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Aim: Over recent years, therapy options and strategies for type 2 diabetes mellitus (T2DM) have developed substantially. This study investigated glucose-lowering treatment in patients with high cardiovascular risk over three decades., Materials and Methods: A total of 2158 patients undergoing elective coronary angiography at a tertiary care hospital in Europe were included in three sequential observational studies (OS): OS1 (1999-2000; n = 672), OS2 (2005-2008; n = 1005) and OS3 (2022-2023; n = 481). Sociodemographic data, patient-reported medication, medical histories and blood samples were analysed., Results: A clear trend towards more complex glucose-lowering therapies was found. A wider array of glucose-lowering drugs was used over time (OS1: 11; OS2: 21; OS3: 25) and the number of different drugs used in combination therapy in a single patient increased to a maximum of five in OS3. Furthermore, substantial differences in applied medication regimens were observed: Sodium-glucose cotransporter-2 inhibitors were the most frequently reported substance class (34.0% of total reported glucose-lowering drugs) in OS3, whilst metformin remained a key component (OS1: 33.9%; OS2: 41.8%; OS3: 32.0%). Other drug classes like sulfonylureas were largely replaced. A total of 69.2% of patients in OS3 achieved an HbA1c level of < 7% (vs. OS1: 51.9%, OS2: 54.7%; p trend < 0.001). Over 25% of patients with T2DM were newly diagnosed at admission (OS1: 43.8%, OS2: 29.7%, OS3: 27.2%; p trend  < 0.001) and had therefore no diabetes-related medication., Conclusion: These real-world data emphasize a marked shift in T2DM treatment towards novel substance classes. However, the use of incretin mimetics remained low. Significantly more patients reached HbA1c targets in the most recent cohort., (© 2024 John Wiley & Sons Ltd.)

Objective: Paediatric autoimmune liver disease (pAILD) is a rare condition with serious health implications. Notwithstanding treatment advancements, areas of uncertainty and knowledge gaps still exist. We here investigated the real-life approach to pAILD management in Europe., Methods: A survey was distributed to members of the European Rare Liver Disease Reference Network (ERN RARE-LIVER) and the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) Hepatology Interest Group. Information was gathered regarding clinical activity, medications used, and access to paediatric drug formulations at each site., Results: Thirty-six centres from 22 European countries responded to the survey. The majority are exclusively paediatric units (86%). Among participants, 80% follow <50 children with pAILD, of which 25%-50% are <10 years old in 44% of centres. All centres use predniso(lo)ne as first-line therapy, alone (15/36) or with azathioprine (21/36). Azathioprine and mycophenolate are the preferred second-line options in centres using first-line steroid monotherapy (11/15) or combined steroid-azathioprine (19/21), respectively. Tacrolimus is used as third-line agent in 15/36 centres. Proactive measurement of drug metabolites and target levels vary widely among centres. Paediatric predniso(lo)ne formulations are commercially available in 7/22 European countries, azathioprine in 3, mycophenolate in 14, tacrolimus in 15 and ursodeoxycholic acid in 14. When paediatric formulations are unavailable, children are treated with magisterial preparations or 'solid' formulations (crushed or intact)., Conclusions: Treatment of pAILD in Europe varies widely in terms of medications used and treatment monitoring. Availability of paediatric drug formulations across Europe is limited. Collaborative initiatives are needed to define evidence-based strategies for management of pAILD and to promote an equal, age-appropriate treatment for affected children., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Introduction: This study aimed to describe the clinical characteristics of patients with pulmonary arterial hypertension, treatment received, and factors predicting initial or earlier combination therapy., Methods: The Adelphi Real World Pulmonary Arterial Hypertension (PAH) Disease Specific Programme™ is a cross-sectional survey with retrospective data collection conducted in the USA, Europe (France, Germany, Italy, Spain, and the UK), and Japan from March to August 2022. Physicians reported patient characteristics, treatment history, and reasons for treatment selection. Descriptive statistics were grouped by country and World Health Organization functional classification. A multivariable Cox regression analysis investigated factors predicting initial or earlier combination therapy use., Results: Data for 1173 patients was provided by 293 physicians. Patients' mean (standard deviation) age was 58.7 (13.8) years and 54.6% were female. Overall, 91.2% of patients were receiving, or had previously received, PAH-specific treatment. About three-quarters of the cohort were still taking the initial treatment strategy: for this group, 54% were prescribed monotherapy and 32% combination therapy; 15% of patients received supportive therapy alone. The proportion of patients receiving PAH-specific treatment was lowest in the USA (82.0%) and highest in France (94.6%). The proportion of patients receiving PAH on combination therapy was lowest in the USA (23.8%) and highest in Germany (36.5%). Treatment was prescribed for PAH in 87.6%, 89.8%, 89.3%, and 75.0% of patients who were functional class I, II, III, and IV, respectively, and combination therapy usage was more likely for those with more advanced functional class. Higher risk status, care by a pulmonologist, Japanese residence, more complete assessments, and hospitalization in the past 12 months were statistically associated with decreased time to combination therapy for PAH. Older age was statistically associated with increased time to combination therapy., Conclusion: In this real-world, geographically diverse sample, monotherapy treatment was common, even among patients with advanced disease., Competing Interests: Declarations. Conflict of Interest: This study was supported by MSD through a data subscription licence. Rogier Klok and Dominik Lautsch are employees of MSD and are Merck & Co., Inc., Rahway, NJ, USA shareholders. R. James White and Carmine Dario Vizza have received consultancy payments from Merck & Co., Inc. Julia Harley, Mark Small and Megan Scott are full-time employees of Adelphi Real World, an agency which received a subscription fee for data access and analysis. Ethical Approval: The survey was submitted to the Pearl Institutional Review Board, a central institutional review board (IRB), where ethical exemption determination was granted on 02/08/23 (Pearl IRB work order #22-ADRW-131). Data collection was undertaken in line with European Pharmaceutical Marketing Research Association [22] guidelines and as such it does not require ethics committee approval. Each survey was performed in full accordance with relevant legislation at the time of data collection, including the US Health Insurance Portability and Accountability Act 1996, [23] the Declaration of Helsinki 1964 [24], and Health Information Technology for Economic and Clinical Health Act legislation [25]. A complete description of the methods of the survey has been previously published and validated [17–20]. Using a check box, patients provided informed consent for use of their anonymized and aggregated data for research and publication in scientific journals. Data were collected in such a way that patients and physicians could not be identified directly; all data were aggregated and de-identified before receipt., (© 2024. The Author(s).)

Background: Recent guidelines on acute coronary syndromes (ACS) recommend initiating lipid-lowering therapy (LLT) as early as possible to obtain >50% low-density-lipoprotein cholesterol (LDL-c) reduction and an LDL-c < 1.4 mmol/l., Methods: A multinational European survey study of ACS patients between 2021-2022 and acquired data on LLT and lipid levels on admission and during 1-year posthospitalization. We compared plasma lipid changes and adherence to post-ACS lipid targets across two in-hospital LLT groups: high-intensity statin (HIS) monotherapy (mono-HIS) and a combination of HIS and ezetimibe (combo-HIS)., Results: Of 286 patients, 268 (94%) received in-hospital HIS and were included in the final analysis. Patients (median age: 61.1 years) had a median baseline LDL-c of 3.3 mmol/l. Mono-HIS was the predominant in-hospital LLT (72.4%). In-hospital combo-HIS was administered in 27.6% of the cases. Patients from high-income countries ( n  = 141) were more likely to receive in-hospital combo-HIS than patients from middle-income countries [ n  = 127; 38.3% vs. 15.7% patients, P  < 0.001). One-year post-ACS, 50 (26.5%) patients from the mono-HIS group received ezetimibe. The target of LDL-c ≤ 55 mg/dl was reached in 85 patients (31.7%), without significant difference between study groups [mono-HIS: 56 (28.9%) and combo-HIS: 29 (39.2%) patients, P  = 0.10]. The target of >50% reduction was achieved more frequently among the combo-HIS group than in the mono-HIS group (50.0% vs. 29.9%, respectively, P  = 0.002)., Conclusion: LDL-c targets were achieved in less than half of the patients post-ACS, regardless of the LLT regimen. Combo-HIS was initiated in-hospital post-ACS in only 28% and was associated with greater LDL-c reduction compared to a staged approach of mono-HIS with up-titration at follow-up., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Bismuth quadruple therapies (BQTs) including bismuth, a proton pump inhibitor (PPI) and two antibiotics have been shown to be highly effective for treating Helicobacter pylori infection even in areas of high bacterial antibiotic resistance., Objective: To describe the time trends of use, effectiveness and safety of BQT in Europe using the European Registry on Helicobacter pylori Management (Hp-EuReg)., Design: Patients registered in the Hp-EuReg from 2013 to 2021 who had received BQT were included. The regimens prescribed, the number of eradication attempts, effectiveness, adherence and safety were analysed. The effectiveness was assessed by modified intention to treat (mITT). Time-trend and multivariate analyses were performed to determine variables that predicted treatment success., Results: Of the 49 690 patients included in the Hp-EuReg, 15 582 (31%) had received BQT. BQT use increased from 8.6% of all treatments in 2013 to 39% in 2021. Single-capsule BQT-containing bismuth, metronidazole and tetracycline-plus a PPI (single-capsule BQT, ScBQT) was the most frequent treatment mode (43%). Schemes that obtained an effectiveness above 90% were the 10-day ScBQT and 14-day BQT using tetracycline plus metronidazole, or amoxicillin plus either clarithromycin or metronidazole. Only ScBQT achieved above 90% cure rates in all the geographical areas studied. Using the ScBQT scheme, adherence, the use of standard or high-dose PPIs, 14-day prescriptions and the use of BQT as first-line treatment were significantly associated with higher mITT effectiveness., Conclusion: The use of BQT increased notably in Europe over the study period. A 10-day ScBQT was the scheme that most consistently achieved optimal effectiveness., Trial Registration Number: NCT02328131., Competing Interests: Competing interests: XC has received research grants and fees for lectures from Allergan. JPG has served as speaker, consultant and advisory member for or has received research funding from Mayoly Spindler, Allergan, Diasorin, Richen, Biocodex and Juvisé. OPN received research funding from Allergan, Mayoly Spindler, Richen, Biocodex and Juvisé. DSB served as a lecturer for Astellas, AstraZeneca, KRKA and Abbott. FM is a consultant for PHATHOM, DaVoltera and has received grants from Allergan, bioMerieux and Mobidiag. The remaining authors declare no conflict of interest., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Objectives: Cenobamate is an antiseizure medication (ASM) approved in Europe as adjunctive therapy for adults with inadequately controlled focal seizures. This post hoc analysis reports onset of efficacy and characterizes time to onset, duration, and severity of the most common treatment‐emergent adverse events (TEAEs) during cenobamate titration. Materials & Methods: Adult patients with uncontrolled focal seizures taking 1 to 3 concomitant ASMs were randomized to receive adjunctive cenobamate or placebo (double‐blind studies C013 and C017) or cenobamate (open‐label study C021). Outcome assessments included efficacy (median percentage change in seizure frequency and onset [studies C013 and C017]) and safety (onset, duration, and severity of TEAEs [all studies]). Results: Onset of efficacy was observed by Weeks 1 to 4 of titration in studies C013 and C017 which used a faster titration schedule than study CO21. In study C013, the median percentage seizure frequency reduction was 36.7% in patients receiving cenobamate versus 16.3% in those taking placebo (p =.002); in study C017, significant differences in seizure frequency emerged in Week 1 and continued throughout titration between all cenobamate groups and placebo (p <.001). The most commonly reported TEAEs were somnolence, dizziness, fatigue, and headache, with first onset of each reported as early as Week 1; however, the majority resolved. Conclusions: Reductions in seizure frequency occurred during titration with initial efficacy observed prior to reaching the target dose. These reductions were regarded as clinically meaningful because they may indicate early efficacy at lower doses than previously expected and had a considerable impact on patient quality of life. Long‐term treatment with adjunctive cenobamate was generally safe and well‐tolerated. [ABSTRACT FROM AUTHOR]

