Bullous pemphigoid (BP) is the most common autoimmune bullous disease and represents a recognized cutaneous immune-related adverse event associated with immune checkpoint inhibitors (ICIs). Management of ICI-induced BP is challenging, as conventional systemic corticosteroids may interfere with antitumor immunity, highlighting the need for effective steroid-sparing therapies. We report a case series of four elderly male patients who developed BP during treatment with ICIs and were successfully managed with dupilumab, an interleukin-4 receptor alpha antagonist. The median age was 72 years, and BP onset occurred a median of 26 weeks after ICI initiation; nivolumab was the trigger drug in all cases. Diagnosis was established through clinical features, histopathology, direct immunofluorescence, and serological detection of IgG antibodies against BP180, including midportion epitopes in some patients. All patients obtained a sustained clinical remission on dupilumab, with a four-year follow-up showing no treatment-related adverse events, no BP relapse despite continued ICI therapy, and no cancer progression. Our findings support the use of dupilumab as a safe and effective steroid-sparing treatment for ICI-induced BP and suggest that non-NC16A BP180 epitopes may aid diagnosis in selected cases.

BACKGROUND:Despite the established association between gliptins and bullous pemphigoid (BP), knowledge of BP risk and its clinical and immunological phenotypes among individual gliptins remains fragmentary. OBJECTIVE:To estimate BP risk among different gliptins, compare the demographic, clinical, and immunological profiles of idiopathic and patients with bullous pemphigoid and gliptin-treated type 2 diabetes (BPT2D-G), and evaluate the diagnostic performance of a BP180-ectodomain enzyme-linked immunosorbent assay. METHODS:Patients with BP and/or type 2 diabetes who visited 2 Italian hospitals during 2019 to 2023 were prospectively enrolled and clinically/immunologically characterized in a case-control study using in-house enzyme-linked immunosorbent assays detecting reactivity to BP180 extracellular epitopes. RESULTS:Overall, gliptin exposure demonstrated a strong association with BP, whereas sitagliptin did not exhibit a comparable effect. BPT2D-G showed a distinctive humoral profile, with high reactivity to other epitopes beyond BP180-noncollagenous 16A domain. A subset of patients, mainly exposed to linagliptin and BP180-noncollagenous 16A domain/BP230 negative, presented milder, often noninflammatory disease: a BP180-ectodomain assay improved diagnostic performances in these patients. LIMITATIONS:Potential residual confounding; limited generalizability; limited data on gliptin exposure duration. The observational design precludes causal inference. CONCLUSION:Different BP risks among gliptins may inform therapeutic choices, favoring sitagliptin in elderly patients. Personalized management of patients with BP180-noncollagenous 16A domain/BP230-negative BPT2D-G may reduce unnecessary use of high-potency topical and systemic corticosteroids. BP180-ectodomain-based diagnostic assays may facilitate BPT2D-G diagnosis.

Growing evidence has linked bullous pemphigoid (BP) to immune checkpoint inhibitor (ICI) therapy in cancer treatment. However, the immunological features of ICI-associated BP (ICI-BP) are not yet fully elucidated. In order to characterize the humoral response in ICI BP patients and investigate whether their epitope profile differs from idiopathic BP (IBP), 53 ICI-BP patients were enrolled, immunologically characterized and compared with 59 IBP patients. ICI-BP had a distinctive IgG humoral profile, with reduced reactivity toward BP230 and recognition of multiple BP180 epitopes beyond the immunodominant extracellular noncollagenous 16A domain (NC16A). Specifically, reactivity to BP180 ectodomain was present in 94% of ICI-BP and 78% of IBP (p=0.044). Moreover, BP180 C-terminal epitope was more frequently targeted in ICI-BP than IBP (72% vs 41%, p=0.002). Notably, the combined use of an in-house BP180 ectodomain ELISA and the commercial BP180 test increased diagnostic sensitivity from 83% to 100%. Enhanced IgG reactivity toward nonimmunodominant epitopes, and especially C-terminal epitope recognition, characterize the humoral immune response in ICI-BP. Our data suggest that combining NC16A and fulllength BP180 ectodomain ELISAs may help reduce diagnostic delay in ICI-BP patients, in whom a timely diagnosis is crucial to appropriately manage the disease and ultimately avoid discontinuation of cancer therapy.

