Targeting high glucose-induced epigenetic modifications at cardiac level: the role of SGLT2 and SGLT2 inhibitors.

BACKGROUND: Sodium-glucose co-transporters (SGLT) inhibitors (SGLT2i) showed many beneficial effects at the cardiovascular level. Several mechanisms of action have been identified. However, no data on their capability to act via epigenetic mechanisms were reported. Therefore, this study aimed to investigate the ability of SGLT2 inhibitors (SGLT2i) to induce protective effects at the cardiovascular level by acting on DNA methylation. METHODS: To better clarify this issue, the effects of empagliflozin (EMPA) on hyperglycemia-induced epigenetic modifications were evaluated in human ventricular cardiac myoblasts AC16 exposed to hyperglycemia for 7 days. Therefore, the effects of EMPA on DNA methylation of NF-κB, SOD2, and IL-6 genes in AC16 exposed to high glucose were analyzed by pyrosequencing-based methylation analysis. Modifications of gene expression and DNA methylation of NF-κB and SOD2 were confirmed in response to a transient SGLT2 gene silencing in the same cellular model. Moreover, chromatin immunoprecipitation followed by quantitative PCR was performed to evaluate the occupancy of TET2 across the investigated regions of NF-κB and SOD2 promoters. RESULTS: Seven days of high glucose treatment induced significant demethylation in the promoter regions of NF-kB and SOD2 with a consequent high level in mRNA expression of both genes. The observed DNA demethylation was mediated by increased TET2 expression and binding to the CpGs island in the promoter regions of analyzed genes. Indeed, EMPA prevented the HG-induced demethylation changes by reducing TET2 binding to the investigated promoter region and counteracted the altered gene expression. The transient SGLT2 gene silencing prevented the DNA demethylation observed in promoter regions, thus suggesting a role of SGLT2 as a potential target of the anti-inflammatory and antioxidant effect of EMPA in cardiomyocytes. CONCLUSIONS: In conclusion, our results demonstrated that EMPA, mainly acting on SGLT2, prevented DNA methylation changes induced by high glucose and provided evidence of a new mechanism by which SGLT2i can exert cardio-beneficial effects.

Late relapse after CAR-T cell therapy for adult patients with hematologic malignancies: A definite evidence from systematic review and meta-analysis on individual data.

Chimeric Antigen Receptor (CAR)-modified T lymphocytes represent one of the most innovative and promising approaches to treating hematologic malignancies. CAR-T cell therapy is currently being used for the treatment of relapsed/refractory (r/r) B-cell malignancies including Acute Lymphoblastic Leukemia, Large B-Cell Lymphoma, Follicular Lymphoma, Multiple Myeloma and Mantle Cell Lymphoma. Despite the unprecedented clinical success, one of the major issues of the approved CAR-T cell therapy - tisagenlecleucel, axicabtagene, lisocabtagene, idecabtagene, ciltacabtagene and brexucabtagene - is the uncertainty about its persistence which in turn could lead to weak or no response to therapy with malignancy recurrence. Here we show that the prognosis of patients who do not respond to CAR-T cell therapy is still an unmet medical need. We performed a systematic review and meta-analysis collecting individual data on Duration of Response from at least 12-month follow-up studies. We found that the pooled prevalence of relapse within the first 12 months after CAR-T infusion was 61% (95% CI, 43%-78%); moreover, one year after the infusion, the analysis highlighted a pooled prevalence of relapse of 24% (95% CI, 11%-42%). Our results suggest that identifying potential predictive biomarkers of response to CAR-T therapy, especially for patients affected by the advanced stage of blood malignancies, could lead to stratification of the eligible population to that therapy, recognizing which patients will benefit and which will not, helping regulators to make decision in that way.

Angiotensin receptor/Neprilysin inhibitor effects in CRTd non-responders: From epigenetic to clinical beside.

