linagliptin and Pemphigoid--Bullous

There have been a number of case reports and small clinical series reporting the potential association between dipeptidyl peptidase-4 inhibitors (DPPIs) for diabetes and the onset of bullous pemphigoid (BP). The aim of this study was to assess the association between DPPI use and BP, and whether this varied according to DPPI type.. We performed a systematic review and meta-analysis according to PRISMA guidelines. We identified five studies with cases and controls. We performed unadjusted and adjusted meta-analyses to assess the potential association.. Limitations were that studies reviewed were retrospective by design which are susceptible to bias and lack of randomisation. Our adjusted analysis supports a significant association between DPPI use and onset of bullous pemphigoid. Vildagliptin had the highest odds of BP. These findings have clinical implications for dermatologists and the management of patients with diabetes and being treated with DPPI agents.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Linagliptin; Pemphigoid, Bullous; Sitagliptin Phosphate; Vildagliptin

Bullous pemphigoid (BP) is an organ-specific autoantibody-mediated autoimmune blistering skin disorder that tends to affect the elderly. Tense blister formation associated with itchy urticarial erythema is clinically observed in BP, and subepidermal blister formation with eosinophilic infiltration is a histopathological characteristic. BP autoantibodies target two hemidesmosomal components in basal keratinocytes: BP180 and BP230. Anti-BP180 autoantibodies play major roles in blister formation. Although the autoantibody-mediated pathomechanism of blister formation has been extensively studied, little is known about how and why immune tolerance to BP180 may be broken in certain elderly individuals. Recently, BP has been increasingly reported in diabetes mellites (DM) patients receiving dipeptidyl peptidase-IV inhibitors (DPP4is), which are widely used anti-DM drugs. Pharmacovigilance and cohort studies have revealed that DPP4is, especially vildagliptin, teneligliptin, and linagliptin, are a potential risk factor for BP onset. Interestingly, it has been revealed that Japanese DPP4i-BP tends to show a non-inflammatory phenotype, with less erythema than normal BP, and that DPP4i-BP autoantibodies target distinct epitopes on BP180. In addition, human leukocyte antigen-DQB1*03:01 was identified as the major haplotype in Japanese DPP4i-BP. This review summarizes the latest understanding of the pathogenesis of BP, with a special focus on the recently recognized DPP4i-BP.

Topics: Asian People; Autoantibodies; Autoantigens; Autoimmunity; Collagen Type XVII; Dipeptidyl-Peptidase IV Inhibitors; Epitopes; Haplotypes; HLA-DQ beta-Chains; Humans; Hypoglycemic Agents; Immune Tolerance; Linagliptin; Non-Fibrillar Collagens; Pemphigoid, Bullous; Pyrazoles; Risk Factors; Thiazolidines; Vildagliptin

Bullous pemphigoid (BP) is a common autoimmune blistering disease in which autoantibodies mainly target the hemidesmosomal component BP180 (also known as type XVII collagen) in basal keratinocytes. Various triggering factors are known to induce BP onset, including radiotherapy, burns, ultraviolet exposure, surgery, and the use of dipeptidyl peptidase-IV inhibitors (DPP4i), which are widely used antihyperglycemic drugs. Here, we present a case of BP triggered by a thermal burn under medication with DPP4i. A 60-year-old man with type II diabetes had been treated with the DPP4i linagliptin for 1 year. After the right forearm experienced a thermal burn, blisters developed around the burned area and gradually spread over the whole body with the production of autoantibodies targeting the non-NC16A domain of BP180. The diagnosis of BP was confirmed by immunohistopathological examination. Upon withdrawal of linagliptin and treatment with topical steroid and minocycline, complete remission was achieved after 4 months. Previously, 13 cases of BP that developed after thermal burns have been reported, and our case shared some of the clinical features of these thermal burn-induced BP cases. Interestingly, the present case also showed the typical clinical, histopathological, and immunological features of the non-inflammatory type of DPP4i-associated BP (DPP4i-BP). Although the pathogenesis of BP remains uncertain, the present case suggests that DPP4i may trigger the onset of BP similarly to a thermal burn. In addition, the clinical and histopathological features of DPP4i-BP may be distinct from other types of BP.

