Review
VASCULITIS HENRY H. ROENIGK, JR., M.D.
Vasculitis is an ill-defined entity. The term, if used alone, includes all inflammatory reactions around and within all blood vessels. Vasculitis or angiitis refers to the primary inflammatory processes involving small and medium-sized blood vessels; it results in organic damage, namely necrosis, fibrinoid degeneration, hyalinization and granulomatous reactions. This means that those vascular inflammations secondary to embolus or inflammation in neighboring tissues are not included. Either a clinical or a pathologic classification alone is unsatisfactory. Classifying vasculitis under "cutaneous" and "systemic" is an oversimplification. Vasculitis is usually the cutaneous sign of a complex benign or malignant pathologic process which may herald a systemic disorder. Thus, the vasculitis lesion which ulcerates may be the presenting sign of a severe systemic disease. Many different terms have been applied to the entity of vasculitis, ranging for polyarteritis nodosa to hypersensitivity angiitis, Wegner's granulomatosis, allergic granulomatosis, and necrotizing vasculitis. The term vasculitis is often used to refer to a hypersensitivity or allergic reaction to drugs. The reaction is primarily in small blood vessels of the skin. ' Classification of Vasculitis The following classification of vasculitis' is based primarily on histopathologic Address for reprints: Henry H. Roenigk, Jr., M.D., Department of Dermatology, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44106.
395
From the Department of Dermatology, The Cleveland Clinic Foundation, Cleveland, Ohio
criteria. The size of the blood vessel involved (small or large), the types of inflammatory cells (polymorphonuclears, lymphocytes or granulomatous), and the evidence of or lack of necrosis of blood vessel walls determines the category of the lesion. Thus, the skin biopsy becomes essential in the diagnosis of vasculitis. Biopsy specimens are best taken from fresh, early (less than 24-hour-old) papular lesions. It is often necessary to take 2 or 3 different lesions for biopsy to obtain a proper diagnosis. It is also important that the specimen be extracted deeply and that the specimen has good subcutaneous fat and even muscle. The excision biopsy rather than the punch biopsy is preferred. Systemic Vasculitis Small-Vessel Vasculitis The types of small-vessel vasculitis are polymorphonuclear, lymphocytic and granulomatous. In the polymorphonuclear type, necrotizing angiitis or vasculitis includes 6 classifications: 1. "Allergic vasculitis" (caused by drugs, infections, neoplasms, idiopathic causes, or erythema elevatum diutinum) 2. Anaphylactoid purpura (HenochSchoenlein)
396
INTERNATIONAL JOURNAL OF DERMATOLOGY
3. Acute febrile neutrophilic dermatosis (Sweet) 4. "Connective tissue" disorders (lupus erythematosus, rheumatoid arthritis) 5. Hypersensitivity angiitis (Zeek) • 6. Pyoderma gangrenosa
-
In lymphocytic vasculitis, we have 7 classifications: 1. Toxic erythema, erythema multiforme, drug eruption 2. Pigmented purpuric eruptions 3. Pityriasis lichenoides et varioliformis ; acuta (Mucha-Habermann) 4. Malignant atrophic papulosis (De5. Dysproteinaemia - Waldenstrom's macroglobulinaemia 6. Acrodermatitis of childhood (Cianotti-Crosti) 7. Atrophie blanche (?) . Cranlomatous vasculitis has 4 classifications: 1. Wegener's granulomatosis 2. Allergic granulomatosis (Churg and Strauss) 3. Infectious granulomatous vasculitis leprosy (Lucio phenomenon), syphilis (Maligna), and tuberculosis) 4. Lethal midline granuloma In large-vessel (often with secondary panniculitis) vasculitis, we categorize polymorphonuclear, lymphocytic and granulomatous. ln the polymorphonuclear type, we have 3 classifications: 1. Polyarteritis nodosa 2. Superficial migratory thrombophlebitis 3. Temporal arteritis V •• In lymphocytic, there are 3: 1. Erythema nodosum (including atypical varieties) 2. Lupus erythematosus 3. Perniosis (chilblains) " .
July-August 1976
Vol. 15
In granulomatous, there are 2: 1. Erythema induratum (tuberculousBazin) 2. Nodular vasculitis (nontuberculous) Clinical Features
Systemic vasculitis encompasses a varied group of conditions with both clinical and pathologic manifestations as noted in the classification. It is difficult to separate cutaneous from systemic aspects, since any of the cutaneous signs may be the sign of more serious systemic vasculitis. Cutaneous Manifestations Cutaneous lesions of vasculitis vary from erythematous macules to purpura, hemorrhagic vesicles, urticarial, nodular and eventually necrotic lesions and ulceration (Figs. 1, 2). The lower extremities are most often affected, but any portion of the skin may show lesions, which may or may not be painful. When the arterioles of the superficial dermis are affected, as in hypersensitivity angiitis, the skin manifestations begin as small urticarial or erythematous maculopapular lesions which usually become petechial but in which brown pigmentation may develop as they evolve. The petechiae are almost always palpable. The raised lesions are indicative of a more exudative and inflammatory response than is produced by simple vascular or thrombocytopenic purpura. The petechiae of bacterial endocarditis are also palpable but usually show a halo of erythema. The hemorrhagic lesions vary from pinpoint size to several centimeters in diameter and may result in blood-filled bullae or extensive areas of superficial hemorrhage or gangrene. The overlying damaged epidermis will usually break down and ulcerate at this point. Most of these lesions occur on the
No. 6
VASCULITIS
•
Roenigk
397
lower extremities, concentrated around the ankles and dorsa of the feet. Other areas of the body are more rarely affected. Systemic Systemic manifestations are common in vasculitis. The association of other vital organ involvement with vasculitis producing small ulceration on the legs has been pointed out by several authors.'' •'• ^ A review of cases of necrotizing angiitis found at autopsy at the Cleveland Clinic by O'Duffy et al." indicates the frequent finding of multiple-system involvement in vasculitis (Table 1). Fever is common but nonspecific in up to 75% of patients with vasculitis. Musculoskeletal pain, symptoms of peripheral neuropathy, and renal disease occur early in the majority of these patients. Renal disease is a common cause of death. The pathologic manifestations may be varied in the kidney, but a needle biopsy and direct immunofluorescence studies is often helpful in establishing a diagnosis of systemic vasculitis. Castrointestinal symptoms also vary, depending on the size of the vessel affected. Abdominal pain, steatorrhea or acute cholecystitis may be presenting signs.
