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Neutrophilic Vascular Dermatoses
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Collagen Vascular Diseases
Neutrophilic Vascular Dermatoses David T. Schreiner, MD, * and joseph L. jorizzo, MDt
The neutrophilic vascular dermatoses are a clinically diverse group of disorders that share many histopathologic and, possibly, pathogenic similarities. Therapeutic approaches to these disorders are remarkably similar. It is important for the internist to identify neutrophilic vascular dermatoses as they may signify underlying internal disease as well as cause significant morbidity in their own right. Table 1 outlines the major neutrophilic vascular dermatoses. A recent textbook chapter focused on pathogenesisrelated issues relating to these disorders.20 The purpose of this review is to familiarize the reader with clinicopathologic and therapeutic considerations in these interesting entities. LEUKOCYTOCLASTIC VASCULITIS
Leukocytoclastic vasculitis is a histologic term referring to the following constellation of microscopic findings: (1) endothelial swelling with frequent occlusion of the blood vessel; (2) infiltration of the blood vessel wall with neutrophils; (3) leukocytoclasia (break-up of nuclei of these neutrophils); (4) fibrinoid necrosis of blood vessel walls; and (5) extravasation of erythrocytes. For a complete discussion, see article by Swerlick and Lawley elsewhere in this volume. SWEET'S SYNDROME
Also known as acute febrile neutrophilic dermatosis, Sweet's syndrome was first described in 1964. 38 It is an uncommon condition, occurring predominantly in females in the 30 to 60 years age range, although it has been described in the elderly and in children. 25 The onset of Sweet's syndrome may be preceded by an upper respiratory infection. The principal features of Sweet's syndrome are: (1) fever; (2) peripheral blood leukocytosis; From the Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina
*Assistant
Professor, Department of Internal Medicine tProfessor and Chairman, Department of Dermatology
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Table 1. Neutrophilic Vascular Dermatoses Leukocytoclastic vasculitis Small vessel (necrotizing venulitis) Large vessel Sweet" s syndrome Pustular vasculitis Beh<;et" s disease Bowel associated dermatosis-arthritis syndrome Erythema nodosum Familial Mediterranean fever Pyoderma gangrenosum
(3) multiple raised, asymmetric, erythematous, sharply marginated, painful cutaneous plaques; (4) a dense dermal infiltrate consisting of mature neutrophils; and (5) rapid response to corticosteroid treatment. 13 Cutaneous lesions are distinctive and are usually the presenting feature of Sweet's syndrome. The plaques may reach diameters of several centimeters and may appear in crops of pustules, vesicles, or bullae. 13. 38 Lesions may occur anywhere, but the most common sites are the face, neck, trunk, and upper extremities. They typically resolve over 4 to 8 weeks but recur in 30 per cent of patients. 38 Approximately 1 week after the appearance of cutaneous lesions, serum sickness-like symptoms appear including fever, myalgias, and arthralgias as well as headache, nausea, and malaise. Additional clinical features include arthritis,23 and conjunctivitis and episcleritis. 14 Malignancy, most commonly hematologic (especially acute myelogenous leukemia), underlies Sweet's syndrome in 10 to 15 per cent of cases. 9 There are a few reports of association with solid tumors including metastatic adenocarcinoma, testicular cancer, and ovarian cancer.9 Sweet's syndrome may occur concomitantly with tumor onset or may precede the diagnosis of malignancy. The presence of anemia, abnormal platelet counts, immature cells in the white blood cell differential, and severe bullous or ulcerative cutaneous disease is infrequent in idiopathic Sweet's syndrome and should alert the clinician to the possibility of malignancy. 9 Other diseases associated with Sweet's syndrome include Sjogren's syndrome, bowel bypass syndrome, systemic lupus erythematosus (SLE), ulcerative colitis, and rheumatoid arthritis. 9 No infectious cause for Sweet's syndrome has been found. Laboratory values in Sweet's syndrome are nonspecific; however, elevations are typically seen in the following tests: white blood cell counts (often more than 20,000 per cm 3), erythrocyte sedimentation rate, and platelets. 14 The differential diagnosis of a patient with apparent Sweet's syndrome includes the other neutrophilic vascular dermatoses as well as erythema multiforme and cutaneous infection. The histopathologic hallmark of Sweet's syndrome is a dense perivascular, predominantly neutrophilic dermal infiltrate. to Leukocytoclasia is a prominent finding as is endothelial swelling; fibrinoid necrosis of blood vessel walls and significant extravasation of erythrocytes, as seen in leukocytoclastic vasculitis, however, are absent. Although the pathogenesis of Sweet's syndrome may involve circulating immune complexes (CICs), the evidence to support this hypothesis is meager. Studies of neutrophil chemotaxis are equivocal. A recent study
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showed that a heat stable, nonlipid factor in the serum of a patient with Sweet's syndrome enhanced neutrophil migration. 21 A recent pathologic study revealed no evidence for fibrin, complement, or immunoglobulin deposition in histologic sections immunochemically stained in 15 patients with Sweet's syndrome. 12 Most reports of treatment for Sweet's syndrome include only one or two patients. There are no randomized controlled trials. Systemic corticosteroids in doses of 0.5 to 1.0 mg per kg per day tapered over 4 to 6 weeks appear to be the most effective treatment. 13, 14 Corticosteroids often afford relief within hours, and skin lesions substantially resolve in 3 to 5 days. 13 Patients respond even if there is underlying malignancy.9 Topical or intralesional corticosteroids may also aid in symptomatic relief. Other efficacious therapies include potassium iodide,28 colchicine,30 dapsone,3 and isotretinoin. 21 Antibiotics have not proved useful in treating Sweet's syndrome. Nonsteroidal anti-inflammatory agents provide only occasional symptomatic relief. 15
PUSTULAR VASCULITIS Pustular vasculitis is a manifestation of a heterogeneous group of disorders characterized by pustules on purpuric bases. The histopathology of these lesions shows changes ranging from those seen in Sweet's syndrome (neutrophilic vascular reaction) to full blown leukocytoclastic vasculitis. The pathogenesis of these disorders may be related to CrC-mediated vessel damage and increased neutrophil migration.
