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Leukocytoclastic vasculitis in association with linear epidermal basement membrane zone immunoglobulin deposition: Linear vasculitis

Open AccessPublished:July 27, 2022DOI:https://doi.org/10.1016/j.clindermatol.2022.07.011

      Abstract

      Cutaneous leukocytoclastic vasculitis (LCV) has a distinctive clinical and light microscopic presentation; however, the etiologic basis of LCV is varied. Most 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 vasculitic and/or vesiculobullous clinical presentations exhibiting an LCV in association with an immunoreactant profile 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 vesiculobullous eruptions with supervening purpura. Two patients with Crohn disease presented with classic palpable purpura with biopsy-proven LCV, and direct immunofluorescence (DIF) studies demonstrated linear immunoglobulin G (IgG) with floor localization on the salt-split skin assay. Four patients with systemic lupus erythematosus (SLE) showed purpuric vesiculobullous lesions, with evidence of a neutrophilic interface dermatitis and LCV in three of the four. The remaining patient had urticarial nonbullous lesions showing small-vessel vasculitiswith a neutrophilic interface dermatitis. In all of the patients with SLE, DIF studies showed linear immunoglobulin deposits within the basement membrane zone (BMZ). These constellation of findings clinically, light microscopically, and by immunofluorescence were those of a vasculitic presentation of bullous systemic lupus erythematosus. Two patients had linear IgA disease, which was drug induced in one and paraneoplastic in the other, and the dominant morphology on biopsy in both cases was an LCV. One patient microscopically demonstrated drug-associated and eosinophilic enriched LCV with DIF studies showing striking linear deposits of IgG suggestive of bullous pemphigoid, which was consistent with a vasculitic presentation of drug-induced 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 BMZ antigen bound to antibody are pathogenically relevant. We propose the designation of linear vasculitis for this unique scenario of LCV and linear immunoglobulin epidermal BMZ staining, which in some cases represents a vasculitic presentation of conventional autoimmune vesiculobullous disease.

      Keywords

      Abbreviations:

      LCV (leukocytoclastic vasculitis), DIF (direct immunofluorescence), SLE (systemic lupus erythematosus), BMZ (basement membrane zone)

      Introduction

      Leukocytoclastic vasculitis (LCV) affecting the skin typically appears as palpable purpura on the legs, whereas less common presentations encompass livedoid ulcerations and hemorrhagic vesiculobullous lesions.
      • Eaf Ekenstam
      • Callen JP.
      Cutaneous leukocytoclastic vasculitis. Clinical and laboratory features of 82 patients seen in private practice.
      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.
      • Sams Jr, WM
      • Thorne EG
      • Small P
      • Mass MF
      • McIntosh RM
      • Stanford RE.
      Leukocytoclastic vasculitis.
      Direct immunofluorescence (DIF) can be an important diagnostic adjunct for determining the nature of the immune complex.
      • Magro CM
      • Roberts-Barnes J
      • Crowson AN.
      Direct immunofluorescence testing in the diagnosis of immunobullous disease, collagen vascular disease, and vascular injury syndromes.
      ,
      • Hintner H
      • Stingl G
      • Schuler G
      • et al.
      Immunofluorescence mapping of antigenic determinants within the dermal-epidermal junction in the mechanobullous diseases.
      For example, a prominent and dominant pattern of granular vascular deposition for immunoglobulin A (IgA) is typical for IgA-associated vasculitis, including Henoch–Schönlein purpura,
      • Crowson AN
      • Magro CM
      • Usmani A
      • McNutt NS.
      Immunoglobulin A-associated lymphocytic vasculopathy: a clinicopathologic study of eight patients.
      whereas 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 (SLE). 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.
      • Magro CM
      • Crowson AN.
      The spectrum of cutaneous lesions in rheumatoid arthritis: a clinical and pathological study of 43 patients.
      • Cacoub P
      • Comarmond C
      • Domont F
      • Savey L
      • Saadoun D.
      Cryoglobulinemia Vasculitis.
      • Karlsberg PL
      • Lee WM
      • Casey DL
      • Cockerell CJ
      • Cruz Jr., PD
      Cutaneous vasculitis and rheumatoid factor positivity as presenting signs of hepatitis C virus-induced mixed cryoglobulinemia.
      • Crowson AN
      • Mihm Jr, MC
      • Magro CM.
      Cutaneous vasculitis: a review.
      Concomitant granular deposits 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 antiendothelial cell antibodies and hence define vascular cofactors that facilitate vascular injury mediated by immune complex deposition.
      • Magro CM
      • Crowson AN.
      The cutaneous pathology associated with seropositivity for antibodies to SSA (Ro): a clinicopathologic study of 23 adult patients without subacute cutaneous lupus erythematosus.
      We present nine patients with varied clinical presentations ranging from autoimmune vesiculobullous disease to palpable purpura, in which 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 BMZ. The term linear vasculitis has been introduced for this interesting hybrid picture of small-vessel vasculitis that overlaps with autoimmune vesiculobullous epidermal BMZ 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 DIF studies showing a linear staining pattern within the epidermal BMZ 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 DIF,
      • Valenzuela R
      • Bergfeld W
      • Deodhar S.
      as well as with the salt-split skin assay
      • Woodley DT.
      Immunofluorescence on salt-split skin for the diagnosis of epidermolysis bullosa acquisita.
      and indirect immunofluorescence
      • Woodley DT.
      Immunofluorescence on salt-split skin for the diagnosis of epidermolysis bullosa acquisita.
      • Crowson AN
      • Magro CM.
      The role of microvascular injury in the pathogenesis of cutaneous lesions of dermatomyositis.
      • Harrist TJ
      • Mihm MC.
      Cutaneous immunopathology. The diagnostic use of direct and indirect immunofluorescence techniques in dermatologic disease.
      in select cases.

