Section Q: Bullous Disease

PATIENT STORY

A 100-year-old black woman with diabetes was brought to the office by her family concerned about the large blister on her leg that started earlier that day (Figure 191-1). This large bulla appeared spontaneously without trauma, and there was no surrounding erythema. The bulla contained clear fluid, and there were no signs of infection. The bulla was drained with a sterile needle and no further bullae developed. The diagnosis is bullosis diabeticorum, a benign self-limited condition.

INTRODUCTION

Bullae are fluid-filled lesions on the skin that are larger than 10 mm in diameter. Bullous diseases are defined by the presence of bullae and vesicles (less than 10 mm in diameter). Bullous diseases are caused by many factors, including infections, bites, drug reactions, inflammatory conditions, and genetic and autoimmune diseases.

APPROACH TO THE DIAGNOSIS

The approach to a patient with a blistering disorder begins with a complete history and physical examination. To make the final diagnosis, laboratory investigations or tissue biopsies may be needed.

DIAGNOSIS

HISTORY

• How did the eruption present?

• Has it changed in morphology or location?

• Has it responded to any therapies?

• Are there any associated symptoms or aggravating factors?

• How has it impacted the patient's life?

• Does the patient have any chronic medical conditions?

• Does the patient take any medications?

• Does the patient have any significant family history?

PHYSICAL EXAMINATION

• Note the location of the eruption.

• Are the bullae flaccid or tense (Figure 191-2)?

• Are there other lesions present (erosions, excoriations, papules, wheals)?

• Is Nikolsky sign positive or negative? (Does the skin shear off when lateral pressure is applied to unblistered skin?)

• Is Asboe-Hansen sign positive or negative (Figure 191-3)? (Do the bullae extend to surrounding skin when vertical pressure is applied?) Sometimes the Asboe-Hansen sign is also attributed to Nikolsky and called a Nikolsky sign, too.

• Is the Darier sign positive or negative? (Do wheals form with rubbing of the skin?)

• Note the skin background (sun-exposed skin, postinflammatory hyperpigmentation, lichenification, and scarring).

• Does the patient have lymphadenopathy or hepatosplenomegaly?

CLINICAL FEATURES

• Autoimmune:

  • In bullous pemphigoid, patients have large, tense bullae that primarily involve the trunk, groin, axilla, proximal extremities, and flexor surfaces (see Figures 191-2A and 191-3; Chapter 192, Bullous Pemphigoid).¹

  • Pemphigus vulgaris is characterized by erosions and flaccid bullae that frequently involve the mouth (Figure 191-4; Chapter 193, Pemphigus). In fact, mucosal membrane involvement may be the initial presentation. If the skin is involved, then Nikolsky and Asboe-Hansen signs are positive.¹

  • Pemphigus foliaceus presents with cutaneous erosions and never involves the mucosal membranes (see Figure 191-2B; Chapter 193, Pemphigus). Nikolsky and Asboe-Hansen signs are positive.¹

  • Pemphigoid gestationis is a condition during pregnancy or during the postpartum period that can have a bullous component. The patient usually presents with urticarial papules and plaques with bullae developing around the umbilicus and extremities. The eruption eventually generalizes and involves the palms and soles. There usually is sparing of the face, scalp, and oral mucosa (Figure 191-5).¹

  • Cicatricial pemphigoid involves the oral mucosa in 90% of cases and the conjunctiva in 66% of cases (Figures 192-3 to 192-5 in Chapter 192, Bullous Pemphigoid). Patients frequently present with a desquamative gingivitis. Cutaneous lesions are seen in 25% of patients.¹

  • Epidermolysis bullosa acquisita presents with trauma-induced blistering and erosions usually on the distal extremities (Figure 191-6). The patient should have background scarring, milia, and nail dystrophy. This usually affects elderly persons.

  • Epidermolysis bullosa simplex also has trauma-induced blistering that can involve the trunk and extremities. This is the most common form of epidermolysis bullosa and usually starts at birth or early childhood. The bullae are intraepidermal (Figure 191-7).

  • Dermatitis herpetiformis classically is a symmetrical, pruritic eruption that involves the extensor surfaces, scalp, and buttocks. The patient presents with pruritic vesicles and crusted papules with overlying excoriations (see Figures 194-11 and 194-12 in Chapter 194, Other Bullous Diseases).¹

  • Linear immunoglobulin (Ig): A bullous dermatosis may produce a ringlike pattern of distribution and can occur in childhood (Figure 191-8). Patients may have mucous membrane involvement in up to 50% of cases.¹

• Traumatic/physical stress:

  • Friction blisters form at sites of pressure and friction, frequently on the distal lower extremities.¹

  • Bullosis diabeticorum is trauma-induced, painless blistering, frequently in an acral distribution, in individuals with diabetes mellitus (Figure 191-9).¹

  • Postburn blistering occurs in the hours after the insult, such as is seen in severe second-degree sunburns.¹ Blistering after cold injury can also occur rapidly (Figure 191-10).

  • Miliaria is caused by keratinous obstruction of the eccrine ducts in response to heat. Small superficial vesicles may involve the face, trunk, or extremities.¹

• Metabolic:

  • Porphyria cutanea tarda (PCT) involves sun-exposed skin, particularly the dorsal hands, forearms, ears, and face. The patient will have associated milia, scarring, and background dyspigmentation. PCT has been associated with hepatitis C infection (see Figure 191-11).¹

• Immunologic:

  • Pityriasis lichenoides et varioliformis acuta (PLEVA) usually presents as a papulonecrotic eruption but may have vesicles resembling varicella (see Figure 191-12). It usually involves the anterior trunk, flexor surfaces of the upper extremities, and the axilla. It is seen more frequently in young men and can go on to become chronic.

  • Allergic-contact and irritant-contact dermatitis, if severe, can cause blistering. Special attention should be given to the location and pattern of involvement. For example, linear vesicles and bullae would suggest a plant-induced dermatitis such as poison ivy, poison oak, or poison sumac (Figure 191-13). Blistering in the periumbilical area is consistent with nickel dermatitis from a belt buckle or pants snap. Involvement of the dorsal feet is frequently seen with footwear dermatitis due to chemicals in the leather (Chapter 152, Contact Dermatitis).²

• Drug:

  • Bullous drug eruptions may be localized to 2 mucosal surfaces with minimal cutaneous involvement or may be generalized, involving all mucosal surfaces and a majority of the skin surface area. Nikolsky and Asboe-Hansen signs are positive on affected skin. Even fixed-drug eruptions can be bullous (Figure 191-14).

• Infections and bites:

  • Bullous arthropod reaction can occur after an insect bite (Figure 191-15).¹

  • Bacterial infections should be considered when evaluating a localized blistering eruption. Amongst these infections is bullous impetigo (Figure 191-16). When evaluating the extremities, vesiculation overlying cellulitis may be associated with the more severe staphylococcal and streptococcal infections, and a thorough evaluation should be conducted to rule out necrotizing fasciitis. As with most bacterial infections, the patient typically presents with fever and has an elevated white blood cell count.²

  • Herpes simplex viruses should always be considered when blistering of the mucosal surfaces is observed. Generalized blistering in the adult could be from disseminated herpes and should prompt an evaluation for immunosuppression. Blistering in a dermatomal distribution is characteristic of herpes zoster (Figures 191-17 and 191-18).²

  • Scabies, tinea, and Candida can also have bullous or pustular presentations in the classic sites of involvement.²

• Hydrostatic.

