Pharmacological and Benefit-Risk Profile of Once-Weekly Basal Insulin Administration (Icodec): Addressing Patients' Unmet Needs and Exploring Future Applications.

Diabetes mellitus (DM) is a chronic metabolic disease affecting over 500 million people worldwide, which leads to severe complications and to millions of deaths yearly. When therapeutic goals are not reached with diet, physical activity, or non-insulin drugs, starting/adding insulin treatment is recommended by international guidelines. A novel recombinant insulin is icodec, a once-weekly insulin that successfully completed phase III trials and that has recently obtained the marketing authorization approval from the European Medicines Agency. This narrative review aims to assess icodec pharmacological and clinical features concerning evidence on benefit-risk profile, as compared to other basal insulins, addressing the potential impact on patients' unmet needs. Icodec is a full agonist, recombinant human insulin analogue characterized by an ultra-long half-life (196 h), enabling its use in once-weekly administration. Phase III randomized clinical trials involving more than 4000 diabetic patients, mostly type 2 DM, documented non-inferiority of icodec, as compared to currently available basal insulins, in terms of estimated mean reduction of glycated hemoglobin levels; a superiority of icodec, compared to control, was confirmed in insulin-naïve patients (ONWARDS 1, 3, and 5), and in patients previously treated with basal insulin (ONWARDS 2). Icodec safety profile was comparable to the currently available basal insulins. Once-weekly icodec has the potential to improve patients' adherence, thus positively influencing patients' treatment satisfaction as well as quality of life, especially in type 2 DM insulin-naïve patients. An improved adherence might positively influence glycemic target achievement, reduce overall healthcare costs and overcome some of the unmet patients' needs. Icodec has the potential to emerge as a landmark achievement in the evolution of insulin therapy, with a positive impact also for the National Health Services and the whole society.

Epidemiological analysis to identify predictors of X-linked hypophosphatemia (XLH) diagnosis in an Italian pediatric population: the EPIX project.

PURPOSE: X-linked hypophosphatemia (XLH) is a rare multi-systemic disease characterized by low plasma phosphate levels. The aim of this study was to investigate the annual XLH prevalence and internally evaluate predictive algorithms' application performance for the early diagnosis of XLH. METHODS: The PediaNet database, containing data on more than 400,000 children aged up to 14 years, was used to identify a cohort of XLH patients, which were matched with up to 10 controls by date of birth and gender. The annual prevalence of XLH cases per 100,000 patients registered in PediaNet database was estimated. To identify possible predictors associated with XLH diagnosis, a logistic regression model and two machine learning algorithms were applied. Predictive analyses were separately carried out including patients with at least 1 or 2 years of database history in PediaNet. RESULTS: Among 431,021 patients registered in the PediaNet database between 2007-2020, a total of 12 cases were identified with a mean annual prevalence of 1.78 cases per 100,000 patients registered in PediaNet database. Overall, 8 cases and 60 matched controls were included in the analysis. The random forest algorithm achieved the highest area under the receiver operating characteristic curve (AUC) value both in the one-year prior ID (AUC = 0.99, 95% CI = 0.99-1.00) and the two-year prior ID (AUC = 1.00, 95% CI = 1.00-1.00) analysis. Overall, the XLH predictors selected by the three predictive methods were: the number of vitamin D prescriptions, the number of recorded diagnoses of acute respiratory infections, the number of prescriptions of antihistamine for systemic use, the number of prescriptions of X-ray of the lower limbs and pelvis and the number of allergology visits. CONCLUSION: Findings showed that data-driven machine learning models may play a prominent role for the prediction of the diagnosis of rare diseases such as XLH.

Safety Monitoring of COVID-19 Vaccines in Persons with Prior SARS-CoV-2 Infection: A European Multi-Country Study.