      Case presentations

      Case 1

      A 21-year-old woman with a 12-year history of Crohn disease presented to a dermatologist with recurrent painfully thin urticarial plaques on the legs that had persisted 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 2 to 3 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 after 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 nonblanching surface component confined to the thighs and legs. There were no blisters, ulcers, or evidence of scarring, although the lesions were 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. DIF 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 and showed striking localization of BMZ 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 results. There was 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, anticentromere, anti-Scl-70, anti-Sm, anti-RNP, anti-Ro, anti-La, anti-DNA, anticardiolipin, reticulin IgG and IgA and antiglomerular 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. Antinuclear antibody was positive at a titer of 1:320 with a speckled pattern without meeting any criteria for lupus, mixed connective tissue disease, or Sjogren disease. C-ANCA was positive at 1:160 with antiproteinase 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, which temporarily stopped her diarrhea, was given. Diarrhea and abdominal cramping returned in November 2003 despite continued treatment of 500 mg 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 50 mg twice a day, with significant clearing of the lesions at 5 days. Skin lesions, however, returned to the anterior portion of the legs in November 2003, despite 2 months of clearing on dapsone 50 mg twice a day. Increased doses of dapsone of 150 mg every day to 200 mg 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 disease. The patient has been lost to follow-up.

      Case 2

      A 56-year-old man with Crohn 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 disease 4 years before 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 postinflammatory 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 LCV. 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 disease and prednisone 30 mg twice a day. This treatment resulted in substantial clearing of the skin lesions, and the steroid was tapered over several weeks to 10 mg 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.

      Case 3

      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 DIF analysis, and routine light microscopy was performed on a skin biopsy from her left arm. Routine light microscopy demonstrated a neutrophilic purpuric vascular reaction (Figure 1A). There was a mixed angiocentric infiltrate of lymphocytes and neutrophils with accompanying red cell extravasation and leukocytoclasia. The DIF 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 BMZ with roof localization using generic salt-split skin.
      Fig 1
      Fig. 1(A) Light microscopy shows a superficial interstitial and perivascular mixed neutrophilic and lymphocytic infiltrate with leukocytoclasia and evidence of vascular compromise revealed by red cell extravasation (400 × hematoxylin and eosin). (B) Examination of the C3d immunohistochemistry preparation under oil reveals a homogeneous linear pattern of staining along the dermal epidermal junction (1000 × diaminobenzidine) (case 3).

      Case 4

      A 30-year-old woman with an established history of SLE presented to her dermatologist with dermatitis for 3 days. She had pruritic papules and papular-vesicles on her hands, arms, face, and neck that were eczematous. Histologic examination of the tissue from the right arm revealed a moderately severe LCV with concomitant intraepidermal pustulation and areas of neutrophilic interface dermatitis (Figure 2A-C).
      Fig 2
      Fig. 2(A) Light microscopy shows intraepidermal pustulation (200 × hematoxylin and eosin [H&E]), (B) areas of neutrophilic interface dermatitis (200 × H&E), (C) and a concomitant necrotizing neutrophilic vascular reaction with prominent mural fibrin deposition, marked leukocytoclasia, and red cell extravasation (400 × H&E). (D) Direct immunofluorescence studies show linear deposits of immunoglobulin G within the BMZ (1000 ×) (case 4).
      Subsequently, 6 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. DIF studies demonstrated a positive lupus band test with all immunoglobulin isotypes deposited in the BMZ consistent with and diagnostic of SLE. In addition, there were homogenous linear deposits of IgG, C3d, C4d, and C5b-9 indicative of antibodies to BMZ component (Figure 2D). Overall, the combined light microscopic findings and DIF profile were consistent with a vasculitic presentation of bullous SLE. The vascular deposition of immunoglobulin and complement was compatible with an immune-based microvascular injury syndrome.

      Case 5

      An 84-year-old woman presented to her dermatologist with itchy and excoriated macular papular dermatitis on her chest, back, abdomen, arms, and legs. She had previously been admitted for colitis and was administered metronidazole and hydralazine. The patient developed a generalized macular papular rash temporally associated with the administration of metronidazole. The patient was discovered to have significant peripheral blood eosinophilia up to 30%. Despite the drugs being discontinued, 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.
      Fig 3
      Fig. 3The biopsy showed features of an incipient urticarial vasculitis revealed by interstitial and perivascular neutrophilic infiltrates with focal mural and perivascular fibrin deposition along with red cell extravasation (400 × hematoxylin and eosin) (case 5).
      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 BMZ, such as bullous pemphigoid.
      • Weigand DA
      • Clements MK.
      Direct immunofluorescence in bullous pemphigoid: effects of extent and location of lesions.
      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.

