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Leukocytoclastic vasculitis has a distinctive clinical and light microscopic presentation; however, the etiologic basis of leukocytoclastic vasculitis is varied. The majority of cases are attributable to immune complex deposition within a vessel wall and represent an Arthus type III immune complex reaction. The prototypic immunoreactant profile is characterized by granular deposits of components of complement activation in concert with immunoglobulin within the cutaneous vasculature. We encountered nine patients with protean skin rashes including those clinically consistent with vesiculobullous eruptions that showed a leukocytoclastic vasculitis however, the immunoreactant profile was characterized by homogeneous linear deposits of immunoglobulin along the dermal epidermal junction in a fashion resembling an autoimmune vesiculobullous disease.
Among the clinical presentations were palpable purpura, urticarial vasculitis and a vesiculobullous eruption with supervening purpura. Two patients with Crohn's disease presented with classic palpable purpura with biopsy proven leukocytoclastic vasculitis while DIF studies demonstrated linear IgG with floor localization on the salt split skin assay. Four patients with systemic lupus erythematosus showed purpuric vesiculobullous lesions with evidence of a neutrophilic interface dermatitis and leukocytoclastic vasculitis in three. One patient had urticarial nonbullous lesions showing small vessel vasculitis and a neutrophilic interface dermatitis. In all patients DIF studies showed linear immunoglobulin deposits within the basement membrane zone. The constellation of findings clinically, light microscopically and by immunofluorescence were those of a vasculitic presentation of bullous SLE. Two patients had linear IgA disease which was drug induced in one and paraneoplastic in one where the dominant morphology on biopsy in both cases was a leukocytoclastic vasculitis. One patient had drug associated eosinophilic enriched leukocytoclastic vasculitis with DIF studies showing striking linear deposits of IgG suggestive of bullous pemphigoid. In all cases typical granular vascular immunoglobulin and complement deposition compatible with immune complex mediated vasculitis was observed. It is likely that local immune complexes derived from basement membrane zone antigen bound to antibody are pathogenically relevant. We propose the designation of linear vasculitis for this unique scenario of leukocytoclastic vasculitis and linear immunoglobulin epidermal basement membrane zone staining which in some cases represents a vasculitic presentation of conventional autoimmune vesiculobullous disease.
Leukocytoclastic vasculitis (LCV) affecting the skin typically appears as palpable purpura on the legs while less common presentations encompass livedoid ulcerations and hemorrhagic vesiculobullous lesions.1 Its etiologic basis is most commonly one attributable to microvascular entrapment of circulating immune complexes consistent with an Arthus type III immune complex reaction, leading to classic complement pathway activation.2 Direct immunofluorescence can be an important diagnostic adjunct for determining the nature of the immune complex.3,4 For example, a prominent and dominant pattern of granular vascular deposition for IgA is typical for IgA associated vasculitis including Henoch Schoenlein Purpura,5 while a positive lupus band test showing all classes of immunoglobulin deposition along the dermal epidermal junction is characteristic for hypocomplementemia urticarial vasculitis in the setting of underlying systemic lupus erythematosus. Mixed cryoglobulinemic vasculitis exhibits a distinctive DIF pattern characterized by highlighting of the intravascular lumens by immunoglobulin; the immunoglobulin isotype of the rheumatoid factor determines the chemical composition of the cryoprecipitate. A nonspecific pattern that corroborates an underlying vascular injury syndrome independent of etiology includes granular deposits of IgM and components of complement activation including C5b-9 within the cutaneous vasculature.7-10 Concomitant granular deposits of immunoglobulin of IgG isotype and complement namely C3 and C5b-9 within keratinocytes could signify anti-Ro and or anti-RNP antibodies. Both anti-Ro and anti-RNP antibodies may function as anti-endothelial cell antibodies and hence define vascular cofactors that facilitate vascular injury mediated by immune complex deposition.11
We present nine patients with varied clinical presentations ranging from autoimmune vesiculobullous disease to palpable purpura where skin biopsies showed an LCV. However, the immunoreactant deposition pattern demonstrated a homogeneous linear deposition within the basement membrane zone BMZ typical for autoimmune vesiculobullous disease targeting the epidermal basement membrane zone. The term linear vasculitis has been introduced for this interesting hybrid picture of small vessel vasculitis that overlaps with autoimmune vesiculobullous epidermal basement membrane zone disease. The clinical features, light microscopic findings, and immunofluorescent profile are discussed in detail for each of the patients.