Eig. 2 — Necrotizing vasculitis. Ulcerations of lower extremities with purpura.
Eig. 1—Necrotizing vasculitis. Papular, purpura lesions with ulceration.
Vascular involveinent of the liver may lead to abnormal liver function tests or a picture of hepatitis. Pancreatitis and diabetes may be manifestations of pancreatic vasculitis. Myocardial infarction
398
INTERNATIONAL JOURNAL OE DERMATOLOGY
Table 1. Clinical Findings in 27 Cases of Necrotizing Angiitis Found at Autopsy Total Sex Male Eemale History of allergy . ., . Eever :. : ,' Trauma '' : V " Edema .' Purpura Arthralgias Dermatologic abnormalities Pulmonary manifestations Muscle abnormalities Neurological abnormalities Ocular abnormalities Gastrointestinal tract dysfunction Abnormal liver .^ function tests Associated malignancies Cardiac abnormalities Hypertension
Percentage
18 9 6 22 7 15 6 11 12 12 14 15 8
67 33 22 81 26 55 22 41 44 44 52 56 30
16
60
15 2 13 14
56 7 48 52
is one of the more common causes of death from systemic vasculitis, but individual episodes are often clinically silent. Asymptomatic pericarditis may be present. Hypertension, probably due to renal cortical ischemia, may be severe. Pulmonary infiltrations are more often found in the granulomatous forms of vasculitis and may be associated with a blood eosinophilia. Almost any manifestation of brain disease may be found when central nervous vasculitis is present. The multifocal nature of the neurologic signs is a clue to their cause; cranial nerve and cortical hemisphere involvement predominate. The most common ocular manifestation of systemic vasculitis is episcleritis. Painful swellings of the epididymis or testes may also be a sign of vasculitis. . Histopathologic Criteria All the histologic changes in the blood vessels take place rapidly, and the time
Vol. 15
July-August 1976
factor for correct interpretation is very important. A necrosis of vascular walls and surrounding perivascular tissues may or may not be accompanied by the presence of material having the staining qualities of fibrinoid. Nonspecific changes such as endothelial swelling and degeneration, thickening of blood vessel walls and thrombosis may be present, which result in the reduction of the lumen and often in thrombosis (Fig. 3). All grades of reaction may occur in a single lesion. Marked cellular infiltration of the vessel walls and perivascular zone, composed predominantly of neutrophils in association with lymphocytes or eosinophils, is present. In necrotizing vasculitis, the neutrophils undergo a characteristic type of disintegration called leukocytoclasis or nuclear dust formation within the necrotic area (Fig. 4). Eosinophils are more prominent in the acute stage and granulomatous reaction. Lymphocytes appear late and may be alone in mild cases. The end result is usually fibrosis and occlusion of the vessel. Table 2 is a summary of the differences between inflammatory and noninflamTable 2.
Differences Between Inflammatory and Noninflammatory Purpuras* Noninflammatory Vasculitis purpura
Perivascular polymorphonuclear cells Leukocytoclasis Vessel wall changes (necrosis, fibrinoid. hyalin, and granuloma) Immunofluorescence (immunoglobul inscomplement) Endothelial swelling Extravascular red blood cells Perivascular lymphocytes * -Fpresent
—absent
4-
—
+ + -14—
—
•
^
-t -F -F
.
•
J
No. 6
VASCULITIS
•
Roenigk
399
Eig. 3—Left, necrotizing vasculitis. Histopathological features of destruction and inflammation of small arteriole. There is a partial tbrombis in the vessel suggesting possible intravascular coagulation. Eig. 4—Right, necrotizing vasculitis. Histopathological features of leukocytoclasis or nuclear dust around the vessel.
matory purpuras which may be difficult to distinguish in the early diagnosis of vasculitis. The polymorphonuclear cell infiltration is not always present in all cases of vasculitis, and is often found in noninflammatory purpuras also. Perivascular lymphocytic infiltration is not always absent in vasculitis, such as in the case of Mucha-Habermann's disease. Laboratory Tests Table 3 describes the abnormalities found in one study of vasculitis.** Specific laboratory studies are helpful in the diagnosis of vasculitis. These include: blood hemoglobin, leukocyte count, serologic test for syphilis, bacterial and fungal culture, lupus erythematosus test, antinuclear factor and coagulation
studies. Search for an underlying infection, neoplasm or other collagen disease is also indicated. Pathophysiology of Vasculitis The diverse clinical and pathologic features of vasculitis have been studied by numerous investigators in order to Table 3. Laboratory Findings in 27 Cases of Necrotizing Angiitis Found at Autopsy
Anemia
Total
Percentage
20
74
Elevated sedimentation rate 11 of 13 Abnormal urine 22 of 26 Leukocytosis 21 Eosinophilia 8 of 24
85 85 78 33
400
INTERNATIONAL JOURNAL OE DERMATOLOGY
July-August 1976
Vol. 15
5. Unknown, 19 of 31
of vasculitis (Fig. 5). Schroeter et al.'* found that igC, IgM, Bi-C, Bj-A were deposited within vessel walls in most cases of livedo vasculitis. In necrotizing vasculitis, IgC, Bi-C, Bi-A, and sometimes IgM were deposited in perivascular spaces. Cream et al.-'' found C.-. and IgM or IgA in necrotizing vasculitis, but no IgG. Handel et al.^ found mainly igC and C3 in dermal perivascular spaces in necrotizing vasculitis. There was no correlation between the level of circulating immunoglobulins and positive immunofluorescent studies. ;
determine the etiology and mechanism of pathologic production of vasculitis. The precipitating cause of vasculitis can be a drug, connective tissue disorder or tumor. We found the specific cause for the vasculitis in 12 of 31 cases of necrotizing vasculitis studies- (Table 4). Winkelmann and Ditto^ and Schroeter et al."* found similar causes for the vasculitis of their patients. Immunofluorescent studies in which fluorescein-conjugated antisera to IgC, IgA, IgM, Bi-A were used have shown evidence of immunoglobin and complement deposition in lesions of some types
Deposition of immunoglobulin and complement in the dermal blood vessels is more likely to be found in the early lesions of cutaneous necrotizing vasculitis. This concept is supported by studies of Cream et al.^ These demonstrated removal of immune complexes within 18 hours from the cutaneous vessels of guinea pigs in which the Arthus reaction was induced. We recently studied intravascular coagulation as a factor in necrotizing vasculitis.- Routine coagulation studies such as clotting time, prothrombin time, platelet count, assays of factors, V, VIII, XIII, partial thromboplastin generation and fibrinolysis were normal. Four patients
Table 4.
