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Autoimmune Ulceration of the leg
J. Blake Goslen, MD
Autoimmune diseases are those disorders characterized by circulating autoantibodies or specific immune effector cells targeted towards a variety of self antigens. These disorders have traditionally included the so-called collagen vascular diseases, such as lupus erythematosus or scleroderma, certain vasculticles, and a variety of immunologically mediated bullous diseases. The collagen vascular diseases and vasculitides, in particular, are occasionally associated with chronic, relapsing lower extremity ulcerations that may be refractory to traditional management schemes. Table 1 offers a classification of such disorders and provides a basis for the discussion which follows. The frequency of these diseases among leg ulcer patients in general is difficult to gauge and depends in large part on the demographics of one’s patient population as well as on efforts made to solicit such patients. For the last 1X months at the University of Pittsburgh, we have seen 303 new patients with leg ulcerations as part of a multidisciplinary wound healing and limb preservation clinic. Of this number, 20 patients (6.6%) have had leg ulcerations that were felt to be directly attributable to a variety of collagen vascular diseases or vasculitides. An understanding of these disorders and their potential to form ulcerations of different types is important in the differential diagnosis of patients with leg ulcerations in general, and management of these patients in particular. The following is a discussion of the most important autoimmune disorders associated with leg ulcerations, with emphasis on practical aspects of diagnosis and management. Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disorder expressed most commonly as a symmetrical, deforming arthropathy. The pathogenesis of RA is unclear but probably involves the interaction of environmental antigens, such as certain infectious agents,
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TABLE 1. Autoimmune Causes of Leg Ulceration Collagen Vascular Diseases Rheumatoid arthritis Systemic lupus erythematosus Scleroderma Dermatomyositis Mixed connective tissue disease Sjogren’s syndrome Behcet’s syndrome Pyoderma gangrenosum Vasculitis Vasculitis associated with collagen vascular disease Necrotizing venulitis Polyarteritis nodosa Granulomatous vasculitis Takayasu’s arteritis Livedoid vasculitis Antiphosphilipid syndrome
an aberrant immunologic defense mechanism. This abnormal immunologic response may be preconditioned by genetic factors. Abnormalities in both cell-mediated and humoral immunity have been postulated. Reviews by Harris and Zvaifler discuss these issues in greater detail. ‘.’ Although RA primarily affects the joints, a host of extraarticular manifestations are frequently seen and can dominate the clinical presentation.“,4 Many of these extraarticular findings involve the skin and include rheumatoid nodules, seen in 20-30% of RA patients, as well as skin changes associated with vasculitic phenomena. Leg ulceration is not uncommon in patients with RA. In a study of 215 RA patients reported by Thurtle and Cawley,” 9% gave a history of leg ulceration. In contrast, only 4% of age- and sex-matched control patients with osteoarthritis reported such an association. Similarly, Wilkinson and Kirk” reported an 8.3% frequency of leg ulceration among 324 consecutive RA patients admitted to their Rheumatology unit. The causes of leg ulceration in RA are mutifactorial. Although vasculitis is an important etiologic factor, it is not the only one; other diagnoses should be considered when one is formulating a differential diagnosis in these patients. with
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Patients with RA may have fragile, atrophic skin. This is particularly true if the patient has previously been treated with systemic corticosteroids.7 Because of this atrophy, even minor trauma to the skin may produce a tear that often evolves into a superficial ulcer. RA patients frequently have joint deformities and disabilities that may predispose them to inadvertant falls or other trauma. Footwear or other appliances may be inappropriately fitted and lead to frictioninduced injury to the skin. Patients who are severely disabled and bedridden may experience pressure-related necrosis of the skin. Ulcers arising from pressure or trauma often occur over bony prominences such as the presacral area, the posterior heels, or overlying the malleoli. Patients with RA may occasionally experience a concomitant peripheral neuropathy. This may be related to vasculitis of the vaso vasorum of peripheral sensory nerves leading to a mild distal sensory neuropathy or to a sensorimotor neuropathy (mononeuritis multiplex). RA patients treated with gold may also develop a peripheral neuropathy.” Compression syndromes such as tarsal or carpal tunnel syndrome may produce a sensory deficit.“’ Regardless of the cause of the peripheral neuropathy, excessive friction or other painful stimuli may not be felt by the patient and typical neuropathic ulcers may occur. These can be seen on the plantar aspect of the foot, overlying the metatarsal heads, as in diabetes, or in other locations, particularly over bony prominences such as the malleoli. Venous insufficiency has been felt by several authors to contribute to leg ulcerations in patients with RA.“,‘” Although the data is largely anecdotal, there are clearly patients with RA and leg ulcerations who have history and physical findings compatible with venous insufficiency. These include patients with a history of deep vein thrombophlebitis and subsequent limb edema associated with typical stasis dermatitis on physical examination. Ulcers in this setting are usually chronic and are located most commonly over the malleoli, especially the medial malleolus. Cawley’” has observed venous pattern ulcers frequently in RA patients with ipsilateral ankle dysfunction. He postulates that malfunction of the ankle joint is responsible for impairing the normal venous pump mechanism.
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Vasculitis is an imp(Jrtant rstrdarticulw maw of RA. Vascular lesions are clinically apparent in fewer than 1% of RA patients; hokvever, autopsy studies indicate that microscopic findings of vasculitis may he fount1 in up t 0 25%. “‘.” Large clinical studies indicate that thtb skin is the most frequently affected organ, with cutaneous lesions occurring in approximately 88% of patients with rheumatoid vasculitis. ” Of these skin manifestations. leg ulwrs ar(’ fixyuently found. Their prevalence ranges from 30-60’~~ in several large reviews. ’ ‘. Immune complex localization in vc~ssel ~~11::is felt by most authors to be the pathogenetic basis of rheumatoid vasculitis. ’ ‘I Immunoglobulins and complement components are frequently founfl in vessels when biopsies are examined by direct immunofluorescence. In afldition, immune cornplexes have been found in the srra of these p;itients when measured by ( ‘1~1 bintling. monoclonwl rheumatoid factor. or othw assays. investigators haw tl&c+cd :lntiOther endothelial cell antibodies in tht, sew of patiwts with RA. Titers as measured hy a srnsitivc> ra with clinical f~aprestlioimmunoassay CfJrWlat~ sion of the vasculitis.‘! A wntributing vasdan insult in many patients lvith rheumatoid vas culitis is ohliteratiw entlarteritis with intimal fdusifm silnilar to proliferation ant1 vasculw that seen in patients with sdcroclc~rm;~. ” “’ ifestation
FIG. 1 Typical punched-out ulcerations on the lower leg and foot in a patient with rheumatoid vasculitis.
