Clinical, Laboratory and Histological Features of Dipeptidyl Peptidase-4 Inhibitor Related Noninflammatory Bullous Pemphigoid.
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SUBMITTER: Kinyo A
PROVIDER: S-EPMC8125701 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC9188788 | biostudies-literature
Project description: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.
| S-EPMC6549357 | biostudies-literature
Project description:ImportanceThe 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.ObjectivesPrimarily 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.Design, setting, and participantsA 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.Main outcomes and measuresPatients 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.ResultsEighty-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/?L; 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.Conclusions and relevanceVildagliptin 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.
| S-EPMC6233738 | biostudies-literature
Project description:The practical implications of complement deposition in direct immunofluorescence (DIF) microscopy and its influence on the disease phenotype are poorly understood. We aimed to investigate whether the presence of complement deposition in DIF microscopy gives rise to differences in the morphological, immunological, and histological characteristics of patients with BP (bullous pemphigoid). We performed a retrospective study encompassing patients with BP in a specialized tertiary referral center. Logistic regression model was utilized to identify variables independently associated with complement deposition. The study included 233 patients with BP, of whom 196 (84.1%) demonstrated linear C3 deposition along the dermal-epidermal junction (DEJ) in DIF analysis. BP patients with C3 deposition had higher mean (SD) levels (645.2 (1418.5) vs. 172.5 (243.9) U/mL; p < 0.001) and seropositivity rate (86.3% vs.64.9%; p = 0.002) of anti-BP180 NC16A and less prevalent neutrophilic infiltrate in lesional skin specimens (29.8% vs. 52.4%; p = 0.041). C3 deposition was found positively associated with the detection of anti-BP180 NC16A autoantibodies (OR, 4.25; 95% CI, 1.38-13.05) and inversely associated with the presence of neutrophils in lesional skin (OR, 3.03; 95% CI, 1.09-8.33). To conclude, complement deposition influences the immunological and histological features of BP. These findings are in line with experimental data describing the pathogenic role of complement in BP.
| S-EPMC7761814 | biostudies-literature
Project description:BackgroundBullous pemphigoid (BP) is the most common autoimmune blistering disease in the West. Oral steroids are the standard treatment.This is an update of the review published in 2005.ObjectivesTo assess treatments for bullous pemphigoid.Search strategyIn August 2010 we updated our searches of the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (Clinical Trials), MEDLINE, EMBASE, and the Ongoing Trials registers.Selection criteriaRandomised controlled trials of treatments for participants with immunofluorescence-confirmed bullous pemphigoid.Data collection and analysisAt least two authors evaluated the studies for the inclusion criteria, and extracted data independently.Main resultsWe included 10 randomised controlled trials (with a total of 1049 participants) of moderate to high risk of bias. All studies involved different comparisons, none had a placebo group. In 1 trial plasma exchange plus prednisone gave significantly better disease control at 1 month (0.3 mg/kg: RR 18.78, 95% CI 1.20 to 293.70) than prednisone alone (1.0 mg/kg: RR 1.79, 95% CI 1.11 to 2.90), while another trial showed no difference in disease control at 6 months.No differences in disease control were seen for different doses or formulations of prednisolone (one trial each), for azathioprine plus prednisone compared with prednisone alone (one trial), for prednisolone plus azathioprine compared with prednisolone plus plasma exchange (one trial), for prednisolone plus mycophenolate mofetil or plus azathioprine (one trial), for tetracycline plus nicotinamide compared with prednisolone (one trial). Chinese traditional medicine plus prednisone was not effective in one trial.There were no significant differences in healing in a comparison of a standard regimen of topical steroids (clobetasol) with a milder regimen (RR 1.00, 95% 0.97 to 1.03) in one trial. In another trial, clobetasol showed significantly more disease control than oral prednisolone in people with extensive and moderate disease (RR 1.09, 95% CI 1.02 to 1.17), with significantly reduced mortality and adverse events (RR 1.06, 95% CI 1.00 to 1.12).Authors' conclusionsVery potent topical steroids are effective and safe treatments for BP, but their use in extensive disease may be limited by side-effects and practical factors. Milder regimens (using lower doses of steroids) are safe and effective in moderate BP. Starting doses of prednisolone greater than 0.75 mg/kg/day do not give additional benefit, lower doses may be adequate to control disease and reduce the incidence and severity of adverse reactions. The effectiveness of adding plasma exchange, azathioprine or mycophenolate mofetil to corticosteroids, and combination treatment with tetracycline and nicotinamide needs further investigation.
