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    ETAS_12 bullous ETAS_12 bullous Document Transcript

    • 12  Bullous and Vesicular Dermatoses Christine J. Ko, MD C o n t e n t s 12.1 Molecular Level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419 12.2 Microscopic Level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421 12.3 Bullous Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422 12.4 Diseases that Can Present with Bullae . . . . . . . . . . 429 12.5 Vesicular Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430 12.6 Common Allergens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433 12.7 Plant Allergens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435 12.8 Tips . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436 12.9 Plant Irritants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437 Bullous and Vesicular Dermatoses  417
    • Committed to Your Future For practice exam questions and interactive study tools, visit the Dermatology In-Review Online Practice Exam and Study System at DermatologyInReview.com/GaldermaSponsored by
    • 12.1  MOLECULAR LEVEL Figure 12-1.Armadillo Family • Plaque proteins that function u TIP in adhesion aMutations: armadillo protein Disorder • Includes beta-catenin beta-catenin............................................ 1.) some pilomatricomas ......................................................................... 2.) colorectal carcinoma (plakoglobin can substitute plakoglobin.............................................. Naxos disease for beta-catenin) in adherens plakophilin 1.............................................. ectodermal dysplasia with skin fragility junctions aAntigenic: armadillo protein Disorder • Plakoglobin (85 kDa) and plakoglobin.............................................. coprecipitates with desmogleins in pemphigus plakophilins in desmosomes ......................................................................... foliaceus and pemphigus vulgaris Bullous and Vesicular Dermatoses  419
    • Cadherins • Calcium-dependent u TIP adhesion molecules aMutations: cadherin Disorder desmoglein 1............................................ striate palmoplantar keratoderma (PPK) type 1 • Classic: E-cadherin, E-cadherin................................................ gastric cancer N-cadherin, P-cadherin aAntigenic: cadherin Disorder • Desmosomal type (has desmoglein 1............................................ pemphigus foliaceus homology to classic desmoglein 1............................................ Ritter’s disease desmogleins 1/3.................................... mucocutaneous pemphigus vulgaris cadherins): desmoglein 1 desmoglein 3.......................................... mucosal pemphigus vulgaris (160 kDa), desmoglein 3 desmocollin.............................................. IgA pemphigus (130 kDa), desmocollins • In adherens junctions and desmosomesEnzymes • Transglutaminase 1: Mutated in lamellar ichthyosis • Transglutaminase 3: 77 kDa, the antigen for dermatitis herpetiformisIntegrins • Found between cell u TIP membranes and aMutations: integrin Disorder basement membrane alpha-6-beta4-integrin...................... junctional epidermolysis bullosa with pyloric atresia aAntigenic: integrin Disorder in focal contacts and beta4-integrin......................................... ocular cicatricial pemphigoid hemidesmosomesIntermediate Filaments (IF) • Found within a variety of cells, many u TIP different types aMutations: IF Disorder keratin 1............................ ichthyosis hystrix • Type I = acidic keratins 9-20, keratins 1/10................... epidermolytic hyperkeratosis (EHK) chromosome 17 ............................................... epidermal nevi with EHK • Type II = basic keratins 1-8, chromosome 12 keratins 1/16................... nonepidermolytic PPK • Type III = vimentin, glial fibrillary acidic keratin 2e........................ ichthyosis bullosa of Siemens keratins 3/12.................. corneal dystrophy of Meesmann protein (GFAP), desmin, peripherin keratins 4/13.................. white sponge nevus of Cannon • Type IV = neurofilaments keratins 5/14.................. epidermolysis bullosa simplex variants • Type V = nuclear lamins keratins 6a/16............... pachyonychia congenita type 1 • Type VI = nestin keratins 6b/17............... pachyonychia congenita type 2 keratin 9........................... epidermolytic PPKPlakins lamin a............................... progeria • Plaque proteins that function in adhesion • Desmoplakin I (250 kDa) and II (210 kDa), envoplakin (210 kDa), periplakin (190 kDa) in desmosomes • Bullous Pemphigoid Antigen 1 (BPAg1) (230 kDa), plectin (500 kDa) in hemidesmosomes420  2011/2012 Dermatology In-Review l Committed to Your Future
    • u TIP u TIPaMutations: plakin Disorder aAntigens Molecular Weights desmoplakin............................................ 1.) striate PPK desmoglein 1............................................ 160 KDa ......................................................................... 2.) left ventricular cardiomyopathy desmoglein 3.......................................... 130 KDa ......................................................................... with woolly hair and striate PPK plakoglobin.............................................. 85 KDa plectin.......................................................... EB with muscular dystrophy BP Ag1......................................................... 230 KDaaAntigenic: plakin Disorder BP Ag 2 (collagen XVII)................... 180 KDa desmo-/envo-/peri-plakin, BPAg1..... paraneoplastic pemphigus desmoplakin I......................................... 250 KDa desmoplakin I and II............................ Stevens-Johnson syndrome desmoplakin II........................................ 210 KDa BPAg1.......................................................... bullous pemphigoid envoplakin................................................ 210 KDa periplakin................................................... 190 KDa plectin.......................................................... 500 KDa12.2  MICROSCOPIC LEVELAdherens Junction • Mediates quick, weak cell: cell adhesion • Contains E-cadherin, P-cadherin, alpha- and beta-catenin, vinculin and radixin; also plakoglobin, like desmosomes • Important in cell signaling; anchors actin at interface of two cell membranesDesmosome • Mediates slow, strong cell: cell adhesion • Contains desmosomal cadherins (desmoglein, desmocollin), desmocalmin (keratocalmin), desmoyokin, band 6 protein, plakophilin; contains plakoglobin, like adherens junctions • Anchors keratin intermediate filaments at interface of two cell membranes u TIPFocal Contact aMutations: connexin Disorder • Contains integrins, vinculin 26 .................................................... 