic drugs can .induce periarteritis nodosa is meager, at best, there is somewhat better evidence that drug reactions can lead to small vessel vasculitis, especially cutaneous vasculitis. ~-a However, only a" small percentage of cases appear to be drug induced. ~,z In a study of 30

Volume ,14, No. 4 (April ,1983}

patients considered to Imve drug hypersensitivity and vasculitis, pathologic evaluation revealed small vessel vasculitis either confined to the skin or involving a number o f sites, especially the liver and kidney. ~ O f particular interest was the absence of necrotizing arteritis or glomernlonephritis. Thus, tile lesions were strikingly different from those of periarteritis nodosa. The patients included in this study had taken a variety of therapeutic drugs; hypersensitivity was considered present principally because o f skin rash, eosinophilia, or unexplained fever; however, a causative role of the drug in the vasculitis was not rigorously established. Certain bacterial infections--such as pseudomonas infections, sometimes bacterial endocarditis, and, rarely, poststreptococcal glomerulonephritis--are associated with vasculitis. In bacterial endocarditis and poststreptococcal glomerulonephritis, it seems likely that immune complexes containing bacterial products initiate the vasculitis, but this has not been documented. Although there is compelling evidence that hepatitis B infection can cause wlrious forms of vasculitis and glomerulonephritis, apparently mediated by immune complexes, there is uncertainty about the frequency with which this oc(:urs. T h e most common form o f hepatitis B-associated vasculitis is seen in the serum sickness-like prodome of acute infection. 79 Complexes containing HBsAg have been found in the circulation, and inHnunoglobulins, C3, and HBsAg have been demonstrated in cutaneous vessel walls in association with venulitis. 79 Evidence has also been obtained that hepatitis B infection can produce necrotizing arteritis, leading to a condition mimicking periarteritis nodosa. 89 However, in some patients there is involvement of small vessels, including venules, and the lesions have been classified as hypersensitivity vasculitides or overlap syndromes. Thus, a single etiologic agent may produce diverse forms of vasculitis of varying severity, which indicates that a classification based on etiologic agents, were it possible, might not be satisfactory. Circulating complexes have been detected in some patients with hepatitis B infection and necrotizing arteritis, and hepatitis antigens have apparently been detected by immunofluorescence in vascular lesions in a few cases. 79 In a few series o f cases of "polyarteritis nodosa" or "systemic necrotizing vasculitis," 40 to 50 per cent of patients had circulating HBsAg. ~9 However, in some series of cases o f systemic vasculitis 9~ or Cutaneous vasculitis, 66 few or no patients had evidence of hepatitis B infection. Similarly discordant results have been reported concerning the frequency of hepatitis B infection in patients with "essential" mixed cryoglobulinemia and glomerulonephritis, rs'~ Further studies are needed to determine the importance of hepatitis B infection in these conditions in populations with high and low carrier rates. Furthermore, because of recent evidence that HBeAg, as well as HBsAg, is found in glomerular deposits in some cases of glomerulonephritis, 9~ further studies of vascular lesions employing 312

VASCULITIDES,GRANULOMATOSES,AND CONNECTIVETISSUEDISEASES(McCluskey & Fienberg)

well-defined antibodies against hepatitis antigens, especially ntonoclonal antibodies, are indicated.

