Paolino Franzese, Vittorio Tancredi, Gaetano Licata, Giuseppe Argenziano, Eugenia Veronica di Brizzi, Maria Maddalena Nicoletti, Caterina Mariarosaria Giorgio
Abstract
The association between dipeptidyl-peptidase-4 inhibitors (DPP-4i), particularly linagliptin, and bullous pemphigoid (BP) is increasingly recognized. This case series describes 17 patients with type 2 diabetes mellitus (T2DM) who developed BP while on linagliptin therapy. Notably, these cases represent 20.5% of the total 83 BP diagnoses made annually in our rare disease referral center, a percentage significantly higher than that reported in previous epidemiological studies.
All patients tested negative for anti-BP180 and anti-BP230 autoantibodies, supporting a drug-induced etiology rather than a classic autoimmune mechanism. Histopathological examination confirmed subepidermal blistering with eosinophilic infiltrates. Discontinuation of linagliptin led to complete remission in all cases, with no recurrence at six-month follow-up. This case series highlights the necessity of increased awareness regarding BP as a potential adverse effect of linagliptin and provides insight into the possible pathophysiological mechanisms underlying this phenomenon.
Introduction
Bullous pemphigoid is the most common autoimmune blistering disorder, classically associated with IgG autoantibodies directed against BP180 and BP230. In recent years, accumulating evidence has linked its onset to pharmacological triggers, particularly DPP-4 inhibitors, with linagliptin being among the most frequently implicated agents. Epidemiological studies suggest a two- to fourfold increased risk of BP in patients receiving DPP-4 inhibitors, reinforcing the need for heightened clinical suspicion when evaluating diabetic patients presenting with blistering dermatoses.
The exact mechanism by which linagliptin induces BP remains incompletely understood. Current hypotheses suggest that DPP-4 inhibition alters immune homeostasis, shifting the balance of inflammatory cytokines and regulatory T-cell function. Increased CXCL10 levels and a reduction in regulatory T-cell activity may contribute to a pro-inflammatory environment, facilitating basement membrane zone damage. Unlike classic autoimmune BP, in which pathogenic autoantibodies mediate subepidermal blistering, the absence of anti-BP180 and anti-BP230 autoantibodies in drug-induced cases suggests a predominantly inflammatory mechanism rather than a loss of self-tolerance.
In this case series, we describe 17 patients diagnosed with BP while on linagliptin therapy. These cases, representing a substantial proportion of BP diagnoses at our center, underscore the need for prompt recognition of this potential drug-related complication in diabetic patients.
Case Series
Methods
We retrospectively analyzed cases of BP diagnosed between 2022 and 2024 at our rare disease referral center. Patients included in this study had been on linagliptin therapy for at least six months prior to BP onset, exhibited clinical features consistent with BP, and had histopathological confirmation of subepidermal blistering with eosinophilic infiltrates. All patients tested negative for anti-BP180 and anti-BP230 autoantibodies by direct immunofluorescence, further supporting a drug-induced etiology.
Results
Seventeen patients, nine males and eight females, met the inclusion criteria. The mean age at BP onset was 71.3 years, with a range between 61 and 81 years. All patients had been taking linagliptin at a dose of 5 mg per day for a minimum of six months before the appearance of BP lesions. The clinical presentation varied, with most patients developing widespread tense bullae associated with intense pruritus, predominantly involving the trunk and extremities.
Histopathological analysis consistently revealed subepidermal blistering with eosinophilic infiltrates. Despite the absence of anti-BP180 and anti-BP230 autoantibodies, direct immunofluorescence demonstrated linear IgG and C3 deposition at the dermoepidermal junction in several cases. Following linagliptin discontinuation, all patients experienced gradual resolution of symptoms, with complete remission achieved within six to ten weeks. No recurrences were observed at six-month follow-up, reinforcing the notion that drug withdrawal is a key therapeutic intervention in these cases.
Discussion
The findings of this study support the growing body of evidence linking linagliptin to BP, with a particularly high incidence among the BP cases diagnosed in our referral center. The proportion of BP cases associated with linagliptin in our cohort, accounting for more than 20% of annual BP diagnoses, is significantly higher than previously reported in broader population studies, where drug-induced BP is estimated to represent 5-10% of cases【1】. This discrepancy suggests that linagliptin-associated BP may be underreported or that certain populations may be particularly susceptible to this adverse effect.
The pathogenesis of BP in patients receiving linagliptin appears to differ from that of classic autoimmune BP, given the consistent absence of BP180 and BP230 autoantibodies. The inflammatory profile observed in these cases suggests that immune dysregulation induced by DPP-4 inhibition plays a central role. The reduction in regulatory T-cell activity, combined with an increase in CXCL10 levels, likely creates a pro-inflammatory microenvironment that predisposes to tissue damage at the dermoepidermal junction. Additionally, the recruitment and activation of eosinophils observed in histopathological samples further support the involvement of inflammatory rather than autoantibody-mediated mechanisms in the pathogenesis of this disease【2】.
Conclusion
Linagliptin, a widely used DPP-4 inhibitor, appears to be a significant trigger for BP, representing more than 20% of cases diagnosed in our rare disease referral center. The absence of BP180 and BP230 autoantibodies in all patients strongly suggests a non-autoimmune, inflammatory-driven pathogenesis rather than classic autoantibody-mediated BP. The high prevalence of linagliptin-induced BP observed in our center, compared to previous epidemiological estimates, raises important clinical and pharmacovigilance considerations.
Prompt recognition of this adverse reaction is essential, as discontinuation of linagliptin consistently resulted in complete remission without recurrence. Further research is needed to identify potential genetic or immunological predispositions to drug-induced BP and to establish standardized screening protocols for patients receiving DPP-4 inhibitors. A better understanding of the immunopathogenic mechanisms underlying this condition will also be crucial in refining diagnostic and therapeutic strategies for drug-induced blistering diseases.
References
- Armanious M, et al. Gliptin-Induced Bullous Pemphigoid: Canadian Case Series of 10 Patients. J Cutan Med Surg. 2021 Mar-Apr.
- Ganeva M, et al. Gliptin-induced bullous pemphigoid. Int J Clin Pharmacol Ther. 2024 Feb.