Materials and Methods:
Nine cases of small vessel vasculitis of the skin in association with direct immunofluorescent(DIF) studies showing a linear staining pattern within the epidermal basement membrane zone for IgG or IgA were prospectively encountered in the routine diagnostic practice of one of the authors. These cases were evaluated through routine light microscopy and direct immunofluorescence (DIF)12, as well as with the salt-split skin assay13 and indirect immunofluorescence13,14,15 in select cases.
A 21-year-old white woman with a 12-year history of Crohn's disease presented to a dermatologist with recurrent painfully thin urticarial plaques on the legs that had been persistent for 8 years. The plaques were precipitated by vigorous exercise, infection, and a second course of infliximab. The lesions gave a stinging sensation and had an intermittent course lasting for two to three weeks before fading completely without scarring or residual pigmentary changes. The episodes were not associated with major swelling of the lips or dysphagia. Additionally, there was a 12-year history of crampy intermittent abdominal pain, bloody diarrhea, fever, and arthralgias. Medications taken by the patient at the time of biopsy had included methotrexate, folate, and minocycline. The lesions seemed to clear with use of various antimicrobials including metronidazole, as well as subsequent to an appendectomy. Prior courses of prednisone had not only been ineffective but may have aggravated the lesions.
On physical examination, the patient had well demarcated deeply violaceous palpable dermal plaques with a non-blanching surface component confined to the thighs and legs. There were no blisters, ulcers, or evidence of scarring, although the lesions were evidently tender. There were no obvious joint effusions or tenderness.
Initial skin biopsy of the leg demonstrated severe pan-dermal vasculitis with no evidence of overlying vesicle/blister formation on hematoxylin and eosin staining. Direct immunofluorescent testing demonstrated striking homogeneous linear staining along the dermal epidermal junction for IgG and an interrupted banding of granular staining along the dermal epidermal junction for IgM. There was granular vascular and focal granular dermal epidermal junction staining for C3. A continuous band of course granular staining for C5b-9 was found both in the vasculature and along the dermal epidermal junction. Salt split skin assay was performed showing striking localization of basement membrane zone staining to the floor of the saline induced split, potentially corroborative of antibodies to type VII collagen. Indirect C4d immunofluorescent assay revealed a continuous band of weak granular staining along the dermal epidermal junction and striking homogeneous vascular staining corroborative of microvascular injury.
Repeat punch biopsy of the posterior aspect of the right calf confirmed the prior results. There were an impressive vascular reaction involving the superficial and deep portions of the dermis. The subcutis was characterized by angiocentric cuffs of disintegrating neutrophils accompanied by luminal and mural fibrin deposition. There was extensive infiltration of the adventitial dermis of the eccrine coil along with permeation of the interstitial spaces of the fat lobule by neutrophils.
Direct immunofluorescence demonstrated prominent homogeneous linear staining for IgG along the dermal-epidermal junction. A similar pattern of deposition was not observed for IgA. There was a focal granular staining pattern for IgM within the superficial dermis. An interrupted band of fine granular staining for C3 was seen along the dermal-epidermal junction along with focal granular staining within the dermal papillary capillaries. There was a continuous band of granular staining along the dermal-epidermal junction for C5b-9.
The following laboratory studies were normal or negative: antiphospholipid, anti-centromere, anti-Scl-70, anti-Sm, anti-RNP, anti-Ro, anti-La, anti-DNA, anticardiolipin, reticulin IgG and IgA and anti-glomerular basement membrane antibodies, urinalysis, serum and urine electrophoresis, complement levels, P ANCA, cryoglobulin, rheumatoid factor, hepatitis B surface antigen, hepatitis C antibody, glucose-6-phosphate dehydrogenase, BUN, creatinine, calcium, alkaline phosphatase, bilirubin, SGOT, sodium, chloride, potassium, albumin and chest radiograph. Anti-neuclear antibody (ANA) was positive at a titer of 1:320 with a speckled pattern without meeting any criteria for lupus, mixed connective tissue disease or Sjogren's disease. C-ANCA was positive at 1:160 with anti-proteinase of 20 units. IgG for parvovirus B19 was also positive, although the quantitative titer was not known. Screening and culture of stool samples were positive for Clostridium difficile.
