POLYARTERITIS NODOSA GROUP

DEFINITION. In 1866 Kussmaul and Maier described for the first time a patient with polyarteritis nodosa. They introduced the term periarteritis nodosa to describe segmental nodules of medium-sized muscular arteries. Because the swelling of the arterial walls often led to occlusion, many of the clinical manifestations were secondary to necrosis. Hence, polyarteritis nodosa is often classified as one of the systemic necrotizing vasculitides. Classic polyarteritis does not involve the lung as compared to allergic angiitis and granulornatosis of Churg- 'This chapter is an updated revision of one by K. F. Austen that appeared in the 17th edition of this textbook. Strauss, which some writers call polyarteritis with pulmonary involvement.

Polyarteritis associated with hepatitis B antigenernia and extending from the medium-sized muscular arteries to arterioles and venules was described in 1970 by Gocke and colleagues. The association of hepatitis B antigen-antibody complexes and polyarteritis provides strong support to the hypothesis that the vasculitides in general are secondary to the deposition of soluble immune complexes. On clinical grounds no criteria have been identified to distinguish between the hepatitis B positive and negative patients except that all positive hepatitis B antigenernia patients had abnormal liver chemistry test results. In some patients there are manifestations of both classic polyarteritis nodosa and allergic angiitis and granulornatosis of Churg-Strauss. Such patients are classified as being in the group with the so-called overlap syndromes. Their diagnosis, work-up, and management are no different from those of other patients in the polyarteritis nodosa group.

The incidence, age distribution, and male-to-female ratio of polyarteritis nodosa are difficult to determine because a diagnostic serologic procedure is lacking, and the spotty distribution of lesions makes biopsy uncertain. Nonetheless, the condition occurs from infancy to old age, with a peak incidence in the fifth and sixth decades of life, and the male to female ratio has been estimated at from 2 to 3:1.

PATHOLOGY. The lesions of polyarteritis involve arteries of medium and small caliber, especially at bifurcations and wit branchings. The segmental process involves the media, i h edema, fibrinous exudation, fibrinoid necrosis, and infiltration of polymorphonuclear neutrophils and extends to the adventitia and intima. Thrombosis and infarction or hemorrhage occur at this stage. Subsequently, the regions of fibrinoid necrosis are replaced by cellular granulation tissue, and the intima proliferates. Finally the involved segment is replaced by scar tissue with associated intimal thickening and periarterial fibrosis. These changes produce partial occlusion, thrombosis and infarction, and palpable or visible aneurysms with occasional rupture.

In allergic angiitis and granulornatosis the acute fibrinoid necrosis with cellular infiltration involves arterioles and venules as well as medium-sized muscular arteries, whereas in classic polyarteritis such vessels are spared except in areas contiguous to involved medium-sized muscular arteries. It is characteristic of the polyarteritis nodosa group for the vascular lesions to be in different stages of evolution, i.e., acute, subacute, and healed. In allergic angiitis and granulornatosis the pulmonary granulornatous lesions in vascular and extravascular sites are accompanied by an intense eosinophilic infiltration. The granulomas often include an eosinophilic core of altered collagen and necrotic eosinophils surrounded by radially arranged macrophages, lymphocytes, plasma cells, and varying numbers of polymorphonuclear leukocytes, both neutrophilic and eosinophilic.

In patients with polyarteritis associated with hepatitis B antigenernia, the specific antigen has been recognized in immune complexes present in the circulation and deposited in affected vessels along with complement proteins. It is presumed that this pathogenetic mechanism prevails in the entire polyarteritis nodosa group, but the basis for arterial deposition is unknown. The deposition of immune complexes in venules and glomeruli is attributed to changes in permeability and to physical trapping.

CLINICAL MANIFESTATIONS AND DIAGNOSIS. The widespread distribution of the arterial lesions produces diverse clinical manifestations, which reflect the particular organ systems in which the arterial supply has been impaired. Among the early symptoms and signs of polyarteritis nodosa are fever, weight loss, and pain in viscera and/or the musculoskeletal system so that the differential diagnosis is of fever of unknown origin. Striking and specific presenting signs may relate to abdominal pain, acute glomerulitis, polyneuritis, or myocardial infarction. Pulmonary manifestations, especially intractable bronchial asthma, would indicate allergic angiitis and gramilornatosis rather than classic polyarteritis nodosa.

Renal. Renal involvement in two forms, renal polyarteritis and a glomerulitis, may occur separately or together. Approximately 70 per cent of patients with polyarteritis nodosa and renalhdisease have renal vasculitis, whereas the other 30 per cent ave glomerulitis. Renal polyarteritis is the most common lesion seen at postmortem examination. Manifestations of the renal involvement include intermittent proteinuria and microscopic hernaturia with occasional hyaline and granular casts. The glomerulitis is manifested by marked microscopic and even macroscopic hematuria, proteinuria, cellular casts, and progressive renal failure. Hypertension reflects healing renal polyarteritis, progressive glomerulitis, or both. Renal involvement is the cause of death in about two thirds of patients with classic polyarteritis nodosa and about one third of those with allergic angiitis and granulomatosis.

