Recommendations on TNFα inhibitor biosimilar use in clinical practice: a comparison of European gastroenterology IBD guidance

Background: Professional associations publish guidance advising gastroenterologists on prescribing biosimilars; however, guidelines differ between countries and change over time. This study aimed to map the presence and content of guidance from European gastroenterology associations on TNFα inhibitor biosimilar use and its development over time. Research design and methods: Guidelines on biosimilar prescribing from national gastroenterology associations in the European Economic Area (EEA) partnered with the European Crohn’s and Colitis Organization (ECCO) were collected. Treatment guidelines and biosimilar position papers from 2010 to 2022 were included. Data were extracted using a template. Results: 26 of 30 EEA countries have an ECCO-partnered gastroenterology association, of which 14 (53.8%) had national guidelines addressing biosimilars, four (15.4%) followed ECCO’s position, and three (11.6%) had treatment guidelines without mentioning biosimilars. From five countries (19.2%) no guidelines were retrieved. Among 18 countries with guidance, 14 (77.8%) associations endorsed initiating biological treatment with biosimilars, and 13 (72.2%) endorsed transitioning from originator to biosimilar. Nine associations published multiple guidelines over time addressing biosimilars; overall, their positions became more encouraging. Conclusions: The majority of gastroenterology associations endorsed biosimilar use. The lack of (up-to-date) guidelines for some associations indicates an area of improvement to support biosimilar use in clinical practice

Liquid demixing of intrinsically disordered proteins is seeded by poly(ADP-ribose)

Intrinsically disordered proteins can phase separate from the soluble intracellular space, and tend to aggregate under pathological conditions. The physiological functions and molecular triggers of liquid demixing by phase separation are not well understood. Here we show in vitro and in vivo that the nucleic acid-mimicking biopolymer poly(ADP-ribose) (PAR) nucleates intracellular liquid demixing. PAR levels are markedly induced at sites of DNA damage, and we provide evidence that PAR-seeded liquid demixing results in rapid, yet transient and fully reversible assembly of various intrinsically disordered proteins at DNA break sites. Demixing, which relies on electrostatic interactions between positively charged RGG repeats and negatively charged PAR, is amplified by aggregation-prone prion-like domains, and orchestrates the earliest cellular responses to DNA breakage. We propose that PAR-seeded liquid demixing is a general mechanism to dynamically reorganize the soluble nuclear space with implications for pathological protein aggregation caused by derailed phase separation