A course of metronidazole was given, which temporarily stopped her diarrhea. Diarrhea and abdominal cramping returned in November of 2003 despite continued treatment 500mg twice a day. Questran resin further aggravated the abdominal discomfort and was subsequently discontinued. Prior treatment with prednisone had been unsuccessful in clearing her skin lesions, and dapsone was initiated at 50mg twice a day with significant clearing of the lesions at five days. Skin lesions, however, returned to the anterior portion of the legs, in November 2003 despite two months of clearing on dapsone 50mg twice a day. Increased doses of Dapsone of 150mg every day to 200mg every day resolved the lesions. A colonoscopy in December 2003 revealed evidence of chronic inflammation of the entire colon consistent with pancolitis. The terminal ileum appeared granular. Multiple random biopsies were obtained and confirmed the diagnosis of Crohn's disease. The patient has been lost to follow up.
A 56-year-old man with Crohn's disease was admitted to the hospital for dehydration secondary to 2 weeks of bloody diarrhea. Concurrently, he developed a severe purpuric reaction on his legs and associated joint and muscular discomfort with swelling of the hand, feet, and knees. The lesions on his legs were asymptomatic and bothersome only in appearance. He had discontinued medication for Crohn's disease 4 years prior and was taking no medications at the time of admission. He additionally suffered from malaise. Periodically, he reported having ulcers in his mouth that cleared with hydrogen peroxide gargle.
On physical examination, the patient had several discrete deeply erythematous to violaceous patches and plaques primarily distributed on his legs and hips with some scattered patches and plaques on his arms and trunk. The largest was 10 cm, located on the inner aspect of the right thigh. Resolving lesions left residual post-inflammatory hyperpigmentation. He additionally had acutely swollen knees, ankles, and wrists, but there were no oral lesions.
A shave biopsy from the right hip was performed and showed necrotizing leukocytoclastic vasculitis. There was a homogeneous band of linear staining for IgG and IgA along the dermal epidermal junction with a predominance of IgG. There was no significant immunoreactivity to IgM or C3. There was a continuous band of fine granular staining for C5b-9 along the dermal epidermal junction.
The patient was treated with mesalamine and iron supplementation for his Crohn's disease and prednisone 30 mg twice a day. This resulted in substantial clearing of the skin lesions, and the steroid was tapered over several weeks to 10mg twice a day. He was intermittently treated with insulin due to the hyperglycemic effects of the oral steroids. The patient remains on this lower dose of steroids. Although he had one deeply erythematous to violaceous plaque appearing on his right leg, his eruption resolved. He has had no joint involvement and no gastrointestinal complaints. His physicians were considering future treatment with various steroid-sparing agents.
An 88-year-old woman saw her dermatologist for a diffuse widespread eruption on her arms. She had previously had a hip replacement and had had osteomyelitis for which she had received antibiotics including vancomycin. A skin biopsy was taken from her left forearm and submitted for direct immunofluorescence (DIF) analysis, while routine light microscopy was performed on a skin biopsy from her left arm. Routine light microscopy demonstrated a neutrophilic purpuric vascular reaction (Figure 1a). In particular, there was a mixed angiocentric infiltrate of lymphocytes and neutrophils with accompanying red cell extravasation and leukocytoclasia. The direct immunofluorescent sample was consistent with IgA vasculitis based on the prominent and dominant granular deposits of IgA within microvessels. In addition, there was concomitant striking homogenous linear deposits of IgA along the dermal epidermal junction exactly recapitulating the pattern observed for linear IgA disease. Immunohistochemistry for C3d on paraffin embedded tissue also demonstrated linear deposits along the dermal epidermal junction (Figure 1b). The patient had circulating IgA antibodies targeting the epidermal basement membrane zone with roof localization using generic salt-split skin.
A 30-year-old woman with an established history of SLE presented to her dermatologist with dermatitis for three days. She had pruritic papules and papular-vesicles on her hands, arms, face, and neck which were eczematous. Histologic examination of the tissue from the right arm revealed a moderately severe leukocytoclastic vasculitis with concomitant intraepidermal pustulation and areas of neutrophilic interface dermatitis (Figure 2a-c).
