Diabetes & Metabolic Syndrome: Clinical Research & Reviews

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Brief Report
ImageDipeptidyl peptidase 4 inhibitors linked bullous pemphigoid in patients with type 2 diabetes mellitus: A series of 13 cases
Alka Jha a, Anoop Misra b, c, d, *, Ritesh Gupta b, Amerta Ghosh b, Kanika Tyagi b,
Koel Dutta b, Bhavya Arora b, Suhail Durani e
a Fortis Flt.Lt. Rajan Dhall Hospital, Vasant Kunj, New Delhi, India
b Fortis-C-DOC Hospital, Diabetes, Endocrinology and Allied Specialties, New Delhi, India
c National Diabetes, Obesity and Cholesterol Foundation(N-DOC), New Delhi, India
d Diabetes Foundation India (DFI), New Delhi, India
e Fortis Memorial Research Institute, Gurugram, India

Keywords:
Diabetes
Dipeptidyl peptidase 4 inhibitors Bullous pemphigoid

a b s t r a c t

Background: Dipeptidyl peptidase 4 (DPP4) inhibitors have increasingly been linked to bullous pem- phigoid, but there is paucity of data from India where about 1.85 million patients have been estimated to use these drugs.
Methods: In 30,000 patients with T2DM seen by us in two tertiary care centres since 2015, we detected
13 cases of bullous pemphigoid linked to DPP4 inhibitors. We used WHO-UMC (World Health Organisation-Uppsala Monitoring Centre) causality assessment system for assessment.

Results: Lesions of bullous pemphigoid appeared at varied intervals (within 1 weekse2 years) after start of DPP4 inhibitors. Implicated drugs were Linagliptin (n, 8), Vildagliptin (n, 4) and Sitagliptin (n, 1). Mostly, lesions were seen after 60 years age, and over trunk and extremities. Skin biopsy was compatible with bullous pemphigoid in two patients. Lesions regressed within a month of stopping DPP4 inhibitors in 9 patients while delayed regression up to 6 months in 4 patients. Overall, skin lesions remitted in all patients and did not recur.
Conclusion: Any new bullous lesion appearing while patient is on DPP4 inhibitors should be considered as bullous pemphigoid and should necessitate prompt withdrawal of the drug.
© 2020 Diabetes India. Published by Elsevier Ltd. All rights reserved.

1. Introduction

Dipeptidyl Peptidase 4 (DPP4) inhibitors, introduced in year 2006, are important second line oral anti-hyperglycemic drugs for treatment of type 2 diabetes (T2DM). DPP4 inhibitors increase incretin and insulin secretion, decrease glucagon levels, and improve glycemic control. In general, they lower HbA1c from 0.7% to 0.97% [1] and are popular because of relative “freedom from side effects”. Seven types of DPP4 inhibitors have been available in India, named here in order of initial date of availability: Sitagliptin, Vil- dagliptin, Saxagliptin, Linagliptin, Tenegliptin, Gemigliptin (with- drawn in 2019) and Evogliptin. While these drugs are used widely previously, sales have further increased in India because of

*Corresponding author. Fortis C-DOC Hospital, Diabetes, Endocrinology and Allied Multi-Speciality, B-16, Chirag Enclave, New Delhi, 110048, India.
E-mail address: [email protected] (A. Misra).
availability of cheaper drugs (e.g. Teneligliptin) and following lowering of prices (e.g. Vildagliptin). Though data are not wholly reliable, the sale of DPP4 inhibitors is estimated at Rs 1800 crore (USD 251,280,000) yearly, is growing at around 40% annually as reported in 2018. Of the 68 million patients with diabetes in India, about 1.85 million are on these drugs [2].

Known adverse effects of DPP4 inhibitors include nasophar- yngitis, headache and upper respiratory tract infection and less common and debatable pancreatitis. Recently there have been several reports of skin related adverse drug reactions including bullous pemphigoid [3e8]. Profile of this specific skin reaction re- mains sparsely researched in Indian subcontinent.
We have been conducting pharmacovigilance program on DPP4 inhibitors since 2015 in our tertiary diabetes centres in Delhi. In this case series we report 13 cases of probable/certain lesions of bullous pemphigoid. Although this adverse drug reaction has been increasingly reported from Western world and Japan, this is first case series from India.

https://doi.org/10.1016/j.dsx.2020.03.001

1871-4021/© 2020 Diabetes India. Published by Elsevier Ltd. All rights reserved.

2. Methods

In 30,000 patients with T2DM seen by us in two tertiary care canters since 2015, we have detected 30 cases of various type of skin lesions associated with usage of DPP4 inhibitors including generalized pruritic rash, fixed drug eruptions, non-specific pig- mented maculopapular lesions and bullous pemphigoid. Our research has been focussed on bullous pemphigoid, diagnosis of which was made by qualified dermatologists (having postgraduate degree) in 13 patients. We used WHO-UMC (World Health Organisation-Uppsala Monitoring Centre) assessment system for causality assessment [9]. All procedures involving human subjects/ patients were approved by an independent review committee, “Ethics Committee for Research” at Fortis C-DOC Hospital, New Delhi. This study is a retrospective data analysis, hence written informed consent from patients/cases was not possible.