      Case 6

      An 80-year-old man presented to his dermatologist in December 2010 with a 3-day history of painful blisters and a crust on the scrotum and buttocks with an erythematous base. His medical history was remarkable for Hodgkin lymphoma diagnosed in November 2010 when he presented with failure to thrive over a 4-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). DIF 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 LCV (Figure 4A-C).
      Fig 4
      Fig. 4(A and B) Examination of the biopsy reveals a neutrophilic interface dermatitis defining a baseline morphology consistent with incipient linear immunoglobulin A disease (A, 200 × hematoxylin and eosin [H&E]; B, 400 × H&E). (B) The higher-power magnification highlights the angiocentric neutrophilic infiltrate accompanied by leukocytoclasia and red cell extravasation indicative of a component of secondary small-vessel vasculitic change (400 × H&E) (case 6). (C) Immunohistochemistry for C3d showed granular staining localized to microvessels reflective of complement pathway activation (400 × diaminobenzidine).

      Case 7

      The patient is a 31-year-old woman with a history of SLE. The clinical features included arthritis, idiopathic thrombocytopenic purpura, anemia, and more recently, an extensive annular and somewhat vasculitic appearing skin eruption (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.
      • Haller O
      • Arnheiter H
      • Lindenmann J
      • Gresser I.
      Host gene influences sensitivity to interferon action selectively for influenza virus.
      ,
      • Wang X
      • Magro CM.
      Human myxovirus resistance protein 1 (MxA) as a useful marker in the differential diagnosis of subcutaneous lymphoma vs. lupus erythematosus profundus.
      The immunofluorescent studies showed a positive lupus band test of IgM isotype, and there were striking homogeneous linear deposits of IgG within the epidermal BMZ.
      Fig 5
      Fig. 5The patient is a 31-year-old woman with a history of systemic lupus erythematosus. (A) She developed an extensive annular and somewhat vasculitic appearing skin eruption clinically suggestive of urticarial vasculitis. (B) The biopsy shows a very subtle interface dermatitis characterized by basilar vacuolar change with rare neutrophils along the dermal epidermal junction (200 × hematoxylin and eosin). At this power, there is conspicuous red cell extravasation within the superficial dermis. (C) Higher magnification shows interstitial and perivascular neutrophils, leukocytoclasia, and extensive red cell extravasation (400 × hematoxylin and eosin) (case 7). (Clinical photos have been provided by Dr. Scott Sanders, New City, New York)

      Case 8

      The patient is a 27-year-old woman with a medical history of SLE. Among her disease signs and symptoms were fever, avascular necrosis of the femoral heads, arthralgia, dermatitis, oral ulcers, and transaminitis. She developed a bullous eruption that was consistent with bullous SLE. A biopsy was performed showing a superficial neutrophilic infiltrate exhibiting a vasocentric and 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). DIF 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.
      Fig 6
      Fig. 6(A and B) On light microscopic examination, there is a striking neutrophilic infiltrate within the dermis that demonstrates both an interstitial and perivascular pattern with concomitant intramural and perivascular fibrin deposition along with striking leukocytoclasia (A, 200 × hematoxylin and eosin; B, 400 × hematoxylin and eosin). Additional immunohistochemical studies for C3d show a homogeneous linear staining pattern of the dermal epidermal junction (B, 1000 × diaminobenzidine) (case 8).

      Case 9

      The patient is a 43-year-old man with a medical history of SLE complicated by Libman–Sacks endocarditis,
      • Hojnik M
      • George J
      • Ziporen L
      • Shoenfeld Y.
      Heart valve involvement (Libman-Sacks endocarditis) in the antiphospholipid syndrome.
      a form of nonbacterial endocarditis associated with SLE and antiphospholipid antibody syndrome, and digital ischemic autoamputation. The patient had a 2-week history of a worsening dermatitis that started 1.5 weeks before 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 LCV (Figure 8A-C). DIF 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.
      Fig 7
      Fig. 7The patient presented with numerous annular erythematous patches having overlying serum filled vesicles. The lesions were most prominent over his right thigh and leg (case 9).
      Fig 8
      Fig. 8(A and B) Histologic examination of the biopsy shows a subepidermal bulla reflective of dermal–epidermal separation in association with superficial neutrophilic infiltrate along with neutrophils accumulating in the blister cavity (A, 400 × hematoxylin and eosin [H&E]; B, 400 × H&E). (B and C) The small vessels in the underlying dermis exhibit typical changes of a leukocytoclastic vasculitis characterized by disintegrating angiocentric neutrophilic infiltrates with marked leukocytoclasia, mural fibrin deposition, and red cell extravasation (B, 400 × H&E; C, 1000 × H&E) (case 9).
      Fig 9
      Fig. 9(A) Direct immunofluorescence studies show linear deposits of immunoglobulin (Ig) G along the dermal–epidermal junction (1000 ×), (B) along with granular deposits within the superficial vasculature for IgG, IgM, IgA, and C3 (1000 ×) (case 9).