Subsequently, six days after the initial biopsy, another specimen from the same area of the right arm was submitted for DIF analysis. Since then, the rash had calmed significantly but there were still flat erythematous papules. Direct immunofluorescent studies demonstrated a positive lupus band test with all immunoglobulin isotypes deposited in the basement membrane zone consistent with and diagnostic of systemic lupus erythematosus (SLE). In addition, there were homogenous linear deposits of IgG, C3d, C4d, and C5b-9 indicative of antibodies to basement membrane Zone (BMZ) component (Figure 2d). Overall the combined light microscopic findings and direct immunofluorescent profile was consistent with a vasculitic presentation of bullous systemic lupus erythematosus. The vascular deposition of immunoglobulin and complement was compatible with an immune based microvascular injury syndrome.
An 84-year-old woman presented to her dermatologist with itchy and excoriated macular papular rashes on her chest, back, abdomen, arms, and legs. She had previously been admitted for colitis and was administered Flagyl and hydralazine. The patient developed a generalized macular papular rash temporally associated with the administration of Flagyl. The patient was discovered to have significant peripheral blood eosinophilia up to 30%. Despite the drugs being discontinued, however, the dermatitis had progressed and became petechial.
The vasculitis noted clinically was captured histologically. There was a modest interstitial and perivascular neutrophilic infiltrate associated with leukocytoclasia and red cell extravasation consistent with an incipient urticarial vasculitis (Figure 3). Concomitant tissue eosinophilia was also noted.
Additionally, analysis of a DIF specimen from the forearm revealed a homogeneous linear staining for IgG, C3 and C4d consistent with an autoimmune vesiculobullous disorder targeting the epidermal basement membrane zone such as bullous pemphigoid.16 Furthermore, there was evidence of a vascular injury syndrome characterized by extensive granular deposits of C5b-9, C3, and fibrinogen in the microvasculature .
The final diagnosis in this case was prebullous urticarial bullous pemphigoid with a supervening urticarial vasculitic component triggered by metronidazole therapy.
An 80-year-old man presented to his dermatologist in December of 2010 with a 3-day history of painful blisters and a crust on the scrotum and buttocks with an erythematous base. His past medical history was remarkable for Hodgkin's lymphoma diagnosed in November of 2010 when he presented with failure to thrive over a four-week period. Histologic examination of a biopsy from the left buttock revealed a neutrophilic interface dermatitis with subepidermal bulla formation and secondary necrolytic epidermal change(Figure 4a). The subjacent dermis exhibited a perivascular neutrophilic infiltrate with red cell extravasation and focal mural fibrin deposition (Figure 4b). C3d studies performed on paraffin embedded formalin fixed tissue demonstrated prominent granular deposits of C3d within the microvasculature(Figure 4c). Direct immunofluorescent studies showed linear deposits of IgA along the dermal epidermal junction. A diagnosis was made of paraneoplastic linear IgA disease with concomitant features of secondary leukocytoclastic vasculitis (Figure 4a-c).
The patient is a 31-year-old female with a history of systemic lupus erythematosus. The clinical features included arthritis, idiopathic thrombocytopenic purpura, anemia and more recently an extensive annular and somewhat vasculitic appearing skin rash (Figure 5). A skin biopsy showed a neutrophilic interface dermatitis and a concomitant neutrophilic vascular reaction associated with red cell extravasation and hemorrhage and focal mural fibrin deposition along with prominent vascular deposits of C3d, C4d, and C5b-9 corroborative of a component of vascular injury(Figure 5b,c). There was concomitant upregulation of type I interferon that was demonstrated by the extent of MXA staining, the surrogate type I interferon marker strongly expressed in viral and autoimmune disease.17,18 The immunofluorescent studies showed a positive lupus band test of IgM isotype, and as well there were striking homogeneous linear deposits of IgG within the epidermal basement membrane zone.