Aims: To assess whether implementation of the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) dyslipidaemia guidelines observed between 2020 and 2021 improved between 2021 and 2022 in the SANTORINI study., Methods and Results: Patients with high or very high cardiovascular (CV) risk were recruited across 14 European countries from March 2020 to February 2021, with 1-year prospective follow-up until May 2022. Lipid-lowering therapy (LLT) and 2019 ESC/EAS risk-based low-density lipoprotein (LDL) cholesterol (LDL-C) goal attainment (defined as <1.4 mmol/L for patients at very high CV risk and <1.8 mmol/L for patients at high CV risk) at 1-year follow-up were compared with baseline. Of 9559 patients enrolled, 9136 (2626 high risk and 6504 very high risk) had any available follow-up data, and 7210 (2033 high risk and 5173 very high risk) had baseline and follow-up LDL-C data. Lipid-lowering therapy was escalated in one-third of patients and unchanged in two-thirds. Monotherapy and combination therapy usage rose from 53.6 and 25.6% to 57.1 and 37.9%, respectively. Mean LDL-C levels decreased from 2.4 to 2.0 mmol/L. Goal attainment improved from 21.2 to 30.9%, largely driven by LLT use among those not on LLT at baseline. Goal attainment was greater with combination therapy compared with monotherapy at follow-up (39.4 vs. 25.5%)., Conclusion: Lipid-lowering therapy use and achievement of risk-based lipid goals increased over 1-year follow-up particularly when combination LLT was used. Nonetheless, most patients remained above goal; hence, strategies are needed to improve the implementation of combination LLT., Competing Interests: Conflict of interest: K.K.R. has received honoraria for consulting, lectures from Abbott Laboratories, Amgen, AstraZeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim, Cargene, CRISPR, Daiichi Sankyo, Eli Lilly Company, Emendobio, Esperion, Kowa, New Amsterdam Pharma, Novartis Corporation, Nodthera, GSK, Novo Nordisk, Pfizer, Regeneron, Sanofi, SCRIBE, Silence Therapeutics, and VAXXINITY. In addition, he has received research grant support to his institution from Amgen, Daiichi Sankyo, Sanofi, Regeneron, and Ultragenyx, plus stock options from New Amsterdam Pharma, Scribe, and Pemi 31. A.L.C. received research grant support from Amryt Pharma, Menarini, Ultragenyx, and Viatris, and lecturing fees from Amarin, Amgen, Amryt Pharma, AstraZeneca, Daiichi Sankyo, Esperion, Ionis Pharmaceutical, Medscaper, Menarini, Merck, Novartis, Peervoice, Pfizer, Recordati, Regeneron, Sandoz, Sanofi, The Corpus, Ultragenyx, and Viatris. M.A. received research grant support and lecturing fees from Alfasigma, Amgen, Amryt, Daiichi Sankyo, Ionis Pharmaceuticals/Akcea Therapeutics, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi, Sobi, Viatris, and Ultragenyx. A.B., R.C., M.L., and J.S. are employees of Daiichi Sankyo. H.T. received grant support and lecturing fees from Daiichi Sankyo and participated in an advisory board run by Daiichi Sankyo. T.S. received consulting fees from Amgen, Novartis, Orion Pharma, and Valio, and lecturing fees from Amarin, Pfizer, and GSK. He is a patient on statin and ezetimibe therapy. U.L. received grant support from Daiichi Sankyo, Novartis, and Amgen and lecturing fees from Daiichi Sankyo, Novartis, Amgen, Sanofi, Boehringer, MSD, Pfizer, Lilly, and AstraZeneca. He has also been a member of advisory boards for Daiichi Sankyo, Novartis, Amgen, Sanofi, Boehringer, and MSD, in addition to donning leadership/fiduciary roles with EAS, ESC, DGK, and DACH., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Gastric cancer (GC) is one of the most lethal malignancies worldwide. Helicobacter pylori is the primary cause of GC; therefore, its eradication reduces the risk of developing this neoplasia. There is extensive evidence regarding quadruple therapy with relevance to the European population. However, in Latin America, data are scarce. Furthermore, there is limited information about the eradication rates achieved by antibiotic schemes in European and Latin American populations., Objective: To compare the effectiveness of standard triple therapy (STT), quadruple concomitant therapy (QCT), and bismuth quadruple therapy (QBT) in six centers in Europe and Latin America., Methods: A retrospective study was carried out based on the LEGACy registry from 2017 to 2022. Data from adult patients recruited in Portugal, Spain, Chile, Mexico, and Paraguay with confirmed H. pylori infection who received eradication therapy and confirmatory tests at least 1 month apart were included. Treatment success by each scheme was compared using a mixed multilevel Poisson regression, adjusting for patient sex and age, together with country-specific variables, including prevalence of H. pylori antibiotic resistance (clarithromycin, metronidazole, and amoxicillin), and CYP2C19 polymorphisms., Results: 772 patients were incorporated (64.64% females; mean age of 52.93 years). The total H. pylori eradication rates were 75.20% (255/339) with STT, 88.70% (159/178) with QCT, and 91.30% (191/209) with QBT. Both quadruple therapies (QCT-QBT) showed significantly higher eradication rates compared with STT, with an adjusted incidence risk ratio (IRR) of 1.25 (p: <0.05); and 1.24 (p: <0.05), respectively. The antibiotic-resistance prevalence by country, but not the prevalence of CYP2C19 polymorphism, showed a statistically significant impact on eradication success., Conclusions: Both QCT and QBT are superior to STT for H. pylori eradication when adjusted for country-specific antibiotic resistance and CYP2C19 polymorphism in a sample of individuals residing in five countries within two continents., (© 2024 The Author(s). United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background: In 2020, WHO guidelines prioritised the use of a standard fully oral short treatment regimen (STR) consisting of bedaquiline, levofloxacin or moxifloxacin, ethionamide, ethambutol, high-dose isoniazid, pyrazinamide, and clofazimine for the management of rifampicin-resistant tuberculosis. A high prevalence of resistance to constituent drugs precluded its widespread use by countries in the WHO European region. We evaluated three 9-month fully oral modified STRs (mSTRs) in which ethionamide, ethambutol, isoniazid, and pyrazinamide were replaced by linezolid, cycloserine, or delamanid (or a combination)., Methods: This multicountry, prospective, single-arm, cohort study examined the effectiveness and safety of mSTRs for fluoroquinolone-susceptible, rifampicin-resistant pulmonary tuberculosis in 13 countries in the WHO European region during 2020-23. We enrolled adults and children of all ages with bacteriologically confirmed rifampicin-resistant, fluoroquinolone-susceptible pulmonary tuberculosis, and children (aged 0-18 years) with clinically diagnosed disease and a confirmed contact with rifampicin-resistant, fluoroquinolone-susceptible tuberculosis. Participants aged 6 years or older received one of two regimens: bedaquiline, linezolid, levofloxacin, clofazimine, and cycloserine; or bedaquiline, linezolid, levofloxacin, clofazimine, and delamanid. Children younger than 6 years received delamanid, linezolid, levofloxacin, and clofazimine. Participants were followed up for 12 months after successful treatment completion to detect recurrence and death. The primary outcome was the cumulative probability of not having an unsuccessful study outcome (defined as treatment failure, on-treatment loss to follow-up, death, or recurrence) before 22 months of study follow-up. The primary safety outcome was the incidence of each adverse event of interest (peripheral neuropathy, optic neuritis, myelosuppression, hepatitis, prolonged QT interval, hypokalaemia, and acute kidney injury) of grade 3 or higher severity during the treatment course., Findings: Between Aug 28, 2020 and May 26, 2021, 7272 patients were screened and 2636 were included in the treatment cohort. 1966 (74·6%) were male, 670 (25·4%) were female, and median age was 43 years (IQR 33-53). Treatment success was recorded for 2181 (82·7%) participants. The cumulative probability of not having an unsuccessful study outcome 22 months after treatment initiation was 79% (95% CI 78-81). Increasing age (adjusted hazard ratio 2·61 [95% CI 1·70-4·04] for people aged >64 years vs 35-44 years), HIV-positive status (1·53 [1·16-2·01]), presence of bilateral cavities (1·68 [1·29-2·19]), smoking history (1·34 [1·05-1·71]), baseline anaemia (1·46 [1·15-1·86]), unemployment (1·37 [1·04-1·80]), elevated baseline liver enzymes (1·40 [1·13-1·73]), and excessive alcohol use (1·47 [1·14-1·89]) were positively associated with unsuccessful study outcomes. In the safety cohort of 2813 participants who received at least one dose, 301 adverse events of interest were recorded in 252 (9·0%) participants with the most frequent being myelosuppression (139 [4·9%] participants, 157 [52·2%] events)., Interpretation: The high treatment success and good safety results indicate considerable potential for the use of mSTRs in programmatic conditions, especially for individuals not eligible for the current WHO-recommended 6-month regimen and in settings with a need for alternative options., Funding: The Global Fund to Fight AIDS, Tuberculosis and Malaria; United States Agency for International Development; Government of Germany; and WHO., Translation: For the Russian translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 World Health Organization. Published by Elsevier Ltd. All rights reserved. This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Background: Cabotegravir + rilpivirine long-acting (CAB + RPV LA) dosed every 2 months (Q2M) is a complete regimen for the maintenance of HIV-1 virologic suppression. In this study, we report month 12 clinical outcomes in patient study participants (PSPs) in the CAB and RPV Implementation Study in European Locations (CARISEL) study., Setting: CARISEL is a phase 3b implementation-effectiveness study., Methods: CARISEL was designed as a 2-arm, unblinded study with centers randomized to either enhanced or standard implementation arms. For PSPs, this study is single arm, unblinded, and interventional; all PSPs switched from daily oral therapy to CAB + RPV LA dosed Q2M. The primary objective was to evaluate the perceived acceptability, appropriateness, and feasibility of CAB + RPV LA implementation for staff participants (presented separately). Clinical secondary endpoints assessed through month 12 included the proportion of PSPs with plasma HIV-1 RNA ≥50 and <50 copies/mL (Snapshot algorithm), incidence of confirmed virologic failure (CVF; 2 consecutive plasma HIV-1 RNA levels ≥200 copies/mL), adherence to injection visit windows, and safety and tolerability., Results: Four hundred thirty PSPs were enrolled and treated; the mean age was 44 years (30% ≥50 years), 25% were women (sex at birth), and 22% were persons of color. At month 12, 87% (n = 373/430) of PSPs maintained HIV-1 RNA <50 copies/mL, with 0.7% (n = 3/430) having HIV-1 RNA ≥50 copies/mL. One PSP had CVF. The safety profile was consistent with previous findings. Overall, the results were similar between implementation arms., Conclusion: CAB + RPV LA Q2M was well tolerated and highly effective in maintaining virologic suppression with a low rate of virologic failure., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Adherence to Helicobacter pylori (H. pylori) eradication treatment is a cornerstone for achieving adequate treatment efficacy., Objective: To determine which factors influence compliance with treatment., Methods: A systematic prospective non-interventional registry (Hp-EuReg) of the clinical practice of European gastroenterologists. Compliance was considered adequate if ≥90% drug intake. Data were collected until September 2021 using the AEG-REDCap e-CRF and were subjected to quality control. Modified intention-to-treat analyses were performed. Multivariate analysis carried out the factors associated with the effectiveness of treatment and compliance., Results: Compliance was inadequate in 646 (1.7%) of 38,698 patients. The non-compliance rate was higher in patients prescribed longer regimens (10-, 14-days) and rescue treatments, patients with uninvestigated dyspepsia/functional dyspepsia, and patients reporting adverse effects. Prevalence of non-adherence was lower for first-line treatment than for rescue treatment (1.5% vs. 2.2%; p < 0.001). Differences in non-adherence in the three most frequent first-line treatments were shown: 1.1% with proton pump inhibitor + clarithromycin + amoxicillin; 2.3% with proton pump inhibitor clarithromycin amoxicillin metronidazole; and 1.8% with bismuth quadruple therapy. These treatments were significantly more effective in compliant than in non-compliant patients: 86% versus 44%, 90% versus 71%, and 93% versus 64%, respectively (p < 0.001). In the multivariate analysis, the variable most significantly associated with higher effectiveness was adequate compliance (odds ratio, 6.3 [95%CI, 5.2-7.7]; p < 0.001)., Conclusions: Compliance with Helicobacter pylori eradication treatment is very good. Factors associated with poor compliance include uninvestigated/functional dyspepsia, rescue-treatment, prolonged treatment regimens, the presence of adverse events, and the use of non-bismuth sequential and concomitant treatment. Adequate treatment compliance was the variable most closely associated with successful eradication., (© 2024 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background: The influence of indications for Helicobacter pylori investigation on prescriptions and effectiveness is unknown. The aim of the study was to assess the impact of indications for H. pylori investigation on prescriptions, effectiveness, compliance, and tolerance., Methods: International, prospective, non-interventional registry of the management of H. pylori infection by European gastroenterologists (Hp-EuReg). Treatment-näive patients registered from 2013 to 2023 at e-CRF AEG-REDCap were analyzed. The effectiveness was assessed by modified intention-to-treat analysis., Results: Overall, 53,636 treatment-naïve cases from 34 countries were included. Most frequent indications were: dyspepsia with normal endoscopy (49%), non-investigated dyspepsia (20%), duodenal ulcer (11%), gastric ulcer (7.7%), and gastroesophageal reflux disease (GERD) (2.6%). Therapy effectiveness varied by indication: duodenal ulcer (91%), gastric ulcer (90%), preneoplastic lesions (90%), dyspepsia with normal endoscopy (89%), GERD (88%), and non-investigated dyspepsia (87%). Bismuth-metronidazole-tetracycline and clarithromycin-amoxicillin-bismuth quadruple therapies achieved 90% effectiveness in all indications except GERD. Concomitant clarithromycin-amoxicillin-tinidazole/metronidazole reached 90% cure rates except in patients with non-investigated dyspepsia; whereas sequential clarithromycin-amoxicillin-tinidazole/metronidazole proved optimal (≥90%) in patients with gastric ulcer only. Adverse events were higher in patients treated for dyspepsia with normal endoscopy and duodenal ulcer compared with the remaining indications (23% and 28%, p < 0.001). Therapeutic compliance was higher in patients with duodenal ulcer and preneoplastic lesions (98% and 99%, p < 0.001)., Conclusion: In Europe, patients with gastric or duodenal ulcers and preneoplastic lesions showed higher H. pylori treatment effectiveness. Bismuth and non-bismuth quadruple therapies achieved optimal results in almost all indications., Trial Registration: ClinicalTrials.gov identifier: NCT02328131., (© 2024 The Author(s). Helicobacter published by John Wiley & Sons Ltd.)