| S-EPMC7138251 | biostudies-literature
Project description:Total knee arthroplasty is one of the safest and most routinely performed orthopedic procedures. As the volume of cases is expected to rise each year, so too will the incidence of uncommon complications. We describe a rare case of bullous pemphigoid, an autoimmune skin blistering disorder, that occurred after total knee arthroplasty in an otherwise healthy patient and led to hospital readmission. Early diagnosis and treatment of this condition may limit its spread and help to avoid comorbid sequelae.
| S-EPMC8141602 | biostudies-literature
Project description:Aims/introductionWe assessed the association between dipeptidyl peptidase-4 inhibitors (DPP-4is) and bullous pemphigoid (BP) and time-dependent changes in the risk for developing BP after DPP-4i initiation.Materials and methodsThe present population-based, real-world study was carried out using the Japanese National Database dataset collected between 2013 and 2018. To assess independent correlations between DPP-4is and the development of BP, the self-controlled case series method was used.ResultsAmong the cohort followed up for a median of 1,540 days, 53,027 patients were likely to develop BP. The possible incidence rate of BP in all 150,328,339 patients was 10.4/100,000 person-years. Among the 9,705,814 patients with type 2 diabetes, 15,634 were likely to develop BP. The possible incidence rate of BP in patients with type 2 diabetes was 38.1/100,000 person-years, whereas that in patients with type 2 diabetes who did and did not use DPP-4is was 40.7 and 30.0/100,000 person-years, respectively. Analysis of the 28,705 patients with type 2 diabetes likely to develop BP after initial DPP-4i use showed a risk ratio of 2.15 (95% confidence interval [CI] 1.75-2.63), 1.70 (95% CI 1.37-2.11), 1.44 (95% CI 1.15-1.82), 1.25 (95% CI 0.98-1.59), 0.84 (95% CI 0.63-1.10), 0.84 (95% CI 0.64-1.11) and 1.05 (95% CI 0.92-1.20), for the risk period of ≤30, 31-60, 61-90, 91-120, 121-150, 151-180 and 181-365 days, respectively.ConclusionsAlthough DPP-4is were associated with increased risk for BP, the risk was particularly significant within 3 months from first use.
| S-EPMC8902379 | biostudies-literature
Project description:Background Bullous pemphigoid has been associated to dipeptidase-4 inhibitors. Objectives Addressing the potential Bullous pemphigoid-dipeptidase-4 inhibitors association based on pharmacovigilance data currently available in Spain in order to obtain a composite disproportionality estimator from all the data generated by the case-non case studies conducted to this date. Setting The Spanish Pharmacovigilance System for Human Use Drugs database. Method Case-non case study based on the Spanish Pharmacovigilance System for Human Use Drugs notifications submitted between 2007 and 2018 (n?=?169,280), using the Medical Dictionary for Regulatory Activities term (Preferred Term) 'pemphigoid' for sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin (n?=?1952). As negative control, we used acetaminophen, while furosemide was the positive control. A pooled reported odds ratio analysis in the French, Japanese, and Spanish national pharmacovigilance databases was performed. On The Spanish Pharmacovigilance System for Human Use Drugs, we conducted a bullous pemphigoid-metformin association analysis within the period 1982-2018. Main outcome measure Adverse reaction cases in pharmacovigilance databases and the disproportionality through the reporting odds ratio. Results Within The Spanish Pharmacovigilance System for Human Use Drugs, we found 45 cases of bullous pemphigoid in dipeptidase-4 inhibitors patients. Median age was 77 years (range 72-82). The median latency period was 7 months (range 0.23-86). The Bullous pemphigoid-dipeptidase-4 inhibitors association was established with a reporting odd ratio?=?70.0 (95% confidence intervals 49.1-10.1). In the combined analysis of the three aforementioned pharmacovigilance databases, the pooled reporting odd ratio was 81.0 (95% confidence intervals 69.5-94.4). Conclusion The composite estimator for the three national pharmacovigilance databases yields clear evidence of a Bullous pemphigoid-dipeptidase-4 inhibitors association, which was statistically significant for both the pharmacological class as a whole and each of the dipeptidase-4 inhibitors agents under investigation. Metformin's role in the incidence of bullous pemphigoid appeared casual rather than causal. No differences between Caucasian and Asian populations were noted.
