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Systemic Necrotizing Vasculitis Jacob Churg, MD Departments of Pathology, Mount Sinai School of Medicine, New York, New York, and Barnert Hospital, Paterson, New Jersey
Systemic necrotizing vasculitis may be idiopathic or associated with a variety of diseases of known etiology. A typical example is polyarteritis nodosa, which is characterized by fibrinoid necrosis and severe inflammation leading to destruction of the walI, narrowing of the lumen, and interference with blood circulation. In addition to the idiopathic form, histologically similar lesions are seen in hepatitis B, rheumatoid arthritis, Kawasaki mucocutaneous lymph node syndrome, and other diseases. Microscopic polyangitis involves mainly small vessels-venules more often than arterioles-but occasionally also small arteries. Its characteristic feature is leukocytoclasia of neutrophilic leukocytes, but fibrinoid necrosis also occurs. Churg-Strauss syndrome consists of granulomas in patients with a background of severe allergy, such as asthma, allergic rhinitis, or occasionally drug sensitization.
Systemic Necrotizing Vasculitis Although cases of necrotizing
vasculitis were mentioned by Rokitansky (1) and by Virchow (2) it was the report on periarteritis nodosa by Kussmaul and Maier (3) that provided a detailed description of a case and established the pathologic criteria for diagnosis. The involved arteries showed grossly visible and palpable nodules that on microscopic examination consisted of inflammatory infiltrates, mainly in and around the adventitial coat. Later studies (4,5) demonstrated that i&unmation also alEcted the medial and the intimal coats of the arteries and suggested an alternate name, polyarteritis nodosa (PAN). Kussmaul and Maier recognized that PAN may affect not only the vessels visible to the naked eye but also small arteries and arterioles. With time, many cases involving only small vessels became known, suggesting the name microscopic PAN (MPAN) (6). Soon afterward, Zeek et al. (7) realized that MPAN often occurred in patients receiving immune antisera or other drugs, such as sulfonamides, and suggested that those cases represented a different entity, which they called hypersensitivity angiitis. In such patients venules and capillaries are involved more prominently than are arterioles. However, similar lesions are seen in cases where hypersensitivity or allergy cannot be demonstrated, and for this reason a more inclusive term-small vessel vasculitis seems preferable (8). Manuscript received April 7, 1994; accepted April 13, 1994. From the March 13,1994 Symposium sponsored by the Society for Cardiovascular Pathology, Inc. (under the Auspices of the United States and Canadian Academy of Pathology), San Francisco, California. Address for reprints; Jacob Churg, MD, 1 Gustave Levy Place, Box 1194, New York, NY 10029; telephone: (201) 977-6649, fax: (201) 9776812. 0 1994 by Elsevier Science Inc.
Polyarteritis Nodosa The latest classification divides PAN into two types: the PAN of Kussmaul and Maier (classical), which involves only medium-sized and small arteries, and microscopic polyangiitis (MPA) which affects venules, capillaries, and arterioles, but in some cases also small and medium-sized arteries (9). Clinical features of classical PAN. In common with many other vasculitides, systemic PAN usually manifests with nonspecific constitutional symptoms such as fever, chills, fatigue, and weight loss (lo), as well as high sedimentation rate, anemia, and leukocytosis. More specific are tests for antineutrophilic cytoplasmic antibodies (ANCA) (l&12). Two types of ANCA are recognized by immunofluorescence microscopy: C-ANCA, in which staining is cytoplasmic, and P-ANCA, in which it is perinuclear. C-ANCA is an expression of antibodies against serine protease 3 and is seen mostly in Wegener’s granulomatosis (13), whereas P-ANCA demonstrates antibodies against myeloperoxidase (14)) but occasionally also those against other cytoplasmic enzymes of neutrophils and monocytes, and is seen in several types of vasculitis and some nonvasculitic diseases (15,16). The distinctive manifestations of PAN are attributable to inflammation, necrosis, thrombosis, and aneurysms of arteries in various organs and are often demonstrable by angiography (17). The most frequently involved organs are the kidneys, gastrointestinal tract, skin, and peripheral nerves. Hematuria and proteinuria are usually caused by glomerulonephritis of the crescentic type, whereas hematuria and loin pain are caused by infarcts. Hypertension is probably caused by narrowing of the larger renal arteries. Mesenteric arteritis 1054-8807B467.00
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Figure 1.
Polyarteritis nodosa (PAN): typical tibrinoid arteritis (hematoxylin-eosinstain, x350).
Figure 2. PAN: arteritis showingextensive destruction of elastic membranes (Victoriablue stain, x140).
and thrombosis are the main causes of abdominal disease with pain, hematemesis, melena, and sometimes intestinal perforation and peritonitis. Cutaneous involvement is manifested by palpable purpura, livedo reticularis, painful nodules, and ulcers. Mononeuritis, especially mononeuritis multiplex and sometimes symmetrical neuropathy, is a very characteristic feature of PAN (as well as of other systemic necrotizing vasculitides). It produces sensory, motor, and trophic disturbances. Other common features of PAN are myalgias and arthralgias; arthritis occurs on occasion. In PAN associated with hepatitis B serious liver disease may be present, but otherwise liver involvement is mild. Pulmonary disease is relatively uncommon. The involved arteries are usually branches of bronchial arteries, but those of pulmonary circulation may also participate. Alveolar capillaritis may cause severe pulmonary hemorrhage and lead to striking radiographic abnormalities. Testicular involvement may provide a diagnostic clue. Pathology of classical PAN. The essential features of necrotizing vasculitis are inflammation and necrosis or disruption of the vascular wall, particularly the arterial wall (Fig. 1). In the acute stage of PAN, the infiltrating cells are predominantly polymorphonuclear leukocytes with an admixture of eosinophils and lymphocytes, whereas in the chronic stage
mononuclear cells-mainly lymphocytes and histiocytespredominate. The inllammatory infiltrate is at first most prominent in the adventitia and perivascular connective tissue, in agreement with the original name, periarteritis nodosa. Disruption of the wall is caused primarily by damage to the elastic lamellae (Fig. 2) and necrosis of the tissue, especially of the medial smooth muscle. It is accompanied by deposition of fibrinoid, probably beginning in the intima and extending into the media. Fibrinoid is a mixture of fibrin, other fibrinogen derivatives, serum proteins, and necrotic tissue, mainly smooth muscle tissue. A section that misses the necrotic segment may show only inflammation, but not all arteries develop prominent fibrinoid necrosis. The lesions of PAN are transmural but segmental, most often located at the points of bifurcation. Thrombosis is an important cause of distal ischemia, infarcts, and necrosis. Eventually, healing of inflammation and organization of the thrombi end in permanent narrowing or occlusion of the vessel (Fig. 3). Another important complication are aneurysms arising in the weakened segments of the wall. Aneurysms may rupture and lead to hemorrhage, sometimes of massive proportions. Aneurysms are also the frequent site of thombosis. Veins are seldom involved in PAN, but if so they are usually by direct extension of inllammation from a nearby artery.