      Discussion

      We have presented nine patients with small-vessel vasculitis of the skin where DIF findings mimicked and/or were indicative of a concurrent autoimmune vesiculobullous disorder targeting the epidermal BMZ. The typical clinical presentation of LCV is characterized by palpable purpura. It may less commonly present as ulcerations and pustules on a purpuric base with or without folliculocentricity and as hemorrhagic bullous lesions. Fixed purpuric urticarial plaques can be observed and usually herald urticarial vasculitis.
      • Mehregan DR
      • Hall MJ
      • Gibson LE.
      Urticarial vasculitis: a histopathologic and clinical review of 72 cases.
      Cutaneous small-vessel vasculitis can be confined to the skin or potentially reflective of a multiorgan vasculitic syndrome.
      • Eaf Ekenstam
      • Callen JP.
      Cutaneous leukocytoclastic vasculitis. Clinical and laboratory features of 82 patients seen in private practice.
      ,
      • Lotti T
      • Ghersetich I
      • Comacchi C
      • Jorizzo JL.
      Cutaneous small-vessel vasculitis.
      A multiorgan 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 multiorgan vasculitic syndrome, including Henoch–Schönlein purpura, microscopic polyangiitis, type II or type III mixed cryoglobulinemia, and granulomatosis with polyangiitis.
      • Magro CM
      • Roberts-Barnes J
      • Crowson AN.
      Direct immunofluorescence testing in the diagnosis of immunobullous disease, collagen vascular disease, and vascular injury syndromes.
      ,
      • Crowson AN
      • Magro CM
      • Usmani A
      • McNutt NS.
      Immunoglobulin A-associated lymphocytic vasculopathy: a clinicopathologic study of eight patients.
      ,
      • Magro CM
      • Crowson AN.
      The spectrum of cutaneous lesions in rheumatoid arthritis: a clinical and pathological study of 43 patients.
      ,
      • Crowson AN
      • Mihm Jr, MC
      • Magro CM.
      Cutaneous vasculitis: a review.
      Small-vessel vasculitis can be reflective of an Arthus type III immune complex reaction comprising immunoglobulin complexed to an 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.
      • Mackel SE
      • Jordon RE.
      Leukocytoclastic vasculitis. A cutaneous expression of immune complex disease.
      • Gower RG
      • Sams Jr, WM
      • Thorne EG
      • Kohler PF
      • Claman HN.
      Leukocytoclastic vasculitis: sequential appearance of immunoreactants and cellular changes in serial biopsies.
      • Mackel SE
      • Tappeiner G
      • Brumfield H
      • Jordan RE.
      Circulating immune complexes in cutaneous vasculitis. Detection with C1q and monoclonal rheumatoid factor.
      • Söderberg D
      • Segelmark M.
      Neutrophil extracellular traps in ANCA-associated vasculitis.
      The immune complexes are seen primarily in the walls of small cutaneous blood vessels that, 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.
      • Swerlick RA
      • Lawley TJ.
      Cutaneous vasculitis: its relationship to systemic disease.
      Although 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 BMZ of the epidermis were unexpected.
      Two of the patients in this series had Crohn disease. There are several skin disorders seen in patients with Crohn disease,
      • Zlatanic J
      • Fleisher M
      • Sasson M
      • Kim P
      • Korelitz BI.
      Crohn's disease and acute leukocytoclastic vasculitis of skin.
      including pyoderma gangrenosum, erythema nodosum,
      • Levitt MD
      • Ritchie JK
      • Lennard-Jones JE
      • Phillips RK.
      Pyoderma gangrenosum in inflammatory bowel disease.
      • Farhi D
      • Cosnes J
      • Zizi N
      • et al.
      Significance of erythema nodosum and pyoderma gangrenosum in inflammatory bowel diseases: a cohort study of 2402 patients.
      • Bernstein CN
      • Blanchard JF
      • Rawsthorne P
      • Yu N.
      The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study.
      Sweet syndrome, epidermolysis bullosa acquisita, acrodermatitis enteropathica,
      • Bernstein CN
      • Blanchard JF
      • Rawsthorne P
      • Yu N.
      The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study.
      ,
      • Travis S
      • Innes N
      • Davies MG
      • Daneshmend T
      • Hughes S.
      Sweet's syndrome: an unusual cutaneous feature of Crohn's disease or ulcerative colitis. The South West Gastroenterology Group.
      and small-vessel vasculitis including LCV.
      • Zlatanic J
      • Fleisher M
      • Sasson M
      • Kim P
      • Korelitz BI.
      Crohn's disease and acute leukocytoclastic vasculitis of skin.
      ,
      • Wakefield AJ
      • Sankey EA
      • Dhillon AP
      • et al.
      Granulomatous vasculitis in Crohn's disease.
      Until the introduction of tumor necrosis factor alpha (TNF-α) inhibitor therapy, an exclusive vasculitic presentation of Crohn disease in the skin was uncommon.
      • Mohan N
      • Edwards ET
      • Cupps TR
      • et al.
      Leukocytoclastic vasculitis associated with tumor necrosis factor-alpha blocking agents.
