Fitzpatrick's Color Atlas and Synopsis of Clinical Dermatology, Seventh Edition

SECTION 6

Genetic and Acquired Bullous Diseases

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Bullous diseases are defined as conditions where cavities filled with fluid form in the superficial layers of skin clinically manifesting as vesicles or blisters. Although vesicles and blisters can arise as secondary lesions in many conditions, in the bullous diseases they are the primary pathologic event. Genetic (hereditary) and acquired (mostly autoimmune) bullous diseases exist.

Hereditary Epidermolysis Bullosa (EB) ICD-9: 757.39 image ICD-10:Q 81 image

image A spectrum of rare genodermatoses in which a disturbed coherence of the epidermis and/or dermis leads to blister formation following trauma. Hence, the designation mechanobullous dermatoses.

image Disease manifestations range from very mild to severely mutilating and even lethal forms that differ in mode of inheritance, clinical manifestations, and associated findings.

image Classification based on the site of blister formation distinguishes three main groups: epidermolytic or EB simplex, junctional EB (JEB), and dermolytic or dystrophic EB (DEB).

image In each of these groups, there are several distinct types of EB based on clinical, genetic, histologic, and biochemical evaluation.

Classification

Based on level of cleavage and blister formation, there are three main types:

• Epidermolytic. Cleavage occurs in keratinocytes: EB simplex (EBS).

• Junctional. Cleavage occurs in basal lamina: junctional EB (JEB).

• Dermolytic. Cleavage occurs in most superficial papillary dermis: dermolytic or dystrophic EB (DEB).

In each of these groups, there are several distinct types of EB based on clinical, genetic, histologic/electronmicroscopic, and biochemical evaluation (Table 6-1). Only the most important are discussed here.

TABLE 6-1 CLASSIFICATION OF EPIDERMOLYSIS BULLOSA

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Epidemiology

The overall incidence of hereditary EB is placed at 19.6 live births per 1 million births in the United States. Stratified by subtype, the incidences are 11 for EBS, 2 for JEB, and 5 for DEB. The estimated prevalence in the United States is 8.2 per million, but this figure represents only the most severe cases, as it does not include the majority of very mild disease going unreported.

Etiology and Pathogenesis

Genetic Defects. Molecules involved are listed in Table 6-1 and localization in the tissue and sites of cleavage are shown in (Fig. 6-1).

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Figure 6-1. Schematic of the components of dermal-epidermal basement membrane (left panel) and levels of dermal-epidermal separation in hereditary and autoimmune bullous diseases with dermal-epidermal cleavage discussed in this Atlas. EBS, epidermolysis bullosa simplex; BP, bullous pemphigoid; PG, pempihgoid gestationis; LAD, linear IgA disease; CP, cicatricial pemphigoid; EBA, epidermolysis bullosa acquisita; DEB, dermolytic epidermolysis bullosa. Modified from Marinkowich MP. Inherited epidermolysis bullosa. [From Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, and Wolff K (eds.). Fitzpatrick's Dermatology in General Medicine 8th edition. New York, McGraw-Hill, 2012, p 649-665.]

Clinical Phenotypes

EB Simplex

A trauma-induced, intraepidermal blistering, based in most cases on mutations of the genes for keratins 5 and 14 resulting in a disturbance of the stability of the keratin filament network (Table 6-1). This causes cytolysis of basal keratinocytes and a cleft in the basal cell layer (Fig. 6-1). Different subgroups have considerable phenotypic variations (Table 6-1), and there are several distinct forms, most of which are dominantly inherited. The two most common are described below.

Generalized EBS (Table 6-1). The so-called Koebner variant is dominantly inherited, with onset at birth to early infancy. Generalized blistering following trauma with a predilection for traumatized body sites such as feet, hands, elbows, and knees. Blisters tense or flaccid (Fig. 6-2) leading to erosions. Rapid healing and only minimal scarring at sites of repeated blistering. Palmoplantar hyperkeratoses may be present. Nails, teeth, and oral mucosa are usually spared.

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Figure 6-2. Generalized EBS (Koebner) This 4-year-old girl has had blistering since very early infancy with predilection for traumatized body sites such as palms and soles and also elbows and knees. Blistering also occurs in other areas such as the forearm, as shown here, and on the trunk. There is hardly any evidence of scarring.

Localized EBS. Weber-Cockayne subtype (Table 6-1). The most common form of EBS. Onset in childhood or later. The disease may not present itself until adulthood, when thick-walled blisters on the feet and hands occur after excessive exercise, manual work, or military training (Fig. 6-3). Increased ambient temperature facilitates lesions. Hyperhidrosis of palms and soles; secondary infection of blisters.