BEH<;ET'S DISEASE Behc;et's disease is a multisystem disease first described in 1937. 3 Although any organ may be affected in Behc;et's disease, the most prominent manifestations include oral and genital aphthous ulcers, uveitis, arthritis, neurologic signs and symptoms, and a variety of cutaneous lesions. 33 The diagnosis of Behc;et's disease is based on clinical criteria because there are no pathognomonic laboratory or histopathologic features of the disease. Table 2 shows the O'DuflY criteria for the diagnosis of Behc;et's disease. 29 Onset of disease is typically in the mid-twenties, although the elderly and Table 2. O'Duffy Criteria for the Diagnosis of Behqet's Disease Aphthous stomatitis Aphthous genital ulcers Uveitis Cutaneous pustular vasculitis (pathergy lesions) Synovitis Meningoencephalitis Diagnosis: At least 3 criteria being present, one being recurrent aphthous ulceration in the absence of inflammatory bowel disease or other autoimmune diseases.
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children may also be affected. I. 7 Prevalence is highest in the Middle-East and Japan, and the disease is relatively uncommon in Northern Europe and the United States. The presence of histocompatibility antigen (HLA)B5 and HLA-B51 seems to confer increased susceptibility to the disease. 8, 41 The cause of Beh<;et's disease is unknown. Current hypotheses implicate autoimmune mechanisms and viral agents as possible causative factors. Recent investigations have demonstrated evidence for herpes simplex type I virus in peripheral blood lymphocytes in patients with Beh<;et's disease. 19 Although anecdotal reports of patients with Beh<;et's disease responding to acyclovirI make this hypothesis intriguing, others have not duplicated these findings. 36 An interaction between CIC-mediated vessel damage and enhanced neutrophil chemotaxis may be involved in the pathogenesis of mucocutaneous and, perhaps, systemic lesions. 17 Histopathologically, mucocutaneous lesions in Beh<;et's disease may demonstrate leukocytoclastic vasculitis or may resemble the neutrophilic vascular reaction seen in patients with Sweet's syndrome. 18. 24 The course of Beh<;et's disease is extremely variable and is characterized by spontaneous exacerbations and remissions. Initial manifestations usually include various combinations of mouth and genital aphthous ulcers, ocular lesions, pustular vasculitic skin lesions, and arthritis. 7 Oral ulcers are painful and they most often occur on the lips, gums, tongue, and buccal mucosa. In contrast, lesions of Reiter's syndrome usually affect the palate, tonsils, and pharynx and are psoriasiform. 35 Genital lesions in Beh<;et's disease usually involve the scrotum or vulva (Fig. 1). The typical cutaneous lesion is a pustular lesion on a purpuric base (pustular vasculitis). Variations include combinations of the following types of lesions: papules, vesicles,
Figure 1. Genital aphthous ulcer in a patient with Behs:et's disease.
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pustules, furuncles and abscesses, erythema nodosum-like lesions, and nonspecific skin reactivity to scratches and injections (pathergy).7 Ocular manifestations of Behc;et's disease include anterior and posterior uveitis, conjunctivitis, corneal ulcers, and arteritis. 7, 42 Blindness is a major complication of Behc;et's disease limited mainly to patients with posterior uveitis. Arthritis is usually monoarticular, asymmetric, and nonerosive in patients with Behc;et's disease. The joints that are most often affected are the knees, ankles, elbows, and wrists. The shoulders, spine, hips, and small joints of the hands and feet are infrequently involved, The arthritis of Behc;et's disease occasionally resembles rheumatoid arthritis; however, joint deformity does not occur and rheumatoid factor is rarely present. 43 Neurologic manifestations of Behc;et's disease include headache, meningoencephalitis, seizures, cranial nerve palsies, ataxia, and hemiplegia. Central nervous system involvement may be life-threatening and usually occurs 1 to 7 years after disease onset. 29 Aphthae-like ulceration with occasional perforation can occur anywhere in the gastrointestinal tract in patients with Behc;et's disease. 22 Ulcerations are seen most often in the terminal ileum and cecum making differentiation from inflammatory bowel disease difficult at times. Patients may develop symptoms mimicking peritonitis, appendicitis, or peptic ulcer disease. Although serious cardiac involvement is rare in Behc;et's disease, there have been reports of myocarditis, myocardial infarction, and valvular disease. 33 Arterial aneurysms and venous thrombosis occur in up to 25 per cent of patients with Behc;et's disease. 35 Anticoagulation and bypass procedures are seldom useful in treating the vascular complications of Behc;et's disease. Subclinical renal involvement is not uncommon although this rarely leads to renal impairment. 32 Pulmonary involvement is also rare; fatalities from pulmonary artery aneurysmal hemorrhage have, however, been reported. 6 The diagnosis of Behc;et's disease is based on clinical criteria (see Table 2). Principal differential diagnostic considerations include Reiter's syndrome, inflammatory bowel disease, rheumatoid arthritis, and SLE. Laboratory findings are nonspecific and may include elevated erythrocyte sedimentation rate and leukocytosis. In general, the complete blood count, clotting factors, complement, rheumatoid factor, and antinuclear antibody tests are normal. The prognosis in Behc;et's disease depends on the degree of major organ involvement. Major sequelae include blindness, central nervous system disease, pulmonary hemorrhage, and the gastrointestinal complications. Many patients spontaneously improve over time. Reported 5-year mortality rates vary from 0 to 41 per cent; this wide range reflects differences in patient populations. 7, 40, 42 Because Behc;et's disease is uncommon, no randomized double-blinded trials of therapy exist. Systemic corticosteroids are the mainstay of treatment, They are efficacious for mucocutaneous lesions but they do not retard disease progression in major organ systems. Colchicine, dapsone, and thalidomide have all been used successfully in small numbers of patients. 17 Immunosuppressive therapy is often required for serious manifestations of