      Before 2003, when the first case of TNF-α inhibitor vasculitis in the setting of Crohn disease was reported, an LCV presentation of Crohn disease had been specifically identified and reported in only three cases.
      • Eaf Ekenstam
      • Callen JP.
      Cutaneous leukocytoclastic vasculitis. Clinical and laboratory features of 82 patients seen in private practice.
      ,
      • Zlatanic J
      • Fleisher M
      • Sasson M
      • Kim P
      • Korelitz BI.
      Crohn's disease and acute leukocytoclastic vasculitis of skin.
      ,
      • Castanet J
      • Lacour JP
      • Perrin C
      • Rodot S
      • Ortonne JP.
      Cutaneous vasculitis with lesions mimicking Degos’ disease and revealing Crohn's disease.
      Four patients were diagnosed as having cutaneous vasculitis, although the terminology LCV was not used.
      • Humbert P
      • Monnier G
      • Billerey C
      • Birgen C
      • Dupond JL.
      Polyneuropathy: an unusual extraintestinal manifestation of Crohn's disease.
      ,
      • Talbot RW
      • Heppell J
      • Dozois RR
      • Beart Jr., RW
      Vascular complications of inflammatory bowel disease.
      Two cases of LCV have been reported in patients with inflammatory bowel disease, but a diagnosis of Crohn disease was not specified.
      • Peeters AJ
      • van den Wall Bake AW
      • Daha MR
      • Breeveld FC.
      Inflammatory bowel disease and ankylosing spondylitis associated with cutaneous vasculitis, glomerulonephritis, and circulating IgA immune complexes.
      ,
      • Newton JA
      • McGibbon DH
      • Marsden RA.
      Leucocytoclastic vasculitis and angio-oedema associated with inflammatory bowel disease.
      Among these reported cases of LCV in the setting of Crohn disease was a case of cutaneous leukocytoclastic associated with prominent vascular thrombosis,
      • Kay MH
      • Wyllie R.
      Cutaneous vasculitis as the initial manifestation of Crohn's disease in a pediatric patient.
      and another case fulfilling the criteria for the syndromic complex of Henoch–Schönlein purpura.
      • Saulsbury FT
      • Hart MH.
      Crohn's disease presenting with Henoch-Schönlein purpura.
      In our experience, the classic vasculitic presentation of Crohn disease is one showing a mixed neutrophilic and granulomatous vasculitis with extravascular neutrophilic and granulomatous infiltrates, with or without folliculocentricity.
      • Magro CM
      • Crowson AN.
      Sterile neutrophilic folliculitis with perifollicular vasculopathy: a distinctive cutaneous reaction pattern reflecting systemic disease.
      ,
      • Crowson AN
      • Nuovo GJ
      • Mihm Jr, MC
      • Magro C.
      Cutaneous manifestations of Crohn's disease, its spectrum, and its pathogenesis: intracellular consensus bacterial 16S rRNA is associated with the gastrointestinal but not the cutaneous manifestations of Crohn's disease.
      Most of the cases of cutaneous vasculitis in the setting of Crohn disease reported since 2003 have been in the context of representing an adverse reaction to TNF-α inhibitor therapy.
      • Mohan N
      • Edwards ET
      • Cupps TR
      • et al.
      Leukocytoclastic vasculitis associated with tumor necrosis factor-alpha blocking agents.
      The two cases we encountered of LCV occurring in association with Crohn 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.
      • Braverman IM
      • Yen A.
      Demonstration of immune complexes in spontaneous and histamine-induced lesions and in normal skin of patients with leukocytoclastic angitis.
      A linear BMZ deposition of IgG and/or C3 would be expected for autoimmune vesiculobullous disorders targeting the epidermal BMZ, such as bullous pemphigoid, cicatricial pemphigoid, linear IgA disease, bullous systemic lupus erythematosus and epidermolysis bullosa acquisita, but not an LCV.
      • Mutasim DF
      • Pelc NJ
      • Supapannachart N.
      Established methods in the investigation of bullous diseases.
      In at least 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.
      • Livden JK
      • Nilsen R
      • Thunold S
      • Schjønsby H.
      Epidermolysis bullosa acquisita and Crohn's disease.
      Epidermolysis bullosa acquisita is associated with Crohn 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.
      • Chen M
      • O'Toole EA
      • Sanghavi J
      • et al.
      The epidermolysis bullosa acquisita antigen (type VII collagen) is present in human colon and patients with Crohn's disease have autoantibodies to type VII collagen.
      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 LCV, whereas the DIF profile demonstrated features of linear IgA disease and IgA-associated vasculitis with confirmatory circulating antibodies of IgA isotype directed at the epidermal BMZ. Vancomycin is the most common cause of drug-induced linear IgA disease,
      • Magro CM
      • Crowson AN.
      The spectrum of cutaneous lesions in rheumatoid arthritis: a clinical and pathological study of 43 patients.