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Figure 4. Microscopic polyangiitis: small vessel vasculitis in sub-
Figure 3. PAN: arteritis in a healing stage with marked narrowing of the lumen (hematoxylin-eosin stain, X140).
cutis (hematoxylin-eosin
Clinical manifestations of microscopic polyangiitis. Manifestations of microscopic polyangiitis (MPA) are attributable to involvement of small vessels and, in some cases, of small and medium-sized arteries. Small vessel disease is seen mainly in the skin. The typical lesion is palpable purpura-that is, raised purpuric spots-especially on the lower extremities. The lesions are at first flat and erythematous or raised, nonhemorrhagic papules. After attaining the typical appearance in about 1 or 2 days, they begin to regress and disappear after 1 week but are usually followed by another crop. In most patients the disease remains limited to the skin, but occasionally it involves the internal organs, especially the kidneys and lungs, and carries a much more serious prognosis. The clinical symptoms are similar to those of PAN, with the addition of glomerulonephritis and pulmonary hemorrhage. Pathology of MPA. The typical lesion, as seen in skin biopsy, is neutrophilic inflammation of small blood vessels, accompanied by endothelial swelling (Fig. 4) and often by fibrin deposition or fibrinoid necrosis. The neutrophilic nuclei tend to fragment, giving rise to the term leukocytoclastic vasculitis (18,19). The affected vessels, mostly postcapillary venules, are located in the superficial layer of the dermis. Inflam-
mation may be accompanied by hemorrhage and may extend into the nearby connective tissue. Similar lesions are found in the disseminated form. Arterioles are involved infrequently. Renal changes are mostly those of necrotizing and crescentic glomerulonephritis, and pulmonary changes include severe capillaritis. Early vascular lesions (less than 24 hours) often show deposits of immunoglobulins, mainly IgM and complement (20). These deposits rapidly disappear. Regressing lesions are dominated by mononuclear cells-that is, lymphocytes and monocytes. It has been suggested, however, that in vasculitis of milder degree or of a special type (e.g., that caused by drug sensitization), inflammation is mainly mononuclear from the beginning (2 1). Etiology and pathogenesis. For many years after its original description, PAN was classified as an idiopathic disease (i.e., without known cause). More recently some specific etiologies have been identified, among them viral infections and sensitization to known antigens. Hepatitis B accounts for at least 10% to 20% and probably more of the infectious cases of PAN (22,23). Other viruses have also been implicated, including hepatitis A and C (24), HIV (25), cytomegalovirus (26)) and herpes zoster (27). Vasculitis is induced by deposition of immune complexes or by direct invasion of the wall
stain,
x350).
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by the infectious agent. Examples of the latter process have been also observed in animals (28). Association of PAN with immune complexes probably dates to the experiments of Arthus (Arthus phenomenon). Vasculitis in humans has been observed after injection of immune serum and after administration of sulfonamides, although it is more often SVV than PAN (29). In SVV, fleeting immune complexes can be found in the vessel walls in the early stages (20). Whether such rapid disappearance accounts for the absence of immune complexes in most cases of PAN, or whether a different mechanism is at play (e.g., cellular immunity), is uncertain. The discovery of the antineutrophilic cytoplasmic antibodies (ANCA) and of antiendothelial antibodies suggests an important role for autoimmunity. Diagnosis and differential diagnosis. Early diagnosis and treatment are very important in preventing severe vascular damage and its sequelae. Vasculitis is an uncommon disease, and in the past it was often omitted from the differential diagnosis in unclear situations. This attitude appears to be changing with the ready availability of the ANCA test. Vasculitis should be suspected in every case where clinical and laboratory evidence of systemic inflammation is combined with localized symptoms involving two or more organs or areas (30), particularly those referable to the skin, kidneys, abdomen, musculoskeletal system, and peripheral nerves. One also needs to eliminate conditions that simulate vasculitis, primarily bacterial and rickettsial infections (meningococcemia, Lyme disease, bacterial endocarditis, typhus, Rocky mountain spotted fever), and embolism from mycotic aneurysm, cholesterol emboli from decaying atheromas (31), or atrial myxoma (32). Once vasculitis is suspected, it should be confirmed by further laboratory tests, especially ANCA, by x-ray studies to demonstrate arterial aneurysms, and by biopsy of skin, muscle, sural nerve, testis, and perhaps kidney. Biopsies of symptomatic areas are generally more fruitful than random biopsies. When the presence of vasculitis is established, further decisions are necessary concerning its type and its possible etiology. PAN, which once encompassed all known arteritides, has now become a diagnosis of exclusion, after elimination of granulomatous vasculitides (Wegener’sand Churg-Strauss’s) and large-vessel vasculitides (Takayasu’sarteritis and giant cell [temporal] arteritis, which on occasion involves smaller vessels). Distinction also needs to be made between classical PAN and microscopic polyangiitis (MPA). One should search for possible cause or association, using clinical, laboratory, and histologic information. Laboratory tests may disclose hepatitis B or C infection; bacterial infection may be demonstrated by blood culture; and other procedures may suggest connective tissue diseases (ANA, rheumatoid factor), cryoglobulins, or antiglomerular basement membrane disease. Clinical data may indicate sensitization or allergy to medications or other substances. When no specific cause is found, a diagnosis of idiopathic PAN or MPA may be entertained.
