HLA alleles associated to susceptibility to gliptin-associated bullous pemphigoid in Italian patients.

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.

Predictive values of relative fat mass and body mass index on cardiovascular health in community-dwelling older adults: Results from the Longevity Check-up (Lookup) 7.

OBJECTIVES: To assess the predictive value of relative fat mass compared to body mass index for hypertension, diabetes, hyperlipidemia, and heightened cardiovascular risk in a cohort of community-dwelling older adults from the Longevity Check-up 7+ cohort. STUDY DESIGN: Retrospective cross-sectional study. MAIN OUTCOME MEASURES: Hyperlipidemia was defined as total cholesterol ≥200 mg/dL or ongoing lipid-lowering treatment. Diabetes was defined either as self-reported diagnosis or fasting blood glucose >126 mg/dL or a random blood glucose >200 mg/dL. Hypertension was defined as blood pressure ≥ 140/90 mmHg or requiring daily antihypertensive medications. Heightened cardiovascular risk was operationalized as having at least two of these conditions. RESULTS: Analyses were conducted in 1990 participants (mean age 73.2 ± 6.0 years; 54.1 % women). Higher proportions of men than women had hypertension and diabetes, while hyperlipidemia was more prevalent in women. Receiver operating curve analysis indicated relative fat mass was a better predictor of hypertension in women and diabetes in both sexes. Body mass index performed better in predicting hyperlipidemia in women. Relative fat mass thresholds of ≥27 % for men and ≥40 % for women were identified as optimal indicators of heightened cardiovascular risk and so were used to defined high adiposity. Moderate correlations were found between high adiposity or body mass index ≥25 kg/m2 and the presence of hypertension, hyperlipidemia and heightened cardiovascular risk, while a strong correlation was found with diabetes. Logistic regression analysis highlighted significant associations between high adiposity and increased odds of hypertension, diabetes, and heightened cardiovascular risk. CONCLUSIONS: Proposed cut-offs for relative fat mass were more reliable indices than the usual cut-offs for body mass index for identifying individuals at heightened cardiovascular risk. Our findings support the role of anthropometric measures in evaluating body composition and the associated metabolic and cardiovascular conditions in older adults.

Lower Adherence to a Mediterranean Diet Is Associated with High Adiposity in Community-Dwelling Older Adults: Results from the Longevity Check-Up (Lookup) 7+ Project.

High adiposity impacts health and quality of life in old age, owing to its association with multimorbidity, decreased physical performance, and frailty. Whether a high adherence to a Mediterranean diet (Medi-Diet) is associated with reduced body adiposity in older adults is unclear. The present study was conducted to assess the prevalence of high adiposity in a large sample of community-dwelling older adults. We also explored the relationship between whole-body adiposity estimated through relative fat mass (RFM) and Medi-Diet adherence. Data were obtained from the Longevity Check-up 7+ (Lookup7+) project database. RFM was estimated from anthropometric and personal parameters using a validated equation. RFM was categorized as high if ≥40% in women and ≥30% in men. Information on diet was collected using a food frequency questionnaire, while Medi-Diet adherence was assessed through a modified version of the Medi-Lite scoring system. Analyses were conducted in 2092 participants (mean age 73.1 ± 5.9 years; 53.4% women). Mean RFM was 39.6 ± 5.14% in women and 29.0 ± 3.6% in men. High adiposity was found in 971 (46.4%) participants and was more frequent in those with a low (54.2%) or moderate (46.4%) Medi-Diet adherence compared with the high-adherence group (39.7%, p < 0.001). Logistic regression indicated that older adults with high Medi-Diet adherence were less likely to have a high RFM. Other factors associated with a greater risk of having high adiposity were older age, female sex, and physical inactivity. Our findings support an association between healthy lifestyles, including a greater adherence to a Mediterranean-style diet, and lower body adiposity in older adults.

Identification of autoantigens and their potential post-translational modification in EGPA and severe eosinophilic asthma.

