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.