1.) Vohwinkel’s syndrome • Anchors actin at interface of cell membrane/ ........................................................... 2.) KID syndrome basement membrane ........................................................... 3.) PPK with deafness 30.3, 31.......................................... erythrokeratoderma variabilisGap Junction 30..................................................... hidrotic ectodermal dysplasia • Contains connexins (make up connexons) • Allows for communication between cells u TIP aMutations: protein DisorderHemidesmosome – Anchoring Filaments BPAg2..........................................generalized atrophic benign EB laminin 5......................................JEB, Herlitz type • Within the basal cell: BPAg1, plectin plectin...........................................EBS with muscular dystrophy • Cell membrane spanners: alpha-6-beta4- alpha-6-beta4-integrin.......junctional epidermolysis bullosa integrin, Bullous Pemphigoid Antigen 2 ..........................................................with pyloric atresia (BPAg2 = type XVII collagen) (180 kDa) aAntigenic: protein Disorder BPAg1 and BPAg2-NC16A.....bullous pemphigoid • Within the lamina lucida: anchoring filaments, BPAg2..........................................lichen planus pemphigoides laminin 5 (400-440 kDa) part of BPAg2.........................linear IgA disease • Anchors keratin intermediate filaments at cell BPAg2-NC16A.........................herpes gestationis BPAg2-C terminal domain.....cicatricial pemphigoid membrane/basement membrane interface laminin 5......................................cicatricial pemphigoid beta4-integrin..........................ocular cicatricial pemphigoidLamina Densa • Contains entactin (nidogen) in a complex with collagen IV and laminin and heparan sulfateTight Junction • Contains occludins and claudins • Important in an intact skin barrier (found in granular layer) Bullous and Vesicular Dermatoses  421
    • 12.3  BULLOUS DISORDERSBullous Pemphigoid (BP) • Clinical: Most common in elderly patients; tense bullae, PEARL noninflammatory base, rupture leads to well-demarcated w  ense Bullae T denuded areas of skin; may also see urticarial, erythematous Bullous pemphigoid plaques; 20% have oral involvement; rarely BP Epidermolysis bullosa acquisita can be localized to the vulva or to a radiation site; risk factors Herpes gestationis include dementia and Parkinson’s disease • Histology: Subepidermal blister with many eosinophils; can have collections of eosinophils in dermal papillae • In urticarial stage of BP, interface dermatitis containing many eosinophils • DIF: Linear basement membrane C3 in ~95%, IgG4 in ~80%; “n-serrated pattern” • IIF: (Ideal substrate: salt-split skin) linear at basement membrane in 70% • Abs: Against BPAg1, BPAg2-NC16A domain •  PAg2 is thought pathogenic; neutrophil B  u TIP elastase and/or matrix metalloproteinase-9 aImmunofluorescence Patterns • Bullous Pemphigoid – linear C3/1gG (92 kDa gelatinase) cleaves BPAg2 in vitro (epidermal side of split skin) • Drug-induced BP: Classically cited • Herpes Gestationis – linear C3/lgG inciting drug is Lasix (furosemide), but • Epidermolysis Bullosa Acquisita – linear lgG + others sulfa drugs and thiol-containing drugs (dermal side of split skin) • Bullous Lupus Erythematusus – linear lgG + others (captopril, penicillamine, gold thiosulfate) •  orphyria Cutanea Tarda – multiple lgs, complement, P may be more common; others are and/or fibrin at junction or around vessels NSAIDS (ibuprofen, phenacetin), penicillin • Cicatricial Pemphigoid – linear C3/lgG, sometimes lgA • Pemphigus – intercellular lgG/C3 derivatives, cardiovascular drugs (enalapril, • Dermatitis Herpetiformis – granular lgA nadolol, practolol); PUVA can also lead to BP • Linear lgA – linear lgA • Treatments: PO steroids, azathioprine, • CBDC – linear lgA mycophenolate mofetil, nicotinamide, tetracycline • Two other disorders can present clinically like BP but have different target autoantigens, so-called anti-p105 and anti-p200 pemphigoidChronic Bullous Disease of Childhood (CBDC) • Clinical: Children with blisters in circular arrangements on the groin/lower extremities and perioral/scalp areas; severe pruritus • Histology: Subepidermal bullae with neutrophils at the dermo-epidermal junction; occasional eosinophils • DIF: Linear IgA • IIF: Circulating IgA in ~50% • Immunoelectron Mapping: IgA localizes to the lamina lucida and occasionally also to the sublamina densa • Abs: Against 97 kDa antigen that is a part of BPAg2 • Treatments: Disease tends to resolve spontaneously, but treatments include dapsone, sulfapyridine, steroids422  2011/2012 Dermatology In-Review l Committed to Your Future
    • Cicatricial Pemphigoid (CP) • Clinical: Patient generally older, ages 60-80; transient vesicles that result in erosions/ ulcers on the oral mucosa in about 100% of patients; uTIP desquamative gingivitis; conjunctiva involved in a bs against: A about 70% and can lead to scarring/symblepharon/ •   orm with mucosal and skin lesions: f BPAg2 (distal C-terminal domain) blindness; skin lesions in 25% (face/neck/scalp/ •  ocular form: beta-4-integrin groin/extremities) •  form associated with malignancy: laminin 5 • Histology: Subepithelial bullae, similar to BP (=epiligrin, BM600, kalinin, nicein) • DIF: Linear C3, IgG, fibrinogen, occasionally IgM/IgA at basement membrane in 90% PEARL • IIF: linear at basement membrane in 20% w  ariant: Brunsting-Perry pemphigoid: no mucosal V • Drug-induced CP: Similar to BP; sulfa drugs involvement, blisters on patches of erythema on head/ (sulfadoxine) and thiol-containing drugs neck with scarring/scarring alopecia w  reatments: Topical/intralesional/PO steroids, dapsone, T (captopril, penicillamine, gold thiosulfate) cyclophosphamide, azathioprine may be most common; others are NSAIDS (indomethacin), topical medications for glaucoma, penicillin derivatives, cardiovascular drugs (practolol, clonidine), Lasix, 5-fluorouracilDermatitis Herpetiformis (DH) (Duhring’s Disease) • Clinical: Often patients are in the 4th decade, severely pruritic grouped vesicles