The Characterization of Polyarteritis Nodosa, Dermatomyositis and Progressive Systemic Sclerosis

The Characterization of Polyarteritis Nodosa, Dermatomyositis and Progressive Systemic Sclerosis From the National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, Bethesda, Maryland

ROGER L. BLACK, M.D. Clinical Assistant Professor of Medicine, Georgeto'Wn University School of Medicine; Senior Investigator, National 1nstit1lte of A rthritis and Metabolic Diseases, National I nstitute~ of 1Iealth

THl<; RHEUMATIC DISEASES, polyarteritis nodosa, dermatomyositis and progressive systemic sclerosis, although each manifested by disorder of various elements of connective tissue, exhibit clinical and pathologir. features sufficiently distinctive in most cases to permit recognition without difficulty. In addition to the diagnostic features, a number of less characteristic but interesting interrelationships have been described in recent years. The classic features will be considered first. POLYARTERITIS NODOSA

Most observers now agree that polyarteritis nodosa represents several, not one, pathologic disorders. It would be difficult to improve upon the classification proposed by Zeek31 which includes (1) classic polyarteritis nodosa of the Kussmaul-Maier type, with multisystem involvement, fever, polyneuritis, and a chronic course; (2) hypersensitivity angiitis, often with a rapidly fatal course with renal, dermal and pulmonary involvement; (3) rheumatic arteritis (fulminating rheumatic fever); (4) allergic granulomatous angiitis, often with asthma, eosinophilia, and a chronic course; (5) temporal arteritis, and (6) a miscellaneous group which may include the arteritis associated with other connective tissue diseases. The vascular lesion varies in terms of size of v~~sel involved, layers affected, character of the infiltrate, degree of necrosis, and presence of thrombus. The classic lesion includes inflammatory infiltrate in all layers, fibrinoid necrosis most prominent in the media, and thrombosis.

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Infarction often occurs in tissue distal to such lesions. At necropsy, lesions are most commonly found in the kidney, heart and adrenals (over 50 per cent of cases), and somewhat less frequently in the gastrointestinal tract, liver and spleen (25 to 50 per (~ent). Pulmonary lesions are found in approximately 25 per cent of eases. Experimental production of the lesions of polyarteritis nodosa has been achieved by the administration of foreign proteins to the guinea pig and rabbit, of streptococci to the rat, and by the induction of hypertension in the rat. Clinical Features

Polyarteritis nodosa may oeeur in patients at any age from one to over 70 years. The disorder is three times more common in males than females. In a typical case early symptoms consist of malaise, weakness, fever, generalized myalgia and arthralgia. When peripheral neuropathy develops the patient is unable to dorsiflex the wrist or ankle and may experience paresthesias or numbness. Skin lesions, such as a crop of nodular (0.5 to 1 cm. in diameter) lesions, may appear on an arm or leg. These are tender and erythematous, and may subsequently ulcerate. Later in the course, skin ulceration, subcutaneous hemorrhages, and even gangrene of a finger or toe may develop. Less frequently cutaneous manifestations consist of a maculopapular eruption. During the early course of his illness, the patient may experience attacks of severe gastrointestinal pain. Such episodes are usually associated with intra-abdominal vascular lesions. It must be remembered, however, that ulceration of the gastrointestinal tract occurs in this disease and surgical intervention may be required. Milder gastrointestinal symptoms sometimes occur including nausea, vomiting, diarrhea and/or constipation. Physical examination of a typical patient reveals evidence of even more widespread involvement. Hypertension associated with hemorrhage in the retina is a late finding and suggests renal involvement and a rapidly fatal course. Other ocular lesions are less common and include episcleritis, ulceration and iridocyclitis. Cardiae manifestations vary from mild tachycardia to congestive failure and occasionally myoeardial infarction. Neurologic assessment reveals both motor and sensory loss in the involved area. Less eommon neurologic manifestations include convulsions, eranial nerve disorders and psychiatrie disturbances. Joint tenderness and swelling resembling rheumatoid arthritis may be present. Although the symptoms and findings in this "typical" case suggest a poor prognosis, the eourse in polyarteritis nodosa is variable and some patients may experience complete remission. 19 There is reason to consider separately patients with pulmonary polyarteritis nodosa. The sex incidenee differs (1: 1). The first manifestations in such cases usually consist of chronie bronchitis, asthma and/or pneumonia. Rose and Spencer18 have emphasized the occurrenee of striking eosinophilia both in peripheral blood and in loeal lesions.