Vasculitis—Associated
Disorders
1. Suspected drug cases, 5 of 31 Hydrochlorothiazide Corticotropin Pentobarbital •Carbenicillin . ,^ Erythromycin
; •-' , ., -. '
2. Connective tissue disorders, 3 of 31 Systemic lupus erythematosus Mixed connective tissue disease 3. Neoplasm, 2 of 31
'.
4. Miscellaneous, 2 of 31 Behcet's syndrome Primary immune deficiency state
fig. 5—Direct immunofluorescence of lesion of vasculitis demonstrations deposition of IgG in dermal blood vessels.
• - .
.
No. 6
VASCULITIS
were found to have cryoprofibrin and dimeric derivatives. These complexes have been shown to precede and accompany coagulation of fibrin.'' The activation of the coagulation mechanism frequently may be due to the underlying disorders. There are similarities between both the Arthus reaction and the Shwartzman phenomenon in vasculitis, and thus much evidence that both coagulation and immunological systems play a role in the pathophysiology of vasculitis (Fig. 6). Specific Types of Vasculitis Necrotizing Angiitis or Vasculitis This is the most frequently encountered variety of vasculitis and may be mild, affecting only the skin on the legs, or severe enough to produce vasculitis of the kidney, malignant hypertension and death. The small vessels of the skin and internal organs are responsible for the lesions. Many other names have been applied to this disorder, including allergic angiitis, systemic allergic vasculitis (McCombs^), hypersensitivity angiitis (Zeek'), anaphylactoid purpura, leukocytoclastic angiitis and Schonlein-Hencoch purpura. The clinical features include hemorrhage into skin, palpable purpura, and papular papulovesicuiar and ulcerative skin lesions (Figs. 1, 2).
•
Roenigk
401
The lesions usually appear initially on the lower legs and ankles and may be associated with pain and edema. Later, lesions may appear on the arms, hands, trunk, face and elsewhere. The diagnosis is confirmed by a skin biopsy of early lesions which shows the characteristic leukocytoclastic reaction and destruction of small blood vessels in the dermis. Systemic involvement takes many forms in necrotizing vasculitis. Arthritis, arthralgias and myositis are frequent. Renal involvement is one of the more serious aspects and may progress to renal failure. Renal biopsy is often necessary to confirm the diagnosis of focal necrotizing glomerulitis or diffuse glomerulonephritis. Central nervous system involvement may be observed as headaches, delusion, mental confusion, diplopia and even cerebral vascular thrombosis and paralysis. Putting the patient to bed while investigating the possible underlying cause of the vasculitis often results in dramatic itTiprovement of the lesion. Once the patient begins to walk again, and if the vasculitis is still active, the lesion will recur. Systemic corticosteroids are widely used to treat necrotizing vasculitis and are usually effective, especially if the vasculitis is only cutaneous. Severe involvement of the kidneys and central
Ag-Ab complex€i
Eig. 6 — Pathophysiology of necrotizing vasculitis.
Infection (Bad - Endoloxln)
Fibrinolytic Factor
402
INTERNATIONAL JOURNAL OE DERMATOLOGY
nervous system may be unresponsive even to massive systemic corticosteroid therapy. McCombs^ found a better shortterm survival in steroid-treated patients compared with patients not treated with steroids. Recently, antimetabolites or immunosuppressive drugs have been used to treat vasculitis. We have used nitrogen mustard intravenously at the Cleveland Clinic for years for vasculitis and related connective tissue disorders with improvement noted. Recently, azathioprine, cyclophosphamide and chlorambucil have been used. Several patients with necrotizing vasculitis and localized intravascular coagulation syndrome have received heparin intravenously with dramatic results. Schamberg's Progessive Pigmentary Disorder Schamberg described a peculiar, slowly progressive pigmentary disorder of the skin that usually is manifested initially as a pin-sized reddish papule. The color may vary from brown to yellow, and the lesion resembles a grain of cayenne pepper. There usually are no subjective symptoms, and this disorder is most often brought to the attention of the physician because of cosmetic reasons. The possibility of sensitivity to drugs, especially aspirin and diuretics, should be considered. Treatment is usually not necessary. Pityriasis Lichenoides et Varioliformis Acuta (Mucha-Habermann's Disease) Much-Habermann's disease is characterized by the sudden appearance of lesions that are polymorphous clinically and may be seen as papules, purpuric vesicles, crust, ulceration and scars. The lesions resemble chicken pox but the course of the disease is much more chronic, lasting from a month to years.
July-August 1976
Vol. 15
The etiology is unknown but this disorder is classified with vasculitis because of the histologic picture described by Szymanski.'" The eruption usually appears in the second or third decade of life, and is more common in men. Treatment with large doses of tetracycline or small doses of methotrexate have been successful. Malignant Atrophic Papulosis (Degos' Disease) The association of the uniquely atrophic white, infarcted skin ulcers with acute gastrointestinal infarctions or perforations or both has been described by Degos. The cutaneous eruption is quite typical and may be scattered over the trunk and upper and lower extremities. The lesions usually begin as small red painless papules, which then acquire an atrophic center of brilliant whiteness (Fig. 7). Occasionally, a red telangiectatic rim surrounds the umbilicated center. Identical lesions are found on the serosal surface of the gastrointestinal tract and may involve all portions of it. The histopathologic findings are quite distinctive; therefore, an excisional biopsy of one of the ulcerated lesions will help to confirm the diagnosis of Degos' disease. Study of the skin lesion has demonstrated a wedge-shaped infarcted area extending deep into the dermis. Homogenization of the connective tissue occurs in the wedge-shaped zone of the dermis. Vasculitis with endothelial proliferation and thrombosis of the small blood vessels have also been found. These findings may place this disorder in the vasculitis category. We reported on 3 patients seen at the Cleveland Clinic with increased serum fibrinogen and cryoprofibrin levels.^^ Immunoglobulins were also elevated, with the IgA fraction being the most consistently increased. Fibrinogen deposition around blood vessels in the skin
No. 6
VASCULITIS
•
Roenigk
403
r
Eig. 7—Left, Degos' disease. White atrophic lesions with a raised telangiectatic border. Eig. 8—Right, Atrophie blanche. Severe painful ulceration with telangiectasis and purpura. Lesions heal leaving white atrophic scars.
