A case series of vildagliptin-associated bullous pemphigoid - Rare side effect

Abstract

Vildagliptin, among the most commonly used, OHA, belongs to group dipeptidyl peptidase-4 inhibitors for managing type 2 diabetes mellitus, has recently been associated with bullous pemphigoid, characterized by fluid-filled blisters and erosions on the skin and mucous membranes. We report the series of three cases of bullous pemphigoid in patients of diabetes, who developed bullous pemphigoid after vildagliptin use.

Introduction

Vildagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is widely used to manage type 2 diabetes mellitus (T2DM). Vildagliptin enhances glycemic control by adjusting insulin and glucagon levels.[1] In contrast, bullous pemphigoid is a rare autoimmune disorder characterized by fluid-filled blisters and skin erosions.[2] A recent large-scale study by Plaquevent et al. has identified a significant association between gliptin use, including vildagliptin and the development of bullous pemphigoid. These studies have shown that skin eruptions occur more frequently in gliptin users than in the general population.[3] Although the exact mechanisms behind this adverse effect are not fully understood, its clinical impact is considerable.[3]

This case series investigates the occurrence and clinical features of bullous pemphigoid in patients treated with vildagliptin. By analyzing the individual cases, we seek to understand the clinical progression, management strategies, and outcomes of vildagliptin-induced bullous pemphigoid.

Case Reports

Case 1

A 47-year-old obese female, diagnosed with T2DM and hypothyroidism for the past 3 years, presented with uncontrolled blood sugar levels despite being on metformin 500 mg BD, glimepiride 1 mg BD, and thyroxine 75 µg for 3 years, respectively. Her fasting blood sugar level (FBSL) was 234 mg/dL, postprandial blood sugar level (PPBSL) was 318 mg/dL, and glycated hemoglobin was 8.7%. Due to inadequate glycemic control, she was initiated on Vildagliptin 50 mg BD. Ten days after commencing vildagliptin, the patient developed erythematous patches on her forearm and abdomen, which progressed to tense bullae that eventually ruptured, leading to the coalescence of adjacent lesions as given in Figure 1a. Subsequently, she was admitted to the department of medicine with similar complaints, and a diagnosis of drug-induced bullous pemphigoid was made by a dermatologist [histopathology image given in Figure 1b]. Vildagliptin was discontinued and topical Clobetasol 0.5% was initiated, resulting in the resolution of her bullous pemphigoid lesions.

Figure 1.

(a) The hands of the subject mentioned in Case-1 showing Bullous Pemphigoid following vildagliptin. (b) The sub-dermal split in Case-1 showing Bullous Pemphigoid following vildagliptin

Case 2

A 55-year-old averagely built female, diagnosed with T2DM, hypertension, and hypothyroidism for the past 7 years, presented with uncontrolled blood sugar levels despite being on metformin 500 mg BD, gliclazide 30 mg BD, and thyroxine 75 µg for 7 years and amlodipine 10 mg 1 OD for the past 5 years, respectively. Her FBSL was 211 mg/dL, PPBSL was 347 mg/dL. Due to inadequate glycemic control, she was initiated on Vildagliptin 50 mg BD. Fifteen days after commencing vildagliptin, the patient developed tense bullae over the forearm, thighs, and abdomen that eventually ruptured, as given in Figure 2a. Subsequently, she was admitted to the dermatology department and a diagnosis of drug-induced bullous pemphigoid was made [histopathology image given in Figure 2b]. Vildagliptin was discontinued, and topical clobetasol 0.5% was initiated, resulting in the resolution of her bullous pemphigoid lesions.

Figure 2.

(a) The hands of the subject mentioned in Case 2 showing Bullous Pemphigoid following vildagliptin. (b) The sub-dermal split in Case 2 showing Bullous Pemphigoid following vildagliptin

Case 3

A 55-year-old male, who was diagnosed with bullous pemphigoid, was receiving azathioprine 100 mg for the past 1.5 years. He also has been suffering from diabetes mellitus (DM) for the past 3 years, his blood sugar levels were poorly controlled with Metformin 500 mg BD. To control his sugar levels, vildagliptin 50 mg OD was initiated. Within 1 week of starting Vildagliptin, his Bullous lesions, which were previously under control, flared up, as shown in Figure 3a. Consequently, he was admitted to the medicine department. The diagnosis of drug-induced bullous pemphigoid was made by the dermatologist [histopathology image given in Figure 3b], following which vildagliptin was discontinued, and Glimepiride 1 mg was added for DM management. In addition, the Azathioprine dose was increased to 125 mg and oral prednisolone was commenced. With this treatment regimen, his condition improved.

Figure 3.

(a) The thigh and arm of the subject mentioned in Case-3 showing Bullous Pemphigoid following vildagliptin. (b) The sub-dermal split in Case-3 showing Bullous Pemphigoid following vildagliptin

Discussion

The cases presented in this study shed light on the potential mechanisms underlying vildagliptin-induced bullous pemphigoid in individual patients. While the precise pathophysiological mechanisms remain nonconclusive, a closer examination of each case offers valuable insights into the immunological mechanism anticipated in the pathogenesis of bullous pemphigoid.[2] One compelling mechanism involves vildagliptin’s impact on immune homeostasis through its modulation of the incretin system. Vildagliptin, a DPP-4 inhibitor, alters the activity of incretin hormones like glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, which play important roles in immune regulation.[3] This alteration in incretin signaling may disrupt immune tolerance mechanisms, leading to the production of auto-antibodies against epidermal antigens, particularly desmoglein, key components of desmosomes involved in maintaining skin integrity.[3] In addition, vildagliptin-induced dysregulation of immune cell function may contribute to the pathogenesis of bullous pemphigoid. By influencing various immune cell subsets such as T-cells, B-cells, and dendritic cells, vildagliptin may disrupt immune surveillance and promote aberrant immune responses. This dysregulated immune activation may result in the production of autoantibodies targeting desmogleins, leading to the formation of intraepidermal blisters characteristic of bullous pemphigoid.[4] Another plausible mechanism involves vildagliptin-mediated molecular mimicry, whereby vildagliptin or its metabolites induce conformational changes in self-antigens that resemble microbial epitopes. This molecular mimicry phenomenon can trigger an autoimmune response, as the immune system fails to distinguish between self and nonself-antigens. In the context of bullous pemphigoid, vildagliptin-induced molecular mimicry may lead to the generation of autoantibodies targeting desmogleins, resulting in the disruption of epidermal adhesion and blister formation.[5] Furthermore, vildagliptin’s impact on the gut microbiota may contribute to the development of autoimmune skin disorders such as bullous pemphigoid.[3] Disruption of gut microbial homeostasis by vildagliptin may trigger systemic immune dysregulation, leading to the expansion of autoreactive T-cell clones and the production of autoantibodies targeting epidermal antigens. This dysregulated immune response may culminate in the formation of intraepidermal blisters characteristic of bullous pemphigoid.[5]

Conclusion

The cases presented underscore the importance of vigilance for cutaneous adverse events in patients receiving vildagliptin therapy. The onset of bullous pemphigoid in these cases highlights a potential association between vildagliptin use and autoimmune skin disorders, warranting further investigation.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.