Characterization of Polyarteritis N odosa and Dermatomyositis 1297 The total course of disease tends to be longer than that of patients beginning with multisystemic disease. Another clinicopathologic variant is Wegener's granulomatosis, manifested by granulomatous lesions throughout the respiratory tract and sometimes other organs, particularly the kidney and spleen. 26 Foci of vascular necrosis are also noted, independent of the granulomas, sometimes involving venules as well as arteries and arterioles: The clinical features include persistent purulent rhinorrhea, epistaxis, antral pain, chronic cough, hemoptysis, and sometimes pleurisy. Mucosal ulcerations and occasionally bone destruction in the nose or palate occur. Later, evidence of widespread multisystem disease may appear. The course is usually rapidly fatal (one to five months). Diagnosis Diagnosis on clinical grounds is not difficult when the signs and symptoms of polyarteritis nodosa are "classic." Often, however, cases simulate other connective tissue disorders. Table 1 contains a list of the common clinical features and their relative prevalence in the three COllnective tissue diseases under discussion. In polyarteritis nodosa, renal, cardiovascular, neurologic and gastrointestinal manifestations predominate. Biopsy of skin, muscle or kidney is the most helpful of the laboratory procedures in the diagnosis of polyarteritis nodosa. Although the presence of arteritis is not specific for polyarteritis nodosa (as indicated by Sokoloff elsewhere in this monograph21 ) the distribution and character of the lesions are of help in supporting the clinical diagnosis. Hematologic examination may show leukocytosis which is sometimes striking. Eosinophilia also occurs. Anemia, an elevated erythrocyte sedimentation rate, or the presence of C-reactive protein are often found but are of little diagnostic help. The urine may contain albumin, red cells, or casts and the blood urea nitrogen level may be elevated, suggesting renal involvement. Table 1.

Comparison of Clinical Manifestations

DERMAL

(RASH,

N.I!:URAL

INTJ<.:STINA.L

(PERIPH-

ARTICULAR

AND/OR

NESS AND

ERAL

RENAL

ATROPHY)

ATROPHY)

NI<:URITIS)

(ARTHRITIS)

++++

++ +++

++ ++++

+++ +

+ +

++ +

+++ +

++++ +

++

++++

++

++

+++

++

+++

++

NODULES,

Polyarteritis nodosa Dermatomyositis Progressive systemic sclerosis

GA8TRQ-

MUSCULAR (WEAK-

(HYPOFUNC- CARDIOPULTION AND/OR VA8MONARY ULCERATION) CULAR

Relative prominence of symptoms indicated in increasing order from 1 to 4 plus marks.

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Treatment

Conservative and supportive therapy offers some relief of symptoms in polyarteritis nodosa. Aspirin, 3.6 gm. in daily divided doses, relieves myalgia and arthralgia in many. Fundtional splints may be indicated in some patients with neUl'opathy.· Special exercises may help maintain muscle tone. Corticosteroid therapy has been especially useful in suppression of symptoms. The Medical Research Council in England has reported a study 14 of the long-term effects (three years) of cortisone in polyarteritis nodosa. A treated group (cortisone beginning at 200 mg. daily and later adjusted to a higher or lower minimum maintenance level as indicated) of 21 patients was compared retrospectively with a noncorticosteroid-treated group of 19. The nontreated group il,1cluded eight patients with hypertension who died within one year of the time of the diagnosis and, hence, biased the study. However, when all patients with hypertension at the start of the study were excluded, the mortality rate in the first year period (but not three year period) was favorable in the treated group. This study suggests that in addition to providing relief of symptoms, corticosteroids may prolong life. There is no suggestion that these agents offer a CUl'e. The newer synthetic corticosteroids, prednisolone, methyl prednisolone, triamcinolone and dexamethasone may be even more advantageous as therapeutic agents because of decreased sodium retaining effect. DERMATOMYOSITIS

Dermatomyositis is a disorder of unknown etiology manifested by inflammation and degeneration primarily involving muscle and skin. Many patients present with predominant muscle involvement, a condition long referred to as polymyositis.:;r~e characteristic patl;l.Ologic lesion occurs in muscle tissue. Areas of foc!11 necrosis are scattered throughout and a diffuse inflammatory component with lymphocytes and monocytes predominating is also seen. Older lesions show fibrosis. Boylan and Sokoloff3 have recently emphasized the importance of vascular lesions in this disease. Sclerotic changes are found in small arteries and arterioles of muscle, skin, and the gastrointestinal tract. Clinical Features