In all pivotal trials of COVID-19 vaccines, the history of previous SARS-CoV-2 infection was mentioned as one of the main exclusion criteria. In the absence of clinical trials, observational studies are the primary source for evidence generation. This study aims to describe the patient-reported adverse drug reactions (ADRs) following the first COVID-19 vaccination cycle, as well as the administration of booster doses of different vaccine brands, in people with prior SARS-CoV-2 infection, as compared to prior infection-free matched cohorts of vaccinees. A web-based prospective study was conducted collecting vaccinee-reported outcomes through electronic questionnaires from eleven European countries in the period February 2021-February 2023. A baseline questionnaire and up to six follow-up questionnaires collected data on the vaccinee's characteristics, as well as solicited and unsolicited adverse reactions. Overall, 3886 and 902 vaccinees with prior SARS-CoV-2 infection and having received the first dose or a booster dose, respectively, were included in the analysis. After the first dose or booster dose, vaccinees with prior SARS-CoV-2 infection reported at least one ADR at a higher frequency than those matched without prior infection (3470 [89.6%] vs. 2916 [75.3%], and 614 [68.2%] vs. 546 [60.6%], respectively). On the contrary side, after the second dose, vaccinees with a history of SARS-CoV-2 infection reported at least one ADR at a lower frequency, compared to matched controls (1443 [85.0%] vs. 1543 [90.9%]). The median time to onset and the median time to recovery were similar across all doses and cohorts. The frequency of adverse reactions was higher in individuals with prior SARS-CoV-2 infection who received Vaxzevria as the first dose and Spikevax as the second and booster doses. The frequency of serious ADRs was low for all doses and cohorts. Data from this large-scale prospective study of COVID-19 vaccinees could be used to inform people as to the likelihood of adverse effects based on their history of SARS-CoV-2 infection, age, sex, and the type of vaccine administered. In line with pivotal trials, the safety profile of COVID-19 vaccines was also confirmed in people with prior SARS-CoV-2 infection.

Safety of Biological Therapies for Severe Asthma: An Analysis of Suspected Adverse Reactions Reported in the WHO Pharmacovigilance Database.

BACKGROUND: The management of uncontrolled severe asthma has greatly improved since the advent of novel biologic therapies. Up to August 2022, five biologics have been approved for the type 2 asthma phenotype: anti-IgE (omalizumab), anti-IL5 (mepolizumab, reslizumab, benralizumab), and anti-IL4 (dupilumab) monoclonal antibodies. These drugs are usually well tolerated, although long-term safety information is limited, and some adverse events have not yet been fully characterized. Spontaneous reporting systems represent the cornerstone for the detection of potential signals and evaluation of the real-world safety of all marketed drugs. OBJECTIVE: The aim of this study was to provide an overview of safety data of biologics for severe asthma using VigiBase, the World Health Organization global pharmacovigilance database. METHODS: We selected all de-duplicated individual case safety reports (ICSRs) attributed to five approved biologics for severe asthma in VigiBase, up to 31st August 2022 (omalizumab, mepolizumab, reslizumab, benralizumab and dupilumab). Descriptive frequency analyses of ICSRs were carried out both as a whole class and as individual products. Reporting odds ratios (ROR) with 95% confidence intervals (CIs) were used as the measure of disproportionality for suspected adverse drug reactions (ADRs) associated with the study drugs compared with either all other suspected drugs (Reference Group 1, RG1) or inhaled corticosteroids plus long-acting ß-agonists (ICSs/LABAs) (Reference Group 2, RG2) or with oral corticosteroids (OCSs) (Reference Group 3, RG3). RESULTS: Overall, 31,724,381 ICSRs were identified in VigiBase and 167,282 (0.5%) were related to study drugs; the remaining reports were considered as RG1. Stratifying all biologic-related ICSRs by therapeutic indication, around 29.4% (n = 48,440) concerned asthma use; omalizumab was mainly indicated as the suspected drug (n = 20,501), followed by dupilumab, mepolizumab, benralizumab and reslizumab. Most asthma ICSRs concerned adults (57%) and women (64.1%). Asthma biologics showed a higher frequency of serious suspected ADR reporting than RG1 (41.3% vs 32.3%). The most reported suspected ADRs included asthma, dyspnea, product use issue, drug ineffective, cough, headache, fatigue and wheezing. Asthma biologics were disproportionally associated with several unknown or less documented adverse events, such as malignancies, pulmonary embolism and deep vein thrombosis with omalizumab; alopecia and lichen planus with dupilumab; alopecia and herpes infections with mepolizumab; alopecia, herpes zoster and eosinophilic granulomatosis with polyangiitis related to benralizumab; and alopecia with reslizumab. CONCLUSIONS: The most frequently reported suspected ADRs of asthma biologics in VigiBase confirmed the presence of well-known adverse effects such as general disorders, injection-site reactions, nasopharyngitis, headache and hypersensitivity, while some others (e.g. asthma reactivation or therapeutic failure) could be ascribed to the indication of use. Moreover, the analysis of signals of disproportionate reporting suggests the presence of malignancies, effects on the cardiovascular system, alopecia and autoimmune conditions, requiring further assessment and investigation.

