867
VAS CULITIS MICHAEL D. LOCKSHIN, M.D. Department of Medicine The Hospital for Special Surgery New York, New York
V ASCULITIS is a descriptive term, not a diagnosis. It may denote specific findings in a histologic specimen, a clinical syndrome common to many diseases, or a single illness. I shall try to place the concept of vasculitis in a usable context and to review data supporting some of the proposed causes and mechanisms. Definition. Necrosis of a blood vessel wall is the defining criterion of vasculitis. Perivascular lymphocyte "cuffing" is insufficient for this diagnosis. The nature and size of the vessel and the simultaneity of lesions are loosely related to the clinical syndrome, with broad overlap. Inflammatory infiltrates in and about the vessel wall classify the illness but are not necessary for diagnosis. Clinical features, such as asthma and eosinophilia, are overrated in their importance. Classification. At present no standard classification for vasculitis, morphologic or clinical, exists. Most investigators temper morphologic facts with clinical judgement to reach a consensus clinicopathologic recognition of major types. My own classification follows these lines and derives from personal experience (Table I). Type A-i polyarteritis nodosa type. In this common form of vasculitis, small and medium-sized arterioles have an acute necrotizing lesion, and an intense polymorphonuclear cell infiltrate surrounds and invades all layers of the blood-vessel wall. Aneurysms, cutaneous infarcts, nasal and palatal ulcers, and leg ulcers occur.1'2 The lesion is nonspecific: it occurs in patients with the separate diagnoses rheumatoid arthritis, systemic lupus erythematosus, cryoglobulinemia, Wegener's granulomatosis, and other illnesses. Visceral disease of varying patterns is often but not invariably present. When there is no apparent associated disease, and when the vasculitis dominates as a clinical feature, the illness is called periarteritis nodosa. Presented before the Section on Medicine of the New York Academy of Medicine April 22, 1979. Address for reprint requests: Department of Medicine, The Hospital for Special Surgery, 535 East 70th Street, New York, N.Y. 10021.
Vol. 55, No. 9, October 1979
M. D. LOCKSHIN
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Bull. N.Y. Acad. Med.
VASCULITIS
869
869
Type A-2 leukocytoclastic (cutaneous) vasculitis. By definition, this manifestation of vasculitis is dermatologic, but visceral disease may occur. Recent ultrathin section studies demonstrate3'4 that the inflammatory lesion occurs in the postcapillary venule; that when the inflammatory infiltrate is leukocytic, hypocomplementemia is present; and when the infiltrate is lymphocytic the patient usually has normal complement levels. This type of vasculitis occurs either alone (cutaneous vasculitis) or in the presence of Sjogren's syndrome, rheumatoid arthritis, periarteritis nodosa, Wegener's granulomatosis, and systemic lupus erythematosus. The lesion is characteristic of Henoch-Schoenlein purpura and vasculitis with cryoglobulinemia. Soter and co-workers suggest that the normocomplementemic, lymphocyte-infiltrate form predominates in patients with rheumatoid arthritis and cryoglobulinemia because C4 binding protein, which permits C3b inactivator to function, is quantitatively greater in these patients.3 The clinical appearance of leukocytoclastic angiitis includes minute hemorrhagic infarcts, often in the legs, or urticaria. Visceral disease is uncommon in patients with no associated illness. However, in individual patients the periarteritis nodosa type (A-1) vasculitis and leukocytoclastic angiitis can and do coexist. Type B. Noninflammatory vasculitis. Noninflammatory vessel wall necrosis of arterioles is characteristic of systemic sclerosis. Similar findings occur in malignant hypertension and pre-eclampsia. Visceral disease, especially renal and cerebral, predominates. Periungual telangiectasia, Raynaud's phenomenon, and occasionally digital gangrene are the only cutaneous findings. Type C. Large vessel disease. Large vessel vasculitis is much more uniform in its clinical presentation: polymyalgia rheumatica, temporal arteritis, and pulseless disease. Overlap, clinical or pathologic, with other types of vasculitis is extremely uncommon. The large vessel disease of relapsing polychondritis is similarly quite distinctive. Type D. Microscopic (capillary) vasculitis. The microscopic forms of vasculitis have not been definitively described. The clinical presentation is that of a systemic illness, with or without cutaneous manifestations. Visceral disease, such as renal, may predominate. There may be some overlap with Type A.2 Type A is the commonest form of vasculitis, the one most studied, and the one most commonly implied by the general term vasculitis. We shall concentrate only on this type.
