Development Of Bullous Pemphigoid Research Articles

Development of bullous pemphigoid with autoantibodies against full‐length BP180 following COVID‐19 infection

Development of bullous pemphigoid with autoantibodies against full‐length <scp>BP180</scp> following <scp>COVID</scp>‐19 infection

Risk of bullous pemphigoid and pemphigus in patients on chronic dialysis: A nationwide population-based cohort study.

Bullous pemphigoid has a high incidence among dialysis patients. However, whether or not chronic dialysis is an independent risk factor of bullous pemphigoid remains unclear. We aimed to investigate the effect of chronic dialysis on the development of bullous pemphigoid and pemphigus. We performed a retrospective cohort study using records from Taiwan's National Health Insurance Research Database between 2008 and 2019. We identified a dialysis cohort that included patients on chronic hemodialysis and peritoneal dialysis, and the hazard ratios (HRs) for bullous pemphigoid and pemphigus were compared with those of a sex-, age-, and index-matched cohort, then the results were adjusted for various confounding factors. Among 93 538 patients on chronic dialysis and 93 538 patients in the control group, 287 and 139 developed incident bullous pemphigoid, and 45 and 35 developed incident pemphigus after a median follow-up of 3.7 and 5.6 years, respectively. The incidence rates of bullous pemphigoid in the dialysis patients and the control group were 74.2 and 25.2 per 100 000 person-years, respectively (difference between groups, P < 0.0001). The incidence rates of pemphigus in the dialysis patients and the control group were 11.6 and 6.3 per 100 000 person-years, respectively (difference between groups, P < 0.01). Cox proportional hazard adjustment showed the HR for bullous pemphigoid in dialysis patients was 2.12 (95% confidence interval [CI] 1.64-2.74, P < 0.0001) compared with the control group. Dialysis patients aged <75 years had an even higher risk of bullous pemphigoid development (5- to 8-fold) than the control group. The adjusted HR for pemphigus was not elevated in dialysis patients (adjusted HR 1.52, 95% CI 0.87-2.67, P = 0.14). Chronic dialysis is an independent risk factor for developing bullous pemphigoid, but not a risk factor for pemphigus. Physicians should be aware of the predisposition of chronic dialysis patients to bullous pemphigoid.

Dramatic deterioration or new‐onset dipeptidyl peptidase‐4 inhibitor‐associated bullous pemphigoid after COVID‐19 vaccination: A possible manifestation of immune reconstitution inflammatory syndrome

AbstractBackgroundMany reports have described the development of bullous pemphigoid (BP) following COVID‐19 vaccination. In dipeptidyl peptidase‐4 inhibitor‐associated BP (DPP‐4i‐BP), cessation of DPP‐4i appears to have a paradoxical effect on the clinical course of the BP. Interestingly, similar paradoxical reactions have been shown to develop after antibody‐based therapies that inhibit pro‐inflammatory cytokine signalling. These heterogenous outcomes could be explained by assuming that DPP‐4i‐BP is a manifestation of immune reconstitution inflammatory syndrome (IRIS). Onset of IRIS could be triggered by a variety of stimuli, including initiation of immune checkpoint blockade and vaccination.ObjectivesTo examine whether the onset of postvaccine BP, although rarely reported, is preferentially observed in DPP‐4i‐BP and whether severe outcomes of IRIS can be predicted by specific cytokine profiles.MethodsThis single‐centre retrospective study was based on the medical records of 63 consecutive outpatients with BP.ResultsExacerbation or new onset BP following COVID‐19 vaccination was observed in 6 of 11 patients with BP who were receiving DPP‐4i. One patient who developed dramatic exacerbation of DPP‐4i‐BP and cytomegalovirus (CMV) disease following COVID‐19 vaccination showed high concentrations of granulocyte‐colony‐stimulating factor and interleukin‐10 after vaccination, both of which have been associated with CMV‐IRIS in other settings.ConclusionsCOVID‐19 vaccine‐induced BP was more frequently associated with DPP‐4i‐BP than with ‘classic’ BP. COVID‐19 vaccination may trigger the shift to infectious IRIS. When infectious IRIS is suspected from the cytokine profile after COVID‐19 vaccination, thorough clinical evaluation for reactivation of CMV should be performed immediately with prompt initiation of anti‐CMV medication if necessary.

