A Rare Case of a Subepidermal Bullous Disorder in a Child

Series Editor: Camila K. Janniger, MD Bullous Systemic Lupus Erythematosus With Lupus Nephritis: A Rare Case of a Subepidermal Bullous Disorder in a Child

Shital Poojary, MD, FCPS, DNB; Sama Rais, MBBS

Bullous systemic lupus erythematosus (BSLE) characterized by a distinct constellation of clini- is a rare subset of systemic lupus erythemato- cal, histologic, and immunologic features.1 Bullous sus (SLE) with bullous lesions in a case fulfilling the systemic lupus erythematosus is extremely rare in American Rheumatism Association (Atlanta) crite- children.2 We report a case of a 9-year-old Indian girl ria, histologically characterized by a neutrophil- with BSLE and lupus nephritis; we review the clinical predominant infiltrate in theCUTIS upper dermis with features as well as the etiopathogenesis of BSLE. immunoglobulin (IgG, IgA, IgM) and C3 deposition at the basement membrane zone (BMZ). It Case Report often is associated with autoimmunity to type VII A 9-year-old girl presented with a blistering eruption collagen (NC1 [noncollagenous domain 1] over her chest, back, arms, and neck of 15 days’ dura- domain), although occasionally other antigens tion; swelling around the eyes and feet of 15 days’ such as laminin 5, laminin 6, and BP230 (bullous duration; and a low-grade fever of 2 months’ dura- pemphigoidDo antigen) have beenNot described. Bullous tion. PhysicalCopy examination revealed multiple tense systemic lupus erythematosus is extremely rare vesicles and bullae overlying urticarial plaques on in children. the neck, chest (Figure 1), back, and arms with no We report here a case of a 9-year-old girl with mucous membrane involvement. The Nikolsky sign BSLE as an initial presentation with lupus nephri- was negative. Other findings on physical examination tis class III, a rare occurrence at such a young included cervical, inguinal, and axillary lymphade- age. Despite the rarity, we suggest that BSLE nopathy; bilateral pitting pedal edema; periorbital should be considered in the differential diagno- edema; and hepatosplenomegaly. A differential diag- sis of subepidermal bullous diseases in children nosis of chronic bullous disease of childhood, child- in view of associated potentially serious sys- hood bullous pemphigoid, bullous drug eruption, and temic manifestations. BSLE was considered. Cutis. 2012;89:17-21. A skin biopsy showed subepidermal bullae con- taining proteinaceous debris with predominantly neutrophils, neutrophilic nuclear dust, basal cell ullous systemic lupus erythematosus (BSLE) is vacuolization, and papillary dermal edema (Figure 2). a rare nonscarring subepidermal bullous erup- Direct immunofluorescence of perilesional skin B tion in systemic lupus erythematosus (SLE) showed a broad granular band of IgG deposits at the dermoepidermal junction (DEJ). IgM, IgA, and C3 From K.J. Somaiya Medical College, Mumbai, India. were negative. Direct immunofluorescence of a renal The authors report no conflict of interest. Correspondence: Shital Poojary, MD, FCPS, DNB, Department of biopsy showed IgG deposits at the basement mem- Dermatology, K.J. Somaiya Medical College, Everard Nagar, brane zone (BMZ). IgM, IgA, and C3 were negative. Sion-Chunnabhatti, Mumbai -400022, Maharashtra, India. Electron microscopy of a renal biopsy showed mild

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albumin 31 (2 g/dL); occult blood 21 (red blood cell count, 15–20 per high-power field [HPF]); pus cells, 3 to 4 per HPF; hyaline casts, 1 to 2 per HPF; and granular casts, 1 to 2 per HPF. Total urinary protein excretion was 1.5 g per day. Chest radiograph showed fissural effusion. Ultra- sonography of the abdomen showed mild hepatosplenomegaly; electrocardiography revealed no abnormalities; antinuclear antibody was positive with a titer of 1:40 (reference range, 1:20); anti-dsDNA was high, 1:20 (reference range, 1:10); and serum C3 levels were low, 11.2 mg/dL (reference range, 88– 200 mg/dL). Enzyme-linked immunosorbent assay for human immunodeficiency virus was nonreactive. Figure 1. Grouped vesicles and bullae overlying urti- Tests for antibodies to type VII collagen were not carial plaques on the neck and upper chest. done due to lack of availability. In view of renal involvement, she was treated with oral prednisolone at a dosage of 1 mg/kg daily, which was tapered over the following 2 months. The cutaneous lesions resolved within 2 weeks. Renal parameters showed considerable improvement along with a rise in complement levels.