Clinics in Dermatoloav
tht*rr may be preferential involvement of one type of vessel only.L’~Z’ The clinical syndromes associated with rheumatoid vasculitis depend largely upon the size of’ the affected vessel. Small to medium-sized vessel involvement often presents clinically as a systemic, necrotizing arteritis with multis>‘stem involvement that may mimic classic polyarteritis nodosa.” Skin findings include infarctive lesions of the nail fold, nail edge, ant1 tligital pulp (@waters lesions), palpable purpura. subcutaneous nodules, lived0 reticularis, and digital gangrene.” The latter may occur in Wi of patients with this severe form of rheumatclifl vasculitis. ” Sharply ’ marginated, deeply punched-out cutaneous ulcers often develop in tlcpentlent areas such as the lower extremity ( P’igurr 1). Adjacent skin is usually normal appearing or only slightly wythematous. These painful lesions are located on the lower one-third of the leg but are often in sites dypicai for vt’IIOW stasis ulcers or the ulcers associated with ncwvasculitic rheumatoid disease. Scott et al’ point out that ulcers occurring in sites such its t hcl upper calf or tlorsum fJf the foot shoukl be c41ws to the diagnosis of vasculitis. Biopsies from the margin of these ulcers or f’rcjrntlw~) tlermal or subcutaneous nodules commonly reveal typical nrcrotizing vasculitis of .sm:dl muscular arteries in the subcutaneous tis~II(~.Specific changes are fibrinoid necrosis of the hlootl \x~ssrl wall with I)fJlymo~~l,honuclear leukcwytt> infiltration. Surrounding leukocytoclasis anal fb.\travasatetl red blood cells in the extra-
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FIG. 2 Necrotizing arteritis of medium-sized artery in subcutaneous tissue in patient with rheumatoid vasculitis (40 x ). vascular connective tissue are typical (Figure 2). Vascular pathology lacking these changes should be interpreted cautiously as reactive changes are commonly seen in vessels when biopsies are obtained from leg ulcers.” On the other hand, the absence of vasculitis on biopsy does not exclude the disease. Well-documented cases exist where biopsies from leg ulcerations have failed to show vasculitis despite an otherwise typical clinical presentation (eg, associated mononeuritis multiplex, digital gangrene, etc.).“.“R The vascular pathology may be segmental, or sampling error may occur to explain these discrepancies. In addition to ulceration and other skin findings, prominent multi-organ involvement is typical for patients with the severe form of rheumatoid vasculitis. Up to 82% of patients experience constitutional symptoms such as weight loss, fatigue, or fever.‘” Hess feels that unexplained weight loss or fatigue in a patient with RA should raise one’s suspicion for early vascular involvement.“’ Most patients (86%) have typical rheumatoid nodules that occur over the extensor aspects of the arms, particularly over the olecranon, as well as over other bony prominences or sites of frequent trauma.‘” Joint disease in patients with rheumatoid vasculitis is severe, with erosions and significant deformity. Interestingly, active synovitis may be present in only 50%.“” Other organs affected include the peripheral nervous system (mononeuritis multiplex), heart
arrhythmia, myocardial infarc(pericarditis, tion), lungs (fibrosing alveolitis, pleurisy with pleural effusion), kidney, eye (scleritis), and gastrointestinal tract (abdominal pain, bleeding). IR.” Laboratory studies frequently demonstrate a normochromic, normocytic anemia, hypocomplementemia, cryoglobulinemia, and a low-titer ANA positivity. Rheumatoid factor is usually present in high titer (> 1:2560), but may be absent or undetectable by the particular assay used_ 1.;.I&Z-I Theofilopoulos” noted that IgG rheumatoid factor or ‘7s IgM rheumatoid factor may be present more frequently in patients with rheumatoid vasculitis than in control RA patients. HLA-Dr4 positivity has been observed in 88% of patients with severe rheumatoid vasculitis.“’ Milder vasculitic disease may also occur in RA patients.” In these cases, vessels of smaller caliber such as postcapillary venules are affected. Clinically, these patients present with palpable purpura typical of hypersensitivity vasculitis. In severe cases, these areas of purpura may become bullous or superfically necrotic. Leg ulcers may evolve from the breakdown of these lesions, and if they are neglected or become secondarily infected, deeper, more substantial ulcerations may develop. In addition, these patients may demonstrate nail fold, nail edge, or digital pulp thromboses. These appear as small, slightly tender papules or purpuric macules that resolve,
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leaving small scars with overlying hyperpigmentation. Lived0 reticularis is also frequently observed. In addition to leukocytoclastic vasculitis, segmental hyalinizing vasculitis or atrophie blanche has been reported in RA. ” ” Although the pathogenesis of these lesions is unclear, anticardiolipin antibodies have been detected in RA, especially in the setting of active disease with extraarticular manifestations.“’ Anticardiolipin antibodies have also been detected in idiopathic lived0 vasculitis:‘” The mortality from untreated severe rheumatoid vasculitis approaches 80%. Ii ” For this reason, if the diagnosis is suspected, systemic therapy is warranted. Previous reports have advocated the use of systemic corticosteroids, either as daily oral prednisone or in an intravenous, pulsed fashion,“’ steroids plus cytotosic agents (cyclophosphamide appears better than azathioprine), I” ’ penicillaminr,“’ chlorambucil,‘.’ sulfones, I.’ methotrexate, I’,” intravenous prostacyclin infusion,‘“’ or plasma exchange combined with immunosuppressive agents. ” ” P’Or fulmisystemic disease, c(xtic(JSterOidS phIS nant, cyclophosphamide or plasmapheresis with atljunctive immunosuppressives is probably the best documented approach. I”,“. “’ E’or milder disease with predominantly skin findings, mrthotrexate or dapsone may produce ulcer healing with minimal toxicity. Topical ulcer care alone is rarely successful in t,he presence of severt’ vasculitis. Attempts at skin grafting are best deferred until vasculitis is controlled and healing is initiated using systemic measures. “’ Vasculitis, although an important cause of leg ulceration, does not account for all the chronic ulcers seen in RA patients.‘” Wilkinson and Kirk’ reported that fewer than 50% of their large series of patients with leg ulcers and rheumatoid arthritis had documented evidence of vasculitis. The other patients had ulcers that closely resembled those seen in patients with vasculitis, yet biopsies were consistently negative, and other clinical findings of vasculitis were absent. Similarly, Scott et al” found a significant number of patients in their series without vasculitis. In this setting, the ulcers were more superficial and tended to localize consistently near the malleoli
FIG. 3 Malleolar ulcer in a patient with long-standing rheumatoid vasculitis.