Regression of cutaneous squamous cell carcinoma after the development of pembrolizumab‐induced bullous pemphigoid

AbstractBullous pemphigoid is a rare complication of immune checkpoint inhibitor treatment. We report a case of pembrolizumab‐induced bullous pemphigoid in a patient with malignant melanoma and concomitant cutaneous squamous cell carcinoma that regressed. A 77‐year‐old woman with metastatic malignant melanoma and a 3‐year history of a growing skin nodule on her left calf was treated with pembrolizumab. Histopathological examination of the skin nodule established the diagnosis of cutaneous squamous cell carcinoma. Seven months after the initiation of pembrolizumab treatment, the patient developed bullous pemphigoid. Discontinuation of pembrolizumab and initiation of oral prednisolone resulted in the resolution of the skin blisters. Additionally, complete response of the metastatic malignant melanoma was noted after pembrolizumab treatment. Furthermore, the cutaneous squamous cell carcinoma completely resolved after the development of bullous pemphigoid. This case supports the hypothesis that the development of bullous pemphigoid is indicative of a sufficient antitumor response after immunotherapy.

Gliptin-induced bullous pemphigoid: withdrawal of gliptin allows for faster control of the disease

Gliptins, also called dipeptidyl peptidase-4 inhibitors, have been incriminated in the development of bullous pemphigoid (BP). To date, there are no recommendations regarding the therapeutic approach for BP during gliptin intake. The aim of this retrospective study was to evaluate the evolution of BP after three months relative to continuation or discontinuation of gliptin. From a series of 372 patients with BP, 40 taking gliptin were included (January 2009 to December 2019). The primary endpoint was complete response, three months after BP diagnosis based on gliptin continuation or discontinuation. The secondary endpoints were complete response after one month and six months. Of BP patients, 67.5% were taking vildagliptin. BP was diagnosed at a mean period of 28.8 months after gliptin initiation. Gliptin was continued and discontinued each in 20 patients. Three months after diagnosis, patients who stopped gliptin had a significatively better clinical status (p = 0.0006). Thirteen patients had complete response when gliptin was stopped, compared to one patient when gliptin was continued. This difference was maintained after six months (p = 0.0031). There was no difference between the treatments received by patients who stopped gliptin and those who continued treatment (p = 0.7515). In this retrospective study, two groups were compared; one that continued gliptin and the other that stopped the drug. The results obtained suggest that stopping gliptin allows for a complete response rate at three months and six months, whereas gliptin maintenance did not allow for complete response.

Bullous Pemphigoid Associated with Dipeptidyl Peptidase 4 Inhibitors for the Treatment of Type 2 Diabetes: A Multicenter Study in Istanbul.

ObjectivesRecent studies have revealed an association between dipeptidyl peptidase 4 inhibitors (DPP4i) and development of bullous pemphigoid (BP). The main aim of our study is to evaluate the association between DPP4i treatment and BP development. The secondary endpoints were to evaluate clinical characteristics and biochemical parameters of the DPP4i associated BP cases and determine the differences of DPP4i associated BP disease than non-DPP4i associated BP cases.MethodsWe designed a retrospective case-control study, comparing type 2 diabetic 58 BP cases to 75 type 2 diabetic controls. Data were collected from three dermatological departments in Istanbul/Turkey, from November 1, 2008, to January 1, 2019. Medical records of each patient’s demographic, clinical characteristics, drugs used, and laboratory data were reviewed.ResultsThere was no statistical difference in age and gender between the patient and control group. The most common prescribed oral antidiabetic for both groups was metformin. The most commonly prescribed DPP4i was vildagliptin. Fourteen (24.1%) out of 58 diabetic patients with BP were using vildagliptin, 12 (20.7%) out of 58 diabetic BP patients were using linagliptin, 6 (10.3%) out of 58 diabetic BP patients were using sitagliptin, and 1 (1.7%) out of 58 diabetic BP patients were using saxagliptin. There was no significant difference between the two groups regarding the DPP4 is use (using DPPi at the time of diagnosis and not). Both groups had similar clinical characteristics, localizations, disease severity, comorbidities, treatment responses, and biochemical parameters. BP patients using DPP4i had statistically less mucosal involvement than BP patients not using DPP4i (p=0.044).ConclusionEven though there was no difference between two groups, when BP develops in diabetic patients, DPP4 is should be questioned and with cooperation with clinician’s consideration of change may be planned.