Topics: Burns; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Humans; Linagliptin; Male; Middle Aged; Pemphigoid, Bullous

Bullous pemphigoid (BP) is an acquired subepidermal autoimmune blistering disease in which there are humoral and cellular responses against the BP180 and BP230 antigens. Dipeptidyl peptidase (DPP)-4 inhibitors enhance endogenous glucagon peptide-1 and glucose-dependent insulinotropic polypeptide secretion with food intake, which leads to insulin secretion, as well as to the reduction of glucagon secretion. Recently, several cases of DPP-4 inhibitor-associated BP have been reported.. To report 3 cases of DPP-4 inhibitor-associated BP, one of which is due to linagliptin use, as well as to review all currently published cases of DPP-4 inhibitor-associated BP.. Three patients diagnosed with BP at our department showed a clear temporal relationship between the introduction of DPP-4 for the treatment of diabetes and the onset of BP. One case was due to linagliptin use, while the other 2 cases were due to an association with vildagliptin-metformin use.. This is the first report of linagliptin-associated BP. Furthermore, 2 other cases of vildagliptin-associated BP are reported.

Topics: Adamantane; Aged; Aged, 80 and over; Dipeptidyl-Peptidase IV Inhibitors; Drug Eruptions; Female; Humans; Linagliptin; Male; Nitriles; Pemphigoid, Bullous; Pyrrolidines; Vildagliptin

Although the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and bullous pemphigoid (BP) has begun to be established, some studies have suggested there are risk differences among DPP-4 inhibitors. We conducted a population-based cohort study to examine the risk differences.. Using the claims databases of the Fukuoka Prefecture Wide-Area Association of Latter-Stage Elderly Healthcare between April 1, 2013 and March 31, 2017, we conducted a retrospective cohort study to compare patients receiving one DPP-4 inhibitor with those who were prescribed another antidiabetic drug. The primary outcome was an adjusted hazard ratio (HR) of the development of bullous pemphigoid during a 3-year follow-up. The secondary outcome was the development of BP requiring systemic steroids immediately after the diagnosis. These were estimated using Cox proportional hazards regression models.. The study comprised 33,241 patients, of which 0.26% (n = 88) developed bullous pemphigoid during follow-up. The percentages of patients with bullous pemphigoid who required immediate systemic steroid treatment was 0.11% (n = 37). We analyzed four DPP-4 inhibitors: sitagliptin, vildagliptin, alogliptin, and linagliptin. Vildagliptin and linagliptin raised the risk of BP significantly (primary outcome, vildagliptin, HR 2.411 [95% confidence interval (CI) 1.325-4.387], linagliptin, HR 2.550 [95% CI 1.266-5.136], secondary outcome, vildagliptin HR 3.616 [95% CI 1.495-8.745], linagliptin HR 3.556 [95% CI 1.262-10.024]). A statistically significant risk elevation was not observed with sitagliptin and alogliptin (primary outcome, sitagliptin, HR 0.911 [95% CI 0.508-1.635], alogliptin, HR 1.600 [95% CI 0.714-3.584], secondary outcome, sitagliptin, HR 1.192 [95% CI 0.475-2.992], alogliptin, HR 2.007 [95% CI 0.571-7.053]).. Not all the DPP-4 inhibitors could induce bullous pemphigoid significantly. Therefore, the association warrants further investigations before generalization.

Topics: Aged; Cohort Studies; Delivery of Health Care; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; East Asian People; Humans; Hypoglycemic Agents; Linagliptin; Pemphigoid, Bullous; Retrospective Studies; Sitagliptin Phosphate; Vildagliptin

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Linagliptin; Pemphigoid, Bullous; Rituximab