Comment Bullous lesions in SLE are uncommon (,5% of SLE patients) and are divided into 3 categories1,3: CUTIS(1) severe basal cell vacuolization, dermal edema, and leukocytoclastic vasculitis may occasionally manifest as frank vesiculation (eg, subacute cutaneous lupus erythematosus with erythema multiforme–like lesions [Rowell syndrome]); (2) a number of primary blistering disorders such as dermatitis herpetiformis (DH), bullous pemphigoid, pemphigus vulgaris, pemphigus Do Notfoliaceus, Copy epidermolysis bullosa acquisita (EBA), and Figure 2. Subepidermal bulla with a predominantly neu- linear IgA bullous dermatosis have been reported in trophilic infiltrate and neutrophilic nuclear dust. Basal cell vacuolization also was noted (H&E, original magnifi- association with SLE; and (3) BSLE. cation 3100). The first case of BSLE was described by Pedro and Dahl4 in 1973. Bullous systemic lupus erythematosus typically affects young adults, chiefly women, often of African and Hispanic descent. It generally presents as mesangial hypercellularity with subendothelial depos- an acute-onset, generalized, vesicobullous eruption, its. Routine investigations revealed the following varying from grouped herpetiform vesicles to large results: hemoglobin, 8.3 g/dL (reference range, 11.5– hemorrhagic bullae that heal without scarring. How- 14.5 g/dL); total white blood cell count, 12,600/mL ever, minimal scarring and milia occasionally have (reference range, 4000–12,000/mL); platelet count, been reported (EBA-like phenotype).3 Erythematous 180,000/mL (reference range, 150,000–350,000/mL); annular plaques, urticarial papules, and targetoid erythrocyte sedimentation rate, 130 mm/h (reference lesions also have been described. In few cases, the range, 0–20 mm/h); serum creatinine, 0.7 mg/dL onset of vesicobullous lesions may coincide with (reference range, 0.3–0.7 mg/dL); urea nitrogen, exacerbation of SLE, particularly lupus nephritis and 21 mg/dL (reference range, 8–23 mg/dL); serum total cardiac vasculitis in 1 reported case.2,3,5 Two cases of protein, 5.5 g/dL (reference range, 6.0–8.0 g/dL); drug-induced BSLE to penicillamine and hydralazine albumin, 2.8 g/dL (reference range, 3.7–5.6 g/dL); and also have been reported.6,7 total globulin, 2.7 g/dL (reference range, 1.9–3.4 g/dL). Histopathology demonstrates a subepidermal Coagulation profile and liver function tests revealed bulla with neutrophilic-predominant inflammation no abnormalities. Urinalysis revealed presence of and neutrophilic dust, sometimes with papillary

18 CUTIS® WWW.CUTIS.COM Copyright Cutis 2012. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. Pediatric Dermatology Poor Good response to dapsone or sulfapyridine Good response to Good response corticosteroids to Good response dapsone, gluten- diet free Response to Treatment Bullae respond respond Bullae rapidly to dapsone

NC1 domain of NC1 type VII collagen (anchoring fibril, kD) 290 and kD 145 Target Target Antigen Type VII collagen Type (anchoring fibril, 145 kD and 290 kD) BP180 (hemidesmosome), LAD285 BP230, BP180 (hemidesmosome) Epidermal tissue transglutaminase IgM, 1 / 2