Inhibition of dipeptidyl-peptidase 4 induces upregulation of the late cornified envelope cluster in keratinocytes.

Dipeptidyl-peptidase 4 (DPP4) is a multifunctional type II transmembrane glycoprotein that is expressed on various cell surfaces. While DPP4 inhibitors have a therapeutic role in the treatment of diabetes mellitus, they are an independent risk factor in the development of bullous pemphigoid. Contrarily, there are reports of improvement in psoriasis with DPP4 inhibition. We investigated the effect of DPP4 inhibition on primary human keratinocytes to determine whether DPP4 modulates keratinocyte inflammatory signaling and keratinocyte homeostasis. We performed RNA sequencing of primary adult human keratinocytes treated with DPP4 inhibitor, identifying 424 differentially expressed genes. Gene ontology analysis revealed significant enrichment of epidermal differentiation and cornified envelope genes. Using three-dimensional organotypic cultures and a pan-late cornified envelope 2 (LCE2) antibody, we demonstrate a dose dependent relationship between DPP4 inhibition and increased expression of LCE2 during epidermal development. The late cornified envelope gene clusters are expressed at the late stages of epithelial development, responding tostimuli such as calcium and ultraviolet light. While its biologic function is not fully understood, mutations in LCE3B/LCE3C confer a 40% increased risk in the development of plaque psoriasis. While we did not identify significant modulation of keratinocyte inflammatory markers, DPP4 inhibition increased expression of the late cornified envelope may offer a potential alternative therapeutic mechanism in psoriasis.

Case of Linagliptin-Induced Bullous Pemphigoid

Bullous pemphigoid is an autoimmune subepidermal blistering condition in which autoantibodies target components of the hemidesmosomal proteins. It typically presents as pruritic bullous lesions in a generalized distribution. Certain drugs such as diuretics, NSAIDs, antibiotics, and ACE inhibitors have been implicated in the development of bullous pemphigoid. Recently, a class of medications for type II diabetes, dipeptidyl peptidase-4 (DPP-4) inhibitors (commonly called gliptins) have been implicated in drug-induced bullous pemphigoid. We report a case of a 73-year-old female with type II diabetes mellitus who presented with biopsy-proven bullous pemphigoid after being treated with linagliptin. After discontinuing linagliptin and receiving first-line treatment, the patient achieved remission by her five-week follow-up. It is imperative that dermatologists and primary care physicians remain aware of this association when diagnosing and treating bullous pemphigoid, particularly in diabetic patients.

Superimposed Effects of Adalimumab and Linagliptin on the Development of Bullous Pemphigoid in a Psoriatic Patient: A Case Report.

Superimposed Effects of Adalimumab and Linagliptin on the Development of Bullous Pemphigoid in a Psoriatic Patient: A Case Report.

Dipeptidyl peptidase 4 inhibitors and bullous pemphigoid − more evidence of a link: a report of three cases

Recently, dipeptidyl peptidase 4 (DPP-4) inhibitors, an antidiabetic medication, have been implicated in the development of bullous pemphigoid, the most common autoimmune cutaneous blistering disorder. In this report we present three cases of DPP-4 associated bullous pemphigoid in our dermatology department. These cases illustrate the importance for clinicians to consider a drug as a trigger for bullous pemphigoid in elderly patients with diabetes.

Possible roles of CXCL13/CXCR5 axis in the development of bullous pemphigoid.