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Figure 6-3. Localized EBS Thick-walled blisters on the soles. The disease presented itself for the first time during military training when this 19-year-old had to march over a long distance.

Junctional EB

All forms of JEB share the pathologic feature of blister formation within the lamina lucida of the basement membrane (Fig. 6-1). Mutations are in the gene for collagen XVII and laminin (Table 6-1). Autosomal recessive, several clinical phenotypes (Table 6-1), three of which are described below.

Herlitz EB (JEB Gravis). Mortality rate is 40% during the first year of life. Generalized blistering at birth (Fig. 6-4) or distinctive and severe periorificial granulation, loss of nails, and involvement of most mucosal surfaces. The skin of these children may be completely denuded, representing oozing painful erosion. Associated findings include all symptoms resulting from generalized epithelial blistering with respiratory, gastrointestinal, and genitourinary organ systems involved.

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Figure 6-4. Junctional epidermolysis bul losa (Herlitz) There are large eroded, oozing, and bleeding areas that occurred intrapartum. When this newborn is lifted up, dislodgment of epidermis and erosions occur with manual handling.

Non-Herlitz EB JEB Mitis. These children may have moderate or severe JEB at birth but survive infancy and clinically improve with age. Periorificial nonhealing erosions during childhood.

Non-Herlitz EB Generalized Atrophic Benign Epider-molysis Bullosa (GABEB). Presents at birth with generalized cutaneous blistering and erosions on the extremities, trunk, face, and scalp. Survival to adulthood is the rule, but blistering on traumatized areas continues (Figs. 6-5 and 6-6). Pronounced with increased ambient temperature, and there is atrophic healing of the lesions. Nail dystrophy, nonscarring or scarring alopecia, mild oral mucous membrane involvement, and enamel defects may occur. Mutations are in the genes for laminin and collagen XVII (Table 6-1).

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Figure 6-5. Generalized atrophic benign epidermolysis bullosa (GABEB) This 19-year-old man has had cutaneous blistering since birth, with blisters and erosions arising on the elbows and knees and also on the trunk and arms following trauma. There is no scarring but some spotty atrophy.

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Figure 6-6. Generalized atrophic benign epidermolysis bullosa (GABEB) This 20-year-old man has had generalized cutaneous blistering since birth. Note: A large erosion on the left lower back and hemorrhagic crusts on the lower arms. Erythema on the back indicates sites of previous blistering.

Dystrophie EpidermOlySiS BullOSa (DEB)

DEB is a spectrum of dermolytic diseases where blistering occurs below the basal lamina (Fig. 6-1); healing is therefore usually accompanied by scarring and milia formation—hence, the name dystrophic. There are four principal subtypes, all due to mutations in anchoring fibril VII collagen (Table 6-1), two of which are described below.

Dominant DEB. Cockayne-Touraine disease. Onset in infancy or early childhood with acral blistering and nail dystrophy; milia and scar formation, which may be hypertrophic or hyperplastic. Oral lesions are uncommon, and teeth are usually normal.

Recessive DEB (RDEB). It comprises a larger spectrum of clinical phenotypes. The localized, less severe form (RDEB mitis) occurs at birth, shows acral blistering, atrophic scarring, and little or no mucosal involvement. Generalized, severe RDEB, the Hallopeau-Siemens variant, is mutilating. There is generalized blistering at birth, and progression and repeated blistering at the same sites (Fig. 6-7) result in remarkable scarring and ulcerations, syndactyly with loss of nails (Fig. 6-8) and even mitten-like deformities of hands and feet, and flexion contractures. There are enamel defects with caries and parodontitis, strictures and scarring in the oral mucous membrane and esophagus, urethral and anal stenosis, and ocular surface scarring; also malnutrition, growth retardation, and anemia. Squamous cell carcinoma in chronic recurrent erosions.

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Figure 6-7. Generalized recessive dystrophic epidermolysis bullosa (RDEB) In this severe disease, blistering occurs often at the same sites, as in this 10-year-old girl. Blisters lead to erosions and these become ulcers that have a low tendency to heal. When healing occurs, it results in scarring. This girl also has enamel defects with caries, strictures of the esophagus, severe anemia, and considerable growth retardation. It is obvious that the large wounds are portal entries for systemic infection.

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Figure 6-8. Generalized recessive dystrophic epidermolysis bullosa (RDEB) Loss of all fingernails, syndactyly, and severe atrophic scarring on the dorsa of hands.

Diagnosis

Based on clinical appearance and history. Histopathology determines the level of cleavage, which is further defined by electron microscopy and/or immunohistochemical mapping. Western blot, Northern blot, restriction fragment length polymorphism analysis, and DNA sequences may then identify the mutated gene.

