Blistering rash in the groin

HOW TO TAKE THE POST-TEST: This Clinical Advisor CME activity consists of 3 articles. To obtain credit, you must also read Itchless, red, and crusted trunk papules and Thick and keratoticlesions on both shins. Then take the post-test here .CASE...

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HOW TO TAKE THE POST-TEST: This Clinical Advisor CME activity consists of 3 articles. To obtain credit, you must also read Itchless, red, and crusted trunk papules and Thick and keratoticlesions on both shins. Then take the post-test here .

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CASE #1: Linear IgA bullous dermatosis

Linear immunoglobulin (Ig)A bullous dermatosis (LABD) was previously thought to be a variant of dermatitis herpetiformis (DH). It wasn’t until 1969 that researchers recognized that patients with vesiculobullous lesions that had histologic findings similar to DH had linear rather than granular deposits of IgA along the basement membrane zone. In 1975, Chorzelski and Jablonska were the first to make the suggestion that LABD was a separate entity.¹ Today, it is widely agreed upon by dermatologists that LABD and DH are distinct disorders.

Both adults and children may develop the disease. In adults, the condition is most commonly termed LABD, whereas in children it is most often referred to as chronic bullous disease of childhood (CBDC).

Histologically, the two diseases are indistinguishable. Clinically, however, LABD most closely resembles DH or bullous pemphigoid (BP) and is often drug-induced. In CBDC, the cutaneous features are unique and usually characterized by annular erythema and blisters (often referred to as a crown of jewels).

The exact incidence of LABD is unknown. In southern England, the incidence has been estimated to be 1 in 250,000 per year. In the United States, the incidence has been estimated to be 0.6 per 100,000 adults. Females are slightly more affected than males. The average age of onset of LABD is after age 60 years. Most children develop the disease by age 3 years and go into spontaneous remission by age 13 years.²

LABD is an acquired, autoimmune blistering disease. The target antigen is most commonly the carboxy terminus of bullous pemphigoid antigen 2 (BPAG2). More specifically, an IgA antibody reacts against a 97 kDa antigen that is a cleaved ectodomain of BPAG2, referred to as LABD97.³ Histologically, there is a less common subtype of LABD that binds to type VII collagen in anchoring fibrils.

There are reports in the literature of LABD being associated with GI diseases (rarely, gluten-sensitive enteropathy),⁴ autoimmune diseases, malignancies, and infections. In adults, the dermatosis commonly occurs as a drug-induced disease and may be more severe than the spontaneously occurring form.

Commonly implicated drugs include vancomycin (most common), lithium (Lithobid), amiodarone (Cordarone, Pacerone), captopril (Capoten), penicillin, amoxicillin, moxifloxacin (Avelox), carbamazepine, phenytoin (Dilantin, Phenytek), psoralen, furosemide (Lasix), oxaprozin (Daypro), interleukin 2, interferon alfa-2a (Roferon-A), diclofenac (Cataflam, Voltaren, Zipsor), statins, tea tree oil, angiotensin receptor antagonists, glyburide (DiaBeta, Glynase), and ustekinumab (Stelara).^5,6

Lesions may develop on normal or erythematous skin as individual tense bullae or herpetiform vesiculobullae. The classic description is that of bullae that are arranged in an annular array or rosette (i.e., crown-of-jewels) configuration.

Patients will often complain of severe pruritus. Bullae preferentially develop on the lower trunk, buttocks, genitalia, and thighs. Up to 75% of patients may have oral mucous membrane involvement, and LABD may sometimes present as a variant of cicatricial pemphigoid.⁷

LABD may be difficult to diagnose clinically in adults because the condition may closely resemble DH or BP. To determine the exact diagnosis, a biopsy with both H&E stain and DIF is needed. Patients with LABD will demonstrate a subepidermal blister with neutrophils in the dermal papillae on H&E stains. This histologic picture may be seen not only in LABD but also in patients with DH or bullous lupus erythematosus.

An antinuclear antibody panel may help to exclude a diagnosis of bullous lupus erythematosus. A DIF will help to distinguish LABD from DH, and biopsies should be obtained from perilesional skin.

