Inhibitor-associated Bullous Pemphigoid Research Articles

Lisinopril prevents bullous pemphigoid induced by dipeptidyl peptidase 4 inhibitors via the Mas receptor pathway.

Recent studies have suggested that dipeptidyl peptidase 4 (DPP4) inhibitors increase the risk of development of bullous pemphigoid (BP), which is the most common autoimmune blistering skin disease; however, the associated mechanisms remain unclear, and thus far, no therapeutic targets responsible for drug-induced BP have been identified. Therefore, we used clinical data mining to identify candidate drugs that can suppress DPP4 inhibitor-associated BP, and we experimentally examined the underlying molecular mechanisms using human peripheral blood mononuclear cells (hPBMCs). A search of the US Food and Drug Administration Adverse Event Reporting System and the IBM® MarketScan® Research databases indicated that DPP4 inhibitors increased the risk of BP, and that the concomitant use of lisinopril, an angiotensin-converting enzyme inhibitor, significantly decreased the incidence of BP in patients receiving DPP4 inhibitors. Additionally, in vitro experiments with hPBMCs showed that DPP4 inhibitors upregulated mRNA expression of MMP9 and ACE2, which are responsible for the pathophysiology of BP in monocytes/macrophages. Furthermore, lisinopril and Mas receptor (MasR) inhibitors suppressed DPP4 inhibitor-induced upregulation of MMP9. These findings suggest that the modulation of the renin-angiotensin system, especially the angiotensin1-7/MasR axis, is a therapeutic target in DPP4 inhibitor-associated BP.

Atypical clinical manifestation and protracted latency are observed in the emerging variant of checkpoint inhibitor-associated bullous pemphigoid.

Abstract Linked Article: Kawsar et al. Br J Dermatol 2022; 187:981–987.

A retrospective case series of 20 patients with immunotherapy-induced bullous pemphigoid with emphasis on management outcomes

To the Editor: Bullous pemphigoid (BP) is well reported in patients receiving programmed cell death protein-1 (PD-1) inhibitors.1 Immune checkpoint inhibitor–associated BP (ICI-BP) is difficult to control and leads to refractory itch, prolonged oral steroids, and therapy interruptions.

Dipeptidyl Peptidase 4 Inhibitor‒Associated Bullous Pemphigoid Is Characterized by an Altered Expression of Cytokines in the Skin

Dipeptidyl peptidase 4 inhibitors (DPP4is), commonly used drugs for treatment of type 2 diabetes, increase the risk for bullous pemphigoid (BP). Currently, the mechanism leading to the loss of immunological tolerance of the cutaneous adhesion molecule BP180 as well as similarities and differences in disease progression between DPP4i-associated BP (DPP4i-BP) and DPP4i-independent regular BP are largely unknown. We analyzed the expression of 32 cytokines and two proteases by Luminex and ELISA assays in samples taken from lesional and nonlesional skin of patients with regular BP or DPP4i-BP and healthy controls. Cytokines mediating B-cell survival and targeting such as BAFF, CCL4, CXCL12, and IL-6 were expressed at a higher level in the lesional regular BP skin than the levels in the lesional DPP4i-BP skin. The DPP4i-BP samples had increased levels of eosinophilic cytokines CCL1, CCL17, CCL26, and IL-5, which correlated with the serum level of anti-BP180 NC16A IgG autoantibodies. The mRNA expression of BAFF, IL6, CCL1, CCL17, CCL26, and IL5 measured by qPCR correlated with the protein levels. Taken together, the cutaneous cytokine profiles were found to provide distinctive molecular fingerprints between regular BP and DPP4i-BP.

1282-P: Genetic Susceptibility of Dipeptidyl Peptidase-4 Inhibitor–Associated Bullous Pemphigoid in Chinese Patients with Type 2 Diabetes

Objective: The rare risk association of bullous pemphigoid (BP) with use of dipeptidyl peptidase-4 inhibitors (DPP-4i) had been reported including genetic association with HLA variants. We assessed genetic susceptibility of BP associated with DPP-4i use in patients with type 2 diabetes (T2D) . Methods: In a prospective cohort of 30,129 Chinese patients with T2D enrolled in the Hong Kong Diabetes Register between 1995 to 2018, we curated multiple case-control cohorts with available genotype data to explore the genetic associations of major histocompatibility complex (MHC) region with DDP-4i-associated BP. Results: During a median follow period of 9 years, 60 patients developed BP (incidence of 2.cases per 10,000 patient-years) . 20 patient developed BP after DPP-4i use, with median exposure to DPP-4i of 1.7 years (incidence of 4.76 cases per 10,000 patient-years) and an adjusted odds ratio of 1.1 (95% CI 0.5-1.6) . 32 patients developed BP and were not exposed to DPP-4i (incidence of 2.87 cases per 10,000 patient-years) . In 1:2 matched case:control cohort of patients who tolerated DPP-4i and did not develop of BP, multiple variants in the second intron of HLA-DQB1 exhibited strong association with DPP4i-associated BP, including the well-reported HLA-DQB1*03: (OR 12.00; 95% CI 1.99-72.35; P-value 6.71e-03) and a novel single nucleotide polymorphism rs281863580 (OR 11.96; 95% CI 4.14-34.54; P-value 4.53e-06) . We additionally identified variants located in other HLA regions that were associated with BP in non-DPP4i users. Conclusion: Multiple genetic polymorphisms in the second intron of HLA-DQB1 were associated with increased susceptibility to incident BP in DPP-4i users. Further exploration of the extended MHC region beyond HLA alleles might identify a combination panel for assessing the genetic risk of BP rather than a single HLA allele. Disclosure M.Shi: None. A.Yang: None. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. E.S.Lau: None. C.H.Tam: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. M.Cheung: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. W.Chan: None. Funding The Hong Kong Government Research Grants Committee Theme-based Research Scheme (T12-402/13N) .2) Impact Research Impact Fund (R4012-18) .