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Course, prognosis, and therapy. Depending upon the extent and severity of vasculitis, the course of PAN and of MPA varies from mild to severe but is often unpredictable. Mild early symptoms can rapidly progress to a life-threatening situation. Prognosis in untreated cases of PAN is poor, with a 5year survival in the range of 10% to 15%. Steroids have improved the survival rate to about 50 % , and further benefit has been achieved by addition of cytotoxics, especially cyclophosphamide (33). Steroids are given in large doses (60-100 mg of prednisone daily), which can be reduced or given on alternate days after the disease is under control. This is judged by the clinical symptoms and by sedimentation rate. The level of ANCA also tends to drop with improvement. With severe or persistent symptoms, cyclophosphamide is added to prednisone, either by mouth (2 mg/kg/day) or intravenously (10 mg/kg, once a month). Because an apparently mild disease may suddenly worsen, some physicians treat all patients from the beginning with steroids and cytotoxics. Treatment should be continued for at least 12 months after disappearance of symptoms. Recently therapy with intravenous immunoglobulin has been tried with some success (34). Patients in renal failure should be placed on dialysis. If the failure is irreversible, transplantation should be considered after disease activity has completely abated. Complications of therapy, mainly infections in immunosuppressed patients, account for a considerable proportion of deaths, and the use of cytotoxic agents calls for particularly careful management. Late complications, such as myocardial and central nervous system infarcts, result from scarring and destruction of the inflamed arteries as well as from hypertension. Cutaneous small-vessel vasculitis usually but not always responds to the withdrawal of the offending agent (e.g., medication) combined with moderate doses of steroids. Prognosis in microscopic polyangiitis is essentially the same as in polyarteritis nodosa.
Churg-Strauss Syndrome (Allergic Granulomatosis) Association of necrotizing vasculitis with asthma and eosinophilia was first recognized by Rackemann and Greene in 1939 as a distinct subset of polyarteritis nodosa (35). Churg and Strauss (36,37) identified vascular and extravascular granuloma of a specific nature as the hallmark of this vasculitis and confirmed its association with asthma, allergic rhinitis, and blood eosinophilia. Clinical features. Churg-Strauss syndrome (CSS) is an uncommon disease but one that is probably underreported (38). It occurs mostly in young adults in their twenties and thirties but also in older children and in old people. The male to female ratio is probably 1:l. Three or four clinical phases can be distinguished (38).
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TheprodromalphQse is manifested by allergic diseases, usually beginning with allergic rhinitis around the age of 25 to 30 years. This rhinitis tends to be severe, with severe sinusitis and large allergic polyps. It is followed within a few years, but is sometimes preceded, by asthma. Both rhinitis and asthma are often accompanied by blood eosinophilia of moderate degree, rarely exceeding 800 cells/mm*. The unusual features of asthma is its relatively late onset and the frequent absence of atopy in the family history. Asthma may be mild initially, but it usually increases in severity until the onset of vasculitis. The latter manifests within a few years, buy sometimes as late as 30 years; on the other hand, it may manifest almost simultaneously with the onset of asthma. Rarely, vasculitis follows allergic rhinitis without asthma. A few cases have been reported in which CSS followed sensitization to a drug (39,40). Vasculitis may be accompanied by a status asthmaticus, but surprisingly, in many patients asthma abates, only to recur after vasculitis has been successfully treated. The next step is eosinophilic inj2rmtive disease. This is most often seen in the lungs as fleeting, patchy, irregularly distributed densities, accompanied by appreciable blood eosinophilia but only slight clinical symptoms, and is often called Li5ffler’s syndrome (41). Other patients have chronic eosinophilic pneumonia with persistent infiltrates and often fever and weight loss (42). Eosinophilic gastroenteritis may cause episodes of abdominal pain, diarrhea, bleeding, and obstruction, as well as eosinophilic peritonitis (43). Blood eosinophilia during the episodes of inliltrative disease is usually more pronounced than with simple atopy and may exceed 1500 cells/mm*, but it tends to be variable or even absent, particularly in patients treated with steroids. The vusczditicphase of CSS often begins in the same manner as PAN with nonspecific constitutional symptoms: fever, malaise, and weight loss, as well as persistent symptoms of infiltrative disease. Organ distribution of the pathologic changes is similar to that of PAN, but with a different emphasis. Pulmonary inliltrates are very common and occasionally lead to confluent nodules, resembling those of Wegener’s granulomatosis. There may be accompanying eosinophilic pleurisy. The dangerous complication is alveolitis with massive hemorrhage (44). Cardiac involvement is the major cause of death. Cardiac failure is attributable to eosinophilic and granulomatous myocarditis and/or to coronary vasculitis (45). Diarrhea, bleeding, and abdominal pain are the usual manifestations of the gastrointestinal disease, but bowel perforation, obstruction, and peritonitis also occur (46). Cutaneous lesions include palpable purpura, livedo reticularis, and focal infarcts, as well as cutaneous and subcutaneous nodules (47). Renal involvement is manifested by hematuria, proteinuria, and occasionally nephrotic syndrome, mostly caused by focal mesangial but sometimes by crescentic glomerulonephritis. Generalized but mild and transient lymphadenopathy is fairly frequent. Occasionally inflammation involves the ureters, prostate, and penis. Peripheral neuropathy-usually mononeuritis multi-
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plex- is very common and tends to appear early. Lesions of the central nervous system, hemorrhage, and infarction are late but serious manifestations. Arthralgias and arthritis occur in about half the patients in the vasculitis phase. Destructive arthritis is uncommon, but rheumatoid factor in the blood is often elevated. Laboratory findings. As in all necrotizing vasculitides, anemia, leukocytosis, elevated sedimentation rate, and C-reactive protein are constant findings. The eosinophil count often exceeds 5OOO/mm*at some point and occasionally reached 30,000/mm2 or more (37). Serum globulin level is often increased, with elevation of IgG and IgM, and notably of IgE (48). Postvasculitic phase. With proper treatment most of the organ damage is repaired, probably in 6 to 12 months. However, peripheral neuropathy may take considerably longer and in some patients persists for years. Allergic symptoms, rhinitis, and asthma usually recur and may be difficult to treat. Hypertension, usually attributable to stenosis of renal arteries, tends to persist. pathology. The features that identify the vasculitis of CSS are eosinophilic intiltration of tissues and specific granulomas.
Pignre 5. Churg-Strauss syndrome(CSS):typicalgranulomain the connectivetissue, showinga stronglyeosinopbiliccenter surrounded by palisading macrophages and many eosinophils (hematoxylin-eosin stain, X540).
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Figure 6. CSS: granulomatousfibrinoidarteritis. There is palisading of macrophagesaround a necrotic artery and many eosinophils in the inflammatory exudate (hematoxylin-eosinstain, X350).