Dermatomyositis may oCCUl' at any age from two to 73 years and more often in females than males (2: 1). Proximal muscle groups are the most prominently affected. The muscle is usually swollen and may be tender on palpation. As the disease advances, atrophic changes occur and the resulting muscle shortening causes apparent joint contractUl'e with consequent difficulty in use of extremities. Skin involvement is variable. Erythema or bluishdisc(')loration about the eyelids is charac-

Characterization of Polyarteritis N odosa and Dermatomyositis 1299

Fig.!. A 5 year old patient with dermatomyositis. Symmetrical ulcerative lesions seen here on the back were also noted anteriorly.

teristic. An erythematous macular rash may be seen over the body generally, and sometimes an exfoliative rash occurs. Edema of the skin is frequent. Ulcerative skin lesions often occur in children with dermatomyositis. Figure 1 is a photograph of such a patient observed by the author and colleagues. These lesions tend to be progressive and are slow in healing. Calcium deposits in the subcutaneous tissue sometimes develop later in the course of the disease. Difficulty in swallowing usually is the result of involvement of the muscles of deglutition. Ulceration of the gastrointestinal tract may develop. Associated interstitial pneumonitis and nonspecific evidence of cardiac involvement are sometimes seen. Joint pain and erythema around tender joints are not uncommon. Arthritis with synovial effusion occurs. Prognosis is difficult to assess in dermatomyositis. Wedgwood, Cook and Cohen27 studied the course of the disease in 26 children and reported that 16 were alive one to three years after onset. Of these, eight were able to carry on normal activities, four had severe crippling and the remaining four had active disease. The mortality rate is higher in children than in adults. The question of mortality rate is complicated somewhat by the association of dermatomyositis with neoplasms. In 697 reported cases of dermatomyositis, 9, 20, 29 malignancy, occurring most frequently in the stomach, breast, lung and ovary, was found in 107. All patients were above age 40.

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Diagnosis

In confirming a clinical impression of dermatomyositis, skin and muscle biopsy provides the most useful information. Unfortunately, histopathologic features are not specific. During the acute phase, urinary creatine excretion is elevated. 5 Normal males excrete less than 100 mg./24 hours; females and children less than 300 mg. Values in dermatomyositis may reach 1 gram or more. Of course some increase in creatine excretion occurs in other diseases associated with muscle breakdown and is therefore not a specific finding. The electrocardiogram may show nonspecific low voltage or conduction defects. Treatment

In patients with mild symptoms, relief of muscle and joint pain may be achieved with salicylate therapy. Splints and active and passive exercises are of value in preventing or overcoming joint contractures. Corticosteroid therapy is often indicated in this disorder and may be life-saving. We have employed prednisone in doses of 10 to 20 mg. daily. The result is not as dramatic as in the other connective tissue diseases, but gratifying increase in appetite and general strength often follows the initiation of treatment. Joint pain decreases. In selected cases with continued weight loss while on corticosteroid therapy, we have administered methyl-testosterone in doses of 20 to 80 mg. daily in an effort to induce positive nitrogen balance. Some patients have had a favorable response. There is no specific or uniformly effective therapeutic agent in this disease. PROGRESSIVE SYSTEMIC SCLEROSIS (SCLERODERMA)

Progressive systemic sclerosis, although involving primarily the skin, frequently presents with widespread visceral disease. The characteristic pathologic lesion in the skin is atrophy of the epidermis and its appendages. Throughout the dermis, hyalinized collagen fibers are apparent. Fibrosis is noted in the skin, as well as the lungs, muscles, myocardium 28 and gastrointestinal tract. Particular emphasis has been given to the renal lesion15 which consists of intimal thickening of the intralobular arteries and fibrinoid necrosis in the smaller vessels, with ischemic lesions in the cortex. Sokoloff24 has described the fibrosis and inflammatory reaction seen in the synovium of patients with progressive systemic sclerosis. Clinical Features

Progressive systemic sclerosis occurs more often in females than males (2: 1). Age of onset ranges from three to 71 years. As with the other connective tissue diseases, the onset is often insidious. Constitutional symptoms occur including slight fever and malaise. The skin may show