The patient is a 27-year-old female with a past medical history of systemic lupus erythematosus. Among her disease signs and symptoms were fever, avascular necrosis of the femoral heads, arthralgia, skin rashes, oral ulcers, and transaminitis. She developed a bullous eruption that was consistent with bullous systemic lupus erythematosus. A biopsy was performed showing a superficial neutrophilic infiltrate exhibiting both a vasocentric as well as interstitial pattern (Figure 6a). There was evidence of vascular compromise characterized by significant leukocytoclasia, red cell extravasation and focal fibrin deposition. Immunohistochemistry for C3d showed a linear staining pattern along the dermal epidermal junction (Figure 6b). Direct immunofluorescence studies disclosed a thin homogeneous linear band of staining along the dermal epidermal junction for IgG, C3d and C4d in concert with a positive lupus band test. Small vessel C5b-9 and fibrinogen staining corroborated the diagnosis of a vascular injury syndrome.
The patient is a 43-year-old male with a past medical history of systemic lupus erythematosus complicated by Libman-Sacks endocarditis19, a form of non-bacterial endocarditis associated with systemic lupus erythematosus and antiphospholipid antibody syndrome, and digital ischemic autoamputation. The patient has a two-week history of a worsening rash that started 1.5 weeks prior to his presentation. He also had muscle weakness. The eruption was characterized by a diffuse vesicular rash with central clearing along with multiple concentric annular hypopigmented patches (Figure 7). The biopsy showed epidermal dermal separation with areas of neutrophilic interface dermatitis. The subjacent superficial dermis exhibited small vessel vasculitic changes compatible with a superficial leukocytoclastic vasculitis (Figure 8a-c). Direct immunofluorescent studies showed striking deposits of C1q, IgG. IgA, and IgM along the dermal epidermal junction; the staining pattern was primarily granular although there was a hint of linearity detected with IgG (Figure 9a). There was concomitant granular vascular staining for IgG, IgM, IgA, and C3(Figure 9b); granular deposits were also identified within the epidermal keratinocytes for IgG and C3.
We have presented nine patients with small vessel vasculitis of the skin where direct immunofluorescence findings mimicked and or were indicative of a concurrent autoimmune vesiculobullous disorder targeting the epidermal basement membrane zone. The typical clinical presentation of leukocytoclastic vasculitis is characterized by palpable purpura. It may less commonly present as ulcerations and pustules on a purpuric base with or without folliculocentricity, hemorrhagic bullous lesions. Fixed purpuric urticarial plaques can be observed and usually heralds urticarial vasculitis.20
Cutaneous small vessel vasculitis can be confined to the skin or potentially reflective of a multi-organ vasculitic syndrome.1,21 A multi-organ small vessel vasculitic process can be a manifestation of collagen vascular disease best exemplified by lupus erythematosus or rheumatoid arthritis, but it also may be part of a primary multi-organ vasculitic syndrome including Henoch Schonlein purpura, microscopic polyangiitis, type II or type III mixed cryoglobulinemia and granulomatosis with polyangiitis.3,5,7,10
Small vessel vasculitis can be reflective of an Arthus type III immune complex reaction comprising immunoglobulin complexed to antigen of varied etiologies versus a pauci-immune variant, where immune complexes are not implicated. The latter would be exemplified by those vasculitic syndromes associated with a positive ANCA, where there is a key role for neutrophil extracellular traps in the induction of small vessel vascular injury.22-25 The immune complexes are seen primarily in the walls of small cutaneous blood vessels which when deposited initiate the classic complement pathway leading to the release of complement proteins such as C5a which will be an impetus to the influx of inflammatory cells into the vessel wall.26 While the DIF findings in our cases highlighted a pattern of microvascular immunoglobulin and complement deposition consistent with a small vessel vasculitis, the striking linear deposits within the basement membrane zone of the epidermis were unexpected.