Dipeptidyl peptidase (DPP)-4 plays a complex role in immune regulation and its inhibition can have effects on the pathogenesis of various skin diseases. Studies have shown that DPP-4 inhibitors are associated with an increased risk of bullous pemphigoid (BP).. To analyse the clinical and histopathological features of cutaneous adverse events in patients on DPP-4 inhibitors.. We performed a retrospective review of patients with suspected DPP-4 inhibitor-associated cutaneous adverse events, at a tertiary teaching hospital from 1 January 2017 to 31 December 2020. Exclusion criteria included previous history of chronic skin disease and lack of histopathological reports or follow-up records. The clinical characteristics, latency period, Naranjo Adverse Drug Reaction Probability Scale and clinical outcomes were evaluated.. In total, 18 patients (10 men, 8 women; mean age 68.6 years, range 38-89 years) were included. The DPP-4 inhibitors used were teneligliptin (n = 6), vildagliptin (n = 6), sitagliptin (n = 4), linagliptin (n = 1) and saxagliptin (n = 1). The mean interval between therapy initiation and lesion onset was 8.8 months (range 1-24 months). The dermatoses noted were BP (n = 12; 66.6%), lichenoid dermatitis (n = 4; 22.2%), psoriasiform dermatitis (n = 1; 5.6%) and spongiotic dermatitis (n = 1; 5.6%). Eight patients (44.4%) had necrotic keratinocytes as one of the distinct histological features. Causality assessment using the Naranjo scale rated the causative role of DPP-4 inhibitors as 'possible' in all patients. Of the 18 patients, 11 (61.1%) noted improvement in their condition following discontinuation of DPP-4 inhibitors, with 5 having complete remission within 6 months of stopping the drug.. DPP-4 inhibitor-associated dermatoses are not necessarily limited to BP. It is necessary to recognize the possibility of other dermatoses in patients on DPP-4 inhibitors as drug substitution/cessation may improve disease morbidity.

Topics: Adult; Aged; Aged, 80 and over; Dermatitis; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exanthema; Female; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Pemphigoid, Bullous; Retrospective Studies

BACKGROUND Bullous pemphigoid is a common pruritic skin lesion reported in elderly patients. It is caused by an immunologic reaction between autoantibodies and hemidesmosome proteins of epithelial cells. The disease is characterized by a symmetrical blister distribution on the body. Diagnosis should be suspected in elderly patients presenting with a tense blister on normal-appearing skin or on an erythematous base. In the literature, several forms of typical bullous pemphigoid after treatment with linagliptin have been reported. However, this is the first reported case of atypical nonbullous pemphigoid after linagliptin intake. CASE REPORT A 77-year-old woman presented with multiple erythematous papules and nodules on the upper extremities and trunk. The patient was being treated with linagliptin for diabetes. Diagnosis was made with biopsy and histopathological studies, followed by direct immunofluorescence. The histopathological study showed a subepidermal blister with an underlying polymorphous infiltrate, mainly of an eosinophilic profile. Direct immunofluorescence showed linear IgG and C3 antibodies to hemidesmosomes at the lamina lucida of the basement membrane. Thus, the diagnosis of atypical nonbullous pemphigoid was made. CONCLUSIONS This report emphasizes the great variety of bullous pemphigoid presentation and the need for a greater level of awareness of the adverse effects of linagliptin. Thus, atypical nonbullous pemphigoid should be considered among the potential differential diagnoses in patients with multiple erythematous papules and nodules on the upper extremities and trunk.

Topics: Aged; Autoantibodies; Basement Membrane; Blister; Female; Humans; Linagliptin; Pemphigoid, Bullous

Topics: Aged, 80 and over; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Linagliptin; Male; Pemphigoid, Bullous

Dipeptidyl peptidase 4 inhibitors (DPP-4i) are associated with an increased risk of developing bullous pemphigoid (BP) in patients with diabetes. Autoantibodies targeting epitopes on the processed BP180, 120-kDa (LAD-1), and 97-kDa (LABD97) linear immunoglobulin (Ig)A dermatosis antigens are the major autoantibodies in DPP-4i-associated BP. However, no case of mucous membrane pemphigoid (MMP) developing during treatment with DPP-4i has been reported. We report a case of MMP associated with DPP-4i. A man in his late 70s presented with oral mucous membrane erosion and a few blisters on his upper chest and back. He had used linagliptin for diabetes for over 1 year when he presented. The immunological characteristics were similar to DPP4i-associated BP: higher reactivity to LAD-1 and LABD97 than to the full-length BP180. The aphthae achieved remission after oral linagliptin was replaced with sitagliptin. However, 6 months later, the aphthae relapsed and any DPP-4i was discontinued. The aphthae disappeared, and now he is completely free from lesions associated with MMP. This case suggests that the DPP-4i may have shared roles in the production of IgG antibodies to LAD-1 or to LABD97 in the pathogenesis of DPP-4i-associated BP and MMP. Our case highlights the possibility of overlooking the mild MMP in DPP-4i-treated diabetes patients with mucosal lesions.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Linagliptin; Male; Mucous Membrane; Pemphigoid, Benign Mucous Membrane; Pemphigoid, Bullous

