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Background: Psoriatic arthritis (PsA) is a common comorbidity in patients with psoriasis (PsO) that leads to significant disease burden. Biologic therapies targeting the interleukin (IL)-23/IL-17 axis have been widely used for PsO, but their comparative effectiveness in preventing PsA remains unclear.

Objective: The study objective was to compare the occurrence of developing incidental PsA among PsO patients treated with interleukin-23 inhibitors (IL23is) or interleukin-17 inhibitors (IL17is).

Methods: A retrospective cohort study was conducted using real-world data from the TriNetX US Collaborative Network, including 53 healthcare organizations. Adult PsO patients treated with IL23is or IL17is between January 2019 and June 2022 were identified. Cox regression analysis was used to assess the risk of PsA incidence, with hazard ratios (HRs) and 95% confidence intervals (CIs) reported. Subgroup analyses were performed based on age, sex, and ethnicity. Sensitivity analyses included comparisons with tumor necrosis factor (TNF) inhibitors (TNFis) to ensure robustness.

Results: A total of 4,580 PsO patients were included in the study, with 2,273 receiving IL23is and 2,307 receiving IL17is. Treatment with IL23is was associated with a significantly lower incidence of PsA compared to IL17is (HR = 0.60, 95% CI 0.44-0.82, P = 0.001). This reduction in risk was particularly notable in the 41- to 65-year age group (HR = 0.42, 95% CI 0.27-0.64, P < 0.001) and among females (HR = 0.57, 95% CI 0.38-0.86, P = 0.007). Subgroup analyses based on ethnicity revealed varying outcomes, with White patients showing a significant risk reduction (HR = 0.55, 95% CI 0.38-0.79, P = 0.001) but no significant risk reduction was observed in Black or African American patients (HR = 1.37, 95% CI 0.37-5.13, P = 0.637). Sensitivity analyses comparing IL23is and TNFis confirmed the robustness of the findings.

Conclusion: IL23is are associated with a lower risk of PsA incidence compared to IL17is in PsO patients, particularly in specific age, sex, and ethnic groups. These findings suggest that IL23is may be more suitable for PsO patients at high risk of PsA and could inform potential updates to treatment guidelines. Further research should focus on refining therapeutic strategies by incorporating patient-specific factors such as comorbidities, ethnicity, and genetic predispositions, which could optimize biologic selection and enhance PsA prevention efforts in clinical practice.

Background: BAT1806/BIIB800 (Tofidence™/tocilizumab-bavi), a biosimilar of tocilizumab, demonstrated a high degree of analytical and functional similarity to reference tocilizumab (TCZ) in a comprehensive comparative analytical assessment. Minor differences with respect to TCZ were observed for some attributes and this study assessed the potential impact of these differences through structure activity relationship characterization.

Methods: Structure activity relationship studies were conducted to assess glycation, glycosylation, charge variants, hydrophobicity, oxidation, and deamidation differences, using a range of investigative techniques. Structure activity relationship studies were performed on one lot each of BAT1806/BIIB800 and TCZ (European Union sourced only) except for glycation, where additional lots sourced from China and the USA were used.

Results: Average total glycated protein content of BAT1806/BIIB800 was higher than TCZ (10.08% vs 1.19%); however, biological activity, including target binding and functional potency, was unaffected. Stress-induced glycation of BAT1806/BIIB800 and TCZ also did not affect the biological activity of the products despite up to 60% total glycation content. Minor differences were observed between BAT1806/BIIB800 and TCZ in glycosylation, charge variants, hydrophobicity, oxidation, and deamidation without a relevant impact on interleukin-6 receptor binding, Fc-receptor binding, and effector functions. In forced degradation studies, oxidation and deamidation trends were comparable between the two products.

Conclusions: Comparative structure activity relationship characterization of BAT1806/BIIB800 and TCZ indicated that there are no relevant differences in quality attributes between BAT1806/BIIB800 and reference TCZ. Observed differences between BAT1806/BIIB800 and TCZ had no functional impact on BAT1806/BIIB800. The results support the conclusion that BAT1806/BIIB800 is similar to TCZ.

Liver cancer poses a global health challenge with limited therapeutic options. Notably, the limited success of current therapies in patients with primary liver cancers (PLCs) may be attributed to the high heterogeneity of both hepatocellular carcinoma (HCCs) and intrahepatic cholangiocarcinoma (iCCAs). This heterogeneity evolves over time as tumor-initiating stem cells, or cancer stem cells (CSCs), undergo (epi)genetic alterations or encounter microenvironmental changes within the tumor microenvironment. These modifications enable CSCs to exhibit plasticity, differentiating into various resistant tumor cell types. Addressing this challenge requires urgent efforts to develop personalized treatments guided by biomarkers, with a specific focus on targeting CSCs. The lack of effective precision treatments for PLCs is partly due to the scarcity of ex vivo preclinical models that accurately capture the complexity of CSC-related tumors and can predict therapeutic responses. Fortunately, recent advancements in the establishment of patient-derived liver cancer cell lines and organoids have opened new avenues for precision medicine research. Notably, patient-derived organoid (PDO) cultures have demonstrated self-assembly and self-renewal capabilities, retaining essential characteristics of their respective in vivo tissues, including both inter- and intratumoral heterogeneities. The emergence of PDOs derived from PLCs serves as patient avatars, enabling preclinical investigations for patient stratification, screening of anticancer drugs, efficacy testing, and thereby advancing the field of precision medicine. This review offers a comprehensive summary of the advancements in constructing PLC-derived PDO models. Emphasis is placed on the role of CSCs, which not only contribute significantly to the establishment of PDO cultures but also faithfully capture tumor heterogeneity and the ensuing development of therapy resistance. The exploration of PDOs' benefits in personalized medicine research is undertaken, including a discussion of their limitations, particularly in terms of culture conditions, reproducibility, and scalability.