Objectives: To describe the clinical characteristics and treatment adherence in European adult hypertensive patients starting treatment with the extemporaneous combination of nebivolol and ramipril (NR-EXC)., Methods: Retrospective database analysis of patients receiving NR-EXC treatment across five European countries (Italy, Germany, France, Poland, Hungary) over a period ranging from 3 to 9 years (until 30 June 2020) according to data availability for the different data sources. Patient demographics, comorbidities, and treatment adherence were evaluated., Results: We identified 592,472 patients starting NR-EXC. Most of them were over 60 years of age, with ramipril most commonly prescribed at 5 mg (from 30.0 to 57.2% of patients across the databases). Notable comorbidities included diabetes (19.2%) and dyslipidemia (18.2%). The study population was also highly subjected to polytherapy with antithrombotics, lipid-lowering agents, and other lowering blood pressure agents as the most co-prescribed medications, as resulted from Italian database. Up to 59% of the patients did not request a cardiologic visit during the study period. Adherence to therapy was low in 56.3% of the patients, and it was high only in 11.1% of them., Conclusions: The combination of nebivolol and ramipril is frequently prescribed in Europe, but adherence to treatment is suboptimal. The transition to a single pill combination could enhance treatment adherence and streamline regimens, potentially leading to significant benefits. Improved adherence not only correlates with better blood pressure control but also reduces the risk of cardiovascular events, underscoring the importance of this development.

Objective: To explore real-life use of the extemporaneous combination of nebivolol and valsartan (NV-EXC) in adult hypertensive patients in Europe., Methods: Retrospective analysis of patients starting NV-EXC treatment conducted using prescription databases in Italy, Germany, Hungary, and Poland. The selection period during which study patients were identified covered a time span ranging from 3 to 9 years (until 30 June 2020) according to availability of the different data sources. Patient demographics, clinical information, and treatment adherence, measured by proportion of days covered, were evaluated. Additionally, the potential eligibility of Italian patients for the single pill combination (SPC) of nebivolol and valsartan over a one-year period was estimated., Results: The study included 170,682 patients initiating NV-EXC across the databases. Most patients were females (from 51 to 60%) and primarily aged over 60 years. Few patients received prescriptions of both available dosages of valsartan (80 and 160 mg) during follow-up (from 3.2 to 8.5%). Common comorbidities included dyslipidemia (19.2%) and diabetes (19.1%). Around 59.5% of patients did not require cardiologic visits during the study period. Adherence to NV-EXC, as indicated by the Italian database, was low in 53.3% of patients, with only 16.1% showing high adherence. The Italian database revealed 680 prevalent NV-EXC users in 2019, estimating a potential 30,222 adult patients eligible for the nebivolol/valsartan SPC., Conclusions: The combination of nebivolol and valsartan is frequently prescribed for hypertension, but adherence remains a challenge. A potential nebivolol/valsartan SPC holds promise in enhancing adherence and optimizing therapeutic outcomes for hypertension management.