Gastrointestinal. Arterial lesions are commonly found in one or more abdominal viscera. The principal manifestation is pain, especially in the umbilical region or right upper quadrant; anorexia, nausea, and vomiting are less prominent. Impaired arterial supply to the bowel can produce mucosal ulcerations, perforation, or infarction with melena or bloody diarrhea. Involvement of appendix, gallbladder, or pancreas can simulate appendicitis, cholecystitis, or hemorrhagic pancreatitis. Liver involvement can range from hepatomegaly with or without jaundice to the signs of extensive hepatic necrosis. Splenomegaly is uncommon. There has been no consistent relationship between the development of necrotizing angiitis and the appearance of liver disease in patients with hepatitis B antigenernia. Some of the observed combinations include necrotizing angiffis as the initial clinical finding, superimposed upon chronic active hepatitis, or appearing simultaneously with an acute hepatitis.

Central and Peripheral Nervous System. Neurologic manifestations are generally late occurrences in the course of polyarteritis nodosa, and their particular presentation reflects the specific brain area compromised. Headache, seizures, and retinal hemorrhages and exudates occur with or without localizing signs referable to the cerebrum, cerebellum, or brain stem; meningeal irritation may occur as a result of subarachnoid hemorrhage. Multiple mononeuropathy, i.e., involvement of several or even many individual nerves at the same or different times, is a common finding and is attributed to arteritis of the vasa nervorum. The peripheral neuropathy is usually asymmetrical with both sensory and motor distribution. The former can be extremely painful, but the latter, with attendant muscular degeneration, has on occasion been so severe as to dominate the clinical presentation

Articular and Muscular. Arthralgias and myalgias are frequent in polyarteritis nodosa. Arthralgias are migratory, generally without swelling, and apparently due to small localized arterial lesions. Muscle pain or weakness reflects either direct involvement of the arterial supply or a peripheral neuropathy.

Cardiac. Polyarteritis of the coronary arteries and their branches has a frequency approaching that of renal polyarteritis and heart failure is responsible for or contributes to death in one sixth to one half of the cases. The clinical manifestations of cardiac involvement are those of partial or complete arterial occlusion as modified by the superimposition of renal hypertension and an appreciable incidence of acute pericarditis without effusion. Whereas the combination of infarction and hypertension commonly leads to left-sided failure, an occasional patient with allergic angfitis and granulornatosis will present with predominantly right-sided decompensation

Genitourinary. Involvement of the ovaries, testes, and epididymis is frequent, though usually asymptomatic. Mucosal ulceration in the bladder can occasionally precipitate gross hernaturia with dysuria.

Cutaneous. Cutaneous involvement of some form is believed to occur in over 25 per cent of those affected with polyarteritis nodosa. The acute cutaneous manifestations include polymorphic exanthemata-purpuric, urticarial, and multiform in character-and severe subcutaneous hemorrhage, resulting from necrotizing arteritis, with secondary gangrene. Ulcerations and a persistent livedo reticularis are associated with the more chronic stage of the disease. A most characteristic but uncommon finding is cutaneous and subcutaneous nodules; these occur at any time in the disease course. The nodules tend to group, appear in crops, are usually movable, may regress in days or persist for months, range in size from a pea to a walnut, and may cause the overlying skin to become reddened or to ulcerate.

Pulmonary. Although the bronchial arteries can be involved in classic polyarteritis, only allergic angiitis and granulomatosis which involves the pulmonary arteries and parenchyma with granulomatous lesions give rise to clinical manifestations. Asthma, when present, is intractable and associated with a marked peripheral eosinophilia. Pneumonic episodes are transient or progressive and may be accompanied by hemoptysis and/or pleuritic pain. Respiratory involvement accounts for about one half of the mortality, with the remainder being attributable to the polyarteritic process in other organs.

COURSE UNTREATED. The course of polyarteritis nodosa is progressive with destruction of vital organs. Intermittent acute episodes resulting from thrombosis of vital or nonvital structures are prominent. Death is most frequently attributed to renal involvement in cases of classic polyarteritis nodosa and to pulmonary lesions in those cases classified as allergic angiitis with granulornatosis. Cardiac fallur caused by a combination of infarction and renal hypertens on is an additional frequent cause of death in both grou0s, and acute vascular accidents in the gastrointestinal tract d'r central nervous system account for much of the remaining mortality. In the retrospective postmortem study of Rose and Spencer, the five-year survival rate was about 10 per cent in classic polyarteritis nodosa, and about 25 per cent in allergic angfitis and granulomatosis if onset was dated from the start of respiratory symptoms. The report of the British Medical Research Council in 1960 placed the 54 months' survival rate in polyarteritis nodosa at nearly 50 per cent. Rare patients with polyarteritis limited to nonvital sites have been reported to experience an unusually long course or even a lasting remission.