was demonstrated by immunofluorescent techniques. All forms of recommended therapy have been ineffective in Degos' disease and most patients die as a result of gastrointestinal or central nervous system involvement. Periarteritis
Nodosa
Periarteritis nodosa is a segmented necrotizing vasculitis of medium-sized muscular arteries. Veins are involved if adjacent arteries are affected by the inflammatory process, which includes the entire vascular wall, intima, media and adventitia with neutrophils, eosinophils and lymphocytes. Eventual thrombosis is responsible for many of the clinical manifestations.
The disease occurs in all age groups but favors the fifth and sixth decades of life and affects men more commonly. Weight loss, fever and tachycardia are the systemic symptoms. Clomerulosclerosis, myocardial infarction, intestinal infarction with bleeding and pain, hypertension and peripheral neuropathy are some of the more serious problems that can develop. Studies have shown that 85% of the patients with periarteritis nodosa die within 6 to 12 months.'^ Cutaneous lesions include purpura, bullae, livedo reticularis with ulceration and urticaria. Subcutaneous nodules following the course of the arteries involved may ulcerate from infarction, and peripheral gangrene of fingers and toes may occur. There is a benign cutaneous
404
INTERNATIONAL JOURNAL OE DERMATOLOGY
form of periarteritis which is not associated with systemic signs.'^ Atrophie
Blanche
Atrophie blanche is characterized by purpuric infiltrated papules and plaques that undergo superficial necrosis and eventually heal with residual white atrophic scars (Fig. 8). They usually occur in women and are extremely painful. The histologic features of prominent fibrinoid material in superficial blood vessels and associated decreased blood fibrinolytic activity in vasculitis described by Cunliffe" have led to effective new therapy for this disease. The combined administration of phenformin and ethylestrenol'5 has resulted in healing of atrophie blanche ulcers. We have treated 6 patients with this combination and can confirm the observations of Gilliam and associates.'-"^ Allergic
Cranulomatosis
Churg and Strauss'« first described this unusual syndrome of necrotizing vasculitis associated with granulomatous vascular and extravascular connective tissue. The disease occurs mainly in women with long-standing asthma that unexpectedly becomes increasingly severe. Fever and eosinophilia occur with weight loss, anemia and recurrent pneumonia. Most cases terminate fatally. The skin lesions, which favor the extremities and trunk, include erythema multiforme-like lesions; maculopapular, purpuric, and pustular lesions;,and deep nodules. The lesion occasionally breaks down and ulcerates. Clinically, the skin lesions are very similar to necrotizing vasculitis. Drug Names azathioprine: Imuran carbenicillin: Geopen, Pyopen chlorambucil: Leukeran cyclophosphamide: Cytoxan ethylestrenol: Maxibolin phenformin: DBI, Meltrol
* '
• .
•' ,
,' -. '
' '
July-August 1976
Vol. 15
References 1. Roenigk, H. H., Jr., Vasculitis—Diagnosis and Management. In Leg Ulcer—Medical and Surgical Management. Edited by Roenigk, H. H., Jr., and Young, J. R. Hagerstown, Harper & Row, 1975, pp. 113-138. 2. Handel, D. W., Roenigk, H. H., Jr, Shainoff, J., and Deodhar, S., Necrotizing vasculitis— etiologic aspects of immunology and coagulopathy. Arch. Dermatol. 111:847, 1975. 3. Winkelmann, R. K., and Ditto, W. B., Cutaneous and visceral syndromes of necrotizing or allergic angiitis: A study of 38 cases. Medicine 43:59, 1965. 4. Schroeter, A. L., Copeman, P. W. M., Jordon, R. E., et al.: Immunofluorescence of cutaneous vasculitis associated with systemic disease. Arch. Dermatol. 104:254, 1971. 5. Cream, J. J., Bryceson, A. D. M., and Ryder, G., Disappearance of immunoglobulin and complement from the arthus reaction and its relevance to studies of vasculitis in man. Br. J. Dermatol. 84:106, 1971. 6. Shainoff, J. R., and Page, I. H., Significance of cryoprofibrin in fibrinogen—fibrin conversion. J. Exp. Med. 116:687, 1962. 7. McCombs, R. P., Systemic "allergic" vasculitis. JAMA 194:1059, 1965. 8. O'Duffy, J. D., Scherbel, A. L., Reedlord, H. E., and McCormock, L. J., Necrotizing angiitis —a clinical review of twenty-seven autopsied cases. Clev. Clin. 0- 32:87, 1965. 9. Zeek, P. M., Periarteritis nodosa and other forms of necrotizing angiitis. N. Engl. J. Med. 248:764, 1953. 10. Szymanski, E. J., Pityriasis lichenoides et varioliformis acuta: histopathological evidence tbat it is an entity distinct from parapsoriasis. A.M.A. Arch. Dermatol. 79:7, 1959. 11. Roenigk, H. H., Jr., and farmer, R. G., Degos' disease (Malignant papulosis): Report of 3 cases with clues to etiology. JAMA 206:1508, 1968. 12. Rose, G. A., and Spencer, H., Polyarteritis nodosa. Quart. J. Med. 26:43, 1957. 13. Diaz-Perez, J. L., and Winkelmann, R. K., Cutaneous periarteritis nodosa. Arch. Dermatol. 110:407, 1974. 14. Cunliffe, W. J., An association between cutaneous vasculitis and decreased blood fibrinolytic activity. Lancet 1:1226, 1968. 15. Gilliam, J. N., Herndon, J. H., and Phystowski, S. D., Eibrinolytic therapy for vasculitis of atrophie blanche. Arch. Dermatol. 109:664, 1974. 16. Churg, J., and Strauss, L., Allergic granulomatosis, allergic angiitis and periarteritis nodosa. Am. J. Pathol. 27:277, 1951.