Introduction: Helicobacter pylori (H. pylori), the most prevalent chronic infection globally, is the major cause of relevant diseases such as gastric cancer, leading to high morbidity and mortality worldwide. Several studies have focused on optimize H. pylori eradication treatment through combination therapies and antibiotic resistance. However, the adverse events profile and its impact, as a primary outcome, remains underexplored.The aim of this review was to summarize the available data on the safety of the most common regimens for H. pylori eradication and its impact on the compliance., Areas Covered: This review encompassed the published evidence from the years 2008 to 2023 regarding both the safety and compliance for most common H. pylori eradication regimens. The main sources for this review comprised MEDLINE, PubMed, and Cochrane electronic databases. Furthermore, it included a safety analysis of unpublished data from the European Registry on H. pylori management (Hp-EuReg)., Expert Opinion: Poor compliance is correlated with significantly lower cure rates, and this is a unique modifiable source of H. pylori treatment failure. Eradication treatments have become complex, involving multiple drugs and dosing intervals. Thus, patient education is crucial; doctors must explain to the patient about potential temporary and most often harmless side effects.

Purpose: The EuroPedHp-registry aims to monitor guideline-conform management, antibiotic resistance, and eradication success of 2-week triple therapy tailored to antibiotic susceptibility (TTT) in Helicobacter pylori-infected children., Methods: From 2017 to 2020, 30 centres from 17 European countries reported anonymized demographic, clinical, antibiotic susceptibility, treatment, and follow-up data. Multivariable logistic regression identified factors associated with treatment failure., Results: Of 1605 patients, 873 had follow-up data (53.2% female, median age 13.0 years, 7.5% with ulcer), thereof 741 (85%) treatment naïve (group A) and 132 (15%) after failed therapy (group B). Resistance to metronidazole was present in 21% (A: 17.7%, B: 40.2%), clarithromycin in 28.8% (A: 25%, B: 51.4%), and both in 7.1% (A: 3.8%, B: 26.5%). The majority received 2-week tailored triple therapy combining proton pump inhibitor (PPI), amoxicillin with clarithromycin (PAC) or metronidazole (PAM). Dosing was lower than recommended for PPI (A: 49%, B: 41%) and amoxicillin (A: 6%, B: 56%). In treatment naïve patients, eradication reached 90% (n = 503, 95% CI 87-93%) and 93% in compliant children (n = 447, 95% CI 90-95%). Tailored triple therapy cured 59% patients after failed therapy (n = 69, 95% CI 48-71%). Treatment failure was associated with PAM in single clarithromycin resistance (OR = 2.47, 95% CI 1.10-5.53), with PAC in single metronidazole resistance (OR = 3.44, 95% CI 1.47-8.08), and with low compliance (OR = 5.89, 95% CI 2.49-13.95)., Conclusions: Guideline-conform 2-weeks therapy with PPI, amoxicillin, clarithromycin or metronidazole tailored to antibiotic susceptibility achieves primary eradication of ≥ 90%. Higher failure rates in single-resistant strains despite tailored treatment indicate missed resistance by sampling error., (© 2022. The Author(s).)

This study aims to understand healthcare professionals' thoughts and motivations about optimal management and treatment of patients with chronic obstructive pulmonary disease (COPD). We conducted a DELPHI survey through an online questionnaire distributed to 220 panellists from six European countries and a discrete choice experiment to describe the relationship between selected clinical criteria and the initial COPD treatment of choice. One hundred twenty-seven panellists (general practitioners [GPs] and pulmonologists) completed the survey. Despite the familiarity and use (89.8%) of the GOLD classification for initial treatment selection, a frequent use of LAMA/LABA/ICS was noted. In fact, panellists agreed that inhaled corticosteroids (ICS) are over-prescribed in the primary care setting. Our study showed that GPs felt less confident than pulmonologists with ICS withdrawal. This mismatch observed between best practice and behaviour indicates the need to increase awareness and efforts to improve the adherence to guidelines in clinical practice., (© 2023. The Author(s).)

In order to characterize the real-world effectiveness and safety of perampanel during clinical use in Europe, we conducted a structured literature search and scoping review of real-world studies conducted in Europe in adolescents (aged ≥ 12 years) or adults who were prescribed perampanel for focal epilepsy or primary generalized tonic-clonic seizures in the context of idiopathic generalized epilepsy, published between January 2016 and July 2021. We identified 29 relevant studies (20 retrospective and 9 prospective) in 3608 patients; median study duration was 12 months. Most patients (76.1%) were receiving two or more antiseizure drugs (ASDs) when perampanel was initiated. The maintenance perampanel dose ranged from 2 to 16 mg/day (most commonly 6 mg/day). Retention rate at 12 months ranged from 46% to 90.5% (median 71.1%). The proportion of patients who were free of seizures during perampanel ranged from 1.8% to 84.6%, but were consistently below 20% in studies where patients had received an average of ≥5 prior ASDs and above 20% where patients had received an average of <5 prior ASDs. The proportion of patients who achieved ≥50% reduction in seizures during perampanel ranged from 20.0% to 85.7%. Across all studies, the incidence of adverse events (AEs) ranged from 18.2% to 67.4% (median 37.1%) and discontinuation due to AEs from 6.2% to 56% (median 12.5%). Discontinuation rates tended to be higher in UK studies than in studies from Italy or Spain. The most commonly reported individual AEs were dizziness/vertigo (median incidence 13.7%), somnolence (median 11.9%), aggression (median 9.8%), irritability (median 9.1%), and cognitive deficits (median 7.0%). There was no relationship between the overall rate of AEs and perampanel dose, perampanel plasma levels, or number of concomitant medications. Our global overview of European observational studies with perampanel provides evidence that this agent is effective and safe in clinical practice in a range of countries, patients, and settings., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JC Estévez has received consultancy fees from Eisai related to this review, and fees for conferences sponsored by Eisai, Bial, UCB and Esteve. I Garamendi has received consultancy fees from Eisai related to this review, and fees as speaker from Bial, Eisai, Esteve, Livanova and UCB., (Copyright © 2022 Elsevier Inc. All rights reserved.)

About two thirds of the patients with major depressive disorder (MDD) do not sufficiently respond to monotherapy with antidepressants (ADs) which makes them reliant on further treatment approaches. Hereby, combination of different ADs and augmentation with second-generation antipsychotics (SGAs) are widely used and recommended psychopharmacotherapeutic strategies. The present secondary analyses are based on an international, naturalistic, cross-sectional multicenter study conducted by the European Group for the Study of Resistant Depression. Comparing socio-demographic and clinical characteristics of 436 adult MDD patients receiving either SGAs (N = 191, 43.8%) or ADs (N = 245, 56.2%), that were additionally administered to their first-line AD psychopharmacotherapy, we aimed to identify possible trajectories of decision-making for clinicians regarding which treatment option to prefer in individual patients. Our most robust findings represent an association of SGA augmentation with the presence of psychotic symptoms, longer mean duration of lifetime psychiatric hospitalizations, employment of further augmentation strategies with mood-stabilizers and benzodiazepines, and a trend towards higher mean daily dosages of their first-line ADs and current suicidal risk. Treatment outcome was not significantly different between patients receiving either SGA augmentation or AD combination. Being aware of limitations inherent to the cross-sectional study design and the lack of randomization, more severe and rather chronic conditions in MDD seemed to encourage clinicians to choose SGA augmentation over AD combination. The fact that mood-stabilizers and/or benzodiazepines were more frequently co-administered with SGAs may represent a requirement of an overall refined psychopharmacotherapy including additional fast-acting agents with potent AD, tranquilizing and anti-suicidal effects in MDD patients experiencing challenging clinical manifestations. New glutamatergic substances seem to be promising in this regard., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: Alan Bell reports consulting fees from AstraZeneca, Bayer and Sanofi; speaker fees from AstraZeneca; and board membership with Thrombosis Canada, Hypertension Canada and the Canadian Cardiovascular Society. Sol Stern reports honoraria from Bayer, Pfizer, Bristol Myers Squibb and Sea Courses Inc. Shaun Goodman reports research grant support from Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Eli Lilly, Esperion, Ferring Pharmaceuticals, Merck, Novartis, Pfizer, Regeneron, Sanofi, Heart and Stroke Foundation of Ontario, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Center for Clinical Research, Duke Clinical Research Institute, New York University Clinical Coordinating Center, PERFUSE Research Institute and TIMI Study Group (Brigham Health). He also reports consulting honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Eli Lilly, Ferring Pharmaceuticals, HLS Therapeutics, JAMP Pharma, Merck, Novartis, PendoPharm of Pharmascience, Pfizer, Regeneron, Sanofi, Servier, Valeo Pharma, Canadian Heart Research Centre and MD Primer, and speaking fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Ferring Pharmaceuticals, HLS Therapeutics, JAMP Pharma, Novartis, PendoPharm of Pharmascience, Pfizer, Regeneron, Sanofi, Servier, Valeo Pharm, Canadian Heart Research Centre and MD Primer. He sits on boards with American Regent of Daiichi-Sankyo and Novo Nordisk and is co-director of the Canadian VIGOUR Centre. All competing interests are outside the submitted work. No other competing interests were declared.