CONCLUSION For many reasons it is impossible to construct an entirely satisfactory classification of vasculitides based on pathologic features, or pathogenetic mechanisms, or etiologic agents. Nevertheless, tire recognition that cyclophosphamide therapy frequently prevents progression of life-threatening manifestations of Wegener's granulomatosis31 and periarteritis nodosa ~ has increased the importance of correct classification and diagnosis. We have emphasized the importance of recognizing that the lesions of Wegener's granulomatosis are not confined to blood vessels and that tire diagnosis can often be established by the finding of characteristic extravascular grannlomas. In contradistinction to periarteritis nodosa or Wegener's granulontatosis, most cases of small vessel vasculitis, which are ttsually tnanifested by cutaneous vasculitis, are not associated witlt serious visceral involvement and do not tlaerefore require cytotoxic therapy. With respect to pathogenesis, the evidence of a role of imntune complexes is fairly substantial (althongh not absolute)in certain forms of vascu!itis, notably in many forms of cutaneous vasculitis, in mixed cryoglobulinemia, and in the vasculitides sometimes associated with hepatitis B infection, SLE, or rheumatoid arthritis. On the other hand, evidence of a role of itnmune complexes in periarteritis nodosa attd Wegeuer's grannlomatosis is itaconclnsive. Part of the uncertainty stems from the difficulty in obtaining appropriate specimens. A more important problem is that at the moment there appears to be no feasible way of demonstrating antigens or specific antibodies in the lesions. As in experimental models, evidence derived from studies of hnman diseases, including the connective tissue diseases, indicates that immnne complexes can prodnce a wide spectrum o f vascular lesions, which affect different types o f vessels (venules and small or medium-size arteries) and have different patterns of distribution among tissues. There is almost no information concerning the properties of the complexes or of host factors that account for these different manifestations. Ttte importance of cellm e d i a t e d m e c h a n i s m s and o f n o n i m m u n o l o g i c mechanisms remains to be elucidated. Little is known of causative agents in the vasculitides and related granulomatosis. There is virtually no evidence to support the widely held belief that therapeutic drugs can cause periarteritis nodosa or account for more than a miniscule fraction o f cases of small vessel vasculitis. The importance of hepatitis B infection as a cause of vasculitis remains to be evaluated, but the suggestion that it is a major cause o f serious vasculitis appears to be a gross" exaggeration.

REFERENCES 1. Soter NA: Clinical presentations and mechanisms of necrotizing angiitis of the skin. J Invest Dermatol 67:354, 1976

2. Soter NA, Mihm big Jr, Gigli I, et al: Two distinct celhdar patterns in cutaneous necrotizing angiitis. J Invest Dermatol 66:344, 1976 3. Mullick FG, McAIlister t l A J r , Wagner BM, et al: Drug-related vasculitis: clinicopathologic correlations in 30 patients. I lum Pathol 10:313, 1979 4. Zeek PM: Periarteritis nodosa and other forms of necrotizing angiitis. New Engl J Med 248:764, 1953 5. Cupps TR: Hypersensitivity vasculitis. In Cupps TR, Fauci A (eds): Tile Vasculitides. Philadelphia, WB Saunders Co, 1981, chapter 5 6. Davson J, Ball J, Platt R: The kidney in periarteritis nodosa. Q J Med 17:175, 1948 7. McDuffie FC, Sams WM, Maldonado JE, et al: Hypocomplementemia with cutaneous vasculltis and arthritis. Mayo Clin Proc 48:340, 1973 8. Sissons JGP, Peters DK, Williams DG, et al: Skin lesions, angio-oedema, and hypocomplementemia. Lancet 2:!350, 1974 9. Feig PU, Soter NA, Yager HM, et al: Vasculitis with urticaria, hypocomplemeutemia, and muhiple system involvement. J Am Assoc Med 236:2085, 1976 I0. Schwartz IIR, McDuffie FC, Black LF, et al: ttypocomplementemic urticarial vasculitis: association with chronic obstructive t)uhuonary disease. Mayo Clin Proc 57:231, 1982 11. Phanuphak P, Kohler PF, Stanford RE, et al: Value of skin biopsy in vasculitis. Clin Res 26:123A, 1978 12. Baart de la Faille-Kuyper Eli, Kater L, Kooicher CJ, et al: IgA deposits in cutaneous blood-vessel walls and mesangium in Henocb-Schonleio purpura. Lancet 1:892, 1973 13. Mehzer M, Franklin EC, Elias K, et al: Cryoglobulinemia: a clinical and laboratory stud).. II. Cryoglobulins with rheumatoid factor activity. Am J Med 40:837, 1966 14. Glass D, Soter NA, Schur PH: Rheumatoid vasculitis. Arthritis Rheum 19:950, 1976 15. Brentjens J, Ossi E, Albiui B, et al: Disseminated immune deposits in lupus erythematosus. Arthritis Rheum 20:962, 1977 16. Estes D, Christian CL: The natural history of systemic lupus erythematous by prospective analysis. Medicine 50:85, 1971 17. Mintz G, Fraga A: Arteritis in systemic lupus erythematosus. Arch Intern Med 116:55,' 1965 18. Weiser MM, Andres GA, Brentjens JJ, et al: Systentic lupus erythematosns and intestinal vasculitis. Gastroenterology 81:570, 1981 19. Johnson RT, Richardson EP: The neurological manifestations ofsytemic lupus eD'thenmtosus: a clinical-pathological study of 24 cases and review of the literature. Medicine 47:337, 1968 20. Baldwin DS, Gallo G: Lupus nephritis. Clin Rheum Dis 1:639, 1975 21. Klemperer P, Pollack AD, Baebr G: Pathology ofdisseminated lupus erythematosus. Arch Pathol 32:569, 1941 22. Sclnnid FR, Cooper NS, Ziff M, et al: Arteritis in rheumatoid arthritis. Am J Med 30:56, 1961 23. Sokoloff L, Wilens SL, BunimJJ: Arteritis of striated muscle in rheumatoid arthritis. Am J Pathol 27:157, 1951 24. Bywaters EGL: Peripheral vascular obstruction in rheumatoid arthritis and its relationship to other vascular lesions. Ann Rheum Dis 16:84, 1957 25. Conn DL, McDuffie FC, Dyck PJ: lmmunopathologic study of sural nerves in rheumatoid arthritis. Arthritis Rheum 15:135, 1972 26. Ball J: Rheumatoid arthritis and polyarteritis nodosa. Ann Rheum Dis 13:277, 1954 27. Wegener F: Ober eine eigeoartiger rhinogene Granulomatose mit besonderer Beteiligung des Arterien Systems und der Nieren. Beitr Pathol Anat 102:36, 1939 28. Fienberg P,: Pathergic granulomatosis (editorial). Am J Med 19:829, 1955 29. Wegener F: About the so-called Wegener's granulomatosis with special reference to the generalized vascular lesions. Morgagni 1:5, 1968 30. Fienberg R: T h e protracted superficial p h e n o m e n o n in