The inflammatory infiltrates contain a large proportion of eosinophils, but sometimes eosinophils are also prominent in other vasculitides, such as PAN or Wegener’s granulomatosis (49). However, in CSS there is striking blood eosinophilia, which is uncommon in other vasculitides, where it rarely exceeds 800 cells/mm*. Granulomas of CSS consist of a core of necrotic eosinophils and necrotic tissue, surrounded by palisading macrophages (epithelioid cells) and multinucleated giant cells (Fig. 5). Granulomas in Wegener’s granulomatosis and in some connective tissue diseases show similar arrangement, but their cores consist of degenerated neutrophils or of tissue undergoing basophilic necrosis. Arteritis in CSS is usually of fibrinoid type (Fig. 6). Fibrinoid is deposited in the intima and in the media, where it is accompanied by degeneration and necrosis of smooth muscle cells. This is followed by intense inflammation, which rapidly acquires a granulomatous character (Fig. 6). Subsequent events are similar to those in PAN. Small vessels, particularly in the skin, are often involved by neutrophilic leukocytoclastic or eosinophilic inflammation. Larger veins may also show inflammation and thrombosis. Special features are noted in some organs. The lungs often show typical changes of asthma in the form of mucous bron-
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chial plugs, eosinophilic bronchitis, and thickening of basement membranes. Rarely, granulomatous inflammation of nasal passages leads to ulcerations and even to septal perforation. Pathogenesls. CSS is an allergic disease. As such it is most likely mediated by an immunologic mechanism or mechanisms, with the immediate hypersensitivity probably playing a major role. Supporting this concept is the frequent elevation of immunoglobulin E (IgE) in the serum during the acute stage of the disease and decrease during remission (48). An acute attack may be precipitated by injection of antigen during the process of desensitization (50). Although immune complexes have not been convincingly demonstrated in the tissues, they are present in the circulation and contain IgE (48). Cellular immunity may also play a role, as suggested by increased ratio of helper to suppressor T cells in the circulation and a large number of helper cells in the granuloma (5152). Autoimmunity is implicated by the frequent presence of P8ANCA in CSS. Perhaps all of these mechanisms play a role, but the important factor is undoubtedly the individual predesposition, called atopy or allergic diathesis. Tissue damage in CSS may be enhanced by the specific proteins liberated from the eosinophilic granules (53). These proteins are toxic to parasites (at which they are directed), but they are also toxic to normal tissues such as heart muscle and may thus contribute to the high incidence of heart disease (54). Dlagnosls. Diagnosis of CSS can usually be made on clinical grounds: the patient has a history of asthma (or, rarely, of only severe allergic rhinitis), blood eosinophilia of over 1,500 cells/mm*, and evidence of systemic vasculitis in two or more extrapulmonary organs (38). Sometimes more than one blood count is needed because of rapid fluctuation of the eosinophilia and the suppressing effect of steroids administered for asthma. Tissue diagnosis (skin, muscle, sural nerve, and sometimes kidney) is used mainly for confirmation. Nowadays nearly every case of severe asthma is treated with steroids, and a biopsy may demonstrate neither granulomas nor vasculitis. As in all necrotizing vasculitides, there is an urgent need for early therapy. In CSS this should be administered on the basis of strong clinical suspicion, without waiting for the biopsy report. Course, prognosis, and therapy. CSS is essentially a selflimited process. However, the damage to the vascular system is so severe that nearly all patients die, usually of cardiac failure, renal failure, or cerebrovascular accident. Steroid therapy has markedly altered the course of the disease, leading to complete or nearly complete recovery in some approximately three fourths of patients. The remaining one fourth have very severe or recurrent disease and benefit from addition of cytotoxic drugs. However, in CSS as in PAN, mild initial symptoms may very suddenly worsen, and it is advisable to add cytotoxics to steroids as soon as the diagnosis is made, Steroids are given in high doses (60 mg/day of prednisone) together with cyclophosphamide (2 mg/kg/day) for several weeks or longer. In very severe cases one may start
with intravenous bolus of methylprodnisolone (1 gm, 1 or 2 times the first day) (55) and intravenous cyclophosphamide (10 mg/kg) (56), repeated if necessary in 7 to 14 days and if permitted by the white cell count. When symptoms have clearly abated, steroids are gradually reduced and azothioprine (2.5 mg/kg/day) may be substituted for cyclophosphamide. Therapy should be continued to at least 6 to 12 months after the onset of remission. Recurrences require retreatment.
20. Braverman IM, Yen A. Demonstration of immune complexes in SpOnand histamine-induced lesions and in normal skin of patients taneous with leukocytoclastic angiitis. J Invest Dermatol 1975;64:105-112. 21. Mullick FG, Mcallister HA, JR, Wagner BM, Fenoglio JJ. Drug-related vasculitis: clinicopathologic correlations in 30 patients. Hum Path01 1979;10:313-325. 22. Christian CL. Hepatitis B virus (HBV) and systemic vascuhtis (editorial). Clin Exp Rheumatol 1991;9:1-2. 23. Marcelin P, Calmus Y, Takahashi H, et al. Latent hepatitis B virus (HBV) infection in systemic necrotizing vasculitis. Clin Exp Rheumatol 1991;9:23-28. 24. Ferri C, Greco F, Longombardo G, Palla P, Marzo E, Moretti A. Hepatitis C virus antibodies in mixed cryoglobulinemia. Clin Exp Rheumatol 1991;9:95-96.
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44. Clutterbuck El, Pusey CD. Severe alveolar haemorrhage in ChurgStrauss syndrome. Eur J Respir Dis 1987;71:158-163. 45. Leung WH, Wong KK, Lau CP, Wong CK, Cheng CH, So KF. Myocardial involvement in Churg-Strauss syndrome: the role of endomyocardial biopsy: case report. J Rheumatol 1989;16:828-831. 46. Nodigliani R, Muschart JM, Galian A, Clauvel JP, Piel-Desruisseaux JL. Allergic granulomatous vasculitis (Churg-Strauss syndrome). Report of a case with widespread digestive involvement. Dig Dis Sci 1981;26:264-270. 47. Strauss L, Churg J, Zak FG. Cutaneous lesions of allergic granulomatosis. J Invest Dermatol 1951;17:349-359. 48. Manger BJ, Krapf FE, Gramatzki M, et al. IgE containing circulating immune complexes in Churg-Strauss vasculitis. Stand J Immunol 1985;21:369-373. 49. Yousem SA, Lombard CM. The eosinophilic variant of Wegener’s granulomatosis. Hum Path01 1988; 19:682-688. 50. Phanuphak P, Kohler PF. Onset of polyarteritis nodosa during allergic hyposensitization treatment. Am J Med 1980;68:479-485.