CUTIS IgA, 1 / 2 C3, Granular/linear IgG, C3 1 / 2 IgA, IgM at BMZ Linear IgG IgG Linear BMZ at IgM Linear IgA at BMZ Linear IgG, C3 Do Direct Immunofluorescence Not CopyIgA at BMZ Granular IgA deposits at tips of dermal papillae Biopsy Subepidermal bulla, papillary neutrophilic microabscesses Subepidermal bulla, Subepidermal variable mixed infiltrate Subepidermal bulla, DH or BP-like Subepidermal bulla, eosinophilic infiltrate Subepidermal bulla, papillary neutrophilic abscesses Tense bullae; annular Tense lesions; face, perineal, mucosal involvement Widespread tense bullae, urticated plaques Clinical Features Pruritic papulovesicles; symmetrical distribution; elbows, knees, buttocks Urticated plaques, tense bullae, nonscarring, fulfill ARA criteria Tense vesicles, Tense milia, scarring Differential Diagnosis of Subepidermal Bullous Disorders in a Child Diagnosis of Subepidermal Bullous Disorders Differential CBDC BP DH Type BSLE BSLE, bullousAbbreviations: systemic lupus erythematosus; ARA, American Rheumatism Association (Atlanta); BMZ, basement membraneepidermolysis zone; NC1,bullosa noncollagenous acquisita; domainCBDC, 1;chronic EBA, bullous disease of childhood; DH, dermatitis herpetiformis; bullous BP, pemphigoid; LAD, linear IgA disease. EBA

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microabcesses resembling DH.1 Other features may SLE) causes tissue injury (in the DEJ), thereby expos- include leukocytoclastic vasculitis, basal cell vacu- ing previously sequestered antigenic epitopes (lam- olization, and presence of mucin. Direct immuno- inin 5 and other BMZ components) to autoreactive fluorescence shows deposition primarily of IgG, in the T and B lymphocytes, leading to a secondary immune presence or absence of IgA, IgM, and C3 along the response against these new epitopes, which are criti- DEJ with 1 of 2 patterns—linear (40%) or granular cal for DEJ adhesion. These target antigens probably (60%)—or both.1 Salt split technique (direct immu- explain the epidermal binding of immunoglobulin nofluorescence and indirect immunofluorescence) on salt split technique in some cases of BSLE, which shows immunoglobulin deposition on the dermal side has been proposed by Yell et al3 to be classified as of the split.1,2 However, there are a few case reports type 3 BSLE. showing deposition of immunoglobulin on only epi- Differential diagnosis of BSLE (Table) includes dermal or both the epidermal and dermal side of split EBA, chronic bullous disease of childhood, bul- skin.3,8 Immune electron microscopy shows deposition lous pemphigoid, and DH, which can be distin- of immunoglobulin on or below the lamina densa guished on the basis of clinical, histopathologic, with a split at the same level. Rappersberger et al9 and immunologic findings. Although the primary reported a split at the lamina lucida in 2 patients with target antigen in both EBA and BSLE is type VII lesions localized to the face. collagen, BSLE differs by absence of scarring and a The diagnostic criteria for BSLE initially proposed dramatic response to dapsone, a difference that re- by Camisa and Sharma10 in 1983 were successively mains unexplained. revised by Camisa and Grimwood11 in 1986 and Although BSLE shows rapid response to dapsone, Gammon and Briggaman12 in 1993. They include the improvement in systemic manifestations does not following: (1) Diagnosis of SLE based on American parallel the cutaneous response. Systemic involve- Rheumatism Association (Atlanta) criteria. (2) Ves- ment (especially renal) requires prednisone therapy icobullous eruption arising on but not limited to alone or in combination with cyclophosphamide or sun-exposed skin. (3) Supepidermal bulla with azathioprine. Similarly, patients with BSLE who do neutrophil-predominant inflammation. (4) Direct im- not respond to dapsone alone or develop adverse munofluorescence showing IgGCUTIS and/or IgA, IgM, and effects to dapsone require other therapeutic options C3 at the BMZ. (5) Circulating antibodies to type VII including corticosteroids, methotrexate, azathioprine, collagen. (6) Immunoglobulin deposits colocalized to and colchicine. anchoring fibrils by immune electron microscopy.10-12 Our patient fulfilled criteria 1 through 4 of bul- Based on the presence/absence of circulating and/ lous SLE.10-12 Thus a final diagnosis of BSLE with or tissue-bound antibodies to type VII collagen, BSLE lupus nephritis class III (International Society of is subdivided into 2 immunologic subtypes: type 1 and Nephrology-Renal Pathology Society study group, typeDo 2.12 The production of theseNot antibodies is regu- 2004) 14 Copy was made. Because tests for antibodies to lated by class II MHC-DRB1 allele 1501. type VII collagen were not available to be performed The major target antigen in BSLE is the NC1 (non- in this patient, it was not possible to classify our collagenous domain 1) domain of type VII collagen (an- patient with type 1 or type 2 BSLE. Although rare, choring fibril), more precisely the fibronectin type III BSLE should be considered in the differential diag- homology units.1,2 Antibodies bound to type VII nosis of subepidermal blistering diseases, even in collagen cause blistering at the DEJ by interfering children, especially because it is sometimes associ- with the normal interaction between type VII colla- ated with life-threatening systemic manifestations. It gen and extracellular matrix components in the BMZ also is important to note that BSLE is diagnosed by a (type IV collagen, laminin 5, and fibronectin), and constellation of features rather than a single diagnos- by complement-mediated inflammatory tissue dam- tic feature. age.1 On immunoblotting, these antibodies recognize the full-length 290 kD type VII collagen protein and REFERENCES the full-length 145 kD recombinant NC1 domain.1,2,8 1. Vassileva S. Bullous systemic lupus erythematosus. Clin Autoantibodies against laminin 5, laminin 6 (a3 and Dermatol. 2004;22:129-138. g2 chain), and BP230 (bullous pemphigoid antigen) 2. Shirahama S, Furukawa F, Yagi H, et al. Bullous systemic (hemidesmosomal protein) also have occasionally lupus erythematosus: detection of antibodies against non- been described.8 Antibodies to multiple and different collagenous domain of type VII collagen. J Am Acad antigens in BSLE can be explained by 2 mechanisms: Dermatol. 1998;38(5, pt 2):844-848. systemic autoimmunity and epitope spreading.13 Epi- 3. Yell JA, Allen J, Wojnarowska F, et al. Bullous systemic tope spread describes an immunologic process wherein lupus erythematosus: revised criteria for diagnosis. Br J a primary autoimmune process (immune complexes in Dermatol. 1995;132:921-928.