Bullous pemphigoid (BP) has been associated with dipeptidyl peptidase-4 inhibitors (DPP4i). Clinical features, outcomes, and risk of BP for new DPP4i (linagliptin, saxagliptin, and alopgliptin) are not well established. Comparison of risk of BP appearance for DPP4i and other oral antidiabetic drugs (OADs) such as sodium glucose cotransporter 2 inhibitors has not been studied to date.. To describe the prevalence, sociodemographic, clinical, and histopathological characteristics, and outcome after drug withdrawal in DPP-4i-associated BP cases from our hospital. To review all Spanish spontaneous notifications of BP where DPP4i or OADs were included as suspected drugs and calculate the reporting odds ratios (RORs).. A retrospective observational study was performed examining the association between DDP4i and BP. Clinical features and RORs were analyzed. Data from the Spanish Pharmacovigilance System (SEFV) are included.. In our center, 28 of 89 patients with BP (31.5%) were under DPP4i treatment; 53.6% were male, and mean age was 80.8 years. BP debuted the first year after DPP4i in 57.2%. BP control was achieved within 3.7 months after drug withdrawal. Regarding SEFV, 22 of 972 spontaneous notifications were related to BP and DPP4i. RORs were superior for DPP4i compared to other OADs. Vildagliptin had the highest ROR.. We present the largest DPP4i-induced BP case series in a single center, with a detailed study of the sociodemographic, clinical, and histopathological characteristics of each patient, and their treatment and outcome. Vildagliptin had the highest risk. DPP4i-associated BP does not seem to have specific clinical characteristics.

Topics: Aged; Aged, 80 and over; Databases, Factual; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Linagliptin; Male; Middle Aged; Pemphigoid, Bullous; Pharmacovigilance; Retrospective Studies; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors; Spain; Vildagliptin

The association between dipeptidyl peptidase 4 inhibitors (DPP-4i) and bullous pemphigoid (BP) has been demonstrated in several studies. The main aim of this study was to estimate the use of DPP-4i treatment in patients diagnosed with BP in our setting.. We selected patients histologically diagnosed with BP in our department between October 2015 and October 2018 and performed a retrospective chart review to assess clinical and epidemiological data and direct immunofluorescence (DIF) patterns.. Of the 70 patients diagnosed with BP during the study period, 50% were diabetic and 88.57% of these were being treated with a DPP-4i when diagnosed with BP. The most common DPP-4i was linagliptin (used in 18.6% of patients), followed by vildagliptin (17.1%). The median latency period between initiation of DPP-4i treatment and diagnosis of BP was 27.5 months for all treatments, 16 months for linagliptin, and 39 months for vildagliptin (log rank < 0.01). A negative DIF result was significantly more common in patients not being treated with a DPP-4i. The DIF pattern most strongly (and significantly) associated with DPP-4i treatment was linear immunoglobulin G deposits along the dermal-epidermal junction. DPP-4i treatment was withdrawn in 87% of patients and 96% of these achieved a complete response.. DPP-4i treatment is very common in patients with BP in our setting. The latency period between start of treatment and onset of BP seems to be shorter with linagliptin than with other types of gliptins. Patients receiving DPP-4i treatment may show different DIF patterns to those not receiving treatment.