Dipeptidyl Peptidase-4 Inhibitor Associated Bullous Pemphigoid with Anti-full-length BP180 and BP230 Antibodies

Dipeptidyl Peptidase-4 Inhibitor Associated Bullous Pemphigoid with Anti-full-length BP180 and BP230 Antibodies

A Case of Dipeptidyl Peptidase-4 Inhibitor-associated Bullous Pemphigoid in which Anti-BP180NC16a Antibody Became Positive during the Course of Treatment

A Case of Dipeptidyl Peptidase-4 Inhibitor-associated Bullous Pemphigoid in which Anti-BP180NC16a Antibody Became Positive during the Course of Treatment

Neutrophil to lymphocyte ratio is predictive of severe complications and mortality in patients with dipeptidyl peptidase-4 inhibitor-associated bullous pemphigoid: A retrospective longitudinal observational study

Neutrophil to lymphocyte ratio is predictive of severe complications and mortality in patients with dipeptidyl peptidase-4 inhibitor-associated bullous pemphigoid: A retrospective longitudinal observational study

Regulatory T cell subsets in bullous pemphigoid and dipeptidyl peptidase-4 inhibitor-associated bullous pemphigoid

BackgroundRegulatory T (Treg) cells play an essential role in peripheral immune tolerance. Bullous pemphigoid (BP) is the most common blistering disease and is caused by autoantibodies to two BP antigens: type XVII collagen and BP230. Recently, we reported that Treg cell dysfunction may cause the production of autoantibodies to BP antigens. Several studies have suggested an association between Treg cells and BP pathogenesis. However, Treg cells are heterogeneous in humans, leading to inconsistent results in previous studies. ObjectiveTo assess functional Treg subsets in BP. MethodsWe examined three distinct Treg subsets in conventional BP (cBP) patients before versus after systemic corticosteroid treatment, dipeptidyl peptidase-4 inhibitor-associated BP (DPP-4i-BP) patients, younger controls and older controls. ResultsWe found that total Treg cells and all Treg cell subsets were increased in cBP patients before treatment and decreased by systemic corticosteroid treatment. In contrast, neither total Treg cells nor all Treg subsets were increased in DPP-4i-BP. Notably, CD45RA− Foxp3hi effector Treg cells positively correlated with disease severity in cBP, whereas CD45RA+Foxp3lo naïve Treg cells positively correlated with the disease severity in DPP-4i-BP. ConclusionThese findings suggest that Treg cells are differently involved in the pathogeneses of cBP and DPP-4i-BP.

Clinical and immunological profile of patients with dipeptidyl peptidase-4 inhibitor-associated bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune blistering disease caused by antibodies against the hemidesmosomal BP180 and/or BP230 proteins. There is an increasing evidence that the use of dipeptidyl peptidase-4 inhibitors, also known as gliptins, increases the risk for BP. The gliptins more frequently associated with BP are vildagliptin and sitagliptin. Clinical, immunological and pathological features of gliptin-associated BP have been reported to be distinct, compared to classic BP. In this study, 15 gliptin-associated BP (g-BP) cases have been compared with 16 consecutive idiopathic BP (i-BP) to clarify whether g-BP has distinctive clinical and immunopathological characteristics. Comorbidities, concomitant treatments, latency of the onset of the disease and the time to achieve the remission were also considered. The mean latency from drug intake to g-BP appearance was 9.4 months (median 10, inter-quartile range [IQR] 6-12). There were no differences in sex and age prevalence between the two groups (g-BP median age 77 years, IQR: 70-84; i-BP: 81 years, IQR: 72-86). There were no differences as far clinical presentation including disease severity, lesions types (urticarial and bullous) or mucosal involvement between g-BP and i-BP cases. The median antibody anti-BP180 and anti-BP230 titers was also similar between the two groups with 29.1 UI/mL (IQR: 12.9-65.3) and 11.8 UI/mL (IQR: 1.7-26.3), respectively. Gliptins were withdrawn in ten out of 15 patients and remission was achieved with systemic corticosteroids (0.3-0.7 mg/Kg daily) alone or in association with doxycycline (100-200 mg daily) within a mean of 8 months. A non-inflammatory phenotype with less erythema, fewer urticarial lesions and fewer eosinophils in skin lesions has been associated with gliptins in selected Japanese BP populations. As reported in European studies, no significant differences among the considered variables in the g-BP and i-BP cases have been found in our study.