OBJECTIVES: We evaluated whether Angiotensin receptor/Neprilysin inhibitors (ARNI) reduce heart failure (HF) hospitalizations and deaths in cardiac resynchronization therapy with defibrillator (CRTd) non-responders patients at 12 months of follow-up, modulating microRNAs (miRs) implied in adverse cardiac remodeling. BACKGROUND: adverse cardiac remodeling characterized by left ventricle ejection fraction (LVEF) reduction, left ventricular end-systolic volume (LVESv) increase, and the 6-minute walking test (6MWT) reduction are relevant pathological mechanisms in CRTd non-responders and could be linked to changes in miRNAs (miRs), regulating cardiac fibrosis, apoptosis, and hypertrophy. METHODS: miRs levels and clinical outcomes (LVEF, cardiac deaths, and 6MWT) were evaluated at baseline and one year of follow-up in CRTd non-responders divided into ARNI-users and Non-ARNI users. RESULTS: At baseline, there were no differences in levels of inflammatory markers, miR-18, miR-145, and miR-181 (p > 0.05) between Non-ARNI users (n 106) and ARNI-users (n 312). At one year of follow-up, ARNI-users vs. Non-ARNI users showed lowest inflammatory markers (p < 0.01) and miR-181 levels (p < 0.01) and higher values of miR-18 (p < 0.01)and miR-145 (p < 0.01). At one year of follow-up, ARNI-users had a higher increase of LVEF (p < 0.01) and 6MWT (p < 0.01) along with a more significant reduction of LVESv (p < 0.01) compared to Non-ARNI users. Cox regression analysis evidenced that ARNI-based therapies increase the probability of anti-remodeling effects of CRTd. Based on symptomatic improvements, echocardiographic and functional classification improvements, 37 (34.9%) patients among ARNI-users became responders, while only twenty (6.4%) patients became responders among Non-ARNi-users. CONCLUSIONS: ARNI might influence epigenetic mechanisms modulating miRs implicated in the adverse cardiac remodeling responses to CRTd.

Overview of the European post-authorisation study register post-authorization studies performed in Europe from September 2010 to December 2018.

BACKGROUND: The European post-authorisation study (EU PAS) register is a repository launched in 2010 by the European Medicines Agency (EMA). All EMA-requested PAS, commonly observational studies, must be recorded in this register. Multi-database studies (MDS) leveraging secondary data have become an important strategy to conduct PAS in recent years, as reflected by the type of studies registered in the EU PAS register. OBJECTIVES: To analyse and describe PAS in the EU PAS register, with focus on MDS. METHODS: Studies in the EU PAS register from inception to 31st December 2018 were described concerning transparency, regulatory obligations, scope, study type (e.g., observational study, clinical trial, survey, systematic review/meta-analysis), study design, type of data collection and target population. MDS were defined as studies conducted through secondary use of >1 data source not linked at patient-level. Data extraction was carried out independently by 14 centres with expertise in pharmacoepidemiology, using publicly available information in the EU PAS register including study protocol, whenever available, using a standardised data collection form. For validation purposes, a second revision of key fields for a 15% random sample of studies was carried out by a different centre. The inter-rater reliability (IRR) was then calculated. Finally, to identify predictors of primary data collection-based studies/versus those based on secondary use of healthcare databases) or MDS (vs. non-MDS), odds ratios (OR) and 95% confidence intervals (CI) were calculated fitting univariate logistic regression models. RESULTS: Overall, 1426 studies were identified. Clinical trials (N = 30; 2%), systematic reviews/meta-analyses (N = 16; 1%) and miscellaneous study designs (N = 46; 3%) were much less common than observational studies (N = 1227; 86%). The protocol was available for 63% (N = 360) of 572 observational studies requested by a competent authority. Overall, 36% (N = 446) of observational studies were based fully or partially on primary data collection. Of 757 observational studies based on secondary use of data alone, 282 (37%) were MDS. Drug utilisation was significantly more common as a study scope in MDS compared to non-MDS studies. The overall percentage agreement among collaborating centres that collected the data concerning study variables was highest for study type (93.5%) and lowest for type of secondary data (67.8%). CONCLUSIONS: Observational studies were the most common type of studies in the EU PAS register, but 30% used primary data, which is more resource-intensive. Almost half of observational studies using secondary data were MDS. Data recording in the EU PAS register may be improved further, including more widespread availability of study protocols to improve transparency.

Deficit of glucocorticoid-induced leucine zipper amplifies angiotensin-induced cardiomyocyte hypertrophy and diastolic dysfunction.