arthritis
without
biopsy
evidence
of
while sparing sites such as the dorsal foot and posterior calf (Figure 3). It is not uncommon for the dermatologist to be confronted with patients of this type (chronic, stable RA without evidence of systemic vasculitis) who present primarily for therapy of recalcitrant leg ulcerations. In this setting, appropriate screening laboratory studies, including biopsy, should be done to exclude vasculitis. Occasionally, patients with Felty’s syndrome may be detected. Felty’s syndrome is characterized by the presence of leukopenia, splenomegaly, and typical RA. Recalcitrant leg ulcers frequently accompany the syndrome, although they were not included in Felty’s original report. ‘I I” These patients also may have hepatomegaly, frequent infections, anemia, and thrombocytopenia. High-titer rheumatoid factor is detectable in 98% and ANA is positive in twothirds of patients. These patients often have granulocyte-specific anti-nuclear antibodies. “’
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Identification of these individuals is important, as splenectomy has been reported to improve blood counts and produce cutaneous ulcer healing. 4e.4h Toxic effects from medications given for RA must also be considered in evaluating patients with leg ulcers. We have recently described a patient with RA and severely painful lower extremity ulcerations and mucosal ulcers who was concomitantly taking methotrexate, salicylates, and nonsteroidal anti-inflammatory drugs to control her RA. Cutaneous ulceration is a well-known side effect from toxic doses of methotrexate. Interestingly, nonsteroidal antiinflammatory agents and aspirin are known to potentiate the toxicity of methotrexate by interfering with renal excretion of the drug or by increasing effective serum methotrexate concentration through competitive inhibition of plasma protein binding. In our patient discontinuation of salicylates and non-steroidal antiinflammatory agents without modification of methotrexate dosage (necessary for arthritis control) resulted in immediate reduction in ulcer pain and subsequent healing.“” Therapy of the non-vasculitic chronic ulcers associated with RA is challenging. Many of these patients respond to agents utilized for rheumatoid vasculitis. Local measures include hyperbaric oxygenation and skin grafting or application of cultured neonatal epidermal allografts.“’ As mentioned previously, patients with Felty’s syndrome may heal after splenectomy.“” Leg ulceration secondary to pyoderma gangrenosum may be associated with RA.4X-“’ Occasionally, these patients are seronegative, making the diagnosis somewhat ambiguous.“’ A full discussion of pyoderma gangrenosum is presented later in this review. A final cause of superficial ulcerating lesions in RA is superficial ulcerating rheumatoid necrobiosis @URN), as reported by Jorizzo et al.“’ In this disorder, yellowish-red plaques develop that superficially ulcerate or form sinus-like burrows into the deeper dermis or subcutaneous tissue. Lesions are usually bilateral over the pretibia1 areas and are refractory to treatment. Biopsies of the ulcer margin reveal changes consistent with necrobiosis lipoidica; yet, diabetes
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mellitus is usually not present. Direct immunofluorescence microscopy may demonstrate granular deposition of IgM at the dermalepidermal junction and/or in superficial vessel walls. Similar lesions have been reported by Baker et al”” and Callen and Ahrens.” In the latter reports, granulomatous vasculitis was seen pathologically. These cases probably represent different phenomena than the rarely reported ulcer due to fistulization of pre-existing rheumatoid nodules.” Although the pathologic changes could be similar, rheumatoid nodules did not antedate the lesions described by Jorizzo, and the pretibial area of the leg would not be a common location for rheumatoid nodulosis. lupus Efythematosus Leg ulceration has been reported relatively frequently is association with systemic lupus erythematosus (SLE). In a series of 520 SLE patients reviewed by Tuffanelli and Dubois,“” chronic lower leg ulcers were observed in 5.6%. Other series have detected leg ulcers in 2-8% of SLE patients.““,“’ In the great majority of these patients, ulcers have been chronic and/or recurrent and have correlated with the presence of active multisystem disease.57-‘9 Brogadir and Myers% also found a significant correlation of ulcer activity and the laboratory findings of hypocomplementemia and elevated anti-DNA antibody titers in the peripheral blood. In some cases, leg ulceration has been the presenting complaint of patients who later were found to have full-blown SLE by standardized criteria.“” Most leg ulcers in SLE are located over the malleolar, supramalleolar, or pretibial areas.66,“J Rarely, ulcers of the buttocks, thighs, or gluteal regions have been reported.“‘0 These ulcers are usually painful, sharply marginated, or punchedout. Their beds may be purulent with variable amounts of granulation tissue. Adjacent skin is usually normal-appearing but can be erythematous, purpuric, or rolled and violaceous (Figure 4). In some cases ulcers resembling livedoid vasculitis are observed with stellate-appearing ulcerations often associated with localized livedo reticularis. These lesions typically heal with a
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(Figure 5). Occasionally, vasculitis of the endarteritis type is seen, with intimal thickening as well as endothelial cell proliferation and degeneration. These lesions may represent the chronic seyulae of earlier acute fibrinoid necrosis and usually involve small arteries.“” True necrotizing vasculitis of medium-sized or large arteries is less frequent, occurring in only d%aof patients with SLE vasculitis reported by Ansari et al.“” Rarely, lesions of both types may occur simultaneously. The pathogenesis of the necrotizing vasculitis associated with SLE is thought to be immune complex-mediated; however, recent reports of anti-endothelial cell antibodies associated with SLE and other collagen vascular diseases suggest that a direct immunologic attack on endothelial cells may be an important associated event.lil’K FIG. 4 Palpable purpura with superficial ulceration in a patient with vasculitis associated with systemic lupus erythematosus (SLE).