      whereas a less frequent complication is one of vancomycin-induced IgA vasculitis.
      • Baden LA
      • Apovian C
      • Imber MJ
      • Dover JS.
      Vancomycin-induced linear IgA bullous dermatosis.
      None of the previously reported cases of vancomycin-associated vasculitis showed concomitant linear deposits of IgA within the epidermal BMZ, 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 SLE. All four of these patients had striking features of LCV; 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 SLE, whereas 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.
      • Crowson AN
      • Magro C.
      The cutaneous pathology of lupus erythematosus: a review.
      For at least three of the patients who presented with vesicular lesions, a pustular vasculitic presentation of bullous SLE, 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 SLE. 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, in classic endogenous causes of small-vessel LCV in patients with SLE, immune complexes composed of rheumatoid factor bound to immunoglobulin and/or an antinuclear antibody bound to nucleosomes are implicated.
      • Magro CM
      • Crowson AN.
      The spectrum of cutaneous lesions in rheumatoid arthritis: a clinical and pathological study of 43 patients.
      ,
      • Magro CM
      • Crowson AN.
      The cutaneous pathology associated with seropositivity for antibodies to SSA (Ro): a clinicopathologic study of 23 adult patients without subacute cutaneous lupus erythematosus.
      It is plausible that a localized derived immune complex originates in the epidermal BMZ, where there is DIF evidence of immunoglobulin targeting epidermal BMZ antigenic epitopes.
      Concerning case five, all 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, whereas the DIF 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 six of the nine patients, the clinical presentation was a vesiculobullous disorder typical for bullous SLE and linear IgA disease 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 was an association between the linear immunoglobulin deposits that form within the BMZ of the epidermis and the development of LCV. In all patients, there were granular deposits of complement and immunoglobulin within vessels typical for the expected DIF profile encountered in a classic Arthus type III immune complex mediated vasculitis. Such a hybrid DIF profile comprising a linear BMZ 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 SLE. 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 non-lesional skin, BPAG2 is detected on the whole surface of the basal cells without its internalization.
      • Kitajima Y
      • Nojiri M
      • Yamada T
      • Hirako Y
      • Owaribe K.
      Internalization of the 180 kDa bullous pemphigoid antigen as immune complexes in basal keratinocytes: an important early event in blister formation in bullous pemphigoid.
      In epidermolysis bullosa acquisita, complexes composed of tissue-bound complement-binding anti-BMZ 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 picture.
      • Gammon WR
      • Briggaman RA.
      Functional heterogeneity of immune complexes in epidermolysis bullosa acquisita.
      Finally, there is also evidence implicating immune complexes in the pathogenesis of bullous SLE. 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 BMZ 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 blisters 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.
      • Gammon WR
      • Briggaman RA
      • Inman 3rd, AO
      • Merritt CC
      • Wheeler Jr., CE
      Evidence supporting a role for immune complex-mediated inflammation in the pathogenesis of bullous lesions of systemic lupus erythematosus.
      The presence of locally produced or hematogenously disseminated epidermal BMZ 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 SLE. There is one reported patient having LCV and concurrent features of bullous pemphigoid.
      • Hsieh FN
      • Yu-Yun Lee J.
      Leukocytoclastic vasculitis concurrent with bullous systemic lupus erythematosus manifesting striking wood-grain and wi-fi sign-like purpuric lesions.
      • Tsuchida T
      • Furue M
      • Kashiwado T
      • Ishibashi Y.
      Bullous systemic lupus erythematosus with cutaneous mucinosis and leukocytoclastic vasculitis.
      • Beer TW
      • Smith HR.
      Bullous pemphigoid associated with cutaneous leukocytoclastic vasculitis.
      In our series, almost half of the patients had bullous SLE.
      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 who may have concurrent antiendothelial cell antibodies contributing to microvascular injury.
      • Magro CM
      • Crowson AN.
      The cutaneous pathology associated with seropositivity for antibodies to SSA (Ro): a clinicopathologic study of 23 adult patients without subacute cutaneous lupus erythematosus.
      ,
      • Vasil KE
      • Magro CM.
      Cutaneous vascular deposition of C5b-9 and its role as a diagnostic adjunct in the setting of diabetes mellitus and porphyria cutanea tarda.