Two of the patients in this series had Crohn's disease. There are several skin disorders seen in patients with Crohn's disease27 including pyoderma gangrenosum, erythema nodosum represent.28-29 30, Sweet's syndrome, epidermolysis bullosa acquisita, acrodermatitis enteropathica 30-31 and small vessel vasculitis including LCV.27,32 Up until the introduction of TNF alpha inhibitor therapy, an exclusive vasculitic presentation of Crohn's disease in the skin was quite uncommon33. Prior to 2003 when the first case of TNF alpha inhibitor vasculitis in the setting of Crohn's disase was reported, an LCV presentation of Crohn's disease had been specifically identified and reported in only three cases.1,27,34 Four patients were diagnosed as having cutaneous vasculitis although the terminology LCV was not used.35,36 Two cases of LCV have been reported in inflammatory bowel disease patients but a diagnosis of Crohn's disease was not specified.37,38 Among these previously reported cases of leukocytoclastic vasculitis in the setting of Crohn's disease was a case of cutaneous leukocytoclastic associated with prominent vascular thrombosis 39 and another case fulfilling the criteria for the syndromic complex of Henoch Schonlein purpura.40 In our experience, the classic vasculitic presentation of Crohn's disease is one showing a mixed neutrophilic and granulomatous vasculitis with extravascular neutrophilic and granulomatous infiltrates with or without folliculocentricity.41,42 Most of the cases of cutaneous vasculitis in the setting of Crohn's disease reported since 2003 have been in the context of representing an adverse reaction to TNF alpha inhibitor therapy.33
The two cases we encountered of LCV occurring in association with Crohn's disease are unusual due to a novel staining pattern on DIF in which a homogeneous linear band of IgG (with lesser amounts of IgA in one of our patients) was associated with LCV. Typically the classic DIF profile in the setting of an LCV is one characterized by granular deposits of immunoglobulin and complement within the microvasculature .43 A linear basement membrane zone deposition of IgG and/or C3 would be expected for autoimmune vesiculobullous disorders targeting the epidermal basement membrane zone such bullous pemphigoid, cicatricial pemphigoid, and, epidermolysis bullosa acquisita but not an LCV . 44 At least in one of the cases, the staining pattern was most reminiscent of epidermolysis bullosa acquisita, given the localization of immunoglobulin staining to the floor of the saline induced split on the DIF skin sample.45 Epidermolysis bullosa acquisita is indeed associated with Crohn's disease whereby its etiologic basis is one of antibodies to type VII collagen however in neither case were there any clinical or histologic features of epidermolysis bullosa acquisita.46
Case 3 had a diffuse skin rash associated with vancomycin exposure. Specific details of the rash were not given however the histologic findings were typical for leukocytoclastic vasculitis while the direct immunofluorescent profile demonstrated features of both linear IgA disease and IgA associated vasculitis with confirmatory circulating antibodies of IgA isotype directed at the epidermal basement membrane zone. Vancomycin is the most common cause of drug induced linear IgA disease7, while a less frequent complication is one of vancomycin induced IgA vasculitis.47 None of the prior reported cases of vancomycin associated vasculitis showed concomitant linear deposits of IgA within the epidermal basement membrane zone nor have cases showing an overlapping morphology of IgA vasculitis and linear IgA disease been reported. The sixth case had typical features of linear IgA disease clinically and histologically; however, there was a supervening vasculitic component recognized histologically.
In four cases (4, 7, 8 and 9), the patients had a diagnosis of systemic lupus erythematosus. All four of these patients had striking features of leukocytoclastic vasculitis; a positive lupus band test was seen in two and linear deposits of immunoglobulin within the BMZ were seen in three. Three of the four patients had vesiculobullous lesions consistent with bullous systemic lupus erythematosus, while one patient had a clinical presentation consistent with urticarial vasculitis. Patients with lupus erythematosus are predisposed to developing vasculitic responses to external and endogenous antigens.6 At least three of the patients who presented with vesicular lesions, a pustular vasculitic presentation of bullous systemic lupus erythematosus based on the concomitant homogeneous linear deposits along the dermal epidermal junction for IgG seemed most reasonable. The positive lupus band test would be expected in any patient with systemic lupus erythematosus. The localization of IgG, IgA, and IgM deposits in the cutaneous vasculature in all three patients was corroborative of an underlying immune based microvascular injury syndrome. In general, when one considers classic endogenous causes of small vessel leukocytoclastic vasculitis in patients with systemic lupus erythematosus, immune complexes composed of rheumatoid factor bound to immunoglobulin and/or an antinuclear antibody bound to nucleosomes are implicated.7,11 It is plausible that a localized derived immune complex originating in the epidermal basement membrane zone where there is direct immunofluorescent evidence of immunoglobulin targeting epidermal basement membrane zone antigenic epitopes.
Concerning case five, all of the findings pointed toward a dysregulated and persistent hypersensitivity response to the administered drug that she received. The histologic findings combined features of urticarial vasculitis and hypereosinophilic syndrome, while the direct immunofluorescent studies showed a pattern characterized by a homogeneous thin linear staining pattern along the dermal epidermal junction characteristic for bullous pemphigoid. The patient likely had a vasculitic presentation of bullous pemphigoid triggered by metronidazole.