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Beh<;et's disease. In uncontrolled trials, chlorambucil 0.1 to 0.2 mg per kg per day is superior to prednisone for remission induction in uveitis. 19 Trials using cyclosporin A have shown some promise but have been hampered by high rates of cyclosporin induced toxicity.5. 19 A recent randomized trial comparing cyclosporin A with chlorambucil plus prednisone for serious ocular disease demonstrated better response in cyclosporin treated patients; however, extraocular manifestations of Beh<;et's disease responded better to the chlorambucil/prednisone combination. 4 Side effects in this trial were considerably higher in the cyclosporin group but renal toxicity was minimized by careful attention to serum drug levels. BOWEL ASSOCIATED DERMATOSIS-ARTHRITIS SYNDROME This syndrome is characterized by cutaneous lesions, fever, myalgia, and arthralgias occurring in as many as 20 per cent of patients following jejunoileal bypass surgery for obesity. 34 In 1983, patients with this syndrome associated with other bowel disease (inflammatory bowel disease and postBillroth 11 surgery) were reported. 16 Cutaneous lesions first appear as erythematous macules and become pustular with purpuric bases in 24 to 48 hours. They occur mainly on the upper trunk, last 2 to 8 days, and recur in bouts every 4 to 6 weeks. Lesions resembling erythema nodosa may also occur. The onset of the syndrome is heralded by flu-like symptoms, followed by synovitis and the cutaneous eruption. Although peripheral joints are principally affected, the arthritis is nonerosive. 34 Histopathologic studies have revealed a neutrophilic vascular reaction that may resemble Sweet's syndrome and may be indistinguishable from the pustular vasculitis lesion in patients with Beh<;et's disease. 16 The pathogenesis may involve formation of CICs secondary to release of bowel floral bacterial antigens which gain access to the circulation from blind intestinal loops or inflamed bowel mucosa. 11 Cutaneous and flu-like symptoms of the bowel associated dermatosisarthritis syndrome may be relieved by surgical correction of affected bowel. Systemic corticosteroids will also dramatically improve these symptoms; the nonlife-threatening, relapsing nature of this illness, however, usually does not justify the risks oflong-term therapy. Tetracycline, metronidazole, and erythromycin have been reported to be beneficial and probably act by reducing bowel flora. 11. 16 ERYTHEMA NODOSUM Erythema nodosum is a distinct entity characterized by painful purpuric nodules usually located on the anterior tibial surface (Fig. 2). Serum sickness-like symptoms often accompany the skin lesions. Although CICmediated vessel damage is one theory of lesion pathogenesis, there is little evidence to support this hypothesis. Recognition of erythema nodosum is important because it is associated with infection (viral, bacterial, and fungal), tuberculosis, sarcoidosis, drug allergy (sulfonamides, iodides, contracep-
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Figure 2. Erythema nodosum; note the typical subcutaneous nodules in this young woman.
tives), inflammatory bowel disease, Behc;:et's disease, and bowel bypass syndrome. 37 In 25 per cent of cases, no underlying disorder is found. It is most often found in females aged between 15 and 25 years. Erythema nodosum is a self-limited condition with lesions lasting 3 to 5 weeks followed by resolution without scarring. Recurrences are uncommon. 39
FAMILIAL MEDITERRANEAN FEVER Familial Mediterranean fever is an autosomal recessive disorder occurring mainly in the Mediterranean basin. 26 Characteristic clinical findings include cutaneous lesions, serum sickness-like symptoms, abdominal pain, and pleuritic pain. Skin lesions may resemble erysipelas, erythema nodosum, or palpable purpura. The onset of disease is usually in the first or second decade. Attacks are self-limited and recurrent; the abdominal pain may be confused with an acute abdomen. Amyloidosis is the major cause of death in familial Mediterranean fever. Histopathologic findings from skin biopsies range from nonspecific perivascular inflammation to leukocytoclastic vasculitis. Circulating immune complexes and complement consumption are demonstrable in about 50 per cent of patients. 26 Oral colchicine is the mainstay of treatment, possibly exerting its beneficial effect by inhibition of neutrophil migration.
PYODERMA GANGRENOSUM Pyoderma gangrenosum is an uncommon skin disease of unknown cause that is frequently a cutaneous manifestation of systemic disease. The
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diagnosis is by clinical means as there are no pathognomonic histopathologic findings. (For a full discussion, see article by Callen in this volume.) In some patients with pyoderma gangrenosum, an associated internal disease is found, usually ulcerative colitis or Crohn's disease. 27 The histopathology changes seen in early lesions may resemble the pustular vasculitis of Beh<;et's disease, bowel associated dermatosis-arthritis syndrome, or Sweet's syndrome.
SUMMARY The neutrophilic vascular dermatoses are a divergent group of disorders with distinct cutaneous manifestations. Diagnosis of these diseases requires clinical acumen because of the lack of pathognomonic histopathologic features. It is important for physicians to recognize these entities because of the large number of possible associated underlying diseases.