Teneligliptin, a DPP-4 Inhibitor, Decreases Plasma Levels of Inflammatory Chemokines During a Standard Meal Test in Patients With Type 2 Diabetes

Dipeptidyl peptidase-4 (DPP-4) rapidly inactivates incretin hormones and several chemokines, thus influencing chemokine function. There have recently been several reports that DPP-4 inhibitor therapy is associated with an increased risk of bullous pemphigoid (BP), an autoimmune skin disease. Previous studies have demonstrated an increase of CCL11/Eotaxin, a DPP-4 substrate, in serum and blister fluid from patients with BP. Serum levels of CCL22/macrophage-derived chemokine (MDC) and CXCL10/IP-10, other DPP-4 substrates, are also elevated in BP patients. In patients with type 2 diabetes, we investigated the effect of treatment with teneligliptin (a DPP-4 inhibitor) for 24 weeks on plasma levels of CCL11/Eotaxin, CCL22/MDC and CXCL10/IP-10 during a meal test. Ten consecutive patients with type 2 diabetes who showed inadequate glycemic control by metformin and/or sulfonylureas were recruited. A standard meal test was performed at baseline and after 24 weeks of treatment with teneligliptin at 20 mg/day. Blood samples were collected at 0, 30, 60 and 120 minutes after ingestion of the meal. In addition to plasma levels of the 3 chemokine, plasma DPP-4 enzyme activity and soluble DPP-4 antigen were measured. Treatment with teneligliptin decreased hemoglobin A1c and reduced fasting plasma DPP-4 activity by 90.1% compared with baseline. Unexpectedly, plasma levels of all 3 chemokines (including CCL11/Eotaxin) were not increased after teneligliptin treatment, and instead were significantly lower at every point during the meal test. Teneligliptin reduced the plasma concentrations of 3 chemokines (DPP-4 substrates) that may be related to the occurrence of DPP4 inhibitor-associated BP (UMIN000012508).

Preferential Reactivity of Dipeptidyl Peptidase-IV Inhibitor-Associated Bullous Pemphigoid Autoantibodies to the Processed Extracellular Domains of BP180.

Bullous pemphigoid (BP) is a common autoimmune blistering disease in which autoantibodies target the hemidesmosomal components BP180 and/or BP230 in basal keratinocytes. In BP, 80 to 90% of autoantibodies target the juxtamembranous extracellular non-collagenous 16th A (NC16A) domain of BP180. Recently, the administration of dipeptidyl peptidase-IV inhibitors (DPP4i), which are widely used as antihyperglycemic drugs, has been recognized to be a causative factor for BP. DPP4i-associated BP (DPP4i-BP) autoantibodies tend to target epitopes on non-NC16A regions of BP180, and the pathomechanism for the development of the unique autoantibodies remains unknown. To address the characteristics of DPP4i-BP autoantibodies in detail, we performed epitope analysis of 18 DPP4i-BP autoantibodies targeting the non-NC16A domains of BP180 using various domain-specific as well as plasmin-digested polypeptides derived from recombinant BP180. Firstly, Western blotting showed that only one DPP4i-BP serum reacted with the epitopes on the intracellular domain of BP180, and no sera reacted with the C-terminal domain of the molecule. In addition, only 2 DPP4i-BP sera reacted with BP230 as determined by enzyme-linked immunosorbent assay. Thus, DPP4i-BP autoantibodies were found to mainly target the non-NC16A mid-portion of the extracellular domain of BP. Interestingly, Western blotting using plasmin-digested BP180 as a substrate revealed that all of the DPP4i-BP sera reacted more intensively with the 97-kDa processed extracellular domain of BP180, which is known as the LABD97 autoantigen, than full-length BP180 did. All of the DPP4i-BP autoantibodies targeting the LABD97 autoantigen were IgG1, and IgG4 was observed to react with the molecule in only 7 cases (38.9%). In summary, the present study suggests that IgG1-class autoantibodies targeting epitopes on the processed extracellular domain of BP180, i.e., LABD97, are the major autoantibodies in DPP4i-BP.

Dipeptidyl-peptidase IV inhibitor–associated bullous pemphigoid: A systematic review and meta-analysis

To the Editor: Dipeptidyl-peptidase IV inhibitors (DPP4is) have recently emerged as a putative triggering factor of bullous pemphigoid (BP). The aim of the current study is to perform a systematic review and metaanalysis summarizing the association of DPP4i with the risk for the development of BP.

Association of Bullous Pemphigoid With Dipeptidyl-Peptidase 4 Inhibitors in Patients With Diabetes

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.

Bullous pemphigoid induced by dipeptidyl peptidase-4 inhibitors. Eight cases with clinical and immunological characterization.

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.