  • Edema blisters form from the osmotic pressure experienced during the third-spacing of fluid. As such, patients usually have a diagnosis of heart failure, cirrhosis, or kidney failure.¹

• Childhood.

  • Transient neonatal pustular melanosis (TNPM) involves pustules or vesicles without associated erythema located in clusters on the forehead, posterior ears, chin, neck, upper chest, back, buttocks, abdomen, and thighs, which spontaneously heal and leave behind pigmented macules. TNPM affects up to 4% of term infants and is more commonly seen in the African-American population (Chapter 116, Pustular Diseases of Childhood).³

  • Acropustulosis of infancy develops during the first few weeks to months of life and spontaneously remits at 2 to 3 years of age. In this condition, crops of vesicles and pustules involve palms and soles, causing pruritus (Chapter 116, Pustular Diseases of Childhood).³

  • Neonatal pemphigus occurs in neonates whose mothers have active pemphigus vulgaris. The patient is born with bullae that spontaneously resolve within 1 to 2 weeks.³

  • Epidermolysis bullosa simplex is a hereditary condition in which minimal friction or trauma causes vesicles, bullae, and erosions. The distal extremities are frequently involved.⁴

  • Congenital infections with herpes simplex virus usually present with vesicles. In addition, a vesicular eruption in the neonate could be caused by neonatal syphilis, which is the only form of syphilis with a vesicular presentation.²

  • Bullous mastocytosis is caused by mast cell accumulation in the skin. The bullous presentation is less common but may involve any area of the body (Figure 191-19). On examination, the Darier sign should be positive and dermatographism should be present. Work-up should be conducted to determine the presence of systemic involvement, which may include a mast cell leukemia. A good lymph node and abdominal examination is recommended to evaluate for lymphadenopathy and hepatosplenomegaly.³

LABORATORY STUDIES AND WORK-UP

If the clinical picture is not clear, various laboratory studies may assist the clinician in making the diagnosis. Some diagnoses should be confirmed by histology even if the diagnosis appears clear. For example, all cases of suspected pemphigus should be biopsied because the management will involve long-term use of potentially toxic medications and it is crucial to know the exact diagnosis. The information in Chapters 192, Bullous Pemphigoid, and 193, Pemphigus, will help one to decide which tests to use in some of the autoimmune blistering diseases. Consulting a dermatologist is very appropriate for many of the more rare and lethal conditions.

• Herpes simplex or varicella zoster virus testing can be done rapidly by polymerase chain reaction (PCR).

• Dermoscopy to see the scabies mites and burrows (Chapter 149, Scabies).

• KOH scraping for possible blistering tinea infections (such as bullous tinea pedis).

• Genetic studies for suspected genetic defects; consider referral to geneticist.

BIOPSY

• Four-millimeter punch biopsy for pathologic evaluation—Biopsy an established lesion including the edge of the blister. A shave biopsy is an alternative as long as the epidermis of the blister stays attached to the specimen.

• Biopsy for direct immunofluorescence (DIF)—Biopsy the perilesional skin and send the specimen in special Michel media or sterile saline and let the lab know to transfer it to Michel media when it arrives. The easiest way to do this is to take a shave biopsy that includes the bulla and the perilesional skin. Then cut the specimen in half and send the perilesional skin for DIF and the blister for standard pathology.

• Consider sending part of the biopsy for bacterial, fungal, and viral cultures and stains if infections are suspected and cultures and other less-invasive studies are not providing the diagnosis. Send the specimens in a sterile urine cup on top of a sterile gauze pad soaked with sterile saline.

FURTHER EVALUATIONS

Patients with cicatricial pemphigoid and toxic epidermal necrolysis need an ophthalmologic evaluation. Patients with several of the epidermolysis bullosa diseases and dermatitis herpetiformis need a gastroenterologic evaluation.

For possible paraneoplastic conditions, such as in epidermolysis bullosa acquisita and cicatricial pemphigoid, thorough cancer screening and studies targeting the patient's symptomatology are indicated.

REFERENCES

PATIENT STORY

A native of Panama was seen for extensive bullous disease that had a classic presentation for bullous pemphigoid (BP) (Figure 192-1). The classic presentation of BP is described as tense blisters that have an erythematous or urticarial base and are often pruritic. The presence of numerous intact bullae seen in this patient made pemphigus vulgaris very unlikely, as pemphigus has flaccid bullae. The Panama patient was treated with a systemic glucocorticoid (prednisone) and responded quickly. The patient eventually had a good outcome with the oral prednisone.

INTRODUCTION

BP is a chronic autoimmune blistering disease, more commonly of older adults, that may cause significant morbidity and poor quality of life. The term pemphigoid refers to its similarity to the blisters seen in pemphigus. However, BP is usually less severe than pemphigus vulgaris and is not considered a life-threatening condition.

EPIDEMIOLOGY

• BP is the most frequent autoimmune blistering disease of the skin and mucosa.

• It typically affects persons older than 65 years of age but can occur at any age.

• There is no racial or gender predilection (a recent British population study, however, suggested an increased prevalence in women).¹

• Its incidence may be on the rise.¹

• Although it is not considered life threatening, it has been associated with an increased risk of mortality (hazard ratio [HR] 2.3, 95% confidence interval [CI] 2 to 2.7).¹

ETIOLOGY AND PATHOPHYSIOLOGY

• BP is a chronic autoimmune disorder of the skin.

• Immunoglobulin (Ig) G antibodies against BP180 antigen of the basement membrane protein are considered pathognomonic and can be found in up to 65% of patients.²

• Anti-BP230 antibodies are present in virtually all patients but are not considered pathognomonic.³

• Binding of antibodies to the basement membrane activates the complement system, leading to chemotaxis of inflammatory cells such as eosinophils and mast cells, which release proteases. The subsequent degradation of hemidesmosomal proteins leads to blister formation.

• There are several morphologically distinct clinical presentations:

  • Generalized bullous form is the most common (see Figure 192-1). Tense bullae occur on both erythematous and normal-appearing skin surfaces. The bullae usually heal without scarring.

  • Localized form of BP is less common and is limited to a small area of involvement (Figure 192-2).

  • Vesicular (also known as "eczematous") form is characterized by clusters of small tense blisters with an urticarial or erythematous base.

  • Other forms are less common and include vegetative (intertriginous vegetating plaques), urticarial (without any bullae), nodular (resembling prurigo nodularis), acral (bullae on palms, soles, and face in children associated with vaccination), and generalized erythroderma (exfoliative lesions with or without vesicles/bullae).

• Pemphigoid gestationis is a variant of BP that occurs during or after pregnancy. Lesions resolve after delivery but may recur with subsequent pregnancies, or in the nonpregnant state (Chapter 78, Pemphigoid Gestationis).⁴

• Drug-induced BP has been reported with drugs containing sulfhydryl groups, including penicillamine, furosemide, captopril, and sulfasalazine.

DIAGNOSIS

CLINICAL FEATURES

• Tense blisters that involve normal or inflamed skin or mucous membranes (see Figures 192-1 and 192-2).

• Development of bullae is typically preceded by a prodromal phase characterized by intense pruritus with or without excoriations and eczematous (or urticarial) lesions. This phase can last for months, making early diagnosis difficult.⁵

• Nikolsky sign, which is the wrinkling and sheetlike peeling of the skin when lateral pressure is applied to unblistered skin, is usually negative.⁶

• Asboe-Hansen sign, also termed indirect Nikolsky sign or Nikolsky II sign, will be negative as well. This sign describes bullae extending to surrounding skin when vertical pressure is applied (see Figure 192-2B).

