Multiple blisters on the extremities

Epidermolysis bullosa acquisita (EBA) is an acquired, primary blistering disorder. Making the correct diagnosis required a conglomeration of clinical, histological and laboratory findings.When faced with cutaneous blisters, one must consider multiple diagnoses ranging from poison ivy to an acquired primary...

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Epidermolysis bullosa acquisita (EBA) is an acquired, primary blistering disorder. Making the correct diagnosis required a conglomeration of clinical, histological and laboratory findings.

When faced with cutaneous blisters, one must consider multiple diagnoses ranging from poison ivy to an acquired primary blistering disorder. History, physical exam, and initial histologic findings can often determine that a primary blistering disorder is present, but then the real work begins because the number of conditions to be considered among the primary blistering diseases is quite large, and sometimes confusing. 

Using clinical clues, histologic findings, and various laboratory results, the correct diagnosis usually can be determined. During the physical exam, the clinician should note the size, locations, and quality of the blisters, as well as inspect the mucous membranes. 

In addition to standard hematoxylin and eosin (H&E) staining, histologic evaluation must include direct immunofluorescence (DIF) studies; serum should also be sent for indirect immunofluorescence testing (IIF).


Making the correct diagnosis in a timely fashion is important because of the significant morbidity, and potential mortality, associated with several blistering conditions. Furthermore, treatment regimens and comorbidities vary according to the pathogenesis of each of these diseases. 


One approach to help differentiate between blistering disorders clinically is to separate them into two fairly distinct groups, determined by the presence or absence of mucosal involvement. 

Disorders that commonly affect the mucosa include benign mucous membrane pemphigoid (cicatricial pemphigoid [CP]), pemphigus vulgaris (PV), and linear IgA disease (LAD).¹ Disorders that typically lack mucosal involvement include porphyria cutanea tarda (PCT), bullous pemphigoid (BP), dermatitis herpetiformis (DH), and bullous systemic lupus erythematosus (bSLE).^1-3 For some conditions, such as EBA, mucosal involvement is variable.¹ 


Noting whether the blisters are tense or fragile may be another helpful clinical clue. Tense blisters tend to be more common in BP, EBA, and bSLE, whereas more fragile blisters tend to be associated with the other disorders previously listed.¹


A lesional biopsy, containing the edge of a blister, should be performed uniformly at the time of patient presentation. Microscopic examination after H&E staining reveals where the blister has occurred within the skin. Location of blister formation is characteristic for each of the primary blistering disorders; an intraepidermal blister is found in PV whereas subepithelial blisters are seen in CP, BP, DH, EBA, bSLE, and PCT.^1-3


In addition to the lesional biopsy, a perilesional biopsy should be performed and DIF studies for pathogenic autoantibodies undertaken on the specimen. DIF patterns of staining are characteristic for each of the autoimmune blistering disorders. An intracellular pattern is diagnostic of the pemphigus group, a vascular pattern is seen in PCT, a dermal papillary pattern is seen in DH, and a basement membrane zone pattern is seen in EBA, BP, CP, bSLE and LAD.⁴ 


Detection of specific autoantibodies helps further distinguish between some of these disorders. For example, LAD and DH each stains for IgA only, but distinguishing between EBA, BP, bSLE, and CP can be difficult using only H&E and DIF.^3,5


Antibodies found in the subepithelial blister are bound to one of multiple proteins in the complex matrix known as the basement membrane zone (BMZ) of the epidermis. Antibodies causing BP are bound to the top of the BMZ, antibodies causing EBA are bound to the bottom of the BMZ, and antibodies in CP can be in either location.⁶ Through special processing using a concentrated salt solution, the BMZ can be split so that antibodies can be localized to either the epidermal side or the dermal side. 


The biopsy from our patient demonstrated a subepithelial blister with IgG antibodies detected in the BMZ; IIF with salt-split processing demonstrated the antibodies to be on the dermal side. That narrowed the diagnosis to EBA, CP and bSLE. The fact that mucosal surfaces are uniformly present in CP but were absent in our patient further narrowed the diagnosis to EBA vs bSLE. Our patient had no other clinical or laboratory criteria for SLE, including negative antinuclear antibodies, precluding the diagnosis of bSLE and supporting the diagnosis of EBA.⁴ 


EBA was first identified as a separate entity in 1895, but diagnostic criteria were not established until 1971.¹ It is extremely rare, with an estimated annual incidence of 0.2 to 0.5 per million.¹ Although EBA usually presents in middle-aged adults, it can present in children and be misdiagnosed as an inherited form of epidermolysis bullosa. Both genders and all ethnicities are equally affected.¹ Prevalence is higher in individuals who are HLA-DR2-positive (relative risk 13.1), indicating a possible genetic predisposition.⁷


EBA develops as a consequence of circulating autoantibodies, usually IgG, against type VII collagen. Anchoring fibrils that serve to anchor the BMZ into the papillary dermis consist in part of type VII collagen. Antibody adherence to the collagen disrupts the anchoring fibrils through an unknown mechanism, causing a subepithelial blister.¹ 


Patients with EBA typically present with blisters in trauma-prone areas such as the dorsal hands, knuckles, elbows, knees, sacral area, and toes; lesions heal with scarring and milia formation. Because of the autoimmune nature of the disease, EBA is often associated with other autoimmune conditions, most commonly inflammatory bowel disease, although other disorders including SLE, thyroiditis, and diabetes have been reported.⁸ 


Treatment of EBA is difficult. The disease is typically chronic with periods of remission and exacerbation; spontaneous resolution is rare. Most cases respond poorly to high-dose immunotherapy typically used for other blistering disorders.⁹ However, many report a good response to colchicine, suggesting it to be first-line treatment for EBA.⁹ Rituximab is rapidly becoming first-line therapy for pemphigus and may hold promise for treating refractory EBA in the future, but more data are needed.⁹


While awaiting biopsy results, our patient was started on high-dose prednisone and mycophenolate mofetil with little response. Once the diagnosis was confirmed, colchicine was added and steroids were tapered. His condition remains in remission, with an occasional blister, on the combination of colchicine and low-dose mycophenolate mofetil. 


K. Jade Kindley is a third-year student at Medical College of Virginia Hospitals, Virginia Commonwealth University, Richmond, where Julia R. Nunley, MD, is a professor of dermatology.


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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 Flat-topped papules on a child’s trunk and Scaly erythematous rash. Then take the post-test here.

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