Vol. 55, No. 9, October 1979
87087
M. D. LOCKSHIN M. D.LCSI
ETIOLOGY AND PATHOGENESIS
Although toxic and genetic factors participate in some forms of vasculitis, submicrobial infectious agents are the most likely initial causes of vasculitis. Infectious agents. Several animal models of vasculitis are either due to or closely associated with infection. Lymphochoriomeningitis virus infection of neonatal mice results in a chronic vasculitis.5 (Postnatal infections cause meningitis.) Equine arteritis virus causes vasculitis in horses,6 probably by direct invasion of the artery wall. Aleutian disease virus causes vasculitis in mink.7 Mycoplasma gallisepticum causes arteritis in turkeys.8 A protozoan, Nosema cuniculi, induces epidemic arteritis in foxes.9 Immunologic amplification of the viral lesion is likely in some instances, and is almost certainly absent in others. In man, evidence is circumstantial but suggestive. Some patients develop periarteritis nodosa following presumably infectious serous otitis media.10 A sizeable minority of periarteritis nodosa patients have chronic hepatitis B (HB) antigenemia.1'1.2 In one dramatic case, an HB negative patient received a blood transfusion subsequently shown to have contained infectious HB. This patient became HB positive, then developed periarteritis nodosa, and later clinical hepatitis.13 HB virus has been identified by immunologic means and by electron microscopy in immune complexes and in the blood-vessel walls. 13 Unexplained, periarteritis nodsa occurs in a small minority of HB antigen carriers. Quantitation of virus, serotype, concatenation of antigen appearance, and immunogenetic constitution of the patients have failed to identify those most likely to develop periarteritis when infected with HB. 1 1 Toxic agents. Administration of noninfectious agents has induced vasculitis in animals and man. In some instances nonimmunologic vascular injury can be postulated. These include deoxycorticosterone and alloxan diabetes vasculitis in rats14 and in man, vasculitis of amphetamine users;15 a recent case report suggested a toxic or allergic vasculitis induced by an intravenous vitamin preparation.16 Genetic. Although lymphocytic choriomeningitis virus vasculitis in mice may have genetic determinants,17 only weak evidence currently suggests that human susceptibility to vasculitis is genetically determined. Glass and co-workers claimed a loose association of HLA All, BW3 with leukocytoclastic angiitis;18 a similar association of HLA B5 with Takayasu arteritis exists.19 Bull. N.Y. Acad. Med.
871
VASCULITIS
VASCULITIS
TABLE II. HEPATITIS ANTIGENS AND CIRCULATING IMMUNE COMPLEXES (CIC) IN HB-PAN (DR. R. INMAN) CIC by Serum HB reactants SBA * CIC HB reactants Patient HBAG HBAB HBCAB Eag Eab mg.Iml. HBAg HBSAb HBCAb CAg AGG cpm cpm cpm cpm
SW Me Ma
By Fo
NHSt
4,924 19,793 12,053 6,524 6,437
120 118 89 136 114
+ +
+ +
+ + +
233
105
0
+ + +
0 0 0 0 0
400 245 175 95 150
7,909 3,515 1,175 2,101
140 137 147 163 156
0
0
5
331
130
4,924
0 0 0
0
0 0 0 0 0
0
0
+
*Staphylococcus A binding assay tNormal human serum
Immunologic. Experimental serum sickness and the frequent though inconsistent demonstration of components of immunologic injury (antigen, complement, and immunoglobulin) at the site of vascular injury lend weight to the hypothesis that vasculitis is immunologically mediated.1'13'20 This has been the subject of recent reviews.' While these data are the strongest to date, it is important to note that the clotting system is simultaneously activated;21 immunologic parameters only partially reflect clinical activity of illness; and the focal nature of vasculitis is not easily explained by immunological mechanisms. In a current series of five well-studied HB-periarteritis nodosa patients, Dr. Robert Inman at our hospital has demonstrated the consistent presence of HBs antigen, HB, antibody, and e antigen in the serum, and the absence of HBs antibody and e antibody despite the clinical variability of disease activity. All patients had circulating immune complexes present, as identified by a noncomplement dependent assay (Staphylococcus A protein binding). The eluted complexes all contained HB, antigen, one contained HB, antibody, and none contained HB, antibody or e antigen (Table II). Other immunologic studies of these and other patients revealed normal lymphocyte responses in remission and in one patient a dramatic IgA rather than IgG anti-HB. Other authors have had somewhat different results. One patient with HB-periarteritis nodosa and five with other vasculitis studied by antibody-dependent cell-mediated cytotoxicity and Raji cell immune complexes had illness activity correlate with positive assays.22 Clq binding and electron microscopy of cryoprecipitate indentiVol. 55, No. 9, October 1979
872
M. D. LOCKSHIN
fied immune complexes in another series.23 Rate-zonal density gradient centrifugation immune complexes did not correlate with HB-periarteritis nodosa,24 but the same author felt that clumped particles in sera did reflect active vasculitis.25 These findings suggest more questions than they answer. Ten years have passed since the first demonstrations of the intimate relation of HB and periarteritis. That decade produced the major advance linking some rheumatic diseases to patient genotype, but it leaves still mysterious the precise way by which one specific virus interacts with a susceptible host to produce a specific, uncommon illness, necrotizing vasculitis (PAN). The clues remain an open challenge to us all.
