Approach to Systemic

Stephen R. K oller, M D William M. Edw ards, M D Richmond, Virginia

Systemic vasculitis is a confusing subject which has been difficult to accumulation of inflammatory cells is classify and understand. Improvements in therapy increase the sometimes seen in the early or later importance of early diagnosis. This paper reviews the clinical and stages of vasculitis, but because such histopathology, by itself, is so non­ pathological differences of the systemic vasculitides, and a working specific, its presence is not considered approach to the differential diagnosis of vasculitis is formulated evidence of systemic necrotizing vas­ based on the size of the vessel involved. Vessel size and histo- culitis. pathology determine to what group of diseases a particular syndrome belongs, thereby allowing subclassification and a more rational approach to management. System of Classification There are two characteristics that may help the clinician differentiate one vasculitic syndrome from the Systemic vasculitis is a confusing classification, although quite helpful, many others. These are vessel size and and controversial subject. Its com­ is not entirely adequate because it is the cellular response to injury. plexity is attested to by the more than based on syndrome identification and one dozen syndromes it encompasses. does not emphasize the histopatho­ Size These syndromes differ not only logic changes within the vessels and There are four groups of pathologically, but also in their clinical the directly due which can arbitrarily be envisioned. settings and therapeutic responses. The to circulatory compromise secondary These are: development of relatively beneficial to those changes. It is the purpose of 1. Large arteries — the large elastic therapeutic regimens has heightened this paper to present a pathophysi­ arteries and their branches the need for early diagnosis. The most ologic approach to the differential 2. Medium arteries — vessels which are widely used classification devised by diagnosis of the systemic vasculitides. visible to the naked eye; these are Zeek1,2 and modified by Braverman3 This paper limits discussion to muscular and supply organs defines several syndromes by clinical those syndromes characterized by a and pathologic criteria (Figure 1). This necrotizing vasculitis, that is, where 3. Small arteries there are inflammatory cells within the a. microscopic arteries — vessels wall of the vessel during the acute 100 to 500 microns in diameter stage of the illness and/or necrosis of b. — vessels whose thick­ part or all of the vessel wall. This ness is approximately equal to From the Division of immunology and the size of the lumen; they are Connective Tissue Diseases, Department of necrotic material when stained with Medicine, Medical College of Virginia, hematoxylin and eosin takes on the less than 100 microns in outside Health Sciences Division, Virginia Com­ pinkish, homogeneous appearance of diameter monwealth University, Richmond, Virginia. 4. Capillaries — vessels with no media Requests for reprints should be addressed fibrin, hence the term “fibrinoid to Dr. Stephen R. Koller, Kenner Army Hospital, Fort Lee, Va 23801. necrosis.” A simple perivascular Despite some overlap, one or two

t h e JO URNAL OF FAM ILY PRACTICE, VOL. 3, NO. 4, 1976 3 6 9 vessel groups may predominate in a Symptoms and signs of large cerebral ischemia or any of the myriad particular syndrome and the symp­ occlusion stem from a compromise in of syndromes that may follow occlu­ toms and signs that ensue can help the the circulation to areas directly sion of the cerebral vasculature. clinician distinguish among the vascu- supplied by the occluded vessel. Symptoms and signs of medium litic syndromes. Although and Involvement of the carotid or sub­ artery occlusion are extremely vari­ venules are often involved in many of clavian artery can induce a change in able. Involvement of cutaneous vessels the vasculitides, the clinical features of the pulse pressure or . can cause ulcerations and gangrene the disease are most often due to Involvement of the vessels of the lower Raynaud’s phenomenon may occur arterial involvement. Therefore, or upper extremities may give inter­ There may be end-organ involvement venous involvement, as such, is mittent . Similarly, there in the central nervous system, kidney ignored. may be symptoms of transitory pancreas, liver, lung, and heart, giving signs and symptoms of vascular insuf­ ficiency and clinical patterns related to disease in these organs. Visual dis­ turbances are noted when the ophthal­ NECROTIZING ANGIITIS mic artery is involved, and there may be headaches as well as tenderness over ------J I I the temporal artery when it is in­ GIANT CELL ALLERGIC WEGENER'S GRANULOMATOSIS AND VARIANTS volved. It is important to note that angiography may be helpful in diag­ nosing medium vessel arteritis because of the and occlusive

POLYARTERITIS HYPERSENSITIVITY ANGIITIS changes visualized.4 NODOSA (LEUCOCYTOCLASTIC ANGIITIS) Small artery involvement may also take many forms. Livedo reticularis is due partially to reflex capillary dilation secondary to arteriolar insufficiency.5 HYPERSENSITIVITY HENOCH- ANGIITIS (ZEEK) SCHONLEIN Small artery occlusions may occur in PURPURA the kidney, brain, and skin as well as other organs. Involvement of the vasa