VASCULITIS HENRY H. ROENIGK, JR., M.D.
Vasculitis is an ill-defined entity. The term, if used alone, includes all inflammatory reactions around and within all blood vessels. Vasculitis or angiitis refers to the primary inflammatory processes involving small and medium-sized blood vessels; it results in organic damage, namely necrosis, fibrinoid degeneration, hyalinization and granulomatous reactions. This means that those vascular inflammations secondary to embolus or inflammation in neighboring tissues are not included. Either a clinical or a pathologic classification alone is unsatisfactory. Classifying vasculitis under "cutaneous" and "systemic" is an oversimplification. Vasculitis is usually the cutaneous sign of a complex benign or malignant pathologic process which may herald a systemic disorder. Thus, the vasculitis lesion which ulcerates may be the presenting sign of a severe systemic disease. Many different terms have been applied to the entity of vasculitis, ranging for polyarteritis nodosa to hypersensitivity angiitis, Wegner's granulomatosis, allergic granulomatosis, and necrotizing vasculitis. The term vasculitis is often used to refer to a hypersensitivity or allergic reaction to drugs. The reaction is primarily in small blood vessels of the skin. ' Classification of Vasculitis The following classification of vasculitis' is based primarily on histopathologic Address for reprints: Henry H. Roenigk, Jr., M.D., Department of Dermatology, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44106.
395
From the Department of Dermatology, The Cleveland Clinic Foundation, Cleveland, Ohio
criteria. The size of the blood vessel involved (small or large), the types of inflammatory cells (polymorphonuclears, lymphocytes or granulomatous), and the evidence of or lack of necrosis of blood vessel walls determines the category of the lesion. Thus, the skin biopsy becomes essential in the diagnosis of vasculitis. Biopsy specimens are best taken from fresh, early (less than 24-hour-old) papular lesions. It is often necessary to take 2 or 3 different lesions for biopsy to obtain a proper diagnosis. It is also important that the specimen be extracted deeply and that the specimen has good subcutaneous fat and even muscle. The excision biopsy rather than the punch biopsy is preferred. Systemic Vasculitis Small-Vessel Vasculitis The types of small-vessel vasculitis are polymorphonuclear, lymphocytic and granulomatous. In the polymorphonuclear type, necrotizing angiitis or vasculitis includes 6 classifications: 1. "Allergic vasculitis" (caused by drugs, infections, neoplasms, idiopathic causes, or erythema elevatum diutinum) 2. Anaphylactoid purpura (HenochSchoenlein)
396
INTERNATIONAL JOURNAL OF DERMATOLOGY
3. Acute febrile neutrophilic dermatosis (Sweet) 4. "Connective tissue" disorders (lupus erythematosus, rheumatoid arthritis) 5. Hypersensitivity angiitis (Zeek) • 6. Pyoderma gangrenosa
-
In lymphocytic vasculitis, we have 7 classifications: 1. Toxic erythema, erythema multiforme, drug eruption 2. Pigmented purpuric eruptions 3. Pityriasis lichenoides et varioliformis ; acuta (Mucha-Habermann) 4. Malignant atrophic papulosis (De5. Dysproteinaemia - Waldenstrom's macroglobulinaemia 6. Acrodermatitis of childhood (Cianotti-Crosti) 7. Atrophie blanche (?) . Cranlomatous vasculitis has 4 classifications: 1. Wegener's granulomatosis 2. Allergic granulomatosis (Churg and Strauss) 3. Infectious granulomatous vasculitis leprosy (Lucio phenomenon), syphilis (Maligna), and tuberculosis) 4. Lethal midline granuloma In large-vessel (often with secondary panniculitis) vasculitis, we categorize polymorphonuclear, lymphocytic and granulomatous. ln the polymorphonuclear type, we have 3 classifications: 1. Polyarteritis nodosa 2. Superficial migratory thrombophlebitis 3. Temporal arteritis V •• In lymphocytic, there are 3: 1. Erythema nodosum (including atypical varieties) 2. Lupus erythematosus 3. Perniosis (chilblains) " .
July-August 1976
Vol. 15
In granulomatous, there are 2: 1. Erythema induratum (tuberculousBazin) 2. Nodular vasculitis (nontuberculous) Clinical Features
Systemic vasculitis encompasses a varied group of conditions with both clinical and pathologic manifestations as noted in the classification. It is difficult to separate cutaneous from systemic aspects, since any of the cutaneous signs may be the sign of more serious systemic vasculitis. Cutaneous Manifestations Cutaneous lesions of vasculitis vary from erythematous macules to purpura, hemorrhagic vesicles, urticarial, nodular and eventually necrotic lesions and ulceration (Figs. 1, 2). The lower extremities are most often affected, but any portion of the skin may show lesions, which may or may not be painful. When the arterioles of the superficial dermis are affected, as in hypersensitivity angiitis, the skin manifestations begin as small urticarial or erythematous maculopapular lesions which usually become petechial but in which brown pigmentation may develop as they evolve. The petechiae are almost always palpable. The raised lesions are indicative of a more exudative and inflammatory response than is produced by simple vascular or thrombocytopenic purpura. The petechiae of bacterial endocarditis are also palpable but usually show a halo of erythema. The hemorrhagic lesions vary from pinpoint size to several centimeters in diameter and may result in blood-filled bullae or extensive areas of superficial hemorrhage or gangrene. The overlying damaged epidermis will usually break down and ulcerate at this point. Most of these lesions occur on the
No. 6
VASCULITIS
•
Roenigk
397
lower extremities, concentrated around the ankles and dorsa of the feet. Other areas of the body are more rarely affected. Systemic Systemic manifestations are common in vasculitis. The association of other vital organ involvement with vasculitis producing small ulceration on the legs has been pointed out by several authors.'' •'• ^ A review of cases of necrotizing angiitis found at autopsy at the Cleveland Clinic by O'Duffy et al." indicates the frequent finding of multiple-system involvement in vasculitis (Table 1). Fever is common but nonspecific in up to 75% of patients with vasculitis. Musculoskeletal pain, symptoms of peripheral neuropathy, and renal disease occur early in the majority of these patients. Renal disease is a common cause of death. The pathologic manifestations may be varied in the kidney, but a needle biopsy and direct immunofluorescence studies is often helpful in establishing a diagnosis of systemic vasculitis. Castrointestinal symptoms also vary, depending on the size of the vessel affected. Abdominal pain, steatorrhea or acute cholecystitis may be presenting signs.