Background: Augmentation with second-generation antipsychotics (SGAs) represents an evidence-based psychopharmacotherapeutic strategy recommended in case of insufficient response to the first-line antidepressant (AD) treatment in major depressive disorder (MDD). Comparative evidence regarding efficacy and prescription preferences of the individual SGAs is scarce., Methods: In the scope of this European, multi-site, naturalistic cross-sectional investigation with retrospective assessment of treatment outcome, we compared sociodemographic and clinical characteristics of 187 MDD patients receiving either quetiapine (n = 150) or aripiprazole (n = 37) as augmentation of their first-line AD psychopharmacotherapy., Results: Comorbid posttraumatic stress disorder and diabetes were significantly associated with aripiprazole augmentation in our primary and post-hoc binary logistic regression analyses. Furthermore, we identified an association between aripiprazole co-administration and the presence of additional psychotic features, higher rates of AD combination treatment, and a longer duration of psychiatric hospitalizations during the lifetime, which, however, lost significance after correcting for multiple comparisons. Regarding treatment outcome, we found a trend of higher response rates and greater reductions in severity of depressive symptoms in MDD patients dispensed quetiapine., Conclusions: Factors associated with a more chronic and severe profile of MDD seem to encourage clinicians to choose aripiprazole over quetiapine, that was, however, administered in the majority of our MDD patients, which might reflect the current approval situation allowing to prescribe exclusively quetiapine as on-label augmentation in MDD in Europe. Given the retrospective assessment of treatment response, the markedly smaller proportion of patients receiving aripiprazole augmentation generally showing an unfavorable disease profile, and the partially heterogeneous statistical robustness of our findings, further studies are required to elaborate on our observation and to generate unambiguous recommendations regarding the choice of first-line SGA augmentation in MDD., (© The Author(s) 2021. Published by Oxford University Press on behalf of CINP.)

Background: Approximately 71 million people are still in need of direct-acting antiviral agents (DAAs). To achieve the World Health Organization Hepatitis C elimination goals, insight into the prevalence and influence of resistance associated substitutions (RAS) is of importance. Collaboration is key since DAA failure is rare and real-life data are scattered. We have established a European collaboration, HepCare, to perform in-depth analysis regarding RAS prevalence, patterns, and multiclass occurrence. Methods: Data were extracted from the HepCare cohort of patients who previously failed DAA therapy. Geno-and subtypes were provided by submitters and mostly based on in-house assays. They were reassessed using the Comet HCV subtyping tool. We considered RAS to be relevant if they were associated with DAA failure in vivo previously reported in literature. Results: We analyzed 938 patients who failed DAA therapy from ten different European countries. There were 239 genotypes (GT) 1a, 380 GT1b, 19 GT2c, 205 GT3a, 14 GT4a, and 68 GT4d infections. Several unusual subtypes (n = 15) (GT1b/g/l, GT3b, GT4k/n/r/t) were present. RAS appeared in over 80% of failures and over a quarter had three or more RAS. Multiclass RAS varied over target region and genotype between 0-48%. RAS patterns such as the Q30R + L31M and Q30R + Y93H in GT1a, the L31V + Y93H and L31V + Y93H for GT1b, and A30K + L31M and A30K/V + Y93H for GT3a all occurred with a prevalence below 5%. Conclusion: RAS occur frequently after DAA failures and follow a specific genotype and drug related pattern. Interpretation of the influence of RAS on retreatment is challenging due to various patterns, patients' characteristics, and previous treatment history. Moving towards HCV elimination, an ongoing resistance surveillance is essential to track the presence of RAS, RAS patterns and gather data for a re-treatment algorithm.

Background and Aims: Few data are available regarding the combination of biologics or small molecules in inflammatory bowel disease (IBD) patients. We report safety and efficacy of such combinations through a retrospective multicentre series., Methods: Combination therapy was defined as the concomitant use of two biologics or one biologic with a small molecule. Patient demographics, disease characteristics and types of combinations were recorded. Safety was evaluated according to the occurrence of serious infection, opportunistic infection, hospitalisation, life-threatening event, worsening of IBD or immune-mediated inflammatory diseases (IMID), cancer and death. Efficacy was evaluated as the physician global assessment of the combination and comparison of clinical/endoscopic scores of IBD/IMID activity prior and during combination., Results: A total of 104 combinations were collected in 98 patients. Concomitant IMID were present in 41 patients. Reasons for starting combination therapy were active IBD (67%), active IMID or extra-intestinal manifestations (EIM) (22%), both (10%) and unclassified in 1. Median duration of combination was 8 months (interquartile range 5-16). During 122 patient-years of follow-up, 42 significant adverse events were observed, mostly related to uncontrolled IBD. There were 10 significant infections, 1 skin cancer and no death. IBD disease activity was clinically improved in 70% and IMID/EIM activity in 81% of the patients. Overall, combination was continued in 55% of the patients., Conclusions: Combination of biologics and small molecules in patients with IBD and IMID/EIM seems to be a promising therapeutic strategy but is also associated with a risk of opportunistic infections or infections leading to hospitalisation in 10%., (© 2021 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Objective: To update and evaluate the recurrence rate of Helicobacter pylori (H. pylori) eradication therapy in recent 10 years., Methods: A systematic search of PubMed, Embase, Cochrane library, and Web of science was performed to identify the studies of recurrence rate of H. pylori published from 2010 to 2019. Stata 15.0 was used for analysis., Results: A total of 31 studies (16,797 participants) were analyzed. The recurrence rate of H. pylori was 9% (95% CI, 8-11%), and it showed an upward trend with the time elapsed after eradication. The annual recurrence rate was 4%, and there was a stable trend with the time elapsed after eradication. Subgroup analyses showed that the recurrence rate of H. pylori eradication by triple therapy was higher than that of quadruple therapy (14% [95% CI, 9-19] vs 12% [95% CI, 7-17]); urban was higher than that of rural (8% [95% CI, 1-14] vs 5% [95% CI, 1-9]); males were higher than that of females (11% [95% CI, 8-14] vs 10% [95% CI, 7-14]); Europe had the highest recurrence rate (16% [95% CI, -1 to 42]), and Africa had the lowest (1% [95% CI, 0-2]). The recurrence rate ofH. pylori was inversely related to the human development index., Conclusions: The recurrence rate of H. pylori showed an increasing trend in recent 10 years, and it is still a knotty public health problem worldwide. The recurrence rate of H. pylori showed an upward trend with the time elapsed after eradication, and the recurrence rate of H. pylori varies by area, gender, and eradication methods., (© 2021 John Wiley & Sons Ltd.)

Aims: The objective was to evaluate the clinical characteristics, management and two-year outcomes of patients with newly diagnosed non-valvular atrial fibrillation at risk for stroke in Nordic countries., Methods: We examined the baseline characteristics, antithrombotic treatment, and two-year clinical outcomes of patients from four Nordic countries., Results: A total of 52,080 patients were enrolled in the GARFIELD-AF. Out of 29,908 European patients, 2,396 were recruited from Nordic countries. The use of oral anticoagulants, alone or in combination with antiplatelet (AP), was higher in Nordic patients in all CHA 2 DS 2 -VASc categories: 0-1 (72.8% vs 60.3%), 2-3 (78.7% vs 72.9%) and ≥4 (79.2% vs 74.1%). In Nordic patients, NOAC ± AP was more frequently prescribed (32.0% vs 27.7%) and AP monotherapy was less often prescribed (10.4% vs 18.2%) when compared with Non-Nordic European patients. The rates (per 100 patient years) of all-cause mortality and non-haemorrhagic stroke/systemic embolism (SE) were similar in Nordic and Non-Nordic European patients [3.63 (3.11-4.23) vs 4.08 (3.91-4.26), p value = .147] and [0.98 (0.73-1.32) vs 1.02 (0.93-1.11), p value = .819], while major bleeding was significantly higher [1.66 (1.32-2.09) vs 1.01 (0.93-1.10), p value < .001]., Conclusion: Nordic patients had significantly higher major bleeding than Non-Nordic-European patients. In contrast, rates of all-cause mortality and non-haemorrhagic stroke/SE were comparable., Clinical Trial Registration: Unique identifier: NCT01090362. URL: http://www.clinicaltrials.gov., Key Message: Nordic countries had significantly higher major bleeding than Non-Nordic-European countries. Rates of mortality and non-haemorrhagic stroke/SE were similar .

Objective: Our aim was to prospectively assess the antibiotic resistance rates in Helicobacter pylori strains in Europe in 2018 and to study the link between antibiotic consumption in the community and H. pylori resistance levels in the different countries., Design: The proportion of primary antibiotic resistance cases of H. pylori and their corresponding risk factors were investigated in 24 centres from 18 European countries according to a standardised protocol. Data on antibiotic consumption in the community were collected for the period 2008-2017. The link between antibiotic consumption and resistance data was assessed using generalised linear mixed models. The model with the best fit was selected by means of the Akaike Information Criterion., Results: H. pylori resistance rates for the 1211 adult patients included were 21.4% for clarithromycin, 15.8% for levofloxacin and 38.9% for metronidazole and were significantly higher in Central/Western and Southern than in the Northern European countries.The best model fit was obtained for the Poisson distribution using 2013 consumption data. A significant association was found between H. pylori clarithromycin resistance and consumption in the community of macrolides (p=0.0003) and intermediate-acting macrolides (p=0.005), and between levofloxacin resistance and consumption of quinolones (p=0.0002) and second-generation quinolones (p=0.0003)., Conclusion: This study confirms the positive correlation between macrolide and quinolone consumption in the community and corresponding H. pylori resistance in European countries. Hence, H. pylori treatment with clarithromycin and levofloxacin should not be started without susceptibility testing in most European countries., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Although the 3Rs are broadly applied in nonclinical testing, a better appreciation of the 3Rs is needed in the field of differentiated or value-added pharmaceutical generics because the minor changes in formulation, dosage form, indication, and application route often do not require additional safety testing. The US FDA and the EU EMA have comprehensive regulations for such drugs based on quality, therapeutic equivalence, and safety guidelines. However, no scientific publications on how the concept of replacement and reduction from 3Rs principles can be applied in the safety assessment of differentiated generics were found in the public domain. In this review, we discuss the application of 3Rs in nonclinical testing requirements for differentiated generics. Practical examples are provided in the form of case studies from regulated markets. We highlight the need for utilization of existing data to establish equivalence (differentiated generic vs innovator) in efficacy and safety. The case studies indicate that data requirements from animal experiments have been reduced to a large extent in some major markets without compromising quality and safety. In this context, we also highlight the problem that on a global scale, a true reduction of animal experiments will only be achieved when all countries adopt similar practices., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Hepatitis D is the smallest virus known to infect humans, the most aggressive, causing the most severe disease. It is considered a satellite or defective virus requiring the hepatitis B surface antigen (HBsAg) for its replication with approximately 10-70 million persons infected. Elimination of hepatitis D is, therefore, closely tied to hepatitis B elimination. There is a paucity of quality data in many resource-poor areas. Despite its aggressive natural history, treatment options for hepatitis D to date have been limited and, in many places, inaccessible. For decades, Pegylated interferon alpha (Peg IFN α) offered limited response rates (20%) where available. Developments in understanding viral replication pathways has meant that, for the first time in over three decades, specific therapy has been licensed for use in Europe. Bulevirtide (Hepcludex ® ) is an entry inhibitor approved for use in patients with confirmed viraemia and compensated disease. It can be combined with Peg IFN α and/or nucleos(t)ide analogue for hepatitis B. Early reports suggest response rates of over 50% with good tolerability profile. Additional agents showing promise include the prenylation inhibitor lonafarnib, inhibitors of viral release (nucleic acid polymers) and better tolerated Peg IFN lambda (λ). These agents remain out of reach for most resource limited areas where access to new therapies are delayed by decades. strategies to facilitate access to care for the most vulnerable should be actively sought by all stakeholders.