Management

There is as yet no causal therapy for EB, but gene therapy is being investigated. Management is tailored to the severity and extent of skin involvement: supportive skin care, supportive care for other organ systems, and systemic therapies for complications. Wound management, nutritional support, and infection control are key.

In EBS, maintenance of a cool environment and use of soft, well-ventilated shoes are important. Blistered skin is treated by saline compresses and topical antibiotics or, in the case of inflammation, with topical steroids. More severely affected JEB and DEB patients are treated like patients in a burn unit. Gentle bathing and cleansing are followed by protective emollients and nonadherent dressings.

Although rare, EB and, in particular, JEB and DEB pose a major health and socioeconomic problem. Organizations such as the Dystrophic Epidermolysis Bullosa Research Association (DEBRA) offer assistance that includes patient education and support.

Pemphigus ICD-9: 694.4 image ICD-10: L10 image

image A serious, acute or chronic, bullous autoimmune disease of skin and mucous membranes based on acantholysis.

image Two major types: pemphigus vulgaris (PV) and pemphigus foliaceus (PF).

image PV: flaccid blisters on skin and erosions on mucous membranes. PF: scaly and crusted skin lesions.

image PV: suprabasal acantholysis. PF: subcorneal acantholysis.

image IgG autoantibodies to desmogleins, transmembrane desmosomal adhesion molecules.

image Serious and often fatal unless treated with immunosuppressive agents.

Classification (See Table 6-2)

TABLE 6-2 CLASSIFICATION OF PEMPHIGUS

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Epidemiology

PV: Rare, more common in Jews and people of Mediterranean descent. In Jerusalem the incidence is estimated at 16 per million, whereas in France and Germany it is 1.3 per million.

PF: Also rare but endemic in rural areas in Brazil (fogo selvagem), where the prevalence can be as high as 3.4%.

Age of Onset. 40-60 years; fogo selvagem also in children and young adults.

Sex. Equal incidence in males and in females, but predominance of females with PF in Tunisia and Colombia.

Etiology and Pathogenesis

An autoimmune disorder. Loss of cell-to-cell adhesion in the epidermis (acantholysis). Occurs as a result of circulating antibodies of the IgG class, which bind to desmogleins, transmembrane glycoproteins in the desmosomes, members of the cadherin superfamily. In PV, desmoglein 3 (in some, also desmoglein 1). In PF, desmoglein 1. Autoantibodies interfere with calcium-sensitive adhesion function and thus induce acantholysis.

Clinical Manifestation

Pemphigus Vulgaris usually starts in the oral mucosa, and months may elapse before skin lesions occur. Less frequently, there may be a generalized, acute eruption of bullae from the beginning. No pruritus but burning and pain in erosions. Painful and tender mouth lesions may prevent adequate food intake. Epistaxis, hoarseness, dysphagia. Weakness, malaise, weight loss.

Skin Lesions. Vesicles and bullae with serous content, flaccid (flabby) (Fig. 6-9), easily ruptured, and weeping (Fig. 6-10), arising on normal skin, randomly scattered, discrete. Localized (e.g., to mouth or circumscribed skin area), or generalized with a random pattern. Extensive erosions bleed easily (Fig. 6-11), crusts particularly on scalp. Since blisters rupture so easily, only painful erosions in many patients (Fig. 6-11).

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Figure 6-9. Pemphigus vulgaris This is the classic initial lesion: flaccid, easily ruptured bulla on normal-appearing skin. Ruptured vesicles lead to erosions that subsequently crust as seen in the two smaller lesions.

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Figure 6-10. Pemphigus vulgaris Widespread confluent flaccid blisters on the lower back of a 40-year-old male who had a generalized eruption including scalp and mucous membranes. The eroded lesions are extremely painful.

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Figure 6-11. Pemphigus vulgaris Widespread confluent erosions that are very painful and bleed easily in a 53-year-old male. There are hardly any intact blisters because they are so fragile and break easily. The blood tracts go sideways because the patient had been lying on his right side before the photograph was taken.

Nikolsky Sign. Dislodging of normal-appearing epidermis by lateral finger pressure in the vicinity of lesions, which leads to an erosion. Pressure on bulla leads to lateral extension of blister.

Sites of Predilection. Scalp, face, chest, axillae, groin, umbilicus. In bedridden patients, there is extensive involvement of back (Fig. 6-11).

Mucous Membranes. Bullae rarely seen, erosions of mouth (see Section 35) and nose, pharynx and larynx, vagina.

Pemphigus Foliaceus has no mucosal lesions and starts with scaly, crusted lesions on an erythematous base, initially in seborrheic areas.