Eig. 2 — Necrotizing vasculitis. Ulcerations of lower extremities with purpura.
Eig. 1—Necrotizing vasculitis. Papular, purpura lesions with ulceration.
Vascular involveinent of the liver may lead to abnormal liver function tests or a picture of hepatitis. Pancreatitis and diabetes may be manifestations of pancreatic vasculitis. Myocardial infarction
398
INTERNATIONAL JOURNAL OE DERMATOLOGY
Table 1. Clinical Findings in 27 Cases of Necrotizing Angiitis Found at Autopsy Total Sex Male Eemale History of allergy . ., . Eever :. : ,' Trauma '' : V " Edema .' Purpura Arthralgias Dermatologic abnormalities Pulmonary manifestations Muscle abnormalities Neurological abnormalities Ocular abnormalities Gastrointestinal tract dysfunction Abnormal liver .^ function tests Associated malignancies Cardiac abnormalities Hypertension
Percentage
18 9 6 22 7 15 6 11 12 12 14 15 8
67 33 22 81 26 55 22 41 44 44 52 56 30
16
60
15 2 13 14
56 7 48 52
is one of the more common causes of death from systemic vasculitis, but individual episodes are often clinically silent. Asymptomatic pericarditis may be present. Hypertension, probably due to renal cortical ischemia, may be severe. Pulmonary infiltrations are more often found in the granulomatous forms of vasculitis and may be associated with a blood eosinophilia. Almost any manifestation of brain disease may be found when central nervous vasculitis is present. The multifocal nature of the neurologic signs is a clue to their cause; cranial nerve and cortical hemisphere involvement predominate. The most common ocular manifestation of systemic vasculitis is episcleritis. Painful swellings of the epididymis or testes may also be a sign of vasculitis. . Histopathologic Criteria All the histologic changes in the blood vessels take place rapidly, and the time
Vol. 15
July-August 1976
factor for correct interpretation is very important. A necrosis of vascular walls and surrounding perivascular tissues may or may not be accompanied by the presence of material having the staining qualities of fibrinoid. Nonspecific changes such as endothelial swelling and degeneration, thickening of blood vessel walls and thrombosis may be present, which result in the reduction of the lumen and often in thrombosis (Fig. 3). All grades of reaction may occur in a single lesion. Marked cellular infiltration of the vessel walls and perivascular zone, composed predominantly of neutrophils in association with lymphocytes or eosinophils, is present. In necrotizing vasculitis, the neutrophils undergo a characteristic type of disintegration called leukocytoclasis or nuclear dust formation within the necrotic area (Fig. 4). Eosinophils are more prominent in the acute stage and granulomatous reaction. Lymphocytes appear late and may be alone in mild cases. The end result is usually fibrosis and occlusion of the vessel. Table 2 is a summary of the differences between inflammatory and noninflamTable 2.
Differences Between Inflammatory and Noninflammatory Purpuras* Noninflammatory Vasculitis purpura
Perivascular polymorphonuclear cells Leukocytoclasis Vessel wall changes (necrosis, fibrinoid. hyalin, and granuloma) Immunofluorescence (immunoglobul inscomplement) Endothelial swelling Extravascular red blood cells Perivascular lymphocytes * -Fpresent
—absent
4-
—
+ + -14—
—
•
^
-t -F -F
.
•
J
No. 6
VASCULITIS
•
Roenigk
399
Eig. 3—Left, necrotizing vasculitis. Histopathological features of destruction and inflammation of small arteriole. There is a partial tbrombis in the vessel suggesting possible intravascular coagulation. Eig. 4—Right, necrotizing vasculitis. Histopathological features of leukocytoclasis or nuclear dust around the vessel.
matory purpuras which may be difficult to distinguish in the early diagnosis of vasculitis. The polymorphonuclear cell infiltration is not always present in all cases of vasculitis, and is often found in noninflammatory purpuras also. Perivascular lymphocytic infiltration is not always absent in vasculitis, such as in the case of Mucha-Habermann's disease. Laboratory Tests Table 3 describes the abnormalities found in one study of vasculitis.** Specific laboratory studies are helpful in the diagnosis of vasculitis. These include: blood hemoglobin, leukocyte count, serologic test for syphilis, bacterial and fungal culture, lupus erythematosus test, antinuclear factor and coagulation
studies. Search for an underlying infection, neoplasm or other collagen disease is also indicated. Pathophysiology of Vasculitis The diverse clinical and pathologic features of vasculitis have been studied by numerous investigators in order to Table 3. Laboratory Findings in 27 Cases of Necrotizing Angiitis Found at Autopsy
Anemia
Total
Percentage
20
74
Elevated sedimentation rate 11 of 13 Abnormal urine 22 of 26 Leukocytosis 21 Eosinophilia 8 of 24
85 85 78 33
400
INTERNATIONAL JOURNAL OE DERMATOLOGY
July-August 1976
Vol. 15
5. Unknown, 19 of 31
of vasculitis (Fig. 5). Schroeter et al.'* found that igC, IgM, Bi-C, Bj-A were deposited within vessel walls in most cases of livedo vasculitis. In necrotizing vasculitis, IgC, Bi-C, Bi-A, and sometimes IgM were deposited in perivascular spaces. Cream et al.-'' found C.-. and IgM or IgA in necrotizing vasculitis, but no IgG. Handel et al.^ found mainly igC and C3 in dermal perivascular spaces in necrotizing vasculitis. There was no correlation between the level of circulating immunoglobulins and positive immunofluorescent studies. ;
determine the etiology and mechanism of pathologic production of vasculitis. The precipitating cause of vasculitis can be a drug, connective tissue disorder or tumor. We found the specific cause for the vasculitis in 12 of 31 cases of necrotizing vasculitis studies- (Table 4). Winkelmann and Ditto^ and Schroeter et al."* found similar causes for the vasculitis of their patients. Immunofluorescent studies in which fluorescein-conjugated antisera to IgC, IgA, IgM, Bi-A were used have shown evidence of immunoglobin and complement deposition in lesions of some types
Deposition of immunoglobulin and complement in the dermal blood vessels is more likely to be found in the early lesions of cutaneous necrotizing vasculitis. This concept is supported by studies of Cream et al.^ These demonstrated removal of immune complexes within 18 hours from the cutaneous vessels of guinea pigs in which the Arthus reaction was induced. We recently studied intravascular coagulation as a factor in necrotizing vasculitis.- Routine coagulation studies such as clotting time, prothrombin time, platelet count, assays of factors, V, VIII, XIII, partial thromboplastin generation and fibrinolysis were normal. Four patients
Table 4.