1.
2.
3.
4.
5.
6.
7.
REFERENCES ter, H. G.: The pathogenesis of Aleutian Christian, C. L. and Sergent, J. S.: Vasdisease of mink. III. Immune complex culitis syndromes: Clinical and experimental models. Am. J. Med. 61:385, arteritis. Am. J. Pathol. 71:331, 1973. 8. Thomas, L., Davidson, M., and 1976. McCluskey R. T.: Studies of PPLO inTravers, R. L., Allison, D. J., Brettle, fection. I. The production of cerebral R. P., et. al.: Polyarteritis nodosa: A polyarteritis by mycoplasma gallisepticlinical and angiographic analysis of 17 cases. Semin. Arthritis Rheum. 8:184, cum in turkeys: The neurotoxic property 1979. of the mycoplasma. J. Exp. Med. 123:897, 1966. Soter, N. A., Austen, K. F, and Gigli, 9. Nordstoga, K., and Westbye, K.: I.: The complement system in necrotizPolyarteritis nodosa associated with ing angiitis of the skin. Analysis of nosematosis in blue foxes. Acta Pathol. complement component activities in Microbiol. Scand. 84:291, 1976. serum of patients with concomitant collagen-vascular disease. J. Invest. 10. Sergent, J. S. and Christian, C. L.: Necrotizing vasculitis after acute serous Dermatol. 63:219, 1974. otitis media. Ann. Int. Med. 81:195, Soter, N. A., Mihm, M. C., Gigli, I., et 1974. al.: Two distinct cellular patterns in cutaneous necrotizing angiitis.J. Invest. 11. Sergent, J. S., Lockshin, M. D., Christian, C. L., et al.: Vasculitis with Dermatol. 63:344, 1976. hepatitis B antigenemia: Long-term obOldstone, M. B. A. and Dixon, F. J.: servations in nine patients. Medicine Pathogenesis of chronic disease associ(Baltimore) 55:1, 1976. ated with persistent lymphocytic choriomeningitis viral infection. II. Re- 12. Trepo, C. and Thivolet, J.: Antigene australien, hepatite i virus et periarterite lationship of the antilymphocytic noueuse. Presse Med. 78:1575, 1970. choriomeningitis immune response to tissue injury in chronic lymphocytic 13. Gocke, D. J., Hsu, K., Morgan, C., et al.: Association between polyarteritis choriomeningitis disease. J. Exp. Med. and Australia antigen. Lancet 2:1149, 131:1, 1970. 1970. Estes, P. C. and Cheville, N. F.: The ultrastructure of vascular lesions in 14. Wexler, R. C.: Polyarteritis nodosa induced in arteriosclerotic male and female equine viral arteritis. Am. J. Pathol. breeder rats by alloxan diabetes. Paroi 58:235, 1970. Arterielle (Paris) 2:221-39, 1975. Porter, D. D., Larsen, A. E., and PorBull. N.Y. Acad. Med.