idiopathic atrophic white scar mimicking blanche.“’ The causes of leg ulceration in SIJX arca multend to tifactorial, although vascular etidOgk% receive the greatest attention in the literature. Of the vascular causes, both active, inflammatory vasculitis and thrombotic, non-vasculitic causes have been described.‘” In their series of 1.50SLE patients, Estes and Christian”” found a 21% incidence of dermal vasculitis, 45% of which progressed to chronic ulceration. Similarly, Gilliam and Sontheimer”’ found a lo-20% incidence. Most SLE-associated vasculitis affects small vessels (small arteries, arterioles, or postcapillary venules). I ti addition to cutaneous ulceration, clinical lesions include urticarial wheals (urticarial vasculitis), palpable purpura, small purpuric macules, or papules around the nail or on the tips of digits or palms and soles. There may be associated localized or diffuse livedo reticularis, implying vasospasm or thrombosis of ascending dermal arterioles.“’ Histologic examination of these lesions typtally reveals a leukocytoclastic vasculitis with fibrinoid necrosis of the vessel walls ant1 prominent, ~~olymorphonuclear cell infiltration
A second major type of vascular event in SLE involves the non-inflammatory thrombosis of small and, occasionally, large vessels, both arterial and venous. Rarely, evidence of vasculitis and non-inflammatory thrombosis may coexist in the same patient .‘ik.‘i!’ (Yinical manifestations of these thrombotic events include recurrent deep vein thrombophlebitis, recurrent spontaneous abortion, CNS or other organ thromboses (eg, cerebrovascular accident, myocardial infarction, etc.), and cutaneous findings, including leg ulcerations, livedo reticularis, Raynaud’s phenomenon, digital gangrene, and Degas’-like cutaneous infarcts.“’ “’ The leg ulcerations may resemble livedoid vasculitis in up to 17% of patients.“’ In fact, in most large series of livedoid vasculitis, SLE, as well as other collagen vascular disorders, are prominently mentioned as associated diagnoses.zx~i7 In other cases, ulcers may more closely resemble venous stasis ulcerations7x (Figure 6). When pathologic material is studied, there is wide-spread evidence of thrombosis of small or medium-sized dermal vessels without significant necrotizing vasculitis. In addition, capillary proliferation, dermal hemorrhage, and endarteritis obliterans-like changes are observed. These changes may include thickened, hyalinized vessels (Figure 7). Direct immunofluorescence microscopy, as in idiopathic livedoid vasculitis, is often l)ositivtl with deposition of fibrinogen,
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FIG.5 Necrotizing venulitis of Ileer dermal vessels in patient with SLE (64 x).
IGM and C3 in the vessel walls and, occasionally, in the overlying basement membrane zone.79 Abundant evidence now exists that relates these thrombocclusive clinical and pathologic findings to the presence of circulating antiphospholipid antibodies.“‘-” These antibodies are a heterogenous group of immunoglobulins (IgG, IgM, and rarely IgA) that react specifically with the phospholipid portion of the prothrombin activator complex, namely factor Xa, factor V, phospholipids, and ionized calcium.k’.w The previously described anticardiolipin antibody and lupus anticoagulant are both antibodies with antiphospholipid specificity. The term lupus anticoagulant, however, is a misnomer as most of the clinical events associated with its presence are thrombotic and not hemorrhagic. Antiphospholipid antibodies may promote thrombosis by binding to endothelial cells and impairing protacyclin releasea or possibly by binding to platelet phospholipids, producing platelet damage that results in enhanced platelet adhesiveness.“” Alternately, an inhibition of fibrinolytic activity via prekallikrein inhibition has been proposed.X7 Using more sensitive assays, anticardiolipin antibodies have been found in 40-60% of patients with SLE.“,“” In this setting there is a significant correlation with thrombotic events, which can occasionally be devastating. Weinstein et aY reported on 38 patients with SLE and concomitant
granular
livedo reticularis. In this group there was a significant association with the presence of anticardiolipin antibodies and CNS disease, renal disease, or vasculitis. Asherson et al’l similarly found devastating large vessel occlusions in four patients with SLE. Alegre observed significant leg ulceration in 30% of patients with circulatory lupus anticoagulant.“’ In addition to SLE, anticardiolipin antibodies have been detected in patients with other connective tissue disorders (eg, rheumatoid arthritis, scleroderma, primary Sjogren’s, or other “lupus-like” syndromes),‘)2m”4 in Sneddon’s syndrome (livedo reticularis and cerebral thrombosis),” idiopathic livedoid vasculitis,“” Degos’ disease (malignant atrophic papulosis),!yi Behcet’s syndrome,v7 malignancy,“” certain hematologic or myeloproliferative disorders,*’ drug-induced SLE syndromes,““‘.“” and even in the acquired immune deficiency syndrome (AIDS).“” Finally, otherwise normal patients have been reported who have either idiopathic or recurrent deep vein thromboembolism, idiopathic stroke, or recurrent fetal loss. For these patients, the term primary antiphospholipid syndrome has been applied.““’ Detection of anticardiolipin antibodies is by a variety of sensitive assays, including a specific enzyme-linked immunosorbent assay (ELISA).“” As a general screen, one may perform a VDRL or RPR, which is reported to be falsely positive
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FIG. 6 Painful, stellate malleolar ulceration ln patient with circulating lupus anticoagulant.
in 30% of patients havjny anticardiolipin antibodies.“’ Activated partial thromboplastin time is often elevated in these patients and does not correct when mixed with equal parts of normal plasma. “” Other causes of leg ulceration in SLE include
FIG. 7 Small vessels in dermis show evidence of thrombosis (see arrows) with sparse inflammatory cell infiltration in a patient with circulating lupus anticoagulant.
Clinics in Dermatology
venous insufficiency, which may or may not be related to the presence of anticardiolipin antibodies. These patients often have a history of recurrent deep vein thrombosis or other thromhocclusive events associated with the antiphospholipid syndrome.‘*~‘* Rarely, lesions of lupus profundus may break down and form punched-out ulcers. These lesions are usually located on the buttocks or proximal thighs and freyuently drain a yellowish material (Figure 8). Biopsy of adjacent skin commonly shows histopathologic changes consistent with lupus panniculitis. On healing, a characteristic depression, resulting from subcutaneous tissue loss, is produced. “I’ Bullous lesions of SLE may become denuded and produce superficial leg ulcerations. Generally, such lesions are multiple and exist in conjunction with intact bullous lesions elsewhere. Armas-Crux et al”” found that ulcers arising from bullae often left depressed and irregularly pigmented skin on healing. Drug-induced lupus syndromes have been reported in association with leg ulceration. Peterson”” described multiple pyoderma gangrenosum-like ulcers present on the proximal thighs and buttocks in a patient taking hydralazine. who also had a systemic SLE-like syndrome. Elevated ANA and anti-histone antibody titers reverted to normal, and ulcers healed promptly after discontinuation of hydralazine. A
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such as that utilized in idiopathic livedoid vasculitis, may be helpful (see discussion under Vasculitis).“’
Scleroderma
FIG. 8 Punched-out ulceration on the thigh overlying area of lupus panniculitis.