1-3 nervorum causes mononeuritis multi­ Figure 1. Currently accepted classification of necrotizing angiitis plex.6 Nodules may be a consequence of small artery disease.7

Table 1 Arteritic Syndromes

HISTOPATHOLOGY VESSEL SIZE

Large Vessel Syndromes Medium Vessel Syndromes Small Vessel Syndromes Involving Involving Involving (Large arteries, (Medium arteries, (Small arteries, medium arteries) small arteries) capillaries)

Granulomatous Allergic angiitis Wegener's granulomatosis temporal arteritis of cranial arteritis Churg and Strauss Takayasu's arteritis

Non-gra nulomatous Polyarteritis nodosa Hypersensitivity angiitis (Acute or chronic Rheumatoid arteritis Henoch-Schonlein purpura Polyarteritis with Serum sickness depending on a. Hepatitis associated Childhood dermatomyositis stage of disease) antigen Subacute bacterial endocarditis b. Methamphetamine Systemic lupus erythematosus Cryoglobulinemia

3 7 0 THE JO URN AL OF FAM ILY PRACTICE, VOL. 3, NO. 4, 1976 Finally, capillary disease has its exclude the diagnosis of giant cell bifurcation, fibrinoid necrosis, and oWn distinct features. Petechiae are arteritis. Therefore, Anderson and various stages of healing of the vessels the hallmark of capillaritis and are Bayles suggest that the diagnosis be are characteristic histological lesions. m0St easily seen in the skin, but may made clinically. They reserve a Vascular and also be found in other organs including temporal artery biopsy for those formation contribute to the clinical bowel, kidney, brain, and joints. patients with known origin or when picture. Fever, abdominal pain, hyper­ the diagnosis is clouded by psycho- tension, neuritis, and musculoskeletal o genic features. However, others feel complaints occur frequency. Approxi­ that a positive biopsy should be mately 80 percent of patients with obtained before committing a patient polyarteritis nodosa will ultimately to any potentially dangerous therapy. have renal involvement. The diagnosis Histopathology Although the polymyalgia rheumatica- is suggested by the multisystem signs The second consideration is histo- giant cell arteritis syndrome is self- and symptoms and is confirmed by the pathology. There are two basic types limiting, lasting one to two years, the biopsy of involved organs or by deep of involvement: (1) Granulomatous, end result may be a severe vascular muscle biopsy. Some investigators, as and (2) Non-granulomatous. catastrophe. Takayasu’s arteritis, a mentioned previously, have found There are some syndromes which syndrome of large vessel granu­ angiography to be of great value in have granulomas and/or giant cells in lomatous arteritis with giant cells, is detecting aneurysms of the medium- the pathologic specimen regardless of found predominantly in young sized branches of the renal, cerebral, when a biopsy is taken. Other syn­ women. Signs and symptoms may and celiac arteries.4,11 About ten dromes are not ordinarily associated resemble those of polymyalgia rheu­ percent of patients with polyarteritis with granulomas. Instead, in the acute matica. In addition, arterial obstruc­ nodosa will have a benign cutaneous stage, polymorphonuclear leukocytes tion may be so severe that pulses may variant manifested by a chronic or are found in the vasculitis lesion. As be quite decreased or absent. Obstruc­ recurrent course and a variable healing takes place, a mononuclear tive lesions have been treated success­ response to corticosteroids, but with a (chronic) reaction occurs. Keeping in fully by arterial grafts. Corticosteroids favorable ultimate outcome.12 These mind that there is overlap and using have provided an effective means of patients have a syndrome charac­ the vessel size and histopathology as a preventing thrombotic disasters and, if terized by subcutaneous nodules, foundation, a partial classification of initiated early in the course of the livedo reticularis, and myalgias. the arteritic syndromes can be formu­ disease, produce a dramatic remission A polyarteritis-like syndrome has lated (Table 1) which is somewhat in any one of the large vessel been described in association with different from that of Zeek (Figure 1). granulomatous syndromes. methamphetamine abuse1,1 and with hepatitis B infections' 4 Two patients have recently been described who had hepatitis-associated-antigen (HAA) and antibody to hepatitis-associated- antigen present in the walls of the involved vessels.14 Rheumatoid vas­ Application of the Classification Medium Vessels with Granulomas culitis is a disease also involving Large Vessels with Granulomas Allergic granulomatosis was first medium-sized vessels and clinically is Giant cell arteritis, a syndrome described by Churg and Strauss,9 and characterized by a more severe rheu­ peculiar to the elderly, is characterized is similar to polyarteritis nodosa in its matoid disease, skin ulcers, gangrene, by fever, headache, fatigue, and arth­ involvement of medium and small high rheumatoid factor titre, and ralgia. It often includes the poly­ arteries. However, the pathology is occasionally hypocomplementemia.1 5 myalgia rheumatica syndrome con­ somewhat different in that granu- sisting of proximal myalgia and a lomata develop in and around the striking increase in the erythrocyte involved vessel and are most often sedimentation rate. Although examina­ accompanied by eosinophils. Symp­ tion of the muscles from patients with toms are also different. Asthma and lung involvement are two features not polymyalgia rheumatica is unrevealing, Small Vessels with Granulomas usually noted in polyarteritis nodosa, there is a typical histological lesion Small arteries, capillaries and occa­ although they are prominent in allergic involving large and medium arteries, sionally medium arteries are prin­ granulomatosis.1 0 especially the carotid and its branches. cipally involved in Wegener’s granu­ This arteritis is a patchy, focal lomatosis which may present clinically panarteritis (Figure 2) which, late in as sinusitis, focal glomerulitis, arthritis, the disease, may result in fibrotic or lower respiratory tract lesions. The occlusion. Headaches, jaw claudication, diagnosis is confirmed by histological studies of soft tissue biopsies of the blindness, cerebrovascular accidents, Medium Vessels with no Granulomas and myocardial infarctions are possible respiratory tract (Figure 4). Recently sequelae to giant cell arteritis. Because Vasculitis of medium and small Liebow described several variants of of the spotty distribution of the vascu­ arteries (Figure 3) is called poly­ Wegener’s granulomatosis on the basis lar lesions, a negative arterial (eg, arteritis nodosa. Acute and chronic of histological structure and natural temporal artery) biopsy does not inflammation, especially at points of history.16