Skin Lesions. Most commonly on face, scalp, upper chest, and abdomen. Scaly, crusted erosions on an erythematous base (Fig. 6-12). In early or localized disease, sharply demarcated in seborrheic areas; may stay localized or progress to generalized disease and exfoliative erythroderma. Initial lesion also a flaccid bulla, but this is rarely seen because of superficial location (see dermatopathology below).

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Figure 6-12. Pemphigus foliaceus The back of this patient is covered by scaly crusts and superficial erosions.

Other Types (See Table 6-2)

Pemphigus Vegetans (PVeg). A PV variant. Usually confined to intertriginous regions, perioral area, neck, and scalp. Granulomatous vegetating purulent plaques that extend centrifugally. In these patients, there is a granulomatous response to the autoimmune damage of PV (Fig. 6-13).

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Figure 6-13. Pemphigus vegetans Papillomatous, cauliflower-like, oozing growths in the groin and pubis of a 50-year-old man.

Drug-Induced PV. Clinically identical to sporadic PV. Several different drugs implicated, most significantly, captopril and D-penicillamine.

Brazilian Pemphigus (Fogo Selvagem). A distinctive form of PF endemic to south central Brazil. Clinically, histologically, and immunopathologically identical to PF. Patients improve when moved to urban areas but relapse after returning to endemic regions. Probably related to an arthropod-borne infectious agent, with clustering similar to that of the black flysimulium nigrimanum. More than 1000 new cases per year are estimated to occur in the endemic regions.

Pemphigus Erythematosus (PE). Synonym: Senear-Usher syndrome. A localized variant of PF largely confined to seborrheic sites. Erythematous, crusted, and erosive lesions in the “butterfly” area of the face, forehead, and presternal and interscapular regions. May have antinuclear antibodies.

Drug-Induced Pemphigus PF. As in PV, associated with D-penicillamine and less frequently by captopril and other drugs. In most, but not all, instances, the eruption resolves after termination of therapy with the offending drug.

Neonatal Pemphigus. Very rare, transplacental transmission from diseased mother; spontaneous resolution.

Paraneoplastic Pemphigus

This is a disease sui generis and is discussed in Section 19.

Laboratory Examinations

Dermatopathology. PV: Light microscopy (select early small bulla or, if not present, margin of larger bulla or erosion): Separation of keratinocytes, suprabasally, leading to split just above the basal cell layer and vesicles containing separated, rounded-up (acantholytic) keratinocytes. PF: Superficial form with acantholysis in the granular layer of the epidermis.

Immunopathology. Direct immunofluorescence (IF) staining reveals IgG and often C3 deposited in lesional and paralesional skin in the intercellular substance of the epidermis. In PE Ig and complement deposits also found at the dermal epidermal junction.

Serum. Autoantibodies (IgG) detected by indirect IF or ELISA. Titer usually correlates with activity of disease. In PV, autoantibodies against a 130-kDa glycoprotein, desmoglein 3, located in desmosomes of keratinocytes. In PF, autoantibodies to a 160-kDa intercellular (cell surface) antigen, desmoglein 1, in desmosomes of keratinocytes.

Diagnosis and Differential Diagnosis

Difficult problem if only mouth lesions are present. Aphthae, mucosal lichen planus, erythema multiforme. Differential diagnosis includes all forms of acquired bullous diseases (see Table 6-3). Biopsy of the skin and mucous membrane, direct IF, and demonstration of circulating autoantibodies confirm a high index of suspicion.

TABLE 6-3 DIFFERENTIAL DIAGNOSIS OF IMPORTANT BULLOUS DISEASES

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Course

In most cases, the disease inexorably progresses to death unless treated aggressively with immunosuppressive agents. The mortality rate has been markedly reduced since treatment has become available. Currently, morbidity mainly related to glucocorticoids and immunosuppressive therapies.

Management

Requires expertise and experience. Treatment to be performed by dermatologist.

Glucocorticoids. 2-3 mg/kg body weight of prednisone until cessation of new blister formation and disappearance of Nikolsky sign. Then rapid reduction to about half the initial dose until patient is almost clear, followed by very slow tapering of dose to minimal effective maintenance dose.

Concomitant Immunosuppressive Therapy. Immunosuppressive agents are given concomitantly for their glucocorticoid-sparing effect:

Azathioprine, 2-3 mg/kg body weight until complete clearing; then tapered.

Methotrexate, either orally or IM at doses of 25-35 mg/wk. Dose adjustments are made as with azathioprine.