more typical peri-malleolar ulcer was reported by Kissin and Williamson”‘7 in association with hydralazine-induced SLE. Fjellner’Ox reported the precipitation of leg ulcers and an SLE-like illness in an additional patient on hydralazine. In this case, the precipitation of ulceration appeared to correlate with systemic zinc administration. Finally, a procainamide-induced SLElike illness with associated lupus anticoagulant was reported by Sanfelippo and Drdyna,““’ in association with lower extremity ulcers. The therapy of SLE-associated leg ulcers is problematic. Most lesions are refractory to routine topical measures, including skin grafting. Optimal management should be directed towards establishing a cause by appropriate biopsies and studies to detect the presence of anticardiolipin antibodies. If vasculitis is detected, systemic corticosteroid therapy in conjunction with cytotoxic agents such as azathioprine or cyclophosphamide may provide the best chance for remission.‘yl.‘ig.a Adjunctive plasma exchange may be expeditious, especially in the presence of high-grade vasculitis or circulating anticardiolipin antibodies.““~“’ In the latter circumstance, antithrombotic therapy,
The term scleroderma refers to a spectrum of disorders, all of which are characterized by a proliferation of fibroblasts and excessive production of matrix proteins (collagen and glycosaminoglycans) in involved tissues. Progressive systemic (PSS) as well as localized forms of scleroderma (morphea) are recognized. The pathogenesis of scleroderma remains unclear. Current investigations have proposed three major hypotheses in an attempt to explain the diverse manifestations of this disorder: 1) primary vascular changes, 2) immunologic dysfunction, and 3) abnormal fibroblast function. ““J’~ Aberrations in these systems may function independently or in concert to produce the clinical picture we recognize as systemic sclerosis. Cutaneous findings, including skin ulceration, are a prominent and often debilitating feature of systemic scleroderma (Figure 9). In a large series of patients described by Tuffanelli and Winkelman,“R 35.4% were found to have skin ulcers at some time during the course of their disease. These ulcers occurred most frequently on the fingertips and on the dorsa of the interphalangeal or metacarpophalangeal joints but also were seen on the legs, specifically over the malleoli and calcaneus, over the knees, on the pretibial areas, and over the dorsal aspects or tips of the toes. These ulcers tend to be painful, slow to heal, and relatively refractory to standard methods of treatment. Predisposing factors include trauma, vascular compromise, and calcinosis cutis. The skin overlying bony prominences in patients with scleroderma is taut and highly vulnerable to trauma. Associated joint contractures and the limited range of motion produced by extensive cutaneous sclerosis also make traumatic events extremely common. Because of underlying vascular disease and the cutaneous hypoxia present in the surrounding skin, these relatively small areas of injury may extend or deepen.“” Secondary infection may occur more
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FIG. 9 Multiple ulcerations on the foot and lower leg in patients with generalized morphea.
commonly in this setting, and a tlehilitating ulceration may form rapidly (Figure IO). Cutaneous calcinosis is a common feature of many patients with systemic sclerosis (especialI\ the CREST variant). Areas of calcinosis are commonly seen where ulcers are most common (eg, over bony prominences). As t,hesr subcutaneous and intracutaneous deposits grow in size, the overlying skin thins out and becomes susceptible to breakdown. Ulcerations in this setting may be seen to extrude calcium, and calcinosis can be palpated in surrounding skin OI observed in biopsy material or radiographs. These ulcers are likewise painful and at risk for secondary infection. Vascular abnormalities are commonly present in patients with scleroderma. IJp to 95%’ of these patients have significant vasospasm. as manifested by Raynaud’s phenomenon. Digital ulcers and gangrene are relatively common in advanced long-standing cases. Biopsies from the margins of these ulcers frequently demonstrate intimal proliferation of small blood vessels with concentric intimal hypertrophy and adventitial fibrosis leading to progressive vessel occlusion (endarteritis obliterans).“7~“” The pathogenesis of these vascular changes is speculative. Primary endothelial cell damage may be responsible and has been observed ultramicroscopically. Such damage may be mediated by specific endothelial cell cytoxic factors known to be present in the sera of patients with scleroderma as well as by anti-endothelial
cell antibodies or circulating immune complexes, 11’)12) Repeated insult to the vascular endothelium leads to enhanced platelet aggreg&ion. A variety of inflammatory mediators and growth factors are then released that may modulate endothelial cell as well as fibroblast function, thereby leading to progressive vascular compromise and/or sclerosis. Vascular leg ulcers in patients with scleroderma are not infrequent. They are usually located acrally, over bony prominences, and may be infarctive appearing or punched out. They are sometimes preceded by an area of purpura that subsequently breaks down. Thomas and Winkelmann”’ have reported a series of patients of this type in whom painful, stellate ulcers developed, which, on healing, left whitish scars typical of atrophie blanche. Biopsy of these lesions revealed classic segmental hyalinizing vasculitis in four patients and endarteritis obliterans in two. An additional, unusual patient had rheumatoid arthritis with atrophie blanche-like scars and ulcers that on biopsy demonstrated a necrotizing arteritis consistent with polyarteritis nodosa. Clearly, heterogeneity exists among even the vascular ulcerations present in scleroderma. Because of the presence of diverse vascular lesions in systemic sclerosis, including those related to vasospasm and/or thrombosis (livedoid vasculitis), anticardiolipin antibody assays have been obtained in several series of scleroderma patients. Some authors have reported no asso-
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mide either alone or in combination with plasmapheresis. GreeP reported dramatic healing in eight patients given azathioprine, while Dau et all= achieved ulcer healing, decreased skin thickness, and decreased ANA titers in 14 of 15 patients with scleroderma, using immunosuppressives and plasma exchange in combination. In patients with calcinosis cutis, colchicine, intralesional steroids, aluminum hydroxide, and etidronate sodium have been utilized to promote healing in separate reports. ‘29~“” Larger controlled studies would be of interest. Other potential therapies include skin grafting with cultured allografts,“7 split-thickness skin grafting in combination with nifedipine, etidronate sodium and aspirin/dypridamole,‘“9 pentoxifylline , lsz topical ketanserin,“” or hydrocolloid dressings.“eZ Obviously, efforts to protect areas subject to trauma with padded devices and properly fitting footwear are critical prophylactic measures.