symmetrically on extensor surfaces/occasionally scalp; pruritus causes vesicles to be transient as scratching results in erosions; presentation can also be nonspecific with papules, urticaria, tense bullae, or polymorphous lesions; spontaneous improvement with cyclic exacerbations • Histology: Suprapapillary vesicles, multilocular, containing mostly neutrophils, papillary dermis and basement membrane zone get destroyed due to inflammatory infiltrate (no festooning), reverse festooning on the roof • DIF: Granular (rarely fibrillar) IgA > C3 in dermal papillae in 100% • IIF: Negative • Abs: Against transglutaminase 3; ELISA testing can be ordered to check for antibodies • In celiac disease, there are often circulating anti-endomysial and anti-gliadin antibodies • DDx: Linear IgA, DH secondary to drug, inflammatory EBA, bullous SLE, BP, HG, erythema multiforme • Associations: HLADQ2 (which is linked to the more commonly cited HLAB8 in a common ancestral haplotype), thyroid disease (40%), small bowel lymphoma (non-Hodgkin’s lymphoma), 90-100% have abnormal jejunal biopsies (similar to celiac sprue patients) but most are asymptomatic in terms of celiac disease • Treatments: Gluten-free diet (gliadin is the soluble, antigenic component in gluten) (rice, oats, corn are allowed), dapsone, sulfapyridone, sulfasalazineDrug-Induced Pemphigus • Inducing drugs: Thiol-containing drugs (captopril, penicillamine, thiopronine) or drugs with disulfide bonds (gold, pyritinol); also drugs that have the potential to release sulfur moieties (penicillins, piroxicam, cephalosporins), pyrazolone derivatives and enalapril (possibly secondary to an amide group), indocin, rifampin Bullous and Vesicular Dermatoses  423
    • • 75% or more like pemphigus foliaceus (especially when secondary MNEMONIC to thiol-drugs), 25% resembles pemphigus vulgaris; pemphigus Subepidermal Split vulgaris-type may be increased now as non-thiol-drugs are often PLAID the culprits Pemphigoid (bullous) • DIF: 90% intercellular Lupus (bullous SLE) • IIF: 70% intercellular Acquisita (EBA) IgA, linearEpidermolysis Bullosa (EB) Dermatitis herpetiformis • Clinical: In all types of EB, minor mechanical trauma leads to blisters, generally non-inflamed, and u TIP healing is with or without scarring/milia; aImportant Subtypes Defects nail dystrophy/alopecia can be present EB simplex. . . . . . . . . . . . . . . . . . . . . . . . . . . eratin 5/14 k in all types (although less common in Weber-Cockayne simplex) Koebner Dowling-Meara (herpetiformis) PEARL aHemidesmosomal Generalized atrophic benign EB. . . . . . . PAg2 B w Helpful Clinical Tips: Grouped blisters are most EB simplex with muscular dystrophy. . . . lectin p commonly seen in Dowling-Meara subtype of EB aJunctional EB simplex; enamel hypoplasia is more characteristic Herlitz. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .aminin 5 l of the junctional subtypes; exuberant granulation tissue periorally/axillary/neck area is most charac- with pyloric atresia. . . . . . . . . . . . . . . . . . . . lpha6-beta4 integrin a teristic of the Herlitz subtype of junctional EB; there EB dystrophic. . . . . . . . . . . . . . . . . . . . . . . . ollagen VII c is increased risk of SCCs in the Hallopeau-Siemens type of recessive dystrophic EB u TIP a lumped tonofilaments are seen on electron C • Uitto suggested classifying GABEB and microscopy in the Dowling Meara subtype of EB simplex; recessive dystrophic EB is secondary to a EB simplex with muscular dystrophy as premature stop codon in collagen VII “hemidesmosomal” rather than junctional based on the molecular localization of defective gene products, but this is not in common classifications • Inheritance Tips: All EB simplex is autosomal dominant except for some rarer subtypes (not listed); “hemidesmosomal” and junctional EB are autosomal recessiveEpidermolysis Bullosa Acquisita (EBA) • Clinical: Classically like dystrophic EB, but in adults: noninflammatory trauma-induced bullae (often on hands/feet) that heal with scarring/milia, increased skin fragility; oral/esophageal involvement possible (CP-like) • Note that the above is the classic presentation in the original reports of EBA; subsequently, BP-like presentations (inflammatory bullae, on trunk/extremities) have been described, and some feel that EBA may be a diverse group of diseases • Histology: Subepidermal, classically noninflammatory (PCT- PEARL like or dystrophic EB-like), but may be inflammatory with  w Associations: Inflammatory neutrophils (DH-like) or eosinophils (BP-like) bowel disease, autoimmune • DIF: Linear IgG, (sometimes IgM, IgA, C3, fibrinogen as well) at disorders (SLE, rheumatoid arthritis, diabetes, Hashimoto’s basement membrane in 100%; on base of salt-split skin (rather thyroiditis), amyloidosis than roof for BP); “u-serrated pattern” • IIF: IgG at basement membrane in 50% • Abs: Against type VII collagen (290 kDa) • Treatments: Often non-satisfactory424  2011/2012 Dermatology In-Review l Committed to Your Future
    • Epidermolytic Hyperkeratosis (Bullous Congenital Ichthyosiform Erythroderma) •  Clinical: Infants are often born or affected early on with blisters that resolve; subsequently  affected patients develop “corrugated” layered scaling that is generalized but prominent over flexural areas • Autosomal dominant, defect in keratin 1/10 • Histology: “Epidermolytic hyperkeratosis,” a characteristic pattern of degeneration of the cells of the spinous layerFogo Selvagem • Clinical: Endemic form of pemphigus foliaceus in rural areas of Brazil, increased incidence in children/young adults; flaccid bullae that rapidly become superficial crusted erosions that can look like eczema or psoriasis or impetigo or seborrhea; can be vegetative or exfoliative; Nikolsky’s sign positive • Possibly this is an infectious disease that is transmitted by the black fly (Simulium) • Histology: Identical to pemphigus foliaceus • Antibody profile identical to pemphigus foliaceus • Treatments: SteroidsHerpes Gestationis (HG) (Pemphigoid Gestationis) •  Clinical: 1:50,000 pregnancies; onset in second or third trimester or postpartum period; can recur with subsequent pregnancies or with oral contraceptive use or menstrual periods; lesions are urticarial papules/plaques around umbilicus that progress to the abdomen and rest of body; blisters are often in a characteristic annular or polycyclic arrangement • Neonate: May be premature or be small for gestational age; <5% will have bullae • Histology: Subepidermal split; is similar to BP • DIF: Linear C3, occasionally IgG at basement membrane; in 100% • IIF: Often negative; 75% of patients have a circulating HG factor (an IgG antibody that fixes complement) • Abs: Against BPAg2, sometimes BPAg1 • Associations: Graves’ disease, rare case reports of associated choriocarcinoma, HLA DR3 and DR4 • Treatments: PO steroidsIgA Pemphigus • Clinical: Middle-aged/elderly patients; subcorneal pustular dermatosis (SPD) type: serpiginous pustules; intraepidermal neutrophilic (IEN) type: flaccid bullae that can start as vesiculopustules, lesions enlarge peripherally, causing annular “flower-like” arrangements; common sites are intertriginous; pruritus common • Histology: Subcorneal or intraepidermal; neutrophils in epidermis, no acantholysis obvious •   IF: 100% intercellular IgA (distinguishes SPD type from subcorneal pustular dermatosis of D Sneddon and Wilkinson), rare C3 • IIF: Intercellular IgA in 50% •  Abs: Against desmocollins in SPD type, sometimes desmogleins •  Associations: IgA gammopathy • Treatments: Dapsone, steroids Bullous and Vesicular Dermatoses  425
    • Linear IgA Disease • Clinical: Can present like DH or BP with urticaria and oral/conjunctival lesions; sometimes lesions are more linear/annular/serpiginous as compared to BP; common sites are intertriginous; rarely has a TEN-like presemtation • Histology: Subepidermal blister that can look like DH with neutrophils along the dermoepidermal junction • DIF: Linear IgA at basement membrane in 100% • IIF: Linear IgA at basement membrane in 20-70% • Abs: Against portion of BPAg2 (linear IgA disease antigen = LAD-1) (97 kDa); note that some patients originally described as having linear IgA with antibodies against type VII collagen may actually have had EBA • Drug-induced: Commonly vancomycin, PCNs, cephalosporins, captopril; also lithium, diclofenac, amiodarone, PUVA, Lasix, IL2, IFN gamma, phenytoin, atorvastatin, second- generation ACE1, angiotensin receptor blockers • Treatments: Dapsone, steroids, other immunosuppressantsParaneoplastic Pemphigus • Clinical: Can resemble severe erythema PEARL multiforme with terrible oral ulcerations or  w riteria — Need 3 major or 2 major plus 2 minor C pemphigus vulgaris, or occasionally bullous Major Criteria or cicatricial pemphigoid; skin lesions can be 1.) Polymorphous mucocutaneous eruption polymorphous with erythematous papules, 2.) Concurrent internal neoplasia, 3.) Characteristic serum immunomonunoprecipitation lichenoid lesions, targetoid lesions, flaccid or findings tense bullae; respiratory failure can lead to death Minor Criteria • Histology: Suprabasilar acantholysis and 1.)  Positive IIF on rat bladder 2.) Positive DIF dyskeratotic keratinocytes with basal vacuolar 3.) Acantholysis on biopsy change • DIF: IgG and C3 intercellular and linear/granular at dermoepidermal junction • IIF: (Best on rat bladder) intercellular IgG • Abs: Against plectin, desmoplakin I (250 kDa) and uTIP II (210 kDa), BPAg1, envoplakin, periplakin, 170 kDa a ssociations: Malignancy, especially non-Hodgkin’s A lymphoma (42%) chronic lymphocytic leukemia antigen, desmoglein 1 and 3 (CLL) (29%), Castleman’ (6%), sarcoma (6%), s • Treatments: The disease occasionally remits with thymoma (6%) treatment of the tumorPemphigus Erythematosus (Senear-Usher Syndrome) • Clinical: An overlap of lupus erythematosus and pemphigus foliaceus with erythematous crusts and hyperkeratotic lesions and occasional bullae on the nose/ears/cheeks/scalp and chest/extremities • Histology: Like pemphigus foliaceus • DIF: Like pemphigus foliaceus and with linear IgG at dermoepidermal junction • Lupus band positive in 80%; ANA positive in 30% • Treatments: PO/topical steroids, sunscreen426  2011/2012 Dermatology In-Review l Committed to Your Future
    • Pemphigus Foliaceus (PF) • Clinical: Male:female 1:1; mean age 50-60; flaccid, superficial bullae that rupture easily (can look like impetigo) or localized/generalized exfoliation with crusting and malodor; Nikolsky’s sign-positive; endemic in Tunisia • Histology: Subcorneal/intragranular acantholysis with “cling ons” = acantholytic cells hanging onto the blister roof; neutrophils can be present in blister cavity and can resemble impetigo histologically so correlate with clinical • DIF: Intercellular IgG4 (may be more prominent in upper layers of epidermis) • IIF: (Guinea pig esophagus best) intercellular in 80% PEARL • Abs: Against desmoglein 1 • Note that desmoglein 1 is mutated in striate PPK w F Substrates and Diseases II Rat Bladder – Paraneoplastic Pemphigus • Note that plakoglobin is mutated in Naxos  uinea Pig Esophagus – Pemphigus Foliaceus G syndrome (autosomal recessive syndrome with Monkey Esophagus – Pemphigus Vulgaris right-sided cardiomyopathy, striated PPK, wooly hair) • Note that despite several recent case reports of neonates with PF, neonates are not usually born with PF despite the fact that maternal autoantibodies against desmoglein 1 can cross the placenta; this is thought to be because desmoglein 3 is expressed throughout the epidermis in the neonate; this is similar to the expression of desmoglein 3 in full-thickness oral epithelium, preventing oral involvement in PF • Drug-induced: Thiol-drugs, sulfa-releasing drugs • DDx: Impetigo, subcorneal pustular dermatosis of Sneddon and Wilkinson (neutrophils only, no acantholytic cells) • Treatments: Similar to pemphigus vulgarisPemphigus Vegetans • Clinical: Two types: Neumann type (starts and ends like PV) and Hallopeau type (begins with pustules); in either type, bullae or pustules quickly turn into vegetating malodorous plaques •   istology: Suprabasilar acantholysis can be subtle; there is marked hyperplasia and papillo- H matosis of the epidermis with characteristic eosinophilic abscesses • Acantholysis in suprabasilar and subcorneal areas • Prominent papillomatosis suggests vegetating nature of the diseasePemphigus Vulgaris (PV) • Clinical: Flaccid, thin-walled bullae, easily ruptured, erosions, crusts, heal with hyperpigmentation, desquamative gingivitis, oral erosions in 60-100%, Nikolsky’s sign positive, blisters spread with pressure on surface of blister (Asboe-Hansen sign) • Histology: Suprabasilar acantholysis with “tombstoning” of basal layer; acantholysis involves hair follicles/adnexae; eosinophils and neutrophils in the infiltrate • Important note: acantholysis can involve hair follicles and sebaceous glands • DIF: Intercellular IgG4 > C3 (may be more prominent in lower epidermis) • IIF: (Monkey esophagus best) intercellular in 80-90%; can follow these titers to follow disease activity • Abs: Against desmoglein 3 (mucosal) and desmoglein 1 and 3 (mucocutaneous) Bullous and Vesicular Dermatoses  427
