OBJECTIVE: Multiple treatment options are recommended for Systemic Lupus Erythematosus (SLE) by clinical guidelines. This study aimed to explore SLE treatment patterns as there is limited real-world data of SLE medication utilisation, especially in childhood-onset SLE (cSLE).
METHODS: We conducted a longitudinal cohort study using five routinely collected healthcare databases from four European countries (United Kingdom, France, Germany, and Spain). We described the characteristics of adult and paediatric patients at time of SLE diagnosis. We calculated the percentage of patients commencing SLE treatments in the first month and year after diagnosis, reported number of prescriptions, starting dose, cumulative dose, and duration of each treatment, and characterised the line of therapy.
RESULTS: We characterised 11,255 patients with a first diagnosis of SLE and included 5718 in our medication utilisation analyses. The majority of adult SLE patients were female (range 80-88 %), with median age of 49 to 54 years at diagnosis. In the paediatric cohort (n = 378), 66-83 % of SLE patients were female, with median age of 12 to 16 years at diagnosis. Hydroxychloroquine and glucocorticoids were common first-line treatments in both adults and children, with second-line treatments including mycophenolate mofetil and methotrexate. Few cases of monoclonal antibody use were seen in either cohort. Initial glucocorticoid dosing in paediatric patients was often higher than in adults.
CONCLUSIONS: Treatment choices for adult SLE patients across four European countries were in line with recent therapeutic consensus guidelines. High glucocorticoid prescriptions in paediatric patients suggests the need for steroid-sparing treatment alternatives and paediatric specific guidelines.

UNASSIGNED: Respiratory syncytial virus (RSV) causes severe lower respiratory tract infections (LRTI) in infants and adults. While the clinical burden was recently estimated in adults in Germany, little is known about the economic burden yet. To fill this gap, we aimed to assess hospital and outpatient healthcare resource utilization (HRU) and costs of RSV infections in adults in Germany.
UNASSIGNED: In this retrospective, observational study on nationwide, representative, anonymized claims data (2015-2018), we identified patients ≥18 years with ICD-10-GM-codes specific to RSV (\'RSV-specific\'). To increase sensitivity, patients with unspecified LRTIs (including unspecified bronchitis, bronchiolitis, bronchopneumonia, and pneumonia) during RSV seasons were also included as cases potentially caused by RSV (\'RSV-possible\'). RSV-related HRU (hospital days, ICU and ventilation treatment, drug dispensation) and direct costs were estimated per episode. Excess costs per episode and for follow-up periods were compared to a matched control cohort. All outcomes were reported per healthcare sector and stratified by age and risk groups as well as disease severity (ICU admission/ventilation).
UNASSIGNED: Direct inpatient and outpatient mean episode costs were 3,473€and 82€, respectively, with substantially higher costs for severe cases requiring intensive care and/or ventilation (10,801€). Direct costs for RSV-specific cases were higher than for RSV-possible cases (inpatients: 6,247€vs. 3,450€; outpatients: 127€vs. 82€). Moreover, costs were significantly higher for RSV patients than for controls and increased over time (inpatients: 5,140€per episode vs 10,093€per year; outpatients: 46€per quarter vs 114€per year).
UNASSIGNED: While the number of RSV-specific cases was low, inclusion of seasonal LRTI cases likely increased the sensitivity to detect RSV cases and allowed a better estimation total costs of RSV.
UNASSIGNED: The economic burden of RSV-LRTI in adults in Germany is substantial, persists long-term and is particularly high in the elderly. This highlights the need for cost-effective prevention measures.

