Bullous pemphigoid (BP) is an organ-specific autoantibody-mediated blistering skin disease that mainly affects the elderly. Typical clinical features include the widespread blisters, often preceded ...by and/or associated with itchy urticarial or eczema-like lesions. BP patients have circulating autoantibodies against BP180 and/or the plakin family protein BP230 both of which are components of hemidesmosomes in basal keratinocytes. Most BP autoantibodies particularly target the epitopes within the non-collagenous NC16A domain of BP180. Clinical findings and murine models of BP have provided evidence of a pathogenic role of anti-NC16A autoantibodies. However, it is largely unknown what triggers the breakage of immunotolerance against BP180 in elderly individuals. The incidence of BP has been increased over the past two decades in several countries. Aside from aging populations, the factors behind this phenomenon are still not fully understood. Neurodegenerative diseases such as multiple sclerosis, Parkinson's disease, and certain dementias are independent risk factors for BP. Recently several case reports have described BP in patients with diabetes mellitus (DM) patients who have been treated with dipeptidyl peptidase-4 inhibitors (DPP-4i or gliptins), which are a widely used class of anti-DM drugs. The association between the use of DPP-4is, particularly vildagliptin, and BP risk has been confirmed by several epidemiological studies. Evidence suggests that cases of gliptin-associated BP in Japan display certain features that set them apart from cases of "regular" BP. These include a "non-inflammatory" phenotype, targeting by antibodies of different immunodominant BP180 epitopes, and a specific association with the human leukocyte antigen (HLA) types. However, recent studies in European populations have found no major differences between the clinical and immunological characteristics of gliptin-associated BP and "regular" BP. The DPP-4 protein (also known as CD26) is ubiquitously expressed and has multiple functions in various cell types. The different effects of the inhibition of DPP-4/CD26 activity include, for example, tissue modeling and regulation of inflammatory cells such as T lymphocytes. Although the pathomechanism of gliptin-associated BP is currently largely unknown, investigation of the unique effect of gliptins in the induction of BP may provide a novel route to better understanding of how immunotolerance against BP180 breaks down in BP.
Dipeptidyl peptidase-4 inhibitors (DPP-4i or gliptins) increase the risk of developing bullous pemphigoid (BP). To clarify, whether gliptin-associated BP has special features, we analyzed the ...clinical, histopathological and immunological features of 27 BP patients, 10 of which previously used gliptin medication. Compared to those who had not previously received gliptins, subjects who had, showed higher BP180-NC16A ELISA (enzyme-linked immunosorbent assay) values, fewer neurological co-morbidities and shorter time to remission, but differences were not statistically significant. The HLA-DQB1*03:01 allele was more commonly present among the BP patients than the control population, but was not more common in those with gliptin history. To determine the effect of gliptins on the expression of the DPP-4/CD-26 protein we performed immunohistochemistry, which showed that the skin expression of DPP-4/CD-26 was increased in BP patients, but not affected by prior gliptin treatment. We conclude that DPP-4i medication is common among BP patients and prior gliptin treatment may be associated with some specific features.
Accurate use of diagnostic codes is crucial for epidemiological and genetic research based on electronic health record (EHR) data.
This retrospective study validated the International Classification ...of Diseases (ICD)-10 diagnostic code L12.0 for bullous pemphigoid (BP) using EHR data from two Finnish university hospitals. We found 1225 subjects with at least one EHR entry of L12.0 between 2009 and 2019. BP diagnosis was based on clinical findings characteristic of BP and positive findings on direct immunofluorescence (DIF), BP180-NC16A enzyme-linked immunosorbent assay (ELISA) or indirect immunofluorescence (IIF) assay.
True BP was found in 901 patients; the positive predictive value (PPV) for L12.0 was 73.6% (95% CI 71.0-76.0). L12.0 was more accurately registered in dermatology units than any specialized health care units (p<0.001). Including patients with multiple L12.0 registrations (≥3), increased the accuracy of the L12.0 code in both dermatology units and other settings.
One diagnostic code of L12.0 is not enough to recognize BP in a large epidemiological data set; including only L12.0 registered in dermatology units and excluding cases with <3 L12.0 record entries markedly increases the PPV of BP diagnosis.
The use of dipeptidyl peptidase 4 (DPP4) inhibitors, (also known as gliptins), is associated with an increased risk of bullous pemphigoid (BP), an autoimmune blistering skin disease. To explore the ...mechanism behind gliptin-associated BP we investigated circulating autoantibodies against the major BP autoantigen BP180 in serum samples from patients with type 2 diabetes (T2D) with preceding gliptin medication (n = 136) or without (n = 136). Sitagliptin was the most frequently prescribed gliptin (125/136 patients). Using an ELISA assay, we showed that IgG autoantibodies against the immunodominant NC16A domain of BP180 were found in 5.9% of gliptin treated and in 6.6% of non-gliptin treated T2D patients. We found that 28% of gliptin treated patients had IgG autoantibodies recognizing the native full-length BP180 in ELISA, but among non-gliptin treated the seropositivity was even higher, at 32%. Further ELISA analysis of additional serum samples (n = 57) found no major changes in the seropositivity against BP180 during a follow-up period of about nine years. In immunoblotting, full-length BP180 was recognized by 71% of gliptin treated and 89% of non-gliptin treated T2D patients, but only by 46% of the age-and sex-matched controls. The chemokine stromal derived factor-1(SDF-1/CXCL12) is one of the major substrates of DPP4. Immunostainings showed that the expression of SDF-1 was markedly increased in the skin of BP patients, but not affected by prior gliptin treatment. We found that the use of gliptins decreased the serum level of SDF-1α in both BP and T2D patients. Our results indicate that the autoantibodies against the linear full-length BP180 are common in patients with T2D, but seropositivity is unaffected by the use of sitagliptin.
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