While patients with LABD will show linear deposition of IgA along the basement membrane zone (BMZ) on a DIF, patients with DH will demonstrate granular IgA in the dermal papillae or along the BMZ. Patients with BP will most commonly display a subepidermal bullae with eosinophils on H&E and linear deposition of C3 and IgG along the BMZ on DIF.

Nearly 60% to 70% of patients with LABD will demonstrate circulating anti-BMZ antibodies of the IgA class.⁷ These antibodies most commonly bind to the epidermal side (roof) of salt-split skin. However, those patients with the less common form of LABD that binds to collagen VII will have IgA antibodies that bind to the dermal side of salt-split skin.

Most patients with LABD will respond to either oral dapsone or sulfapyridine therapy. The results are impressive, with most patients having a clinical response within two to three days. Some cases respond to topical steroids alone, and in severe cases, oral prednisone may be added to achieve complete control of the disease.

Other treatments that have been reported as effective include mycophenolate mofetil (CellCept), azathioprine (Azasan, Imuran), cyclosporine (Gengraf, Neoral, Sandimmune), topical calcineurin inhibitors, colchicine (Colcrys), dicloxacillin, trimethoprim/sulfamethoxazole (Bactrim, Septra, Sulfatrim), erythromycin, and IV immunoglobulin (IVIG). All treatments are off-label. Rarely, those patients who have an associated gluten-sensitive enteropathy may respond to a gluten-free diet.

Drug-induced LABD is usually a self-limited eruption that resolves within two to six weeks after cessation of the drug. However, some cases have persisted for months.

The idiopathic form of the disease generally responds well to dapsone or sulfapyridine, and these cases tend to persist for years with spontaneous remission in several patients. In children, the untreated disease usually will resolve spontaneously by adolescence.

Given the possibility for spontaneous remission in both adults and children, repeated attempts to taper medications should be made in case spontaneous remission has occurred.

The diagnosis of LABD was confirmed on H&E and DIF in this patient. The man was treated with dapsone, and the lesions resolved on follow-up. He was advised to avoid vancomycin.

CASE #2: Bullous pemphigoid

During the 18th century, every blistering disorder was termed pemphigus. In 1953, Lever was the first to recognize BP as a distinct disorder based on its specific clinical and histologic features.8 In the 1960s, Jordon, Beutner, and colleagues determined that patients with BP had tissue-bound and circulating autoantibodies that were directed against the cutaneous BMZ.⁹

BP is the most common autoimmune blistering disorder to occur in the skin. It most commonly occurs in the elderly, with an average age of onset of 65 to 75 years. The disorder tends to be more predominant in males than females. The exact incidence is unknown, but it is estimated that there are at least 6 to 7 new cases per million population.¹⁰ The disease also occurs in children, but rarely.

BP is an autoimmune blistering disorder that is associated with both a humoral and cellular immune response. The target self-antigens are the BP antigen 180 (BP180, BPAG2, or type XVII collagen) and the BP antigen 230 (BP230 or BPAG1). BPAG2 is a transmembrane protein, whereas BPAG1 is a cytoplasmic protein that belongs to the plakin family. Both of these antigens are an integral part of the hemidesmosome, which promotes epithelial-stromal adhesion of the stratified epithelia of the skin and mucous membranes.

Nearly all individuals have circulating autoantibodies to BPAG2. More specifically, these autoantibodies are targeted against the noncollagenous NC16A domain that is located extracellularly but close to the transmembrane domain. Once these autoantibodies bind to their target antigen, a subepidermal blister forms, and a cascade of events involving complement activation, recruitment of inflammatory cells, and liberation of various chemokines and proteases ensues.

BP may also be drug-induced; the most common offenders include furosemide, analgesics, D-penicillamine (Cuprimine, Depen), penicillin, sulfasalazine (Azulfidine), potassium iodide, gold, and captopril.