TYPICAL DISTRIBUTION

• Flexural surfaces of the arms and legs.

• Lower abdomen and groin.

• Mucous membranes are involved in 10% to 25% of cases.

BIOPSY

Biopsy is required for establishing diagnosis and to differentiate BP from other conditions that can have a similar clinical presentation:

• A scoop shave or 4-mm punch biopsy from the edge of an early blister, including part of the normal-appearing skin for hematoxylin and eosin (H&E) staining, shows a subepidermal blister and an eosinophil-rich mixed dermal inflammatory infiltrate. If the scoop shave contains sufficient perilesional skin, cut this off and send it for direct immunofluorescence (DIF). DIF is considered the gold standard in the diagnosis of BP.

• The skin collected from around the lesion should be transported in Michel or Zeus medium for DIF. If these media are not available, send the specimen for DIF in sterile saline–soaked gauze and alert the laboratory to transfer the specimen into Michel medium as soon as possible. DIF demonstrates linear IgG and/or complement C3 deposits at the dermal–epidermal junction.

• Alternatively, an enzyme-linked immunosorbent assay (ELISA) blood test for BP180 antibodies can be performed for characterization of circulating antibodies.⁷ If the ELISA blood test is negative for BP180 antibodies, then it can be performed for BP230 antibodies.

DIFFERENTIAL DIAGNOSIS

• Cicatricial pemphigoid (Figures 192-3, 192-4, 192-5)—Predominant mucosal involvement; lesions heal with prominent scarring; IgG localizes to blister floor on IDIF.

• Dermatitis herpetiformis—Grouped vesicles; extensor distribution (Chapter 194, Other Bullous Diseases).

• Epidermolysis bullosa acquisita—IgG localizes to blister floor on IDIF (Chapter 194, Other Bullous Diseases).

• Erythema multiforme—Targetoid lesions; associated with infections such as Mycoplasma pneumoniae and herpes simplex virus (HSV), drugs such as sulfa drugs and phenytoin, cancer, or autoimmune disease; linear IgG immunofluorescence is negative (Chapter 185, Erythema Multiforme, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis).

• Linear IgA dermatosis—Usually drug-induced (e.g., vancomycin⁸); DIF demonstrates IgA deposits. Also called chronic bullous dermatosis of childhood (Chapter 191, Overview of Bullous Disease, including Figure 192-4).

MANAGEMENT

The objectives of therapy in BP are to decrease troublesome symptoms, resolve active lesions, and prevent recurrences associated with the blistering lesions.

FIRST LINE

High-potency topical corticosteroids are considered first-line treatment for moderate to severe generalized disease (e.g., clobetasol).⁹ SORⒶ Initial disease control and 1-year survival rates in extensive BP are better with the topical approach when compared with oral prednisolone.¹⁰

Oral corticosteroids.⁹ SORⒶ

• Prednisone 0.5 to 0.75 mg/kg per day.¹¹

• Increase dose until new blisters cease to develop.

• Reduce dose approximately 10% every 2 to 3 weeks to reach dose of 15 to 20 mg/day.

Adjuvant antibiotic treatment should be considered for all patients:

• Tetracycline (1.5 to 2 g/day) with or without niacinamide (1.5 to 2 g/day).¹² SORⒷ Both tetracycline and niacinamide come in 500-mg capsules and may be taken 3 to 4 times daily. Niacinamide contains niacin (vitamin B₃) and is available over the counter. Doxycycline 100 mg twice daily is an alternative.

SECOND LINE

Steroid-sparing drugs and adjuvant therapy for patients whose disease is not controlled with steroids and doxycycline. Before starting any of the following systemic medications, be aware of the laboratory tests needed to initiate and continue such therapy:

• Dapsone is an antineutrophilic antibiotic that is an alternative to tetracycline and doxycycline (Figure 192-6).⁹ SORⒷ

• Azathioprine 50 to 200 mg divided bid or tid (first-line adjuvant).⁹ SORⒷ

• Mycophenolate mofetil 0.5 to 2 g/day divided bid or tid (less hepatotoxic than azathioprine).¹³ SORⒸ

Disease resistant to combination of corticosteroids and steroid-sparing agents:

• Intravenous immunoglobulin (IVIG) can produce a rapid and dramatic but very transient response; requires multiple cycles of IVIG. SORⒸ

• Plasmapheresis can be considered for patients with severe resistant disease requiring high doses of systemic steroids to improve symptoms and reduce steroid dose.¹⁴ SORⒸ

• Case reports and small series of successful therapy of refractory BP with rituximab,¹⁵ etanercept,^16,17 or omalizumab¹⁸ have been published in the recent medical literature.

  • Rituximab has proved to offer promising results for recalcitrant bullous pemphigoid. In a retrospective study, the combination of rituximab and IVIG resulted in sustained remission for 83% of patients in the study with no side effects or complications.¹⁹ SORⒷ

  • Etanercept has proven beneficial in patients with psoriasis coinciding with BP. Etanercept is a tumor necrosis factor (TNF) antagonist and can help to control symptoms of both BP and psoriasis which are mediated by TNF.¹⁷ SORⒷ

  • Omalizumab has also been used as a treatment for select patients with BP. The exact mechanism for resolution of BP symptoms with omalizumab is not completely understood. One theory includes decreased numbers of IgE, eosinophils, and mast cells; another theory involves eosinophil apoptosis and decreased circulating cytokines.²⁰ SORⒷ

REFER

• Dermatology consultation for recommending therapy based on extent of disease and for changes in therapy when required. When second-line therapies are needed, referral to a dermatologist is especially important.

• Nutrition consultation if patient is having difficulty maintaining weight.

FOLLOW-UP

• Ask patient about recurrent lesions, pruritus, and side effects from treatment.

• Perform periodic skin examinations looking for new lesions to adjust dose of prednisone and to monitor for lymphadenopathy and skin cancer in patients using immunosuppressive medications.

• Monitor for drug-specific laboratory abnormalities (e.g., glucose and triglycerides with steroid use; complete blood count [CBC], renal function, and liver function tests for azathioprine and other immunosuppressive medications).

• Make sure patients do not run out of their medications, because this can result in recurrent lesions (Figure 192-7).

• Adjust treatment if patient relapses by increasing steroid dose or adding an immunosuppressive agent.

• Taper steroids slowly after dissipation of disease flare.

PATIENT EDUCATION

• Avoid mechanical irritation, direct sun exposure, dental prostheses, extremes of temperature.

• Recommend high-protein, low-carbohydrate, and low-fat diet; calcium and vitamin D supplementation for patients on corticosteroids.

• Provide information on wound care, stress reduction, appropriate exercise, and side effects of medications.

REFERENCES

PATIENT STORY

A young man presented with painful blisters on his face and mouth (Figure 193-1). The patient was referred to dermatology. Suspecting pemphigus vulgaris (PV), the physician performed shave biopsies for histopathology and direct immunofluorescence of facial vesicles/bullae to confirm the presumed diagnosis. The patient was started on 60 mg of prednisone daily until the pathology confirmed PV. Steroid-sparing therapy was then discussed and started 2 weeks after initial presentation.

INTRODUCTION

Pemphigus is a rare group of autoimmune bullous diseases of the skin and mucous membranes characterized by flaccid bullae and erosions. The word pemphigus is derived from the Greek word pemphix, which means bubble or blister. The three main types of pemphigus are PV, pemphigus foliaceus (PF), and paraneoplastic pemphigus (PNP). Pemphigus causes significant morbidity and mortality and can be fatal if left untreated. Although pemphigus is not curable, it can be controlled with systemic steroids and immunosuppressive medications. These medications can be lifesaving, but they also place pemphigus patients at risk for a number of complications.

