Drug-induced localised bullous pemphigoid

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A 66-year-old man presented to the dermatology outpatient department with a history of multiple fluid-filled, tense blisters on the anterior aspect of the left leg (shin) for 5 months. These bullae were preceded by intense pruritus and did not rupture spontaneously. The bullae healed with atrophic scarring and hyper- and hypopigmentation of the surrounding skin. The patient was a known diabetic for the past 2 years, for which he was being treated with oral hypoglycaemic agents, metformin (1g) and voglibose (0.3 mg) taken twice daily. However, two months prior to the appearance of lesions, vildagliptin (50 mg) orally twice daily was initiated in view of inadequate diabetes control. His HbA1c was 7.8 and fasting blood sugar was 160 mg/dL. The patient denied any history of trauma preceding the lesions and had no significant family, medical or surgical history.

Examination revealed a few tense bullae overlying erythematous skin on the left shin, with scarring, atrophy,and hyper- and hypopigmentation in the surrounding area [Figure 1a]. Scarring was associated with milia formation [Figure1b].Based on the clinical features, differential diagnoses of localised bullous pemphigoid (BP), pemphigus vulgaris, diabetic dermopathy, pyoderma gangrenosum and irritant contact dermatitis were considered. Asboe-Hansen sign was positive with bullae expanding with a rounded margin. Nikolsky sign was negative, and the Tzanck smear showed abundant eosinophils, without acantholytic cells. A subepidermal split was appreciated on histopathology of thelesion. Fibrin and cell-rich inflammatory infiltrate, predominantly composed of eosinophils and lymphocytes, was seen in the blister cavity, with similar infiltrates at the base of bullae and the superficial dermis [Figures 2a and 2b]. Perilesional direct immunofluorescence (DIF) revealed linear IgG and C3 deposits at the dermo-epidermal junction (DEJ) [Figures 2c and 2d]. Serological testing was not done due to resource and financial constraints. Based on the above findings and in the light of the temporal correlation with drug intake (Naranjo Adverse Drug Reaction Scale score of 7), a diagnosis of gliptin-induced localised BP was confirmed. Vildagliptin was then omitted, and glimepiride (2 mg) once daily was prescribed alongside metformin. As new lesions continued to appear despite topical potent corticosteroid application (clobetasol propionate 0.05%) and antihistamine, oral dapsone (100 mg) daily was added after conducting baseline haematological investigations. After one month, the patient showed significant improvement with no new lesions and healing of older ones. At 4 months, dapsone was stopped, and his disease is well controlled [Figure 3].

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Figure 1a:

Lesion over the left leg showing scarring and atrophy with both hyper- and hypopigmentation.

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Figure 1b:

Resolving lesion showing milia formation (yellow arrow) and scarring.

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Figure 2a:

Microphotograph showing subepidermal split (Haematoxylin & eosin, 100x)

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Figure 2b:

Microphotograph showing fibrin and cell-rich inflammatory infiltrate composed of predominantly eosinophils and lymphocytes at the base of the bulla and superficial dermis (Haematoxylin & eosin, 400x).

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Figure 2c:

DIF of perilesional skin showing IgG deposits at DEJ (100x)

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Figure 2d:

DIF of perilesional skin showing C3 deposits at DEJ (100x)

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Figure 3:

Significant improvement in older lesions and scarring, with no new lesions post-treatment.

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Bullous pemphigoid (BP) is a sub-epidermal immunobullous disorder, occurring due to autoantibodies against BPAg1 and BPAg2 antigens at the DEJ. BP usually has a generalised manifestation. Localised BP is a rare manifestation of BP wherein lesions are limited to a localised site, having a relatively better prognosis. Two variants of localised BP have been described:1) plaques with scarring and 2) bullous with minimal scarring.¹ Based on the clinical presentation, our patient is more likely to have the latter variant. As is well known, sera of patients with BP primarily reacts with two antibodies, anti-BP230 and anti-BP180. However, low titres of BP180 in patients with localised BP are thought to explain the difference in manifestations.²

A literature review of 108 cases with localised BP showed a female predominance, with lower limbs being the most common site of involvement. The underlying cause was identified to be trauma in 63%, radiation therapy in 32.3%, and prior history of surgery in 29.3% cases.³

Our patient fulfilled the clinical, DIF, and histological criteria for localised BP.³

Dapsone has been used extensively in bullous dermatoses, including for BP. In a retrospective study involving 41 patients with autoimmune bullous disorders, four patients achieved partial remission at 2 months, and three patients achieved complete remission at 6 months with dapsone, with a significant reduction in the required prednisolone equivalent dose.⁴

Many cases of BP have been linked to the use of dipalmitoyl phosphatase inhibitors, gliptins. Gliptin-induced BP tend to have a better prognosis, with lesions appearing on apparently normal skin as compared to an erythematous base in generalised BP.⁵ The pathogenesis has been attributed to IgG autoantibodies targeting epitopes in the mid portion of the extracellular domain of BP180, in contrast to the juxta-membranous NC16A domain in cases of classical BP.⁶ Cases have been reported for gliptin-associated localised BP. However, such patients had a prior history of a concurrent local trigger.³

Therefore, localised BP should be considered in the differential diagnoses for patients presenting with recurrent local blistering disease. However, misdiagnosis is common, and confirmation with histology, serology, and DIF is essential.