REFERENCES 1. Amman AI, Johnson A, Fyfe GA, et al: Beh<;et syndrome. J Pediatr 107:41-43, 1985 2. Aram H: Acute febrile neutrophilic dermatosis (Sweet's syndrome): Response to dapsone. Arch Dermatol 120:245-247, 1984 3. Beh<;et H: Uber residivivierende, aphthose, durch ein irrus verursachte geschwire an Mund, am Ayge und an den Genitalien. Dermatol Wochenschr 105:1152-1157, 1937 4. Ben Ezra D, Cohen E, Chajek T, et al: Evaluation of conventional treatment versus Cyclosporin A in Beh<;et's syndrome. Transpl Proc 20(suppl 4):136-143, 1988 5. Binder AI, Graham EM, Sanders MD, et al: Cyclosporin A in the treatment of severe Beh<;et's uveitis. Br J Rheum 26:285-291, 1987 6. Cadman EC, Lundberg B, Mitchell MS: Pulmonary manifestations in Beh<;et's syndrome. Arch Intern Med 136:944-947, 1976 7. Chajek T, Fainaru M: Beh<;et's disease. Report of 41 cases and a review of the literature. Medicine 54:179-196, 1975 8. Chajek-Shaul T, Pisanty S, Knobler H, et al: HLA-B51 may serve as an immunogenetic marker for a subgroup of patients with Beh<;et's syndrome. Am J Med 83:666-672, 1987 9. Cohen P, Kurzrock R: Sweet's syndrome and malignancy. Am J Med 82:1220-1226, 1987 10. Crow KD, Kerdel-Vegas F, Rook A: Acute febrile neutrophilic dermatosis: Sweet's syndrome. Dermatologica 139:123-134, 1969. 11. Ely PH: The bowel bypass syndrome: A response to bacterial peptidoglycans. J Am Acad Dermatol 2:473-487, 1980 12. Going JJ, Going SM, Myskow MW, et al: Sweet's syndrome: Histological immunohistochemical study of 15 cases. J Clin Pathol 40:175-179, 1987 13. Greer KE, Cooper PH: Sweet's syndrome (acute febrile neutrophilic dermatosis). Clin Rheum Dis 8:427-441, 1982 14. Gunawardena DA, Gunawardena KA, Ratanayka RS, et al: The clinical spectrum of Sweet's syndrome (acute febrile neutrophilic dermatosis): A report of eighteeen cases. Br J Dermatol 92:363-373, 1975 15. Hoffman GS: Treatment of Sweet's syndrome (acute febrile neutrophilia dermatosis) with indomethacin. J Rheumatol 4:201-206, 1977 16. Jorizzo JL, Apisarnthanarax, P, Subrt P, et al: Bowel bypass syndrome without bowel bypass: Bowel associated dermatosis-arthritis syndrome. Arch Intern Med 143:457-461, 1983 17. Jorizzo JL, Hudson RD, Schmalstieg FC, et al: Beh<;et's syndrome: Immune regulation, circulating immune complexes, neutrophil migration, and colchicine therapy. J Am Acad Dermatol 10:205-214, 1984
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18. Jorizzo JL, Solomon AR, Cavallo T: Beh<;et's syndrome: Immunopathologic and histopathologic assessment of pathology lesions is useful in diagnosis and follow-up. Arch Pathol Lab Med 109:747-751, 1985 19. Jorizzo JL: Beh<;et's disease: An update based on the 1985 International Conference in London, England. Arch Dermatol 122:556-558, 1986 20. Jorizzo JL: Neutrophilic dermatoses: Sweet's syndrome and pyoderma gangrenosum. In Gallin Jl, Goldstein IM, Synderman R (eds): Inflammation: Basic Principles and Clinical Correlates. New York, Raven Press, 1988, pp 785-802 21. Kaplan SS, Wechsler HL, Basford RE, et al: Increased plasma chemoattractant in Sweet's syndrome. J Am Acad Dermatol 12:1013-1021, 1985 22. Kasahara Y, Tanaka S, Nihino M, et al: Intestinal involvement in Beh<;et's disease: Review of 136 surgical cases in the Japanese literature. Dis Colon Rec 24:103-106, 1981 23. Krauser RE, Schumacher HR: The arthritis of Sweet's syndrome. Arthritis Rheum 18:3541, 1975 24. Lakhampal S, Tani K, Lie JT, et al: Pathologic features of Beh<;et's syndrome. Hum PathoI16:790-795, 1985 25. Levin DL, Esterly MB, Herman JJ, et al: The Sweet syndrome in children. J Pediatr 99:73-78, 1981 26. Meyerhoff J: Familial Mediterranean fever: Report of a large family, review of the literature, and discussion of the frequency of amyloidosis. Medicine 59:66-77, 1980 27. Mir-Madjlessi SH, Taylor JS, Farmer RG: Clinical course and evolution of erythema nodosum and pyoderma gangrenosum in chronic ulcerative colitis: A study of 42 patients. Am J Gastroenterol 80:615-620, 1985 28. Myatt AE, Baker DJ, Byfield DM: Sweet's syndrome: A report on the use of potassium iodide. Clin Exp Dermatol 12:345-349, 1987 29. O'Duffy JD, Goldstein NP: Neurologic involvement in seven patients with Beh<;et's disease. Am J Med 61:171-178, 1976 30. Petrozzi JW, Warthan TL: Sweet's syndrome: Unique local response to streptococcal antigen. Cutis 17:267-272, 1976 31. Prieto J, Suarez J, Civeria P: Acyclovir and Beh<;et's disease [letter]. Ann Intern Med 101:565-566, 1984 32. Rosenthal T, 'Veiss P, Gafni J: Renal involvement in Beh<;et's syndrome. Arch Intern Med 138:1122-1124, 1978 3,3. Schreiner DT, Jorizzo JL: Beh<;et's disease and complex aphthosis. Dermatol Clin 5:769778, 1987 34. Shagrin JW, Frame B, Duncan H: Polyarthritis in obese patients with intestinal bypass. Ann Intern Med 75:377-380, 1971 35. Shimuzu T, Ehrlich GE, Goro I, et al: Beh<;et's disease. Semin Arthritis Rheum 8:223260, 1979 36. Sozen T, Ates B: Beh<;et's syndrome and acyclovir [letter]. Ann Intern Med 101:406, 1984 37. Stolman LP, Rosenthal D, Yawosky R, et al: Pyoderma gangrenosum and rheumatoid arthritis. Arch Dermatol 111:1020-1023, 1975 38. Sweet RD: An acute febrile neutrophilic dermatosis. Br J Dermatol 76:349-356, 1964 39. White JW: Erythema nodosum. Dermatol Clin 3:119-127, 1985 40. Wolf SM, Schotland DL, Phillips LL: Involvement of nervous system in Beh<;et's syndrome. Arch Neurol 12:315-325, 1965 41. Yazici H, Tuzun Y, Pazarli H, et al: The combined use of HLA-B5 and pathergy test as diagnostic markers of Beh<;et's disease in Turkey. J Rheumatol 7:207-210, 1980 42. Yazici H, Tuzun S, Pazarli H, et al: Influence of age of onset and patient's sex on the prevalence and severity of manifestations of Beh<;et's syndrome. Ann Rheum Dis 43:783789, 1984 43. Yurkakul S, Yazici H, Tuzun Y, et al: The arthritis of Beh<;et's disease: A prospective study. Ann Rheum Dis 42:505-515, 1983 Department of Dermatology Bowman Gray School of Medicine 300 S. Hawthorne Road Winston-Salem, NC 27103 Ooseph L. Jorizzo, MD)
Collagen Vascular Diseases
Neutrophilic Vascular Dermatoses David T. Schreiner, MD, * and joseph L. jorizzo, MDt