Vasculitis—Associated
Disorders
1. Suspected drug cases, 5 of 31 Hydrochlorothiazide Corticotropin Pentobarbital •Carbenicillin . ,^ Erythromycin
; •-' , ., -. '
2. Connective tissue disorders, 3 of 31 Systemic lupus erythematosus Mixed connective tissue disease 3. Neoplasm, 2 of 31
'.
4. Miscellaneous, 2 of 31 Behcet's syndrome Primary immune deficiency state
fig. 5—Direct immunofluorescence of lesion of vasculitis demonstrations deposition of IgG in dermal blood vessels.
• - .
.
No. 6
VASCULITIS
were found to have cryoprofibrin and dimeric derivatives. These complexes have been shown to precede and accompany coagulation of fibrin.'' The activation of the coagulation mechanism frequently may be due to the underlying disorders. There are similarities between both the Arthus reaction and the Shwartzman phenomenon in vasculitis, and thus much evidence that both coagulation and immunological systems play a role in the pathophysiology of vasculitis (Fig. 6). Specific Types of Vasculitis Necrotizing Angiitis or Vasculitis This is the most frequently encountered variety of vasculitis and may be mild, affecting only the skin on the legs, or severe enough to produce vasculitis of the kidney, malignant hypertension and death. The small vessels of the skin and internal organs are responsible for the lesions. Many other names have been applied to this disorder, including allergic angiitis, systemic allergic vasculitis (McCombs^), hypersensitivity angiitis (Zeek'), anaphylactoid purpura, leukocytoclastic angiitis and Schonlein-Hencoch purpura. The clinical features include hemorrhage into skin, palpable purpura, and papular papulovesicuiar and ulcerative skin lesions (Figs. 1, 2).
•
Roenigk
401
The lesions usually appear initially on the lower legs and ankles and may be associated with pain and edema. Later, lesions may appear on the arms, hands, trunk, face and elsewhere. The diagnosis is confirmed by a skin biopsy of early lesions which shows the characteristic leukocytoclastic reaction and destruction of small blood vessels in the dermis. Systemic involvement takes many forms in necrotizing vasculitis. Arthritis, arthralgias and myositis are frequent. Renal involvement is one of the more serious aspects and may progress to renal failure. Renal biopsy is often necessary to confirm the diagnosis of focal necrotizing glomerulitis or diffuse glomerulonephritis. Central nervous system involvement may be observed as headaches, delusion, mental confusion, diplopia and even cerebral vascular thrombosis and paralysis. Putting the patient to bed while investigating the possible underlying cause of the vasculitis often results in dramatic itTiprovement of the lesion. Once the patient begins to walk again, and if the vasculitis is still active, the lesion will recur. Systemic corticosteroids are widely used to treat necrotizing vasculitis and are usually effective, especially if the vasculitis is only cutaneous. Severe involvement of the kidneys and central
Ag-Ab complex€i
Eig. 6 — Pathophysiology of necrotizing vasculitis.
Infection (Bad - Endoloxln)
Fibrinolytic Factor
402
INTERNATIONAL JOURNAL OE DERMATOLOGY
nervous system may be unresponsive even to massive systemic corticosteroid therapy. McCombs^ found a better shortterm survival in steroid-treated patients compared with patients not treated with steroids. Recently, antimetabolites or immunosuppressive drugs have been used to treat vasculitis. We have used nitrogen mustard intravenously at the Cleveland Clinic for years for vasculitis and related connective tissue disorders with improvement noted. Recently, azathioprine, cyclophosphamide and chlorambucil have been used. Several patients with necrotizing vasculitis and localized intravascular coagulation syndrome have received heparin intravenously with dramatic results. Schamberg's Progessive Pigmentary Disorder Schamberg described a peculiar, slowly progressive pigmentary disorder of the skin that usually is manifested initially as a pin-sized reddish papule. The color may vary from brown to yellow, and the lesion resembles a grain of cayenne pepper. There usually are no subjective symptoms, and this disorder is most often brought to the attention of the physician because of cosmetic reasons. The possibility of sensitivity to drugs, especially aspirin and diuretics, should be considered. Treatment is usually not necessary. Pityriasis Lichenoides et Varioliformis Acuta (Mucha-Habermann's Disease) Much-Habermann's disease is characterized by the sudden appearance of lesions that are polymorphous clinically and may be seen as papules, purpuric vesicles, crust, ulceration and scars. The lesions resemble chicken pox but the course of the disease is much more chronic, lasting from a month to years.
July-August 1976
Vol. 15
The etiology is unknown but this disorder is classified with vasculitis because of the histologic picture described by Szymanski.'" The eruption usually appears in the second or third decade of life, and is more common in men. Treatment with large doses of tetracycline or small doses of methotrexate have been successful. Malignant Atrophic Papulosis (Degos' Disease) The association of the uniquely atrophic white, infarcted skin ulcers with acute gastrointestinal infarctions or perforations or both has been described by Degos. The cutaneous eruption is quite typical and may be scattered over the trunk and upper and lower extremities. The lesions usually begin as small red painless papules, which then acquire an atrophic center of brilliant whiteness (Fig. 7). Occasionally, a red telangiectatic rim surrounds the umbilicated center. Identical lesions are found on the serosal surface of the gastrointestinal tract and may involve all portions of it. The histopathologic findings are quite distinctive; therefore, an excisional biopsy of one of the ulcerated lesions will help to confirm the diagnosis of Degos' disease. Study of the skin lesion has demonstrated a wedge-shaped infarcted area extending deep into the dermis. Homogenization of the connective tissue occurs in the wedge-shaped zone of the dermis. Vasculitis with endothelial proliferation and thrombosis of the small blood vessels have also been found. These findings may place this disorder in the vasculitis category. We reported on 3 patients seen at the Cleveland Clinic with increased serum fibrinogen and cryoprofibrin levels.^^ Immunoglobulins were also elevated, with the IgA fraction being the most consistently increased. Fibrinogen deposition around blood vessels in the skin
No. 6
VASCULITIS
•
Roenigk
403
r
Eig. 7—Left, Degos' disease. White atrophic lesions with a raised telangiectatic border. Eig. 8—Right, Atrophie blanche. Severe painful ulceration with telangiectasis and purpura. Lesions heal leaving white atrophic scars.