Characterization of Polyarteritis N odosa and Dermatomyositis 1301

Fig. 2. Hand8 of a patient with progressive systemic sclerosis. The thick, tight skin, areas of vitiligo, and increased pigmentation are apparent.

mild edema, pigmentation, and/or vitiligo (Fig. 2). The patches of thickening vary greatly in size and distribution but hands, forearms, face and upper chest are frequent sites. When the face is involved, t.he patient may have difficulty opening the mouth. Patients often have Raynaud's phenomenon and some may have ulcers, atrophy or gangrene of fingers and toes. Subcutaneous calcium deposits appear later. Esophageal involvement is indicated by difficulty in swallowing solid food. Constipation alternating with diarrhea suggests malfunction of the intestinal tract, and the malabsorption syndrome may develop. Cardiac symptoms, although not common, may occur, and include dyspnea, orthopnea, arrythmia and congestive failure. Cor pulmonale may occur. Dyspnea also suggests pulmonary involvement. In such cases pulmonary fibrosis may follow with decreased vital capacity. The abrupt onset of hypertension may indicate the presence of the renal lesion of progressive systemic sclerosis. When this occurs, uremia and death follow usually within a few monthsP Articular manifestations closely resemble those of rheumatoid arthritis, with joint swelling, redness, warmth, tenderness and effusion. Small and large joints both may be inflamed. Peripheral neuropathy has been reported.!l The course of progressive systemic sclerosis is usually less rapid than that of polyarteritis nodosa or dermatomyositis. In the absence of renal involvement, prognosis may be good for longevity. Patients have lived with the disease for over 30 years. Diagnosis Biopsy of the skin, gastrointestinal tract or kidney may yield tissue of diagnostic importance.

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Radiographic examination is also helpful in the diagnosis of progressive systemic sclerosis, where esophageal rigidity and lack of peristalsis may be found. Depressed small bowel activity and the fibrotic pulmonary lesions of the disease may also be found by radiography. Soft tissue calcification may suggest progressive systemic sclerosis or dermatomyositis. Resorption of the distal phalanges is seen in some patients with the former. As in the case of the other connective tissue disorders, nonspecific electrocardiographic changes are sometimes found, including low voltage, T-wave depression, and conduction disturbances. Anemia, elevation of the erythrocyte sedimentation rate and presence of C-reactive protein, though sometimes found, are of no diagnostic value. Treatment

Conservative management with aspmn 2.4 to 4.8 grams per day, exercises, and resting splints has been effective in bringing relief to patients with mild forms of the disease. In severely ill patients we 16 have employed corticosteroids in doses equivalent to prednisone, 10 to 20 mg daily. The response in most has been favorable with diminution in skin swelling and tightness, improvement in ventilating capacity, and decrease in joint inflammation. Ijttle improvement was observed in the gastrointestinal or renal manifestations, however. Whenever corticosteroids are employed in the management of any of these diseases, careful observation for the appearance of undesirable side effects is necessary. Osteoporosis with fracture, peptic ulceration and mental aberrations are among the most important. Less well established forms of therapy have been suggested. Chelation with 3 grams of ethylenediamine tetra-acetic acid given intravenously in 500 m!. of 5 per ecnt dextrose solution over a 3,Yz hour period has been found effective in reducing subcutaneous calcium deposits12 and has resulted in improvement in skin and gastrointestinal manifestations. 30 Relaxin, an ovarian hormone of pregnancy, has also been administered in doses of 2.5 to 80 mg. daily after priming with diethylstilbestrol, 1 mg. daily.6 Although improvement in the skin has been observed, this form of therapy is still in the investigative stage. Severe anaphylaxis has been reported,13 and death has followed the administration of as little as 1 mg. of relaxin. 6 COMMENT

Although the classic clinical and pathologic features of each of these three diseases permit their characterization as separate entities, an increasing number of interrelationships and transitional or "overlapping" cases are being observed (Table 2). Most prominent is the occurrence

Characterization of Polyarteritis N odosa and Dermatomyositis 1303 Table 2.