Poor prognosis in heart failure and the lack of real breakthrough strategies validate targeting myocardial remodelling and the intracellular signalling involved in this process. So far, there are no effective strategies to counteract hypertrophy, an independent predictor of heart failure progression and death. Glucocorticoid-induced leucine zipper (GILZ) is involved in inflammatory signalling, but its role in cardiac biology is unknown. Using GILZ-knockout (KO) mice and an experimental model of hypertrophy and diastolic dysfunction, we addressed the role of GILZ in adverse myocardial remodelling. Infusion of angiotensin II (Ang II) resulted in myocardial dysfunction, inflammation, apoptosis, fibrosis, capillary rarefaction and hypertrophy. Interestingly, GILZ-KO showed more evident diastolic dysfunction and aggravated hypertrophic response compared with WT after Ang II administration. Both cardiomyocyte and left ventricular hypertrophy were more pronounced in GILZ-KO mice. On the other hand, Ang II-induced inflammatory and fibrotic phenomena, cell death and reduction in microvascular density, remained invariant between the WT and KO groups. The analysis of regulators of hypertrophic response, GATA4 and FoxP3, demonstrated an up-regulation in WT mice infused with Ang II; conversely, such an increase did not occur in GILZ-KO hearts. These data on myocardial response to Ang II in mice lacking GILZ indicate that this protein is a new element that can be mechanistically involved in cardiovascular pathology.

Drugs-Induced Pathological Gambling: An Analysis of Italian Spontaneous Reporting System.

Pathological gambling has been reported as a direct complication of Parkinson's disease and its pharmacological treatment based on dopamine agonists. Moreover, further medications (not dopamine agonists) were associated to the occurrence of gambling disorder. We aim to analyze the spontaneous reports of gambling disorder on the whole Italian territory with a focus on Campania Region (Southern Italy) from January 1st 2002 to July 31st 2018. We analyzed gambling disorder's reports across the 2002-2018 period in the Italian spontaneous reporting database (Rete Nazionale di Farmacovigilanza-RNF), with a focus on Campania region. 94 suspected cases of gambling disorder associated to apomorphine, aripiprazole, cabergoline, levodopa, levodopa and derivatives in association with entacapone/benserazide and carbidopa, pergolide, pramipexole, ropinirole, and rotigotine were reported into the RNF. Of these cases, two related to pramipexole and one to aripiprazole were sent to Campania Pharmacovigilance Regional Centre. Although it is widely recognized that dopamine agonists may induce behavioral disorders, Parkinson's disease is itself associated to pathological gambling, compulsive shopping and eating. Since our results could not clarify the correlation between Parkinson's disease, its pharmacological treatment and pathological gambling, in order to better define this correlation there is a need to conduct further ad hoc observational studies.

Strengths, weaknesses and future challenges of biosimilars' development. An opinion on how to improve the knowledge and use of biosimilars in clinical practice.

Biosimilars started receiving the marketing authorization by European Medicine Agency since 2006. The development of biosimilars follows a well-defined step-wise approach, the so-called comparability exercise, which aims to compare non-clinical (mainly quality features and biological activity) and clinical (efficacy and safety profiles) features of new biosimilars with their respective reference products. Despite the undeniable advantages of such procedure, some concerns (such as the absence of switching studies or the evaluation of efficacy and safety in all therapeutic indications) still exist about its. In particular, the European regulatory framework on biosimilars approval does not include the conduction of switching studies demonstrating the interchangeability to be carried out before marketing authorization. This is one of the main aspects that negatively affects healthcare professionals' clinical decisions on switch. In order to achieve a better knowledge on safety and efficacy of biosimilar drugs, real world data should be collected and post-marketing efficacy and safety clinical studies (including those evaluating specific endpoints, therapeutic regimens and patients population), should be planned. also the conduction of well-designed switching studies is highly advisable, especially in the case of biosimilar drugs used in oncology settings. Lastly, considering the critical role of antidrug antibodies on efficacy/safety profile of biologic drugs, studies based on therapeutic drug monitoring would be useful in order to achieve treatment optimization. Implementing the above strategies could be helpful to fill the gap in knowledge observed in the present European biosimilar regulatory framework.