BackgroundBullous pemphigoid (BP) and mucous membrane pemphigoid (MMP) are rare autoimmune blistering disorders characterized by autoantibodies (autoAbs) targeting dermo-epidermal junction components such as BP180 and BP230. The differential diagnosis, based on both the time of appearance and the extension of cutaneous and/or mucosal lesions, is crucial to distinguish these diseases for improving therapy outcomes and delineating the correct prognosis; however, in some cases, it can be challenging. In addition, negative results obtained by commercially available enzyme-linked immunosorbent assays (ELISAs) with BP and MMP sera, especially from patients with ocular involvement, often delay diagnosis and treatment, leading to a greater risk of poor outcomes.ObjectivesOur aim was to find potentially different reactivity profiles in BP and MMP and improve available approaches for diagnosis with focus on ocular MMP.MethodsTwo cohorts of 90 BP and 90 MMP, recruited from different Italian clinical centers, were characterized also employing a novel ELISA based on the BP180 extracellular domain (ECD-BP180).ResultsImmunoglobulin G (IgG) reactivity to BP180 and BP230 in MMP sera was significantly reduced in comparison with BP, mostly affecting BP230 and E-1080 (53% and 36% in BP vs. 11% and 3% in MMP, respectively, p < 0.0001). The combined sensitivity of BP180-NC16A and ECD-BP180 ELISAs was greater compared to BP180-NC16A and BP230 ELISAs both in BP (97% and 92%, respectively) and in MMP (42% and 31%, respectively). The present study shows that MMP patients with ocular involvement rarely reacted to BP180 by IgG in contrast with patients with oral and/or cutaneous involvement (p = 0.0245 and p = 0.0377, respectively), suggesting that an oral and/or cutaneous MMP positive to BP180 hardly evolves to ocular MMP. Of note, one-third of ocular MMP showed immunoglobulin A (IgA) reactivity to ECD-BP180 by immunoblotting.ConclusionsThe present study provides several hints to perform a correct and timely diagnosis in BP and MMP, which is crucial for improving therapy outcomes and delineating the correct prognosis.

Bullous pemphigoid (BP) is the most common autoimmune bullous disease, whose main autoantigens are hemidesmosomal components BP180 and BP230. Although recent studies found no association between COVID-19 vaccines and BP, since mass vaccinations started, more than 90 vaccine-associated BP cases have been reported. To find an agreement among real-life clinical observations and recent epidemiologic data, we further investigated this topic. A total of 64 patients with BP onset in 2021 were demographically, clinically, and serologically characterized: 14 (21.9%) vaccine-associated patients (VA) developed BP within 5 weeks from the first/second vaccine dose. VA and vaccine-non-associated (VNA) patients had similar demographics and clinical and immunological characteristics. Noteworthy, the monthly distribution of BP onset during mass vaccinations paralleled vaccine administration to the elderly in the same catchment area. Additionally, in 2021, BP onsets in April–May and June–July significantly increased (p = 0.004) and declined (p = 0.027), respectively, compared to the three years before vaccination campaigns (2018–2020). Interestingly, VA and VNA patients showed statistically significant differences in the use of inhalers and diuretics. Our findings suggest that the COVID-19 vaccine may constitute an accelerating factor that, together with other triggering factors, could act in genetically predisposed individuals with possible sub-clinical autoreactivity against BP antigens, slightly accelerating BP onset.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Bullous pemphigoid (BP) is the most common autoimmune bullous disease: it most commonly affects individuals over 70 years old and impacts severely on their quality of life. BP represents a paradigm for an organ-specific autoimmune disease and is characterized by circulating IgG autoantibodies to hemidesmosomal components: BP180 and BP230. While the crucial role of these autoantibodies in triggering BP inflammatory cascade is fully acknowledged, many ancillary etiological mechanisms need to be elucidated yet. Cutaneous melanoma is due to a malignant transformation of skin melanocytes, that produce and distribute pigments to surrounding keratinocytes. Melanoma is the most fatal skin cancer because of its increasing incidence and its propensity to metastasize. Several data such as: i) reported cases of concomitant melanoma and BP; ii) results from association studies; iii) BP onset following immune check-point inhibitors therapy; iv) expression of BP antigens in transformed melanocytes; and vi) circulating autoantibodies to BP antigens in melanoma patients suggest an intriguing, although unproven, possible association between melanoma and BP. However, a possible causative link is still debated and the putative pathogenetic mechanism underlying this association is unclear. This review aims to describe and discuss the possible relationship between BP and melanoma and give an overview of the speculations for or against this association. Of note, if demonstrated, this association could unwrap considerations of clinical relevance that represent new research frontiers.