Topics: Dipeptidyl-Peptidase IV Inhibitors; Humans; Linagliptin; Pemphigoid, Bullous; Retrospective Studies; Vildagliptin

Recent studies revealed the risk of bullous pemphigoid (BP) in patients with diabetes mellitus (DM) taking dipeptidyl peptidase 4 (DPP-4) inhibitors. To clarify the relationship between taking DPP-4 inhibitors and the risk of BP among patients with DM, we conducted a cohort study by using the National Health Insurance Research Database of Taiwan from 1 January 2009 to 31 December 2015. We identified 6340 patients with DM taking DPP-4 inhibitors and 25 360 DM patients who had not taken DPP-4 inhibitors during the 7-year follow-up period. Compared with the non-DPP-4 inhibitor group, patients taking DDP-4 inhibitors had a higher risk of BP (adjusted hazard ratio [aHR], 2.382; 95% confidence interval (CI), 1.163-4.883; P = 0.017]. Among the DPP-4 inhibitors available in Taiwan, vildagliptin showed the highest risk of BP (aHR, 2.849; 95% CI, 1.893-4.215; P < 0.001), followed by saxagliptin (aHR, 2.657; 95% CI, 1.770-3.934; P < 0.001). Subgroup analysis revealed that the higher risk of BP was observed in patients older than 65 years (aHR, 2.403; 95% CI, 1.590-3.627; P < 0.001). This study revealed that treatment with DPP-4 inhibitors, especially vildagliptin, was significantly associated with an increased risk of BP among DM patients.

Topics: Adamantane; Adult; Age Factors; Aged; Case-Control Studies; Databases, Factual; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Incidence; Linagliptin; Male; Middle Aged; Pemphigoid, Bullous; Piperidines; Risk Factors; Sitagliptin Phosphate; Taiwan; Uracil; Vildagliptin; Young Adult

Bullous pemphigoid (BP) is the most common autoimmune subepidermal bullous diseases. Autoantibodies against hemidesmosomal adhesion proteins might be involved in the developing process. BP usually affects the elderly with high mortality whereas the drug-induced BP is often improved and rarely relapses after the withdrawal of the suspected drug. An accumulated evidence suggests that dipeptidyl peptidase-4 inhibitor (DPP-4I), which has been widely used as the antidiabetic drug improves glycemic control with little risk for hypoglycemia, could be an inducer of DPP-4I-associated BP (DPP-4I-BP). While the precise mechanism remains unclear, a unique immunological profile with human leukocyte antigen (HLA)-DQB1*03:01 could be a biomarker of genetic susceptibility to DPP-4I-BP. Here, we encountered an interesting case of DPP-4I-BP with HLA-DQB1*03:01, which was likely triggered by scabies. A 56-year-old Japanese male with type 2 diabetes on hemodialysis was referred to our hospital due to worsened blisters. Prior to his admission, he had been on linagliptin, a DPP-4I, for 5 months. He then suffered from scabies 2 weeks before his admission while the treatment with ivermectin failed to improve his symptom. Based on his clinical symptom, positive for anti-BP180 autoantibody in serum, and the pathological alterations of skin biopsy specimens, he was diagnosed with DPP-4I-BP. Importantly, he also carried an HLA-DQB1*03:01 allele. Oral prednisolone was subsequently administered after the discontinuation of linagliptin, and his symptom gradually disappeared. Given the fact that the DPP-4I-BP could be a life-threating disease, we should be cautious of prescribing DPP-4I in hemodialysis patients, whose immune system could be impaired.

Topics: Alleles; Autoantibodies; Biopsy; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucocorticoids; HLA-DQ beta-Chains; Humans; Linagliptin; Male; Middle Aged; Pemphigoid, Bullous; Prednisolone; Renal Dialysis; Scabies; Treatment Outcome

Topics: Aged, 80 and over; Dipeptidyl-Peptidase IV Inhibitors; Humans; Linagliptin; Male; Pemphigoid, Bullous; Vildagliptin

Topics: Aged; Aged, 80 and over; Biopsy; Blister; Drug-Related Side Effects and Adverse Reactions; Geriatrics; Humans; Linagliptin; Male; Pemphigoid, Bullous; Pruritus