Machine learning-based algorithms applied to drug prescriptions and other healthcare services in the Sicilian claims database to identify acromegaly as a model for the earlier diagnosis of rare diseases.

Acromegaly is a rare disease characterized by a diagnostic delay ranging from 5 to 10 years from the symptoms' onset. The aim of this study was to develop and internally validate machine-learning algorithms to identify a combination of variables for the early diagnosis of acromegaly. This retrospective population-based study was conducted between 2011 and 2018 using data from the claims databases of Sicily Region, in Southern Italy. To identify combinations of potential predictors of acromegaly diagnosis, conditional and unconditional penalized multivariable logistic regression models and three machine learning algorithms (i.e., the Recursive Partitioning and Regression Tree, the Random Forest and the Support Vector Machine) were used, and their performance was evaluated. The random forest (RF) algorithm achieved the highest Area under the ROC Curve value of 0.83 (95% CI 0.79-0.87). The sensitivity in the test set, computed at the optimal threshold of predicted probabilities, ranged from 28% for the unconditional logistic regression model to 69% for the RF. Overall, the only diagnosis predictor selected by all five models and algorithms was the number of immunosuppressants-related pharmacy claims. The other predictors selected by at least two models were eventually combined in an unconditional logistic regression to develop a meta-score that achieved an acceptable discrimination accuracy (AUC = 0.71, 95% CI 0.66-0.75). Findings of this study showed that data-driven machine learning algorithms may play a role in supporting the early diagnosis of rare diseases such as acromegaly.

Medication review and deprescribing in different healthcare settings: a position statement from an Italian scientific consortium.

Recent medical advancements have increased life expectancy, leading to a surge in patients affected by multiple chronic diseases and consequent polypharmacy, especially among older adults. This scenario increases the risk of drug interactions and adverse drug reactions, highlighting the need for medication review and deprescribing to reduce inappropriate medications and optimize therapeutic regimens, with the ultimate goal to improving patients' health and quality of life. This position statement from the Italian Scientific Consortium on medication review and deprescribing aims to describe key elements, strategies, tools, timing, and healthcare professionals to be involved, for the implementation of medication review and deprescribing in different healthcare settings (i.e., primary care, hospital, long-term care facilities, and palliative care). Challenges and potential solutions for the implementation of medication review and deprescribing are also discussed.

Frequency and timing of adverse reactions to COVID-19 vaccines; A multi-country cohort event monitoring study.

INTRODUCTION: During the COVID-19 pandemic, EMA set-up a large-scale cohort event monitoring (CEM) system to estimate incidence rates of patient-reported adverse drug reactions (ADRs) of different COVID-19 vaccines across the participating countries. This study aims to give an up to date and in-depth analysis of the frequency of patient-reported ADRs after the 1st, 2nd, and booster vaccination, to identify potential predictors in developing ADRs and to describe time-to-onset (TTO) and time-to-recovery (TTR) of ADRs. METHODS: A CEM study was rolled out in a period ranging from February 2021 to February 2023 across multiple European countries; The Netherlands, Belgium, France, the United Kingdom, Italy, Portugal, Romania, Slovakia and Spain. Analysis consisted of a descriptive analyses of frequencies of COVID-19 vaccine-related ADRs for 1st, 2nd and booster vaccination, analysis of potential predictors in developing ADRs with a generalized linear mixed-effects model, analysis of TTO and TTR of ADRs and a sensitivity analysis for loss to follow-up (L2FU). RESULTS: A total of 29,837 participants completed at least the baseline and the first follow-up questionnaire for 1st and 2nd vaccination and 7,250 participants for the booster. The percentage of participants who reported at least one ADR is 74.32% (95%CI 73.82-74.81). Solicited ADRs, including injection site reactions, are very common across vaccination moments. Potential predictors for these reactions are the brand of vaccine used, the patient's age, sex and prior SARS-CoV-2 infection. The percentage of serious ADRs in the study is low for 1st and 2nd vaccination (0.24%, 95%CI 0.19--0.31) and booster (0.26%, 95%CI 0.15, 0.41). The TTO was 14 h (median) for dose 1 and slightly longer for dose 2 and booster dose. TTR is generally also within a few days. The effect of L2FU on estimations of frequency is limited. CONCLUSION: Despite some limitations due to study design and study-roll out, CEM studies can allow prompt and almost real-time observations of the safety of medications directly from a patient-centered perspective, which can play a crucial role for regulatory bodies during an emergency setting such as the COVID-19 pandemic.