    • • ELISA: Testing against dsg1 and/or dsg3 can be used to follow disease activity • Drug-induced: Pyrazolone derivatives, thiol-drugs, rifampin, penicillins, cephalosporins • Associations: Various HLA markers (DR4, DR14, B15, etc.) • Treatments: Steroids, azathioprine, mycophenolate mofetil, cyclophosphamide, IVIg u TIPPorphyrias aDisease: Inheritance Enzyme Defect • Porphyria, Congenital Acute intermittent porphyria – AD. . . . . . . . . . . . orphobilinogen deaminase P Erythropoietic Porphyria Congenital erythropoietic porphyria – AR. . . . . roporphyrinogen synthetase III U (Gunther’s) Porphyria cutanea tarda – sporadic and AD. . . . Uroporphyrinogen decarboxylase • Clinical: Severe Hepato-erythropoietic porphyria – AR. . . . . . . . roporphyrinogen decarboxylase U photosensitivity that Hereditary coproporphyria – AD. . . . . . . . . . . . . . oproporphyrinogen oxidase C leads to mutilation Variegate porphyria – AD. . . . . . . . . . . . . . . . . . . . rotoporphyrinogen oxidase P if light not avoided, Erythropoietic protoporphyria – AD and AR. . . Ferrochelatase erythrodontia • Treatment: Sun avoidance, bone marrow transplant PEARL Porphyria Cutanea Tarda w Board Tips: Variegate porphyria has • Clinical: Dorsal hands/scalp/face with blisters that heal a characteristic emission peak at with scarring/milia, hypertrichosis, hyperpigmentation, 626 nm; gallstones associated with sclerodermoid changes erythropoietic protoporphyria; no porphyrins in urine in erythropoietic • Histology: Minimal inflammatory infiltrate, fibrin cuffing protoporphyria; no skin changes in (PAS +) of vessels is type IV collagen, caterpillar bodies acute intermittent porphyria in epidermis, festooning of papillary dermis at base of blister • DIF: Linear IgG, IgM, IgA, C3, fibrinogen at basement PEARL membrane and around vessels w Dx of Non-inflammatory D  • IIF: Negative Bullae: PCT, pseudoporphyria, non-inflammatory EBA, bullous  •   orphyrin profile: Urine uroporphyrin/coproporphyrin, P diabeticorum, suction or friction stool isocoproporphyrin bullae, EB, patient on dialysis   •  Associations: Hemochromatosis (C282Y gene), hepatitis C, HIV, lupus erythematosus, hematologic malignancies • Treatment: Phlebotomy, antimalarials Porphyria, Erythropoietic Protoporphyria Type PEARL  •  Clinical: Pain with sun exposure, waxy thickening w Distinguish variegate and hereditary copropor-  of knuckles/nose, gallstones, liver failure phyria by porphyrin profile: the latter should • Histology: Eosinophilic thickened deposits have much more coproporphyrin in urine and around blood vessels in upper/mid dermis stool than the former • Treatment: Beta carotene, N-acetylcysteine Porphyria, Variegate and Hereditary Coproporphyria • Clinical: Skin manifestations like PCT with acute MNEMONIC abdominal attacks like acute intermittent porphyria Let’s Really Party Hard T(w)onight LasixPseudoporphyria (see Mnemonic) Retinoids • Drug-induced: NSAIDS – most commonly Pyridoxine naprosyn, nabumetone, oxaprozin, also Celebrex; Hemodialysis Thiazides tanning beds; hemodialysis; tetracycline; nalidixic Tanning Beds acid; thiazides; furosemide; cyclosporine; etretinate; NSAIDS isotretinoin; amiodarone • Urine, blood, fecal porphyrins are normal428  2011/2012 Dermatology In-Review l Committed to Your Future
    • Staphylococcal Scalded Skin Syndrome Ritter’s Disease) ( • Clinical: Patients present with fever, skin tenderness and erythema that leads to a generalized superficial exfoliation; generally a disease of infants or young children but occasionally adults with decreased renal function • Histology: Separation is subcorneal •  nfectious agent is Staphylococci group 2 phage type 71, which produces an exfoliative I toxin that cleaves desmoglein 1Stevens-Johnson Syndrome • Clinical: Patients are sick with fever, severe PEARL mucosal/conjunctival ulcerations and occasional w Drug-induced: Major causes = sulfonamides,  GU/GI involvement anticonvulsants, NSAIDS, allopurinol • Abs: Against desmoplakin I and II have been describedTransient Bullous Dermolysis of the Newborn • May be a variant of dominant dystrophic EB • Mutations have been found in type VII collagen • Blisters usually disappear by age 212.4  DISEASES THAT CAN PRESENT WITH BULLAEBullous Diabeticorum • Clinical: Tense blisters on non-inflamed base, generally on legs/acral, often appear suddenly • Histology: Intra-or sub-epidermal bullae, non-inflammatory • DIF: Generally negativeBullous Impetigo • Fragile bullae resembling pemphigus; easy rupture leads to annular crusted lesions • Often secondary to Staphylococci group 2 phage type 71Bullous Insect Bite • Clinical: May be more common in patients with chronic lymphocytic leukemia • Histology: Typical findings of an insect bite (intraepidermal spongiosis with eosinophils and dermal inflammation with eosinophils), but intraepidermal spongiosis is more severe and confluent creating bullaeBullous Lichen Planus • Lichen planus can sometimes present with bullae (as can any interface dermatitis); true bullous lichen planus is thought to arise secondary to extensive interface change (and therefore bullae arise in existing lesions of lichen planus) • Some patients have features of lichen planus as well as bullous pemphigoid, and blisters arise on normal skin (not in pre-existing lesions of lichen planus); some have referred to this as lichen planus pemphigoides; these patients often have circulating antibodies against BPAg2 • DIF can show IgM and C3 in colloid bodies Bullous and Vesicular Dermatoses  429