313

HUMAN PATHOLOGY

31. 32. 33.

34. 35. 36. 37. 38. 39.

40. 41.

42.

43. 44. 45. 46. 47.

48. 49. 50. 51.

52. 53. 54. 55. 56. 57.

Volume 14, No. 4 (April t983)

pathergic (Wegener's) granulo,natosis, ttum Pathol 12:458, 1981 Wolff SM, Fauci AS, Horn RG, et al: Wegener's granulomatosis. Ann Intern Med 81:513, 1974 Fanci AS, Wolff SM: Wegener's granulomatosis and related diseases. I)M 23:1, 1977 Fienberg R: Necrotizing grannlomatosis and angiitis of the hmgs with massive splenic necrosis and focal thrombotic granulomatous glomerulonephritis. Am J Clin Pathol 23:413, 1953 Walton EW: Giant-cell granuloma of the respiratory tract (Wegener's granulomatosis). Br Med J 2:265, 1958 Churg J, Strauss L: Allergic granulomatosis, allergic angiitis and periarteritis nodosa. Am J Pathol 27:277, 1951 Rose GA, Spencer H: l'olyarteritis nodosa. Q j Med 26:43, 1957 Chumbley LC, ttarrison EG, DeRemee RA: Allergic granulomatosis and angiitis (Churg-Strauss syndrome): report and analysis of 30 cases. Mayo Clin Proc 52:477, 1977 Fanci AS: Vasculitis. in Parker CW (ed): Clinical Immunology. l~hiladerphia, WB Saunders Co, 1980, p 473 Leber PD, McCluskey RT: hnmune complex diseases. In Zweifach BW, Grant L, McCluskey RT (eds): The Inflammatory Process, 2nd Ed, vol 3. New York, Academic Press, 1974, p 401 Dixon l:J, VazquezJJ, Weigle WO, et al: Pathogenesis of serum sickness. Arch Pathol 65:18, 1958 Dixon FJ, Feldman J D, Vazquez J J: Experimental glomerulonephritis: the patlmgenesis of a laboratory model resembling the spectrum of human glomerulonephritis. J Exp Med 113:899, 1961 Brentjens JR, O'Connell DW, Albini B, et ali Experimental chronic serum sickness in rabbits that received daily multiple and high doses of antigen: a systemic disease. Ann NY Acad Sci 254:603, 1975 Christian CL, Sergent JS: Vasculitis syndromes: clinical and experimental models. Am J Med 61:385, 1976 Cochrane CG: Mechanisms involved in the deposition of immune complexes in tissues. J Exp Med 134:75s, 1971 Germuth FG Jr, Heptinstall RtI: The development of arterial lesions following prolonged sensitization to bovine gamma globulin. Bull Johns Hopkins Hosp 100:58, 1957 Couser WG, Salant DJ: In situ immune complex formation and glomerular injury. Kidney Int 17:1, 1980 McCluskey RT, Benacerraf B: Localization of colloidal substances in vascular endotbelium: a mechanism of tissue damage. II. Experimental serum sickness with acute glomerulonephritis induced passively in mice by antigen-antibody complexes in antigen excess. AmJ Patho135:275, 1959 McCluskey RT, Bhan AK: Immune complexes and renal diseases. Clin hnmunol Allergy 1:397, 1980 Ohta G, Cohen S, Singer EJ, et al: Demonstration of gamma globulin in vascular lesions of experimental necrotizing arteritis in the rat. Proc Soc Exp Biol Med 102:187, 1959 Koffler D, Agnello V, Thoburn R, et al: Systemic lupus erythematosus: prototype of immune complex nephritis in man. J Exp Med 134:169s, 1971 Mellors RC, Ortega LG: Analytical pathology. III. New observations on the pathngenesis of glomerulonephritis, lipid nephrosis, periarteritis nodosa and secondary amyloidosis in man. Am J Pathol 32:455, 1956 Freedman P, Peters JH, Kark RM: Localization of gamma globulin in the diseased kidney. Arch Intern Med 105:524, 1960 Paronetto F, Strauss L: Immunocytochemical observations in periarteritis nodosa. Ann Intern Med 56:289, 1962 Bnrkholder P: Immunology and immunohistopathology of renal diseases. In Becker EL (.ed): Structural Basis of Renal Disease. New York, Harper ~ind Row, 1968, p 211 Williams RC Jr: Immune Complexes in Clinical and Experimental Medicine. Cambridge, ttarvard University Press, 1980, p 231 Mclntosh RM, Tinglof B, Kaut'man D, et al: Immunohistology in renal disease. Q J Med 40:385, 1971 Hu CH, O'Loughlin S, Winkelmann RK: Cutaneous manifes-

