Blisters and erosions


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Case #1

A 60-year-old man with a history of Hashimoto thyroiditis and rheumatoid arthritis presents with a 3-month history of painful blisters and erosions, which initially presented in his oral mucosa and spread to his skin. Two months ago, he was prescribed captopril for blood pressure control. Examination reveals erosions of his oropharyngeal mucosa and flaccid bullae on his scalp, face, neck, trunk, and groin. These bullae are positive for direct and indirect Nikolsky sign. 

Case #2

A 70-year-old man who recently began therapy with a diuretic and an angiotensin-converting enzyme inhibitor for hypertension presents with tense blisters on his skin. He had been prescribed a topical corticosteroid for intractable eczema 1 month earlier. Examination reveals tense blisters filled with serous fluid localized to the trunk and flexural aspects of the extremities. The oral cavity, face, and neck are free of lesions. Results of a test for a Nikolsky sign are negative. 

Case #1Pemphigus vulgaris (PV) is an autoimmune bullous disease characterized clinically by flaccid blisters and erosions on the skin and mucous membranes, and histologically by acantholysis.1 Annual incidence rates range from 0.76 to 32 cases per million, and it is...

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Case #1

Pemphigus vulgaris (PV) is an autoimmune bullous disease characterized clinically by flaccid blisters and erosions on the skin and mucous membranes, and histologically by acantholysis.1 Annual incidence rates range from 0.76 to 32 cases per million, and it is more frequently diagnosed in the fourth and fifth decades of life, especially in people of Jewish and Mediterranean ancestry.1-3

This condition is associated with a high mortality rate; however, the introduction of corticosteroids dramatically improved prognosis.3,4 It remains a life-threatening disease, largely due to complications of treatment.4 PV is also associated with other autoimmune diseases, including autoimmune thyroid diseases, myasthenia gravis, Sjögren syndrome, and rheumatoid arthritis.3 Triggering factors include medications and viral infections, but, in most cases, the trigger cannot be identified.3,5 PV is mediated by autoantibodies against desmosomes, which results in intraepidermal blisters, and it is the most common category of pemphigoid diseases.1,6

Clinically, PV classically presents with flaccid blisters that easily rupture, leaving painful erosions.7 Lesions initially present on the mucous membranes, especially the oral mucosa, and are followed by cutaneous involvement months later, most commonly on the scalp, face, neck, trunk, and groin.1,3,7 During active PV, both the direct and indirect Nikolsky signs are positive.1,7 The direct Nikolsky sign refers to exfoliation of the epidermis with slight rubbing of perilesional skin, and the indirect Nikolsky refers to that ability to laterally shift and enlarge the intact blister with pressure.1,7 The two major forms of PV are the mucosal dominant type and the mucocutaneous type.1

Diagnosis of PV is based on a combination of clinical and histopathologic features. Histologically, PV is characterized by the presence of acantholysis, which refers to the loss of keratinocyte adhesion, with formation of suprabasilar blisters.7 The residual basal keratinocytes at the base of the blister floor on the dermoepidermal junction zone result in the characteristic “tombstone effect.”1 Direct immunofluorescence shows intercellular immunoglobulin (Ig) G with or without C3 deposition on the cell surfaces of the keratinocytes in a honeycomb-like pattern.1,7 Indirect immunofluorescence shows a reticular pattern of desmoglein-3 IgG autoantibodies against epithelial surfaces.1,7 Finally, an enzyme-linked immunosorbent assay (ELISA) result is positive for IgG or IgA autoantibodies against desmoglein-1 and desmoglein-3.1 ELISA is highly sensitive and specific for these PV autoantibodies; however, it is not a routine test and is indicated in difficult cases.7

The differential diagnosis for PV includes bullous pemphigoid (BP); however, this condition is characterized by tense blisters that typically do not involve the mucous membranes.8 The differential diagnosis may also include pemphigus foliaceus (PF); however, unlike PV, PF rarely involves the mucous membranes. Another condition that should be considered is dermatitis herpetiformis; however, it usually presents with pruritic papules and vesicles symmetrically distributed on the extensor surfaces instead of bullae.9 Erythema multiforme is another condition that is in the differential for PV, although it is characterized by a papule, vesicle, or a bulla surrounded by a purpuric macule or plaque resulting in a target sign.10 Also, test results for a direct Nikolsky sign are negative.10

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The primary objective in treatment of PV is to heal the lesions, to decrease the associated impairment in function, and to maintain remission.1,2,6 Glucocorticoids alone or in combination with a steroid-sparing immunosuppressive agent are the gold standard of treatment.1,2,6 As a result of the introduction of oral glucocorticoids in PV therapy, its mortality rate has dropped from 75% to <10%.2 Unfortunately, it is associated with many side effects, including metabolic syndrome, cataracts, and loss in bone density.2 Azathioprine and mycophenolate mofetil are the first-line steroid-sparing agents.1,6 Other interventions that may be effective include high-dose intravenous immunoglobulin (IVIG) and rituximab, though the optimal dose of rituximab is unknown and its efficacy and safety need to be evaluated against oral glucocorticoids.6

The patient in our case was successfully treated with a course of oral corticosteroids with IVIG. The patient was then transitioned to azathioprine and the corticosteroid dose was reduced, with the goal of eliminating the need for corticosteroids completely. He is also on concomitant calcium and vitamin D supplements and bisphosphonates.