The neutrophilic vascular dermatoses are a clinically diverse group of disorders that share many histopathologic and, possibly, pathogenic similarities. Therapeutic approaches to these disorders are remarkably similar. It is important for the internist to identify neutrophilic vascular dermatoses as they may signify underlying internal disease as well as cause significant morbidity in their own right. Table 1 outlines the major neutrophilic vascular dermatoses. A recent textbook chapter focused on pathogenesisrelated issues relating to these disorders.20 The purpose of this review is to familiarize the reader with clinicopathologic and therapeutic considerations in these interesting entities. LEUKOCYTOCLASTIC VASCULITIS
Leukocytoclastic vasculitis is a histologic term referring to the following constellation of microscopic findings: (1) endothelial swelling with frequent occlusion of the blood vessel; (2) infiltration of the blood vessel wall with neutrophils; (3) leukocytoclasia (break-up of nuclei of these neutrophils); (4) fibrinoid necrosis of blood vessel walls; and (5) extravasation of erythrocytes. For a complete discussion, see article by Swerlick and Lawley elsewhere in this volume. SWEET'S SYNDROME
Also known as acute febrile neutrophilic dermatosis, Sweet's syndrome was first described in 1964. 38 It is an uncommon condition, occurring predominantly in females in the 30 to 60 years age range, although it has been described in the elderly and in children. 25 The onset of Sweet's syndrome may be preceded by an upper respiratory infection. The principal features of Sweet's syndrome are: (1) fever; (2) peripheral blood leukocytosis; From the Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina
*Assistant
Professor, Department of Internal Medicine tProfessor and Chairman, Department of Dermatology
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Table 1. Neutrophilic Vascular Dermatoses Leukocytoclastic vasculitis Small vessel (necrotizing venulitis) Large vessel Sweet" s syndrome Pustular vasculitis Beh<;et" s disease Bowel associated dermatosis-arthritis syndrome Erythema nodosum Familial Mediterranean fever Pyoderma gangrenosum
(3) multiple raised, asymmetric, erythematous, sharply marginated, painful cutaneous plaques; (4) a dense dermal infiltrate consisting of mature neutrophils; and (5) rapid response to corticosteroid treatment. 13 Cutaneous lesions are distinctive and are usually the presenting feature of Sweet's syndrome. The plaques may reach diameters of several centimeters and may appear in crops of pustules, vesicles, or bullae. 13. 38 Lesions may occur anywhere, but the most common sites are the face, neck, trunk, and upper extremities. They typically resolve over 4 to 8 weeks but recur in 30 per cent of patients. 38 Approximately 1 week after the appearance of cutaneous lesions, serum sickness-like symptoms appear including fever, myalgias, and arthralgias as well as headache, nausea, and malaise. Additional clinical features include arthritis,23 and conjunctivitis and episcleritis. 14 Malignancy, most commonly hematologic (especially acute myelogenous leukemia), underlies Sweet's syndrome in 10 to 15 per cent of cases. 9 There are a few reports of association with solid tumors including metastatic adenocarcinoma, testicular cancer, and ovarian cancer.9 Sweet's syndrome may occur concomitantly with tumor onset or may precede the diagnosis of malignancy. The presence of anemia, abnormal platelet counts, immature cells in the white blood cell differential, and severe bullous or ulcerative cutaneous disease is infrequent in idiopathic Sweet's syndrome and should alert the clinician to the possibility of malignancy. 9 Other diseases associated with Sweet's syndrome include Sjogren's syndrome, bowel bypass syndrome, systemic lupus erythematosus (SLE), ulcerative colitis, and rheumatoid arthritis. 9 No infectious cause for Sweet's syndrome has been found. Laboratory values in Sweet's syndrome are nonspecific; however, elevations are typically seen in the following tests: white blood cell counts (often more than 20,000 per cm 3), erythrocyte sedimentation rate, and platelets. 14 The differential diagnosis of a patient with apparent Sweet's syndrome includes the other neutrophilic vascular dermatoses as well as erythema multiforme and cutaneous infection. The histopathologic hallmark of Sweet's syndrome is a dense perivascular, predominantly neutrophilic dermal infiltrate. to Leukocytoclasia is a prominent finding as is endothelial swelling; fibrinoid necrosis of blood vessel walls and significant extravasation of erythrocytes, as seen in leukocytoclastic vasculitis, however, are absent. Although the pathogenesis of Sweet's syndrome may involve circulating immune complexes (CICs), the evidence to support this hypothesis is meager. Studies of neutrophil chemotaxis are equivocal. A recent study
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showed that a heat stable, nonlipid factor in the serum of a patient with Sweet's syndrome enhanced neutrophil migration. 21 A recent pathologic study revealed no evidence for fibrin, complement, or immunoglobulin deposition in histologic sections immunochemically stained in 15 patients with Sweet's syndrome. 12 Most reports of treatment for Sweet's syndrome include only one or two patients. There are no randomized controlled trials. Systemic corticosteroids in doses of 0.5 to 1.0 mg per kg per day tapered over 4 to 6 weeks appear to be the most effective treatment. 13, 14 Corticosteroids often afford relief within hours, and skin lesions substantially resolve in 3 to 5 days. 13 Patients respond even if there is underlying malignancy.9 Topical or intralesional corticosteroids may also aid in symptomatic relief. Other efficacious therapies include potassium iodide,28 colchicine,30 dapsone,3 and isotretinoin. 21 Antibiotics have not proved useful in treating Sweet's syndrome. Nonsteroidal anti-inflammatory agents provide only occasional symptomatic relief. 15
PUSTULAR VASCULITIS Pustular vasculitis is a manifestation of a heterogeneous group of disorders characterized by pustules on purpuric bases. The histopathology of these lesions shows changes ranging from those seen in Sweet's syndrome (neutrophilic vascular reaction) to full blown leukocytoclastic vasculitis. The pathogenesis of these disorders may be related to CrC-mediated vessel damage and increased neutrophil migration.
