Acta Dermato-Venereologica 98-10CompleteContent | Page 18
SHORT COMMUNICATION
983
Dipeptidyl Peptidase-4 Inhibitor-associated Bullous Pemphigoid: Recurrence with Epitope Spreading
Hiroyuki TAKAMA 1,2 *, Makiko YOSHIDA 1 , Kentaro IZUMI 3 , Takeshi YANAGISHISTA 1 , Jun MUTO 1 , Yuichiro OHSHIMA 1 , Wataru
NISHIE 3 , Hiroshi SHIMIZU 3 , Masashi AKIYAMA 2 * and Daisuke WATANABE 1
Departments of Dermatology, 1 Aichi Medical University, 1-1 Yazako, Karimata, Nagakute, Aichi, 480-1195, 2 Nagoya University Graduate
School of Medicine, Aichi, and 3 Graduate School of Medicine, Hokkaido University, Hokkaido, Japan. E-mails: [email protected] and
[email protected]
Accepted Jul 27, 2018; Epub ahead of print Aug 7, 2018
Bullous pemphigoid (BP) is the most common autoim-
mune blistering disease that affects the skin and muco-
sae. Many cases of BP associated with oral intake of
dipeptidyl peptidase-4 inhibitors (DPP4Is) have been
reported recently (1–5). We report here a case of a woman
with BP associated with DPP4Is. Interestingly, epitope
spreading of anti-BP180 antibodies was observed when
her disease recurred.
CASE REPORT
An 86-year-old woman visited our hospital with a complaint of
general itching. She had been prescribed linagliptin, a DPP4I,
for diabetes at a clinic. Blisters appeared on her lower limbs 6
weeks after initiation of oral linagliptin treatment, and the number
of blisters gradually increased. At first, her attending physician
suspected an allergic reaction to linagliptin. He changed the
patient’s treatment from linagliptin to anagliptin, another DPP4I,
but the blister formation continued. At the patient’s first visit to
our hospital (defined as day 0), multiple blisters were seen scat-
tered on both legs (Fig. 1a). A biopsy specimen from a bullous
eruption on her right thigh showed a subepidermal blister with
eosinophil infiltration (Fig. 1b). Direct immunofluorescence
revealed linear deposition of IgG and complement component
C3 at the dermoepidermal junction (Fig. 1c). In analyses of the
patient’s serum, enzyme-linked immunosorbent assay (ELISA)
for the non-collagenous 16A (NC16A) domain of BP180 was
negative, but ELISA for full-length (FL) BP180 was positive.
DPP4I-associated BP was suspected, and oral anagliptin was
discontinued on day 10. After cessation of anagliptin, blister
formation gradually diminished, and the patient’s anti-FL-BP180
antibody titres decreased immediately. On day 150, blister forma-
tion had stopped completely. Although itching and erythematous
plaques on the extremities were seen intermittently, the symptoms
were controlled with topical clobetasol propionate.
On day 185, blisters relapsed bilaterally on the patient’s lower
legs and trunk, although she had not taken any additional DPP4Is
and continued using topical clobetasol propionate. At this time,
ELISA for the NC16A domain of BP180 using the patient’s serum
became positive, whereas the titres of her anti-FL-BP180 antibo-
dies continued decreasing (Fig. 1d, Table I). Because the patient
had hyperglycaemia, we prescribed oral low-dose prednisolone
(7.5 mg/day) and minocycline. Blister formation stopped within
one week, but itching and erythematous plaques on the extremities
remained. We substituted mizoribine in place of minocycline, and
her symptoms were gradually relieved. She became negative for
anti-BP180 NC16A antibodies on day 220. She stopped treatment
of her own volition on day 297. Her symptoms did not recur, and
ELISA results for her serum have remained negative for both the
NC16A domain of BP180 and FL BP180.
DISCUSSION
In 2017, Benzaquen et al. (6) confirmed for the first time
in a case-control study that DPP4Is are associated with
an increased risk of developing BP in diabetic patients
(adjusted odds ratio (OR) 2.64; 95% confidence interval
(CI): 1.19–5.85; p = 0.02). Izumi et al. (7) also reported
autoantibody profiles of patients with DPP4I-associated
BP. They suggested that DPP4I-associated BP involves
autoantibodies targeting the mid-portion of BP180, but
not the NC16A domain. DPP4 is a cell-surface plasmi-
nogen receptor that is able to activate plasminogen to
plasmin. Plasmin is a major serine protease that is known
to cleave BP180 within the juxtamembranous extracel-
Fig. 1. Clinical and histopathological features and chronological changes in anti-BP180 antibody titres. (a) A clinical feature on the right thigh
during the patient’s first visit to our hospital. Tense blisters and erosions were observed. (b) A biopsy specimen from the exanthema on the patient’s
lower leg showed a subepidermal blister with eosinophil infiltration (haematoxylin-eosin, original magnification ×200). (c) Recurrent exanthema with
blisters and erosions on the left chest. (d) Chronological changes in titres of anti-BP180 NC16A antibodies and anti-FL-BP180 antibodies in the patient’s
serum. When BP recurred (black arrowheads), anti-BP180 NC16A antibodies became positive, and anti-FL-BP180 antibodies continued decreasing (day
185, 25 weeks after discontinuing DPP4I treatment).
This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta
Journal Compilation © 2018 Acta Dermato-Venereologica.
doi: 10.2340/00015555-3010
Acta Derm Venereol 2018; 98: 983–984