Background: It remains unclear whether combination antiretroviral therapy (ART) regimens differ in their ability to fully suppress human immunodeficiency virus (HIV) replication. Here, we report the results of two cross-sectional studies that compared levels of cell-associated (CA) HIV markers between individuals receiving suppressive ART containing either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI)., Methods: CA HIV unspliced RNA and total HIV DNA were quantified in two cohorts (n = 100, n = 124) of individuals treated with triple ART regimens consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) plus either an NNRTI or a PI. To compare CA HIV RNA and DNA levels between the regimens, we built multivariable models adjusting for age, gender, current and nadir CD4 + count, plasma viral load zenith, duration of virological suppression, NRTI backbone composition, low-level plasma HIV RNA detectability, and electronically measured adherence to ART., Results: In both cohorts, levels of CA HIV RNA and DNA strongly correlated (rho = 0.70 and rho = 0.54) and both markers were lower in NNRTI-treated than in PI-treated individuals. In the multivariable analysis, CA RNA in both cohorts remained significantly reduced in NNRTI-treated individuals (p adj = 0.02 in both cohorts), with a similar but weaker association between the ART regimen and total HIV DNA (p adj = 0.048 and p adj = 0.10). No differences in CA HIV RNA or DNA levels were observed between individual NNRTIs or individual PIs, but CA HIV RNA was lower in individuals treated with either nevirapine or efavirenz, compared to PI-treated individuals., Conclusions: All current classes of antiretroviral drugs only prevent infection of new cells but do not inhibit HIV RNA transcription in long-lived reservoir cells. Therefore, these differences in CA HIV RNA and DNA levels by treatment regimen suggest that NNRTIs are more potent in suppressing HIV residual replication than PIs, which may result in a smaller viral reservoir size., Funding: This work was supported by ZonMw (09120011910035) and FP7 Health (305522)., Competing Interests: AP, JV, NK, FW, Md, DD, MB, CS, AW, JP, PR, BB No competing interests declared, (© 2021, Pasternak et al.)

Objectives: To assess current practices around the use of combination immunosuppression in paediatric inflammatory bowel disease (PIBD) with a focus on the subsequent withdrawal process., Methods: A web-based, 43-question survey., Results: Surveys were completed by 70 paediatric gastroenterologists (PGs) from 27 nations across Europe, North America, Oceania and Asia from 62 centres covering approximately 15,000 PIBD patients (median of 200 patients [interquartile range (IQR) 130-300] per centre). Routine use of co-immunosuppression was significantly higher with infliximab (IFX) versus adalimumab (ADL) ([61/70, 87.1%] compared with [23/70, 32.9%]; P < 0.01). Thiopurines (azathioprine [AZA] or 6-mercaptopurine) were the preferred option overall for co-immunosuppression. They were favoured with either IFX or ADL (76% and 77%, respectively) and in both ulcerative colitis (UC) and Crohn disease (CD) (84% and 69%) compared with methotrexate (MTX).Immunomodulators were the preferred choice as the initial drug to be withdrawn from the combination therapy rather than anti-tumour necrosis factor-alpha (anti-TNFα) therapy (59/67, 88% [P < 0.01]). The most common withdrawal time was after 6-12 months, with this decision usually based on clinical assessment rather than a scheduled withdrawal time (51/67, 76% vs 16/67, 24%). Indicators of mucosal healing and therapeutic drug monitoring results tended to be the most important "clinical factors" in the withdrawal decision (P = 0.05)., Conclusion: Most PG's favour initial withdrawal of immunomodulator (usually thiopurines) rather than biologic therapy in the step-down process, usually after 6-12 months based on sustained clinical remission. This survey precedes an in-depth, multicentre study of clinical outcomes of withdrawal of co-immunosuppression in PIBD., Competing Interests: Conflicts of interest: D.C.W. has received speaker's fees, travel support and participated in medical board meetings with AbbVie, Roche, Nestle Health Sciences. R.K.R. has received speaker's fees, travel support and participated in medical board meetings with Abbvie, Janssen, Takeda, Celltrion, Pharmacosmos and Nestle. J.V.L. has received speaker's fees, travel support and research support and participated in medical board meetings with AbbVie, Janssen, Novalac, Otsuka and Nestlé Health Sciences. E.W. has received speaker's fees, travel support and participated in medical board meetings with AbbVie and Nestlé Health Sciences and speaker's fee from Janssen and Mead Johnson Nutrition., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Introduction: The safety of Helicobacter pylori eradication treatments and to what extent adverse events (AEs) influence therapeutic compliance in clinical practice are hardly known. Our aim was to assess the frequency, type, intensity, and duration of AEs, and their impact on compliance, for the most frequently used treatments in the "European Registry on Helicobacter pylori management.", Methods: Systematic prospective noninterventional registry of the clinical practice of European gastroenterologists (27 countries, 300 investigators) on the management of H. pylori infection in routine clinical practice. All prescribed eradication treatments and their corresponding safety profile were recorded. AEs were classified depending on the intensity of symptoms as mild/moderate/severe and as serious AEs. All data were subject to quality control., Results: The different treatments prescribed to 22,492 patients caused at least 1 AE in 23% of the cases; the classic bismuth-based quadruple therapy was the worst tolerated (37% of AEs). Taste disturbance (7%), diarrhea (7%), nausea (6%), and abdominal pain (3%) were the most frequent AEs. The majority of AEs were mild (57%), 6% were severe, and only 0.08% were serious, with an average duration of 7 days. The treatment compliance rate was 97%. Only 1.3% of the patients discontinued treatment due to AEs. Longer treatment durations were significantly associated with a higher incidence of AEs in standard triple, concomitant, bismuth quadruple, and levofloxacin triple or quadruple therapies., Discussion: Helicobacter pylori eradication treatment frequently induces AEs, although they are usually mild and of limited duration. Their appearance does not interfere significantly with treatment compliance., Competing Interests: The remaining list of authors, their affiliations, contributions and conflicts of interests are listed in Supplementary file 1. Contribution Log, available online at http://links.lww.com/AJG/B961., (Copyright © 2021 by The American College of Gastroenterology.)

Background: Patients at high risk of bleeding requiring percutaneous coronary intervention (PCI) need careful evaluation of both their thrombotic and their bleeding risks. In these patients, a polymer-free metallic stent coated with biolimus-A9 (BA9-DCS) followed by 1‑month dual antiplatelet therapy (DAPT) could be a safe option; however, real-world data are still lacking. We analyzed the performance of the device in a real-world scenario., Methods: Patients assessed as being at high risk of bleeding with an indication for PCI were treated with BA9-DCS and DAPT consisting of aspirin (100 mg/day) and clopidogrel (75 mg/day) for at least 1 month, followed by either oral anticoagulation or single antiplatelet therapy. No exclusion criteria were used. The primary endpoint was the occurrence of an adverse event after PCI, i.e. severe bleeding requiring hospitalization, ischemic or hemorrhagic stroke, clinically driven stent thrombosis, myocardial infarction or cardiac death., Results: Overall, 89 patients were enrolled in this study [median age 75 (66-81) years; 27 females (30%)] and 171 interventions were performed. During a median follow-up of 203 (145-273) days the primary endpoint occurred in 20 patients (23%): 12 (13%) had clinically significant bleeding, four (5%) ischemic stroke and four (5%) died from cardiac causes related neither to stent thrombosis nor to acute myocardial infarction. Female gender emerged as the only statistically significant predictor of an adverse event (adjusted hazard ratio (HR) 3.3; 95% confidence interval (CI): 1.2-8.7, p = 0.017)., Conclusion: In real-world patients at high risk of bleeding, implantation of the polymer-free metallic stent coated with Biolimus-A9 (Biofreedom®; Biosensors Europe, Morges, Switzerland) followed by 1 -month DAPT showed encouraging results without any stent thrombosis.

