Biagio Didona

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 ofcancer therapy.

Background: Monoallelic damaging variants in PHIP (MIM*612870), encoding the Pleckstrin Homology Domain Interacting Protein, have been associated with a novel neurodevelopmental disorder, also termed Chung–Jansen syndrome (CHUJANS, MIM#617991). Most of the described individuals show developmental delay (DD)/intellectual disability (ID), obesity/overweight, and variable congenital anomalies, so the condition can be considered as an ID–overweight syndrome. Case Description: We evaluated a child presenting with DD/ID and a craniofacial phenotype reminiscent of a Pitt–Hopkins syndrome (PTHS)-like condition. We performed a clinical exome analysis on his biological sample, as well as an in silico prediction of the obtained data. At the same time, we interrogated the DeepGestalt technology powered by Face2Gene (F2G), using a frontal image of the proband, and clinically reviewed the earlier CHUJANS patients. In this child, we found a novel PHIP pathogenetic variant, which we corroborated through a protein modeling approach. The F2G platform supported the initial clinical hypothesis of a PTHS-like condition, while the clinical review highlighted the lack of the main frequent CHUJANS clinical features in this child. Conclusions: The unusual clinical presentation of this novel patient resembles a PTHS-like condition. However, a novel variant in PHIP has been unexpectedly detected, expanding the phenotypic spectrum of CHUJANS. Notably, PTHS (MIM#610954), which is a different ID syndrome caused by heterozygous variants in TCF4 (MIM*610954), is not classically considered in the differential diagnosis of CHUJANS nor has been cited in the previous studies. This could support other complex diagnoses and invite further patients’ descriptions.

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.

Autoimmune bullous diseases are a heterogeneous group of rare conditions clinically characterized by the presence of blisters and/or erosions on the skin and on the mucous membranes. Practically, they can be divided into two large groups: the pemphigoid group and the pemphigus group, depending on the depth of the autoimmune process on the skin. Family history of autoimmune disease can often be found, and demonstrating that genetic predisposition is crucial in the development of them. Moreover, numerous environmental risk factors, such as solar radiation, drugs and infections, are known. This study aimed to evaluate how seasonality can affect the trend of BP and PV, especially considering the number of hospitalizations recorded over the course of individual months. The total number of hospitalizations in the twelve months of the year was evaluated. Further, blood chemistry assay and, for some patients, enzyme-linked immunosorbent assay were executed in order to evaluate antibodies. Regarding the severity of the disease BPDAI (Bullous Pemphigoid Area Index) and PDAI (Pemphigus Disease Area Index), score systems were used. Results showed a complex interplay between environmental factors such as seasons and autoimmune conditions.

The knowledge regarding the risk of bullous pemphigoid (BP) in patients with type 2 diabetes (T2D) taking dipeptidyl peptidase 4 inhibitors (DPP4 | POSTER

Pemphigus vulgaris (PV) belongs to the group of autoimmune blistering diseases. PV can affect not only mucous membranes, but also the skin and it is characterized by serum IgG autoantibodies against desmoglein 1 and 3, two major components of desmosomes. The introduction of glucocorticoids improved dramatically the prognosis of patients affected by PV. However, long-term use of high dose corticosteroids and adjuvant steroid-sparing immunosuppressants can lead to several adverse events. Rituximab, a chimeric anti-CD20 monoclonal antibody, has been recently approved as in-label therapy for PV, leading to an improvement of the prognosis and higher remission rate. Furthermore, other anti B-cell therapies and several anti-CD20 biosimilars have been introduced in the clinical practice. We focused on present and future therapeutic approaches in PV

Cutis laxa (CL) is a group of rare cutaneous disease, inherited or acquired, characterized by inelastic, redundant, wrinkled, loose skin, with loss of elasticity and features of premature aging [...].

Palmoplantar keratodermas (PPKs) are characterized by thickness of stratum corneum and epidermal hyperkeratosis localized in palms and soles. PPKs can be epidermolytic (EPPK) or non epidermolytic (NEPPK). Specific mutations of keratin 16 (K16) and keratin 1 (K1) have been associated to EPPK, and NEPPK. Cases of mosaicism in PPKs due to somatic keratin mutations have also been described in scientific literature. We evaluated a patient presenting hyperkeratosis localized monolaterally in the right palmar area, characterized by linear yellowish hyperkeratotic lesions following the Blaschko lines. No other relatives of the patient showed any dermatological disease. Light and confocal histological analysis confirmed the presence of epidermolityic hyperkeratosis. Genetic analysis performed demonstrates the heterozygous deletion NM_006121.4:r.274_472del for a total of 198 nucleotides, in KRT1 cDNA obtained by a palmar lesional skin biopsy, corresponding to the protein mutation NP_006112.3:p.Gly71_Gly137del. DNA extracted from peripheral blood lymphocytes did not display the presence of the mutation. These results suggest a somatic mutation causing an alteration in K1 N-terminal variable domain (V1). The deleted sequence involves the ISIS subdomain, containing a lysine residue already described as fundamental for epidermal transglutaminases in the crosslinking of IF cytoskeleton. Moreover, a computational analysis of the wild-type and V1-mutated K1/K10 keratin dimers, suggests an unusual interaction between these keratin filaments. The mutation taster in silico analysis also returned a high probability for a deleterious mutation. These data demonstrate once again the importance of the head domain (V1) of K1 in the formation of a functional keratinocyte cytoskeleton. Moreover, this is a further demonstration of the presence of somatic mutations arising in later stages of the embryogenesis, generating a mosaic phenotype.