Gliptin-induced dyshidrosiform bullous pemphigoid: A rare occurrence

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Dyshidrosiform bullous pemphigoid (BP) is an uncommon variant of BP, which usually presents as periodic vesiculobullous eruptions that predominantly affect the palms and soles of elderly individuals. Drug-induced dyshidrosiform BP is scarcely reported. We hereby report a case of gliptin-induced dyshidrosiform BP, which was treated with omalizumab.

A 79-year-old man visited the dermatology outpatient department with a 20-day history of multiple pruritic blisters of various sizes along with erosions on the bilateral palms and soles. He was a known case of diabetes for the last 25 years, managed with metformin and dapagliflozin. There was no family history of similar lesions or a history of any drug reaction in the past. For the past one year, he had been on vildagliptin. On cutaneous examination, multiple tense vesicles and bullae, ranging from 1×1 cm to 3×2 cm, were observed on an erythematous base, along with erosions measuring 2×5 cm in size, over the bilateral hands and feet [Figure 1]. No mucosal involvement was seen. A differential diagnosis of diabetic bullae, friction bullae, pseudoporphyria, and dyshidrosiform BP was made. A Tzanck smear revealed predominant eosinophils. A biopsy, along with direct immunofluorescence (DIF) was taken from the intact vesicles on the right palm. Histopathological examination showed a subepidermal blister cavity filled with a mixed inflammatory cell of eosinophils and neutrophils, while DIF showed immunoglobulin G (IgG) and C3 along the basement membrane in a linear pattern (4+ intensity) [Figures 2a-c]. The correlation of the clinical history, histopathology, and immunopathology established the diagnosis of dyshidrosiform BP. Given the recent use of vildagliptin, a final diagnosis of vildagliptin-induced dyshydrosiform BP was made.

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Figure 1:

Multiple tense vesicles, bullae, and erosions on bilateral palms and soles.

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Figure 2a:

Hyperkeratosis, acanthosis, and subepidermal split with inflammatory infiltrate. (Haematoxylin and eosin, 40x)

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Figure 2b:

Subepidermal split containing plenty of neutrophils and eosinophils. (Haematoxylin and eosin, 400x)

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Figure 2c:

Direct immunofluorescence showing linear IgG deposits along the dermo-epidermal junction 40x.

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The patient was treated with intravenous steroids under a cover of systemic antibiotics in view of secondary infection. The patient received 8 mg/day of intravenous dexamethasone for six days, followed by 6 mg/day for three days. Given the absence of new lesions, the patient was discharged on 30 mg oral prednisolone. Due to poor glycaemic control, insulin therapy was initiated. Ancillary investigations revealed serum immunoglobulin E (IgE) level to be 1,228 IU/mL. Considering the age, poor glycaemic parameters due to steroid use, and high total serum IgE, the patient was considered for injectable omalizumab. The patient was treated with tapering doses of oral corticosteroids, alongside a monthly dose of omalizumab, administered as a single subcutaneous dose of 300 mg over the next three months. Each dose was followed by a 2-hour observation for anaphylaxis. The patient showed significant improvement and has remained stable on follow-up for four months with no recurrence [Figure 3].

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Figure 3:

Post-treatment with oral steroids and omalizumab, resulting in complete resolution.

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BP has several clinical variants. These variants differ in terms of their clinical presentation, age of onset, and progression. They include vegetans, nodularis, vesicular, papular, eczematous, and erythrodermic among others. Dyshidrosiform BP is a rare variant characterised by haemorrhagic to purpuric bullae that are often confined to the palms and soles. The mechanism underlying this predilection for palms and soles remains unclear.¹ While drug-induced BP is not rare, the dyshidrosiform variant triggered by drugs has been seldom reported. Baclofen and cephalexin have been implicated in isolated cases.^2,3

Omalizumab, a monoclonal antibody that targets serum IgE, has emerged as a promising agent for treating BP. In drug-induced BP, especially with dipeptidyl peptidase 4 (DPP-4) inhibitors, elevated serum IgE levels reflect a Th2-skewed immune response characterised by eosinophil activation and intense pruritus.⁴ IgE autoantibodies against BP180 contribute to mast cell degranulation and blister formation. Raised IgE may correlate with more severe or treatment-resistant disease, supporting the use of targeted therapies like omalizumab. Omalizumab binds to free IgE preventing interaction with FcεRI, thereby reducing the release of inflammatory cytokines and preventing the destructive immune cascade. As dyshidrosiform BP shares this IgE-BP180-mediated mechanism, omalizumab makes a viable targeted therapy.⁵ A correlation between total serum IgE levels and anti-basement membrane zone antibody levels has also been reported in BP.⁶

Gliptins, a class of DPP-4 inhibitors, have been strongly associated with BP, although their association with dyshidrosiform BP has not been noted. Gliptin-induced BP may involve preferential targeting of non-collagenous 16 A domain of BP180 with impaired proteolytic processing and elevated CCL11/eotaxin levels driving eosinophil recruitment and blister formation. A genetic susceptibility, particularly of the HLA-DQB1*03:01 allele, further supports its distinct autoimmune pathogenesis.⁷

To the best of our knowledge, this is the first reported case of gliptin-induced dyshydrosiform BP. The importance of this report lies in sensitising the readers to the possibility that such an entity can mimic various dermatoses. Early diagnosis, elimination of the offending agent, and prompt treatment can help achieve faster clinical remission in such presentations.