Cyclophosphamide, 100-200 mg daily, with reduction to maintenance doses of 50-100 mg/d. Alternatively, cyclophosphamide “bolus” therapy with 1000 mg IV once a week or every 2 weeks in the initial phases, followed by 50-100 mg/d po as maintenance.

Mycophenolate mofetil (1 g twice daily).

Plasmapheresis, in conjunction with glucocorticoids and immunosuppressive agents.

High-dose intravenous immunoglobulin (IVIG) (2 g/kg body weight every 3-4 weeks) has glucocorticoid-sparing effects.

Rituximab (monoclonal antibody to CD20) targets B cells, the precursors of (auto) antibody-producing plasma cells. Given as intravenous therapy once a week for 4 weeks shows dramatic effects in some and at least partial remission in other patients. Serious infections may be seen.

Other Measures. Cleansing baths, wet dressings, topical and intralesional glucocorticoids, antimicrobial therapy in documented bacterial infections. Correction of fluid and electrolyte imbalance.

Monitoring. Clinical, for improvement of skin lesions and development of drug-related side effects. Laboratory monitoring of pemphigus antibody titers and for hematologic and metabolic indicators of glucocorticoid- and/or immunosuppressive-induced adverse effects.

Bullous Pemphigoid (BP) ICD-9: 694.5 image ICD-10: L12.0 image

image A bullous autoimmune disease usually in elderly patients.

image Pruritic papular and/or urticarial lesions with large tense bullae.

image Subepidermal blisters with eosinophils.

image C3 and IgG at epidermal basement membrane, antibasement membrane IgG autoantibodies in serum.

image Autoantigens are keratinocyte hemidesmosome proteins.

image Therapy includes topical and systemic glucocorticoids and other immunosuppressives.

Epidemiology

Age of Onset. Sixty to eighty years.

Sex. Equal incidence in males and in females. No known racial predilection.

Incidence. The most common bullous autoimmune disease. Seven per million in Germany and France. Far more common in authors' experience in very old people.

Etiology and Pathogenesis

Interaction of autoantibody with BP antigen [BPAG1 (BP230) and BPAG2 (type XVII collagen)] in hemidesmosomes of basal keratinocytes (Fig. 6-1) is followed by complement and mast cell activation, attraction of neutrophils and eosinophils, and release of multiple bioactive molecules from inflammatory cells.

Clinical Manifestation

Often starts with a prodromal eruption (urticarial, papular lesions) and evolves in weeks to months to bullae that may appear suddenly as a generalized eruption. Initially moderate or severe pruritus; later, tenderness of eroded lesions. No constitutional symptoms, except in widespread, severe disease.

Skin Lesions. Erythematous, papular, or urticarial-type lesions (Fig. 6-14) may precede bullae formation by months. Bullae: small (Fig. 6-14) or large (Fig. 6-15) tense, firm-topped, oval or round; arise in normal, erythematous, or urticarial skin and contain serous (Fig. 6-15) or hemorrhagic fluid. Localized or generalized, usually scattered but also grouped in arciform and serpiginous patterns. Bullae rupture less easily than in pemphigus, but sometimes large, bright red, oozing, and bleeding erosions occur. Usually, however, bullae collapse and transform into crusts.

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Figure 6-14. Bullous pemphigoid Early lesions in a 75-year-old female. Note urticarial plaques and a small, tense blister with a clear serous content.

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Figure 6-15. Bullous pemphigoid This 77-year-old male has a generalized eruption with confluent urticarial plaques and multiple tense blisters. The condition is severely pruritic.

Sites of Predilection. Axillae; medial aspects of thighs, groins, abdomen; flexor aspects of forearms; lower legs (often first manifestation); generalized.

Mucous Membranes. Practically only in the mouth (10-35%); less severe and painful and less easily ruptured than in pemphigus.

Laboratory Examinations

Dermatopathology. Light Microscopy. Neutrophils in “Indian-file” alignment at dermal-epidermal junction; neutrophils, eosinophils, and lymphocytes in papillary dermis; subepidermal bulla.

Electron Microscopy. Junctional cleavage, i.e., split occurs in lamina lucida of basement membrane (see Fig. 6-1).

Immunopathology. Linear IgG deposits along the basement membrane zone. Also C3, which may occur in the absence of IgG.

Serum. Circulating antibasement membrane IgG antibodies detected by IIF in 70% of patients. Titers do not correlate with course of disease. Autoantibodies recognize two types of antigens. BPAG1 is a 230-kDa glycoprotein that has high homology with desmoplakin I and is part of hemidesmosomes. BPAG2 is a transmembranous 180-kDa polypeptide (type XVII collagen).

Hematology. Eosinophilia (not always).