was demonstrated by immunofluorescent techniques. All forms of recommended therapy have been ineffective in Degos' disease and most patients die as a result of gastrointestinal or central nervous system involvement. Periarteritis
Nodosa
Periarteritis nodosa is a segmented necrotizing vasculitis of medium-sized muscular arteries. Veins are involved if adjacent arteries are affected by the inflammatory process, which includes the entire vascular wall, intima, media and adventitia with neutrophils, eosinophils and lymphocytes. Eventual thrombosis is responsible for many of the clinical manifestations.
The disease occurs in all age groups but favors the fifth and sixth decades of life and affects men more commonly. Weight loss, fever and tachycardia are the systemic symptoms. Clomerulosclerosis, myocardial infarction, intestinal infarction with bleeding and pain, hypertension and peripheral neuropathy are some of the more serious problems that can develop. Studies have shown that 85% of the patients with periarteritis nodosa die within 6 to 12 months.'^ Cutaneous lesions include purpura, bullae, livedo reticularis with ulceration and urticaria. Subcutaneous nodules following the course of the arteries involved may ulcerate from infarction, and peripheral gangrene of fingers and toes may occur. There is a benign cutaneous
404
INTERNATIONAL JOURNAL OE DERMATOLOGY
form of periarteritis which is not associated with systemic signs.'^ Atrophie
Blanche
Atrophie blanche is characterized by purpuric infiltrated papules and plaques that undergo superficial necrosis and eventually heal with residual white atrophic scars (Fig. 8). They usually occur in women and are extremely painful. The histologic features of prominent fibrinoid material in superficial blood vessels and associated decreased blood fibrinolytic activity in vasculitis described by Cunliffe" have led to effective new therapy for this disease. The combined administration of phenformin and ethylestrenol'5 has resulted in healing of atrophie blanche ulcers. We have treated 6 patients with this combination and can confirm the observations of Gilliam and associates.'-"^ Allergic
Cranulomatosis
Churg and Strauss'« first described this unusual syndrome of necrotizing vasculitis associated with granulomatous vascular and extravascular connective tissue. The disease occurs mainly in women with long-standing asthma that unexpectedly becomes increasingly severe. Fever and eosinophilia occur with weight loss, anemia and recurrent pneumonia. Most cases terminate fatally. The skin lesions, which favor the extremities and trunk, include erythema multiforme-like lesions; maculopapular, purpuric, and pustular lesions;,and deep nodules. The lesion occasionally breaks down and ulcerates. Clinically, the skin lesions are very similar to necrotizing vasculitis. Drug Names azathioprine: Imuran carbenicillin: Geopen, Pyopen chlorambucil: Leukeran cyclophosphamide: Cytoxan ethylestrenol: Maxibolin phenformin: DBI, Meltrol
* '
• .
•' ,
,' -. '
' '
July-August 1976
Vol. 15
References 1. Roenigk, H. H., Jr., Vasculitis—Diagnosis and Management. In Leg Ulcer—Medical and Surgical Management. Edited by Roenigk, H. H., Jr., and Young, J. R. Hagerstown, Harper & Row, 1975, pp. 113-138. 2. Handel, D. W., Roenigk, H. H., Jr, Shainoff, J., and Deodhar, S., Necrotizing vasculitis— etiologic aspects of immunology and coagulopathy. Arch. Dermatol. 111:847, 1975. 3. Winkelmann, R. K., and Ditto, W. B., Cutaneous and visceral syndromes of necrotizing or allergic angiitis: A study of 38 cases. Medicine 43:59, 1965. 4. Schroeter, A. L., Copeman, P. W. M., Jordon, R. E., et al.: Immunofluorescence of cutaneous vasculitis associated with systemic disease. Arch. Dermatol. 104:254, 1971. 5. Cream, J. J., Bryceson, A. D. M., and Ryder, G., Disappearance of immunoglobulin and complement from the arthus reaction and its relevance to studies of vasculitis in man. Br. J. Dermatol. 84:106, 1971. 6. Shainoff, J. R., and Page, I. H., Significance of cryoprofibrin in fibrinogen—fibrin conversion. J. Exp. Med. 116:687, 1962. 7. McCombs, R. P., Systemic "allergic" vasculitis. JAMA 194:1059, 1965. 8. O'Duffy, J. D., Scherbel, A. L., Reedlord, H. E., and McCormock, L. J., Necrotizing angiitis —a clinical review of twenty-seven autopsied cases. Clev. Clin. 0- 32:87, 1965. 9. Zeek, P. M., Periarteritis nodosa and other forms of necrotizing angiitis. N. Engl. J. Med. 248:764, 1953. 10. Szymanski, E. J., Pityriasis lichenoides et varioliformis acuta: histopathological evidence tbat it is an entity distinct from parapsoriasis. A.M.A. Arch. Dermatol. 79:7, 1959. 11. Roenigk, H. H., Jr., and farmer, R. G., Degos' disease (Malignant papulosis): Report of 3 cases with clues to etiology. JAMA 206:1508, 1968. 12. Rose, G. A., and Spencer, H., Polyarteritis nodosa. Quart. J. Med. 26:43, 1957. 13. Diaz-Perez, J. L., and Winkelmann, R. K., Cutaneous periarteritis nodosa. Arch. Dermatol. 110:407, 1974. 14. Cunliffe, W. J., An association between cutaneous vasculitis and decreased blood fibrinolytic activity. Lancet 1:1226, 1968. 15. Gilliam, J. N., Herndon, J. H., and Phystowski, S. D., Eibrinolytic therapy for vasculitis of atrophie blanche. Arch. Dermatol. 109:664, 1974. 16. Churg, J., and Strauss, L., Allergic granulomatosis, allergic angiitis and periarteritis nodosa. Am. J. Pathol. 27:277, 1951.