FIG. 10 Chronic ulceration of the volar aspect of the great toe in a patient with systemic sclerosis. Other digits on the same foot were removed previously because of gangrenous ulcers.
ciation, whereas others have demonstrated elevations in titers that appeared to have limited correlation to the reported findings of the antiphospholipid syndrome.‘“‘“” Formulating effective therapy for patients with scleroderma leg ulcerations is problematic and suffers from a large number of anecdotal reports in the literature. Several investigators have reported success with vasodilator agents such as nitrates, prazosin, a-methyldopa, hydralazine, captopril, or prostaglandin infusion (pGR,).‘““,l”” Woo et alIZ have reported healing of leg ulcers secondary to ischemia and vasospasm with nifedipine starting at 10 mg 3 times a day and progressing to 40 mg 3 times a day. Others have utilized antiplatelet agents, such as aspirin and dipyridamole in combination, ketanserin, or dazoxiban, either alone or combined with vasodilators.‘24 Greer and Dau et al~s7~~zx have reported the successful use of azathioprine or cyclophospha-
Miscellaneous Collagen Vascular Diseases
Several other illnesses, which may have autoimmune pathogeneses, occasionally produce primary leg ulcerations. These include dermatomyositis, mixed connective tissue disease, primary Sjogren’s syndrome, Behcet’s syndrome, and pyoderma gangrenosum.
Dermatomyositis
Dermatomyositis is characterized by muscle weakness and cutaneous findings, which are considered typical. These include a violaceous hue with edema of the eyelids (heliotrope) as well as poikilodermic patches over bony prominences such as the knuckles and proximal interphalangeal joints (Gottron’s papules). Calcinosis of dermis, subcutaneous tissue, and muscle may occur, especially in childhood dermatomyositis. As in scleroderma, these areas of calcinosis, if close to the skin surface, are prone to breakdown and subsequent ulcerationlBS (Figure 11). Rarely, one sees chronic, indolent, undermined ulcerations over the malleoli in dermatomyositis, unassociated with calcinosis cutis.1”6
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eral ulcerations, including leg ulcers, are occasionally seen. ““‘.“” Vascular lesions, such as necrotizing vasculitis and atrophie blanche, which are well documented in SLE and scleroderma, are unusual in MCTD. The presence of lupus anticoagulant with associated thromboembolim has been reported. “W The prognosis in MCTD is relatively good, and response to systemic corticosteroid is usually prompt.‘“g Sjogren’s Syndrome
Primary Sjogren’s syndrome may be accompanied by a Felty’s-like syndrome with leg ulcers similar to those occurring in RA but without arthritis.“’ Anticardiolipin antibodies have also been found in a single patient with primary Sjogren’s, livedo reticularis with biopsy evidence of thrombi in small cutaneous blood vessels, and catastrophic CNS infarction.‘” BehCet’s Syndrome FIG. 11 Ulceration secondarytocalcinosiscutison extensor aspect of the knee in a patient dermatomyositis.
the with
These may occur in association with a focal livedo reticularis pattern on the ankles and legs. Other findings include tender dermal nodules, periungual infarcts, and digital ulceration.“” These clinical findings have been attributed to cutaneous vasculitis. although biopsy substantiation in the literature has not been extensive. In general, vaculitis is more common in childhood dermatomyositis, often associated with visceral as well as cutaneous involvement. In adults, vasculitis has been observed in 9.2%’ of patients in one series, many of whom had an associated underlying malignancy. I,” Mixed Connective Tissue Disease (MCTD)
This disorder presents with overlapping features of SLE, scleroderma, and dermatomyositis and is characterized serologically by a high-titer ANA to ribonucleoprotein (RNP). ‘.‘!’ Skin findings in MCTD are non-specific and reflect features that one would expect to see in SLE, scleroderma, or dermatomyositis. Periph-
This illness is characterized by oral apthosis and by at least two of the following clinical findings: genital aphthae, arthritis, posterior cutaneous pustular vasculitis, and uveitis. may tneningoencephalitis. ’ I2 Thrombophlebitis accompany this syndrome and can predispose patients to leg ulcers of the venous stasis type. Anticardiolipin antibodies are found in approximately 18% of patients with Behqet’s and may form the basis for the increased incidence of vascular thrombosis.‘” In addition, recalcitrant leg ulcerations associated with a leukocytoclastic vasculitis and profound pathergy has been reported by Plotkin et al. I”’These ulcers were multiple, punched-out lesions located on the dorsum of the foot. Despite the pronounced neutrophilic infiltrate present on biopsy, these lesions failed to respond to colchicine but did respond to prednisone and chlorambucil. Lee et al”’ have reported a case of Behqet’s associated with ulcers over the dorsa of the feet that demonstrated a bullous, necrotizing vasculitis on biopsy. Infiltrating cells were lymphohistiocytic in contrast to the more typical polymorphonuclear leukocyte. Lesions in this case responded to systemic and intralesional corticosteroids combined with dapsone. An additional therapy reported to be helpful
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cline,“” rifampin, “’ or cyclosporine.152 A recent report by Prystowsky et al*“’ demonstrated the usefulness of high-dose, pulse corticosteroid therapy in six of eight patients with refractory PG. Hyperbaric oxygen therapy followed by skin grafting has also been utilized successfUlly.“‘* Vasculitis
FIG. 12 Typical ulceration of pyodermagangrenosum, with boggy, undermined borders.