VASCULITIS
15. Citron, B. P., Halpern, M., McCarron, M., et al.: Necrotizing angiitis associated with drug abuse. N. Engl. J. Med. 283: 1003, 1970. 16. Perillo, R. P., Tedesco, F. J., and Wise, L.: The role of additives in allergic vasculitis during intravenous hyperalimentation. Digest Dis. 20:1191, 1975. 17. Oldstone, M. B. A., Dixon, F. T., Mitchell, G. F, etal.: Histocompatibility-linked genetic control of disease susceptibility. Murine lymphocytic choriomeningitis virus infection. J. Exp. Med. 137:1201, 1973. 18. Glass, D., Soter, N. A., Gibson, D., et al.: Association between HLA and cutaneous necrotizing vasculitis. Arthritis Rheum. 19:945, 1976. 19. Naito, S., Arakawa, K., Saito, S., et al.: Takayasu's disease: Association with HLA-B5. Tissue Antigens 12:143, 1978. 20. Conn, D. L., McDuffie, F. C. Holley, K. E., et al.:. Immunological mechanisms in systemic vasculitis. Mayo Clin. Proc. 51:511, 1976.
Vol. 55, No. 9, October 1979
873
21. Sun, N. C. J., Conn, D. L., Schroeter, A. L., et al.: Skin fibrinolytic activity in cutaneous and systemic vasculitis. Mayo Clin. Proc. 51:216, 1976. 22. Fye, K. H., Becker, M. J., Theophilopoulos, A. N., et al.: Immune complexes in hepatitis B antigen-associated periarteritis nodosa. Am. J. Med. 62:783, 1977. 23. Gower, R. G., Sausker, W. F, Kohler, P. F., et al.: Small vessel vasculitis caused by hepatitis virus immune complexes. J. Allergy Clin. Immunol. 62:222, 1978. 24. Prince, A. M. and Trepo, C.: Role of immune complexes involving SH antigen in pathogenesis of chronic active hepatitis and polyarteritis nodosa. Lancet 1:1309, 1971. 25. Trepo, C. G., Zuckerman, A. J., Bird, R. C., et al.: The role of circulating hepatitis B antigen/ antibody immune complexes in the pathogenesis of vascular and hepatic manifestations in polyarteritis nodosa. J. Clin. Pathol. 27: 863, 1974
VAS CULITIS MICHAEL D. LOCKSHIN, M.D. Department of Medicine The Hospital for Special Surgery New York, New York
V ASCULITIS is a descriptive term, not a diagnosis. It may denote specific findings in a histologic specimen, a clinical syndrome common to many diseases, or a single illness. I shall try to place the concept of vasculitis in a usable context and to review data supporting some of the proposed causes and mechanisms. Definition. Necrosis of a blood vessel wall is the defining criterion of vasculitis. Perivascular lymphocyte "cuffing" is insufficient for this diagnosis. The nature and size of the vessel and the simultaneity of lesions are loosely related to the clinical syndrome, with broad overlap. Inflammatory infiltrates in and about the vessel wall classify the illness but are not necessary for diagnosis. Clinical features, such as asthma and eosinophilia, are overrated in their importance. Classification. At present no standard classification for vasculitis, morphologic or clinical, exists. Most investigators temper morphologic facts with clinical judgement to reach a consensus clinicopathologic recognition of major types. My own classification follows these lines and derives from personal experience (Table I). Type A-i polyarteritis nodosa type. In this common form of vasculitis, small and medium-sized arterioles have an acute necrotizing lesion, and an intense polymorphonuclear cell infiltrate surrounds and invades all layers of the blood-vessel wall. Aneurysms, cutaneous infarcts, nasal and palatal ulcers, and leg ulcers occur.1'2 The lesion is nonspecific: it occurs in patients with the separate diagnoses rheumatoid arthritis, systemic lupus erythematosus, cryoglobulinemia, Wegener's granulomatosis, and other illnesses. Visceral disease of varying patterns is often but not invariably present. When there is no apparent associated disease, and when the vasculitis dominates as a clinical feature, the illness is called periarteritis nodosa. Presented before the Section on Medicine of the New York Academy of Medicine April 22, 1979. Address for reprint requests: Department of Medicine, The Hospital for Special Surgery, 535 East 70th Street, New York, N.Y. 10021.
Vol. 55, No. 9, October 1979
M. D. LOCKSHIN
868
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Bull. N.Y. Acad. Med.