58. 59. 60.

61. 62. 63. 64.

65. 66.

67. 68.

69. 70. 71.

72. 73. 74. 75. 76. 77.

78. 79. 80. 81.

314

tations of Wegener's granulomatosis. Arch Dermatol 113:175, 1977 Shasby DM, Schwarz MI, Forstot JZ, et al: Pulmonary immune complex deposition in Wegener's granulomatosis. Chest 81:338, 1982 Balow J, Antonovych T, Fauci AS, et al: The nephritis of Wegener's granulomatosis. Kidney Int 14:706(abs), 1978 Nowoslawski A: hnmunopathological features of rheumatoid arthritis. In Muller W, Harverth HG, Fehr K (eds): Rheumatoid Arthritis. New York, Academic Press, 1971, p 325 Tan EM, Kunkel HG: An immunofluorescent stud)' of the skin lesions in systemic lupus erythematosus. Arthritis Rheum 1:37, 1966 Biesecker G, l.avin L, Siskind M, et al: Cutaneous localization of the membrane attack complex in discoid and systemic lupus erytbematosis. N Engl J Med 306:264, 1982 Gianetti A, Serri F, Bernasconi C: hmnunofluorescent studies of the skin in mixed cryoglobulinemia and SchonleinHenoch purpura. Acta Dermatovener 56:211, 1976 Maggiore Q, Bartolomeo A, L'Abbate A, et al: Glomerular localization of circulating antiglobulin activity in essential mixed cryoglobulinenfia with glomerulonephritis. Kidney Int 21:387, 1982 Schroeter AL, Copeman PWM, Jordan RE, et al: hnmunofluorescence of cutaneous vasculitis associated with systemic disease. Arch Dermatol 104:254, 1971 Sams WM, Claman HN, Kohler PF, et al: lluman necrotizing vasculitis: immunoglobulins'and complement in vessel walls of cutaneous lesions and normal skin. J Invest Dermatol 64:441, 1975 Mackel SE, Tappeiner G, Brumfield H, et al: Circulating immune complexes in cutaneous vasculitis. J Clin Invest 64:1652, 1979 Braverman IM, Yen A: Demonstration of immune complexes in spontaneous and lfistamine-induced lesions and in norreal skin of patients with leucocytoclastic angiitis. J Invest Dermatol 64:105, 1975 Geltner D, Franklin .EC, Frangione B: Antiidiotypic activity in the IgM fractions of mixed cryoglobulins. J Immunol 125: 1530, 1980 Theofilopoulos AN: Evahmtion and clinical significance of circulating immune complexes. Prog Clin hmnunol 4:63, 1980 Izui S, Lambert PH, Miescher PA: Failure to detect circulating DNA-anti-DNA complexes by four radioimmunological methods in patients with systemic lupus erythematosus. Clin Exp Immnnol 30:384, 1977 Levinsky RJ, Barrat TM: IgA immune complexes in HenochSchonlein purpura. Lancet 2:1100, 1979 Pussell BA, Scott DM, Lockwood CM, et al: Value of immtme-complex assays in diagnosis and management. Lancet 2:359, 1978 Kammer GM, Soter NA, Schur PJ: Circulating immune colnplexes in patients with necrotizing vasculitis. Clin Immunol humunopathol 15:658, 1980 Phauuphak P, Kohler PF, McIntosh et al: Polyarteritis nodosa: a distinct or an overlap vasculitis? Clin Res 26:123A, 1978 Abuelo JG, Druet P: Circulating immune complexes in the general hospital population and in patients who have renal disease. Am J Clin Pathol 73:547, 1980 Onyewotu II, Johnson PM, johnson GD, et al: Enhanced uptake by guinea-pig macrophages of radio-iodinated human aggregated immunoglobulin G in the presence ofsera from rheumatoid patients with cutaneous vasculitis. Clin Exp Immunol 19:267, 1975 Levo Y, Gorevil PD, Kassab HH, et al: Association between hepatitis B virus and essential mixed cryoglobulinemia. N Engl J Med 296:1501, 1977 DieustagJL: Hepatitis B as an immune complex disease. Semin Liver Dis 1:45, 1981 Agnello J: Complement deficiency states. Medicine 57:1, 1978 Henson PM, Cochrane CG: Acute immune complex disease in rabbits: the role of complement and of a leukocyte-

