Gliptin-induced Pemphigus

Abstract

This case highlights the development of gliptin-induced pemphigus in a patient shortly after initiating gliptin therapy for diabetes. It is essential to differentiate drug-induced pemphigus from idiopathic cases, as they can be clinically and histopathologically indistinguishable. A detailed medical history, including medication use, is crucial to identifying drug-induced conditions. The time interval between initiating the suspected drug and the onset of skin manifestations can vary widely from case to case. Improvement of the lesions following drug cessation confirms the diagnosis of drug-induced pemphigus.

INTRODUCTION

Drug-induced pemphigus, although rare, is a critical consideration for healthcare providers when patients present with characteristic skin lesions that correlate with the introduction of gliptins and a history of recent medication changes. Patients may experience intense pruritus that is unresponsive to antihistamines. Histopathology showed features suggestive of pemphigus, confirming the gliptin-induced pemphigus diagnosis. Timely recognition, discontinuation of the offending drug, and appropriate management can lead to a favorable result, as observed in this case.

CASE REPORT

A female in her 70s with a known diabetes and hypertension history for the past 12 years came to the dermatology outpatient department with fluid-filled lesions and erythematous crusted plaques associated with erosions on the buttocks, upper and lower limbs, back, axilla, thighs, nape, and scalp.

Since the patient had diabetes, she had been on metformin for the past 12 years. Her blood sugar levels were poorly controlled with conventional antidiabetic medications, leading to the initiation of Gliptins in February 2023. A few weeks after starting gliptins, she began experiencing the above complaints. On examination, the largest erythematous plaques measured 5 cm × 8 cm (buttocks) and the smallest measured 1 cm × 1 cm (chest), with itching and burning [Figure 1]. Oral cavity erosions on the posterior pharyngeal wall, discharge from the eyes, genital erosions on the labia minora, and a crusted lesion on the left palm. Crusted plaques on the scalp and face. Nikolsky’s sign and Bulla’s spread sign were negative. She also presented with bilateral pitting edema of the feet.

Figure 1.

Pretreatment: Multiple, erosions of variable sizes along with crusting present on the upper and lower back, bilateral arms, buttocks, and back of thighs

All routine hematological investigations were within normal limits, except for elevated C-reactive protein, D-dimer, HbA1C, and urea. Desmoglein (Dsg1) and Dsg3 autoantibodies were highly positive.

Urine analysis revealed a trace of protein, glucose, and acetone, with decreased serum total protein, albumin, and globulin.

Histopathological findings of a skin biopsy displayed characteristic features of pemphigus, including stratified squamous epithelium showing a suprabasal cleavage with a tombstone appearance of basal cells with villi formation. The roof is separated from the floor in places. The blister cavity contains fibrin, red blood cell, and a few acantholytic cells. The dermis has a superficial perivascular inflammatory infiltrate composed of lymphocytes and a few eosinophils. Subepidermal separation or papillary microabscesses are not evident [Figure 2].

Figure 2.

H&E stain: 40 X, 100 X: Stratified squamous epithelium showing a suprabasal cleavage with a tombstone appearance of basal cells with villi formation. The blister cavity contains fibrin, red blood cell, and a few acantholytic cells. The dermis has a superficial perivascular inflammatory infiltrate composed of lymphocytes and a few eosinophils. Subepidermal separation or papillary microabscesses are not evident

Gliptin was discontinued and transitioned to insulin 22 units twice daily before meals and a combination of oral glimepiride 2 mg and metformin 500 mg twice daily. According to the protocol given by Pasricha et al., one cycle of DCP (dexamethasone cyclophosphamide pulse therapy) was given for 3 days.[1]

Significant improvement of the lesions was observed 2 weeks after discontinuing the drug [Figure 3].

Figure 3.

Posttreatment: Healed lesions with dried exudates

DISCUSSION

Pemphigus vulgaris (PV) and bullous pemphigoid (BP) are autoimmune bullous diseases characterized by the production of pathogenic autoantibodies that target specific proteins expressed in the skin. PV autoantibodies target Dsg1, Dsg3, and transmembrane glycoproteins of skin epidermal cells, leading to desmosome attachment and loss of acantholysis. PV patients usually have anti-Dsg3 antibodies with or without anti-Dsg1 antibodies. The difference in antibody profile affects the clinical phenotypes, including mucosa-predominant type and mucosal type PVs.[2]

Dipeptidyl peptidase-4 inhibitors (DPP-4I), or gliptins, are diabetes medications that improve glucose control without increasing the risk of hypoglycemia. Recently, several cases of bullous pemphigoid associated with DPP-4I have been reported.[3]

DPP-4I prescriptions have increased due to their effectiveness and safety. However, since the first description by Skandalis et al., an increasing number of diabetic patients have developed bullous pemphigoid after taking DPP-4I.[3] However, to our knowledge, only Okauchi et al. reported a patient who developed PV after 6 months of DPP-4I therapy, namely sitagliptin.[4]

According to EudraVigilance, until March 2015, 170 cases of bullous pemphigoid were associated with DPP-4I.[5]

Certain drugs, typically containing thiol or phenol, can cause pemphigus. However, sitagliptin lacks such a chemical structure. DPP-4I can influence the immune system and lead to skin inflammation. Dipeptidyl peptidase-4, known as the human CD26 cell surface antigen, is present in several tissues, including T lymphocytes and endothelial and epithelial cells. A high expression of CD26 on the surface of CD4+ T cells correlates with the production of T helper (Th) 1 cytokines such as interferon-γ and interleukin-2.[6]

Recently, Th1 dysfunction has been implicated in the pathogenesis of PV, especially in its early stages.[7]

Thus, DPP-4I may impair Th1 functions through an altered cytokine network, triggering PV and BP. Further studies are needed to demonstrate the relationship between DPP-4I and the development of PV.

CONCLUSION

The increasing number of patients with diabetes worldwide and the numerous benefits of gliptins in managing the disease are expected to lead to a rise in the use of gliptins. Despite developing evidence of the association between DPP-4I (gliptin) and vesiculobullous disorders like PV/BP, no specific individual risk factors have been identified to predict the likelihood of developing PV/BP in patients treated with gliptins. Furthermore, the time between exposure to gliptins and the onset of disease varies, so any diabetic patient taking gliptins should be considered at risk of developing vesiculobullous disorders. It is advisable to use certain gliptins, such as vildagliptin, cautiously. Further research is needed to determine the gliptin molecular components involved in vesiculobullous disorders and to identify high-risk patients. Individual risk factors that help predict the susceptibility to developing disease in patients treated with gliptins have been recognized.

Declaration of patient consent

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

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.