Diagnosis and Differential Diagnosis

Clinical appearance, histopathology, and immunology permit a differentiation from other bullous diseases (see Table 6-3).

Management

Systemic prednisone with starting doses of 50-100 mg/d continued until clear, either alone or combined with azathioprine, 150 mg daily, for remission induction and 50-100 mg for maintenance; in refractory cases, IVIG; plasmapheresis. In milder cases, sulfones (dapsone), 100-150 mg/d. Low-dose methotrexate 2.5-10 mg weekly PO is effective and safe in elderly. In very mild cases and for local recurrences, topical glucocorticoid or topical tacrolimus therapy may be beneficial. Tetracycline ± nicotinamide has been reported to be effective in some cases.

Course and Prognosis

Patients often go into a permanent remission after therapy and do not require further therapy; local recurrences can sometimes be controlled with topical glucocorticoids. Some cases go into spontaneous remission without therapy.

Cicatricial Pemphigoid ICD-9: 694.6 image ICD-10: L12.1 image

image A rare disease, largely of the elderly.

image Ocular involvement may initially manifest as unilateral or bilateral conjunctivitis with burning, dryness, and foreign-body sensation.

image Blisters that rupture easily and also erosions resulting from epithelial fragility in the conjunctivae; mouth; oropharynx; and, more rarely, the nasopharyngeal, esophageal, genital, and rectal mucosae.

image Chronic involvement results in scarring, symblepharon (Fig. 6-16), and, in severe disease, fusion of the bulbar and palpebral conjunctiva. Entropion and trichiasis result in corneal irritation, superficial punctate keratinopathy, corneal neovascularization, ulceration, and blindness.

image Scarring also in the larynx; stricture formation in esophagus, dysphagia, or dynophagia.

image Blisters on skin in roughly 30% of patients.

image Brunsting-Perry pemphigoid describes a subset of patients whose skin lesions recur at the same sites, mainly on the head and neck and scalp, and also lead to scarring.

image Antigens to which autoantibodies may be directed include BPAG1, BPAG2, integrin subunits ß4 and a6, type VII collagen, and laminin 332.

image Management: mild involvement—topical corticosteroids, calcineurin inhibitors (tacrolimus, pimecrolimus). Moderate and severe involvement: dapsone in combination with prednisone. Some patients require more aggressive immunosuppressive treatment with cyclophosphamide or azathioprine, in combination with glucocorticoids, also high-dose IVIGs, rituximab. Surgical intervention for scarring and supportive measures.

image Synonym: Mucous membrane pemphigoid.

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Figure 6-16. Cicatricial pemphigoid This condition in a 78-year-old female started with bilateral conjunctival pain and foreign body sensation as the first symptoms. The conjunctiva then became erosive with scarring and fibrous tracts between eyelids and the eye.

Pemphigoid Gestationis (PG) ICD-9:646.8 image ICD-10: L12.8 image

image A rare pruritic and polymorphic inflammatory bullous dermatosis of pregnancy and the postpartum period.

image Estimated incidence from 1 in 1700 to 1 in 10,000 deliveries.

image Extremely pruritic eruption mainly on the abdomen but also on other areas, with sparing of the mucous membranes. Lesions vary from erythematous, edematous papules and urticarial plaques (Fig. 6-17A) to vesicles and tense bullae (Fig. 6-17B).

image Usually begins from the fourth to the seventh month of pregnancy, can also occur in the first trimester and in the immediate postpartum period. May recur in subsequent pregnancies; if it does, it is likely to begin earlier.

image PG can be exacerbated by the use of estrogen and progesterone-containing medications.

image Histopathologically it is a subepidermal blistering condition (see Fig. 6-1) with linear deposition of C3 along the basement membrane zone with concomitant IgG deposition in roughly 30% of patients.

image Serum contains IgG antibasal membrane antibodies, but these are detected in only 20% of patients by IIF. ELISA and immunoblotting assays detect autoantibodies in >70%, directed to BP180 (type XVII collagen) in hemidesmosomes. They are avid complement-fixing IgG1 antibodies that bind to amniotic epithelial basement membrane.

image Some 5% of babies born to mothers with PG have urticarial, vesicular, or bullous lesions, which resolve spontaneously during the first weeks. There is a slight increase in premature and small-for-gestational-age births. Some reports revealed significant fetal death and premature deliveries, whereas others have suggested no increase in fetal mortality.

image Management: Prednisone, 20-40 mg/d but sometimes higher doses required; tapered gradually during the postpartum period.