VASCULITIS
869
869
Type A-2 leukocytoclastic (cutaneous) vasculitis. By definition, this manifestation of vasculitis is dermatologic, but visceral disease may occur. Recent ultrathin section studies demonstrate3'4 that the inflammatory lesion occurs in the postcapillary venule; that when the inflammatory infiltrate is leukocytic, hypocomplementemia is present; and when the infiltrate is lymphocytic the patient usually has normal complement levels. This type of vasculitis occurs either alone (cutaneous vasculitis) or in the presence of Sjogren's syndrome, rheumatoid arthritis, periarteritis nodosa, Wegener's granulomatosis, and systemic lupus erythematosus. The lesion is characteristic of Henoch-Schoenlein purpura and vasculitis with cryoglobulinemia. Soter and co-workers suggest that the normocomplementemic, lymphocyte-infiltrate form predominates in patients with rheumatoid arthritis and cryoglobulinemia because C4 binding protein, which permits C3b inactivator to function, is quantitatively greater in these patients.3 The clinical appearance of leukocytoclastic angiitis includes minute hemorrhagic infarcts, often in the legs, or urticaria. Visceral disease is uncommon in patients with no associated illness. However, in individual patients the periarteritis nodosa type (A-1) vasculitis and leukocytoclastic angiitis can and do coexist. Type B. Noninflammatory vasculitis. Noninflammatory vessel wall necrosis of arterioles is characteristic of systemic sclerosis. Similar findings occur in malignant hypertension and pre-eclampsia. Visceral disease, especially renal and cerebral, predominates. Periungual telangiectasia, Raynaud's phenomenon, and occasionally digital gangrene are the only cutaneous findings. Type C. Large vessel disease. Large vessel vasculitis is much more uniform in its clinical presentation: polymyalgia rheumatica, temporal arteritis, and pulseless disease. Overlap, clinical or pathologic, with other types of vasculitis is extremely uncommon. The large vessel disease of relapsing polychondritis is similarly quite distinctive. Type D. Microscopic (capillary) vasculitis. The microscopic forms of vasculitis have not been definitively described. The clinical presentation is that of a systemic illness, with or without cutaneous manifestations. Visceral disease, such as renal, may predominate. There may be some overlap with Type A.2 Type A is the commonest form of vasculitis, the one most studied, and the one most commonly implied by the general term vasculitis. We shall concentrate only on this type.
Vol. 55, No. 9, October 1979
87087
M. D. LOCKSHIN M. D.LCSI
ETIOLOGY AND PATHOGENESIS
Although toxic and genetic factors participate in some forms of vasculitis, submicrobial infectious agents are the most likely initial causes of vasculitis. Infectious agents. Several animal models of vasculitis are either due to or closely associated with infection. Lymphochoriomeningitis virus infection of neonatal mice results in a chronic vasculitis.5 (Postnatal infections cause meningitis.) Equine arteritis virus causes vasculitis in horses,6 probably by direct invasion of the artery wall. Aleutian disease virus causes vasculitis in mink.7 Mycoplasma gallisepticum causes arteritis in turkeys.8 A protozoan, Nosema cuniculi, induces epidemic arteritis in foxes.9 Immunologic amplification of the viral lesion is likely in some instances, and is almost certainly absent in others. In man, evidence is circumstantial but suggestive. Some patients develop periarteritis nodosa following presumably infectious serous otitis media.10 A sizeable minority of periarteritis nodosa patients have chronic hepatitis B (HB) antigenemia.1'1.2 In one dramatic case, an HB negative patient received a blood transfusion subsequently shown to have contained infectious HB. This patient became HB positive, then developed periarteritis nodosa, and later clinical hepatitis.13 HB virus has been identified by immunologic means and by electron microscopy in immune complexes and in the blood-vessel walls. 13 Unexplained, periarteritis nodsa occurs in a small minority of HB antigen carriers. Quantitation of virus, serotype, concatenation of antigen appearance, and immunogenetic constitution of the patients have failed to identify those most likely to develop periarteritis when infected with HB. 1 1 Toxic agents. Administration of noninfectious agents has induced vasculitis in animals and man. In some instances nonimmunologic vascular injury can be postulated. These include deoxycorticosterone and alloxan diabetes vasculitis in rats14 and in man, vasculitis of amphetamine users;15 a recent case report suggested a toxic or allergic vasculitis induced by an intravenous vitamin preparation.16 Genetic. Although lymphocytic choriomeningitis virus vasculitis in mice may have genetic determinants,17 only weak evidence currently suggests that human susceptibility to vasculitis is genetically determined. Glass and co-workers claimed a loose association of HLA All, BW3 with leukocytoclastic angiitis;18 a similar association of HLA B5 with Takayasu arteritis exists.19 Bull. N.Y. Acad. Med.