BEH<;ET'S DISEASE Behc;et's disease is a multisystem disease first described in 1937. 3 Although any organ may be affected in Behc;et's disease, the most prominent manifestations include oral and genital aphthous ulcers, uveitis, arthritis, neurologic signs and symptoms, and a variety of cutaneous lesions. 33 The diagnosis of Behc;et's disease is based on clinical criteria because there are no pathognomonic laboratory or histopathologic features of the disease. Table 2 shows the O'DuflY criteria for the diagnosis of Behc;et's disease. 29 Onset of disease is typically in the mid-twenties, although the elderly and Table 2. O'Duffy Criteria for the Diagnosis of Behqet's Disease Aphthous stomatitis Aphthous genital ulcers Uveitis Cutaneous pustular vasculitis (pathergy lesions) Synovitis Meningoencephalitis Diagnosis: At least 3 criteria being present, one being recurrent aphthous ulceration in the absence of inflammatory bowel disease or other autoimmune diseases.
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children may also be affected. I. 7 Prevalence is highest in the Middle-East and Japan, and the disease is relatively uncommon in Northern Europe and the United States. The presence of histocompatibility antigen (HLA)B5 and HLA-B51 seems to confer increased susceptibility to the disease. 8, 41 The cause of Beh<;et's disease is unknown. Current hypotheses implicate autoimmune mechanisms and viral agents as possible causative factors. Recent investigations have demonstrated evidence for herpes simplex type I virus in peripheral blood lymphocytes in patients with Beh<;et's disease. 19 Although anecdotal reports of patients with Beh<;et's disease responding to acyclovirI make this hypothesis intriguing, others have not duplicated these findings. 36 An interaction between CIC-mediated vessel damage and enhanced neutrophil chemotaxis may be involved in the pathogenesis of mucocutaneous and, perhaps, systemic lesions. 17 Histopathologically, mucocutaneous lesions in Beh<;et's disease may demonstrate leukocytoclastic vasculitis or may resemble the neutrophilic vascular reaction seen in patients with Sweet's syndrome. 18. 24 The course of Beh<;et's disease is extremely variable and is characterized by spontaneous exacerbations and remissions. Initial manifestations usually include various combinations of mouth and genital aphthous ulcers, ocular lesions, pustular vasculitic skin lesions, and arthritis. 7 Oral ulcers are painful and they most often occur on the lips, gums, tongue, and buccal mucosa. In contrast, lesions of Reiter's syndrome usually affect the palate, tonsils, and pharynx and are psoriasiform. 35 Genital lesions in Beh<;et's disease usually involve the scrotum or vulva (Fig. 1). The typical cutaneous lesion is a pustular lesion on a purpuric base (pustular vasculitis). Variations include combinations of the following types of lesions: papules, vesicles,
Figure 1. Genital aphthous ulcer in a patient with Behs:et's disease.
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pustules, furuncles and abscesses, erythema nodosum-like lesions, and nonspecific skin reactivity to scratches and injections (pathergy).7 Ocular manifestations of Behc;et's disease include anterior and posterior uveitis, conjunctivitis, corneal ulcers, and arteritis. 7, 42 Blindness is a major complication of Behc;et's disease limited mainly to patients with posterior uveitis. Arthritis is usually monoarticular, asymmetric, and nonerosive in patients with Behc;et's disease. The joints that are most often affected are the knees, ankles, elbows, and wrists. The shoulders, spine, hips, and small joints of the hands and feet are infrequently involved, The arthritis of Behc;et's disease occasionally resembles rheumatoid arthritis; however, joint deformity does not occur and rheumatoid factor is rarely present. 43 Neurologic manifestations of Behc;et's disease include headache, meningoencephalitis, seizures, cranial nerve palsies, ataxia, and hemiplegia. Central nervous system involvement may be life-threatening and usually occurs 1 to 7 years after disease onset. 29 Aphthae-like ulceration with occasional perforation can occur anywhere in the gastrointestinal tract in patients with Behc;et's disease. 22 Ulcerations are seen most often in the terminal ileum and cecum making differentiation from inflammatory bowel disease difficult at times. Patients may develop symptoms mimicking peritonitis, appendicitis, or peptic ulcer disease. Although serious cardiac involvement is rare in Behc;et's disease, there have been reports of myocarditis, myocardial infarction, and valvular disease. 33 Arterial aneurysms and venous thrombosis occur in up to 25 per cent of patients with Behc;et's disease. 35 Anticoagulation and bypass procedures are seldom useful in treating the vascular complications of Behc;et's disease. Subclinical renal involvement is not uncommon although this rarely leads to renal impairment. 32 Pulmonary involvement is also rare; fatalities from pulmonary artery aneurysmal hemorrhage have, however, been reported. 6 The diagnosis of Behc;et's disease is based on clinical criteria (see Table 2). Principal differential diagnostic considerations include Reiter's syndrome, inflammatory bowel disease, rheumatoid arthritis, and SLE. Laboratory findings are nonspecific and may include elevated erythrocyte sedimentation rate and leukocytosis. In general, the complete blood count, clotting factors, complement, rheumatoid factor, and antinuclear antibody tests are normal. The prognosis in Behc;et's disease depends on the degree of major organ involvement. Major sequelae include blindness, central nervous system disease, pulmonary hemorrhage, and the gastrointestinal complications. Many patients spontaneously improve over time. Reported 5-year mortality rates vary from 0 to 41 per cent; this wide range reflects differences in patient populations. 7, 40, 42 Because Behc;et's disease is uncommon, no randomized double-blinded trials of therapy exist. Systemic corticosteroids are the mainstay of treatment, They are efficacious for mucocutaneous lesions but they do not retard disease progression in major organ systems. Colchicine, dapsone, and thalidomide have all been used successfully in small numbers of patients. 17 Immunosuppressive therapy is often required for serious manifestations of