The question arises as to mechanisms by which the linear BMZ pattern was associated with vasculitis in our cases. In at least four of the nine patients, the clinical presentation was a vesiculobullous disorder typical for bullous systemic lupus erythematosus and linear IgA disease respectively but complicated by small vessel vasculitis. One could also argue that Case 5 represented an urticarial phase of bullous pemphigoid with supervening vasculitis. In the other patients, the clinical presentations and the histologic findings were not typical for an autoimmune vesiculobullous disorder. Regardless of whether these cases of linear vasculitis were de novo primary cases of vasculitis or an autoimmune vesiculobullous disorder with vasculitic changes, there is an association between the linear immunoglobulin deposits that form within the basement membrane zone of the epidermis and the development of leukocytoclastic vasculitis. In all patients, there were granular deposits of complement and immunoglobulin within vessels typical for the expected direct immunofluorescent profile encountered in a classic Arthus type III immune complex mediated vasculitis. Such a hybrid DIF profile comprising a linear basement membrane zone pattern with a granular vascular pattern suggests that immune complexes are likely involved pathogenetically. In addition in the setting of linear IgA disease cutaneous vascular localization of circulating IgA could activate the alternate complement cascade, contributing pathogenetically to the development of small vessel vasculitis.
There is a precedent suggesting immune complex formation in the setting of epidermolysis bullosa acquisita, bullous pemphigoid, and bullous systemic lupus erythematosus. One study showed that bullous pemphigoid antigen 2 is complexed to bullous pemphigoid antigen associated antibody of IgG isotype where it is internalized as an immune complex derived from the lateral apical cell membrane. In nonlesional skin, BPAG2 is detected on the whole surface of the basal cells without its internalization.48 In epidermolysis bullosa acquisita, complexes composed of tissue-bound complement-binding anti-basement membrane zone autoantibodies and type VII procollagen are seen. The tissue complexes in epidermolysis bullosa acquisita are heterogeneous in the ability to activate complement and generate complement-derived chemotactins, hence accounting for the inherent heterogeneity of the histologic picture49.
Finally, there is also evidence implicating immune complexes in the pathogenesis of bullous systemic lupus erythematosus. In one study, skin was obtained from four consecutive patients with blisters and 14 control lupus patients without blisters. All patients in both groups had immune deposits at the basement membrane zone with an equivalent incidence of the major Ig classes. Deposits in patients with blisters were slightly more intense, and a linear pattern of fluorescence seen in 75% of these patients was not seen in controls. The leukocyte attachment assay showed significantly greater cell attachment in patients with blisters than in patients without patients and greater cell attachment in peribullous than normal skin from the same patient. Organ culture showed complement-dependent migration of leukocytes and histologic features similar to those in spontaneous lesions in skin from the patient with blisters but not in skin from the patient without blisters.50
The presence of locally produced or hematogenously disseminated epidermal basement membrane zone derived immune complexes could be the basis of the small vessel vascular injury syndrome. There is minimal literature precedent on the coexistence of an autoimmune vesiculobullous disorder and supervening small vessel vasculitis. Not surprisingly, the majority of the reported patients have small vessel vasculitis in the setting of bullous systemic lupus erythematosus. There is one reported patient having leukocytoclastic vasculitis and concurrent features of bullous pemphigoid.51-53 In our series, almost half of the patients had bullous systemic lupus erythematosus.
There may be predisposing factors that could result in the preferential entrapment of immune complexes For example the preferential localization of immune complexes in blood vessels will occur in vessels that have been previously damaged by other mechanisms including C5b-9 mediated endothelial cell injury in patients with underlying diabetes mellitus or in lupus patients with anti-endothelial cell antibodies11,54.
Vesiculobullous disorders, comprising bullous pemphigoid, linear IgA disease, and bullous systemic lupus erythematosus, can be complicated by immune complex mediated vasculitis. Conversely a primary vasculitic process can be associated with epidermal basement membrane zone antibodies best exemplified by leukocytoclastic vasculitis in the setting of Crohn's disease. This series serves to expand the spectrum of clinical diseases associated with epithelial basement membrane zone antibodies.
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