Background: The long-acting anticholinergic (LAMA) aclidinium was approved in Europe in 2012 to relieve symptoms in adults with chronic obstructive pulmonary disease (COPD). A Post-Authorisation Safety Study (PASS) was initiated to assess potential cardiovascular safety concerns for aclidinium., Objective: To estimate the adjusted incidence rate ratio (IRR) for hospitalisation for heart failure in patients with COPD who were new users of aclidinium, tiotropium, other LAMA, long-acting beta-agonists/inhaled corticosteroids (LABA/ICS), and LAMA/LABA were compared with initiators of LABA., Methods: This population-based cohort study included patients with COPD aged ≥40 years initiating COPD medications in the Clinical Practice Research Datalink (CPRD) GOLD in the United Kingdom from 2012 to 2017. Medications were identified via general practice prescriptions. The first-ever hospitalisations for heart failure were identified in the Hospital Episode Statistics, and general practitioner records from the CPRD. Poisson regression models were used to estimate the IRR for hospitalisation for heart failure in users of COPD medications versus LABA, adjusting for clinically relevant covariates., Results: The study included 4350 new users of aclidinium, 23,405 of tiotropium, 6977 of other LAMAs, 3122 of LAMA/LABA, 26,093 of LABA/ICS, and 5678 of LABA. Mean age was 69-70 years across medication groups. Aclidinium users had the highest proportion of severe COPD, and LABA users had the lowest (35% vs 19%, respectively). Crude incidence rates per 1000 person-years for the first-ever hospitalisation for heart failure ranged from 6.9 in LABA to 9.5 in aclidinium. Using LABA as reference, adjusted IRRs (95% confidence interval) for first-ever hospitalisation for heart failure were 0.90 (0.53-1.53) for aclidinium, 1.02 (0.69-1.51) for tiotropium, 0.86 (0.50-1.47) for other LAMAs, 1.09 (0.41-2.92) for LAMA/LABA, and 1.01 (0.69, 1.48) for LABA/ICS., Conclusion: The study did not find increased risks of hospitalisations for heart failure in new users of aclidinium, tiotropium, other LAMAs, LAMA/LABA, and LABA/ICS compared with LABA., Competing Interests: CR, EP, JA, NSM, SPG, and ERF are salaried employees of RTI Health Solutions, a nonprofit research organisation that conducts research with multiple pharmaceutical companies and has an independent right to publish the results of this study. AR is an employee of BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom. AL is an employee of BioPharmaceuticals R&D, AstraZeneca, Barcelona, Spain. SD is an employee of BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, United States. The authors report no other conflicts of interest in this work., (© 2021 Rebordosa et al.)

Aims: Data on the effect of liraglutide on glycemic endpoints in people with T2DM using multiple daily insulin injections (MDI) are scarce, especially in the context of ethnicity., Methods: This is a secondary analysis of the placebo-controlled randomized clinical "MAGNA VICTORIA" trials in Western European (WE) and South Asian (SA) people with T2DM. Participants had inadequate glycemic control despite using metformin and/or sulfonylurea derivatives and/or insulin. Participants were assigned to liraglutide (1.8 mg) or placebo for 6 months, in addition to standard care. The primary endpoint number of participants reaching target HbA1c was compared for liraglutide versus placebo in the complete dataset and MDI-treated participants using Chi-square test. Liraglutide's efficacy in WE and SA was compared using a generalized linear model., Results: Forty-five subjects were randomized to liraglutide and 51 to placebo. In each group, one participant did not complete the study. Liraglutide-treated patients reached target HbA1c more frequently: 23/45 (51%) vs 11/51 (22%), relative probability 2.4 (1.3-4.3), p = 0.002. Subgroup analysis in 43 MDI participants showed that the proportion reaching target HbA1c using liraglutide was significantly higher than in placebo: 9/22 (41%) vs 1/21 (5%), p = 0.005. There was no difference between WE and SA in terms of liraglutide efficacy (p = 0.18)., Conclusions: Liraglutide treatment resulted in increased chance of reaching target HbA1c as compared to placebo. Liraglutide efficacy was sustained in participants using MDI regimens and those of SA descent. Liraglutide should be considered for T2DM people with inadequate glycemic control despite MDI.

Background:  Hepatitis C virus (HCV) genotype (GT) 1 is the most common HCV GT in Western and Central Europe. The main focus of this present work is to analyze the change of baseline characteristics of 17 093 HCV-patients with genotype 1a/1b with antiviral therapy in Germany between 2004 and 2018. We analyzed five periods: (i) 2004-2007, (ii) 2008-2010, (iii) 2010-2013, (iv) 2014-2016, (v) 2017-2018., Methods:  The present analysis is based on five German non-interventional registry studies and comprises data on 17 093 HCV-GT1 patients documented between 2004 and 2018 [ML17071, ML19464, ML21645, ML25724 (Peginterferon alfa-2a ® non-interventional study [PAN]) and the German Hepatitis C-Registry (DHC-R)., Findings:  Overall, 7662 patients were infected with HCV GT1a and 9431 patients with HCV GT1b. GT1a patients were younger (46.5 years vs. 51.2 years) and more often male (70 % vs. 52 %). Previous or ongoing drug abuse was documented more frequently for GT1a patients throughout the study periods with highest frequencies in the most recent period (2017-2018; 44 % for GT1a and 10.3 % for GT1b). Metabolic comorbidities, such as those who are overweight and those with diabetes mellitus, were associated with HCV GT1b-infected women. The GT1a ratio increased from 33.6 % (2004-2007) to 50 % (2017-2018). A relevant change in the GT1a/1b ratio was observed over time in men (2004-2007: 38 %/63 %; 2017-2018: 59 %/41 %). In contrast, only 30 % of women had GT1a infection throughout all study periods without relevant changes. There were no regional differences within Germany in HCV GT1a/1b distribution despite a higher proportion of GT1b-infected women in East Germany in 2004-2007 (86 %)., Conclusion:  A marked increase of GT1a infection associated with drug use was observed in men, but not women, in Germany between 2004 and 2018. The present data show a fundamental change in HCV epidemiology, which has an impact on therapy management and general care of hepatitis C patients in Germany., Competing Interests: Karl-Georg Simon hat in den letzten 3 Jahren Zuwendungen (z. B. Vortragshonorare, Forschungsgelder oder Beraterhonorare) erhalten von: AbbVie GmbH & Co.KG, Falk Pharma, Gilead Sciences GmbH, MSD Sharp & Dohme GmbH.Yvonne Serfert hat keine Interessenkonflikte.Peter Buggisch hat in den letzten 3 Jahren Zuwendungen (z. B. Vortragshonorare, Forschungsgelder oder Beraterhonorare) erhalten von: AbbVie, Gilead, MSD.Stefan Mauss hat in den letzten 3 Jahren Zuwendungen (z. B. Vortragshonorare, Forschungsgelder oder Beraterhonorare) erhalten von: AbbVie, Gilead, MSD.Klaus H. W. Boeker hat in den letzten 3 Jahren Zuwendungen (z. B. Vortragshonorare, Forschungsgelder oder Beraterhonorare) erhalten von: AbbVie, Gilead.Hartwig Klinker hat in den letzten 3 Jahren Zuwendungen (z. B. Vortragshonorare, Forschungsgelder oder Beraterhonorare) erhalten von: AbbVie, BMS, Gilead, Janssen, MSDTobias Müller hat keine Interessenkonflikte.Uta Merle hat in den letzten 3 Jahren Zuwendungen (z. B. Vortragshonorare, Forschungsgelder oder Beraterhonorare) erhalten von: CSL-Behring, FALK.Dietrich Hüppe hat in den letzten 3 Jahren Zuwendungen (z. B. Vortragshonorare, Forschungsgelder oder Beraterhonorare) erhalten von: AbbVie GmbH & Co. KG, Falk Pharma, Ferring Arzneimittel GmbH.Michael P. Manns hat in den letzten 3 Jahren Zuwendungen (z. B. Vortragshonorare, Forschungsgelder oder Beraterhonorare) erhalten von: AbbVie, BMS, Gilead, Merck (MSD)Heiner Wedemeyer hat in den letzten 3 Jahren Zuwendungen (z. B. Vortragshonorare, Forschungsgelder oder Beraterhonorare) erhalten von: Abbott, AbbVie, Altimmune, Biotest, BMS, BTG, Dicerna, Gilead, Janssen, Merck/MSD, MYR GmbH, Novartis, Roche, Siemens, Transgene., (Thieme. All rights reserved.)

Sotagliflozin, a dual sodium-glucose co-transporter (SGLT)1/SGLT2 inhibitor, is currently approved in Europe as an adjunct to optimal insulin therapy in adults with type 1 diabetes (T1D) and a body mass index (BMI) ≥ 27 kg/m 2 . In this post hoc analysis, efficacy at 24 weeks and safety at 52 weeks from pooled phase 3 clinical trials were evaluated in patients with baseline BMI ≥ 27 kg/m 2 . Sotagliflozin 200 mg and 400 mg added to insulin reduced glycated haemoglobin level and increased time in range assessed by continuous glucose monitoring versus placebo and also reduced body weight and systolic blood pressure. Differences in efficacy endpoints between sotagliflozin and placebo tended to be greater among patients with BMI ≥ 27 kg/m 2 compared to those with baseline BMI < 27 kg/m 2 . Consistent with published results for the entire population, fewer severe hypoglycaemia and documented hypoglycaemia ≤3.1 mmol/L events and a higher incidence of diabetic ketoacidosis occurred with sotagliflozin versus placebo in patients with BMI ≥ 27 kg/m 2 . Sotagliflozin as an adjunct to optimized insulin therapy in overweight/obese patients with T1D addressed some unmet needs and may help achieve optimal glycaemic control, mitigating weight gain without increasing hypoglycaemia risk in this high-risk population., (© 2020 John Wiley & Sons Ltd.)

Background Ticagrelor reduces ischemic risk but increases bleeding in patients with prior myocardial infarction. Identification of patients at lower bleeding risk is important in selecting patients who are likely to derive more favorable outcomes versus risk from this strategy. Methods and Results PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) randomized 21 162 patients with prior myocardial infarction in a 1:1:1 fashion to ticagrelor 60 mg or 90 mg twice daily or placebo, with ticagrelor 60 mg approved for long-term use. TIMI major or minor bleeding was the primary end point for this analysis. Causes of bleeding were categorized by site and etiology, and independent predictors were identified. At 3 years, ticagrelor 60 mg increased the rate of TIMI major or minor bleeding by 2.0% versus placebo (1.4% placebo versus 3.4% ticagrelor). The bleeding excess was driven primarily by spontaneous gastrointestinal bleeds. A history of spontaneous bleeding requiring hospitalization and the presence of anemia were independent predictors of bleeding but not of ischemic risk. Patients with at least 1 risk predictor had 3-fold higher rates of bleeding with ticagrelor 60 mg versus those who had neither (absolute risk increase, 4.4% versus 1.5%; P =0.01). Patients with neither predictor had a more favorable benefit profile with ticagrelor 60 mg versus placebo including lower mortality (hazard ratio, 0.79; 95% CI, 0.65-0.96; P interaction = 0.03). Conclusions In patients with prior myocardial infarction, bleeding with ticagrelor 60 mg twice daily is predominantly spontaneous gastrointestinal. A history of spontaneous bleeding requiring hospitalization or the presence of anemia identifies patients at higher risk of bleeding, and the absence of either identifies patients likely to have a more favorable net benefit with ticagrelor. Registration URL https://www.clinicaltrials.gov/. Unique identifier: NCT01225562.