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51. Winkelman RK, Buecchner SV, Powell FC, Banks PM. The T-lymphocyte and cutaneous Churg-Strauss granuloma. Acta Dermatologica & Venereologica (Stockholm) 1983;63:199-204. 52. Kus J, Bergin C, Miller R, Ongley R, Churg A, Emerson D. Lymphocyte subpopulationsin allergic granulomatosis and angiitis (Churg-Strauss syndrome). Chest 1985;87:826-827. 53. Ackerman SJ, Loegering DA, Venge P, et al. Distinctive cationic proteins of the human eosinophil granule: major basic protein, eosinophil cationic protein, and eosinophilderived neurotoxin. Am Assoc Immunol 198312977-2982. 54. Sasano H, Virmani R, Patterson RH, Robinowitz M, Guccion JG. Eosinophilic products lead to myocardial damage. Hum Path01 1989;20: 850-857. 55. MacFadyen R, Tron V, Keshmiri M, Road JD. Allergic angiitis of Churg and Strauss syndrome: response to pulse methylprednisolone. Chest 1987;91:629-631. 56. Chow CC, Li EKM, Lai FMM. Allergic granulomatosis and angiitis (Churg-Strauss syndrome): response to “pulse” intravenous cyclophosphamide. Ann Rheum Dis 1989;48:605-608.
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Systemic Necrotizing Vasculitis Jacob Churg, MD Departments of Pathology, Mount Sinai School of Medicine, New York, New York, and Barnert Hospital, Paterson, New Jersey
Systemic necrotizing vasculitis may be idiopathic or associated with a variety of diseases of known etiology. A typical example is polyarteritis nodosa, which is characterized by fibrinoid necrosis and severe inflammation leading to destruction of the walI, narrowing of the lumen, and interference with blood circulation. In addition to the idiopathic form, histologically similar lesions are seen in hepatitis B, rheumatoid arthritis, Kawasaki mucocutaneous lymph node syndrome, and other diseases. Microscopic polyangitis involves mainly small vessels-venules more often than arterioles-but occasionally also small arteries. Its characteristic feature is leukocytoclasia of neutrophilic leukocytes, but fibrinoid necrosis also occurs. Churg-Strauss syndrome consists of granulomas in patients with a background of severe allergy, such as asthma, allergic rhinitis, or occasionally drug sensitization.
Systemic Necrotizing Vasculitis Although cases of necrotizing
vasculitis were mentioned by Rokitansky (1) and by Virchow (2) it was the report on periarteritis nodosa by Kussmaul and Maier (3) that provided a detailed description of a case and established the pathologic criteria for diagnosis. The involved arteries showed grossly visible and palpable nodules that on microscopic examination consisted of inflammatory infiltrates, mainly in and around the adventitial coat. Later studies (4,5) demonstrated that i&unmation also alEcted the medial and the intimal coats of the arteries and suggested an alternate name, polyarteritis nodosa (PAN). Kussmaul and Maier recognized that PAN may affect not only the vessels visible to the naked eye but also small arteries and arterioles. With time, many cases involving only small vessels became known, suggesting the name microscopic PAN (MPAN) (6). Soon afterward, Zeek et al. (7) realized that MPAN often occurred in patients receiving immune antisera or other drugs, such as sulfonamides, and suggested that those cases represented a different entity, which they called hypersensitivity angiitis. In such patients venules and capillaries are involved more prominently than are arterioles. However, similar lesions are seen in cases where hypersensitivity or allergy cannot be demonstrated, and for this reason a more inclusive term-small vessel vasculitis seems preferable (8). Manuscript received April 7, 1994; accepted April 13, 1994. From the March 13,1994 Symposium sponsored by the Society for Cardiovascular Pathology, Inc. (under the Auspices of the United States and Canadian Academy of Pathology), San Francisco, California. Address for reprints; Jacob Churg, MD, 1 Gustave Levy Place, Box 1194, New York, NY 10029; telephone: (201) 977-6649, fax: (201) 9776812. 0 1994 by Elsevier Science Inc.
Polyarteritis Nodosa The latest classification divides PAN into two types: the PAN of Kussmaul and Maier (classical), which involves only medium-sized and small arteries, and microscopic polyangiitis (MPA) which affects venules, capillaries, and arterioles, but in some cases also small and medium-sized arteries (9). Clinical features of classical PAN. In common with many other vasculitides, systemic PAN usually manifests with nonspecific constitutional symptoms such as fever, chills, fatigue, and weight loss (lo), as well as high sedimentation rate, anemia, and leukocytosis. More specific are tests for antineutrophilic cytoplasmic antibodies (ANCA) (l&12). Two types of ANCA are recognized by immunofluorescence microscopy: C-ANCA, in which staining is cytoplasmic, and P-ANCA, in which it is perinuclear. C-ANCA is an expression of antibodies against serine protease 3 and is seen mostly in Wegener’s granulomatosis (13), whereas P-ANCA demonstrates antibodies against myeloperoxidase (14)) but occasionally also those against other cytoplasmic enzymes of neutrophils and monocytes, and is seen in several types of vasculitis and some nonvasculitic diseases (15,16). The distinctive manifestations of PAN are attributable to inflammation, necrosis, thrombosis, and aneurysms of arteries in various organs and are often demonstrable by angiography (17). The most frequently involved organs are the kidneys, gastrointestinal tract, skin, and peripheral nerves. Hematuria and proteinuria are usually caused by glomerulonephritis of the crescentic type, whereas hematuria and loin pain are caused by infarcts. Hypertension is probably caused by narrowing of the larger renal arteries. Mesenteric arteritis 1054-8807B467.00
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Figure 1.
Polyarteritis nodosa (PAN): typical tibrinoid arteritis (hematoxylin-eosinstain, x350).