    • Bullous Lupus Erythematosus • Clinical: Non-inflamed bullae • Histology: Can look like dermatitis herpetiformis • DIF: Linear IgG, IgM, IgA, C3, fibrinogen • IIF: Generally negative • Abs: Against type VII collagen u TIPBullous Mastocytosis a irect Histamine Releasers: Opiates, succinylcholine, D • IgE-mediated releasers: PCN d-tubocurarine, polymixin B, radiocontrast, vancomycin, thiamineComa Blister • Clinical: Tense blister at pressure sites • Histology: Intra- or sub-epidermal blister with eccrine gland necrosis • DIF: Generally negativeCongenital Syphilis • Unlike other forms of syphilis, congenital syphilis can present with bullaeDrug-Induced Bullae • Any drug eruption (fixed drug, erythema multiforme, etc.) can eventuate in bullaeFriction Blister • Clinical: Bullae on inflamed or non-inflamed base, usually soles/hands • Histology: Generally intraepidermal (usually within granular layer)Sucking Blister • Clinical: A blister or denuded area seen in neonates, secondary to sucking the area of the blister in utero; generally seen on the hand/wrist/forearm12.5  VESICULAR DISORDERSAcropustulosis of Infancy • Clinical: Recurrent extremely pruritic vesicular eruption (in crops) on palms/soles of infants/ toddlers, need to rule out scabies; onset usually 3–6 months, disappears by age 3-4 years old; very difficult to treat; dapsone may be helpful • Histology: Subcorneal vesicle containing neutrophilsAcute Eczematous Dermatitis • Intraepidermal vesicles due to spongiosis with exocytosis of neutrophils and lymphocytes • DDx: Allergic contact dermatitis (eosinophils), irritant contact dermatitis (epidermal necrosis, neutrophils, usually few to no eosinophils), acute nummular dermatitis (few eosinophils), id reaction, photodermatitisAllergic Contact Dermatitis • A type IV hypersensitivity reaction (delayed hypersensitivity) (cell-mediated) • A hapten combines with a protein within Langerhans cells to produce the reaction • Patch testing is the gold standard for diagnosis • Irritant contact dermatitis is more common than allergic contact dermatitis (~4:1) • Recent study in the JAAD suggests that occupational dermatitides may have an allergic etiology in more cases than previous statistics indicate430  2011/2012 Dermatology In-Review l Committed to Your Future
    • Atopic Dermatitis • Clinical: In infants presents on the cheeks/extensors (spares diaper area); in childhood and adulthood is more chronic with lichenification and increased involvement of flexural areas • Associated with a family or personal history of atopy (asthma, hayfever, allergic rhinitis) • Increased susceptibility to viral (herpes, molluscum, papilloma), bacterial (especially S. aureus), and dermatophyte infections • Affects 10-20% of the population; associated with filaggrin mutations • Histology: Shows spongiotic dermatitis, often with eosinophils • Hertoghe’s sign: thinning of lateral eyebrows •  Th2 type reaction (IL4, IL5, IL6, IL10, IL13) • Major criteria (of Hanifin): need 3 1.) Pruritus 2.) Typical morphology and distribution 3.) Chronicity 4.) Personal or family history of atopy • Minor criteria: need 3/23 (not all listed): xerosis, hyperlinear palms, increased IgE, increased S. aureus infections, hand/foot dermatitis, nipple dermatitis, cheilitis, conjunctivitis, Dennie-Morgan fold, anterior cataracts, facial pallor, pityriasis alba, intolerance to wool, perifollicular accentuation • Pathogenesis related to filaggrin mutationsEczematous Dermatitis • Broad category that includes allergic/irritant dermatitis, atopic dermatitis, seborrheic dermatitis, etc. • Dermatitis associated with systemic disease: – Familial Leiner’s disease – fatal disease of infants with seborrhea, diarrhea and death due to sepsis, associated with decreased C3/C5 – Hyper IgE disease (Job’s) – AD – recurrent pyogenic infections associated with severe IgE elevation and deficient chemotaxis – Wiskott-Aldrich – XLR – purpura, thrombocytopenia, severe infections/lymphoma; WASP gene – Chronic granulomatous disease – XLR – perioral dermatitis, cervical adenitis, lung and bone granulomas/infections, death in childhood, secondary to defect in neutrophils; CGD gene – Langerhans cell histiocytosis – presentation may mimic that of an eczematous dermatitis, especially seborrheic dermatitis-like, in infants, with involvement of scalp and intertriginous areasErythema Toxicum Neonatorum • Clinical: Papules and pustules that start within 48 hours of birth lasting 2-3 days; affects the face/trunk/proximal extremities; spares the palms/soles; scraping and Gram stain reveals eosinophils; germ tubes would be seen in Candidal infection; clinically often looks like a “flea-bitten” rash • Histology: Intraepidermal blister (in hair follicle) containing eosinophils • Affects up to 40-50% of infants, cause unknown • Note: Baby’s skin has small hair follicles, small eccrine glands, increased number of nuclei in the collagen Bullous and Vesicular Dermatoses  431
    • Grover’s Disease (Transient Acantholytic Dyskeratosis) • Clinical: Pruritic folliculitis over the chest/abdomen/occasionally back, generally in middle- aged men • Histology: Can resemble pemphigus vulgaris, Darier’s, eczematous dermatitis, Hailey-HaileyIncontinentia Pigmenti • Clinical: Presents with different stages: vesicles/bullae (1st 2 weeks of life) that become hyperkeratotic and verrucous (2-6 weeks of life), resolving with hyperpigmentation and sometimes hypopigmentation; may have abnormal teeth and/or alopecia • Histology: Evidence of spongiosis with eosinophils and apoptotic keratinocytes •  X-linked dominant, gene mutation in NEMOIrritant Contact Dermatitis • Irritants produce a reaction in almost all people exposed to the irritant and is not dependent on an immunologic (memory) reaction • Common irritants include acids (including phenol, which can be neutralized by isopropyl alcohol), alkalis, detergents, fiberglass (removed with talcum powder), hydrocarbons, mace, metal salts, tear gas (choloroacetophenone), water • Chlorinated compounds are also irritants and can also produce chloracne; examples of chlorinated compounds include chloronaphthalene, chlorodiphenyl, dichlorobenzonitrile, tetrachloroazooxybenzene; dioxin in the Vietnam war; cutting oils • Chloracne is characterized by follicular papules, especially in the retroauricular/malar/scrotal areaMiliaria Crystallina • Clinical: Like drops of water on the skin • Histology: Subcorneal blister (fragile) formed near the eccrine duct coming to the surface • The only miliaria of newborn as it takes several days to get miliaria rubra • Is from mechanical obstruction; can see with sunburn or febrile illnessMiliaria Rubra (Prickly Heat) • Clinical: Lesions are small pruritic papules with erythema, seen in sweating with occlusive coverings • Histology: Sweat duct obstructed in deeper epidermis, spongiotic vesicles with inflammatory cells • Bacteria are a factor in obstructionPhotodermatitis • Often on face/arms/V of chest • Can resemble an airborne contact dermatitis, but photodermatitis generally spares the upper eyelids, retroauricular and submental areasPustular Psoriasis • Generalized form (von Zumbusch): clinically patients are usually sick with fever/chills; body is erythrodermic with pustules forming confluent “lakes of pus”; often a preceding history of plaque-type psoriasis • May be induced by withdrawal of steroids, iodides, terbinafine, minocycline, salicylates432  2011/2012 Dermatology In-Review l Committed to Your Future