LABORATORY FINDINGS. Leukocytosis, predominantly polyrnorphonuclear, is apparent in over 75 per cent of the cases of polyarteritis nodosa or allergic angiitis and granulematosis, eosinophilia often being marked in the latter group. Hypocomplementernia, which has not been observed in classic polyarteritis nodosa, has been present in patients with hepatitis B antigenernia. The erythrocyte sedimentation rate is customarily elevated. Abnormalities in the urine sediment, especially hernaturia and proteinuria, reflect renal involvement. Abnormalities of the electrocardiogram and electroencephalogram are those expected on the basis of arterial occlusive disease or those secondary to the metabolic disturbances of uremia. Lesions apparent on chest roentgenograms are the rule in patients with allergic anghtis and granulomatosis. The findings range from transient or progressive infiltration to consolidation, cavitation, or scarring; upper and lower lobes are involved with equal frequency. As none of these findings is specific, antemortem diagnosis of polyarteritis depends upon biopsy. Since the arterial involvement is segmental and spotty in distribution, it is advisable to obtain tissue from a symptomatic site, and it is essential to section completely the entire specimen. A deep, open surgical biopsy, including subcutaneous tissue and underlying muscle, should be obtained whenever possible from a skeletal muscle exhibiting pain and tenderness. Involvement of the epididymis and testes is sufficiently common to make this a useful biopsy site if palpation reveals the typical nodularity of segmental vas cular lesions. Needle and surgical biopsies of internal organs with clinical involvement, such as liver or kidney, are gaining in favor. As an alternative or additional procedure, angiography to detect aneurysms of medium-sized muscular arteries in renal, hepatic, or intestinal sites may be helpful.

DIFFERENTIAL DIAGNOSIS. The differential diagnosis of the polyarteritis group includes not only the constituent syndromes but also all those conditions associated with systemic necrotizing vasculitis. The key differences between classic polyarteritis nodosa and other causes of necrotizing vasculitis include the absence of extravascular granulomas, sparing of the pulmonary arteries, failure of venous involvement except by contiguous spread, and predilection for medium-sized arteries. For allergic angiitis and granulomatosis the striking granulomatous response excludes all but Wegener's granulomatosis. The prominence of bronchial asthma, peripheral eosinophilia, and the usual absence of necrotizing lesions in the upper respiratory tract permit a tentative clinical distinction between allergic angiitis and granulomatosis and Wegener's granulornatosis. Underlying connective tissue diseases are still recognized by their clinical characteristics even when necrotizing arteritis becomes prominent. For example, cases of rheumatoid arthritis with ulcerating cutaneous lesions and peripheral neuropathy often exhibit prominent rheumatoid nodules and a high titer of rheumatoid factor. The specificities of the immunoglobulins which accompany active systemic lupus erythematosus or mixed cryoglobulinemia are distinctive; in addition, in the presence of active renal disease both entities manifest a reduced serum complement level not generally observed in classic polyarteritis nodosa. The giant cell arteritides (i.e., temporal arteritis, Takayasu's arteritis) lack the glomerulitis, peripheral neuropathy, and cutanous manifestations notable in polyarterifis nodosa. The combination of progressive nephritis and pulmonary hemorrhage seen in Goodpasture's syndrome is unlike polyarteritis nodosa. The drug-induced hypersensitivity vasculitis group may be difficult to separate on purely clinical grounds, although the history of antecedent drug administration, infrequency of gastrointestinal manifestations, and absence of nodules along arteries are useful points. The clinical presentation in Henoch-Schonlein purpura is distinctive.

TREATMENT. The commonly employed nonsteroidal antiinflammatory agents have little or no effect on the polyarteritis group; thus, corticosteroids have been employed most widely. Large doses, in the range of 40 to 60 mg of prednisone per day, afford symptomatic relief but probably have little effect on the one-year survival statistics. In our series of 17 patients falling within the polyarteritis group, including two with allergic angiitis and granulomatosis and six with hepatitis Bassociated polyarteritis, 14 experienced dramatic remission with the introduction of cyclophosphamide at a dose of 2 mg per kilogram per day. lt was subsequently possible to reduce the cyclophosphamide and to taper the steroids to every other day and yet maintain a remission and in some instances resolution of microaneurysms on repeat celiac axis angiography was noted