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Figure 6-17. Pemphigoid gestationis (A) Erythematous papules that were highly pruritic and had appeared on the trunk and abdomen of this 33-year-old pregnant female (third trimester). At this time, there were no blisters and diagnosis was established by biopsy and immunopathology. (B) Urticarial lesions and vesicles in another patient who had similar eruptions in previous pregnancies.

Dermatitis Herpetiformis (DH) ICD-9:694.0 image ICD-10: L13.0 image

image A chronic, recurrent, intensely pruritic eruption occurring symmetrically on the extremities and the trunk.

image Consists of tiny vesicles, papules, and urticarial plaques that are arranged in groups.

image Associated with gluten-sensitive enteropathy (GSE).

image Characterized histologically by papillary collection of neutrophils.

image Granular IgA deposits in paralesional or normal skin are diagnostic.

image Responds to sulfa drugs and, to a lesser extent, to a gluten-free diet.

Epidemiology

Prevalence in Caucasians varies from 10 to 39 per 100,000 persons.

Age of Onset. Most common at 30-40 years; may occur in children.

Sex. Male:female ratio is 2:1.

Etiology and Pathogenesis

The GSE probably relates to IgA deposits in the skin. Patients have antibodies to transglutaminases (Tgs) that may be the major autoantigens. Epidermal Tg autoantibody probably binds to Tg in the gut and circulates either alone or as immune complexes and deposits in the skin. IgA activates complement via the alternative pathway, with subsequent chemotaxis of neutrophils releasing their enzymes and producing tissue injury.

Clinical Manifestation

Pruritus, intense, episodic; burning or stinging of the skin; rarely, pruritus may be absent. Symptoms often precede the appearance of skin lesions by 8-12 h. Ingestion of iodides and overload of gluten are exacerbating factors.

Systems Review. Laboratory evidence of smallbowel malabsorption is detected in 10-20%. GSE occurs in nearly all patients and is demonstrated by small-bowel biopsy. There are usually no systemic symptoms.

Skin Lesions. Erythematous papules or wheallike plaques; tiny firm-topped vesicles, sometimes hemorrhagic (Fig. 6-18); occasionally bullae. Lesions are arranged in groups (hence the name herpertiformis). Scratching results in excoriations, crusts (Fig. 6-19). Postinflammatory hyper- and hypopigmentation at sites of healed lesions.

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Figure 6-18. Dermatitis herpetiformis These are the classic early lesions. Papules, urticarial plaques, small grouped vesicles, and crusts on the elbow of a 23-year-old male.

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Figure 6-19. Dermatitis herpetiformis A 56-year-old male patient with a generalized highly pruritic eruption. The diagnosis can be made upon first sight by the distribution of the lesions. Most heavily involved are the sacral and gluteal areas (note butterfly-like distribution) and (not seen in this picture) the knees, elbows; the scapular areas. Upon close inspection, there are grouped papules, small vesicles, crusts, and erosions on an erythematous base and there is postinflammatory hypo- and hyperpigmentation.

Sites of Predilection. Typical and almost diagnostic: extensor areas—elbows (Fig. 6-18), knees. Strikingly symmetrical. Buttocks, scapular, and sacral areas (Figs. 6-19 and 6-20). Here, often in a “butterfly” fashion. Scalp, face, and hairline.

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Figure 6-20. Dermatitis herpetiformis Pattern of distribution.

Laboratory Examinations

Immunogenetics. Association with HLA-B8, HLA-DR, and HLA-DQ.

Dermatopathology. Biopsy is best from early erythematous papule. Microabscesses (polymorphonuclear cells and eosinophils) at the tips of the dermal papillae. Dermal infiltration of neutrophils and eosinophils. Subepidermal vesicle.

Immunofluorescence. Of perilesional skin, best on the buttocks. Granular IgA deposits in tips of papillae. Diagnostic. Also found are C3 and C5 and alternative complement pathway components.

Circulating Autoantibodies. Antireticulin antibodies of the IgA and IgG types, thyroid antimicrosomal antibodies, and antinuclear antibodies can be present. Putative immune complexes in 20-40% of patients. IgA antibodies binding to the intermyofibril substance of smooth muscles (antiendomysial antibodies) are present in most patients and have specificity for Tgs.

Other Studies. Steatorrhea (20-30%) and abnormal D-xylose absorption (10-73%). Anemia secondary to iron or folate deficiency. Endoscopy of small bowel: blunting and flattening of the villi (80-90%) in the small bowel as in celiac disease. Lesions are focal; verification is by small-bowel biopsy.

Diagnosis and Differential Diagnosis

Grouped papulovesicles at predilection sites accompanied by severe pruritus are highly suggestive. Biopsy usually diagnostic, but IgA deposits in perilesional skin detected by IF are the best confirming evidence. Differential diagnosis is to allergic contact dermatitis, atopic dermatitis, scabies, neurotic excoriations, papular urticaria, and bullous autoimmune disease (see Table 6-3).

