Bullous pemphigoid induced by dipeptidyl peptidase-4
inhibitors. Eight cases with clinical and immunological
, Marta Ivars-Lle
, Daniel L
, Takashi Hashimoto
, Pilar Iranzo
, Ramon M. Pujol
, and Josep E. Herrero-Gonzalez
Department of Dermatology, Hospital del
Mar, Parc de Salut Mar, Institut Hospital del
Mar d’Investigacions M
Dermatology, School of Medicine,
University Clinic of Navarra, Pamplona,
Department of Dermatology,
Kurume University School of Medicine, and
Kurume University Institute of Cutaneous
Cell Biology, Fukuoka, Japan, and
Department of Dermatology, Hospital
Clinic de Barcelona, Barcelona, Spain
Josep E. Herrero Gonzalez, MD, PhD
Department of Dermatology
Hospital del Mar
ıtim, 25-29, 08003 Barcelona
na, MD, PhD
Department of Dermatology
School of Medicine
University Clinic of Navarra
PO Box 4209 Pamplona 31080
Conﬂict of Interest Disclosure:
Background Dipeptidyl peptidase-4 (DPP-4) inhibitors have increasingly been identiﬁed as
causative agents of bullous pemphigoid. The clinical and immunological characteristics of
this pemphigoid variant are still unclear. The objective of our study was to analyze the
clinical and immunological features of patients with pemphigoid induced by DPP-4
Methods All patients diagnosed with DPP-4 inhibitor-associated bullous pemphigoid at
dermatology departments in three Spanish centers during the period 2013 to 2015 were
included. ELISA assays for the NC16A domain of BP180 and BP230 were performed.
Immunoblot studies using epidermal/dermal extracts and the C-terminal, NC16A and
LAD-1 regions of BP180 were also carried out.
Results A total of eight patients were identiﬁed (5 treated with vildagliptin, 2 with linagliptin,
and one with sitagliptin). Of these, four presented the classical inﬂammatory phenotype of
bullous pemphigoid and four a noninﬂammatory phenotype. The ELISA for BP180 (NC16A
domain) was positive in six patients at diagnosis. Most patients reacted to more than one
BP180 antigenic site (LAD-1 and/or C-terminal domain) on the immunoblot. Two patients
showed no reaction against the NC16A domain of BP180 on either the ELISA or
immunoblot but recognized either LAD-1 or both LAD-1 and the C-terminal domain. Only
one of the NC16A-negative patients had a noninﬂammatory subtype of bullous pemphigoid.
Conclusions Patients with DPP-4 inhibitor-induced BP may present either an inﬂammatory
or a noninﬂammatory phenotype of BP. IgG response against other BP180 regions
different from the NC16A domain, such as LAD-1 and the C-terminal domain, could be
pathogenically relevant to the onset of DPP-4 inhibitor-induced BP.
Bullous pemphigoid (BP) is the most common cutaneous
autoimmune blistering disease. It typically affects elderly
patients and is associated with signiﬁcant rates of morbidity and
Mucosal involvement is usually present in about 20–
30% of patients.
Most patients with BP have circulating autoan-
tibodies directed against one of two hemidesmosomal proteins
(BP180 and BP230).
Antibodies directed against the extracellu-
lar NC16A domain of BP180 protein have been shown to play a
relevant role in the pathogenicity of this disease.
the vast majority of patients no causative agent is identiﬁed, in
rare instances development of the disease has been linked to
the use of certain drugs.
This drug-induced variant of BP usu-
ally shares common clinical, histopathological, and immunoﬂuo-
rescence ﬁndings with conventional BP.
pathogenic mechanisms underlying this peculiar drug-related
BP subtype are unknown, and only few studies that character-
ize the epitope speciﬁcities have been performed.
Oral dipeptidyl peptidase-4 (DPP-4) inhibitors, so-called glip-
tins (vildagliptin, sitagliptin, linagliptin, and saxagliptin), have
been introduced in recent years for the treatment of type 2
International Journal of Dermatology 2018, 57, 810–816 ª 2018 The International Society of Dermatology