Case #2

Bullous pemphigoid (BP) is an autoimmune bullous disease mediated by autoantibodies directed against hemidesmosomes and characterized by tense, pruritic bullae.11,12 Annual incidence ranges from six to 14 cases per million, and it increases sharply with age; peak manifestation is at 70 years, making it the only autoimmune disease in which incidence increases with age.12,13

Patients typically have a chronic course with recurrences and a poor prognosis, mostly due to side effects of treatment, the advanced age of the patient, and other associated medical conditions.12 The most common associated diseases include neurologic and cardiovascular diseases and malignancies.12,14 Triggering factors include medications, especially diuretics, analgesics, captopril, and antibiotics; physical agents, including radiation therapy; surgical procedures and burns; and herpes virus infections.12,15 However, a triggering factor can only be identified in approximately 15% of cases.4 Possible causes of BP include an imbalance between autoreactive T helper (Th) cells and T regulatory cells, Toll-like receptor activation, and Th17/interleukin 17 pathway overactivation.11 Autoantibodies against the structural components of the hemidesmosome (BP180 and BP230) induce complement activation, recruitment of inflammatory cells, and the release of proteolytic enzymes.11

Clinically, BP presents with large, pruritic, tense serous or hemorrhagic blisters localized to the trunk and flexural aspects of the extremities.13,16 These lesions appear on erythematous, urticarial, eczematous lesions or apparently normal skin, the blisters evolve into eroded or crusted areas, and the lesions heal without scarring.16 Typically, BP does not involve the oral cavity, face, or neck.17 Lesions are preceded by intractable pruritic eczema-like or urticarial eruption, called the nonbullous phase, that lasts weeks to months.11

Diagnosis of BP is based on a combination of clinical, histopathologic, and immunologic criteria.18 Histologically, BP is characterized by subepidermal blisters with an eosinophilic infiltration.13 Direct immunofluorescence (DIF) demonstrating deposition of both IgG and C3 along the basement membrane is the gold standard for BP diagnosis.18 The salt-split DIF technique showing IgG/C3 deposit at the blister roof can be used to distinguish between BP and other bullous conditions.13 Another technique helpful for BP diagnosis is indirect immunofluorescence, which is positive for anti-bullous pemphigoid antigen 1and 2 at the basement membrane on monkey esophagus (monkey esophagus is a standard substrate for indirect immunofluorescence in BP).19 Finally, positive enzyme-linked immunosorbent assay (ELISA) results for autoantibodies against BP180 and BP230 are also indicative for BP.18

The differential diagnosis includes acquired epidermolysis bullosa (AEB) and bullous systemic lupus erythematosus (SLE). AEB commonly presents with tense vesicles and bullae located primarily on the extensor surfaces of the extremities and on the mucous membranes, unlike BP.10 Bullous SLE presents with large, tense, widespread and symmetrically distributed bullae typically on the upper part of the trunk, proximal upper extremities, neck, and face.13,20 However, both AEB and bullous SLE only demonstrate IgG deposits on the base of the blister.20 BP in the nonbullous phase may resemble chronic prurigo, eczema, and urticaria; however, it is very difficult to treat and will eventually progress to the classic bullae of BP.16

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Treatment goals for BP are to alleviate the symptoms, shorten the duration of each flare, and maintain remission.11,20 Historically, the mainstay of BP treatment involved systemic corticosteroids.11,18 However, recent literature indicates that topical clobetasol propionate is equally effective and superior to oral prednisolone with regard to overall survival, disease control, and adverse event profile in patients with extensive BP.18 Thus, topical clobetasol is now the first-line treatment for active BP.18 The first-line immunosuppressive and steroid-sparing therapy is azathioprine.18 Other therapies that may be useful include mycophenolate mofetil, methotrexate, intravenous immunoglobulin, and cyclophosphamide.11

The patient in our case is currently managed with topical clobetasol.

Melinda Liu, BA, is a medical student and Maura Holcomb, MD, is a dermatology resident at Baylor College of Medicine in Houston.


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