3. Results

In our series, lesions of bullous pemphigoid appeared at varied intervals after initiation of drug (Table 1). In a few cases (n, 4) le- sions developed within 1e3 weeks, while in smaller number of patients (n, 2) these occurred up to 1e2 years after start of DPP4 inhibitors. Mostly, these lesions were seen after 60 years age (n, 8). Implicated drugs were Linagliptin (n, 8), Vildagliptin (n, 4) and Sitagliptin (n, 1). In most of our patients skin lesions were seen over trunk and extremities (Figs. 1 and 2). Only one patient showed mild oral mucosal involvement. Skin biopsy was possible for two pa- tients and histological findings (Figs. 3 and 4, patient 13 in Table 1) were compatible with bullous pemphigoid. In all these patients, DPP4 inhibitors were immediately stopped. Additional therapy for bullous pemphigoid included topical steroids (n, 7) or oral steroids (n, 6) for a period of 10e14 days. No patient requiredShowing tense bullous lesions on lateral side of abdomen in 56 year old male on Linagliptin (described as case 13 in Table 1).immunosuppressive treatment. Specifically, lesions in 9 patients regressed within a month of stopping DPP4 inhibitors while delayed regression up to 6 months in 4 patients. Overall, skin le- sions remitted in all patients and did not recur. After stopping DPP4 inhibitors, all patients were continued on metformin.

4. Discussion

Bullous pemphigoid is the common cutaneous autoimmune blistering skin disease. Typical clinical features include widespread bullous lesions and occurrence in elderly. Bullous pemphigoid is associated with significant rates of morbidity and mortality. It is caused by the binding of autoantibodies to specific antigens (referred to as bullous pemphigoid antigens, BP 230 (BPAg1) and BP
180 (BPAg2, COL17)), found in the lamina lucida region of the basement membrane on the hemidesmosomes of epithelial basal cells. Binding of antigen to antibody activates both leukocytes and complements, leading to degranulation of mast cells, activation of neutrophils and eosinophil, and production of proteolytic enzymes that cause localized damage to the basement membrane at dermo- epidermal junction and vesicle formation in the subepithelial re- gion [10].

Although no causative agent is identified in most patients; in rare instances development of the disease has been linked to the
Fig. 4. Photograph of full thickness skin biopsy under light microscopy X40 from the bullous lesion on the lateral side of abdomen of 56 year old male (described as case 13 in Table 1) stained with hematoxylin-eosin showing inflammatory infiltrates consist- ing of few eosinophils, neutrophils rare plasma cell and fibrin exudates. Additionally, upper dermal edema and perivascular lymphocytic infiltrates are shown use of certain drugs like spironolactone, nonsteroidal anti- inflammatory drugs, captopril, phenacetin, penicillamine, etarna- cept, tibolone and systemic antibiotics [11]. This drug-induced variant of bullous pemphigoid usually shares common clinical, histopathological, and immunofluorescence findings with con- ventional bullous pemphigoid.

The intrinsic pathogenic mechanism underlying this peculiar drug-related bullous pemphigoid subtype is unknown.
Since the introduction of DPP4 inhibitors, several reports of patients developing bullous pemphigoid have been published. Some observational studies (case-control design) have shown increased risk [odds ratios (OR) ranging between 1.58 and 3.16] of bullous pemphigoid with the use of DPP4 inhibitors [3e8]. In a recent retrospective case control study from northern Israel, Kridin and Bergman [3] identified 82 patients with diabetes who received a new diagnosis of bullous pemphigus with DPP4 inhibitors, computed to be 3- fold increase risk as compared to metformin. In this study, Vildagliptin was most strongly [adjusted OR 10.67 (95% CI 5.09e22.36)] linked to bullous pemphigoid, followed by Lina- gliptin [adjusted OR 6.65 (95% CI 2.24e19.72)]. No significant as- sociation was seen with sitagliptin.

Similar high odds for bullous pemphigoid with Vildagliptin have been seen in studies from France [adjusted OR: 2.64 (95% CI 1.19e5.85)]5 and Switzerland [adjusted OR: 2.48 (95% CI 0.75e8.3)] [6], Finland [OR:10.4 (95% CI 4.56e23.80)]7 and Korea [adjusted OR:1.81 (95% CI 1.31e2.50)]8 as well. Interestingly, potential signal for bullous pemphigoid with DPP4 inhibitors wasalso observed in the Cardiovascular and Renal Microvascular Outcome Study with Linagliptin (CARMELINA) trial, where a numerically more cases of bullous pemphigoid events were reported with Linagliptin (Linagliptin vs. placebo: seven vs. zero events). Only a few some case reports have been published implicating Linagliptin [3] and Sitagliptin [12]. Previously, two cases reports have been described from India (Vildagliptin [13], Teneligliptin [14]).

In our case series reports we observed more cases of bullous pemphigoid with Linagliptin; reason could be because in our setup the proportional use of Linagliptin is approximately 50% followed by use of Vildagliptin (30%), Sitagliptin (15%) and others (Ten- egliptin and Evogliptin, 5%). The time periods from the start of the drug intake to the onset of symptoms are quite variable. Bene et al. [4]. Reported a median time of 10 months, with a range from 8 days to 37 months and similar trend was observed in our case series (14 dayse24 months).This adverse drug reaction of DPP4 inhibitors is beginning to get more research attention. With increasing use of these drugs, high index of suspicion for often difficult to treat bullous pemphigoid should be considered by all clinicians. It is likely that after patent expiry of Vildagliptin in December 2019 in India and thus avail- ability of cheaper drug, these drugs will be increasingly used.

Declaration of competing interest
No potential conflicts of interest.

Acknowledgements
No financial support and sponsorship. I would like to thank our pathologist Dr Nitin Kumar Dumeer for his support.

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