VASCULITIDES,GRANULOMATOSES,AND CONNECTIVETISSUEDISEASES(McCluskey & Fienberg}

82. 83. 84.

85. 86.

dependent release of vasoactive amines from platelets.J Exp bled 133:554, 1971 Fauci AS, Haynes BF, Katz P: The spectrum of vasculitis: clinical, pathologic and therapeutic considerations. Ann Intern bled 89:660, 1978 Germuth FG, Pollack AD: Immune complex disease. III. The granulomatous manifestations. Johns Hopkins bled J 121:254, 1967 Ginsburg C, blcCluskey RT, Nepon JT, et al: Antigen and receptor-driven regulatory mechanisms. X. The induction and suppression of hapten-specific granulomas. AmJ Pathol 106:421, 1982 Bhan AK, Colvin RB, Cosimi B, et al: Nature of cellular infiltrate in renal allograft rejection. Kidney Int 21:293(abs), 1982 Thomas L, Davidson hi, blcCluskey RT: Studies of PPLO infection. I. The production of cerebral polyarteritis by Mycoplasma gallisepticuns in turkeys: the neurotoxic property of the mycoplasma. J Exp bled 123:897, 1966

315

87. Rich AR: Role of hypersensitivity in periarteritis as indicated by 7 cases developing during serum sickness and sulfonamide therapy. Bull Johns Hopkins Hosp 7 I: 123, 19-12 88. Citron P, Halpern M, McCarron hi, et al: Necrotizing anglitis associated with drug abuse. N Engl J bled 283:1003, 1970 89. Sergent JS, Lockshin MD, Christian CL, et al: Vasculitis with hepatitis B antigenemia. Medicine 55:1, 1976 90. Cohen RD, Conn DL, llstrup DM: Clinical features, prognosis and response to treatment in polyarteritis. Mayo Clin Proc 55:146, 1980 91. PoppJW, DienstagJL, Wands JR, et al: Essential mixed cryoglobulinemla without evidence for hepatitis B virus. Ann Intern bled 92:379, 1980 92. Collins AB, Bhan AK, DienstagJC, et al: Hepatitis B immune complex glomerulonephritis: simultaneous glomerular deposition of hepatitis B surface and E antigens. Clin Immunol lmmunopathol 26:137, 1983 93. Fauci AS, Katz P, Haynes BF, et al: Cyclophosphamide therapy of severe systemic necrotizing vasculitis. N Engl J bled 301:235, 1979