Data regarding the clinical characteristics of patients with dipeptidyl-peptidase IV inhibitors (DPP4i)-associated BP is inconclusive. We aimed to characterize the clinical features of patients with DPP4i-associated BP, and to assess whether there are phenotypic differences associated with different agents belonging to the DPP4i class. A retrospective prevalence study was performed, including all consecutive patients diagnosed with BP throughout the years 2000 to 2019. The study included 397 patients with BP, of whom 58 (14.6%) were DPP4i-associated. Compared to other patients with BP, patients with DPP4i-associated BP had a more prominent male preponderance (60.3% vs 41.0%; P = .006), presented more frequently with extensive disease (60.3% vs 46.3%; P = .049), had greater truncal (96.6% vs 85.5%; P = .019) and cephalic (51.7% vs 33.6%; P = .008) involvement, and had less frequent peripheral eosinophilia (25.9% vs 51.9%; P < .001). Compared to patients with vildagliptin-associated BP, those with linagliptin-associated BP were managed by higher dosage of systemic corticosteroids in order to achieve disease control (prednisone > 1 mg/kg: 68.2% vs 40.0%; P = .046). In conclusion, DPP4i-associated BP seems to have a unique clinical profile characterized by male predominance, extensive disease, truncal and cephalic involvement, and less peripheral eosinophilia. Linagliptin may be associated with a harder course necessitating more aggressive therapy.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Linagliptin; Male; Pemphigoid, Bullous; Retrospective Studies

Despite several recent reports on the elevated risk of bullous pemphigoid in patients with type 2 diabetes treated with dipeptidyl peptidase-4 (DPP-4) inhibitors, evidence on the absolute risk and comparative safety against other antidiabetics is limited.. To characterize the incidence rate of bullous pemphigoid associated with DPP-4 inhibitor use compared with second-generation sulfonylureas.. This cohort study used data from 2 large commercial insurance claims databases (Optum Clinformatics Data Mart from October 17, 2006, to December 31, 2018, and IBM MarketScan Research Database from October 17, 2006, to December 31, 2017) and Medicare data from January 1, 2006, to December 31, 2016. Patients with type 2 diabetes who initiated treatment with DPP-4 inhibitors or second-generation sulfonylurea were included.. The primary outcome of the study was bullous pemphigoid, identified using diagnosis codes. After 1:1 propensity score matching, the incidence rates of bullous pemphigoid and the hazard ratios (HRs) with 95% CIs comparing patients who initiated DPP-4 inhibitor and second-generation sulfonylurea therapy were estimated. Subgroup analyses by age, sex, race, and individual DPP-4 agents were performed. The results from each database were pooled using inverse-variance fixed-effects meta-analysis.. A total of 1 664 880 patients who initiated DPP-4 inhibitors (51.0% female; mean [SD] age, 63.9 [9.7] years) and sulfonylurea (50.4% female; mean [SD] age, 63.9 [9.9] years) were included. The incidence rate of bullous pemphigoid per 1000 person-years was 0.42 in the DPP-4 inhibitor group vs 0.31 in the sulfonylurea group (HR, 1.42; 95% CI, 1.17-1.72). Higher rates per 1000 person-years for DPP-4 inhibitor vs sulfonylurea groups were seen in those who were 65 years or older (0.79 vs 0.49; HR, 1.62; 95% CI, 1.32-1.99), white (0.93 vs 0.54; HR, 1.70; 95% CI, 1.30-2.24), and treated with linagliptin (1.20 vs 0.55; HR, 1.68; 95% CI, 1.16-2.43).. This study found that patients who initiated DPP-4 inhibitor therapy had higher risk of bullous pemphigoid than those who initiated second-generation sulfonylurea therapy. Clinicians should be aware of this rare adverse effect of DPP-4 inhibitors in subgroups of patients who are older, white, and linagliptin users.

Topics: Administrative Claims, Healthcare; Age Factors; Aged; Case-Control Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Prescriptions; Female; Humans; Incidence; Linagliptin; Male; Middle Aged; Pemphigoid, Bullous; Retrospective Studies; Risk Assessment; Risk Factors; Sulfonylurea Compounds; United States

Dipeptidyl peptidase 4 (DPP-4) inhibitors are increasingly used these days in management of diabetes. There has been reported in a few case reports of increasing association between DPP-4 inhibitor use and bullous pemphigoid (BP). We report a case of association between linagliptin use and BP and subsequent treatment with rituximab.