Risk of gastrointestinal complications associated to NSAIDs, low-dose aspirin and their combinations: Results of a pharmacovigilance reporting system.

Gastrointestinal (GI) complications are one of the most limiting cause of use of NSAIDs. Beyond others well defined factors, history of peptic ulcer, older age, Helicobacter pylori infection and use of gastrotoxic drugs may affect their GI safety profile. In particular, the risk of GI complications associated to the use of antiplatelet drugs, especially low-dose acetylsalicylic acid (LDA) should deserve much attention. However, only few studies have focused on the effect of combination LDA/NSAIDs on the GI tract compared with the monotherapy and much less studies assessed this effect with multiple NSAIDs use. We aimed to characterize the GI safety profile of NSAIDs and LDA as monotherapy or their combinations in real-life conditions by analysing spontaneous adverse drug reactions (ADRs) reporting system in a Southern Italy. We used the case/non-case method in the Italian Pharmacovigilance Network (RNF). Cases were reports of GI events in the RNF between January 2007 and December 2011. Non-cases were all other reports during the same period. The association between NSAID and suspected GI ADRs was calculated using the reporting odds ratio (ROR) with 95% confidence intervals as a measure of disproportionality while adjusting for age, and concomitant use of antineoplastic agents or drugs for cardiovascular diseases. Sub-analysis were performed within the NSAID class. Among the 2816 adverse drug reactions recorded, we identified 374 (13.3%) cases of GI complications. Upper GI complications were the most frequently reported type of events. The highest associations were found for the combined use of NSAIDs and/or LDA, whilst the lowest associations were for their respective monotherapy. Looking at individual NSAIDs the highest association with GI events was observed for ketorolac exposure followed by nimesulide, diclofenac, aspirin, ketoprofen, and ibuprofen. This study highlights the primary role of the national spontaneous reporting system to bring out potential signals, such as the inappropriate drug use pattern, which however, have to be furtherly studied in-depth with ad hoc population-based studies.

Risk of acute and serious liver injury associated to nimesulide and other NSAIDs: data from drug-induced liver injury case-control study in Italy.

AIM: Drug-induced liver injury is one of the most serious adverse drug reactions and the most frequent reason for restriction of indications or withdrawal of drugs. Some nonsteroidal anti-inflammatory drugs (NSAIDs) were withdrawn from the market because of serious hepatotoxicity. We estimated the risk of acute and serious liver injury associated with the use of nimesulide and other NSAIDs, with a prevalence of use greater than or equal to 5%. METHODS: This is a multicentre case-control study carried out in nine Italian hospitals from October 2010 to January 2014. Cases were adults, with a diagnosis of acute liver injury. Controls presented acute clinical disorders not related to chronic conditions, not involving the liver. Adjusted odds ratio (ORs) with 95% confidence interval (CI) were calculated initially with a bivariate and then multivariate analysis. RESULTS: We included 179 cases matched to 1770 controls. Adjusted OR for acute serious liver injury associated with all NSAIDs was 1.69, 95% CI 1.21-2.37. Thirty cases were exposed to nimesulide (adjusted OR 2.10, 95% CI 1.28-3.47); the risk increased according to the length of exposure (OR > 30 days: 12.55, 95% CI 1.73-90.88) and to higher doses (OR 10.69, 95% CI 4.02-28.44). Risk of hepatotoxicity was increased also for ibuprofen, used both at recommended dosages (OR 1.92, 95% CI 1.13-3.26) and at higher doses (OR 3.73, 95% CI 1.11-12.46) and for ketoprofen ≥ 150 mg (OR 4.65, 95% CI 1.33-10.00). CONCLUSION: Among all NSAIDs, nimesulide is associated with the higher risk, ibuprofen and high doses of ketoprofen are also associated with a modestly increased risk of hepatotoxicity.

Therapeutic drug monitoring of second-generation antipsychotics in pediatric patients: an observational study in real-life settings.