EPIDEMIOLOGY

Epidemiology of the three major types of pemphigus:

• PV (Figures 193-1, 193-2, 193-3, 193-4).

  • Most common form of pemphigus in the United States.

  • Annual incidence is 0.75 to 5 cases per 1 million.¹

  • Usually occurs between 30 and 50 years of age.²

  • Increased incidence in people of Ashkenazi Jewish and Mediterranean origin.²

  • Pemphigus vegetans is an even rarer vegetative variant form of PV (Figures 193-5 and 193-6).

• Pemphigus foliaceus (Figures 193-7, 193-8, 193-9, 193-10)—Superficial form of pemphigus.

  • More prevalent in Africa (Figures 193-11 and 193-12).¹

  • Variant forms include pemphigus erythematosus (resembles the malar rash of lupus erythematosus) and fogo selvagem.

  • Fogo selvagem is an endemic form of PF seen in Brazil and affects teenagers and individuals in their twenties.¹

• Paraneoplastic pemphigus.

  • Onset at age 60 years and older.

  • Associated with occult neoplasms, commonly lymphoreticular, (e.g., non-Hodgkin lymphoma and chronic lymphocytic leukemia).

  • Can also be associated with benign neoplasms, such as thymoma and Castleman disease (angiofollicular lymph node hyperplasia).²

ETIOLOGY AND PATHOPHYSIOLOGY

• The basic abnormality in all three types of pemphigus is acantholysis—a process in which keratinocytes separate from one another. This occurs as a result of autoantibody formation against desmoglein (the adhesive molecule that holds epidermal cells together). Separation of epidermal cells leads to formation of intraepidermal clefts, which enlarge to form bullae.¹

• The mechanism that induces the production of these autoantibodies in most individuals is unknown. Yet PF may be triggered by drugs, most commonly thiol compounds such as penicillamine, captopril, piroxicam, and others like penicillin and imiquimod.³ An environmental trigger in the presence of susceptible human leukocyte antigen (HLA) gene is suggested to induce autoantibodies in fogo selvagum.¹

• The autoantibodies in pemphigus are usually directed against desmoglein 1 and 3 (Dsg1 and Dsg3). Dsg1 is present predominantly in the superficial layers of the epidermis, whereas Dsg3 is expressed in deeper epidermal layers and in mucous membranes. As a result, clinical presentation depends on the antibody profile. In PV, a limited mucosal disease occurs when only anti-Dsg3 antibody is present, but extensive mucosal and cutaneous disease occurs when both anti-Dsg1 and anti-Dsg3 antibodies are present. In PF, mucosal lesions are absent, and the cutaneous lesions are superficial because of isolated anti-Dsg1 antibody.

• Like PV, PNP demonstrate antibodies against desmogleins 1 and 3 but also against all the members of the plakin family. These autoantibodies form a reliable marker for this type of pemphigus.

DIAGNOSIS

CLINICAL FEATURES

• Pemphigus vulgaris (see Figures 193-1, 193-2, 193-3, 193-4)—Classical lesions are flaccid bullae that rupture easily, creating erosions. Because bullae are short-lived, erosions are the more common presenting physical finding (Figure 193-13). Lesions are typically tender and heal with postinflammatory hyperpigmentation that resolves without scarring. A positive Asboe-Hansen or Nikolsky sign may be present, but neither of these signs is diagnostic. A positive Asboe-Hansen sign occurs when a bulla extends to surrounding skin while pressure is applied directly to the bulla. The Nikolsky sign is positive when skin shears off while lateral pressure is applied to unblistered skin during active disease.

• Pemphigus vegetans—A variant of PV commonly affecting intertriginous areas, where flaccid pustules and erosions heal with vegetating proliferation of the epidermis (see Figures 193-5 and 193-6).

• Pemphigus foliaceus—Characterized by the presence of multiple red, pruritic erosions with scale and crust described like "cornflakes." Intact blisters are rare as the disease is superficial, and mucosa is not involved. Lesions are distributed in seborrheic pattern (face, scalp, upper trunk) (see Figures 193-7, 193-8, 193-9, 193-10, 193-11, 193-12).

• PNP (Figure 193-14)—Typically presents with severe and painful oral erosions. Skin lesions can be similar to PV, although lichen planus, morbilliform, or erythema multiforme–like lesions may also be seen in addition to blisters and erosions. Another distinctive feature is the presence of epithelial necrosis and lichenoid changes in the lesions as well as extensive and painful mucosal involvement. Pulmonary involvement secondary to acantholysis of bronchial mucosa is seen in 30% to 40% of cases of PNP.

TYPICAL DISTRIBUTION

• PV—Common mucosal site is oral mucosa, although any stratified squamous epithelium may be involved. Skin lesions may follow mucosal lesions weeks to months after presentation of mucosal lesions. The skin lesions usually manifest on the scalp, face, and upper torso. PV should be suspected if an oral ulcer persists beyond one month (Figures 193-1, 193-3, and 193-15).

• Pemphigus vegetans—Usually seen in intertriginous areas such as the axilla, groin, and genital region (see Figures 193-5 and 193-6).

• PF—Initially affects face and scalp, though it may progress to involve the chest and back (see Figures 193-7, 193-8, 193-9, 193-10, 193-11, 193-12). When the facial involvement in PF is in a lupus-like pattern, this is called pemphigus erythematosus (Figure 193-16).

• PNP—Common sites include oral mucosa and conjunctiva (see Figure 193-14). Columnar and transitional epithelia may also be involved in addition to stratified squamous epithelium.

LABORATORY STUDIES

• Circulating desmoglein antibody levels may be measured in the blood using indirect immunofluorescence. This is usually not necessary unless the diagnosis is suspected and further data is needed.

• A complete blood count and a comprehensive metabolic profile—including liver function tests, creatinine, and glucose—need to be provided with their baseline levels because systemic therapies have significant toxicities.

• Patients at risk for steroid-induced osteoporosis should have a dual-energy X-ray absorptiometry (DEXA) scan performed.

BIOPSY

• Skin biopsy is essential for accurate diagnosis. The depth of acantholysis and the site of deposition of antibody complexes help differentiate pemphigus from other bullous diseases. Two specimens should be sent. Perform a shave of the edge of the bulla to include the surrounding normal-appearing epidermis. This biopsy should be of the freshest lesion with an intact bulla, if possible. Cut the specimen in half, and send the portion with the bulla in formalin for routine histopathology. The second half should be perilesional adjacent normal skin. This is sent on a gauze pad soaked in normal saline or Michel solution for direct immunofluorescence (DIF). Routine histopathology demonstrates suprabasal acantholysis, and DIF shows antibody deposition in the intercellular spaces of the epidermis. The pattern of the DIF fluorescence is described as chicken wire (Figure 193-17).

DIFFERENTIAL DIAGNOSIS

• Bullous pemphigus—Bullae are tense because they occur in the deeper subepidermal layer. Mucous membrane involvement is rare. Biopsy illustrates subepidermal acantholysis and immunoglobulin deposition along the basement membrane (Chapter 192, Bullous Pemphigoid).³

• Cicatricial pemphigoid—Also known as mucous membrane pemphigoid. Usually affects oral mucosa and conjunctiva. Lesions heal with scarring, which results in irreversible sequelae, such as blindness, subglottic stenosis, and esophageal strictures.³ Histology demonstrates antibody complexes in the basement membrane with submucosal infiltrate and prominent fibroblast proliferation (Chapter 192, Bullous Pemphigoid).