      Conclusions

      Vesiculobullous disorders comprising bullous pemphigoid, linear IgA disease, and bullous SLE can be complicated by immune complex-mediated vasculitis. Conversely, a primary vasculitic process can be associated with epidermal BMZ antibodies best exemplified by LCV in the setting of Crohn disease. This series serves to expand the spectrum of clinical diseases associated with epithelial BMZ antibodies.

      Acknowledgements

      E. David Wright, M.D., Grand River Health, Rifle, Colorado, USA
      Mark A. Bechtel, M.D., The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
      G. Scott Drew, D.O., Mid Ohio Dermatology Associates, Marion, Ohio, USA
      Maria Colavincenzo, M.D., Northwestern Medicine, Chicago, Illinois, USA
      Mary Ann Michelis, M.D., Hackensack University Medical Center, Hackensack, New Jersey, USA
      Henry J. Lee, M.D., Weill Cornell Medicine, New York, New York, USA
      Silvia E. Mancebo, M.D., Weill Cornell Medicine, New York, New York, USA
      Elizabeth C. Moore, D.O., Weill Cornell Medicine, New York, New York, USA
      Scott Sanders, M.D., Scott Sanders Dermatology, New City, New York, USA

      References

        • Eaf Ekenstam
        • Callen JP.
        Cutaneous leukocytoclastic vasculitis. Clinical and laboratory features of 82 patients seen in private practice.
        Arch Dermatol. 1984; 120: 484-489
        • Sams Jr, WM
        • Thorne EG
        • Small P
        • Mass MF
        • McIntosh RM
        • Stanford RE.
        Leukocytoclastic vasculitis.
        Arch Dermatol. 1976; 112: 219-226
        • Magro CM
        • Roberts-Barnes J
        • Crowson AN.
        Direct immunofluorescence testing in the diagnosis of immunobullous disease, collagen vascular disease, and vascular injury syndromes.
        Dermatol Clin. 2012; 30: 763-798
        • Hintner H
        • Stingl G
        • Schuler G
        • et al.
        Immunofluorescence mapping of antigenic determinants within the dermal-epidermal junction in the mechanobullous diseases.
        J Invest Dermatol. 1981; 76: 113-118
        • Crowson AN
        • Magro CM
        • Usmani A
        • McNutt NS.
        Immunoglobulin A-associated lymphocytic vasculopathy: a clinicopathologic study of eight patients.
        J Cutan Pathol. 2002; 29: 596-601
        • Crowson AN
        • Magro C.
        The cutaneous pathology of lupus erythematosus: a review.
        J Cutan Pathol. 2001; 28: 1-23
        • Magro CM
        • Crowson AN.
        The spectrum of cutaneous lesions in rheumatoid arthritis: a clinical and pathological study of 43 patients.
        J Cutan Pathol. 2003; 30: 1-10
        • Cacoub P
        • Comarmond C
        • Domont F
        • Savey L
        • Saadoun D.
        Cryoglobulinemia Vasculitis.
        Am J Med. 2015; 128: 950-955
        • Karlsberg PL
        • Lee WM
        • Casey DL
        • Cockerell CJ
        • Cruz Jr., PD
        Cutaneous vasculitis and rheumatoid factor positivity as presenting signs of hepatitis C virus-induced mixed cryoglobulinemia.
        Arch Dermatol. 1995; 131: 1119-1123
        • Crowson AN
        • Mihm Jr, MC
        • Magro CM.
        Cutaneous vasculitis: a review.
        J Cutan Pathol. 2003; 30: 161-173
        • Magro CM
        • Crowson AN.
        The cutaneous pathology associated with seropositivity for antibodies to SSA (Ro): a clinicopathologic study of 23 adult patients without subacute cutaneous lupus erythematosus.
        Am J Dermatopathol. 1999; 21: 129-137
        • Valenzuela R
        • Bergfeld W
        • Deodhar S.
        Interpretation of Immunofluorescent Patterns in Skin Diseases. 66-80. ASCP Press, Chicago, IL1984: 111-120
        • Woodley DT.
        Immunofluorescence on salt-split skin for the diagnosis of epidermolysis bullosa acquisita.
        Arch Dermatol. 1990; 126: 229-231
        • Crowson AN
        • Magro CM.
        The role of microvascular injury in the pathogenesis of cutaneous lesions of dermatomyositis.
        Hum Pathol. 1996; 27: 15-19
        • Harrist TJ
        • Mihm MC.
        Cutaneous immunopathology. The diagnostic use of direct and indirect immunofluorescence techniques in dermatologic disease.
        Hum Pathol. 1979; 10: 625-653
        • Weigand DA
        • Clements MK.
        Direct immunofluorescence in bullous pemphigoid: effects of extent and location of lesions.
        J Am Acad Dermatol. 1989; 20: 437-440
        • Haller O
        • Arnheiter H
        • Lindenmann J
        • Gresser I.
        Host gene influences sensitivity to interferon action selectively for influenza virus.
        Nature. 1980; 283: 660-662
        • Wang X
        • Magro CM.
        Human myxovirus resistance protein 1 (MxA) as a useful marker in the differential diagnosis of subcutaneous lymphoma vs. lupus erythematosus profundus.
        Eur J Dermatol. 2012; 22: 629-633
        • Hojnik M
        • George J
        • Ziporen L
        • Shoenfeld Y.
        Heart valve involvement (Libman-Sacks endocarditis) in the antiphospholipid syndrome.
        Circulation. 1996; 93: 1579-1587
        • Mehregan DR
        • Hall MJ
        • Gibson LE.
        Urticarial vasculitis: a histopathologic and clinical review of 72 cases.
        J Am Acad Dermatol. 1992; 26: 441-448
        • Lotti T
        • Ghersetich I
        • Comacchi C
        • Jorizzo JL.
        Cutaneous small-vessel vasculitis.
        J Am Acad Dermatol. 1998; 39: 667-687
        • Mackel SE
        • Jordon RE.
        Leukocytoclastic vasculitis. A cutaneous expression of immune complex disease.
        Arch Dermatol. 1982; 118: 296-301
        • Gower RG
        • Sams Jr, WM
        • Thorne EG
        • Kohler PF
        • Claman HN.
        Leukocytoclastic vasculitis: sequential appearance of immunoreactants and cellular changes in serial biopsies.
        J Invest Dermatol. 1977; 69: 477-484
        • Mackel SE
        • Tappeiner G
        • Brumfield H
        • Jordan RE.
        Circulating immune complexes in cutaneous vasculitis. Detection with C1q and monoclonal rheumatoid factor.
        J Clin Invest. 1979; 64: 1652-1660
        • Söderberg D
        • Segelmark M.
        Neutrophil extracellular traps in ANCA-associated vasculitis.
        Front Immunol. 2016; 7: 256
        • Swerlick RA
        • Lawley TJ.
        Cutaneous vasculitis: its relationship to systemic disease.