PURPOSE: Available guidelines on therapeutic drug monitoring of second-generation antipsychotics were designed for adults; therefore, they cannot be transferred as such in pediatric patients, who may have different drug absorption, distribution, metabolism, and elimination. Moreover, available tools that guide dosing in neuropsychiatric pediatric patients are scant, leading to the possibility of reduced efficacy and/or increased risks of toxicity. Here we describe the results of observational therapeutic drug monitoring conducted in three pediatric neuropsychiatry units across Italy in 2012-2014, with the following aims: (1) to describe the distribution of plasma concentrations of second-generation antipsychotics in our pediatric patients and (2) to identify clinical covariates associated with plasma drug levels. METHODS: Five hundred fifty-six plasma trough concentrations of the second-generation antipsychotics risperidone (plus 9-hydroxy-risperidone), aripiprazole, olanzapine, and quetiapine were measured from 172 pediatric outpatients overall. The distribution of drug concentrations was described and correlated with drug doses and clinical variables. RESULTS: Risperidone plasma levels were lower than in adults (median 13.6 ng/ml), with a high inter-patient (78.9%) but lower intra-patient (34.2%) variability. In multiple regression analyses, risperidone plasma levels depended only on drug dose (p < 0.001). Aripiprazole plasma levels were similar to those described in adults (median 165.8 ng/ml) and were widely distributed, with an inter-patient variability of 81.1%, while the intra-patient variability was much lower (29.3%). Multiple regression analyses indicated that aripiprazole plasma levels were influenced by the daily doses (p < 0.001) and by the number of concomitant drugs (p < 0.01). CONCLUSION: Our study described the distribution of plasma levels of SGAs in a real-life setting involving pediatric patients, significantly increasing the amount of available data for this fragile population. If confirmed in larger dataset, these data may contribute to the definition of optimal therapeutic window for risperidone and aripiprazole plasma levels in pediatric patients.

Vitamin D deficiency in type 2 diabetic patients with hypogonadism.

INTRODUCTION: Both type 2 diabetes and secondary hypogonadism may be associated with low vitamin D levels. AIM: The aim of this study was to evaluate 25-hydroxyvitamin D (25(OH)D) concentrations in type 2 diabetic males with and without hypogonadism. METHODS: We performed a case-control study among 122 male adults with type 2 diabetes, 51 with associated hypogonadism (Group 1) and 71 with normal gonadal function (Group 2). One hundred age-matched nondiabetic males with normal gonadal function served as a control group. MAIN OUTCOME MEASURES: Levels of 25(OH)D were assessed by a chemiluminescent immunoassay in all patients. Morning testosterone, pituitary, thyroid, parathyroid hormones, fasting glucose, and hemoglobin A1c were also evaluated. RESULTS: The overall diabetic population showed a mean 25(OH)D concentration (22.3 ± 6.09 ng/mL) significantly lower than the control group (34.3 ± 7.2, P < 0.001), with 81% of diabetic patients presenting 25(OH)D deficiency (<20 ng/mL) or insufficiency (20-29.9 ng/mL). The lowest 25(OH)D concentration was found in Group 1 (20.1 ± 6.58 ng/mL). Concentration of 25(OH)D was significantly lower in the 42 patients with hypogonadotropic hypogonadism as compared with the 9 patients with hypergonadotropic hypogonadism (19.4 ± 7.06 vs. 23.8 ± 6.11 ng/mL, P < 0.001). No difference in erectile dysfunction (ED) prevalence between Group 1 and Group 2 was found, nor was there a correlation between the severity of ED and vitamin D levels (r = -0.10, P = 0.39). CONCLUSIONS: These results show that type 2 diabetic patients with hypogonadism present lower 25(OH)D concentration and higher prevalence of vitamin D deficiency, compared with patients without hypogonadism. The finding that 25(OH)D concentrations were similar between type 2 diabetic patients with hypergonadotropic hypogonadism and those with normal gonadal function deserves further study.

Predictors of mortality in atypical antipsychotic-treated community-dwelling elderly patients with behavioural and psychological symptoms of dementia: a prospective population-based cohort study from Italy.