• Dermatitis herpetiformis—Grouped vesicles and erosions resembling herpes commonly seen on extensor aspects of extremities and buttocks. It is associated with gluten-induced enteropathy. Biopsy reveals neutrophilic microabscesses at the tips of dermal papillae with deposition of immunoglobulin (Ig) A antibody complexes. Blood tests for antigliadin and antiendomysial antibodies can help diagnose the gluten-induced enteropathy (Chapter 194, Other Bullous Diseases).

• Linear IgA dermatosis—Typical lesions are described as "string of pearls," which is an urticarial plaque surrounded by vesicles. Histologically, IgA antibodies are deposited in a linear fashion along the basement membrane (Chapter 191, Overview of Bullous Diseases).⁴

• Porphyria cutanea tarda—Bullae seen on sun-exposed areas, especially on the dorsum of the hands. Serum iron, ferritin, transaminase, and 24-hour urine porphyrins levels are elevated. Elevations in urine porphyrins are diagnostic (Chapter 194, Other Bullous Diseases).

• Hailey-Hailey disease (benign familial pemphigus)—A genodermatosis with crusted erosions and flaccid vesicles distributed in the intertriginous areas (Figure 193-18). It most closely resembles pemphigus vegetans clinically, but its pathophysiology is completely different from that of true pemphigus. It is called benign because it is not life-threatening. A 4-mm punch biopsy is adequate to make this diagnosis, as the histology is different from pemphigus.

MANAGEMENT

Treatment of pemphigus should be undertaken in consultation with a dermatologist. Treatment is directed initially at disease control and remission followed by disease suppression. The goal is to eventually discontinue all medications and achieve complete remission. Unfortunately, this goal may be difficult to achieve.

SYSTEMIC THERAPY

Corticosteroids

Systemic corticosteroids are considered first-line therapy in all types of pemphigus.^4-6 SORⒷ

• Mild disease may be controlled with prednisone 40 mg/day, but for rapidly progressive and extensive disease, a higher dose of prednisone (60 to 80 mg/day) is initiated. SORⒸ The dose may be increased by 50% every 1 to 2 weeks until disease activity is controlled. In most cases, a dose of approximately 60 mg of prednisone daily will need to be continued for at least 1 month. Once remission is induced, the dose is tapered by 25% every 1 to 2 weeks to the lowest dose needed to suppress recurrence of new lesions.¹

• Pulse therapy with intravenous methylprednisolone 1 g/day for 5 days may be tried in severe cases in an attempt to decrease the cumulative dose of steroids, especially when high-dose oral steroids are ineffective.⁷ SORⒸ

• High-dose and prolonged treatment with steroids can have serious side effects. Consequently, it is advisable to start adjuvant steroid-sparing therapy within 2 to 4 weeks of treatment. Adjuvant agents have a lag period of 4 to 6 weeks before they become effective, so starting them sooner allows for earlier steroid taper. They may be used alone to maintain remission after steroid withdrawal.

Adjuvant agents

• Adjuvant therapies have improved the treatment of PV and help prevent chronic steroid use. Despite not achieving complete remission, adjuvant therapies lower the chance for PV relapse by 29%.⁸

• Adjuvant agents include azathioprine, cyclophosphamide, mycophenolate, dapsone, and intravenous immunoglobulin.^7-11 In addition, anti-CD20 biologics such as rituximab offer promising results for targeted therapy against autoreactive B cells. Steroid efficacy is enhanced when combined with a cytotoxic drug.⁴

• Azathioprine and mycophenolate mofetil (CellCept) are often the preferred adjuvants for PV.^7,8,10,12 SORⒷ

• Azathioprine was less effective than mycophenolate mofetil in achieving remission in one study with 40 participants (risk ratio 0.72; 95% confidence interval [CI] 0.52 to 0.99).^10,12 In 13 (72%) of 18 patients with pemphigus receiving oral methylprednisolone and azathioprine, complete remission was achieved after a mean of 74 (±127) days, compared with 20 (95%) of 21 patients receiving oral methylprednisolone and mycophenolate in whom complete remission occurred after a mean of 91 (±113) days. A greater percentage of patients treated with azathioprine suffered adverse effects compared with those on mycophenolate.

• In one open-label randomized controlled trial (RCT) of four treatment regimens for PV, the most efficacious cytotoxic drug that reduced the use of steroids was azathioprine, followed by cyclophosphamide (IV pulse therapy) and mycophenolate mofetil.⁴ SORⒷ

• Standard dosing for azathioprine is 50 mg per day. Standard dosing for mycophenolate is 1000 mg to 1500 mg twice daily. Azathioprine is significantly less expensive, but patients may experience more side effects.^4,5,8,10-12 Monitoring while on azathioprine include frequent complete blood count and liver enzymes. Patients also need thiopurine methyltransferase (TPMT) levels checked before initiation of azathioprine. Deficiency of TPMT would render the patient unable to efficiently metabolize medication and may result in severe pancytopenia.

• Dapsone is an alternative adjuvant for pemphigus.⁷ SORⒸ In one small study, 8 (73%) of 11 patients receiving dapsone versus 3 (30%) of 10 receiving placebo reached the primary outcome of a prednisone dosage of 7.5 mg per day or less. This was not statistically significant and only showed a trend to efficacy of dapsone as a steroid-sparing drug in maintenance-phase PV.¹³

• Intravenous immunoglobulin (IVIG) may be used as adjuvant therapy in refractory cases of pemphigus.^7,14-16 SORⒷ In one RCT, it was used as a 5-day cycle to treat pemphigus that was relatively resistant to systemic steroids. In this multicenter study of 61 patients with PV or foliaceus, there was a decrease in disease activity subsequent to the cycle of IVIG.¹⁶ SORⒷ

• Rituximab is a chimeric monoclonal antibody against CD20 on B lymphocytes. It leads to depletion of pathogenic B cells for up to 12 months, resulting in a reduction of pathogenic autoantibodies. Rituximab is infused weekly for 4 consecutive weeks in addition to the standard immunosuppressive treatment. It has shown promise in several case reports and cohort studies in the treatment of PNP and refractory cases of PV and foliaceus.^6,17,18 SORⒷ Monoclonal antibody therapy with rituximab has shifted the treatment paradigm of PV from complete immune suppression to only targeting the pathologic B cells that eventually produce the disease-causing antibodies.

• In a recent, prospective, parallel-group, randomized trial of 25 hospitals in France, dual therapy of rituximab with short-term prednisone (tapered over 3–6 months) proved to be more effective and safer than using prednisone alone (tapered over 12–18 months) in newly diagnosed adult patients being treated for the first time. By 2 years, 89% of patients on the combined treatment achieved complete remission compared to only 34% of patients only on prednisone (95% CI 38.4-71.7; p < 0.0001).¹⁹

• Veltuzumab and ofatumumab are next-generation anti-CD20 biologics that offer promising effects for the treatment of PV. Studies show possible efficacy of veltuzumab in treating refractory PV and will have the added benefit of being administered subcutaneously. Ofatumumab is currently undergoing phase 3 clinical trials.⁶

Treating and preventing complications of therapy

• Osteoporosis prevention—Long-term therapy with oral prednisone is a significant risk factor for osteoporosis. All patients should receive supplemental calcium and vitamin D based on their age, gender, and normal dietary intake. A DEXA scan early in the course of the disease can be a helpful baseline. One study showed that alendronate therapy given to patients with immunobullous disease on long-term steroids resulted in statistically significant increases in bone mineral density at the lumbar spine and femoral neck.²⁰

• Thrush is a common complication of high-dose steroids in pemphigus (Figure 193-19). This should be treated with oral fluconazole or another antifungal to prevent Candida esophagitis. If the patient is complaining of pain or difficulty swallowing, consider the diagnosis of Candida esophagitis and treat accordingly.