        Med Clin North Am. 1989; 73: 1221-1235
        • Zlatanic J
        • Fleisher M
        • Sasson M
        • Kim P
        • Korelitz BI.
        Crohn's disease and acute leukocytoclastic vasculitis of skin.
        Am J Gastroenterol. 1996; 91: 2410-2413
        • Levitt MD
        • Ritchie JK
        • Lennard-Jones JE
        • Phillips RK.
        Pyoderma gangrenosum in inflammatory bowel disease.
        Br J Surg. 1991; 78: 676-678
        • Farhi D
        • Cosnes J
        • Zizi N
        • et al.
        Significance of erythema nodosum and pyoderma gangrenosum in inflammatory bowel diseases: a cohort study of 2402 patients.
        Medicine (Baltimore). 2008; 87: 281-293
        • Bernstein CN
        • Blanchard JF
        • Rawsthorne P
        • Yu N.
        The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study.
        Am J Gastroenterol. 2001; 96: 1116-1122
        • Travis S
        • Innes N
        • Davies MG
        • Daneshmend T
        • Hughes S.
        Sweet's syndrome: an unusual cutaneous feature of Crohn's disease or ulcerative colitis. The South West Gastroenterology Group.
        Eur J Gastroenterol Hepatol. 1997; 9: 715-720
        • Wakefield AJ
        • Sankey EA
        • Dhillon AP
        • et al.
        Granulomatous vasculitis in Crohn's disease.
        Gastroenterology. 1991; 100: 1279-1287
        • Mohan N
        • Edwards ET
        • Cupps TR
        • et al.
        Leukocytoclastic vasculitis associated with tumor necrosis factor-alpha blocking agents.
        J Rheumatol. 2004; 31: 1955-1958
        • Castanet J
        • Lacour JP
        • Perrin C
        • Rodot S
        • Ortonne JP.
        Cutaneous vasculitis with lesions mimicking Degos’ disease and revealing Crohn's disease.
        Acta Derm Venereol. 1995; 75: 408-409
        • Humbert P
        • Monnier G
        • Billerey C
        • Birgen C
        • Dupond JL.
        Polyneuropathy: an unusual extraintestinal manifestation of Crohn's disease.
        Acta Neurol Scand. 1989; 80: 301-306
        • Talbot RW
        • Heppell J
        • Dozois RR
        • Beart Jr., RW
        Vascular complications of inflammatory bowel disease.
        Mayo Clin Proc. 1986; 61: 140-145
        • Peeters AJ
        • van den Wall Bake AW
        • Daha MR
        • Breeveld FC.
        Inflammatory bowel disease and ankylosing spondylitis associated with cutaneous vasculitis, glomerulonephritis, and circulating IgA immune complexes.
        Ann Rheum Dis. 1990; 49: 638-640
        • Newton JA
        • McGibbon DH
        • Marsden RA.
        Leucocytoclastic vasculitis and angio-oedema associated with inflammatory bowel disease.
        Clin Exp Dermatol. 1984; 9: 618-623
        • Kay MH
        • Wyllie R.
        Cutaneous vasculitis as the initial manifestation of Crohn's disease in a pediatric patient.
        Am J Gastroenterol. 1998; 93: 1014
        • Saulsbury FT
        • Hart MH.
        Crohn's disease presenting with Henoch-Schönlein purpura.
        J Pediatr Gastroenterol Nutr. 2000; 31: 173-175
        • Magro CM
        • Crowson AN.
        Sterile neutrophilic folliculitis with perifollicular vasculopathy: a distinctive cutaneous reaction pattern reflecting systemic disease.
        J Cutan Pathol. 1998; 25: 215-221
        • Crowson AN
        • Nuovo GJ
        • Mihm Jr, MC
        • Magro C.
        Cutaneous manifestations of Crohn's disease, its spectrum, and its pathogenesis: intracellular consensus bacterial 16S rRNA is associated with the gastrointestinal but not the cutaneous manifestations of Crohn's disease.
        Hum Pathol. 2003; 34: 1185-1192
        • Braverman IM
        • Yen A.
        Demonstration of immune complexes in spontaneous and histamine-induced lesions and in normal skin of patients with leukocytoclastic angitis.
        J Invest Dermatol. 1975; 64: 105-112
        • Mutasim DF
        • Pelc NJ
        • Supapannachart N.
        Established methods in the investigation of bullous diseases.
        Dermatol Clin. 1993; 11: 399-418
        • Livden JK
        • Nilsen R
        • Thunold S
        • Schjønsby H.
        Epidermolysis bullosa acquisita and Crohn's disease.
        Acta Derm Venereol. 1978; 58: 241-244
        • Chen M
        • O'Toole EA
        • Sanghavi J
        • et al.
        The epidermolysis bullosa acquisita antigen (type VII collagen) is present in human colon and patients with Crohn's disease have autoantibodies to type VII collagen.
        J Invest Dermatol. 2002; 118: 1059-1064
        • Baden LA
        • Apovian C
        • Imber MJ
        • Dover JS.
        Vancomycin-induced linear IgA bullous dermatosis.
        Arch Dermatol. 1988; 124: 1186-1188
        • Kitajima Y
        • Nojiri M
        • Yamada T
        • Hirako Y
        • Owaribe K.
        Internalization of the 180 kDa bullous pemphigoid antigen as immune complexes in basal keratinocytes: an important early event in blister formation in bullous pemphigoid.
        Br J Dermatol. 1998; 138: 71-76
        • Gammon WR
        • Briggaman RA.
        Functional heterogeneity of immune complexes in epidermolysis bullosa acquisita.
        J Invest Dermatol. 1987; 89: 478-483
        • Gammon WR
        • Briggaman RA
        • Inman 3rd, AO
        • Merritt CC
        • Wheeler Jr., CE
        Evidence supporting a role for immune complex-mediated inflammation in the pathogenesis of bullous lesions of systemic lupus erythematosus.
        J Invest Dermatol. 1983; 81: 320-325
        • Hsieh FN
        • Yu-Yun Lee J.
        Leukocytoclastic vasculitis concurrent with bullous systemic lupus erythematosus manifesting striking wood-grain and wi-fi sign-like purpuric lesions.
        J Clin Rheumatol. 2019; 25: e104-e105
        • Tsuchida T
        • Furue M
        • Kashiwado T
        • Ishibashi Y.
        Bullous systemic lupus erythematosus with cutaneous mucinosis and leukocytoclastic vasculitis.
        J Am Acad Dermatol. 1994; 31: 387-390
        • Beer TW
        • Smith HR.
        Bullous pemphigoid associated with cutaneous leukocytoclastic vasculitis.
        Int J Dermatol. 1998; 37: 940-942
        • Vasil KE
        • Magro CM.
        Cutaneous vascular deposition of C5b-9 and its role as a diagnostic adjunct in the setting of diabetes mellitus and porphyria cutanea tarda.
        J Am Acad Dermatol. 2007; 56: 96-104