There is both a nonbullous and a bullous phase of BP. In the nonbullous phase, the clinical appearance can be very polymorphic. Patients most often complain of mild or severe pruritus that may be associated with excoriated, eczematous, and/or urticarial lesions. Tense blisters on an erythematous base predominate the bullous stage of the disease. The bullae are usually 1 cm to 4 cm in diameter, contain clear or hemorrhagic fluid, and may persist for several days.

After the bullae rupture, large denuded areas that may become crusted are left behind. On healing, these lesions may leave residual postinflammatory hyper- and/or hypopigmentation and milia. Lesions tend to be symmetric and occur predominately within flexural areas of the limbs and lower trunk, including the abdomen. Approximately 10% to 30% of patients will have oral mucous membrane involvement.¹¹

BP that occurs in pregnancy is called pemphigoid gestationis. This eruption most commonly occurs during the second or third trimester of pregnancy and appears as pruritic papules and/or bullae that begin periumbilically and then generalize. Childhood BP more commonly involves the palms, soles, and mucous membranes.

The differential diagnosis of bullous pemphigoid may include LABD, DH, bullous lupus, pemphigus vulgaris, porphyria cutanea tarda, bullous impetigo, epidermolysis bullosa, drug reactions, contact dermatitis, urticaria, and arthropod reactions.

On H&E staining, a subepidermal bulla with perivascular lymphocytes and eosinophils is most commonly observed. Eosinophilic spongiosis and dermal edema also may be present. In rare cases, the inflammatory infiltrate may be sparse; this is termed cell-poor BP.

If numerous eosinophils are found within the dermis of an elderly patient, even without blistering, a diagnosis of BP is highly likely. DIF of perilesional skin reveals C3 and IgG at the BMZ. On indirect immunofluorescence of salt-split skin, circulating autoantibodies bind to the roof of the blister.

Epidermolysis bullosa acquisita (EBA) patients often demonstrate subepidermal cell-poor bullae on H&E staining, and DIF will also show linear deposition of complement and IgG along the BMZ.

Since cell-poor BP and EBA may appear identical on H&E and DIF, EBA must be considered in a patient diagnosed with BP who is responding poorly to treatment. In contrast to BP, patients with EBA will have localization of autoantibodies to the floor of the blister on indirect immunofluorescence.

BP 180 enzyme-linked immunosorbent assay (ELISA) and BP 230 ELISA may also be performed to aid in the diagnosis; these assays have a sensitivity of 72% and 59% and a specificity of 94.1% and 99.2%, respectively.¹² However, DIF still remains the gold standard, with a sensitivity of 90.8% and a specificity of 98%.¹²

The mainstay of treatment is systemic corticosteroids at a dosage of 0.5 mg/kg/day to 1.0 mg/kg/day. The disease rapidly improves within one to two weeks, and steroids are then tapered over a period of months. Topical cortico­steroids alone are also a well-accepted treatment option for mild disease.

Other treatments are often used as second-line therapy and include azathioprine, mycophenolate mofetil, methotrexate (Rheumatrex, Trexall), chlorambucil (Leukeran), cyclophosphamide, cyclosporine, nicotinamide, tetracycline (Sumycin), IVIG, plasma exchange, and rituximab (Rituxan). All treatments are off-label.

BP is generally a self-limited disease that spontaneously remits within five to six years in adults and within one year in children. Approximately 10% to 15% of patients will relapse on discontinuation of therapy.¹³ The estimated death rate during the first year has varied between 10% and 40%, depending on the series.^14,15 However, much of the morbidity and mortality is related to side effects of drug therapy; with better treatments, pemphigoid patients now have similar mortality to age-matched controls.

The H&E and DIF confirmed the diagnosis of BP in this patient. The woman was treated with systemic and topical corticosteroids. After remission, the systemic corticosteroids were tapered and the patient currently remains disease-free. 

Kerri Robbins, MD, is an instructor in the Department of Dermatology at Baylor College of Medicine in Houston.

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HOW TO TAKE THE POST-TEST: This Clinical Advisor CME activity consists of 3 articles. To obtain credit, you must also read Itchless, red, and crusted trunk papules and Thick and keratoticlesions on both shins. Then take the post-test here .

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