Topics: Aged; Anti-Bacterial Agents; Clobetasol; Dipeptidyl-Peptidase IV Inhibitors; Drug Eruptions; Humans; Linagliptin; Male; Minocycline; Pemphigoid, Bullous; Prednisone; Rituximab; Treatment Outcome

Topics: Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Female; Glucocorticoids; Humans; Hypoglycemic Agents; Linagliptin; Male; Pemphigoid, Bullous; Prednisone; Renal Insufficiency, Chronic; Withholding Treatment

Bullous pemphigoid (BP) is an autoimmune blistering skin disorder. Recently, BP induced by dipeptidyl peptidase-4 (DPP-4) inhibitors has been a concern. Although DPP-4 inhibitors are commonly used in the Asian population because of their safety and efficacy, BP associated with DPP-4 inhibitors is sometimes seen in clinical settings. Here, we report five Japanese cases of BP associated with the agents. In the present cases, BP occurred in older adults using four different DPP-4 inhibitors, which showed various clinical manifestations in terms of latency period for BP, sex, glycemic control and diabetes duration. Withdrawal of DPP-4 inhibitors was effective in improving BP, and achieved remission even in cases requiring oral steroid administration and intravenous immunoglobulin therapy. Clinicians should note the importance of early diagnosis of this clinical condition and initiate prompt withdrawal of DPP-4 inhibitors.

Topics: Aged, 80 and over; Asian People; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Japan; Linagliptin; Male; Pemphigoid, Bullous; Pyrimidines; Sitagliptin Phosphate

Topics: Adamantane; Aged; Aged, 80 and over; Autoantibodies; Autoantigens; Collagen Type XVII; Dipeptidyl-Peptidase IV Inhibitors; Epitopes; Female; Humans; Immunoglobulin A; Immunoglobulin E; Immunoglobulin G; Linagliptin; Male; Membrane Glycoproteins; Middle Aged; Nitriles; Non-Fibrillar Collagens; Pemphigoid, Bullous; Piperidines; Pyrrolidines; Sitagliptin Phosphate; Uracil; Vildagliptin

Dipeptidyl peptidase-4 (DPP-4) inhibitors have increasingly been identified as causative agents of bullous pemphigoid. The clinical and immunological characteristics of this pemphigoid variant are still unclear. The objective of our study was to analyze the clinical and immunological features of patients with pemphigoid induced by DPP-4 inhibitors.. All patients diagnosed with DPP-4 inhibitor-associated bullous pemphigoid at dermatology departments in three Spanish centers during the period 2013 to 2015 were included. ELISA assays for the NC16A domain of BP180 and BP230 were performed. Immunoblot studies using epidermal/dermal extracts and the C-terminal, NC16A and LAD-1 regions of BP180 were also carried out.. A total of eight patients were identified (5 treated with vildagliptin, 2 with linagliptin, and one with sitagliptin). Of these, four presented the classical inflammatory phenotype of bullous pemphigoid and four a noninflammatory phenotype. The ELISA for BP180 (NC16A domain) was positive in six patients at diagnosis. Most patients reacted to more than one BP180 antigenic site (LAD-1 and/or C-terminal domain) on the immunoblot. Two patients showed no reaction against the NC16A domain of BP180 on either the ELISA or immunoblot but recognized either LAD-1 or both LAD-1 and the C-terminal domain. Only one of the NC16A-negative patients had a noninflammatory subtype of bullous pemphigoid.. Patients with DPP-4 inhibitor-induced BP may present either an inflammatory or a noninflammatory phenotype of BP. IgG response against other BP180 regions different from the NC16A domain, such as LAD-1 and the C-terminal domain, could be pathogenically relevant to the onset of DPP-4 inhibitor-induced BP.

