From glycemic control to autoimmune crisis: A case of vildagliptin-induced pemphigus vulgaris

INTRODUCTION

Dipeptidyl peptidase-4 (DPP-4) inhibitors represent a significant advancement in the management of type 2 diabetes, offering effective glycemic control with minimal risk of hypoglycemia. However, recent reports have documented associations between DPP-4 inhibitors and various dermatological adverse effects, including autoimmune blistering diseases.^[1] Pemphigus vulgaris, a rare but potentially life-threatening autoimmune blistering disorder, has been increasingly reported in association with DPP-4 inhibitor use.^[2,3] The pathophysiological mechanism underlying this association remains incompletely understood, though it may involve molecular mimicry or direct immune system modulation.^[4]

CASE REPORT

A 59-year-old male with a 12-year history of type 2 diabetes mellitus presented to our dermatology clinic with a 2-month history of progressive, painful oral ulcers and widespread skin blistering. His diabetes had been well-controlled on metformin 1000 mg twice daily until 6 months prior, when vildagliptin 50 mg twice daily was added due to suboptimal glycemic control (Hemoglobin A1c [HbA1c] 8.2%). The patient had no personal or family history of autoimmune diseases and was not taking any other medications known to induce pemphigus.

The patient initially developed painful oral ulcers that progressively worsened, making eating and drinking difficult. Subsequently, he noticed the appearance of fluid-filled blisters on his chest and back, which quickly ruptured, leaving painful erosions. The lesions gradually spread to involve his entire trunk and extremities. He denied fever, weight loss, or other systemic symptoms but reported significant functional impairment and weight loss due to the inability to maintain adequate nutrition.

Physical examination revealed extensive mucocutaneous involvement with severe functional impact [Figure 1a-c]. Oral examination showed multiple shallow, painful erosions affecting the buccal mucosa, tongue, and gingiva, with areas of hemorrhagic crusting on the lips extending to the perioral skin [Figure 1c]. Cutaneous examination revealed numerous flaccid bullae and extensive erosions with peripheral collarettes of scale distributed over the chest, back, abdomen, and extremities [Figure 1a and 1b]. The lesions demonstrated the characteristic flaccid nature of pemphigus bullae, with many having already ruptured, leaving shallow, irregular erosions. Some areas showed confluent erosions, particularly over the chest and abdomen. Many lesions showed evidence of secondary bacterial infection with purulent exudate. Nikolsky’s sign was positive in areas of seemingly normal skin adjacent to active lesions.

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Figure 1:

(a) Initial presentation showing extensive cutaneous involvement with multiple erosions and ruptured bullae distributed across the chest, abdomen, and trunk, with characteristic peripheral scaling and confluent areas of involvement, (b) Posterior view demonstrating widespread distribution of lesions with various stages of healing and active erosions extending across the entire back, (c) Severe oral involvement with extensive mucosal erosions, hemorrhagic lip crusting, and significant difficulty with oral opening.

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Laboratory investigations showed normal complete blood count, liver function tests, and renal function. HbA1c was 7.1%, indicating improved glycemic control since vildagliptin initiation. A 4-mm punch biopsy was obtained from the edge of a fresh bullous lesion on the chest for histopathological examination. Histopathological examination revealed suprabasal acantholysis with formation of intraepidermal bullae. The basal keratinocytes remained attached to the basement membrane, creating a characteristic “tombstone” appearance. The blister cavity contained acantholytic keratinocytes and inflammatory debris. The dermis showed a mild perivascular lymphocytic infiltrate. These histopathological features, combined with the clinical presentation of flaccid bullae and positive Nikolsky’s sign, were consistent with pemphigus vulgaris.

Based on the clinical presentation, histopathological findings, and temporal relationship with vildagliptin initiation, a diagnosis of vildagliptin-induced pemphigus vulgaris was established. Vildagliptin was immediately discontinued, and diabetes management was optimized with increased metformin dosing, addition of glimepiride 1 mg, and lifestyle modifications.