BACKGROUND: Allergen immunotherapy is the only modifying treatment of the natural course of respiratory allergic diseases; however, the lack of evidence leads to little inconclusive results. Real life studies are on the rise and are becoming a valuable tool to confirm and complement findings from clinical trials. The objective of this study was to evaluate the effectiveness and safety of a depigmented-polymerized undiluted subcutaneous extract of grass and olive pollen, under routine clinical practice conditions.
METHODS: This was an observational, retrospective, longitudinal, single-center study on the use of a 2-pollen (grass mix and Olea europaea) undiluted subcutaneous extract over at least 3 consecutive years. Data were collected from 76 patients (n = 44 female; median age: 12.5 years old) diagnosed with allergic rhinoconjunctivitis with/without allergic asthma due to sensitization to both grasses and O. europaea. Primary and secondary effectiveness endpoints were symptom severity, concomitant medication, and immunological profile before and after completing the immunotherapy. A 2-year follow-up of patients\' symptoms and medication history after completing the subcutaneous immunotherapy (SCIT) was performed.
RESULTS: There was a significant improvement of symptoms and medication consumption after 3 years of SCIT treatment, and a significant decrease in specific IgE levels for grasses and O. europaea was observed after finishing the treatment.
CONCLUSIONS: Three years treatment of allergic patients using an undiluted mixture of two allergen extracts was shown to be safe and effective for rhinitis and asthma, with efficacy maintained for at least 2 years after finishing SCIT. These results reinforce the importance of real life clinical data in addition to those from clinical trials, helping to individualize allergic treatments.

BACKGROUND: Clinical development for orphan drugs presents significant difficulties and challenges. There is no unique or standard design, conduct, and outcome assessment methodology and it is sometimes impractical to fit design models of rare disease trials in any practiced and well-known framework. In the European Union (EU) these challenges encompass a broad array of subjects, including trial design, study outcomes, patient recruitment, trial conduct ethics, trial cost, and chances of success. This literature-based review study aims to provide a thorough overview of the critical aspects of rare disease trials in the EU by analyzing the current landscape of rare disease trials, highlighting key challenges, delving into regulatory and research initiatives and innovation in trial designs, and proposing multi-faceted solutions to implement effective rare disease clinical trials in the region.
CONCLUSIONS: Traditional clinical trial designs, validation, and evaluation methodologies used for nonorphan drugs often prove unsuitable for orphan drugs, given the small patient populations, sometimes fewer than 1000 cases. There is an increasing need for accessible therapies and both regulators as well as industry are trying to develop affordable and effective drugs to address this need. Despite several steps that have been taken, the timely development of drugs remains a challenge. One of the reasons behind the long development timeline is the recruitment, retention, and conduct of rare disease trials. To optimize the development timelines of orphan drugs in the EU, it is important to ensure that the safety and efficacy of the product is not compromised. Industry and regulatory agencies must implement innovative trial designs, devise flexible policies, and incorporate real-world data for assessing clinical outcomes.
CONCLUSIONS: Collaboration among academic institutions, pharmaceutical companies (both small and major), patient groups, and health authorities is crucial in overcoming obstacles related to clinical trials and providing assistance and creative ideas. The ultimate objective of granting rare disease patients timely and affordable access to medications with a positive balance between benefits and risks is to be met.

OBJECTIVE: The FreeStyle Libre (FSL) intermittently scanned continuous glucose monitoring (isCGM) system continually measures interstitial glucose levels and provides the data to users in numerical and graphical formats that guide users in their daily diabetes self-management. Although numerous studies have demonstrated the glycemic benefits of FSL in pediatric and adult populations, few studies have characterized FSL use specifically by Japanese adults with type 1 or 2 diabetes. We utilized established CGM metrics to assess glycemic control in a large cohort of Japanese adults with type 1 and 2 diabetes.
METHODS: A total of 3,463 anonymized FSL users provided categorization into one of four therapy groups of interest: type 1 diabetes (n = 1,768), type 2 diabetes-multiple daily injections (MDI) (n = 612), type 2 diabetes-basal (BOI) (n = 343), and type 2 diabetes-non-insulin (NIT) (n = 740). Established CGM metrics were used to assess glycemic control.
RESULTS: All study groups showed relatively good glycemic control. Type 1 diabetes users showed the highest glucose variability (SD, 61 mg/dL; and %CV, 40%), above the established target level (%CV ≤ 36%). type 2 diabetes-MDI and type 2 diabetes-BOI users had similar levels of glucose variability (both within target). Type 2 diabetes-NIT users had the highest mean % time in range (TIR) (84.3%) and largest percentage of users that met the target of %TIR > 70% (87.4%). In contrast, type 1 diabetes users had the lowest mean %TIR (62.6%) and the lowest percentage meeting the established %TIR target (30.5%).
CONCLUSIONS: By utilizing CGM devices in daily diabetes care, both healthcare professionals and patients can monitor glycemic excursions and gain insights into their historical glucose control patterns.