Topics: Adamantane; Aged; Aged, 80 and over; Autoantigens; Collagen Type XVII; Dipeptidyl-Peptidase IV Inhibitors; Dystonin; Female; Humans; Immunoglobulin G; Linagliptin; Male; Nitriles; Non-Fibrillar Collagens; Pemphigoid, Bullous; Phenotype; Pyrrolidines; Sitagliptin Phosphate; Vildagliptin

Topics: Aged, 80 and over; Antibodies; Autoantigens; Collagen Type XVII; Dipeptidyl-Peptidase IV Inhibitors; Epitopes; Female; Humans; Linagliptin; Non-Fibrillar Collagens; Pemphigoid, Bullous; Pyrimidines; Recurrence

The association of bullous pemphigoid (BP) with the use of dipeptidyl-peptidase 4 (DPP-4) inhibitors among patients with diabetes has recently emerged. The risk of developing BP during treatment with new DPP-4 inhibitor agents like linagliptin is yet to be established. The clinical features and the prognostic outcomes of patients with DPP-4 inhibitor-associated BP are yet to be established.. Primarily to estimate the association between DPP-4 inhibitor exposure and the development of BP, and secondarily to characterize the clinical features and history of patients with DPP-4 inhibitor-associated BP.. A retrospective case-control study of the intake of different DPP-4 inhibitor agents and metformin and occurrence of BP among patients with diabetes in a tertiary care referral center for autoimmune bullous diseases in northern Israel. Included were 82 consecutive patients with diabetes and immunopathologically validated BP diagnosed between January 1, 2011, and December 31, 2017, and 328 age-, sex-, and ethnicity-matched control participants with diabetes but without BP.. Patients with diabetes and BP and exposure to DPP-4 inhibitors were followed up for a median of 2.0 years and compared with other patients with diabetes and BP who were not exposed to DPP-4 inhibitors regarding clinical and immunological features, laboratory analyses, treatments, and clinical outcomes.. Eighty-two patients with BP and 328 age- and sex-matched control participants were enrolled; mean (SD) age, 79.1 (9.1) years; and 44 patients were female (53.7%). Overall, DPP-4 inhibitor intake was associated with a 3-fold increased risk for BP (adjusted odds ratio [OR], 3.2; 95% CI, 1.9-5.4). The adjusted ORs for vildagliptin and linagliptin were 10.7 (95% CI, 5.1-22.4) and 6.7 (95% CI, 2.2-19.7), respectively. The association of DPP-4 inhibitor use with BP was independent of the use of metformin and was stronger among male (OR, 4.46; 95% CI, 2.11-9.40) than female (OR, 1.88; 95%, CI 0.92-3.86) patients and strongest in patients younger than 70 years (OR, 5.59; 95% CI, 1.73-18.01). Patients with DPP-4 inhibitor-associated BP presented with higher mucosal involvement (22.2% vs 6.5%; P = .04) and lower mean (SD) peripheral eosinophil counts (399.8 [508.0] vs 1117.6 [1847.6] cells/μL; P = .01) than those with BP who had not been exposed to DPP-4 inhibitor. Discontinuation of DPP-4 inhibitor treatment was followed by improved clinical outcomes.. Vildagliptin and, to a lesser extent, linagliptin are associated with an increased risk of BP. This may partly explain the increasing incidence of BP in Israel. Discontinuation of DPP-4 inhibitor treatment in patients with diabetes should be considered when BP is diagnosed.

Topics: Age Factors; Aged; Aged, 80 and over; Case-Control Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Eruptions; Eosinophils; Female; Humans; Hypoglycemic Agents; Israel; Leukocyte Count; Linagliptin; Male; Metformin; Mucous Membrane; Pemphigoid, Bullous; Retrospective Studies; Risk Assessment; Sex Factors; Vildagliptin

Topics: Aged; Diabetes Mellitus; Drug Eruptions; Female; Humans; Hypoglycemic Agents; Linagliptin; Pemphigoid, Bullous

Topics: Autoantibodies; Autoantigens; Humans; Immunoglobulin G; Linagliptin; Non-Fibrillar Collagens; Pemphigoid, Bullous

Topics: Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Linagliptin; Male; Middle Aged; Pemphigoid, Bullous