in cases of recalcitrant leg ulceration associated with Behqet’s syndrome has been oral prostaglandin E, (OP 1206) which functions as a potent vasodilator as well as a strong inhibitor of platelet aggregation. I46 Pyoderma Gangrenosum (PG)
Pyoderma gangrenosum is a disorder of unknown pathogenesis. No consistent immunologic abnormality has been found in patients with this disease, although defects in cell-mediated immunity and circulating immune complexes have been detected. PG is associated with a variety of disease states, many of which are felt to have an autoimmune basis. Cutaneous ulceration is the hallmark of this disease; the majority of these ulcers are present on the lower extremities. Typically, these lesions begin as tender papulopustules, which o biopsy demonstrate a pronounced neutrophilic infiltrate. As the lesion evolves, the ulcer borders become raised, purple in color, and undermined. Characteristic cribiform scarring is produced as the lesions heal (Figure 12). Therapy for PG includes systemic and intralesional corticosteroids, dapsone,‘“” clofazimine,‘47 azathioprine, “* cyclophosphamide, M!’ minocy-
The term vasculitis encompasses a spectrum of distinct clinicopathologic diagnoses in which inflammation and necrosis of blood vessels of various sizes occurs. Clinical manifestations may vary depending on the degree and size of vessel involvement. Past classifications of these disorders have not been consistent and have been based on divergent criteria such as speculative of etiology, size and anatomic distribution affected vessels, or on histopathology findTable 2 presents a useful classification ings. ‘56~‘57 based largely on vessel size and the histologic type of vessel involvement. Included in this clas-
TABLE 2. Classification of Vasculitis I. Necrotizing venulitis (hypersensitivity vasculitis) A. Henoch-Schonlein purpura 6. Essential mixed cryoglobulinemia C. Waldenstrom’s hyperglobulinemic purpura D. Vasculitis associated with collagen vascular disease E. Nodular vasculitis F. Urticarial Vasculitis G. Serum sickness (drug-induced) II. Polyarteritis Nodosa (PAN) A. Systemic B. Cutaneous C. PAN-like vasculitis secondary (eg, Hairy Cell leukemia)
to malignancy
Ill. Granulomatous vasculitis A. Wegener’s granulomatosis 8. Churg-Strauss syndrome C. Lymphomatoid granulomatosis IV. Large vessel arteritis A. Giant cell arteritis (temporal arteritis) B. Takayasu’s arteritis V. Other A. Segmental hyalinizing vasculitis (livedoid vasculitis) B. Antiphospholipid syndrome
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sification is livetloitl vasculitis and the ant iphosSCktYJderma, ant1 miscellaneous other rheumapholid syntlrome, which ;lre important in out t(~1~~g-i~ disorders was thoroughly reviewed. In discussion of vascular syndromes proflucing ~‘u the remaining section, tniscellaneous vasculitaneous ulceration, but pathogenetically pr~~bw- tides commonly associated with leg ulceration bly represent thrombotic tlisor(lcrs anti tlo newt will be summarizetl. involve inflammation ant1 necrosis of vessels a> a primary event. Necrotizing Venulitis Vasculitis most likely rt~pt’esettt~ an tttttnunt~ complex-mediatetl event in \vhich circulating imThis disortler is characterized pathologicall> mune complexes of ;i critical sixt, ar(~ ci~~pwitrvi try a leukocytoclastic vasculitis affecting postin vessel walls, activate rhcl ~omplemrnt c;ts~ capillary venules (Figure 5). Palpable purpura catle. anti, via specific chemoattt.a~tants, Ott- is often the clinical hallmark of this disease, alcourage the accumulation of infammator~~ cells. though other lesions such as urticarial wheals. These cells (particularly the l)ol~tnot~phonu~~lea I’ vesicles, notlules, hemorrhagic bullae, pustules, may occur. Leg ulcers in this setleukocyte) release proteases that then art* f’rec~ or ulcerations to inflict tlamagr on thr surroutitling kJkJd ye>tiny are usually superficial and may arise from se,. ,:,ti I’lh The initial permc,ahility of t hc vessel vc&les or hemorrhagic bullae; often they are sut2~oundcd by a rim of purpura or typical palpwall may be metliated hy tiistamint~ from degrdnulatetl mast cells 01’ front spr~c+ic antiahit] purpura is present elsewhere”‘” (Figure 18). purpura has entlothelial cell antibotlirs. ’ “’ “” Other invwt I~ .i \‘;tt’iattt of atlult Henoch-Schonlcin hec,tt drscribrtl in which ulcers occurred within gators have, postulatetl t.tlll-metiiatrtl tnr&tnisms to explain certain types i~t’ vascuiitis. larger plaques of ~Julpum “‘I This appearance \Vits chafdcteristic ant1 in all cases ~vas associatetl especially those characterizetl by ,granulomat ous I\ ith IgA &position in vessel walls. inflammation. “” The ctttan~‘ous ~-nant!‘t~st;~tttrtt~ 01 \‘;LIYOIL> Ntacrotizing venulitis has been associated with vasculitities can vary from palpabkh put~l.~ut~;iTV)
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associated livedo reticularis, which, in the cutaneous variant, may radiate from the ulcers in a “starburst”-like configuration. Patients often have associated arthralgia, myalgia, and neuralgia. Electromyographic abnormalities may elicit objective findings characteristic of mononeuritis multiplex. PAN may be associated with otitis media,‘7” hepatitis B infection,“’ hairy cell leukemia,‘76 and, in the case of the cutaneous variant, Crohn’s disease. ‘7’i.‘ii
FIG.14 Punched-out ulcerationson the calf in a patient with cutaneous polyarteritis nodosa.
107
FIG. 13 Palpable purpura of the lea and ankle with evidence of superficial ulceration
When adequate, deep biopsies are obtained from nodules or from the edge of cutaneous ulcers; a necrotizing vasculitis of small to mediumsized muscular arteries is seen (Figure 15). Immunofluorescence may reveal immunoreactants (most commonly IgM), C3, or fibrin in the vessel walls when biopsies are taken of early lesions. Ii* The therapy of systemic PAN should include systemic corticosteroids combined with cyclophosphamide. Oral or intravenous protocols have been described. Recent data indicate that the prognosis of this disease can be improved from a 15% 5-year survival to 60%’with the regimen. In cutaneous PAN, a variety of less aggressive therapies have been used successfully, including sulfones, I”’ antituberculous therapy,‘“’ eorticosteroids,‘78 and azathioprine.‘” In some cases, cyclophosphamide is required.17’; Granulomatous Vasculitis
Of the granulomatous vasculidites noted in Table 2, Wegener’s granulomatosis is most likely to demonstrate ulceration. In the review by Hu et al, lx’45% of patients had skin lesions, of which 28% had specific histopathologic findings. These lesions occurred commonly, but not exclusively, on the lower extremity and included purpura and ecchymoses, which were ulcerated if inflammation was severe. In these cases pathologic findings usually demonstrated a necrotizing vasculitis. Granulomatous vasculitis was seen in
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FIG. 15 Medium-sized artery in subcutaneous tissue cut tangentially showing necrotizing vasculitis (40 x ).
only two patients. In this setting representati\-cl cutaneous lesions included erythematous papulonodules that sometimes ulcerated (Figure 16). Similar findings were reported in a series b> Reed.‘“’ Interestingly, in 1X patients reportctl by Fauci and Wolff, lh5ulceration was the most common cutaneous finding. In addition to cutaneous disease, Wegenrr’s is characterized typically by a necrotizing granulomatous vasculitis involving the upper and lower respiratory tract and the renal glomeruli. Recent reports of the detection of highly specific anti-cytoplasmic antibodies in this disease may
in paFIG. 16 Granulomatousarteritis tient with Wegener’s granulomatosis. Note multinucleated giant ceil (see arrow) (40 x ).
provide a non-invasive means of diagnosis in ambiguous cases. M ‘G Therapy of Wegener’s granulomatous is most appropriately systemic corticosteroids and cyclophosphamide in combination. “” Granulomatous vasculitis is also observed in (‘burg-Strauss disease and lymphomatoid granulomatosis. The former is most commonly associated with asthma, eosinophilia, and vasculitis and presents on the skin as erythematous, subcutaneous nodules. I” Illceration of these lesions is not reported frequently, despite the fact that the affected vessel (medium-sized
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Rc.17 Largevesselwithgranulomatous vasculitis secondary to lymphomatoid granulomatosis (40 x ).