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4. Pedro SD, Dahl MV. Direct immunofluorescence of 9. Rappersberger K, Tschachler E, Tani M, et al. Bullous dis- bullous systemic lupus erythematosus. Arch Dermatol. ease in systemic lupus erythematosus. J Am Acad Dermatol. 1973;107:118-120. 1989;21(4, pt 1):745-752. 5. Burge S, Shomberg K, Wojnarowska F. Bullous eruption of 10. Camisa C, Sharma HM. Vesiculobullous systemic SLE—a case report and investigation of the relationship lupus erythematosus. report of two cases and a review of of anti-basement-membrane-zone antibodies to blistering. the literature. J Am Acad Dermatol. 1983;9:924-933. Clin Exp Dermatol. 1991;16:133-138. 11. Camisa C, Grimwood RE. Indirect immunofluorescence 6. Condon C, Phelan M, Lyons JF. Penicillamine-induced in vesiculobullous eruption of systemic lupus erythemato- type II bullous systemic lupus erythematosus. Br J sus [letter]. J Invest Dermatol. 1986;86:606. Dermatol. 1997;136:474-475. 12. Gammon WR, Briggaman RA. Bullous SLE: a pheno- 7. Fleming MG, Bergfeld WF, Tomecki KJ, et al. Bullous typically distinctive but immunologically heterogeneous systemic lupus erythematosus. Int J Dermatol. 1989;28: bullous disorder. J Invest Dermatol. 1993;100:28S-34S. 321-326. 13. Chan LS, Vanderlugt CJ, Hashimoto T, et al. Epitope 8. Chan LS, Lapiere JC, Chen M, et al. Bullous systemic spreading: lessons from autoimmune skin diseases. J Invest lupus erythematosus with autoantibodies recognizing Dermatol. 1998;110:103-109. multiple skin basement membrane components, bullous 14. Weening VD, D’Agati JJ, Schwartz MM, et al. The clas- pemphigoid antigen 1, laminin-5, laminin-6, and type VII sification of glomerulonephritis in systemic lupus erythe- collagen. Arch Dermatol. 1999;135:569-573. matosus revisited. Am Soc Nephrol. 2004;15:241-250. CUTIS

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