Immunotherapy with checkpoint inhibitors has become the cornerstone of systemic treatment for non-oncogene addicted non-small-cell lung cancer. Despite its pivotal role, a significant proportion of patients-approximately 70-85%-either exhibit primary resistance to PD-1 blockade or develop acquired resistance following an initial benefit, even in combination with chemotherapy and/or anti-CTLA-4 agents. The phenomenon of primary and acquired resistance to immunotherapy represents a critical clinical challenge, largely based on our incomplete understanding of the mechanisms of action of immunotherapy, and the resulting lack of accurate predictive biomarkers. Here, we review the definitions and explore the proposed mechanisms of primary and acquired resistance, including those related to the tumor microenvironment, systemic factors, and intrinsic tumor characteristics. We also discuss translational data on adaptive changes within tumor cells and the immune infiltrate following exposure to checkpoint inhibitors. Lastly, we offer a comprehensive overview of current and emerging therapeutic strategies designed to prevent primary resistance and counteract acquired resistance.

Background: Glucagon-like peptide 1 receptor agonists have shown promising results in obesity treatment. In France, semaglutide 2.4-mg (Wegovy) has benefited from an early-access program from July 2022 to September 2023.

Objective: This study aimed to describe the user profile of semaglutide 2.4-mg and the dosage patterns under real-world conditions during this period.

Methods: Between July 2022 and September 2023, semaglutide 2.4-mg initiators were identified through the nationwide APMO database (Accès Précoce-Médicaments Onéreux), built from the French National Health Data System (SNDS). The cohort was followed up until 31 December 2023. A sequence analysis was used to build clusters of dose escalation regimens.

Results: Among the 6990 adult patients who started treatment, the median age was 49.0 years, with a majority of women (65.8%). The study revealed significant regional variations in initiation rates, with the highest in Ile-de-France (including Paris). Three groups of users were identified: standard adherence (74.5%), early discontinuation (13.0%), and high-dose initiation (12.5%). Factors influencing these clusters included age, with younger patients (25-34 years) more likely to discontinue early (odds ratio: 1.35 [95% confidence interval 1.05-1.75]). The use of anti-emetics during the first 5 months of the follow-up period was higher in the early-discontinuation group (15.7%) compared with the high-dose initiation group (9.0%) and standard adherence group (12.3%).

Conclusions: This study involved a substantial number of real-life semaglutide 2.4-mg users and highlights the importance of monitoring treated patients from a public health perspective, given the broad prescription to come and the potential risks associated with misuse.

Myasthenia gravis (MG) is a rare autoimmune disease characterised by exertion-induced muscle weakness that can lead to potentially life-threatening myasthenic crises. Detectable antibodies are directed against specific postsynaptic structures of the neuromuscular junction. MG is a chronic condition that can be improved through therapies, but to date, not cured. Standard treatment has been unchanged for decades and includes symptomatic treatment with acetylcholine-esterase inhibitors and disease-modifying treatment with steroids, steroid-sparing immunosuppressants and thymectomy. Overall, a relevant proportion of patients does not achieve a satisfactory clinical improvement under standard treatment. Additionally, long-term therapy with steroids can cause significant side effects and latency to clinical improvement with standard steroid-sparing immunosuppressants and after thymectomy can take months to years. In recent years, treatment of MG has changed fundamentally due to improved evidence from phase 3 trials and the regulatory approval of complement inhibitors and FcRn inhibitors as add-on treatment options. This provides new optimism for substantially more patients reaching minimal manifestation status and has led to a shift in treatment strategy with more targeted therapies being employed early in the course of the disease, especially in patients with high disease activity. In this focussed review, we provide an overview of the diagnosis, classification and standard treatment of MG, followed by data from randomised controlled trials on the modern drugs already available for therapy and those still in the final stages of clinical development. In the second part, we provide an overview of real-world data for already approved therapies and outline how the availability of new biologicals is changing both clinical decision-making and patient journey.

Background: With the expiration of patents for multiple biotherapeutics, biosimilars are gaining traction globally as cost-effective alternatives to the original products. Glycosylation, a critical quality attribute, makes glycosimilarity assessment pivotal for biosimilar development. Given the complexity of glycoanalytical profiles, assessing glycosimilarity is nontrivial.