PURPOSE: To evaluate the effect of a broad range of covariates on the survival of a real-life long-term follow-up cohort of community-dwelling patients with behavioural and psychological symptoms of dementia who were new users of atypical antipsychotic medications (APMs). METHODS: This was a prospective cohort study of 1,618 subjects aged ≥65 years with dementia and BPSD ("behavioural and psychological symptoms of dementia") who were new users of atypical APMs and registered in a Dementia Evaluation Unit of Campania Region (Italy) from September 2006 to March 2010. The potential of baseline features to predict mortality was assessed with the Cox proportional hazards model. RESULTS: The average follow-up was 309 days. Of the 1,618 new users of atypical antipsychotics, 9.3 % experienced at least one adverse event, including death (5.1 %), drug therapeutic failure (3.0 %), extrapyramidal symptoms (0.5 %) and stroke (0.2 %). The crude all-cause mortality rate was 6.0 per 100 person-years [95 % confidence interval (CI) 4.8-7.4]; the rate was higher in patients aged >85 years (9.0 per 100 person-years, 95 % CI 6.4-12.7) and among male patients (7.5 per 100 person-years, 95% CI 5.3-10.6). In the multivariate analysis, only age was associated to all-cause mortality [hazard ratio (HR) 1.1; 95 % CI 1.0-1.1 and HR 1.4; 95 % CI: 0.9-2.2, respectively). In contrast, hallucination (HR 0.4; 95 % CI 0.2-0.6) and dosage change (HR 0.4; 95 % CI 0.2-0.78) were significantly associated with a lower risk of all-cause mortality. CONCLUSIONS: Among our patient cohort, the mortality rate of patients with BPSD receiving long-term treatment with atypical APMs was lower than that reported in other studies, and only age was found to be significant predictor factor of mortality.

Rational use of antibiotics for the management of children's respiratory tract infections in the ambulatory setting: an evidence-based consensus by the Italian Society of Preventive and Social Pediatrics.

BACKGROUND: Several guidelines for the management of respiratory tract infections in children are available in Italy, as well as in other European countries and the United States of America. However, poor adherence to guidelines and the sustained inappropriate use of antibiotics have been reported. In the outpatient setting, almost half of antibiotics are prescribed for the treatment of common respiratory tract infections. In Italy the antibiotic prescription rate is significantly higher than in other European countries, such as Denmark or the Netherlands, and also the levels of antibiotic resistance for a large variety of bacteria are higher. Therefore, the Italian Society of Preventive and Social Paediatrics organised a consensus conference for the treatment of respiratory tract infections in children to produce a brief, easily readable, evidence-based document. METHODS: The conference method was used, according to the National Institute of Health and the National Plan Guidelines. A literature search was performed focusing on the current guidelines for the treatment of airway infections in children aged 1 month-18 years in the ambulatory setting. RESULTS: Recommendations for the treatment of acute pharyngitis, acute otitis media, sinusitis, and pneumonia have been summarized. Conditions for which antibiotic treatment should not be routinely prescribed have been highlighted. CONCLUSION: This evidence-based document is intended to accessible to primary care pediatricians and general practice physicians in order to make clinical practice uniform, in accordance with the recommendations of the current guidelines.

Safety Monitoring of mRNA COVID-19 Vaccines in Children Aged 5 to 11 Years by Using EudraVigilance Pharmacovigilance Database: The CoVaxChild Study.

Although the safety profiles of mRNA COVID-19 vaccines (mRNA-1273 and BNT162b2) were evaluated in pre-authorization clinical trials, real-world data allow us to better define their benefit/risk ratio in the paediatric population. The current study aimed to evaluate the safety profiles of mRNA COVID-19 vaccines in children by analysing the pharmacovigilance data of the European spontaneous reporting system database EudraVigilance (EV) in the period from 1 January 2021, to 1 October 2022. During our study period, overall 4838 ICSRs related to mRNA COVID-19 vaccines referring to 5-11-year-old subjects were retrieved from EV, of which 96.9% were related to BNT162b2 and 49.3% were related to males. A total of 12,751 Adverse Events Following Immunization (AEFIs) were identified, of which 38.7% were serious. The most frequently reported AEFIs were pyrexia, headache, and vomiting. Only 20 Individual Case Safety Reports (ICSRs) reported Multisystem Inflammatory Syndrome (MIS) as an AEFI, all related to BNT162b2. The majority of MIS cases were females, and six cases were completely resolved at the time of reporting. Our results show a favourable risk-benefit profile for all mRNA COVID-19 vaccines in this paediatric sub-population, supporting their use in children. Considering the peculiarity and fragility of children, continuous safety monitoring of COVID-19 vaccines is required.

