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Dermatology Diagnosis

When An Elderly Patient Presents With Blistering Skin Lesions On His Feet And Legs

An 82-year-old male presented to our hospital with worsening blisters on his feet and lower legs that coincided with acute worsening of his lower extremity edema over the preceding two weeks. The patient noted mild pruritus, pain and limited ability to walk secondary to his pain and significant edema. 

The patient’s past medical history was pertinent for heart failure with reduced ejection fraction, seizure disorder, hypertension, glaucoma and ascending aortic aneurysm (incidental finding on computed tomography (CT)). Active medications included levetiracetam, amlodipine and metoprolol. The patient’s laboratory values were unremarkable with the exception of elevated brain natriuretic peptide and eosinophilia. 

We initially considered the lower extremity bullae to be edema blisters given their location in dependent areas and onset corresponding with the acute onset of his lower extremity edema. Initial treatment included intravenous furosemide for diuresis and volume control. Despite improvement in the patient’s volume status and edema, he continued to have progressive development of bullae to his feet and lower legs. Given the persistent skin lesions, we performed punch biopsies of the bilateral lower legs that we sent out for histopathology and direct immunofluorescence analysis. 

 Key Questions To Consider 

1. What are the differential diagnoses for a blistering skin disease? 

2. What diagnostic testing should one perform or order to identify specific blistering skin diseases? 

3. What is the most common etiology of blistering skin diseases? 

4. What are some potential sequelae of unidentified or untreated blistering skin diseases? 

Answering The Key Diagnostic Questions 

1. The most common blistering skin diseases include pemphigus vulgaris, paraneoplastic pemphigus, bullous pemphigoid, cicatricial pemphigoid, dermatitis herpetiformis and linear IgA dermatosis. 

2. Testing should include histopathologic analysis and direct immunofluorescence examination of punch biopsies along with serum indirect immunofluorescence examination. 

3. Many bullous dermatoses are autoimmune in nature. 

4. If left untreated, some of these blistering skin conditions can last for years with periods of remission and exacerbation. Fatality may also occur with certain diagnoses in debilitated patients. 


What The Diagnostic Testing Revealed 

Tissue histopathology exam revealed subepidermal bullous dermatosis with numerous eosinophils and findings favoring bullous pemphigoid. The direct immunofluorescence exam suggested pemphigoid based on linear IgG, including IgG4, basement membrane zone antibody reactivity and linear C3 basement membrane staining. In order to distinguish pemphigoid from pemphigoid variants, further basement membrane zone antibody panel testing confirmed the diagnosis of bullous pemphigoid with the presence of BP 180 and 230 IgG antibodies. 

Given the patient’s age and comorbidities, initial treatment included doxycycline, topical corticosteroids (betamethasone twice daily) and local wound care. After discharge, the patient transferred to a skilled nursing facility given his limited ambulation and need for continued wound care. 

What You Should Know About Blistering Skin Diseases And Bullous Pemphigoid 

There is a wide variety of blistering skin diseases that can affect the lower extremity. Some of these disorders are very debilitating and may have serious sequelae. Many bullous dermatoses are autoimmune in nature. The most common autoimmune bullous dermatoses include pemphigus vulgaris, paraneoplastic pemphigus, bullous pemphigoid, cicatricial pemphigoid, dermatitis herpetiformis and linear IgA dermatosis.1 

Bullous pemphigoid is a chronic, autoimmune, blistering dermatosis, which occurs mostly in elderly patients.2 This disorder mostly affects individuals over the age of 50 with peak incidence among individuals who are 60 to 80 years of age. Bullous pemphigoid does not show a predilection toward any race or gender. Most commonly, bullous pemphigoid presents as tense subepidermal bullae on any skin surface. Bullous pemphigoid can affect the lower extremities, most often in flexural areas of the skin. Occasionally, urticarial lesions precede bulla formation or may be the only manifestation of the disease.2 

One must perform a skin biopsy to diagnose bullous pemphigoid. Punch biopsies should come from the edge of a blister for histopathologic analysis and from normal, perilesional or urticarial skin for direct immunofluorescence studies. Histopathologic analysis shows a subepidermal blister with a polymorphous inflammatory infiltrate with predominantly eosinophils.2 Direct immunofluorescence studies typically show a dense band of IgG and complement C3 at the basement membrane. Further indirect immunofluorescence studies (IDIF), performed on the patient’s serum, are necessary if direct immunofluorescence is positive. The indirect immunofluorescence studies show the presence of circulating IgG autoantibodies that target the skin basement membrane in the patient’s serum.3,4 

Treatment of bullous pemphigoid aims to decrease blister formation, promote healing and prevent recurrence. Anti-inflammatory agents and immunosuppressants are the mainstays of treatment.5,6 Doxycycline is an effective initial treatment and has fewer adverse effects than corticosteroids and immunosuppressants.7,8,9 Mild cases may only require topical corticosteroids. 