    • Seborrheic Dermatitis • Development of seborrheic dermatitis is related to Malassezia furfur and sebum production • Seen in infants and post-pubertally; greasy, well-demarcated pink to salmon-colored thin plaques on the face/scalp/chest/back/intertriginous areasStasis Dermatitis • Subacute to chronic dermatitis with hemosiderin, dilated capillaries in fibrotic dermis • May be exacerbated by application of topical steroids or topical antibiotics if a concomitant allergic contact dermatitis is presentSubcorneal Pustulosis of Sneddon and Wilkinson • Histology: Subcorneal pustules with many neutrophils, no “cling ons” • DDx: Pustular psoriasis, impetigo, pemphigus foliaceus, acropustulosis of infancy, IgA pemphigusTransient Neonatal Pustular Melanosis • Clinical: Affects 4% of blacks, <1% of whites; flaccid vesiculopustules (non-inflamed base) develop over 1-2 days which rupture and leave a collarette of scale, resolving with hyperpigmented macules that last 1-2 weeks • Sites commonly affected are the forehead, neck • Histology: Subcorneal pustules (sterile); hyperpigmented macules show increased basilar pigmentation12.6  COMMON ALLERGENSFragrance Mix • Contains cinnamic alcohol and aldehyde, hydroxycitronellal, isoeugenol, eugenol, oak moss absolute, alpha-amyl cinnamic aldehyde, geraniol • Found in perfumes, cinnamon oil/powder, cassia oil, flavoring agents, toilet soaps, bath tissue • Balsam of Peru, another allergen, is also a fragrance; from the Myroxylon pereirae tree; is found naturally in tomatoes/citrus; in colaGold • Patients allergic to gold often also react to nickel and cobaltCobalt • Patients often also react to gold/nickel • Found in jewelry, cosmetics, cementsImidazolidinyl Urea = Germall 115 = Tristat • A preservative, a formaldehyde-releaser • Found in cosmetics/creams/lotions/hair conditioner/shampoo/deodorants, OTC meds, adhesives, bubble baths, cleaning agents, latex emulsions, inks, soaps • Cross-reacts with formaldehyde and diazolidinyl ureaLanolin • Found in wool alcohol, wool wax, wool fat, adhesives, cosmetics, topical medications (creams/lotions/ointments), soaps Bullous and Vesicular Dermatoses  433
    • • From sheep fleece • Lanolin-sensitive patients can sometimes tolerate one formulation but not another • Common allergy among leg ulcer patientsMethylchloroisothiazinolone = Kathon CG = 5-chloro-2-methyl-4-isothiazolin-3-one • Found in cosmetics, skin/hair products, “acid” permanent waves, industrial water systems, cooling oils, soaps, latex emulsions, moist toilet paper, mascara, biocides • A preservative • May cause airborne contact dermatitisNeomycin • Most common sensitizing topical antibiotic • Found in topical antibiotics, first-aid creams, ear drops, nose drops • Cross-reactivity with other aminoglycosides; allergy to bacitracin often coexistsNickel • Most common allergen • Found in jewelry, alloys, pigments, dentures, orthopedic appliances, scissors, razors, eyeglass frames, eating utensils •  Can test for the presence of nickel by using dimethylglyoximePara-Phenylenediamine PEARL • Found in hair dyes, inks, photodeveloping solutions, w ross-reactivity with azo- and aniline  C textile dyes dyes, procaine, benzocaine, PABA, • Found in henna tattoos para-aminosalicylic acid, sulfonamidesPara-Tert-Butylphenol Formaldehyde Resin • Found in shoes, watch straps, do-it-yourself glues, plywood, insulation, automobiles, motor oils, inks, papers, film developers, disinfectants, deodorants, dental bonding, rubber, raincoat • May cause depigmentationQuaternium-15 = Dowicil 200 • A preservative, a formaldehyde-releaser • Found in cosmetics, household cleaners/polishes, creams/lotions, shampoo, latex paints, topical meds, metal working fluids, adhesives • Not all patients allergic to this are allergic to formaldehydeRosin (Colophony) • Found in adhesive tape, cosmetics, insulating tape, glossy paper, flypaper, polish, paints, inks, epilation wax, rosin bags for baseball players, varnishes, violin bows, chewing gum • From Pinus palustris and Pinus caribaea (conifers) • A.k.a. abietic acidThimerosal (Merthiolate) • Preservative in vaccines (e.g., hepatitis), eyedrop solutions, cosmetics, nasal sprays • Cross-reactivity with mercury or due to the thiosalicylic acid component • Cross-reacts with piroxicam434  2011/2012 Dermatology In-Review l Committed to Your Future
    • Chromate • Found in leather, cements, some green felts (pool tables)Thiuram Mix • In rubber (prevents degradation), latex, adhesives, pesticides, medications like Antabuse • Found in condoms, adhesives, diaphragms, repellents, fungicides • Includes four chemicals12.7  PLANT ALLERGENS (Often cause acute vesiculation and erythema in linear arrays)Family Alliaceae • Includes garlic, onions, chives • Most important allergen in garlic is diallyl disulfide • Garlic is also an irritantFamily Alstroemeriaceae and Family Liliaceae • Peruvian lily (alstroemeria) and tulips • Finger dermatitis in florists/garderners handling tulip bulbs • Allegen is tulipalin A (a metabolized product of tuliposide A) • Tulipalin A = alpha-methylene-gamma-butyrolactoneFamily Anacardiaceae (Toxicodendron Genus) PEARL • Initially Toxicodendron plants were classified as Rhus w U  rushiol is found in mango peel, poison ivy (toxi- codendron toxicarum), poison oak (toxicodendron • Allergen is urushiol, a pentadecacatechol diversilobum in western U.S.), sumac, gingko fruit • Causes black dot dermatitis (allergen is a cross-reactor – ginkgolic acid), lac- • Plants have characteristic leaves arranged in quer tree, cashew nut, Indian marking nut, black varnish tree, Brazilian pepper tree threesFamily Apiaceae (Formerly Umbelliferae), Moraceae, Rutaceae • Apiaceae includes celery, fennel, hogweed, parsnip • Moraceae includes the fig tree • Rutaceae includes citrus (lime, bergamot orange, lemon, rue) • These families can cause phototoxicity due to furocoumarins (psoralens and angelicins)Family Asteraceae (Formerly Compositae) • Clinically see chronic lichenification of face/neck/hands/arms (light-exacerbated); areas of involvement commonly include the upper eyelids, retroauricular area, and submental area (airborne) • From artichokes, broomweed, chamomile, chrysanthemum, liverwort, ragweed, sagebrush, chicory, endives, tarragon, sunflower, marigold, dandelion • Allergen is sesquiterpene lactone • Permethrin (Elimite) is derived from chrysanthemumsFamily Lamiaceae • Includes lavender, thyme, spearmint (allergen = carvone), peppermint (allergen = menthol) Bullous and Vesicular Dermatoses  435