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Beh<;et's disease. In uncontrolled trials, chlorambucil 0.1 to 0.2 mg per kg per day is superior to prednisone for remission induction in uveitis. 19 Trials using cyclosporin A have shown some promise but have been hampered by high rates of cyclosporin induced toxicity.5. 19 A recent randomized trial comparing cyclosporin A with chlorambucil plus prednisone for serious ocular disease demonstrated better response in cyclosporin treated patients; however, extraocular manifestations of Beh<;et's disease responded better to the chlorambucil/prednisone combination. 4 Side effects in this trial were considerably higher in the cyclosporin group but renal toxicity was minimized by careful attention to serum drug levels. BOWEL ASSOCIATED DERMATOSIS-ARTHRITIS SYNDROME This syndrome is characterized by cutaneous lesions, fever, myalgia, and arthralgias occurring in as many as 20 per cent of patients following jejunoileal bypass surgery for obesity. 34 In 1983, patients with this syndrome associated with other bowel disease (inflammatory bowel disease and postBillroth 11 surgery) were reported. 16 Cutaneous lesions first appear as erythematous macules and become pustular with purpuric bases in 24 to 48 hours. They occur mainly on the upper trunk, last 2 to 8 days, and recur in bouts every 4 to 6 weeks. Lesions resembling erythema nodosa may also occur. The onset of the syndrome is heralded by flu-like symptoms, followed by synovitis and the cutaneous eruption. Although peripheral joints are principally affected, the arthritis is nonerosive. 34 Histopathologic studies have revealed a neutrophilic vascular reaction that may resemble Sweet's syndrome and may be indistinguishable from the pustular vasculitis lesion in patients with Beh<;et's disease. 16 The pathogenesis may involve formation of CICs secondary to release of bowel floral bacterial antigens which gain access to the circulation from blind intestinal loops or inflamed bowel mucosa. 11 Cutaneous and flu-like symptoms of the bowel associated dermatosisarthritis syndrome may be relieved by surgical correction of affected bowel. Systemic corticosteroids will also dramatically improve these symptoms; the nonlife-threatening, relapsing nature of this illness, however, usually does not justify the risks oflong-term therapy. Tetracycline, metronidazole, and erythromycin have been reported to be beneficial and probably act by reducing bowel flora. 11. 16 ERYTHEMA NODOSUM Erythema nodosum is a distinct entity characterized by painful purpuric nodules usually located on the anterior tibial surface (Fig. 2). Serum sickness-like symptoms often accompany the skin lesions. Although CICmediated vessel damage is one theory of lesion pathogenesis, there is little evidence to support this hypothesis. Recognition of erythema nodosum is important because it is associated with infection (viral, bacterial, and fungal), tuberculosis, sarcoidosis, drug allergy (sulfonamides, iodides, contracep-
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Figure 2. Erythema nodosum; note the typical subcutaneous nodules in this young woman.
tives), inflammatory bowel disease, Behc;:et's disease, and bowel bypass syndrome. 37 In 25 per cent of cases, no underlying disorder is found. It is most often found in females aged between 15 and 25 years. Erythema nodosum is a self-limited condition with lesions lasting 3 to 5 weeks followed by resolution without scarring. Recurrences are uncommon. 39
FAMILIAL MEDITERRANEAN FEVER Familial Mediterranean fever is an autosomal recessive disorder occurring mainly in the Mediterranean basin. 26 Characteristic clinical findings include cutaneous lesions, serum sickness-like symptoms, abdominal pain, and pleuritic pain. Skin lesions may resemble erysipelas, erythema nodosum, or palpable purpura. The onset of disease is usually in the first or second decade. Attacks are self-limited and recurrent; the abdominal pain may be confused with an acute abdomen. Amyloidosis is the major cause of death in familial Mediterranean fever. Histopathologic findings from skin biopsies range from nonspecific perivascular inflammation to leukocytoclastic vasculitis. Circulating immune complexes and complement consumption are demonstrable in about 50 per cent of patients. 26 Oral colchicine is the mainstay of treatment, possibly exerting its beneficial effect by inhibition of neutrophil migration.
PYODERMA GANGRENOSUM Pyoderma gangrenosum is an uncommon skin disease of unknown cause that is frequently a cutaneous manifestation of systemic disease. The
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diagnosis is by clinical means as there are no pathognomonic histopathologic findings. (For a full discussion, see article by Callen in this volume.) In some patients with pyoderma gangrenosum, an associated internal disease is found, usually ulcerative colitis or Crohn's disease. 27 The histopathology changes seen in early lesions may resemble the pustular vasculitis of Beh<;et's disease, bowel associated dermatosis-arthritis syndrome, or Sweet's syndrome.
SUMMARY The neutrophilic vascular dermatoses are a divergent group of disorders with distinct cutaneous manifestations. Diagnosis of these diseases requires clinical acumen because of the lack of pathognomonic histopathologic features. It is important for physicians to recognize these entities because of the large number of possible associated underlying diseases.