THE JO URNAL OF FAM ILY PRACTICE, VOL. 3, NO. 4, 1976 371 Small Vessels without Granulomas The most commonly seen of the necrotizing angiitides is the group re­ ferred to as leukocytoclastic angiitis involving polymorphonuclear leuko­ cytes throughout the wall of the small blood vessels, especially the arterioles venules and capillaries (Figure 5) Leukocytoclasis, nuclear dust, and fibrinoid necrosis are the classical histological features. In most cases an etiology cannot be established, but occasionally an underlying systemic disorder such as Henoch-Schonlein purpura, sub-acute bacterial endo­ ca rd itis, or cryoglobulinemia is present. The systemic manifestations of leukocytoclastic angiitis depend upon the organ involved but com­ monly involve the bowel, skin, joints, and kidney. Cutaneous lesions include erythem atous macules, petechiae, ecchym oses, vesicles, and rarely Figure 2. Periarteritis of a temporal artery illustrating the typical mononuclear cell necrotic pustules and urticaria. The infiltrate, focal necrosis, narrowed vascular lumen, and giant cells (Hematoxylin-eosin, small vessels may be involved more chronically with mononuclear cells, as is often seen in systemic lupus erythematosus. Nodular or palpable purpura is not specific for any diagnosis or etiological agent, for it implies the presence of some degree of inflammatory response which is not found in purpura due to thrombocytopenia. Once a diagnosis of small vessel vasculitis is made, a thorough search for the etiology should be undertaken. Additional history should be obtained, such as detailed drug exposure and hepatitis exposure, to facilitate the diagnoses of serum sickness associated with certain drugs and serum sickness as a prodrome of HAA positive hepatitis. Appropriate diagnostic tests such as blood cultures, antinuclear antibody determinations, LE cell preparations, and cryoglobulin determinations should be done. It is important to note that numer­ ous infectious agents can damage endothelium and cause a systemic vasculitis. The most common orga­ nisms known to do this in man are the rickettsiae and neisseria. In addition, disseminated intravascular coagulation and thrombotic thrombocytopenia purpura may cause diffuse vascular occlusion. These syndromes should not be confused with a primary vascu­ litis disease even though they may mimic or accompany vasculitis. The Figure 3. Small artery from a patient with cutaneous polyarteritis nodosa. Note tne clinician must recognize septicemia intense inflammatory infiltrate both within the vessel wall and in the surrounding and disseminated intravascular coagu- tissues, and the obliterated vascular lumen (Hematoxylin-eosin, X297.60).