    • Family Primulaceae • Primula obconica (primrose) • Allergen is primin (2-methoxy-6-pentyl-benzoquinone), a quinoneFamily Urticaceae • Includes nettles (Urtica dioica) • These plants contain histamine, acetylcholine, and serotonin among other products, allowing them to cause urticaria upon contact PEARL w ommon Allergens by Site C eyelids r  ubber, nail products (ethyl methacrylate, methyl methacrylate, tosylamide formalde- hyde, resin, glutaraldehyde, benzalkonium chloride), eye products forehead hat band (rubber), leather scalp/retroauricular hair dye/products, permanent wave perioral gum, foods neck fragrance earlobe nickel abdomen nickel trunk formaldehyde axillary vault deodorant axillary folds clothing dyes, formaldehyde back of women bra strap (rubber), nickel wrist chromates (leather) hands gloves (latex, rubber especially thiurams), ethyl methacrylate in dentists/surgeons waist rubber perianal suppositories (“caine” anesthetics) shins socks (rubber) feet (spares toe webs) s  hoes (rubber especially mercaptobenzothiazole, chromates in leather) ulcers bacitracin, neomycin, lanolin penis poison ivy, rubber/latex (condoms)12.8  TIPS • Cotton, silk, nylon, linen rarely sensitize; 100% u TIP polyester may be best for formaldehyde- aixocortol pivalate tests for Class A corticosteroid T sensitive patients allergy (predicts allergy to hydrocortisone, prednisone) • Spandex contains mercaptobenzathiazole audesonide tests for Class B and D corticosteroid B allergy (predicts allergy to triamcinolone and • Glyceryl thioglycolate is in acid permanent hydrocortisone butyrate) waves • Tosylamide formaldehyde resin and ethyl u TIP acrylate can cause dermatitis near nails a orticosteroid Classes C • TRUE test does not test for gold allergy and  Class A: Hydrocortisone, methylprednisdone, only tests for formaldehyde and quaternium-15 prednisone, prednisolone (but not other formaldehyde releasers) allergy Class B: amcinonide, budesonide, desonide, flucinonide, fluocinolone acetonide, halcinonide, • Melaleuca plant (tea tree oil) – allergen is triamcinolone d-limonene Class C: betamethasone, dexamethasone, flucortisone • Castor bean – allergen is ricin Class D: aclomethasone, betamethasone valerate436  2011/2012 Dermatology In-Review l Committed to Your Future
    • • Lichens – allergen is usnic acid, evenic acid, atronorin • Latex allergy – can cross-react with avocado, banana, chestnut, kiwi • Hydroquinone can be found in rubber products • Cocamidopropyl betaine – putative allergen is amidoamine; found in shampoos, cosmetics, and conditioners • Glutaraldehyde and benzalkonium chloride (found in baby wipes) are both cold sterilizers • Disperse blue dyes are a major cause of textile allergy • Ethylenediamine – a preservative; cross-reacts with hydroxyzine12.9  PLANT IRRITANTSFamily Alliaceae • Includes garlic, radish (thiocyanates in the bulbs are irritating)Family Amaryllidaceae • Includes daffodil, narcissus, hyacinth • Bulbs contain calcium oxalateFamily Araceae • Includes the dumb cane plant (Dieffenbachia), a very common house plant • Irritant is calcium oxalateFamily Euphorbiaceae • Includes the croton plant, spurges • Phorbol esters are the irritantFamily Ranunculaceae • Includes buttercups and marigolds • The irritant is protoanemoninFamily Solanaceae • Includes capsaicin (neutralized with vinegar) A CK NO W L E DGME NT S Gary Cole, MD Edward Jeffes, MD, PhD Bruce E. Strober, MD, PhD REF E R E NC E S1. Verraes S, et al. Respective contribution of neutrophil elastase and matrix metalloproteinase 9 in the degrada- tion of BP180 (type XVII collagen) in human bullous pemphigoid. J Invest Dermatol 2001 Nov; 117(5): 1091-6.2. Vassileva S. Drug-induced pemphigoid: bullous and cicatricial. Clin Dermatol 1998; 16: 379-87.3. Bedane C, et al. Bullous pemphigoid and cicatricial pemphigoid autoantibodies react with ultrastructur- ally separable epitopes on the BP180 ectodomain: Evidence that BP180 spans the lamina lucida. J Invest Dermatol 1997; 108: 901-907.4. Sardy M, et al. Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis. J Exp Med 2002; 195: 747-757.5. Sollid LM. Molecular basis of celiac disease. Annu Rev Immunol 2000; 18: 53-81. Bullous and Vesicular Dermatoses  437
    • 6. Price P, et al. The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases. Immunol Rev 1999; 167: 257-274.7. Cunningham MJ, Zone JJ. Thyroid abnormalities in dermatitis herpetiformis. Ann Intern Med 1985; 102: 194-196.8. Collin P, Reunala T. Recognition and management of the cutaneous manifestations of celiac disease: a guide for dermatologists. Am J Clin Dermatol 2003; 4: 13-20.9. Brenner S, Bialy-Golan A, Ruocco V. Drug-induced pemphigus. Clin Dermatol 1998; 16: 393-397.10. Uitto J, Pulkkinen L. Molecular genetics of heritable blistering disorders. Arch Dermatol 2001; 137: 1458-1461.11. Chen M, 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: 1059-1064.12. Chan LS, Chen M, Woodley DT. Epidermolysis bullosa acquisita in the elderly. J Geriatr Dermatol 1996; 4: 47-52.13. Shornick JK, Black MM. Secondary autoimmune diseases in herpes gestationis (pemphigoid gestationis). J Am Acad Dermatol 1992; 26: 563-566.14. Djahansouzi S, et al. Herpes gestationis may present itself as a paraneoplastic syndrome of choriocarcino- ma—a case report. Gynecol Oncol 2003; 89: 334-337.15. Herron MD, Zone JJ. Dermatitis herpetiformis and linear IgA bullous dermatosis. In Bolognia JL, Jorizzo JL, Rapini RP, Eds. Dermatology. London: Mosby, 2003; 479-489.16. Amagai M. Pemphigus. In Bolognia JL, Jorizzo JL, Rapini RP, Eds. Dermatology. Mosby, London, 2003; 449-462.17. Foedinger D, et al. Autoantibodeis to desmoplakin I and II in patients with erythema multiforme. J Exp Med 1995; 181: 169-179.18. Kucenic MJ, Belsito DV. Occupational allergic contact dermatitis is more prevalent than irritant contact der- matitis: A 5-year study. J Am Acad Dermatol 2002; 46: 695-699.438  2011/2012 Dermatology In-Review l Committed to Your Future
    • NOTES Bullous and Vesicular Dermatoses  439
    • NOTES440  2011/2012 Dermatology In-Review l Committed to Your Future