CXCL13 recruits CXCR5+ follicular helper T (Tfh) cells in inflammatory lesions to develop secondary lymphoid organs. Tfh cells activate B cells to produce antibodies during humoral immune responses. Indeed, as previous reports suggested, CXCR5+ cell numbers were increased in the peripheral blood of bullous pemphigoid (BP) patients when compared with healthy donors, and the ratio of CXCR5+ cells was positively correlated with the anti-BP180-NC16A titers. From the above findings, in this report, we hypothesized that a chemokine related to CXCR5+ cells, namely CXCL13, may play a role in the development of BP. We performed immunohistochemical staining of CXCR5, CXCL13, LL37, CXCL10 and CCL20 for 10 cases of BP and 10 cases of pemphigus vulgaris (PV), and quantitatively analyzed the staining by digital microscopy. Moreover, we investigated the CXCL10 and CXCL13 production in BP and PV patients by enzyme-linked immunosorbent assay. The immunomodulatory effects of LL37 on the production of T-helper 17-related chemokines were evaluated using monocyte-derived M2 macrophages. Immunohistochemical staining and digital microscopic analysis showed that the ratios of CXCR5+ , CXCL13+ and LL37+ cells in the dermis were significantly higher in BP patients than in PV patients. Notably, the ratio of CXCL13+ cells was positively correlated with the anti-BP180-NC16A titers. Moreover, the serum levels of CXCL13 were positively correlated with the anti-BP180-NC16A titers. Furthermore, CD163+ M2 macrophages stimulated by LL37 in vitro produced CXCL10 and CCL20. In the lesional skin of BP, CD163+ macrophages CXCL10 and CCL20 were produced. The serum levels of CXCL10 were negatively correlated with the anti-BP180-NC16A titers. The present study results indicate that the mechanism of the development of BP may involve the CXCL13/CXCR5-mediated migration of Tfh cells.

Association Between Medication Use and Bullous Pemphigoid

The association between the use of medications and the development of bullous pemphigoid (BP) is unclear. To assess the associations between previous exposure to certain medications and BP. For this systematic review and meta-analysis, PubMed, the Cochrane Central Register of Controlled Trials, and Embase were searched for relevant studies from inception to February 20, 2020. Case-control or cohort studies and randomized clinical trials that examined the odds or risk of BP in patients with previous medication use were included. No geographic or language limitations were imposed. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guideline was followed. The Newcastle-Ottawa Scale was used to evaluate the risk of bias of included observational studies; Cochrane Collaboration's tool was used for randomized clinical trials. Aggregate data were used to conduct a random-effects model meta-analysis if the included studies were sufficiently homogenous. Subgroup analyses were performed for use of various medications of the same category. Odds ratio (OR), hazard ratio, and risk ratio of bullous pemphigoid in association with medication use. This meta-analysis included 13 case-control studies, 1 cohort study, and 1 randomized clinical trial with a total of 285 884 participants. The meta-analysis of case-control studies showed a significant association of BP with previous use of aldosterone antagonists (pooled OR, 1.75; 95% CI, 1.28-2.40), dipeptidyl peptidase 4 inhibitors (pooled OR, 1.92; 95% CI, 1.55-2.38), anticholinergics (pooled OR, 3.12; 95% CI, 1.54-6.33), and dopaminergic medications (pooled OR, 2.03; 95% CI, 1.34-3.05). One cohort study found an increased risk of BP among patients receiving dipeptidyl peptidase 4 inhibitors (hazard ratio, 2.38; 95% CI, 1.16-4.88; P = .02). One trial found a higher occurrence of BP in patients with diabetes receiving linagliptin (0.2% in diabetes group vs 0% in the placebo group). The findings of this systematic review and meta-analysis suggest that aldosterone antagonists, dipeptidyl peptidase 4 inhibitors, anticholinergics, and dopaminergic medications are associated with BP. These medications should be judiciously prescribed, particularly in high-risk patients who are elderly and have disabling neurologic disorders.

Bullous pemphigoid and dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized controlled trials.