Figure 2. PAN: arteritis showingextensive destruction of elastic membranes (Victoriablue stain, x140).
and thrombosis are the main causes of abdominal disease with pain, hematemesis, melena, and sometimes intestinal perforation and peritonitis. Cutaneous involvement is manifested by palpable purpura, livedo reticularis, painful nodules, and ulcers. Mononeuritis, especially mononeuritis multiplex and sometimes symmetrical neuropathy, is a very characteristic feature of PAN (as well as of other systemic necrotizing vasculitides). It produces sensory, motor, and trophic disturbances. Other common features of PAN are myalgias and arthralgias; arthritis occurs on occasion. In PAN associated with hepatitis B serious liver disease may be present, but otherwise liver involvement is mild. Pulmonary disease is relatively uncommon. The involved arteries are usually branches of bronchial arteries, but those of pulmonary circulation may also participate. Alveolar capillaritis may cause severe pulmonary hemorrhage and lead to striking radiographic abnormalities. Testicular involvement may provide a diagnostic clue. Pathology of classical PAN. The essential features of necrotizing vasculitis are inflammation and necrosis or disruption of the vascular wall, particularly the arterial wall (Fig. 1). In the acute stage of PAN, the infiltrating cells are predominantly polymorphonuclear leukocytes with an admixture of eosinophils and lymphocytes, whereas in the chronic stage
mononuclear cells-mainly lymphocytes and histiocytespredominate. The inllammatory infiltrate is at first most prominent in the adventitia and perivascular connective tissue, in agreement with the original name, periarteritis nodosa. Disruption of the wall is caused primarily by damage to the elastic lamellae (Fig. 2) and necrosis of the tissue, especially of the medial smooth muscle. It is accompanied by deposition of fibrinoid, probably beginning in the intima and extending into the media. Fibrinoid is a mixture of fibrin, other fibrinogen derivatives, serum proteins, and necrotic tissue, mainly smooth muscle tissue. A section that misses the necrotic segment may show only inflammation, but not all arteries develop prominent fibrinoid necrosis. The lesions of PAN are transmural but segmental, most often located at the points of bifurcation. Thrombosis is an important cause of distal ischemia, infarcts, and necrosis. Eventually, healing of inflammation and organization of the thrombi end in permanent narrowing or occlusion of the vessel (Fig. 3). Another important complication are aneurysms arising in the weakened segments of the wall. Aneurysms may rupture and lead to hemorrhage, sometimes of massive proportions. Aneurysms are also the frequent site of thombosis. Veins are seldom involved in PAN, but if so they are usually by direct extension of inllammation from a nearby artery.
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Figure 4. Microscopic polyangiitis: small vessel vasculitis in sub-
Figure 3. PAN: arteritis in a healing stage with marked narrowing of the lumen (hematoxylin-eosin stain, X140).
cutis (hematoxylin-eosin
Clinical manifestations of microscopic polyangiitis. Manifestations of microscopic polyangiitis (MPA) are attributable to involvement of small vessels and, in some cases, of small and medium-sized arteries. Small vessel disease is seen mainly in the skin. The typical lesion is palpable purpura-that is, raised purpuric spots-especially on the lower extremities. The lesions are at first flat and erythematous or raised, nonhemorrhagic papules. After attaining the typical appearance in about 1 or 2 days, they begin to regress and disappear after 1 week but are usually followed by another crop. In most patients the disease remains limited to the skin, but occasionally it involves the internal organs, especially the kidneys and lungs, and carries a much more serious prognosis. The clinical symptoms are similar to those of PAN, with the addition of glomerulonephritis and pulmonary hemorrhage. Pathology of MPA. The typical lesion, as seen in skin biopsy, is neutrophilic inflammation of small blood vessels, accompanied by endothelial swelling (Fig. 4) and often by fibrin deposition or fibrinoid necrosis. The neutrophilic nuclei tend to fragment, giving rise to the term leukocytoclastic vasculitis (18,19). The affected vessels, mostly postcapillary venules, are located in the superficial layer of the dermis. Inflam-
mation may be accompanied by hemorrhage and may extend into the nearby connective tissue. Similar lesions are found in the disseminated form. Arterioles are involved infrequently. Renal changes are mostly those of necrotizing and crescentic glomerulonephritis, and pulmonary changes include severe capillaritis. Early vascular lesions (less than 24 hours) often show deposits of immunoglobulins, mainly IgM and complement (20). These deposits rapidly disappear. Regressing lesions are dominated by mononuclear cells-that is, lymphocytes and monocytes. It has been suggested, however, that in vasculitis of milder degree or of a special type (e.g., that caused by drug sensitization), inflammation is mainly mononuclear from the beginning (2 1). Etiology and pathogenesis. For many years after its original description, PAN was classified as an idiopathic disease (i.e., without known cause). More recently some specific etiologies have been identified, among them viral infections and sensitization to known antigens. Hepatitis B accounts for at least 10% to 20% and probably more of the infectious cases of PAN (22,23). Other viruses have also been implicated, including hepatitis A and C (24), HIV (25), cytomegalovirus (26)) and herpes zoster (27). Vasculitis is induced by deposition of immune complexes or by direct invasion of the wall
stain,
x350).
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by the infectious agent. Examples of the latter process have been also observed in animals (28). Association of PAN with immune complexes probably dates to the experiments of Arthus (Arthus phenomenon). Vasculitis in humans has been observed after injection of immune serum and after administration of sulfonamides, although it is more often SVV than PAN (29). In SVV, fleeting immune complexes can be found in the vessel walls in the early stages (20). Whether such rapid disappearance accounts for the absence of immune complexes in most cases of PAN, or whether a different mechanism is at play (e.g., cellular immunity), is uncertain. The discovery of the antineutrophilic cytoplasmic antibodies (ANCA) and of antiendothelial antibodies suggests an important role for autoimmunity. Diagnosis and differential diagnosis. Early diagnosis and treatment are very important in preventing severe vascular damage and its sequelae. Vasculitis is an uncommon disease, and in the past it was often omitted from the differential diagnosis in unclear situations. This attitude appears to be changing with the ready availability of the ANCA test. Vasculitis should be suspected in every case where clinical and laboratory evidence of systemic inflammation is combined with localized symptoms involving two or more organs or areas (30), particularly those referable to the skin, kidneys, abdomen, musculoskeletal system, and peripheral nerves. One also needs to eliminate conditions that simulate vasculitis, primarily bacterial and rickettsial infections (meningococcemia, Lyme disease, bacterial endocarditis, typhus, Rocky mountain spotted fever), and embolism from mycotic aneurysm, cholesterol emboli from decaying atheromas (31), or atrial myxoma (32). Once vasculitis is suspected, it should be confirmed by further laboratory tests, especially ANCA, by x-ray studies to demonstrate arterial aneurysms, and by biopsy of skin, muscle, sural nerve, testis, and perhaps kidney. Biopsies of symptomatic areas are generally more fruitful than random biopsies. When the presence of vasculitis is established, further decisions are necessary concerning its type and its possible etiology. PAN, which once encompassed all known arteritides, has now become a diagnosis of exclusion, after elimination of granulomatous vasculitides (Wegener’sand Churg-Strauss’s) and large-vessel vasculitides (Takayasu’sarteritis and giant cell [temporal] arteritis, which on occasion involves smaller vessels). Distinction also needs to be made between classical PAN and microscopic polyangiitis (MPA). One should search for possible cause or association, using clinical, laboratory, and histologic information. Laboratory tests may disclose hepatitis B or C infection; bacterial infection may be demonstrated by blood culture; and other procedures may suggest connective tissue diseases (ANA, rheumatoid factor), cryoglobulins, or antiglomerular basement membrane disease. Clinical data may indicate sensitization or allergy to medications or other substances. When no specific cause is found, a diagnosis of idiopathic PAN or MPA may be entertained.