Exploring the level of agreement among different drug-drug interaction checkers: a comparative study on direct oral anticoagulants.

BACKGROUND: Direct oral anticoagulants (DOACs) may be involved in drug-drug interactions (DDIs) potentially increasing the risk of adverse drug reactions. This study aimed to evaluate the level of agreement among interaction checkers (ICs) and DOACs' summary of product characteristics (SPCs), in listing DDIs and in attributing DDIs' severity. RESEARCH DESIGN AND METHODS: The level of agreement among five ICs (i.e. INTERCheck WEB, Micromedex, Lexicomp, Epocrates, and drugs.com) in identifying potential DDIs and in attributing severity categories was evaluated using Gwet's AC1 on all five ICs and by comparing groups of four- and two-pair sets of ICs. RESULTS: A total of 486 potentially interacting drugs with dabigatran, 556 for apixaban, 444 for edoxaban, and 561 for rivaroxaban were reported. The level of agreement among the ICs in identifying potential DDIs was poor (range: 0.12-0.16). Similarly, it was low in 4 and 2 sets analyses. The level of agreement among the ICs in classifying the severity of potential DDIs was poor (range: 0.32-0.34), also in 4 and 2 sets analyses. CONCLUSIONS: The heterogeneity among different ICs and SPCs underscores the need to standardize DDI datasets and to conduct real-world studies to generate evidence regarding the frequency and clinical relevance of potential DOAC-related DDIs.

Post-marketing active surveillance of Guillain Barré Syndrome following COVID-19 vaccination in persons aged ≥12 years in Italy: A multi-database self-controlled case series study.

BACKGROUND: Recently published studies have reported association of COVID-19 vaccine ChAdOx1-S (Vaxzevria) with Guillain Barré Syndrome (GBS). Less is known about the safety of other COVID-19 vaccines with respect to GBS outcome. This study investigated the association of COVID-19 vaccines with GBS in more than 15 million persons aged ≥12 years in Italy. METHODS: Study population was all individuals aged ≥12 years who received at least one dose of COVID-19 vaccines, admitted to emergency care/hospital for GBS from 27 December 2020-30 September 2021 in Italy. Identification of GBS cases and receipt of at least one dose of mRNA-1273 (Elasomeran), BNT162b2 (Tozinameran), ChAdOx1-S (Vaxzevria) and Ad26.COV2.S (Janssen) through record linkage between regional health care and vaccination registries. Relative Incidence (RI) was estimated Self-controlled case series method adapted to event-dependent exposure using in the 42-day exposure risk period after each dose compared with other observation periods. RESULTS: Increased risk of GBS was found after first (RI = 6.83; 95% CI 2.14-21.85) and second dose (RI = 7.41; 2.35-23.38) of mRNA-1273 and first dose of ChAdOx1-S (RI = 6.52; 2.88-14.77). Analysis by age found an increased risk among those aged≥60 years after first (RI = 8.03; 2.08-31.03) and second dose (RI = 7.71; 2.38-24.97) of mRNA-1273. The first dose of ChAdOx1-S was associated with GBS in those aged 40-59 (RI = 4.50; 1.37-14.79) and in those aged ≥ 60 years (RI = 6.84; 2.56-18.28). CONCLUSIONS: mRNA-1273 and ChAdOx1-S vaccines were associated with an increased risk of GBS however this risk resulted in a small number of excess cases. Limitations were loss of GBS outpatient cases and imprecision of the estimates in the subgroup analysis due to a low number of events.

Comparing clinical trial population representativeness to real-world users of 17 biologics approved for immune-mediated inflammatory diseases: An external validity analysis of 66,639 biologic users from the Italian VALORE project.