An increasing body of evidence suggests that dipeptidyl-peptidase 4 (DPP-4) inhibitors could play a role in the development of bullous pemphigoid. The knowledge regarding this association is based on case reports, pharmacovigilance database analyses, and observational studies. Data from randomized clinical trials are a relevant source of information on adverse events. Since no single trial has a sufficient power to assess the risk of very rare adverse events, such as pemphigoid, metanalyses of RCTs could be a useful tool for exploring this issue. An extensive Medline, Embase and Cochrane Database search for sitagliptin or vildagliptin, omarigliptin or saxagliptin or alogliptin or trelagliptin or anagliptin or linagliptin or gemigliptin or evogliptin or teneligliptin was performed up to September 30th, 2019. All trials performed on type 2 diabetes, with duration ≥24 weeks, and comparing DPP4i with placebo or active drugs were collected. The study has been registered on PROSPERO (#153344). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for pemphigoid. A total of 138 eligible trials were identified (61,514 patients in DPP-4 inhibitors and 59,661 patients in the control group). Only six trials reported at least one case of pemphigoid (17 and 1 cases in DPP4i and control groups, respectively). DPP-4 inhibitors were associated with an increased risk of pemphigoid (MH-OR 4.44 [1.31, 15.00], p = 0.020). A separate analysis for trials with linagliptin showed a significant increase of BP with the active drug (MH-OR 4.69 [1.09, 20.22]; p = 0.04). In conclusion, available data from randomized controlled trials seem to confirm the association between DPP-4 inhibitors and bullous pemphigoid. This association could be limited to one molecule of the class (i.e., linagliptin), although data on other DPP4-i (e.g., vildagliptin) are insufficient to rule out similar detrimental effects.

Potential linkage between dipeptidyl peptidase-4 inhibitor use and the risk of pancreatitis/pancreatic cancer.

Dipeptidyl peptidase (DPP)-4 inhibitors, a class of oral hypoglycemic agents, are widely used, especially in Asian populations, as they have been shown to be well-tolerated and to cause relatively few hypoglycemic events despite exerting a potent glucose-lowering effect by promoting endogenous insulin secretion, besides also having extra-pancreatic effects. Meanwhile, use of DPP-4 inhibitors has been reported to be associated with the development of bullous pemphigoid (BP), a rare autoimmune blistering skin disease1 , even though the absolute increase in the risk of development of BP is relatively low.

The Development of Bullous Pemphigoid in a Known Case of Psoriasis Vulgaris: a case report

The Development of Bullous Pemphigoid in a Known Case of Psoriasis Vulgaris: a case report

Skin Disease and Neurological Conditions of the Elderly

Summarize and review the body of literature associating neurological diseases of the elderly with cutaneous disease. A growing body of evidence supports a close association between Parkinson’s disease and seborrheic dermatitis or rosacea, as well as a higher risk of melanoma. Development of bullous pemphigoid has also been found to be at higher incidence in those with multiple sclerosis. In some cases, skin disease may suggest early diagnosis of a developing neurologic condition, while in others, presence of a neurologic condition should prompt careful evaluation for cutaneous disease. Elderly patients with neurodegenerative conditions should prompt evaluation for both benign facial dermatologic disease and bullous disease. Further research might elicit antigenic cross-reactivity between CNS epitopes and those in the skin.

Development of Bullous Pemphigoid While Receiving PD-1 Checkpoint Inhibitor Nivolumab

Monoclonal antibodies against PD-1 are becoming increasingly important agents in the oncologist's armamentarium against a variety of cancers, including melanoma and squamous cell carcinoma. Most reported cutaneous reactions to these agents are mild and resolve with a conservative treatment approach. We present two cases of patients treated with anti-PD-1 agents who developed bullous pemphigoid shortly after initiation of therapy. We then review the literature of anti-PD-1-associated bullous pemphigoid, which is likely a bona fide side effect of anti-PD-1 therapy. Finally, we discuss management of these cases, where the risks of bullous pemphigoid must be weighed against the benefits of anti-PD-1 treatment. As the number of indications for PD-1 monoclonal antibodies expands, dermatologists will need to recognize their cutaneous adverse events and assist oncologists in the management of such complications.