| S-EPMC7192859 | biostudies-literature
Project description:Bullous pemphigoid (BP) is a rare autoimmune skin blistering disease, characterized by the presence of autoantibodies against hemidesmosomal autoantigens. Cytokine expression is altered in BP patients, and several of these differently expressed cytokines, including IL-1α, IL-1β, IL-8, and TNF-α, contribute to disease pathogenesis. Since genetic polymorphisms in the genes of these cytokines might be implicated in susceptibility to BP disease, we aimed at testing this implication in susceptibility to BP in an Iranian cohort. Blood samples were collected from the subjects and genomic DNA was extracted. To detect the single nucleotide polymorphisms (SNPs), IL-1α (rs1800587), IL-1β (rs1143627, rs16944, rs1143634), IL-8 (rs4073), and TNF-α (rs1799964, rs1800630, rs1799724, and rs361525) genes were genotyped in BP patients and healthy controls as well as IL-8 (rs4073) in pemphigus vulgaris (PV) patients. Quantitative gene expression was evaluated by RT-PCR analysis. A significant difference was observed in the distribution of genotypes or alleles of IL-8 SNP between the BP patients and controls. The A-allele of IL-8 SNP is significantly more prevalent in the control individuals compared to the BP patient. To further validate this observation, we included PV patients as an additional control. Again, the A-allele of IL-8 SNP is significantly more prevalent in the PV compared to the BP patients. While we observed a trend toward significant differences regarding alleles of TNF-α rs1799724 as well as alleles of TNF-α rs1799964, this difference was, however, not evident after correction for multiple analysis. There was no significant difference in all other studied SNPs. In contrast to IL-1α, IL-1β, and TNF-α, IL-8 gene expression levels were significantly higher in the patients than that of controls. The minor allele in IL-8 SNP might play a protective role in susceptibility to BP in Iranian patients. Although higher expression levels of IL-8 gene was found in the patients compared with healthy controls, these levels, however, suggest no association with the examined polymorphism. Moreover, further investigation revealed an elevation in gene expression between wild and polymorphic genotypes of IL-1α rs1800587 and TNF-α rs361525 in the patient group and these SNPs are therefore associated with altering the levels of gene expression.
| S-EPMC6455081 | biostudies-literature
Project description:Pemphigus and bullous pemphigoid are autoantibody-mediated blistering skin diseases. In pemphigus, keratinocytes in epidermis and mucous membranes lose cell-cell adhesion, and in pemphigoid, the basal keratinocytes lose adhesion to the basement membrane. Pemphigus lesions are mediated directly by the autoantibodies, whereas the autoantibodies in pemphigoid fix complement and mediate inflammation. In both diseases, the autoantigens have been cloned and characterized; pemphigus antigens are desmogleins (cell adhesion molecules in desmosomes), and pemphigoid antigens are found in hemidesmosomes (which mediate adhesion to the basement membrane). This knowledge has enabled diagnostic testing for these diseases by enzyme-linked immunosorbent assays and dissection of various pathophysiological mechanisms, including direct inhibition of cell adhesion, antibody-induced internalization of antigen, and cell signaling. Understanding these mechanisms of disease has led to rational targeted therapeutic strategies.
| S-EPMC5560122 | biostudies-other