372 THE JO URN AL OF FAM ILY PRACTICE, VOL. 3, NO. 4, 1976 Figure 4. Section from a lung biopsy of a patient with Figure 5. Leukocytoclastic angiitis involving a dermal arteri­ Wegener's granulomatosis. Pathological changes consistent of ole. Note the endothelial disruption, nuclear dust, and mild arteritis and venulitis in addition to a peri-bronchiolar perivascular inflammatory infiltrate (Hematoxylin-eosin, granuloma (Hematoxylin-eosin, X45). X750).

lation early despite the similarities of in rheumatoid disease, hepatitis- References these specific syndromes to systemic associated polyarteritis, and rneth- 1. Zeek PM: Periarteritis nodosa: A critical review. Am J Clin Pathol vasculitis of undetermined etiology. amphetamine-associated polyarteritis. 22:777-788, 1952 Systemic steroids may be of benefit in 2. Zeek PM: Periarteritis nodosa and other forms of necrotizing angiitis. N Engl J alleviating symptoms of arthritis, Med 248:764-722, 1953 dermatitis, or abdominal distress asso­ 3. Braverman IM: Skin Signs of System ic Disease. Philadelphia, WB ciated with vasculitis, but they should Saunders, 1970, pp 199-238 Approach to Treatment not be used indiscriminately. 4. Leonhardt ETG, Jakobson H, Ringvist OTA: Angiographic and clinico- The approach to treatment begins At the present time any classifica­ physiologic investigation of a case of poly tion of necrotizing angiitis is a arteritis nodosa. Am J Med 53:242-256, with making the correct diagnosis. The 1 97 2 clinician should look for signs and compromise. However, with increasing 5. Fitzpatrick TB, Arndt KA, Clark WH, Jr, et al (eds): Dermatology in General symptoms that might enable him or understanding of the pathophysio­ Medicine. New York, McGraw-Hill, 1971, p logical mechanisms underlying inflam­ 971 her to distinguish the size of the vessel 6. Conn L, McDuffie FC, Dyck PS: involved. When medium or large vessel mation and inflammatory vascular Immunopathologic study of sural nerves in syndromes, a more rational approach . Arthritis Rheum disease is suspected, arteriograms may 15:135-143, 1972 be helpful. Pathology is then impor­ to the vasculitides can be expected. 7. Sokoloff L, Orbison JL, Smith DE: The pathophysiology of peripheral blood tant to distinguish the granulomatous Until that time comes, the classifica­ vessels in collagen diseases. In Orbison JL, from the non-granulomatous diseases. tion of necrotizing angiitis presented Smith DE (eds): The Peripheral Blood Vessels. Baltimore, William s and W ilkins Co, Once a histological diagnosis is made, a here may be useful to the clinician 1963, pp 300-308 sub-diagnosis should then be sought. It caring for patients with vasculitic 8. Anderson LG, Bayles TB: Poly myalgia rheumatica and giant cell arteritis. must be remembered that there will be syndromes. DM, January, 1974, p 16 9. Churg J, Strauss L: Allergic granulo an occasional patient with an over­ matosis, allergic angiitis, and periarteritis lapping clinical picture. Cryoglobuli­ nodosa. Am J Pathol 27:277-294, 1951 10. Sokolov RA, Rachmaninoff N, nemia, for example, most often causes Kaine HD: Allergic granulomatosis. Am J arteriolar and capillary disease, but Med 32:131-140, 1962 11. Bron KM, Gajaraj A: Demonstration may occasionally be associated with of hepatic aneurysms in polyarteritis nodosa polyarteritis syndrome.1 7 by arteriography. N Engl J Med 282:1024 1025, 1970 Treatment should be limited and 12. Borrie P: Cutaneous polyarteritis Acknowledgements nodosa. Br J Dermatol 87:87-95, 1972 directed at as specific a syndrome as We are indebted to Drs. Marion Waller 13. Citron BP, Halpern M, McCarron M, Possible. Steroids are the drug of and Shaun Ruddy of the Division of et al: Necrotizing angiitis associated with Immunology and Connective Tissue Dis­ drug abuse. N Engl J Med 283:1003-1011, choice in the large vessel diseases and eases, Medical College of Virginia, and Dr. 1 9 7 0 Edward Abell of the Department of 14. Gocke DJ, Hsu K, Morgan C, et al: cytotoxic agents should probably be Dermatology, Medical College of Virginia Vasculitis in association with Australian employed in severe cases of Wegener’s for reviewing this manuscript. We also antigen. J Exp Med 134:330S-336S, 1971 appreciate the cooperation of the Depart­ 15. Franco A, Schur PH: Hypocomple- granulomatosis.18 Appropriate thera­ ment of Pathology for the use of their mentemia in rheumatoid arthritis. Arthritis peutic measures should be employed pathologic material. Rheum 14:231-238, 1971

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