Dipeptidyl peptidase IV inhibitors, a risk factor for bullous pemphigoid: Retrospective multicenter case-control study from France and Switzerland.

Case reports have suggested an association between dipeptidyl peptidase-4 inhibitors (DPP4is) and development of bullous pemphigoid (BP). To evaluate the association between DPP4i treatment and development of BP. We conducted a retrospective 1:2 case-control study, comparing case patients with diabetes and BP with age- and sex-matched control patients with diabetes issued from Swiss (Bern) and French (Marseille) dermatologic departments from January 1, 2014, to July 31, 2016. We collected 61 case patients with diabetes and BP and 122 controls. DPP4is were associated withan increased risk for development of BP (adjusted odds ratio, 2.64; 95% confidence interval, 1.19-5.85; P=.02), with vildagliptin showing the highest adjusted odds ratio (3.57 [95% confidence interval, 1.07-11.84; P=.04]). Stratified analysis showed a stronger association in males and patients age 80yearsorolder. DPP4i withdrawal and the initiation of first-line treatments led to clinical remission in 95% of cases. This was a retrospective study in tertiary referral hospitals. We focused the analysis on DPP4i intake, without analyzing the potential isolated effect of metformin. DPP4is, especially vildagliptin, are associated with an increased risk for development of BP. Their use needs to be carefully evaluated, particularly in high-risk patients, such as males and those age 80years or older.

The impact of the CYP2D6 gene polymorphism on the risk of pemphigoid.

Studies concerning the etiopathogenesis of numerous diseases emphasize the involvement of genetically determined impairments of xenobiotic metabolism. Nowadays, more attention has been drawn to the role of cytochrome P450 and its isoenzymes in the course of dermatological diseases, including pemphigoid, the most frequently occurring autoimmune bullous disease, whose etiopathogenesis has not been completely elucidated. The aim of the study was to find out whether there was any relationship between the CYP2D6 gene polymorphism and the development of bullous pemphigoid (BP). The study included 221 subjects, 71 patients with BP, and 150 healthy volunteers constituting a control group. The identification of CYP2D6 (CYP2D6*1, CYP2D6*3, CYP2D6*4) gene alleles was performed using the polymerase chain reaction-fragment length polymorphism method. A higher frequency of the CYP2D6*3/CYP2D6*4 genotype was observed in patients with BP (P = 0.0033) than in controls. The relative risk of developing BP expressed with the odds ratio was nearly four times higher in subjects in whom the presence of the CYP2D6*3 allele was detected (odds ratio 3.8; P = 0.0234). The study results may suggest the impact of CYP2D6 gene polymorphism (A2637 deletion) on a higher prevalence of bullous pemphigoid.

Development of bullous pemphigoid after change of dialysis membrane

A 75-year-old Japanese man presented with pruritic blisters and macules on his trunk and extremities. He had been on hemodialysis for 4 years because of chronic renal failure, and in recent months, a polymethylmethacrylate membrane had been used for dialysis. After a change in dialysis membrane to a cellulose triacetate membrane, pruritic tense blisters developed on the extremities in combination with marked blood eosinophilia. Physical examination showed erythematous macules and tense blisters on the trunk and extremities. A biopsy specimen of an erythematous macule showed subepidermal vesicles and eosinophils that attached to the dermal-epidermal junction. Serum level of eosinophilic cationic protein was elevated. From clinical, histological, and immunological findings, a diagnosis of bullous pemphigoid was made. New blisters continued to erupt during the period in which the patient used the cellulose triacetate membrane dialyzer, and even after the use of clobetasol propionate. It resolved only after the patient came back to the use of a synthetic membrane dialyzer. We discontinued the use of clobetasol propionate, and neither bullous eruptions nor blood eosinophilia recurred. These observations suggest that cellulose membrane may be involved in the development of bullous pemphigoid through activation of eosinophils in the blood and the skin lesion, as in the present case.