Interrelationships Between Some Connective Tissue Disorders

RHEUMATOID ARTHRITIS

Occurrence of arteritis3, 24, 25 •.. , Occurrence of Sjogren's syndrome4 • • . • • . . . . . Rheumatoid factor . III serum,1 10 ..... Antinuclear factor • In serum 7 ........ Occurrence with agammaglobulinemia 32 • • • . , . ,

•

SYSTEMIC LUPUS ERYTHEM-

PROPOLY-

GRESSIVE

ATOSUS

ARTERITIS NODOSA

DERMATOMYOSITIS

SYSTEMIC SCLEROSIS

+++

++

+++

+

++

+++ ++++ +

++ ++ ++++

+ +

++* + +

++ ++ +

+

+

++

Relative prominence is indicated in increasing order from 1 to 4 plus.

* Polymyositis or myopathy.

of arteritis. Although most characteristic of polyarteritis nodosa, arteritic lesions are present in the skeletal muscle of rheumatoid arthritis patients22 in the early rheumatoid nodule,23 and in the synovium. In rheumatoid arthritis, (in contrast with polyarteritis nodosa), the arterial lesion is less widespread, less often necrotic and usually lacks thrombosis. 22 Arteritis also occurs in progressive systemic sclerosis25 and dermatomyositis. 3 Sjijgren's syndrome, characterized by keratoconjunctivitis sicca and xerostomia, is most often associated with rheumatoid arthritis but also occurs in patients with the other rheumatic disorders including progressive systemic sclerosis and polymyositis. 2 , 4 Rheumatoid factor, a macroglobulin of the 19S variety, is present in the serum of over 80 per cent of cases of rheumatoid arthritis. This macroglobulin has some of the characteristics of an antibody and reacts with gamma globulin coated particles (sheep red blood cells, latex particles, bentonite particles, etc.) causing agglutination or flocculation. This serum factor has also been identified in up to 50 per cent of patients with progressive systemic sclerosis, in 10 to 20 per cent of patients with dermatomyositis, and in the occasional polyarteritis nodosa patient with arthritis. I • 10 Similarly antinuclear factor (characteristically demonstrated in high titer in sera from systemic lupus erythematosus patients) has been observed in low titers in some patients with dermatomyositis and progressive systemic sclerosis. 7 The presence of these factors (rheumatoid and antinuclear) in the various disorders have led some to the hypothesis that a disordered immune mechanism may be a common denominator in the rheumatic diseases. Against this hypothesis is the

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fact that agammaglobulinemia has been reported in association with rheumatoid arthritis, dermatomyositis and progressive systemic sclerosiH in some patients. 32 However, as mentioned by Glynn and Holborow, 8 not all antibodies are confined to the gamma globulin group of proteins and cell-bound rather than circulating antibodies may be pathogenically related to the rheumatic diseases. Further work in this area must be done before these diseases may be regarded as expressions of autoimmunity. REFERENCES 1. Bloch, K. J. and Bunim, J. J.: Simple, Rapid Diagnostic Test for Rheumatoid