The efficacy and the safety of eltrombopag in pediatric patients with severe aplastic anemia: a systematic review.

Background: Acquired aplastic anemia (AAA) in pediatric patients is a rare disorder characterized by hypocellular bone marrow and pancytopenia. Eltrombopag, an oral thrombopoietin receptor agonist, provides a hematologic improvement in adults with severe aplastic anemia (SAA) refractory to immunosuppressive therapy (IST). The association of ELT and IST was approved by the US Food and Drug Administration (FDA) for adults and children ≥2 years of age as a first-line treatment for SAA. However, the effects of ELT on pediatric patients with SAA remain controversial and limited. Methods and findings: We conducted a systematic review of the most recent literature from Pubmed, Web of Science, and Embase, published up to 20th December 2022, in order to evaluate the available evidence on the efficacy and safety of ELT added to IST for the treatment of SAA in the pediatric population. Conclusion: Eltrombopag added to the IST has shown a good safety profile, without manifestations of excessive toxic effects, although not all the results obtained from our studies support the addition of ELT to the IST in the first-line treatment of children with SAA. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42022325859.

Drug Utilization and Measurement of Medication Adherence: A Real World Study of Psoriasis in Italy.

Exceptional advances have been made with systemic treatment for psoriasis (PSO). However, that disease still represents a heavy burden in terms of impact on healthcare systems worldwide. This study comprehensively assesses medication adherence in a real world setting in Italy across all phases-initiation, implementation, and persistence-of PSO therapies. By distinguishing between switches and swaps, it provides unique insights into the patient's own approach to prescribed therapy as well as clinical decision-making processes, enhancing our understanding of medication adherence and discontinuation in a real world daily setting. The study's refined methodology for assessing persistence, considering variations in refill gaps and complex dosing regimens, shows that anti-interleukin (IL) therapies are associated with longer periods of adherence compared with other available therapeutic strategies. Among the selected drugs, ixekizumab and secukinumab were the ones with higher rate of treatment adherence at the expense of anti-TNF-α and anti-PDE4 agents. Notably, patients who opt for swaps are approximately 2.8 times more likely to discontinue their PSO therapy within one year. These findings carry practical implications for optimizing medication adherence, including tailored patient counseling, monitoring, and therapeutic adjustments, highlighting the need for a comprehensive and patient-centered approach to managing these conditions.

A Pharmacovigilance Study on the Safety of Axicabtagene Ciloleucel Based on Spontaneous Reports from the EudraVigilance Database.

During pre-approval clinical trials, the safety of axi-cel, a second-generation CAR-T-cell therapy directed against CD19, which dramatically improved the prognosis of intractable B-cell lymphomas, has been investigated only in about 400 patients. Therefore, additional information on this issue is urgently needed. In the present paper, we evaluated the 2905 ICSRs with axi-cel as the suspected drug that had been uploaded in the EudraVigilance database from 1 January 2018 to 31 December 2022. About 80% of the reported adverse events were serious, and about 20% of them did not fully resolve or caused death. The adverse events most-frequently reported were Nervous system disorders (25.6%) and, among them, immune-effector-cell-associated neurotoxicity syndrome, followed by Immune system disorders (23.1%), General disorders and administration site conditions (12.0%), Blood and lymphatic system disorders (7.2%), and Infections and infestations (5.8%). Disproportionality analysis showed that the frequency of reported adverse events related to the nervous system was higher with axi-cel than with the other approved CAR-T-cells, except brexu-cel. In conclusion, real-world pharmacovigilance data showed that nervous system and immune system disorders are the adverse events most reported in axi-cel-related ICSRs and suggest that axi-cel could be more neurotoxic than other CAR-T-cells.

Association between Sex-Related ALOX5 Gene Polymorphisms and Lung Atopy Risk.