To date, no population-based studies have specifically explored the external validity of pivotal randomized clinical trials (RCTs) of biologics simultaneously for a broad spectrum of immuno-mediated inflammatory diseases (IMIDs). The aims of this study were, firstly, to compare the patients' characteristics and median treatment duration of biologics approved for IMIDs between RCTs' and real-world setting (RW); secondly, to assess the extent of biologic users treated for IMIDs in the real-world setting that would not have been eligible for inclusion into pivotal RCT for each indication of use. Using the Italian VALORE distributed database (66,639 incident biologic users), adult patients with IMIDs treated with biologics in the Italian real-world setting were substantially older (mean age ± SD: 50 ± 15 years) compared to those enrolled in pivotal RCTs (45 ± 15 years). In the real-world setting, certolizumab pegol was more commonly used by adult women with psoriasis/ankylosing spondylitis (F/M ratio: 1.8-1.9) compared to RCTs (F/M ratio: 0.5-0.6). The median treatment duration (weeks) of incident biologic users in RW was significantly higher than the duration of pivotal RCTs in almost all indications for use and most biologics (4-100 vs. 6-167). Furthermore, almost half (46.4%) of biologic users from RW settings would have been ineligible for inclusion in the respective indication-specific pivotal RCTs. The main reasons were: advanced age, recent history of cancer and presence of other concomitant IMIDs. These findings suggest that post-marketing surveillance of biologics should be prioritized for those patients.

Myasthenia Gravis Treatment: From Old Drugs to Innovative Therapies with a Glimpse into the Future.

Myasthenia gravis (MG) is a rare autoimmune disease that causes debilitating muscle weakness due to impaired neuromuscular transmission. Since most (about 80-90%) MG patients present autoantibodies against the acetylcholine receptor, standard medical therapy consists of symptomatic treatment with acetylcholinesterase inhibitors (e.g., pyridostigmine). In addition, considering the autoimmune basis of MG, standard therapy includes immunomodulating agents, such as corticosteroids, azathioprine, cyclosporine A, and cyclophosphamide. New strategies have been proposed for the treatment of MG and include complement blockade (i.e., eculizumab, ravulizumab, and zilucoplan) and neonatal Fc receptor antagonism (i.e., efgartigimod and rozanolixizumab). The aim of this review is to provide a detailed overview of the pre- and post-marketing evidence on the five pharmacological treatments most recently approved for the treatment of MG, by identifying both preclinical and clinical studies registered in clinicaltrials.gov. A description of the molecules currently under evaluation for the treatment of MG is also provided.

Pharmacological Therapies of Spinal Muscular Atrophy: A Narrative Review of Preclinical, Clinical-Experimental, and Real-World Evidence.

Spinal muscular atrophy (SMA) is a rare neuromuscular disease, with an estimated incidence of about 1 in 10,000 live births. To date, three orphan drugs have been approved for the treatment of SMA: nusinersen, onasemnogene abeparvovec, and risdiplam. The aim of this narrative review was to provide an overview of the pre- and post-marketing evidence on the pharmacological treatments approved for the treatment of SMA by identifying preclinical and clinical studies registered in clinicaltrials.gov and in the EU PAS register from their inception until the 4 January 2023. The preclinical evidence on the drugs approved for SMA allowed a significant acceleration in the experimental phase of these drugs. However, since these drugs had been authorized through accelerated programs, the conduction of post-marketing studies was requested as a condition of their marketing approval to better understand their risk-benefit profiles in real-world settings. As of the 4 January 2023, a total of 69 post-marketing studies concerning the three orphan drugs approved for SMA were identified in clinicaltrials.gov (N = 65; 94.2%) and in the EU PAS register (N = 4; 5.8%). Currently, ongoing studies are primarily aimed at providing evidence concerning the risk-benefit profile of the three drugs in specific populations that were not included in the pivotal trials and to investigate the long-term safety and clinical benefits of these drugs. Real-world data sources collecting information regarding the natural history of the disease and post-marketing surveillance of the available therapies are increasingly becoming essential for generating real-world evidence on this rare disease and its orphan drugs.

Global incidence and prevalence of differentiated thyroid cancer in childhood: systematic review and meta-analysis.