Objective: This study proposes a Python-based automated tool for rapid estimation of glycosimilarity index (GI).

Materials and methods: A comprehensive analytical glycosimilarity comparison of the trastuzumab originator product, Herclon (Roche), with five marketed biosimilars:Trasturel (Reliance Life Sciences), Canmab (Biocon), Vivitra (Zydus Ingenia), Hertraz (Mylan), and Biceltis (Cipla), has been performed. Similarly, a comparison between the bevacizumab originator product, Avastin (Roche), and its five biosimilars: Abevmy (Mylan), Krabeva (Biocon), Ivzumab (RPG LifeSciences), Bryxta (Zydus), and Advamab (Alkem Labs), is presented. Glycan profile  has been assessed using liquid chromatography-fluorescence detection, and the  data have been integrated using the XGBoost-machine learning algorithm to quantify glycan composition. The GI has been calculated by combining profile similarity and compositional similarity, estimated on the basis of the criticality and tolerance of each glycan.

Results: The tool enabled rapid GI estimation (< 1 min/sample) with reduced errors compared with Excel (> 10 min/sample). Biosimilars exhibited high GI with several exceeding 95%, while the lowest GI observed were 87.80% for trastuzumab and 92.39% for bevacizumab.

Conclusions: The Python-based tool offers a high-throughput and a reliable platform for glycosimilarity assessment, outperforming traditional analysis. Minor variations in glycosylation patterns were observed among the biosimilars, suggesting a modest glycosimilarity variation (GI range between 80 and 100%). However, the limited number of innovator batches analyzed constrained the establishment of definitive tolerance limits. Future studies should focus on analyzing larger datasets to improve accuracy and define precise tolerance limits, enhancing the tool's reliability and its potential to accelerate biosimilar development.

Eculizumab, a humanized monoclonal antibody targeting complement C5, is the first approved drug for complement-mediated diseases and indicated to treat paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, myasthenia gravis, and neuromyelitis optica spectrum disorder. The introduction of eculizumab has improved the prognosis of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome to near-normal life expectancy and quality of life. Administration of eculizumab resulted in a rapid and sustained reduction in hemolytic activity and a consequent risk of thrombosis in paroxysmal nocturnal hemoglobinuria, and thrombotic microangiopathy in atypical hemolytic uremic syndrome, respectively. Nevertheless, many patients still have difficulty accessing eculizumab treatment because of its high costs. Biosimilars to reference eculizumab may increase patient access to treatment by creating market competition and eventually decreasing treatment costs. Clinical use of biosimilars in Europe in the last 15 years has demonstrated that they are as safe and effective as their reference products, and can also drive cost reductions and increase patients' access to treatment. This review aims to increase awareness about the importance of biosimilars of reference eculizumab and their entry for use in patients with paroxysmal nocturnal hemoglobinuria or atypical hemolytic uremic syndrome based on the accumulated experience of other previously approved biosimilars, and to provide an overview of the stringent biosimilar development pathway in general and the concept of extrapolation in particular.

Type 1 diabetes (T1D) is a chronic autoimmune disorder characterized by the destruction of insulin-producing beta cells in the pancreas, leading to insulin deficiency and chronic hyperglycemia. The main current therapeutic strategies for clinically overt T1D - primarily exogenous insulin administration combined with blood glucose monitoring - fail to fully mimic physiological insulin regulation, often resulting in suboptimal or insufficient glycemic control. Islet cell transplantation has emerged as a promising avenue for functionally replacing endogenous insulin production and achieving long-term glycemic stability. Here, we provide an overview of current islet replacement strategies, ranging from islet transplantation to stem cell-derived islet cell transplantation, and highlight emerging approaches such as immunoengineering. We examine the advancements in immunosuppressive protocols to enhance graft survival, innovative encapsulation, and immunomodulation techniques to protect transplanted islets, and the ongoing challenges in achieving durable and functional islet integration. Additionally, we discuss the latest clinical outcomes, the potential of gene editing technologies, and the emerging strategies for islet cell regeneration. This review aims to highlight the potential of these approaches to transform the management of T1D and improve the quality of life of individuals affected by this condition.

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), remains challenging to manage, with a substantial proportion of patients not responding to conventional therapies or developing complications. The tumor necrosis factor (TNF) superfamily member TL1A has emerged as an important player in the pathogenesis of IBD, influencing pathways of inflammation and fibrosis. This leading article reviews the role of TL1A in IBD, evaluates the efficacy of anti-TL1A therapies in clinical trials, and discusses future directions for research and treatment. TL1A is implicated in IBD through its interaction with death domain receptor 3 (DR3), promoting T-cell activation and contributing to both inflammatory responses and fibrotic changes. Phase 2 clinical trials of anti-TL1A agents have demonstrated promising results, showing improvements in endoscopic and histologic outcomes for both UC and CD. Phase 2 and 3 clinical trials are ongoing, which are expected to provide further clarity on the efficacy and safety of TL1A-targeting agents in treating IBD.