Discussion:
BP is an autoimmune disease that causes bullae, erosions, and erythema
on the skin and mucosal surfaces. It is characterized by autoantibodies
targeting hemidesmosomal proteins BP180 and BP230 involved in adhesion
at the epidermal-dermal junction [1]. A wide variety of drugs
(diuretics, spironolactone, furosemide, antihypertensives, and
antibiotics) have been associated with development of BP in elderly
persons [2]. Recently, there have been increasing reports that use
of DPP-4 inhibitors is also associated with the development of BP
[3-6]. Several retrospective case-control studies have compared the
frequency of DPP-4 inhibitor use between BP patients with diabetes and
control diabetes patients without BP, demonstrating an association of
DPP-4 inhibitors with the development of BP [8-10]. Accordingly,
patients who are using DPP-4 inhibitors should be warned to report
new-onset diffuse itching, urticarial lesions, or blisters.
Izumi et al. reported that DPP-4 inhibitor-associated BP featured less
prominent erythema clinically and showed little evidence of histological
inflammation with scanty infiltration of eosinophils into the skin,
suggesting it was an atypical form of non-inflammatory BP [11]. It
was also suggested that drug-induced BP could have a relatively
favorable outcome compared with typical BP. Our Cases 1 and 3 were
examples of this non-inflammatory phenotype of DPP-4
inhibitor-associated BP, presenting with less erythema and minor
infiltration of eosinophils into the skin on histological examination
(Figure 1 and Table 1). On the other hand, there have been reports that
most patients with DPP-4 inhibitor-associated BP have typical clinical
manifestations and histological features of this disease [9,12].
According to these authors, there are no significant differences of
either symptoms or cutaneous eosinophil infiltration between BP arising
in diabetic patients with or without prior DPP-4 inhibitor therapy
[9,12].
Benzaquen et al. reported that discontinuation of DPP-4 inhibitor
therapy had a favorable impact on the outcome of BP in 19 patients with
diabetes, because 95% of them achieved clinical remission after
stopping DPP-4 inhibitors and receiving first-line treatment for BP
[8]. A retrospective case-control study also demonstrated that
clinical outcomes were less favorable among 13 patients with diabetes
who continued DPP-4 inhibitors compared to 19 patients who discontinued
DPP-4 inhibitors, with eight of the 13 patients who continued DPP-4
inhibitors dying between 2 months and 4.9 years after the initial
diagnosis of BP [9]. These findings suggested that discontinuation
of DPP-4 inhibitor therapy may be associated with better clinical
outcomes. Taking the results from these studies together [8, 9], it
can be suggested that administration of DPP-4 inhibitors should be
discontinued immediately when a diagnosis of BP is made. However, we
experienced two cases of DPP-4 inhibitor-associated BP with unfavorable
outcomes despite immediate withdrawal of DPP-4 inhibitor therapy and
initiation of first-line treatment for BP with an oral steroid and a
high-potency topical steroid. Both patients were elderly women over 80
years old.
In Case 1, skin lesions showed multiple relapses despite discontinuation
of DPP-4 inhibitor therapy and initiation of treatment for BP. She
received intravenous steroid pulse therapy, IVIG, and plasmapheresis in
hospital on several occasions. Eventually, she died after a fall,
probably from cerebral herniation associated with a subdural hematoma.
We speculate that repeated hospitalization and steroid therapy for
treatment of BP can cause muscle weakness, resulting in a fall. In Case
2, symptoms of BP were improved by treatment with oral prednisolone and
cyclosporine, but the patient died after deterioration of her general
condition. Immunosuppressive therapy can lead to compromised immunity in
older patients with diabetes, triggering opportunistic infections.
Immunosuppressive therapy may also promote the development or
progression of cancer. Although we could not identify the pulmonary
nodular lesions detected by computed tomography in this patient, she may
have died of lung metastasis from primary colon cancer, although the
possibility that opportunistic pulmonary infection was associated with
her death cannot be excluded. We speculate that persistent
immunomodulatory effects of DPP-4 inhibitor despite its withdrawal and
use of immunosuppressants may induce carcinogenesis or promote
development of colon cancer with pulmonary metastasis. It was recently
reported that control of BP and relapse of this condition did not differ
between patients who stopped or continued treatment with DPP-4
inhibitors [13]. This report and our experience suggest that it is
important for clinicians to pay close attention to the clinical course
of DPP-4 inhibitor-associated BP, even after discontinuation of DPP-4
inhibitor therapy.
The mechanisms responsible for BP associated with DPP-4 inhibitor
therapy remain to be determined. DPP-4 (CD26) is highly expressed by T
cells, especially CD4+ T cells. It is possible that inhibition of DPP-4
may be associated with development of autoimmune skin diseases, because
autoreactive T cells are involved in the pathogenesis of BP [14]. A
previous study demonstrated that the HLA-DQB1*03:01 allele is a
biomarker for genetic susceptibility to BP associated with DPP-4
inhibitors in a Japanese population [15], suggesting an association
between HLA class II and this drug-induced autoimmune disease. Our Case
3 was positive for the HLA-DQB1*03:01 allele, in agreement with this
report (Table 1). We previously demonstrated that sitagliptin, another
DPP-4 inhibitor, reduced circulating CD4+ T cells in patients with type
2 diabetes, especially causing a decline of regulatory T cells [16].
These cells play a very important role in the immune system by
suppressing immune responses and maintaining tolerance, and prevent the
development of autoimmune diseases by suppressing T cell activation
[17]. In fact, a very recent study demonstrated that dysfunction of
regulatory T cells is associated with induction of autoantibodies to
bullous pemphigoid antigens in mice and humans [18]. Another
possibility is that inhibition of DPP-4 augments the activity of eotaxin
(CCL11), a DPP-4 substrate, resulting in recruitment of eosinophils to
the skin [19].
In conclusion, we experienced 3 patients with type 2 diabetes who
developed DPP-4 inhibitor-associated BP. Despite prompt discontinuation
of DPP-4 inhibitor therapy and initiation of first-line treatment for
BP, the outcome was unfavorable in two patients. Accordingly, clinicians
should carefully monitor the course of DPP-4 inhibitor-associated BP
even after withdrawal of DPP-4 inhibitor therapy, especially in very
elderly patients.