Objective: Differentiated thyroid cancer (DTC) is rare in childhood and adolescence although it represents the most frequent endocrine malignancy in this population. DTC includes both papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC). Most pediatric DTCs are PTCs, while FTCs are rare. To date, no systematic reviews on the global epidemiology of pediatric and adolescent DTC have been published. This systematic review and meta-analysis aims to estimate the overall incidence and prevalence of DTCs in patients aged 0-19 years. Methods: The systematic research was conducted from January 2000 to December 2021 through MEDLINE via PubMed, Cochrane Library, and Embase databases. Two separate meta-analyses were performed for PTC and FTC. Results: After the selection phase, a total of 15 studies (3,332 screened) met the inclusion criteria and are reported in the present systematic review. Five studies were conducted in Europe, five in North America, two in South America, one in Asia, one reported data for 49 countries and territories across the five continents, and one from both the USA and Africa. Most of the studies (n = 14) reported data obtained from national registries, and only one provided information collected from hospital medical records. Beyond the actual trend over time, our study reported a pooled global incidence rate (IR) of PTC and FTC in the pediatric age of 0.46 (95% CI: 0.33-0.59) and 0.07 (95% CI: 0.02-0.12) per 100,000 person-years, respectively. The highest IRs were recorded among Caucasian girls, and the lowest in black or other races/ethnicities. Conclusion: Our data confirm that DTC in the pediatric population is a rare condition. The pooled IRs of the studies included in this meta-analysis are ~0.5 for PTC, which is the most common histological type when both genders and all age groups are considered. The implementation of a prospective international registry on pediatric DTC, as part of the wider European Registries for Rare Endocrine Conditions, has been recently proposed. In addition to providing relevant information on the clinical behavior of this rare disease, standardization of data collection will be pivotal to fill current gaps and allow an accurate estimation of the real incidence and risk factors of DTC.

Anaphylaxis due to antiallergic and antiasthmatic biologics.

PURPOSE OF REVIEW: To provide a better understanding of the risk of anaphylaxis due to antiallergic and antiasthmatic biologics through an analysis of data reported in literature and in clinical trials, and by conducting a retrospective descriptive analysis of individual case safety reports on VigiBase, the WHO International Pharmacovigilance database. RECENT FINDINGS: Analysis of the data, as described, demonstrated safety of the antiallergic and antiasthmatic biologics with a low incidence of anaphylaxis. SUMMARY: Biologic therapies have revolutionized the treatment of many diseases, such as atopic dermatitis, nasal polyps, spontaneous chronic urticarial and severe asthma with a precise immunological action, in the sphere of precision medicine.Albeit these drugs are generally well tolerated, generating real-world evidence is crucial to re-evaluate clinically relevant adverse events, such as anaphylaxis, allowing to confirm their safety profile in particular in special populations such as paediatric patients.

Suspected adverse reactions to medications and food supplements containing Serenoa repens: A worldwide analysis of pharmacovigilance and phytovigilance spontaneous reports.

The safety of Serenoa repens (SR)-containing products was evaluated conducting a retrospective worldwide analysis of pharmaco- and phytovigilance report forms of suspected adverse reactions (SARs) collected up to 31 January 2022. Multivariate logistic regression was performed to estimate the odds ratios (ORs) of serious SAR. A total of 1810 report forms were analysed; 92% of subjects were males, with a median age of 69 years; 44% of cases were defined as serious. Subjects exposed to dietary supplements had a higher risk of developing serious SARs (OR: 1.60 [95% CI: 1.20-2.15]), as subjects exposed to 2-5 (OR: 1. 83 [95% CI: 1.30-2.58]) or more than 5 (OR: 3.45 [95% CI: 2.36-5.06]) suspect/interacting products. The probability of experiencing serious SAR was higher for subjects exposed to concomitant products (OR: 1.55 [95% CI: 1.15-2.08]), to more than four active compounds (OR: 4.38 [95% CI: 3.21-5.99]) and to SR for more than 14 days (OR: 1.89 [95% CI: 1.10-3, 22]), and lower for subjects exposed to higher doses of SR (OR: of 0.34 [95% CI: 0.20-0.58]). This evidence improves awareness on safety of SR containing products, suggesting the need of a further update of periodic reviews by national and international regulatory agencies.

Hidradenitis suppurativa and psoriasis: the odd couple.