REFERENCES 1. Amman AI, Johnson A, Fyfe GA, et al: Beh<;et syndrome. J Pediatr 107:41-43, 1985 2. Aram H: Acute febrile neutrophilic dermatosis (Sweet's syndrome): Response to dapsone. Arch Dermatol 120:245-247, 1984 3. Beh<;et H: Uber residivivierende, aphthose, durch ein irrus verursachte geschwire an Mund, am Ayge und an den Genitalien. Dermatol Wochenschr 105:1152-1157, 1937 4. Ben Ezra D, Cohen E, Chajek T, et al: Evaluation of conventional treatment versus Cyclosporin A in Beh<;et's syndrome. Transpl Proc 20(suppl 4):136-143, 1988 5. Binder AI, Graham EM, Sanders MD, et al: Cyclosporin A in the treatment of severe Beh<;et's uveitis. Br J Rheum 26:285-291, 1987 6. Cadman EC, Lundberg B, Mitchell MS: Pulmonary manifestations in Beh<;et's syndrome. Arch Intern Med 136:944-947, 1976 7. Chajek T, Fainaru M: Beh<;et's disease. Report of 41 cases and a review of the literature. Medicine 54:179-196, 1975 8. Chajek-Shaul T, Pisanty S, Knobler H, et al: HLA-B51 may serve as an immunogenetic marker for a subgroup of patients with Beh<;et's syndrome. Am J Med 83:666-672, 1987 9. Cohen P, Kurzrock R: Sweet's syndrome and malignancy. Am J Med 82:1220-1226, 1987 10. Crow KD, Kerdel-Vegas F, Rook A: Acute febrile neutrophilic dermatosis: Sweet's syndrome. Dermatologica 139:123-134, 1969. 11. Ely PH: The bowel bypass syndrome: A response to bacterial peptidoglycans. J Am Acad Dermatol 2:473-487, 1980 12. Going JJ, Going SM, Myskow MW, et al: Sweet's syndrome: Histological immunohistochemical study of 15 cases. J Clin Pathol 40:175-179, 1987 13. Greer KE, Cooper PH: Sweet's syndrome (acute febrile neutrophilic dermatosis). Clin Rheum Dis 8:427-441, 1982 14. Gunawardena DA, Gunawardena KA, Ratanayka RS, et al: The clinical spectrum of Sweet's syndrome (acute febrile neutrophilic dermatosis): A report of eighteeen cases. Br J Dermatol 92:363-373, 1975 15. Hoffman GS: Treatment of Sweet's syndrome (acute febrile neutrophilia dermatosis) with indomethacin. J Rheumatol 4:201-206, 1977 16. Jorizzo JL, Apisarnthanarax, P, Subrt P, et al: Bowel bypass syndrome without bowel bypass: Bowel associated dermatosis-arthritis syndrome. Arch Intern Med 143:457-461, 1983 17. Jorizzo JL, Hudson RD, Schmalstieg FC, et al: Beh<;et's syndrome: Immune regulation, circulating immune complexes, neutrophil migration, and colchicine therapy. J Am Acad Dermatol 10:205-214, 1984
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18. Jorizzo JL, Solomon AR, Cavallo T: Beh<;et's syndrome: Immunopathologic and histopathologic assessment of pathology lesions is useful in diagnosis and follow-up. Arch Pathol Lab Med 109:747-751, 1985 19. Jorizzo JL: Beh<;et's disease: An update based on the 1985 International Conference in London, England. Arch Dermatol 122:556-558, 1986 20. Jorizzo JL: Neutrophilic dermatoses: Sweet's syndrome and pyoderma gangrenosum. In Gallin Jl, Goldstein IM, Synderman R (eds): Inflammation: Basic Principles and Clinical Correlates. New York, Raven Press, 1988, pp 785-802 21. Kaplan SS, Wechsler HL, Basford RE, et al: Increased plasma chemoattractant in Sweet's syndrome. J Am Acad Dermatol 12:1013-1021, 1985 22. Kasahara Y, Tanaka S, Nihino M, et al: Intestinal involvement in Beh<;et's disease: Review of 136 surgical cases in the Japanese literature. Dis Colon Rec 24:103-106, 1981 23. Krauser RE, Schumacher HR: The arthritis of Sweet's syndrome. Arthritis Rheum 18:3541, 1975 24. Lakhampal S, Tani K, Lie JT, et al: Pathologic features of Beh<;et's syndrome. Hum PathoI16:790-795, 1985 25. Levin DL, Esterly MB, Herman JJ, et al: The Sweet syndrome in children. J Pediatr 99:73-78, 1981 26. Meyerhoff J: Familial Mediterranean fever: Report of a large family, review of the literature, and discussion of the frequency of amyloidosis. Medicine 59:66-77, 1980 27. Mir-Madjlessi SH, Taylor JS, Farmer RG: Clinical course and evolution of erythema nodosum and pyoderma gangrenosum in chronic ulcerative colitis: A study of 42 patients. Am J Gastroenterol 80:615-620, 1985 28. Myatt AE, Baker DJ, Byfield DM: Sweet's syndrome: A report on the use of potassium iodide. Clin Exp Dermatol 12:345-349, 1987 29. O'Duffy JD, Goldstein NP: Neurologic involvement in seven patients with Beh<;et's disease. Am J Med 61:171-178, 1976 30. Petrozzi JW, Warthan TL: Sweet's syndrome: Unique local response to streptococcal antigen. Cutis 17:267-272, 1976 31. Prieto J, Suarez J, Civeria P: Acyclovir and Beh<;et's disease [letter]. Ann Intern Med 101:565-566, 1984 32. Rosenthal T, 'Veiss P, Gafni J: Renal involvement in Beh<;et's syndrome. Arch Intern Med 138:1122-1124, 1978 3,3. Schreiner DT, Jorizzo JL: Beh<;et's disease and complex aphthosis. Dermatol Clin 5:769778, 1987 34. Shagrin JW, Frame B, Duncan H: Polyarthritis in obese patients with intestinal bypass. Ann Intern Med 75:377-380, 1971 35. Shimuzu T, Ehrlich GE, Goro I, et al: Beh<;et's disease. Semin Arthritis Rheum 8:223260, 1979 36. Sozen T, Ates B: Beh<;et's syndrome and acyclovir [letter]. Ann Intern Med 101:406, 1984 37. Stolman LP, Rosenthal D, Yawosky R, et al: Pyoderma gangrenosum and rheumatoid arthritis. Arch Dermatol 111:1020-1023, 1975 38. Sweet RD: An acute febrile neutrophilic dermatosis. Br J Dermatol 76:349-356, 1964 39. White JW: Erythema nodosum. Dermatol Clin 3:119-127, 1985 40. Wolf SM, Schotland DL, Phillips LL: Involvement of nervous system in Beh<;et's syndrome. Arch Neurol 12:315-325, 1965 41. Yazici H, Tuzun Y, Pazarli H, et al: The combined use of HLA-B5 and pathergy test as diagnostic markers of Beh<;et's disease in Turkey. J Rheumatol 7:207-210, 1980 42. Yazici H, Tuzun S, Pazarli H, et al: Influence of age of onset and patient's sex on the prevalence and severity of manifestations of Beh<;et's syndrome. Ann Rheum Dis 43:783789, 1984 43. Yurkakul S, Yazici H, Tuzun Y, et al: The arthritis of Beh<;et's disease: A prospective study. Ann Rheum Dis 42:505-515, 1983 Department of Dermatology Bowman Gray School of Medicine 300 S. Hawthorne Road Winston-Salem, NC 27103 Ooseph L. Jorizzo, MD)