871
VASCULITIS
VASCULITIS
TABLE II. HEPATITIS ANTIGENS AND CIRCULATING IMMUNE COMPLEXES (CIC) IN HB-PAN (DR. R. INMAN) CIC by Serum HB reactants SBA * CIC HB reactants Patient HBAG HBAB HBCAB Eag Eab mg.Iml. HBAg HBSAb HBCAb CAg AGG cpm cpm cpm cpm
SW Me Ma
By Fo
NHSt
4,924 19,793 12,053 6,524 6,437
120 118 89 136 114
+ +
+ +
+ + +
233
105
0
+ + +
0 0 0 0 0
400 245 175 95 150
7,909 3,515 1,175 2,101
140 137 147 163 156
0
0
5
331
130
4,924
0 0 0
0
0 0 0 0 0
0
0
+
*Staphylococcus A binding assay tNormal human serum
Immunologic. Experimental serum sickness and the frequent though inconsistent demonstration of components of immunologic injury (antigen, complement, and immunoglobulin) at the site of vascular injury lend weight to the hypothesis that vasculitis is immunologically mediated.1'13'20 This has been the subject of recent reviews.' While these data are the strongest to date, it is important to note that the clotting system is simultaneously activated;21 immunologic parameters only partially reflect clinical activity of illness; and the focal nature of vasculitis is not easily explained by immunological mechanisms. In a current series of five well-studied HB-periarteritis nodosa patients, Dr. Robert Inman at our hospital has demonstrated the consistent presence of HBs antigen, HB, antibody, and e antigen in the serum, and the absence of HBs antibody and e antibody despite the clinical variability of disease activity. All patients had circulating immune complexes present, as identified by a noncomplement dependent assay (Staphylococcus A protein binding). The eluted complexes all contained HB, antigen, one contained HB, antibody, and none contained HB, antibody or e antigen (Table II). Other immunologic studies of these and other patients revealed normal lymphocyte responses in remission and in one patient a dramatic IgA rather than IgG anti-HB. Other authors have had somewhat different results. One patient with HB-periarteritis nodosa and five with other vasculitis studied by antibody-dependent cell-mediated cytotoxicity and Raji cell immune complexes had illness activity correlate with positive assays.22 Clq binding and electron microscopy of cryoprecipitate indentiVol. 55, No. 9, October 1979
872
M. D. LOCKSHIN
fied immune complexes in another series.23 Rate-zonal density gradient centrifugation immune complexes did not correlate with HB-periarteritis nodosa,24 but the same author felt that clumped particles in sera did reflect active vasculitis.25 These findings suggest more questions than they answer. Ten years have passed since the first demonstrations of the intimate relation of HB and periarteritis. That decade produced the major advance linking some rheumatic diseases to patient genotype, but it leaves still mysterious the precise way by which one specific virus interacts with a susceptible host to produce a specific, uncommon illness, necrotizing vasculitis (PAN). The clues remain an open challenge to us all.
1.
2.
3.
4.
5.
6.
7.
