Case reports
Case 1: An 82-year-old woman with a long history of type 2 diabetes started to take linagliptin (5 mg/day) in addition to the combination of basal insulin and a glinide. Nine months later, linagliptin was switched to teneligliptin (20 mg/day) at a different hospital. After a further six months, she presented with pruritic erythema on the trunk and limbs, followed by development of blisters on the left arm (Fig. 1 a). She consulted a dermatologist at our university hospital. Examination revealed diffuse bullae and generalized edematous erythema. Histological examination of a skin biopsy specimen with hematoxylin and eosin (H-E) staining showed subepidermal blisters and scanty eosinophil infiltration (Fig. 1 b). Direct immunofluorescence demonstrated linear deposits of immunoglobulin G (IgG) along the epidermal basement membrane (Fig. 1c; yellow arrows). The serum level of anti-BP180 antibody (non-collagen 16A domain; NC16A) was elevated to 328 U/mL. BP was diagnosed from these findings.
After hospitalization, treatment with prednisolone (40 mg/day) and cyclosporine (150 mg/day) was initiated, while teneligliptin was discontinued because it was suspected to be the cause of BP. However, her skin lesions did not improve and serum anti-BP 180 antibody increased to 10000 U/mL on January 10, 2017. Intravenous steroid pulse therapy was commenced, as well as administration of intravenous immunoglobulin (IVIG) and plasmapheresis on several occasions. Subsequently, her skin lesions improved and anti-BP180 antibody decreased to 109 U/mL on March 13, 2017. However, her symptoms showed repeated exacerbation after discharge from hospital. Therefore, the patient was readmitted and received intravenous steroid pulse therapy, IVIG and plasmapheresis, but her skin lesions did not respond. After that, she had a fall and developed confusion. Emergency head computed tomography revealed new bleeding into an existing chronic subdural hematoma (Fig. 2a). The patient died two weeks later, possibly from cerebral herniation.
Case 2: An 89-year-old woman with long-standing type 2 diabetes started treatment with sitagliptin (50 mg/day), which was switched to vildagliptin (100 mg/day) at a different hospital. Three years after initiation of vildagliptin therapy, she presented with erythema and small tense blisters on her limbs and trunks. She visited a local dermatology clinic and was referred to the department of dermatology at our university hospital. On examination, she had tense bullae and erythema on her chest and limbs (Fig. 1a), along with scars due to scratching on her back. Histological examination of a skin biopsy specimen from the right leg with H-E staining revealed blisters with fibrin precipitates and infiltration of eosinophils into the epidermis and dermis (Fig.1b). Direct immunofluorescence showed linear staining for IgG along the epidermal basement membrane (Fig. 1c; yellow arrows). Serum anti-BP180 NC16A antibody was elevated to 3450 U/mL. BP was diagnosed on the basis of these findings. Vildagliptin was discontinued immediately and treatment was started with prednisolone (30 mg/day), doxycycline (100 mg/day), and niceritrol (500 mg/day). Despite this regimen, new blisters continued to appear, so cyclosporine (150 mg/day) was added to her therapy. Subsequently, the skin lesions gradually improved and did not relapse when prednisolone and cyclosporine were tapered. She continued prednisolone at a dose of 10 mg / day with no recurrence of blistering and erythema. Three months later, she became unconsciousness after a history of poor health for several days. Cardiopulmonary arrest occurred when she was transported to the emergency department of our university hospital. Although emergency treatment was initiated, the patient could not be revived. Laboratory tests performed upon arrival showed leukocytosis of 27400 /µl and elevation of serum C-reactive protein to 11.91 mg/dl. Whole body computed tomography revealed multiple nodular lesions in the middle to lower lobes of both lung (Fig. 2b), and suspected ascending colon cancer (Fig. 2c; red arrow) with para-aortic lymphadenopathy (Fig. 2 c: yellow arrows).
Case 3.
A 67-year-old man with type 2 diabetes commenced treatment with alogliptin (12.5 mg/day). The dose of alogliptin was subsequently increased to 25 mg/day and metformin (500 mg/day) was added. After 3.5 years, he developed generalized blisters on his skin and intraorally. He presented to the department of dermatology at our university hospital. On examination, several areas of edematous erythema without blistering were found on his thigh and in the oral cavity (Fig. 1a). Histological examination of a skin biopsy specimen with H-E staining showed subepidermal blisters with scanty eosinophil infiltration into the skin (Fig. 1b). Direct immunofluorescence demonstrated linear deposits of IgG along the epidermal basement membrane (Fig. 1c; yellow arrows). Serum anti-BP180 antibody was negative, but BP was diagnosed from the other findings. Alogliptin was discontinued immediately and treatment with prednisolone (20 mg/day) was started. The dose of prednisolone was tapered to 4 mg/day as his symptoms gradually improved, and he currently remains in remission.