• Steroid-induced diabetes may also occur. This can be treated with metformin and monitoring of blood sugars and hemoglobin A_1c.

LOCAL THERAPY

• Solitary lesions may be treated with topical high-potency steroids, such as clobetasol, or with intralesional steroid injections, for example, 20 mg/mL triamcinolone acetonide. Isolated oral lesions may be treated with steroid paste, sprays, or lozenges.

• Normal saline compresses or bacteriostatic solutions such as potassium permanganate are useful in keeping lesions clean. Oral hygiene is crucial. Mouthwashes such as chlorhexidine 0.2% or 1:4 hydrogen peroxide may be used. Topical anesthetics may be used for pain.⁷

PROGNOSIS

Pemphigus is a chronic group of diseases that are potentially life-threatening. There is no cure, and the long-term use of steroids and immunosuppressive drugs puts patients at risk for a number of complications, including infections, sepsis, steroid-induced diabetes, and steroid-induced osteoporosis. Some patients can go into remission, while others will need systemic therapy for life. Complications of treatment have become the greatest source of morbidity and mortality in pemphigus.

FOLLOW-UP

Prolonged follow-up is needed for medication adjustment and to monitor disease activity and drug side effects.

PATIENT EDUCATION

• Educate patients regarding disease, complications, and side effects of medications.

• Advise patients on avoiding trauma to skin such as with contact sports. Similarly, oral lesions may be aggravated by nuts, spicy foods, chips, or dental appliances.

• Instruct patients on wound care to prevent infections and relieve local discomfort.

• Provide information on support groups such as the International Pemphigus Pemphigoid Foundation.

REFERENCES

INTRODUCTION

There are a number of bullous diseases other than pemphigus and bullous pemphigoid that are important to recognize. Porphyria cutanea tarda is a disease that has no extracutaneous manifestations (Figures 194-1, 194-2, 194-3). Dystrophic epidermolysis bullosa belongs to a family of inherited diseases where blister formation can be caused by even minor skin trauma due to mechanical fragility. PLEVA (pityriasis lichenoides et varioliformis acuta) is a minor cutaneous lymphoid dyscrasia that can appear suddenly and persist for weeks to months. Dermatitis herpetiformis is a recurrent eruption that is usually associated with gluten-induced enteropathy.

PORPHYRIA CUTANEA TARDA

PATIENT STORY

A middle-aged woman presented with tense blisters on the dorsum of her hand (Figure 194-1). One bulla was intact, and the others had ruptured, showing erosions. Work-up showed elevated porphyrins in the urine (which fluoresced orange-red under a Wood lamp) and the patient was diagnosed with porphyria cutanea tarda.

EPIDEMIOLOGY

• Porphyria cutanea tarda (PCT) is the most common type of porphyria disorder.¹

• PCT occurs mostly in middle-aged adults (typically 30 to 50 years of age) and is rare in children.

• It may occur in women on oral contraceptives and in men on estrogen therapy for prostate cancer.^2,3

• Alcohol, pesticides, and chloroquine have been implicated as chemicals that induce PCT.^1,3

• PCT is equally common in both genders.

• There is an increased incidence of PCT in persons with hepatitis C^4-6 and HIV⁷ (see Figure 194-2).

ETIOLOGY AND PATHOPHYSIOLOGY

• The porphyrias are a family of illnesses caused by various metabolic derangements in the metabolism of porphyrin, the chemical backbone of hemoglobin. Whereas the other porphyrias (acute intermittent porphyria and variegate porphyria) are associated with well-known systemic manifestations (abdominal pain, peripheral neuropathy, and pulmonary complications), PCT has no extracutaneous manifestations. Photosensitivity is seen (as with variegate porphyria). PCT is associated with a reduction in hepatic uroporphyrinogen decarboxylase (fifth enzyme in hemoglobin synthesis).

RISK FACTORS

• Hepatitis C.

• Alcohol-induced liver injury.

• Hemochromatosis³ (iron overload)—50% of cases of PCT are associated with the same gene mutation for hemochromatosis.³

• Use of estrogens.

• Cigarette smoking.

• Patients on dialysis.

• Exposure to pesticides (halogenated hydrocarbons).

• HIV infection.⁷

DIAGNOSIS

CLINICAL FEATURES

The classic presentation is that of blistering (vesicles and tense bullae) on photosensitive "fragile skin" (similar to epidermolysis bullosa). Scleroderma-like heliotrope suffusion of the eyelids and face may be seen. As the blisters heal, the skin takes on an atrophic, scarlike appearance. Excoriations, erosions, and milia can be seen in sun exposure areas, mainly the dorsa of the hands. Hypertrichosis (especially on the cheeks and temples) (see Figure 194-3) may occur and even be the presenting feature.

TYPICAL DISTRIBUTION

Classically, the dorsa of the hands are affected (see Figures 194-1 and 194-2).

LABORATORY STUDIES

The diagnosis can be confirmed by the orange-red fluorescence of the urine when examined under a Wood lamp. Urine also can turn red to brown after exposure to sunlight for several hours. Increased plasma iron may be seen (associated with increased hepatic iron in the Kupffer cells). Diabetes is said to occur in 25% of individuals.

• Twenty-four-hour urine collection for porphyrins—These will be elevated in PCT.

• Skin biopsy may help confirm PCT if the other information is not clear.

• Once the diagnosis is made, secondary causes of PCT should be investigated:

  • Serum for ferritin, iron, and iron-binding capacity to look for hemochromatosis.

  • Order liver function tests, and if abnormal order tests for hepatitis B and C.

  • Consider α-fetoprotein and liver ultrasound if considering cirrhosis and/or hepatocellular carcinoma.

  • Order an HIV test.

DIFFERENTIAL DIAGNOSIS

• The acral vesiculobullous lesions may suggest nummular or dyshidrotic eczema. In younger individuals, the acral blistering may suggest epidermolysis bullosa. The lesions may also suggest erythema multiforme bullosum. The heliotrope suffusion may suggest dermatomyositis, and the atrophic changes may suggest systemic sclerosis.

• Polymorphous light eruption; you also can see papules, plaques, vesicles in sun-exposed areas.

• Bullous drug eruptions; check for drug exposure.

MANAGEMENT

• If the onset is associated with alcohol ingestion, estrogen therapy, or exposure to pesticides, reducing exposure is warranted.^1,3

• Phlebotomy of 450–500 mL of blood biweekly until the hemoglobin is decreased to 11 g or serum ferritin below 20 ng/mL is associated with biochemical and clinical remission within a year.⁸

• Low-dose hydroxychloroquine or chloroquine can help maintain remissions. Standard dose of hydroxychloroquine is 100–200 mg and chloroquine is 125 mg two times per week for at least 6–12 months,⁹ whereas high-dose chloroquine can exacerbate the illness² due to hepatotoxicity.¹⁰

• Sun protection clothing, regular use of broad-spectrum sunscreens.

• Treatment of hepatitis C has shown resolution of PCT.^5,6

FOLLOW-UP

• Periodic clinical follow-up until remission is achieved is necessary, along with constant education and reinforcement of the need to avoid precipitants.