The efficacy of pembrolizumab in the treatment-naïve non-small-cell lung cancer (NSCLC) patients was proved in the KEYNOTE-024 randomized trial. The aim of this systematic literature review was to identify and summarize the real world evidence (RWE) of overall survival (OS) in previously untreated patients with NSCLC receiving pembrolizumab monotherapy. A systematic search was conducted in PubMed (MEDLINE®) and EMBASE databases. Analyses were focused on survival data (median OS and survival rates at specific time points). To explore the population comparable with the KEYNOTE-024 study, we focused on studies enrolling at least 50% of patients at stage IV of cancer and ECOG performance status 0-2. A total of 41 RWE studies covering over 7600 advanced NSCLC patients naïve to systemic treatment were identified. Overall, survival outcomes reported in those studies vary considerably (median OS range: 3.0-34.6 months). Most RWE studies reported median OS shorter to that reported in KEYNOTE-024 (26.3 months), but about half of reported OS medians were in range of 95% confidence interval for OS as reported in KEYNOTE-024 trial (18.3-40.4 months). Patients with similar characteristics of stage and performance status to those of KEYNOTE-024 trial benefited the same with pembrolizumab monotherapy as their survival outcomes (18.9-22.8 months) were consistent with those reported in the clinical trial. RWE data showed substantially worse outcomes in patients with ECOG-PS 2+ compared to ECOG-PS 0-1 patients.

UNASSIGNED: Randomized clinical trials (RCTs) represent the mainstay for the approval of new treatments. However, stringent inclusion criteria often cause them to depart from the daily clinical practice. Real-world (RW) evidence have a complementing role, filling the gap between the efficacy of a treatment and its effectiveness. Immune checkpoint inhibitors (ICIs) have changed the treatment scenario for non-small cell lung cancer (NSCLC); immune-related adverse events (irAEs) could become life-threatening events, when not timely managed. We performed a systematic review and meta-analysis on the RW impact of irAEs through the years.
UNASSIGNED: The systematic review focused on irAEs occurred in locally advanced or metastatic NSCLC patients, treated with ICIs in a RW setting. We queried two electronic databases (Embase and Medline) from 1996 to August 2022. We then conducted a meta-analysis dividing the results in two cohorts (2015-2018 and 2019-2021). We described the prevalence of patients with irAEs of any or severe grade (G). Estimates were expressed as proportions up to the second decimal point (effect size, ES). IrAEs of interest were those involving the skin, the liver, the endocrine system or the gastro-intestinal system.
UNASSIGNED: Overall, 21 RW studies on 5,439 patients were included in the quantitative and qualitative synthesis. The prevalence of G≥3 irAEs was slightly lower in the 2015-2018 subgroup, while the prevalence of irAEs of any grade was similar for both periods. Overall, we observed a higher ES for gastrointestinal, hepatic and lung irAEs, while a lower ES was reported for skin or endocrine irAEs. Endocrine irAEs were reported in 10 out of 21 studies, with a slight increase in the most recent studies, while cutaneous toxicities were mostly reported in two studies lead within the first time-period. Pulmonary, gastrointestinal, and hepatic toxicities, showed a more heterogeneous distribution of ES over time.
UNASSIGNED: Our findings showed that the frequency of irAEs remained stable across the two calendar periods examined in our meta-analysis. This finding suggests that RW data might not be able to identify a potential learning curve in detection and management of irAEs.