Bullous pemphigoid (BP), although a rare disease, is the most frequent subepidermal autoimmune disorder. Treatment with gliptins, used for type 2 diabetes, was reported as associated with BP onset. To identify HLA alleles that may reflect a higher susceptibility to BP in the Italian population, we analysed 30 patients affected by idiopathic bullous pemphigoid (IBP) and 86 gliptin-associated BP (GABP) patients. A significant association between HLA-DQB1*03:01 allele and IBP and GABP patients was found. Of note, both IBP and GABP were significantly associated with one of the following haplotypes: DRB1*11:01, DRB3*02:02, DQA1*05:05, DQB1*03:01 or DRB1*11:04, DRB3*02:02, DQA1*05:05 and DQB1*03:01. These data identify, for the first time, potential markers of susceptibility to BP in the Italian population, especially when associated with gliptin intake.

Abstract missing (Short communication)

Bullous pemphigoid (BP) is the most common autoimmune bullous disease characterized by autoantibodies against hemidesmosomal components: BP180 and BP230. Although a causal association between vaccine and BP has never been proved, since mass vaccination against COVID-19 started, more than 90 vaccine-associated BP were reported. Of note, a recent study comparing very large cohorts of vaccinated and not-vaccinated individuals found no increased incidence of BP in vaccinated people, concluding that COVID-19 vaccine does not directly cause BP. To bring to an agreement among real-life clinical observations on patients with new-onset BP after COVID-19 vaccine and recent epidemiologic data, a cohort study was performed. Fifty-nine BP patients visiting our institute in 2021 were clinically and immunologically characterized. Fourteen patients (23.7%), experiencing BP onset 1-34 days after the first or second dose, were considered vaccine-associated. Vaccine-associated and non-associated patients had the same M/F ratio (1.3) and similar disease severity (mean BPDAI: 41.1 vs 38.6) and mean age (76.7 vs 79.5 years). Interestingly, BP230 reactivity was higher in vaccine-associated patients (87.5% vs 41.4%, p=0.042), while no other significant differences in autoantibodies profiles and titers were found. Noteworthy, the comparison of the monthly distribution of BP onset throughout the year before and during mass vaccination showed significant differences: in 2021, BP onsets on April-May and June-July increased (p=0.009) and declined (p=0.064) compared to 2018-2020, respectively. In conclusion, our findings suggest that COVID-19 vaccine may be considered an accelerating factor rather than an inducing one: vaccination, in genetically predisposed individuals with sub-clinical autoreactivity against BP antigens, of which high BP230 reactivity at diagnosis could represent an indicator, could slightly anticipate BP onset without increasing its incidence.

Pemphigus is a life-threatening autoimmune blistering disease affecting skin and mucous membranes. Despite its etiopathogenesis remains largely unknown, several trigger and predisposing factors have been reported. Pemphigus is caused by autoantibodies that target desmoglein 1 and desmoglein 3, impacting desmosome function. However, circulating autoantibodies are often the consequence of a precipitating factor that occurs in predisposed individuals. This review aims to describe and discuss almost all trigger and predisposing factors reported as possible or probable cause of the disease. Among the reported trigger factors that may induce or exacerbate pemphigus, we have found of particular interest: drug intake (especially thiol- and phenol-containing compounds), vaccines, infections, as well as some reports about pregnancy, radiations, emotional stress, pesticides and physical trauma. Moreover, we discuss the possible role of food intake in pemphigus onset and particular attention is given to dietary factors containing thiol, phenol and tannin compounds. A trigger factor is “the straw that breaks the camel’s back,” and often acts together with predisposing factors. Here we discuss how pemphigus onset may be influenced by genetic susceptibility and comorbidities like thyroid diseases, malignancies and other autoimmune disorders.To identify other hitherto unknown trigger and predisposing factors, well designed prospective studies are needed. In this context, future research should explore their connection with the aim to advance our understanding of pemphigus pathogenesis.