REFERENCES ter, H. G.: The pathogenesis of Aleutian Christian, C. L. and Sergent, J. S.: Vasdisease of mink. III. Immune complex culitis syndromes: Clinical and experimental models. Am. J. Med. 61:385, arteritis. Am. J. Pathol. 71:331, 1973. 8. Thomas, L., Davidson, M., and 1976. McCluskey R. T.: Studies of PPLO inTravers, R. L., Allison, D. J., Brettle, fection. I. The production of cerebral R. P., et. al.: Polyarteritis nodosa: A polyarteritis by mycoplasma gallisepticlinical and angiographic analysis of 17 cases. Semin. Arthritis Rheum. 8:184, cum in turkeys: The neurotoxic property 1979. of the mycoplasma. J. Exp. Med. 123:897, 1966. Soter, N. A., Austen, K. F, and Gigli, 9. Nordstoga, K., and Westbye, K.: I.: The complement system in necrotizPolyarteritis nodosa associated with ing angiitis of the skin. Analysis of nosematosis in blue foxes. Acta Pathol. complement component activities in Microbiol. Scand. 84:291, 1976. serum of patients with concomitant collagen-vascular disease. J. Invest. 10. Sergent, J. S. and Christian, C. L.: Necrotizing vasculitis after acute serous Dermatol. 63:219, 1974. otitis media. Ann. Int. Med. 81:195, Soter, N. A., Mihm, M. C., Gigli, I., et 1974. al.: Two distinct cellular patterns in cutaneous necrotizing angiitis.J. Invest. 11. Sergent, J. S., Lockshin, M. D., Christian, C. L., et al.: Vasculitis with Dermatol. 63:344, 1976. hepatitis B antigenemia: Long-term obOldstone, M. B. A. and Dixon, F. J.: servations in nine patients. Medicine Pathogenesis of chronic disease associ(Baltimore) 55:1, 1976. ated with persistent lymphocytic choriomeningitis viral infection. II. Re- 12. Trepo, C. and Thivolet, J.: Antigene australien, hepatite i virus et periarterite lationship of the antilymphocytic noueuse. Presse Med. 78:1575, 1970. choriomeningitis immune response to tissue injury in chronic lymphocytic 13. Gocke, D. J., Hsu, K., Morgan, C., et al.: Association between polyarteritis choriomeningitis disease. J. Exp. Med. and Australia antigen. Lancet 2:1149, 131:1, 1970. 1970. Estes, P. C. and Cheville, N. F.: The ultrastructure of vascular lesions in 14. Wexler, R. C.: Polyarteritis nodosa induced in arteriosclerotic male and female equine viral arteritis. Am. J. Pathol. breeder rats by alloxan diabetes. Paroi 58:235, 1970. Arterielle (Paris) 2:221-39, 1975. Porter, D. D., Larsen, A. E., and PorBull. N.Y. Acad. Med.
VASCULITIS
15. Citron, B. P., Halpern, M., McCarron, M., et al.: Necrotizing angiitis associated with drug abuse. N. Engl. J. Med. 283: 1003, 1970. 16. Perillo, R. P., Tedesco, F. J., and Wise, L.: The role of additives in allergic vasculitis during intravenous hyperalimentation. Digest Dis. 20:1191, 1975. 17. Oldstone, M. B. A., Dixon, F. T., Mitchell, G. F, etal.: Histocompatibility-linked genetic control of disease susceptibility. Murine lymphocytic choriomeningitis virus infection. J. Exp. Med. 137:1201, 1973. 18. Glass, D., Soter, N. A., Gibson, D., et al.: Association between HLA and cutaneous necrotizing vasculitis. Arthritis Rheum. 19:945, 1976. 19. Naito, S., Arakawa, K., Saito, S., et al.: Takayasu's disease: Association with HLA-B5. Tissue Antigens 12:143, 1978. 20. Conn, D. L., McDuffie, F. C. Holley, K. E., et al.:. Immunological mechanisms in systemic vasculitis. Mayo Clin. Proc. 51:511, 1976.
Vol. 55, No. 9, October 1979
873
21. Sun, N. C. J., Conn, D. L., Schroeter, A. L., et al.: Skin fibrinolytic activity in cutaneous and systemic vasculitis. Mayo Clin. Proc. 51:216, 1976. 22. Fye, K. H., Becker, M. J., Theophilopoulos, A. N., et al.: Immune complexes in hepatitis B antigen-associated periarteritis nodosa. Am. J. Med. 62:783, 1977. 23. Gower, R. G., Sausker, W. F, Kohler, P. F., et al.: Small vessel vasculitis caused by hepatitis virus immune complexes. J. Allergy Clin. Immunol. 62:222, 1978. 24. Prince, A. M. and Trepo, C.: Role of immune complexes involving SH antigen in pathogenesis of chronic active hepatitis and polyarteritis nodosa. Lancet 1:1309, 1971. 25. Trepo, C. G., Zuckerman, A. J., Bird, R. C., et al.: The role of circulating hepatitis B antigen/ antibody immune complexes in the pathogenesis of vascular and hepatic manifestations in polyarteritis nodosa. J. Clin. Pathol. 27: 863, 1974