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Course, prognosis, and therapy. Depending upon the extent and severity of vasculitis, the course of PAN and of MPA varies from mild to severe but is often unpredictable. Mild early symptoms can rapidly progress to a life-threatening situation. Prognosis in untreated cases of PAN is poor, with a 5year survival in the range of 10% to 15%. Steroids have improved the survival rate to about 50 % , and further benefit has been achieved by addition of cytotoxics, especially cyclophosphamide (33). Steroids are given in large doses (60-100 mg of prednisone daily), which can be reduced or given on alternate days after the disease is under control. This is judged by the clinical symptoms and by sedimentation rate. The level of ANCA also tends to drop with improvement. With severe or persistent symptoms, cyclophosphamide is added to prednisone, either by mouth (2 mg/kg/day) or intravenously (10 mg/kg, once a month). Because an apparently mild disease may suddenly worsen, some physicians treat all patients from the beginning with steroids and cytotoxics. Treatment should be continued for at least 12 months after disappearance of symptoms. Recently therapy with intravenous immunoglobulin has been tried with some success (34). Patients in renal failure should be placed on dialysis. If the failure is irreversible, transplantation should be considered after disease activity has completely abated. Complications of therapy, mainly infections in immunosuppressed patients, account for a considerable proportion of deaths, and the use of cytotoxic agents calls for particularly careful management. Late complications, such as myocardial and central nervous system infarcts, result from scarring and destruction of the inflamed arteries as well as from hypertension. Cutaneous small-vessel vasculitis usually but not always responds to the withdrawal of the offending agent (e.g., medication) combined with moderate doses of steroids. Prognosis in microscopic polyangiitis is essentially the same as in polyarteritis nodosa.
Churg-Strauss Syndrome (Allergic Granulomatosis) Association of necrotizing vasculitis with asthma and eosinophilia was first recognized by Rackemann and Greene in 1939 as a distinct subset of polyarteritis nodosa (35). Churg and Strauss (36,37) identified vascular and extravascular granuloma of a specific nature as the hallmark of this vasculitis and confirmed its association with asthma, allergic rhinitis, and blood eosinophilia. Clinical features. Churg-Strauss syndrome (CSS) is an uncommon disease but one that is probably underreported (38). It occurs mostly in young adults in their twenties and thirties but also in older children and in old people. The male to female ratio is probably 1:l. Three or four clinical phases can be distinguished (38).
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TheprodromalphQse is manifested by allergic diseases, usually beginning with allergic rhinitis around the age of 25 to 30 years. This rhinitis tends to be severe, with severe sinusitis and large allergic polyps. It is followed within a few years, but is sometimes preceded, by asthma. Both rhinitis and asthma are often accompanied by blood eosinophilia of moderate degree, rarely exceeding 800 cells/mm*. The unusual features of asthma is its relatively late onset and the frequent absence of atopy in the family history. Asthma may be mild initially, but it usually increases in severity until the onset of vasculitis. The latter manifests within a few years, buy sometimes as late as 30 years; on the other hand, it may manifest almost simultaneously with the onset of asthma. Rarely, vasculitis follows allergic rhinitis without asthma. A few cases have been reported in which CSS followed sensitization to a drug (39,40). Vasculitis may be accompanied by a status asthmaticus, but surprisingly, in many patients asthma abates, only to recur after vasculitis has been successfully treated. The next step is eosinophilic inj2rmtive disease. This is most often seen in the lungs as fleeting, patchy, irregularly distributed densities, accompanied by appreciable blood eosinophilia but only slight clinical symptoms, and is often called Li5ffler’s syndrome (41). Other patients have chronic eosinophilic pneumonia with persistent infiltrates and often fever and weight loss (42). Eosinophilic gastroenteritis may cause episodes of abdominal pain, diarrhea, bleeding, and obstruction, as well as eosinophilic peritonitis (43). Blood eosinophilia during the episodes of inliltrative disease is usually more pronounced than with simple atopy and may exceed 1500 cells/mm*, but it tends to be variable or even absent, particularly in patients treated with steroids. The vusczditicphase of CSS often begins in the same manner as PAN with nonspecific constitutional symptoms: fever, malaise, and weight loss, as well as persistent symptoms of infiltrative disease. Organ distribution of the pathologic changes is similar to that of PAN, but with a different emphasis. Pulmonary inliltrates are very common and occasionally lead to confluent nodules, resembling those of Wegener’s granulomatosis. There may be accompanying eosinophilic pleurisy. The dangerous complication is alveolitis with massive hemorrhage (44). Cardiac involvement is the major cause of death. Cardiac failure is attributable to eosinophilic and granulomatous myocarditis and/or to coronary vasculitis (45). Diarrhea, bleeding, and abdominal pain are the usual manifestations of the gastrointestinal disease, but bowel perforation, obstruction, and peritonitis also occur (46). Cutaneous lesions include palpable purpura, livedo reticularis, and focal infarcts, as well as cutaneous and subcutaneous nodules (47). Renal involvement is manifested by hematuria, proteinuria, and occasionally nephrotic syndrome, mostly caused by focal mesangial but sometimes by crescentic glomerulonephritis. Generalized but mild and transient lymphadenopathy is fairly frequent. Occasionally inflammation involves the ureters, prostate, and penis. Peripheral neuropathy-usually mononeuritis multi-
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plex- is very common and tends to appear early. Lesions of the central nervous system, hemorrhage, and infarction are late but serious manifestations. Arthralgias and arthritis occur in about half the patients in the vasculitis phase. Destructive arthritis is uncommon, but rheumatoid factor in the blood is often elevated. Laboratory findings. As in all necrotizing vasculitides, anemia, leukocytosis, elevated sedimentation rate, and C-reactive protein are constant findings. The eosinophil count often exceeds 5OOO/mm*at some point and occasionally reached 30,000/mm2 or more (37). Serum globulin level is often increased, with elevation of IgG and IgM, and notably of IgE (48). Postvasculitic phase. With proper treatment most of the organ damage is repaired, probably in 6 to 12 months. However, peripheral neuropathy may take considerably longer and in some patients persists for years. Allergic symptoms, rhinitis, and asthma usually recur and may be difficult to treat. Hypertension, usually attributable to stenosis of renal arteries, tends to persist. pathology. The features that identify the vasculitis of CSS are eosinophilic intiltration of tissues and specific granulomas.