Wound management in bullous pemphigoid aims to prevent infection, prevent scarring and provide a moist wound healing environment to promote healing.10 One should leave small blisters intact to prevent infection. However, clinicians should puncture and drain large blisters, and leave the roof intact to create a biologic barrier and prevent infection. Bullous pemphigoid wounds are superficial with damage limited to the epidermis so recommended wound products include non-adherent gauze, transparent film, hydrocolloid and hydrogel dressings.10 

The course of bullous pemphigoid varies. While this disease is self-limiting, it may last for many years. Approximately one-half of treated cases resolve within six years.11 There can be variable morbidity and mortality associated with bullous pemphigoid. 

The presence of bullae and erosions in combination with immunosuppressant use increases the risk of developing secondary infections. Possible cutaneous wound complications include delayed healing and scarring. While uncommon, mortality associated with bullous pemphigoid does occur and is often associated with effects of medication clinicians use to treat this skin disorder. 

In Conclusion 

While generally rare, bullous pemphigoid is one of the more common autoimmune dermatoses. The clinical presentation includes tense serous or hemorrhagic bulla on any skin surface, but with a predilection for flexor surfaces. While this disorder is self-limiting, it can last for many years with possible associated mortality. Treatment of bullous pemphigoid involves anti-inflammatory and immunosuppressant agents that aim to decrease blister formation and prevent recurrence. 

Dr. Hoffman is an attending physician in the Department of Orthopedics at Denver Health Medical Center and the Highland/Presbyterian St. Luke’s Medical Center Residency Program in Denver. She is an Assistant Professor in the Department of Orthopedics at the University of Colorado School of Medicine. 

Dermatology Diagnosis
By Kristine Hoffman DPM, FACFAS

1. Bickle KM, Roark TR, Hsu S. Autoimmune bullous dermatoses: a review. Am Fam Physician. 2002;65(9):1861-1817. 

2. Kershenovich R, Hodak E, Mimouni D. Diagnosis and classification of pemphigus and bullous pemphigoid. Autoimmun Rev. 2014;13(4-5):477-481. 

3. Weigand DA, Clements MK. Direct immunofluorescence in bullous pemphigoid: effects of extent and location of lesions. J Am Acad Dermatol. 1989;20(3):437-440. 

4. Mutasim DF, Adams BB. Immunofluorescence in dermatology. J Am Acad Dermatol. 2001;45(6):803- 822. 

5. Terra JB, Potze WJ, Jonkman MF. Whole body application of a potent topical corticosteroid for bullous pemphigoid. J Eur Acad Dermatol Venereol. 2014;28(6):712-718. 

6. Gual A, Iranzo P, Mascaró Jr JM. Treatment of bullous pemphigoid with low-dose oral cyclophosphamide: a case series of 20 patients. J Eur Acad Dermatol Venereol. 2014;28(6):814-818. 

7. Chalmers JR, Wojnarowska F, Kirtschig G, et al. A randomised controlled trial to compare the safety, effectiveness and cost-effectiveness of doxycycline (200 mg/day) with that of oral prednisolone (0.5 mg/kg/day) for initial treatment of bullous pemphigoid: the Bullous Pemphigoid Steroids and Tetracyclines (BLISTER) trial. Health Technol Assess. 2017;21(10):1-90. 

8. Williams HC, Wojnarowska F, Kirtschig G, et al. Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trial. Lancet. 2017;389(10079):1630-1638. 

9. Grantham HJ, Stocken DD, Reynolds NJ. Doxycycline: a first-line treatment for bullous pemphigoid? Lancet. 2017;389(10079):1586-1588. 

10. Grada A, Obagi Z, Phillips T. Management of chronic wounds in patients with pemphigus. Chronic Wound Care Mgmt Res. 2019(6):89-98. 

11. Stanley JR. Bullous pemphigoid. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s Dermatology in General Medicine. (5th ed.) New York: McGraw-Hill, Health Professions Division;1999:666–679. 

Additional Reference 

12. Diercks GF, Pas HH, Jonkman MF. Immunofluorescence of autoimmune bullous diseases. Surg Pathol Clin. 2017;10(2):505-512. 

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