Background: The chronic airway inflammation in severe eosinophilic asthma (SEA) suggests potential autoimmune aetiology with unidentified autoantibodies analogous to myeloperoxidase (MPO) in ANCA-positive EGPA (eosinophilic granulomatosis with polyangiitis). Previous research has shown that oxidative post-translational modification (oxPTM) of proteins is an important mechanism by which autoantibody responses may escape immune tolerance. Autoantibodies to oxPTM autoantigens in SEA have not previously been studied. Methods: Patients with EGPA and SEA were recruited as well as healthy control participants. Autoantigen agnostic approach: Participant serum was incubated with slides of unstimulated and PMA-stimulated neutrophils and eosinophils, and autoantibodies to granulocytes were identified by immunofluorescence with anti-human IgG FITC antibody. Target autoantigen approach: Candidate proteins were identified from previous literature and FANTOM5 gene set analysis for eosinophil expressed proteins. Serum IgG autoantibodies to these proteins, in native and oxPTM form, were detected by indirect ELISA. Results: Immunofluorescence studies showed that serum from patients with known ANCA stained for IgG against neutrophils as expected. In addition, serum from 9 of 17 tested SEA patients stained for IgG to PMA-stimulated neutrophils undergoing NETosis. Immunofluorescent staining of eosinophil slides was evident with serum from all participants (healthy and with eosinophilic disease) with diffuse cytoplasmic staining except for one SEA individual in whom subtle nuclear staining was evident. FANTOM5 gene set analysis identified TREM1 (triggering receptor expressed on myeloid cells 1) and IL-1 receptor 2 (IL1R2) as eosinophil-specific targets to test for autoantibody responses in addition to MPO, eosinophil peroxidase (EPX), and Collagen-V identified from previous literature. Indirect ELISAs found high concentrations of serum autoantibodies to Collagen-V, MPO, and TREM1 in a higher proportion of SEA patients than healthy controls. High concentrations of serum autoantibodies to EPX were evident in serum from both healthy and SEA participants. The proportion of patients with positive autoantibody ELISAs was not increased when examining oxPTM compared to native proteins. Discussion: Although none of the target proteins studied showed high sensitivity for SEA, the high proportion of patients positive for at least one serum autoantibody shows the potential of more research on autoantibody serology to improve diagnostic testing for severe asthma. Clinical trial registration: ClinicalTrials.gov, identifier, NCT04671446.

Immunosuppressive treatment and radiotherapy in kidney transplant patients: A systematic review.

BACKGROUND: Immunosuppression (IS) therapy may contribute to cancer development. Some authors have proposed to reduce immunosuppression drugs dose in case of viral infections, in immunosuppression-related diseases, and in patients undergoing radiotherapy. The present analysis reports the results of a systematic review on kidney transplant recipients undergoing immunosuppression and radiotherapy. AIM: To define if it is necessary reduce immunosuppression drugs during radiotherapy. METHODS: The literature search was based on three electronic databases (Pubmed, Scopus, and Web of Science) using selected keywords linked through the "AND" and "OR" Boolean operators to build specific strings for each electronic search engine. Two researchers independently screened the citations, and disagreement was resolved by discussion or through the intervention of a third author. The review was conducted and reported according to the PRISMA statement. Extracted data were narratively synthesized, and, where possible, frequencies, percentages, and ranges were calculated. RESULTS: The literature search resulted in 147 citations. After abstracts screening, 21 records were selected for full-text evaluation. Fifteen of these were excluded, leaving six papers considered suitable for analysis. There is still no clear evidence that withdrawing antimetabolites and/or calcineurin inhibitors and/or mammalian target of rapamycin-inhibitors, as opposed to continuing maintenance IS, improves patient survival in kidney transplant recipients with cancer undergoing radiotherapy. Only few retrospective studies on small cancer patient cohorts are available in this setting, but without comparison of different immunosuppression treatments. Even where immunosuppression therapy was described, patient survival seemed to be correlated only with cancer stage and type. CONCLUSION: The results of this systematic review do not support the reduction of immunosuppression dose in patients undergoing radiotherapy.

COVID-19 in liver transplant recipients: incidence, hospitalization and outcome in an Italian prospective double-centre study.

Liver transplant (LT) recipients are vulnerable to SARS-CoV-2-infection (COVID-19), due to immunosuppression and comorbidities. This study aimed to evaluate the impact of COVID-19 on LT recipients compared to general population in the Campania region. In this prospective double-centre study, we enrolled all consecutive adult LT recipients with confirmed SARS-CoV-2-infection. Data were collected at diagnosis of COVID-19 and during follow-up and compared with the regional population. Thirty LT recipients (3.28%) developed SARS-CoV-2-infection (76.66% male, median age 62.61 years). Sixteen (53.33%) were symptomatic. Common symptoms were fever, cough, fatigue, and anosmia. Twenty-five (83.33%) were outpatients, 5 (16.66%) required hospitalization (6.66% admitted to Intensive Care Unit, 6.62% developed Acute Respiratory Distress Syndrome and 6.66% died). Immunosuppressors were in 3 (10%) patients. Incidence rate of COVID-19 was similar between LT patients and general population (3.28% vs 4.37%, p = 0.142) with higher rate of symptoms in LT patients (53.33% vs 15.87%, p < 0.000). At univariate analysis, hospitalization and case fatality rates were higher in LT patients compared to general population (16.66% vs 4.54%, p = 0.001; and 6.66% vs 1.76%, p = 0.041, respectively). At multivariable logistic regression analysis, LT patients with COVID-19 were more frequently symptomatic (OR 5.447 [95% CI 2.437-12.177], p < 0.000), whereas hospitalization and death for COVID-19 were not significatively associated with LT condition (p = 0.724 and p = 0.462, respectively) and were comparable with general population. LT is not a risk factor for acquiring COVID-19. Nonetheless, LT patients are more frequently symptomatic, although comparable to the general population for hospitalization rate and mortality.