Course

Prolonged, for many years, with a third of the patients eventually having a spontaneous remission.

Management

Systemic Therapy. Dapsone. 100-150 mg daily, with gradual reduction to as low as 50 mg twice a week. Dramatic response, often within hours. Obtain a glucose-6-phosphate dehydrogenase level before starting sulfones; obtain methemoglobin levels in the initial 2 weeks, and follow blood counts carefully.

Sulfapyridine. 1-1.5 g/d, with plenty of fluids, if dapsone contraindicated or not tolerated. Monitor for casts in urine and kidney function.

Diet. A gluten-free diet may suppress the disease or allow reduction in the dosage of dapsone or sulfapyridine, but response is very slow.

Linear IgA Dermatosis (LAD) ICD-9: 702.8 image

image A rare, immune-mediated, subepidermal blistering skin disease defined by the presence of homogeneous linear deposits of IgA at the cutaneous basement membrane zone (Fig. 6-1).

image No association with GSE.

image LAD most often occurs after puberty.

image Clinically similar to DH, but there is more blistering. Patients present with annular or grouped papules, vesicles, and bullae (Fig. 6-21), distributed symmetrically on trunk and extremities. Very pruritic but less severe than DH.

image Mucosal involvement ranges from asymptomatic oral erosions and ulceration to severe oral disease alone, or severe generalized cutaneous involvement and oral disease similar to that in cicatricial pemphigoid.

image It is identical with chronic bullous disease of childhood (CBDC), which is a rare blistering disease that occurs predominantly in children <5 years (Fig. 6-22).

image Circulating autoantibodies against various epidermal basement membrane antigens.

image LAD has been associated with drugs: vancomycin, lithium, phenytoin, sulfamethoxazole/trimethoprim, furosemide, captopril, diclofenac, and others.

image There is a small risk of lymphoid malignancies, and associated ulcerative colitis has been reported.

image Management: Patients respond to dapsone or sulfapyridine but in addition, most may require low-dose prednisone. Patients do not respond to a gluten-free diet.

Image

Figure 6-21. Linear IgA dermatosis There are multiple grouped, confluent vesicles, bullae, and crusts on an urticarial and erythematous base. There were similar lesions on the trunk and the upper extremities.

Image

Figure 6-22. Linear IgA dermatosis (chronic, bullous disease of childhood) Extensive blistering on the upper extremities and trunk in a 7-year-old child. Note: blisters are both tense and flaccid. They are grouped and there is no notable inflammation.

Epidermolysis Bullosa Acquisita (EBA) ICD-9: 694.8 image ICD-10:L12.3 image

image A chronic subepidermal bullous disease associated with autoimmunity to the type VII collagen within the anchoring fibrils in the basement membrane zone (see Fig. 6-1).

image Four types: the classic mechanobullous presentation is a noninflammatory, blistering eruption with acral distribution that heals with scarring and milia formation. It is a mechanobullous disease marked by skin fragility. Scars in traumatized regions such as the dorsa of the hands, knuckles, elbows, knees, sacral area, and toes. Resembling porphyria cutanea tarda (see Section 10) or hereditary epidermolysis bullosa.

image Bullous pemphigoid-like presentation: widespread inflammatory vesiculobullous eruption associated with erythematous or urticarial skin lesions involving the trunk, skin folds in addition to the extremities (Fig. 6-23).

image Cicatricial pemphigoid-like presentation has prominent mucosal involvement—erosions and scarring in the mouth, esophagus, conjunctiva, anus, and vagina.

image The IgA bullous dermatosis-like presentation shows vesicles arranged in an annular fashion, reminiscent of linear IgA bullous dermatosis, DH, or CBDC.

image Histopathology: subepidermal blisters.

image Immunopathology: linear IgG (plus IgA, gM, factor B, and properdin) at the dermal-epidermal junction.

image Antibodies in sera bind to a 290-kDa band in Western blots containing type VII collagen. ELISA specific for antibodies to type VII collagen.

image Treatment difficult. In the mechanobullous form, patients are refractory to high doses of systemic glucocorticoids, azathioprine, methotrexate, and cyclophosphamide, which are somewhat helpful in the inflammatory BP-like form of the disease. Some EBA patients improve on dapsone and high doses of colchicine. Supportive therapy.

Image

Figure 6-23. Epidermolysis bullosa acquisita This is the bullous pemphigoid-like presentation with tense bullae, erosions, and crusts on an erythematous base. There is also postinflammatory pigmentation due to previous blistering.