artery) is the same size as that affected in PAN.lX9 Lymphomatoid granulomatosis may show protean skin manifestions, including subcutaneous or dermal nodules (60%) and, less freFIG. 18 Necrotic ulceration on the posterior calf in a quently, a maculopapular rash or macular patient with erythema induratum. erythema. Ulceration is rare and nonspecific in appearance; it occurred in 7% of the patients reported by James et al.‘” Biopsy of affected areas typically demonstrates an angiodestructive, angioinvasive, granulomatous vasculitjs, with pleomorphic, large cells and a polymorphic inflammatory cell infiltrate (Figure 1’7). Sarcoidosis may rarely present as a granulomatous vasculitis. Petri et al’“’ have reported one such patient with tender, pretibial leg ulcers showing granulomatous vasculitis on biopsy, who also had evidence of pulmonary and hepatic sarcoidosis. Erythema lnduratum (Nodular Vasculitis) Erythema induratum is a disease of middleaged or younger women and rarely of males. Clinical findings include tender, persistent, or recurrent nodules that may ulcerate, with a site of predilection in the posterior aspect of the lower third of the calves (Figure 18). Ulcerations formed are usually irregular and shallow and may have bluish borders. A few patients have had an associated past or present history of tuberculosis.‘92-‘M
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FIG. 19 Lobular, granulomatouspanniculitis in a patient with etythema Induratum. Note thrombosed vessel (arrow) and giant cell (arrowhead) (40x).
Histopathologic findings include a lobular pan niculitis early on and la&r. a dermal granulomatous and tuberculoid response that ran extend into fat (Figure 19). Vasculitis may occur; in 50% of cases caseation necrosis may be founcl (usually in ulcerated areas). Lesions may respond to antituberculosus therapy, ‘!” oral potassium iodide”‘” 6SKI X0-%,‘iOO mgid), or may resolve spontaneously.
Takayasu’s Arteritis
This disorder affects large vessels, including the aorta and its major branches. Pyoderma gangrenosum-like leg ulcers have been reported frequently in CJapan and rarely in the U.S. in association with typical Takayasu’s arteritis elsewhere. I!lli.,!li
Livedoid Vasculitis (Segmental Hyalinizing Vasculitis)
This disorder was originally reported by Feldaker et al’!‘”as an uncommon, seasonal condition in which irregularly shaped, stellate ulcers develop in an area of macula purpura on the lower legs and ankles, principally in women. (Figure 20) The ulcers tend to be painful, chronic, or recurrent and heal with characteristic white, depressed scars with telangiectasias at the margins
catrophie blanche). Many patients have associated livrdo reticularis. Pathologic findings demonstrate a V-shaped cutaneous infarct with vessels in the mid to lower
FIG.20 Stellate ulcerations near the lateral malleolus In a patient with livedoid vasculitis.
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found defective tissue plasminogen activator release and impaired fibrinolysis.“’ Prostacyclin release by vascular endothelium may also be impaired. “” The recent finding of antiphospholipid antibodies in some but not all cases of livedoid vasculitis merits further long-term studies. Therapy of atrophie blanche has included nicotinic acid,% aspirin and dipyridamole, as well as other anti-platelet regimens,“‘,““’ minidose heparin,‘” nifedipine,“‘” pentoxifylline,“““~2”’ oral ketansermPo7 cyclophosphamide,‘“’ and the fibrinolytic agents phenformin and ethyestren01.2”x
References
RG.21 Thrombosisofdermalvesselwith hyalinization of the vessel wall (arrow) and sparse surrounding infiltration in patient with livedoid vasculitis (64 x ).
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dermis showing thickening, endothelial proliferation, hyalinization, and focal thrombi. Inflammation surrounding the vessel is usually sparse and no leukocytoclasis is seen, although extravasated red blood cells indicate that vascular integrity has been compromised (Figure 21). Livedoid vasculitis and atrophie blanche have been associated with a variety of secondary disorders, including collagen vascular disease in 15%, arterial and venous insufficiency, essential cryoglobulinemia, lymphoma, chronic myelogenous leukemia, polyarteritis nodosa, and Sjogren’s syndrome.;?X.7”.7’,‘99~2”’ An idiopathic form of livedoid vasculitis, unassociated with discernible systemic disease, also exists.“” Recently, cases resembling livedoid vasculitis, both clinically and histopathologically, have been reported in conjunction with circulating anticardiolipin antibodies.‘“’ The pathogenesis of livedoid vasculitis is unclear, but recent evidence suggests that vascular thrombosis is the initiating event. Shornick et arm have shown by electron microscopy that fibrin deposition within vessels is the earliest pathologic finding. Other investigators have
3. Bacon PA. Extra-articular rheumatoid arthritis. In: McCarty DJ, ed. Arthritis and Allied Conditions: A Textbook of Rheumatology. Philadelphia: Lea and Febiger, 1989, pp 1967-98. manifestations of rheumatoid 4. Hurd ER. Extra-articular arthritis. Sem Arthritis Rheum 1979;8:151-76. 5. Thurtle OA, Cawley MID. The frequency of leg ulceration in rheumatoid arthritis: A survey. .J Rheumatol 1983;10:507-509. 6. Wilkinson M, Kirk J. Leg ulcers complicating rheumatoid arthritis. Scot Med J 1965;10:175-82. 7. Gottlieb NL, Penneys NS. Spontaneous skin tearing during systemic corticosteroid treatment. JAMA 1980;243: 1260-61. 8. Kissel JT, Slivka AP, Warmolts JR, Mendell JR. The clinical spectrum of necrotizing angiopathy of the peripheral nervous system. Ann Neural 1985;18:251-57. 9. Weiss JJ, Thompson GR, Lazaro R. Gold toxicity presenting as peripheral neuropathy. Clin Rheumatol 1982; 1285-89. 10. McGuigan L. Burke D. Fleming A. Tarsal tunnel svndromeind peripheral neuropathi in rheumatoid disease. Ann Rheum Dis 1983;42:1W-31. 11. Jorizzo JL, Daniels JC. Dermatologic conditions reported in patients with rheumatoid arthritis. J Am Acad Dermat01 1983;8:439-57. 12. Cawley MID. Vasculitis and ulceration in rheumatic diseases of the foot. Bailliere’s Clin Rheumatol 1987; 1:31533.
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Address for correspondence: J. Blake Goslen, M.D., Department of Dermatology and Otolaryngology, University of Pittsburgh School of Medicine, 3601 Fifth Avenue, Pittsburgh, PA 15213