Humoral Response to 2-dose BNT162b2 mRNA COVID-19 Vaccination in Liver Transplant Recipients.

BACKGROUND & AIMS: In the context of the Italian severe acute respiratory syndrome coronavirus 2 vaccination program, liver transplant (LT) recipients were prioritized for vaccine administration, although the lower response to vaccines is a well-known problem in this population. We aimed to evaluate immunogenicity of BNT162b2 mRNA vaccine in LT recipients and healthy controls and to identify factors associated with negative response to vaccine. METHODS: In a cohort of adult patients with LT, we prospectively evaluated the humoral response (with anti-Spike protein IgG-LIAISON SARS-CoV-2 S1/S2-IgG chemiluminescent assay) at 1 and 3 months after 2-dose vaccination. A group of 307 vaccinated health care workers, matched by age and sex, served as controls. RESULTS: Overall, 492 LT patients were enrolled (75.41% male; median age, 64.85 years). Detectable antibodies were observed in the 75% of patients, with a median value of 73.9 AU/mL after 3 months from 2-dose vaccination. At multivariable analysis, older age (>40 years; P = .016), shorter time from liver transplantation (<5 years; P = .004), and immunosuppression with antimetabolites (P = .029) were significantly associated with non-response to vaccination. Moreover, the LT recipients showed antibody titers statistically lower than the control group (103 vs 261 AU/mL; P < .0001). Finally, in both controls and LT patients, we found a trend of inverse correlation between age and antibody titers (correlation coefficients: -0.2023 and -0.2345, respectively). CONCLUSIONS: Three months after vaccination, LT recipients showed humoral response in 75% of cases. Older age, shorter time from transplantation, and use of antimetabolites were factors associated with non-response to vaccination, and LT recipients at risk of non-response to vaccination needed to be kept under close monitoring.

Immune-checkpoint inhibitors in renal transplanted patients affected by melanoma: a systematic review.

Kidney transplantation leads to an increased risk of cancer. Melanoma is one of the most frequent neoplasms in kidney transplant recipients. Transplanted patients were excluded from trials with checkpoint inhibitors in melanoma. The authors performed a systematic review regarding the use of anti-PD1 and anti-CTLA4 agents in renal transplanted patients with melanoma. Thirty-four cases were included (24 progressive disease, eight partial responses and one stable disease) but no complete response were reported. Fourteen graft rejections were observed, especially with anti-PD1 agent. The median time from the start of immune-checkpoint inhibitor and rejection was 21 days. Response rate was similar between patients with rejection and patients without rejection. The benefit of immune-checkpoint inhibitors versus the risk of allograft rejection should be carefully weighted for each patient. A multidisciplinary approach should be considered to discuss the most appropriate treatment for every case, given the aggressiveness of melanoma in these subsets of patients.

Management of the kidney transplant patient with Cancer: Report from a Multidisciplinary Consensus Conference.

INTRODUCTION: Cancer is the second most common cause of mortality and morbidity in Kidney Transplant Recipients (KTRs). Immunosuppression can influence the efficacy of cancer treatment and modification of the immunosuppressive regimen may restore anti-neoplastic immune responses improving oncologic prognosis. However, patients and transplant physicians are usually reluctant to modify immunosuppression, fearing rejection and potential graft loss. Due to the lack of extensive and recognised data supporting how to manage the immunosuppressive therapy in KTRs, in the context of immunotherapy, chemotherapy, radiotherapy and loco-regional treatments, a Consensus Conference was organised under the auspices of the European Society of Organ Transplantation and the Italian Society of Organ Transplantation. The conference involved a multidisciplinary group of transplant experts in the field across Europe. METHODS: The overall process included a) the formulation of 12 specific questions based on the PICO methodology, b) systematic literature review and summary for experts for each question, c) a two-day conference celebration and the collection of experts' agreements. The conference was articulated in three sessions: "Immunosuppressive therapy and immunotherapy", "Systemic therapy", "Integrated Therapy", while the final experts' agreement was collected with a televoting procedure and defined according to the majority criterion. RESULTS: Twenty-six European experts attended the conference and expressed their vote. A total of 14 statements were finally elaborated and voted. Strong agreement was found for ten statements, moderate agreement for two, moderate disagreement for one and uncertainty for the last one. CONCLUSIONS: The consensus statements provide guidance to transplant physicians caring for kidney transplant recipients with cancer and indicate key aspects that need to be addressed by future clinical research.