PATIENT EDUCATION

• Avoidance of potential precipitants (alcohol, estrogens, pesticides, cigarette smoking) and avoidance of excess sunlight exposure (to avoid hypersensitivity) are important. Avoidance of trauma and careful wound care is also necessary.

EPIDERMOLYSIS BULLOSA

PATIENT STORY

A 34-year-old pregnant woman presents with active blistering in her axilla, and past history revealed that she lost her fingernails and toenails (Figure 194-4A) as a young child. She was diagnosed as a child with recessive dystrophic epidermolysis bullosa. None of her children had been affected because her husband was neither affected nor a carrier (Figure 194-4B). A topical steroid ointment helped relieve the pain and calm the blistering in her axilla.

EPIDEMIOLOGY

• Dystrophic epidermolysis bullosa belongs to a family of inherited diseases characterized by skin fragility and blister formation caused by minor skin trauma¹¹ due to mutations of the gene COL7A1, which encodes type VII collagen. The defect is located in the basal membrane zone (BMZ), altering the function, adhesion and integrity of the basal membrane of the skin and mucosa.¹² There are autosomal recessive, autosomal dominant, and sporadic types. The severity of this disease may vary widely, from mild skin blisters to gastrointestinal, cardiac, or ocular involvement, as well as scarring, milia, and deformities. Onset is in childhood, and in later years severe dystrophic deformities of hands and feet are characteristic, affecting quality of life¹³ (Figure 194-5). Malignant degeneration, especially squamous cell carcinoma, is common in sun-exposed areas.¹⁴

ETIOLOGY AND PATHOPHYSIOLOGY

• Dystrophic epidermolysis bullosa has vesiculobullous skin separation occurring at the sub-basal lamina level, as opposed to junctional epidermolysis bullosa, which blisters at the intralamina lucida layer; epidermolysis bullosa simplex (Figure 194-6), which blisters at the intraepidermal layer; and Kindler syndrome, in which blisters are in multiple layers.¹⁵

DIAGNOSIS

CLINICAL FEATURES

Acral skin fragility and blistering are the hallmark in childhood. Minor trauma can induce severe blistering. As the disease progresses initially, painful and ultimately debilitating dystrophic deformities such as joint and tendon contractures, pseudosyndactyly, and dystrophic nails are typical. Repeated blistering of the hands can lead to fusion of the fingers and the "mitten" deformity (see Figure 194-5). Other clinical features include oral blisters, oral fibrosis, ankyloglossia (fusion of the tongue with mouth floor), esophageal erosions, and strictures.^16-18

TYPICAL DISTRIBUTION

The typical distribution is acral (hands and feet), although blistering may extend proximally secondary to trauma. Other systems involved include gastrointestinal, commonly esophagus, small intestine; ocular with corneal abrasions; dilated cardiomyopathy; genitourinary stenosis; and osteoporosis.^16-19

LABORATORY STUDIES AND BIOPSY

There are no laboratory tests to confirm the diagnosis. A punch biopsy can provide adequate tissue for the dermatopathologist to differentiate among the different forms of epidermolysis bullosa—simplex, junctional, dystrophic, and Kindler syndrome—via transmission electron microscopy (TEM), immunofluorescence antigen mapping (IFM), or genetic testing.¹⁷

DIFFERENTIAL DIAGNOSIS

• Erythema multiforme bullosum may have a similar appearance, but the distribution is less apt to be limited to the distal extremities.

• The appearance of an acral blistering on fragile skin is also characteristic of PCT, but the age of onset of PCT is typically in middle age and not in childhood.

• The first appearance of the condition may be confused, with staphylococcal scalded skin syndrome (see Chapter 122, Impetigo).²⁰

MANAGEMENT

Management is primarily prevention of trauma, careful wound care, and treatment of complicating infections. Other supportive measures such as pain management, nutritional support, and electrolyte balance are often necessary with a multidisciplinary team.²¹

• Gentamicin (topical or intralesional) is a promising therapy in the treatment of recessive dystrophic epidermolysis bullosa that induces production of type VII collagen, accelerating wound healing and reducing blistering formation.²²

• Occupational therapy may help with contractures. In some cases, surgical release of fingers/toes is necessary.¹⁷

• Screening the skin for squamous cell carcinoma is important in the dystrophic form.¹⁷

• Cyclosporine and mycophenolate mofetil have shown benefit as long-term therapy.²³

• Bone marrow transplantation is currently under clinical investigation, and preliminary results are promising.²⁴

FOLLOW-UP

Periodic skin examinations should be done to help manage symptoms and screen for malignancy.

PATIENT EDUCATION

Avoid trauma, and come in early if there are any signs of infection or malignancy.

PITYRIASIS LICHENOIDES ET VARIOLIFORMIS ACUTA (PLEVA)

PATIENT STORY

A 22-year-old man presented with a varicelliform eruption that he has had for 6 weeks (Figure 194-7). Initially, he was diagnosed with varicella and given a course of acyclovir. Then he was misdiagnosed with scabies and treated with permethrin. A correct diagnosis of PLEVA was made by clinical appearance and confirmed with biopsy. His skin lesions cleared with oral tetracycline.

EPIDEMIOLOGY

• PLEVA or Mucha-Habermann disease and pityriasis lichenoides chronica are maculopapular erythematous eruptions that can occur in crops of vesicles that can become hemorrhagic over a course of weeks to months, leaving smallpox-like scars (Figures 194-7 and 194-8).²⁵

• It occurs predominately in a pediatric population, median 8 years.²⁶

• PLEVA occurs in preschool and preadolescent children as well.²⁷

• There is a predilection for males in the second and third decades.

ETIOLOGY AND PATHOPHYSIOLOGY

• PLEVA has traditionally been classified as a benign papulosquamous disease. However, there is increasing evidence that suggests that PLEVA should be considered a form of cutaneous lymphoid dysregulation of T cells.²⁸ It may even evolve into an indolent form of mycosis fungoides (see Chapter 180, Cutaneous T-Cell Lymphoma).²⁹

• Cases of PLEVA associated with human herpesvirus 7 (HHV-7) and human herpesvirus 8 (HHV-8), Epstein-Barr virus (EBV), and parvovirus B19 have been reported. This suggests that it could be an inflammatory condition due to dysregulation of T cells rather than a lymphoproliferative disorder.^30,31

DIAGNOSIS

CLINICAL FEATURES

PLEVA occurs with crops of maculopapular and papulosquamous lesions that can vesiculate and form hemorrhagic vesicles (see Figures 194-7 and 194-8). Although it resembles varicella, with multiple polymorphic lesions, new crops of lesions continue to appear over weeks and months. It can be thought of as "chickenpox that lasts for weeks to months."

TYPICAL DISTRIBUTION

Lesions typically occur over the anterior trunk and flexural aspects of the proximal extremities. The face is spared.

LABORATORY STUDIES

There are no specific laboratory tests for PLEVA except biopsy.

Dermoscopy findings have been described but do not replace biopsy for diagnosis.³²

BIOPSY

A punch biopsy is helpful in making the diagnosis. It may be necessary to differentiate PLEVA from lymphomatoid papulosis (see "Differential Diagnosis" below).

DIFFERENTIAL DIAGNOSIS

• Varicella—A varicella direct fluorescent antibody test can confirm acute varicella. If no viral testing was done and what appeared to be varicella persists, PLEVA should be considered (Chapter 129, Chickenpox).

• Secondary syphilis—Direct fluoresce antibody, PCR and serology test help to establish the diagnosis (Chapter 225, Syphilis).

