Bullous Pemphigoid Triggered by Thermal Burn Under Medication With a Dipeptidyl Peptidase-IV Inhibitor: A Case Report and Review of the Literature

Bullous pemphigoid (BP) is a common autoimmune blistering disease in which autoantibodies mainly target the hemidesmosomal component BP180 (also known as type XVII collagen) in basal keratinocytes. Various triggering factors are known to induce BP onset, including radiotherapy, burns, ultraviolet exposure, surgery, and the use of dipeptidyl peptidase-IV inhibitors (DPP4i), which are widely used antihyperglycemic drugs. Here, we present a case of BP triggered by a thermal burn under medication with DPP4i. A 60-year-old man with type II diabetes had been treated with the DPP4i linagliptin for 1 year. After the right forearm experienced a thermal burn, blisters developed around the burned area and gradually spread over the whole body with the production of autoantibodies targeting the non-NC16A domain of BP180. The diagnosis of BP was confirmed by immunohistopathological examination. Upon withdrawal of linagliptin and treatment with topical steroid and minocycline, complete remission was achieved after 4 months. Previously, 13 cases of BP that developed after thermal burns have been reported, and our case shared some of the clinical features of these thermal burn-induced BP cases. Interestingly, the present case also showed the typical clinical, histopathological, and immunological features of the non-inflammatory type of DPP4i-associated BP (DPP4i-BP). Although the pathogenesis of BP remains uncertain, the present case suggests that DPP4i may trigger the onset of BP similarly to a thermal burn. In addition, the clinical and histopathological features of DPP4i-BP may be distinct from other types of BP.

FIgURe 1 | (a) Tense blisters and erosions of less than 2 cm in diameter developed over the thermal burn scar on the right forearm. Circumscribed erythematous lesions were also found. (B) Small erosions of less than 5 mm in diameter were found on the trunk without erythema. (C) Histopathological examination of the blister shows sub-epidermal blistering with some eosinophilic infiltration in the dermis. Scale bar: 100 µm. (D) Direct immunofluorescence shows linear IgG autoantibody deposits at the basement membrane zone (arrowheads). on the right forearm, which were treated with a topical antibiotic ointment. However, multiple blisters and erosions gradually developed over the body over the course of 2 months. Physical examination revealed tense blisters and erosions of 5 mm to 2 cm in diameter with circumscribed erythematous lesions predominantly on the right forearm ( Figure 1A). Blisters and erosions less than 5 mm in diameter without erythema were found on the face, the trunk, and the left leg ( Figure 1B). Although BP180 NC16A chemiluminescent enzyme immunoassay (CLEIA) was negative (5.9 U/mL; normal, <9.0 U/mL), histopathological examination of the blister showed sub-epidermal blister formation with some eosinophilic infiltration in the dermis ( Figure 1C). Direct immunofluorescence showed linear deposition of IgG autoantibodies along the dermal-epidermal junction (Figure 1D), and 1 M NaCl-split skin indirect immunofluorescence revealed circulating IgG autoantibodies reacting with the epidermal side of the artificial blisters (not shown). Notably, enzyme-linked immunosorbent assay (ELISA) using full-length recombinant BP180 was positive (index value, 41.8; normal, <4.64) (1). Based on these findings, the diagnosis of bullous pemphigoid (BP) was made. Linagliptin was withdrawn 2 days after the referral, and treatment with a topical steroid and minocycline at 100 mg/day was started. His skin lesions gradually improved, and ELISA with full-length recombinant BP180 became negative (index value, 1.03). Complete remission off therapy was achieved 4 months later (Figure 2). Although no DPP4i was re-administered, blisters appeared on the left forearm 16 months later, when he developed cellulitis on the right leg. The histopathology of the blister showed sub-epidermal blistering with scant eosinophilic infiltration in the dermis (not shown), which was consistent with BP. BP180 NC16A CLEIA was still negative (<3 U/mL). Topical steroid, minocycline at 200 mg/day, and nicotinamide at 1,500 mg/day were initiated, and the lesions completely resolved 2 months later. At 2 months after the cessation of treatment, no recurrence was observed (Figure 2).

INtRoDUCtIoN
Bullous pemphigoid is a common autoimmune blistering disease in which autoantibodies target the hemidesmosomal components BP180 (also known as type XVII collagen) and/or BP230 at the dermal-epidermal junction (3). Clinically, tense blister formation associated with itchy urticarial erythema is typically observed in BP patients, and sub-epidermal blister formation with eosinophilic infiltration is histopathologically observed (3). Although the etiology of BP remains unclear, various factors, including radiotherapy, burns, ultraviolet (UV) exposure, trauma, surgical procedures, topical medications, and infections are known to trigger the onset of the disease (4,5). Recently, emerging evidence reports that the use of DPP4i, which are widely used to treat patients with diabetes mellitus, increases the risk of BP onset (6-9).  Frontiers in Immunology | www.frontiersin.org April 2018 | Volume 9 | Article 542 (5,(52)(53)(54)(55)(56)(57)(58)(59)(60)(61) suggesting that the present case had a unique clinical course. Interestingly, linagliptin, which is a DPP4i, was administered to our case until the onset of BP. DPP4i-associated BP (DPP4i-BP) is a unique, recently reported subtype of BP that develops with the administration of DPP4i medications such as vildagliptin, sitagliptin, and linagliptin (6-9). DPP4i-BP tends to show scant erythema and low levels of autoantibodies targeting the NC16A domain of BP180 or the absence of such autoantibodies (1,73). In our case, BP developed after 1 year of DPP4i administration, in which erythema was scantly observed and autoantibodies specifically targeted the non-NC16A domain of BP180. In addition, complete remission was achieved after the withdrawal of DPP4i and the initiation of treatment with topical steroid and systemic minocycline. Histopathologically, eosinophilic infiltration was not evident. These characteristics closely resembled those of the non-inflammatory type of DPP4i-BP (1, 73); therefore, DPP4i use may also be involved in the development of the disease. It should be noted that a recent study reported that 18% of DPP4i-BP cases relapsed even after the withdrawal of DPP4i (7). Although the immunohistopathological results were uncertain, the present case developed BP-like blisters when he suffered from cellulitis 16 months after complete remission, indicating that DPP4i was also associated with the BP onset in the present case.

CoNCLUDINg ReMaRKs
In conclusion, we reported a case of BP induced by a thermal burn. Interestingly, the patient received DPP4i and showed the typical clinical, histopathological, and immunological characteristics of the non-inflammatory type of DPP4i-BP. Although the pathogenesis of thermal burn-induced BP and DPP4i-BP remains uncertain, BP may occur due to various triggering factors.

etHICs stateMeNt
This report on a single patient complies with the Declaration of Helsinki. The patient gave written informed consent for the publication of this report.
aUtHoR CoNtRIBUtIoNs YM, WN, and KIzumi drafted the paper. KS, MH, KIto, and KH were involved in treating the patient and collecting the clinical data. HS supervised the writing of the manuscript.

aCKNoWLeDgMeNts
The authors thank the patient and express their appreciation to Hiroko Azuma for her technical assistance.

FUNDINg
This work was supported in part by a Grant-in-Aid for Scientific Research (B) (#24390274 to WN) and Challenging Exploratory Research (#15K15409 to WN).