Psoriasis and hidradenitis suppurativa are chronic inflammatory skin diseases that can develop together, negatively impacting on the patient's quality of life. We aimed to review the most up-to-date information regarding the epidemiology, pathogenesis, clinical presentation and possible therapeutical choices in patients with both psoriasis and hidradenitis suppurativa, thus linking these two autoimmune and autoinflammatory conditions. A narrative review of articles dating from 2017 to 2022 has been performed using the PubMed database. We analyzed the case reports and case series found in the literature regarding patients who suffered from both psoriasis and HS. Psoriasis arose before hidradenitis suppurativa in the majority of cases, while only a minority of them had hidradenitis suppurativa before psoriasis. Interestingly, some patients suffered from paradoxical hidradenitis suppurativa following biological therapy administered to treat the already present psoriasis. Lastly, new biological drugs have been marketed with great success for the outcome of psoriasis, but similar progress did not happen for hidradenitis. Novel therapeutic approaches and lines of research are needed for the treatment of these pathologies, even if concomitant, in order to improve patient's quality of life.

Exploring the Use of Monoclonal Antibodies and Antiviral Therapies for Early Treatment of COVID-19 Outpatients in a Real-World Setting: A Nationwide Study from England and Italy.

BACKGROUND: Real-world data on early treatment of coronavirus disease 2019 (COVID-19) outpatients with newly approved therapies are sparse. AIM: To explore the pattern of use of monoclonal antibodies (mAbs)/antiviral therapies approved for early COVID-19 treatment in non-hospitalized patients from England and Italy from December 2021 to October 2022. METHODS: Public national dashboards on weekly mAb/antiviral use and/or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection diagnoses from the Italian Medicines Agency, the Italian National Institute of Health, National Health Service in England and the UK Government were explored. Prevalence of antiviral use in outpatients during the entire study period and every two weeks was calculated, as a whole and by class and compounds. An interrupted time-series (ITS) analysis was carried out to assess the impact of predominant SARS-CoV-2 variants over time on the prevalence of use of mAbs/antivirals in England and Italy. RESULTS: Overall, 77,469 and 195,604 doses of mAbs/antivirals were respectively administered to a total of 10,630,903 (7.3 per 1000) and 18,168,365 (10.8 per 1000) patients diagnosed with SARS-CoV-2 infection in England and Italy. Prevalence of use every two weeks increased from 0.07% to 3.1% in England and 0.9% to 2.3% in Italy during the study period. Regarding individual compounds, sotrovimab (prevalence of use, 1.6%) and nirmatrelvir/ritonavir (1.6%) in England, and nirmatrelvir/ritonavir (1.7%) and molnupiravir (0.5%) in Italy, reported the highest prevalence during a 2-week period. In the ITS analysis, the transition from Delta to Omicron variant predominance was associated with a significant increase in the use of sotrovimab, molnupiravir, remdesivir and nirmatrelvir/ritonavir in both England and Italy, with a reduction of other marketed mAbs. The extent of the increase was higher in England than in Italy for all these drugs except for nirmatrelvir/ritonavir. CONCLUSIONS: In this dual nationwide study, the prevalence of use of mAbs/antivirals against SARS-CoV-2 for early outpatients' treatment increased slowly up to 2.0-3.0% of all patients diagnosed with SARS-CoV-2 infection in both England and Italy from December 2021 to October 2022. The trend of individual drug use varied in relation to predominant SARS-CoV-2 variants with some differences across countries. In line with scientific societies' guidelines, nirmatrelvir/ritonavir was the most frequently prescribed antiviral in both countries in the most recent period.

An overview of methodological flaws of real-world studies investigating drug safety in the post-marketing setting.

INTRODUCTION: The evaluation of the post-marketing safety profile of drugs is a continuous monitoring process for approved and marketed medicines and it is crucial for detecting new adverse drug reactions. As such, real-world studies are essential to complement pre-marketing evidence with information concerning drug risk-benefit profile and use in wider patient populations and they have a great potential to support post-marketing drug safety evaluations. AREAS COVERED: A detailed description of the main limitations of real-world data sources (i.e. claims databases, electronic healthcare records, drug/disease registers and spontaneous reporting system databases) and of the main methodological challenges of real-world studies in generating real-world evidence is provided. EXPERT OPINION: Real-world evidence biases can be ascribed to both the methodological approach and the specific limitations of the different real-world data sources used to carry out the study. As such, it is crucial to characterize the quality of real-world data, by establishing guidelines and best practices for the assessment of data fitness for purpose. On the other hand, it is important that real-world studies are conducted using a rigorous methodology, aimed at minimizing the risk of bias.