Atopy is an exaggerated IgE-mediated immune response to foreign antigens in which metabolic abnormalities of the leukotrienes (LTs) pathway play a crucial role. Recent studies have described sex as a key variable in LT biosynthesis, partly explaining why treatment with anti-LT drugs in atopic subjects leads to better control of symptoms in women. In addition, variability in LT production is often associated with single nucleotide polymorphisms (SNPs) in the arachidonate 5-lipoxygenase (ALOX5) gene, which encodes the leukotriene-synthesizing enzyme machinery, 5-lipoxygenase (5-LO). This study aimed to investigate whether two SNPs of ALOX5 are implicated in sex differences in allergic diseases in a prospective cohort of 150 age- and sex-matched atopic and healthy subjects. Rs2029253 and rs2115819 were genotyped using allele-specific RT-PCR, and serum levels of 5-LO and LTB4 were measured by ELISA. Both polymorphisms are significantly more common in women than in men, and their influences on LT production vary as a function of sex, leading to a decrease in men's and an increase in women's serum levels of 5-LO and LTB4. These data represent a new resource for understanding sex-related differences in lung inflammatory diseases, partly explaining why women are more likely to develop allergic disorders than men.

Hyaluronic acid-based fillers in patients with autoimmune inflammatory diseases.

The use of hyaluronic acid (HA)-based aesthetic therapies is growing steadily, and according to the International Society of Aesthetic Plastic Surgery, more than 4.3 million aesthetic procedures using HA were performed in 2019, an increase of 15.7% than 2018. More people are offering these types of services, often without proper training or qualifications. Therefore, there is an increasing number of reports in the literature relating to possible adverse events, with subsequent therapeutic problems and more or less serious consequences for patients. The aim of this research is to carry out a review of the literature in order to evaluate the impact of hyaluronic acid-based fillers in patients with autoimmune inflammatory diseases, in particular scleroderma and Systemic Lupus Erythematosus (SLE). Although HA plays a central role in the inflammatory process, the use of HA-based fillers in patients with autoimmune inflammatory diseases is still controversial. HA, in fact, in inflamed tissues helps to propagate the inflammatory response and, injected in the form of a dermal filler, could potentially promote reactivation of the underlying disease. For this reason, many specialists do not perform HA-based aesthetic treatments in patients with scleroderma or SLE. However, recent scientific evidence suggests that the use of HA-based fillers in patients with scleroderma can lead to improvement of skin lesions, with satisfactory results. In the literature, there are no clinical studies that contraindicate the administration of HA-based dermal fillers in patients with inflammatory disease.

Do immune checkpoint inhibitors share the same pharmacological feature in the risk of cardiac arrhythmias?

BACKGROUND: Despite the available evidence showing an association between cardiac arrhythmia and Immune Checkpoint Inhibitors (ICIs), few studies have compared this risk between ICIs. OBJECTIVES: We aim to evaluate Individual Case Safety Reports (ICSRs) of ICIs-induced cardiac arrhythmias and compare the reporting frequency of cardiac arrhythmias among ICIs. METHODS: ICSRs were retrieved from the European Pharmacovigilance database (Eudravigilance). ICSRs were classified based on the ICI reported (pembrolizumab, nivolumab, atezolizumab, ipilimumab, durvalumab, avelumab, cemiplimab, and dostarlimab). If more than one ICI was reported, the ICSR was classified as a combination of ICIs. ICSRs of ICI-related arrhythmias were described and the reporting frequency of cardiac arrhythmias was assessed by applying the reporting odds ratio (ROR) and its 95 % confidence interval (95 %CI). RESULTS: A total of 1262 ICSRs were retrieved, of which 147 (11.65 %) were related to combinations of ICIs. A total of 1426 events of cardiac arrhythmias were identified. The three most reported events were atrial fibrillation, tachycardia, and cardiac arrest. Ipilimumab was associated with a reduced reporting frequency of cardiac arrhythmias compared to all other ICIs (ROR 0.71, 95 %CI 0.55-0.92; p = 0.009). Anti-PD1 was associated with a higher reporting frequency of cardiac arrhythmias than anti-CTLA4 (ROR 1.47, 95 %CI 1.14-1.90; p = 0.003). CONCLUSION: This study is the first comparing ICIs for the risk of cardiac arrhythmias. We found that ipilimumab was the only ICI associated with a reduced reporting frequency. Further high-quality studies are needed to confirm our results.