• Pityriasis lichenoides chronica is the chronic form of PLEVA and can be distinguished from PLEVA by length of time and biopsy (Figure 194-9). It has a more low-grade clinical course than PLEVA, and the lesions appear over a longer course of time with relapse and remission periods.

• Erythema multiforme (Chapter 185) is a hypersensitivity syndrome with abrupt onset in which symmetric target lesions are seen. The target lesions have epidermal disruption in the center with vesicles and/or erosions. Look for the target lesions to help differentiate this from PLEVA.

• Lymphomatoid papulosis presents in a manner similar to PLEVA with recurrent crops of pruritic papules at different stages of development that appear on the trunk and extremities. Usually it is chronic and self-limited. Although it has histologic features that suggest lymphoma, lymphomatoid papulosis (LP) alone is not fatal. It is important to differentiate LP from PLEVA, because patients with LP need to be worked up for coexisting malignancy. Patients with LP tend to be older, and a punch biopsy can make the diagnosis.

• Gianotti-Crosti syndrome (papular acrodermatitis of childhood) may resemble PLEVA, but the lesions are usually acral in distribution (Figure 194-10).⁵ The erythematous papules and vesicles are found on the extremities and sometimes on the face. It is a benign syndrome associated with many childhood viruses that may last 2 to 8 weeks.

• Bullous arthropod reactions can be distinguished from PLEVA with a good clinical history and physical exam.

MANAGEMENT

FIRST LINE

• Oral macrolides are first-line treatment.³³ Oral erythromycin 30–50 mg /kg/day is given in divided dosing 3–4 times per day for 1–4 months.³⁴

• Doxycycline 100 mg twice daily is an alternative. The efficacy of macrolides and tetracyclines is probably from their anti-inflammatory properties rather than their antibacterial effects.

• Narrowband UVB may be used 2–3 times per week.³³

• Topical steroids such as triamcinolone 0.1% twice daily may decrease the itching.

SECOND LINE

• UVA1 phototherapy has been used with some success.³⁵

• Recalcitrant cases or ulceronecrotic PLEVA can be treated with tumor necrosis factor (TNF)-α inhibitors, intravenous immunoglobulin, or methotrexate.^36,37

FOLLOW-UP

Long term follow-up is recommended due to small risk of T-cell malignant transformation.³³

PATIENT EDUCATION

PLEVA is usually a self-limited disease. There are treatments that can help the symptoms and may shorten the illness.

DERMATITIS HERPETIFORMIS

PATIENT STORY

A young man with a past history of diarrhea and malabsorption carries a past diagnosis of gluten-induced enteropathy. Despite a gluten-free diet, he continues to have a pruritic eruption on his elbows, knees, abdomen, and buttocks (Figures 194-11 and 194-12). Although the most likely diagnosis is dermatitis herpetiformis, a punch biopsy was performed to confirm this before starting the patient on oral dapsone.

EPIDEMIOLOGY

• Dermatitis herpetiformis is a chronic recurrent symmetric vesicular eruption that is usually associated with diet-related enteropathy, more specifically gluten hypersensitivity. It is a specific extraintestinal manifestation of gluten enteropathy.³⁸ It most commonly occurs in the 20- to 40-year-old age group. Men are affected more often than women. Usually more common in Caucasians. In 80% to 90% of cases there is a strong association with genotype HLA DQ2, HLA DQ8, and HLA DR3.^38,39

ETIOLOGY AND PATHOPHYSIOLOGY

• The disease is related to gluten and other diet-related antigens that cause the development of circulating immune complexes and their subsequent deposition in the skin. The term herpetiformis refers to the grouped vesicles that appear on extensor aspects of the extremities and trunk; the disease is not a viral infection or related to the herpes viruses. It is characterized by the deposition of granular immunoglobulin (Ig) A along the tips of the dermal papillae. The majority of patients will also have blunting and flattening of jejunal villi, which leads to diarrhea even to the point of steatorrhea and malabsorption.

DIAGNOSIS

CLINICAL FEATURES

The clinical eruption is characterized by severe itching, burning, or stinging in the characteristic extensor distribution (knees, elbows, back, buttocks, and the extensor aspect of the forearms). Herpetiform vesicles, papules, and urticarial plaques may be seen. Because of the intense pruritus, characteristic lesions may be excoriated beyond recognition (see Figures 194-11 and 194-12). The condition has relapses and remissions that are related to the gluten-restricted diet.

TYPICAL DISTRIBUTION

Classically, the lesions (or excoriations) are seen in the extensor aspects of the extremities, shoulders (see Figure 194-11), lower back, and buttocks (see Figure 194-12).

LABORATORY STUDIES

If the patient has gluten-induced enteropathy, antigliadin and antiendomysial antibodies may be present in 80% of the cases of dermatitis herpetiformis. A blood test for antigliadin antibody is a sensitive test for gluten-induced enteropathy.

BIOPSY

Diagnosis is confirmed by a punch biopsy. It is best to biopsy new crops of lesions or intact vesicles. A standard histologic examination will show microabscesses of neutrophils in the dermal papillae, subepidermal vesicles, perivascular lymphocytic infiltrate, and few eosinophils. Direct immunofluorescence reveals granular deposits of IgA and complement within the dermal papillae, with almost 100% specificity and sensitivity.³⁸

DIFFERENTIAL DIAGNOSIS

• Scabies may have a similar appearance with pruritus, papules, and vesicles. If the lesions and distribution suggest scabies, it should be ruled out with skin scraping looking for the mite, feces, and eggs. If the scraping is negative, but the clinical appearance suggests scabies, empiric treatment with permethrin should be considered as well. If the lesions persist, consider a punch biopsy to look for dermatitis herpetiformis (Chapter 149, Scabies).

• Nummular and dyshidrotic eczema may also be diagnostic considerations, but response to steroids in eczema may be helpful in differentiation (Chapters 151, Atopic Dermatitis, and 153, Hand Eczema).

• The classic differential for PCT is pseudoporphyria (caused by nonsteroidal anti-inflammatory drugs [NSAIDs] such as naproxen), epidermolysis bullosa acquisita, and variegate porphyria.

• IgA bullous dermatosis: differs from dermatitis herpetiformis because in IgA bullous dermatosis the deposit of IgA is linear instead of the granular pattern seen in DH and often is caused by drugs.

• Bullous arthropod bites; patient may recall insect exposure.

MANAGEMENT

• With a gluten-free diet, 80% of patients will show improvement in the skin lesions (see Figure 194-12). The degree of benefit is dependent on the strictness of the diet.^38,39

• A gluten-free diet may help the enteropathy and decrease the subsequent development of small bowel lymphoma.³⁸

• Dapsone at an initial dose of 100–200 mg daily or 0.5–1 mg/kg/day with gradual reduction to a 25- to 50-mg maintenance level may be necessary indefinitely.³⁸ Monitor complete blood count (CBC), liver function test due to risk of hemolysis, methemoglobinemia. Some clinicians, recommend checking glucose-6-phosphate dehydrogenase (G6PD) activity prior to start of treatment.

• Rituximab has been used in recalcitrant cases with good outcome, serologic and immunologic remission.⁴⁰

FOLLOW-UP

Follow-up is needed to control the disease and monitor nutritional status.

PATIENT EDUCATION

Nutritional counseling is important for all patients with gluten-induced enteropathy. Persons with dermatitis herpetiformis and gluten-induced, enteropathy should not eat wheat and barley but can eat rice, oats, and corn. Patients can get information, dietary guidelines, and educational materials online via support groups such as https://www.gluten.org and https://www.celiac.org.

REFERENCES