Pignre 5. Churg-Strauss syndrome(CSS):typicalgranulomain the connectivetissue, showinga stronglyeosinopbiliccenter surrounded by palisading macrophages and many eosinophils (hematoxylin-eosin stain, X540).
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Figure 6. CSS: granulomatousfibrinoidarteritis. There is palisading of macrophagesaround a necrotic artery and many eosinophils in the inflammatory exudate (hematoxylin-eosinstain, X350).
The inflammatory infiltrates contain a large proportion of eosinophils, but sometimes eosinophils are also prominent in other vasculitides, such as PAN or Wegener’s granulomatosis (49). However, in CSS there is striking blood eosinophilia, which is uncommon in other vasculitides, where it rarely exceeds 800 cells/mm*. Granulomas of CSS consist of a core of necrotic eosinophils and necrotic tissue, surrounded by palisading macrophages (epithelioid cells) and multinucleated giant cells (Fig. 5). Granulomas in Wegener’s granulomatosis and in some connective tissue diseases show similar arrangement, but their cores consist of degenerated neutrophils or of tissue undergoing basophilic necrosis. Arteritis in CSS is usually of fibrinoid type (Fig. 6). Fibrinoid is deposited in the intima and in the media, where it is accompanied by degeneration and necrosis of smooth muscle cells. This is followed by intense inflammation, which rapidly acquires a granulomatous character (Fig. 6). Subsequent events are similar to those in PAN. Small vessels, particularly in the skin, are often involved by neutrophilic leukocytoclastic or eosinophilic inflammation. Larger veins may also show inflammation and thrombosis. Special features are noted in some organs. The lungs often show typical changes of asthma in the form of mucous bron-
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chial plugs, eosinophilic bronchitis, and thickening of basement membranes. Rarely, granulomatous inflammation of nasal passages leads to ulcerations and even to septal perforation. Pathogenesls. CSS is an allergic disease. As such it is most likely mediated by an immunologic mechanism or mechanisms, with the immediate hypersensitivity probably playing a major role. Supporting this concept is the frequent elevation of immunoglobulin E (IgE) in the serum during the acute stage of the disease and decrease during remission (48). An acute attack may be precipitated by injection of antigen during the process of desensitization (50). Although immune complexes have not been convincingly demonstrated in the tissues, they are present in the circulation and contain IgE (48). Cellular immunity may also play a role, as suggested by increased ratio of helper to suppressor T cells in the circulation and a large number of helper cells in the granuloma (5152). Autoimmunity is implicated by the frequent presence of P8ANCA in CSS. Perhaps all of these mechanisms play a role, but the important factor is undoubtedly the individual predesposition, called atopy or allergic diathesis. Tissue damage in CSS may be enhanced by the specific proteins liberated from the eosinophilic granules (53). These proteins are toxic to parasites (at which they are directed), but they are also toxic to normal tissues such as heart muscle and may thus contribute to the high incidence of heart disease (54). Dlagnosls. Diagnosis of CSS can usually be made on clinical grounds: the patient has a history of asthma (or, rarely, of only severe allergic rhinitis), blood eosinophilia of over 1,500 cells/mm*, and evidence of systemic vasculitis in two or more extrapulmonary organs (38). Sometimes more than one blood count is needed because of rapid fluctuation of the eosinophilia and the suppressing effect of steroids administered for asthma. Tissue diagnosis (skin, muscle, sural nerve, and sometimes kidney) is used mainly for confirmation. Nowadays nearly every case of severe asthma is treated with steroids, and a biopsy may demonstrate neither granulomas nor vasculitis. As in all necrotizing vasculitides, there is an urgent need for early therapy. In CSS this should be administered on the basis of strong clinical suspicion, without waiting for the biopsy report. Course, prognosis, and therapy. CSS is essentially a selflimited process. However, the damage to the vascular system is so severe that nearly all patients die, usually of cardiac failure, renal failure, or cerebrovascular accident. Steroid therapy has markedly altered the course of the disease, leading to complete or nearly complete recovery in some approximately three fourths of patients. The remaining one fourth have very severe or recurrent disease and benefit from addition of cytotoxic drugs. However, in CSS as in PAN, mild initial symptoms may very suddenly worsen, and it is advisable to add cytotoxics to steroids as soon as the diagnosis is made, Steroids are given in high doses (60 mg/day of prednisone) together with cyclophosphamide (2 mg/kg/day) for several weeks or longer. In very severe cases one may start
with intravenous bolus of methylprodnisolone (1 gm, 1 or 2 times the first day) (55) and intravenous cyclophosphamide (10 mg/kg) (56), repeated if necessary in 7 to 14 days and if permitted by the white cell count. When symptoms have clearly abated, steroids are gradually reduced and azothioprine (2.5 mg/kg/day) may be substituted for cyclophosphamide. Therapy should be continued to at least 6 to 12 months after the onset of remission. Recurrences require retreatment.
20. Braverman IM, Yen A. Demonstration of immune complexes in SpOnand histamine-induced lesions and in normal skin of patients taneous with leukocytoclastic angiitis. J Invest Dermatol 1975;64:105-112. 21. Mullick FG, Mcallister HA, JR, Wagner BM, Fenoglio JJ. Drug-related vasculitis: clinicopathologic correlations in 30 patients. Hum Path01 1979;10:313-325. 22. Christian CL. Hepatitis B virus (HBV) and systemic vascuhtis (editorial). Clin Exp Rheumatol 1991;9:1-2. 23. Marcelin P, Calmus Y, Takahashi H, et al. Latent hepatitis B virus (HBV) infection in systemic necrotizing vasculitis. Clin Exp Rheumatol 1991;9:23-28. 24. Ferri C, Greco F, Longombardo G, Palla P, Marzo E, Moretti A. Hepatitis C virus antibodies in mixed cryoglobulinemia. Clin Exp Rheumatol 1991;9:95-96.
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nodosa and asthma. (abstract).
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