Treatment was initiated with oral prednisolone 1 mg/kg/day (60 mg daily), along with topical antiseptic care and prophylactic oral antifungal therapy. The patient showed gradual improvement over the following weeks, with decreased formation of new lesions and healing of existing erosions. Oral lesions began to heal within the 1^st week of treatment, significantly improving the patient’s ability to eat and maintain nutrition.

At 4-week follow-up, there was dramatic improvement with complete re-epithelialization of cutaneous lesions, leaving only residual post-inflammatory hyperpigmentation distributed in the same pattern as the original lesions [Figure 2a and 2b]. The oral mucosa had healed completely with restoration of normal function for eating and speaking [Figure 2c]. No new blister formation was observed, and Nikolsky’s sign had become negative. Prednisolone was gradually tapered over the subsequent 8 weeks without recurrence of lesions. At the 3-month follow-up, the patient had achieved complete remission with minimal residual hyperpigmentation and no active lesions. His diabetes remained well-controlled on metformin and glimepiride therapy with an average HbA1c of 7.1%.

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Figure 2:

(a) Follow-up at 4 weeks showing complete healing of anterior cutaneous lesions with residual postinflammatory hyperpigmentation in the same distribution pattern as original lesions, (b ) Posterior view at 4 weeks, demonstrating complete re-epithelialization with only residual hyperpigmentation, which contrasts dramatically with the initial presentation, (c) Facial view at 4 weeks showing complete resolution of oral mucosal involvement with restoration of normal lip and perioral skin integrity.

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DISCUSSION

This case illustrates a rare but clinically significant adverse effect of vildagliptin therapy. The temporal relationship between drug initiation and symptom onset, along with improvement following discontinuation, strongly suggests a causal relationship.^[3] DPP-4 inhibitor-associated pemphigus vulgaris has been increasingly recognized, with several case reports documenting similar presentations across different agents in this class.^[1,2,4]

The pathogenesis of DPP-4 inhibitor-induced pemphigus remains unclear but may involve several mechanisms. DPP-4 is expressed on various immune cells and plays a role in immune regulation. Inhibition of this enzyme may disrupt normal immune homeostasis, potentially triggering autoimmune responses in susceptible individuals.^[4] In addition, molecular mimicry between DPP-4 inhibitors and desmosomal proteins has been proposed as a potential mechanism.^[4]

The clinical presentation in our case was typical of pemphigus vulgaris, with prominent mucosal involvement preceding cutaneous manifestations.^[5] The presence of flaccid bullae, positive Nikolsky’s sign, and characteristic histopathological features of suprabasal acantholysis with tombstone appearance of basal keratinocytes strongly supported the diagnosis. While immunofluorescence studies would provide additional confirmatory evidence, the combination of classic clinical presentation and pathognomonic histopathological features allowed for confident diagnosis of pemphigus vulgaris.^[5]

The dramatic response to treatment, as documented in the follow-up images [Figures 2a-c], highlights an important distinction between drug-induced and idiopathic pemphigus vulgaris. Drug-induced pemphigus typically shows more rapid and complete resolution following offending drug discontinuation compared to idiopathic cases, which often require prolonged immunosuppressive therapy. This excellent prognosis when drug-induced pemphigus is recognized early underscores the importance of clinical awareness among healthcare providers.

Management of drug-induced pemphigus follows similar principles to idiopathic pemphigus, with the crucial addition of offending drug discontinuation.^[6] Early recognition and prompt treatment are crucial for preventing complications and minimizing morbidity. In our case, discontinuation of vildagliptin combined with systemic corticosteroids resulted in excellent clinical outcomes.

CONCLUSION

This case report adds to the growing body of evidence linking DPP-4 inhibitors to autoimmune blistering diseases. Healthcare providers should be aware of this potential adverse effect and maintain clinical suspicion when diabetic patients on DPP-4 inhibitors develop new-onset blistering lesions. Early recognition, prompt drug discontinuation, and appropriate treatment are crucial for optimal outcomes. Further research is needed to better understand the pathogenesis of this association and identify potential risk factors.