Arthritis-Bentonite Flocculation Test. J.A.M.A. 169: 307, 1959. 2. Bloch, K. J. and others: Sj6gren's Syndrome 1. Serologic Reactions in Patients with Sj6gren's Syndrome with and without Rheumatoid Arthritis. Arthritis & Rheum. 3: 287, 1960. 3. Boylan, R. C. and Sokoloff, L.: Vascular Lesions in Dermatomyositis. Arthritis & Rheum. 3: 379, 1960. 4. Bunim, J. J.: A Broader Spectrum of Sj6gren's Syndrome and Its Pathogenetic Implications. Ann. Rheumat. Dis. 20: 1, 1961. 5. Domzalski, C. A. and Morgan, V. C.: Dermatomyositis: Diagnostic Features and Therapeutic Pitfalls. Am. J. Med. 19: 370, 1955. 6. Evans, J. A.: Relaxin (Releasin) Therapy in Diffuse Progressive Scleroderma; A Preliminary Report. A.M.A. Arch. Dermat. 79: 150, 1959. 7. Friou. G. J.: Significance of Lupus Globulin-Nucleoprotein Reaction. Ann. Int. Med. 49: 866, 1958. 8. Glynn, L. E. and Holborow, E. J.: Immunological Aspects of Rheumatoid Disease: A Review. Ann. Rheumat. Dis. 19: 197, 1960. 9. Heathfield, K. W. G. and Williams, J. R. B.: Diagnosis of Polymyositis. Lancet 1: 1157 (May 28) 1960. 10. Kellgren, J. H. and Ball, J.: Clinical Significance of Rheumatoid Serum Factor. Brit. M. J. 1: 523, 1959. 11. Kibler, R. F. and Rose, F. C.: Peripheral Neuropathy in "Collagen Diseases"--Case of Scleroderma Neuropathy. Brit. M. J. 1: 1781, 1960. 12. Klein, R. and Harris, S. B.: Treatment of Scleroderma, Sclerodactylia and Caleinosis by Chelation (EDTA). Am. J. Med. 19: 798, 1955. 13. Levine, R. A., Kossmann, R. J. and Rogoff, B.: Medical Intelligence-Anaphyla!"tic Reaction to Relaxin. New England J. Med. 263: 693, 1960. 14. Medieal Research Council-Treatment of Polyarteritis Nodosa with Cortisone: Results after Three Years. Brit. M. J. 1: 1399, 1960. 15. Moore, H. C. and Sheehan, H. L.: The Kidney of Seleroderma. Lancet 1: 68 (Jan. 12) 1952. 16. Rodnan, G. P., Black, R. L., Bollet, A. J. and Bunim, J. J.: Observations on Usc of Prednisone in Patients with Progressive Systemic Sclerosis (Diffuse Seleroderma). Ann. Int. Med. 44: 16, 1956. 17. Rodnan, G. P., Schreiner, G. E. and Black, R. 1,.: Renal Involvement in Progressive Systemic Sclerosis (Generalized Scleroderma). Am. J. Med. 23: 445, 1957. 18. Rose, G. A. and Spencer, H.: Polyarteritis Nodosa. Quart. J. Med. 26: 43, 1957. 19. Rose, G. A.: Natural History of Polyarteritis. Brit. M. J. 2: 1148, 1957. 20. Shy, G. N.: Some Metabolic and Endocrinologic Aspects of Disorders of Striated Muscle. In Adams, R. (ed.): Disorders of the Motor Unit. Baltimore, Williams & Wilkins, 1961, Vo!. 38. 21. Sokoloff, L.: Biopsy in Rheumatic Diseases. M. CLIN. NORTH AMERICA 45: 1171, 1961.

Characterization of Polyarteritis N odosa and Dermatomyositis 1305 22. l:-lokoloff, L., Wilens, S. L. and Bunim, J. J.: Arteritis of Striated Muscle in Rheumatoid Arthritis. Am. J. Path. 27: 157, 1951. 23. Sokoloff, L., McCluskey, R. T. and Bunim, J. J.: Vascularity of Early Subcutaneous Nodule of Rheumatoid Arthritis. Arch. Path. 55: 475, 1953. 24. l:-lokoloff, L.: l:-lome Aspects of Pathology of Collagen Diseases. Bull. New York Acad. Med. 32: 760, 1956. 25. Sokoloff, L. and Bunim, J. J.: Vaseular Lnsions in Rheumatoid Arthritis. J. Chronie Dis. 5: 668, 1957. 26. Walton, Eo W.: Giant-Cell Granuloma of the Respiratory Tract (Wegener's Granulomatosis). Brit. M. J. 2: 265, 1958. 27. Wndgwood, R. J. P., Cook, C. D. and Cohen, J.: Dermatomyositis-··Heport of 26 Cases in Children with a Discussion of Endocrine Therapy in ]3. Pcdiatrics 12: 447, 1953. 28. Weiss, l:-l., l:-ltead, E. A. Jr., Warren, J. V. and Bailey, O. T.: Scleroderma Heart Disease, with a Consideration of Certain Other Visceral Manifestations of Scleroderma. Arch. Int. Med. 71: 749,1943. 29. Williams, R. C. Jr.: Dermatomyositis and Malignancy: Review of the Literature. Ann. Int. Med. 50: 1174,1959. 30. Winkelmann, R. K.: Treatment of Scleroderma. Proc. Staff Meet. Mayo Clin. 34: 55,1959. 31. Zeek, P. M.: Medical Progress: Periarteritis Nodosa and Other Forms of Necrotizing Angiitis. New England J. Med. 248: 764, 1953. 32. ZifI, M.: Genetics, Hypersensitivity and Connective Tissues Diseases (Editorial). Am. J. Med. 30: 1, 1961.

National Institute of Arthritis and Metabolic Diseases Bethesda, Maryland