Fabry disease is a progressive, X-linked lysosomal disorder caused by reduced or absent α-galactosidase A activity due to GLA variants. The effects of migalastat were examined in a cohort of 125 Fabry patients with migalastat-amenable GLA variants in the followME Pathfinders registry (EUPAS20599), an ongoing, prospective, patient-focused registry evaluating outcomes for current Fabry disease treatments. We report annualised estimated glomerular filtration rate (eGFR) and Fabry-associated clinical events (FACEs) in a cohort of patients who had received ≥3 years of migalastat treatment in a real-world setting. As of August 2022, 125 patients (60% male) had a mean migalastat exposure of 3.9 years. At enrolment, median age was 58 years (males, 57; females, 60) with a mean eGFR of 83.7 mL/min/1.73 m2 (n = 122; males, 83.7; females, 83.8) and a median left ventricular mass index of 115.1 g/m2 (n = 61; males, 131.2; females, 98.0). Mean (95% confidence interval) eGFR annualised rate of change in the overall cohort (n = 116) was -0.9 (-10.8, 9.9) mL/min/1.73 m2/year with a similar rate of change observed across patients with varying levels of kidney function at enrolment. Despite population age and baseline morbidity, 80% of patients did not experience a FACE during the mean 3.9 years of migalastat exposure. The incidence of renal, cardiac, and cerebrovascular events was 2.0, 83.2, and 4.1 events per 1000 patient-years, respectively. These data support a role of migalastat in preserving renal function and multisystem effectiveness during ≥3 years of migalastat treatment in this real-world Fabry population.

OBJECTIVE: To assess the evolution of the COVID-19 pandemic in Brazil and its macro-regions, considering disease incidence and mortality rates, as well as identifying territories with still rising disease indices and evaluating vaccine coverage and population adherence to COVID-19 immunization.
METHODS: An ecological study conducted in Brazil with COVID-19 cases and deaths reported between February 2020 and April 2024, obtained through the Coronavirus Panel. Historical series were constructed from incidence and mortality rates to assess the pandemic\'s evolution, and temporal trends were estimated using the Seasonal Trend Decomposition using Loess (STL) method. The Spatial Variation in Temporal Trends (SVTT) technique was employed to identify clusters with significant variations in temporal trends. Vaccination was analyzed considering the percentage of vaccinated and unvaccinated population in each municipality of the country.
RESULTS: Brazil recorded a total of 38,795,966 cases and 712,038 deaths from COVID-19 during the study period. Incidence and mortality rates showed three waves of the disease, with a fourth wave of smaller amplitude. Four clusters with significant case growth and two with increased deaths were identified. Vaccine coverage varied among municipalities, with some regions showing low vaccination rates and others with high immunization adherence.
CONCLUSIONS: The study provided a comprehensive overview of coronavirus behavior in Brazil, and its results highlight the ongoing importance of vaccination and the need to direct efforts and resources to areas of higher risk.

Over the past two decades, diabetes pharmacopoeia has flourished, with new drugs that, on top of their glucose-lowering efficacy, have been shown to protect the heart and the kidney. Despite these new opportunities, metformin retains a pivotal role among glucose-lowering agents. As one of the few available insulin sensitizers, metformin is an effective, safe, and overall well-tolerated drug backed by over 60 years of clinical experience, including evidence for potential benefits beyond glucose reduction across different ages, sexes, genetic backgrounds, geographical areas, and stages of disease. Although there is some discussion of whether metformin offers the most effective front-line option in newly diagnosed type 2 diabetes (T2D), it remains a natural companion to all other glucose-lowering agents. Furthermore, metformin comes at a very low cost and, as such, it has extremely high cost-effectiveness, particularly given the serious economic burden associated with diabetes complications. This financial advantage is particularly relevant in resource-constrained healthcare systems, where the affordability of metformin may be instrumental in implementing an effective treatment in an evergrowing number of individuals. We present here compelling real-world evidence in support of the clinical efficacy and cost-effectiveness of metformin across different patient populations, highlighting areas where more population-based studies are needed to further incorporate and consolidate its use in the pharmacological management of T2D.