Autoimmune bullous diseases (AIBDs) are a heterogeneous group of life-threatening disorders associated with subepidermal or intraepidermal blistering. Skin barrier alterations and prolonged immunosuppressive treatments increase the risk of infections in patients with AIBDs, who are considered fragile. COVID-19 pandemic had a heavy impact on these patients. Although advances have been made in terms of prevention and treatment of COVID-19, this topic remains significant as the pandemic and its waves could last several years and, so far, a relevant proportion of the population worldwide is not vaccinated. This review is a 2022 update that summarizes and discusses the pandemic's burden on AIBD patients mainly considering relevant studies in terms of: (i) sample dimension; (ii) quality of control populations; (iii) possible standardization by age, gender and country. The findings show that: (i) the risk of COVID-19 infection and its severe course were comparable in AIBD patients and in the general population, except for rituximab-treated patients that presented a higher risk of infection and severe disease; (ii) the mortality rate in COVID-19-infected bullous pemphigoid patients was higher than in the general population, (iii) 121 cases of AIBD onset and 185 cases of relapse or exacerbation occurred after COVID-19 vaccination and a causal relationship has not been demonstrated so far. Altogether, acquired knowledge on COVID-19 pandemic could also be important in possible, albeit undesirable, future pandemic scenarios.

GENERAL COMMENTARY article Front. Med., 16 March 2023Sec. Dermatology Volume 10 - 2023 | https://doi.org/10.3389/fmed.2023.1160672

Bullous pemphigoid (BP) is an autoimmune bullous disease caused by circulating autoantibodies toward the hemidesmosomal antigens BP180 and BP230. Cases of BP have been described following vaccinations against tetanus, poliomyelitis, diphtheria, influenza, pneumococcus, meningococcus, hepatitis B and rabies. The putative mechanism by which COVID-19-vaccines may induce BP has not been clarified. An Italian multicentre study was conducted to collect clinical, histopathological and immunopathological data of patients with BP associated with COVID-19-vaccines. Twenty-one cases were collected, including 9 females and 12 males (M/F = 1.3) with a median age at diagnosis of 82 years. Seventeen patients received the COMIRNATY Pfizer-BioNTech vaccine, two the Moderna mRNA-1273 vaccine, one the ChAdOx1/nCoV-19-AstraZeneca/ Vaxzevria vaccine and one received the first dose with the ChAdOx1/nCoV-19-AstraZeneca/Vaxzevria vaccine and the second dose with the COMIRNATY Pfizer-BioNTech vaccine. Median latency time between the first dose of anti-SARS-CoV-2 vaccine and the onset of cutaneous manifestations was 27 days. Median BPDAI at onset was 42. Eleven out of seventeen patients (65%) had positive titres for anti-BP180 antibodies with a median value of 106.3 U/mL on ELISA; in contrast, only five out of seventeen (29%) were positive for anti-BP230 antibodies, with a median of 35.3 U/mL. In conclusion, in terms of mean age, disease severity at diagnosis and clinical phenotype vaccine-associated BP patients seem to be similar to idiopathic BP with an overall benign course with appropriate treatment. On the other hand, the slight male predominance and the reduced humoral response to BP230 represent peculiar features of this subset of patients.

The knowledge regarding the risk of bullous pemphigoid (BP) in patients with type 2 diabetes (T2D) taking dipeptidyl peptidase 4 inhibitors (DPP4i) is based on case reports, pharmacovigilance database analyses, randomized clinical trials and retrospective observational studies. To further investigate the relationship between taking DPP4i and the risk of BP and to characterize demographic, clinical and immunological profile of DPP4i associated patients we conducted a prospective case-control study in an Italian population. Two hundred and nine BP and 308 T2D consecutive patients were enrolled in two referral centers for autoimmune bullous diseases from 2019 to 2022. One hundred and eight patients were BP, while one hundred and one were T2D BP (48%), demonstrating a high prevalence of T2D in BP patients. Almost half of T2D BP patients were DPP4i users showing that 1 of 4 BP patients had an induced disease caused by a known drug. Overall, DPP4i intake was associated with a 2.3-fold increased risk for BP (95% CI, 1.7-3.0) and the most used DPP4i was linagliptin with a 2.1-fold increased risk for BP (95% CI, 1.2-3.7). It is interesting to note that mean age increased together with the male proportion from 108 non-T2D BP to 51 non-DPP4i users T2D PB and to 50 DPP4i users T2D PB (75.0 years old and male 50%; 77.9 years old and male 51%; 80.0 years old and male 60%, respectively). Immunoglobulin (Ig)G humoral response of DPP4i users BP to BP180 and BP230 antigens was reduced in frequency and titers compared with those of patients non-DPP4i users. In particular, a peculiar immunological profile was characterized by reactivity to multiple BP180 epitopes. This study demonstrates that treatment with DPP4i, especially linagliptin, was significantly associated with an increased risk of BP among T2D patients. In addition, DPP4i users BP present specific demographic and immunological features.