Background: Despite the overall neutral results of the GLOBAL-LEADERS trial, results from a prespecified subgroup analysis showed that patients from Western Europe had a significantly lower rate of the primary endpoint when treated with ticagrelor monotherapy. Therefore, we aimed to examine the regional disparities in patients' baseline characteristics and their response to ticagrelor monotherapy., Methods: Patients' baseline characteristics and the treatment effects of ticagrelor combined with aspirin for 1 month, followed by ticagrelor monotherapy for 23-months versus 12-months of standard dual antiplatelet therapy (DAPT) were compared according to participating countries. The primary endpoint was a composite endpoint of all-cause death or new Q-wave myocardial infarction at two years., Results: Significant variances in patients' baseline characteristics were found between participating countries. The primary endpoint varied significantly according to the country (P interaction  = 0.027). Patients from France (1.6% versus 5.2%, HR: 0.31, 95%CI: 0.13-0.73) and The Netherlands (2.4% versus 4.8%, HR, 0.50, 95%CI: 0.26-0.94) had lower rates of the primary endpoint when allocated to ticagrelor monotherapy, compared with the standard DAPT regimen. Of the 26 baseline and post-randomization factors explored, variance in the rate of complex PCI between countries was identified as the top contributor to this regional interaction., Conclusions: Patients' baseline characteristics varied between participating countries in the GLOBAL-LEADERS trial. There is a significant regional variance in the treatment effect of ticagrelor monotherapy, which could partly be explained by the differences in complex PCI being performed., Clinical Trial Registration: ClinicalTrials.gov (NCT01813435)., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: Janus kinase inhibitors (JAKi) have been approved for use in various immune-mediated inflammatory diseases. With five agents licensed, it was timely to summarise the current understanding of JAKi use based on a systematic literature review (SLR) on efficacy and safety., Methods: Existing data were evaluated by a steering committee and subsequently reviewed by a 29 person expert committee leading to the formulation of a consensus statement that may assist the clinicians, patients and other stakeholders once the decision is made to commence a JAKi. The committee included patients, rheumatologists, a gastroenterologist, a haematologist, a dermatologist, an infectious disease specialist and a health professional. The SLR informed the Task Force on controlled and open clinical trials, registry data, phase 4 trials and meta-analyses. In addition, approval of new compounds by, and warnings from regulators that were issued after the end of the SLR search date were taken into consideration., Results: The Task Force agreed on and developed four general principles and a total of 26 points for consideration which were grouped into six areas addressing indications, treatment dose and comedication, contraindications, pretreatment screening and risks, laboratory and clinical follow-up examinations, and adverse events. Levels of evidence and strengths of recommendations were determined based on the SLR and levels of agreement were voted on for every point, reaching a range between 8.8 and 9.9 on a 10-point scale., Conclusion: The consensus provides an assessment of evidence for efficacy and safety of an important therapeutic class with guidance on issues of practical management., Competing Interests: Competing interests: DA has received grants from AbbVie, Novartis and Roche, consulting and lecture fees from Abbvie, Amgen, Celgene, Lilly, Medac, Merck Sharpe & Dohme, Novartis, Pfizer, Roche, Sandoz and Sanofi/Genzyme. W-HB has received a research grant from Pfizer and honoraria for advice from Abbvie, Alimirall, BMS, Celgene, Janssen, Leo, Lilly, Novartis and UCB. TD received study support and/or consulting fees by AbbVie, Celgene, Eli-Lilly, EMD/Merck, Janssen, Novartis, Pfizer, Roche, Sanofi, UCB Pharma. MD: grants from Pfizer, Abbvie, UCB, Janssen, Novartis and honoraria from Pfizer, Abbvie, UCB, Janssen, MSD, Novartis, BMS, Celgene, Biogen, Sandoz. PE: grants from AbbVie, Novartis, Samsung, Lilly and honoraria from AbbVie, Novartis, BMS, Gilead, Samsung, Lilly. XB, KG received consultancy and lecture fees from Novartis, Pfizer and Roche and investigational grants from Roche. EBL reports grants from Green pharma, Seoul, grants from Handoc, Seoul, and personal fees from Pfizer. PTN has received research grants and funding for clinical trials and honoraria for advice and lectures on behalf of Abbvie, BMS, Boehringer Ingelheim, Celgene, Eli-Lilly, Gilead, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, UCB Pharma. JEP has consulted for Amgen, AbbVie, BMS, Celltrion, Gilead, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Samsung, Sandoz, Sanofi, Teva, UCB. RMF has received research grants and funding for clinical trials and honoraria for adbice from Abbvie, Amgen, Astra-Zeneca, BMS, Celltrion, Lilly, Gilead, GSK, Janssen, Novartis, Pfizer, Regeneron, Roche, Sandoz, Sanofi, Tahio and UCB. DvdH received consulting fees AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli-Lilly, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma and is Director of Imaging Rheumatology bv. JDI has received research funding or honoraria from Abbvie, Bristol-Myers Squibb, Eli Lilly, Gilead, Janssen, Merck, Pfizer, Roche. AK has received lecture fees from Bristol-Myers Squibb, Celgene, Merck Sharp and Dohme and Pfizer. JK received grant support for clinical research from Abbvie, BMS, Lilly, Novartis, Pfizer and consulted with Abbvie, BMS, Lilly, Novartis, Pfizer and Regeneron/Sanofi. IBM has received research funding or honoraria from Abbvie, Astra Zeneca, Celgene, GSK, Lilly, Boehringer, Pfizer, Janssen, Novartis, UCB, BMS, Sanofi. WPM has served as a consultant, and/or received honoraria and/or has received research/educational grants from AbbVie, Boehringer Ingelheim, Celgene, Eli Lilly and Company, Galapagos, Janssen, Novartis, Pfizer and UCB Pharma, and is Chief Medical Officer of CARE Arthritis Limited. MV: no conflict of interest. JSS has received research Grants for his institution from AbbVie, BMS, Lilly, MSD, Pfizer, Roche and honoraria for consultancies and/or speaking engagements: Abbvie, Amgen, Astra-Zeneca, Astro-Celltrion, BMS, Celgene, ILTOO, Janssen, Lilly, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB. MS-M has no conflicts of interest. LST received grant support from Janssen, GSK and Pfizer and honoraria for consultations and/or speaking engagements from Janssen, Pfizer, Sanofi, Abbvie and Lilly. TT received grants from Astellas, AbbVie GK, Eisai; speaking fee from: AbbVie GK, Eli Lilly Japan, Astellas, Eisai, Gilead, Pfizer Japan; and consultancy fees from: Astellas, AbbVie GK, Gilead. YT has received speaking fees and/or honoraria from Daiichi-Sankyo, Eli Lilly, Novartis, YL Biologics, Bristol-Myers, Eisai, Chugai, Abbvie, Astellas, Pfizer, Sanofi, Asahi-kasei, GSK, Mitsubishi-Tanabe, Gilead, Janssen and has received research grants from Mitsubishi-Tanabe, Chugai, Abbvie, Takeda, UCB, Daiichi-Sankyo, Eisai. MT: Speaker for BMS, Falk Foundation, Gilead and MSD; advisory boards for Albireo, BiomX, Boehringer Ingelheim, Falk Pharma GmbH, Genfit, Gilead, Intercept, MSD, Novartis, Phenex and Regulus. He further received unrestricted research grants from Albireo, Cymabay, Falk, Gilead, Intercept, MSD and Takeda. He is also co-inventor of patents on the medical use of norUDCA (filed by the medical University of Graz as previous employer). FvdB received consultancy and/or speaker fees from Abbvie, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer and UCB. MdW has received honoraria for consultancies and speaking through Stichting Tools from AbbVie, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer, Roche. RW: honoraria for speaking engagements and advice from Galapagos, Gilead and Celltrion. KLW received grant support from BMS and Pfizer and honoraria for consultations and /or speaking engagements from Pfizer, BMS, Abbvie, Gilead, Galapagos, Lilly, GSK, UCB. RX received consultancy and/or speaker fees from Abbvie, Lilly, Pfizer, UCB, Janssen., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Despite treatment according to the current management recommendations, a significant proportion of patients with rheumatoid arthritis (RA) remain symptomatic. These patients can be considered to have 'difficult-to-treat RA'. However, uniform terminology and an appropriate definition are lacking., Objective: The Task Force in charge of the " Development of EULAR recommendations for the comprehensive management of difficult-to-treat rheumatoid arthritis" aims to create recommendations for this underserved patient group. Herein, we present the definition of difficult-to-treat RA, as the first step., Methods: The Steering Committee drafted a definition with suggested terminology based on an international survey among rheumatologists. This was discussed and amended by the Task Force, including rheumatologists, nurses, health professionals and patients, at a face-to-face meeting until sufficient agreement was reached (assessed through voting)., Results: The following three criteria were agreed by all Task Force members as mandatory elements of the definition of difficult-to-treat RA: (1) Treatment according to European League Against Rheumatism (EULAR) recommendation and failure of ≥2 biological disease-modifying antirheumatic drugs (DMARDs)/targeted synthetic DMARDs (with different mechanisms of action) after failing conventional synthetic DMARD therapy (unless contraindicated); (2) presence of at least one of the following: at least moderate disease activity; signs and/or symptoms suggestive of active disease; inability to taper glucocorticoid treatment; rapid radiographic progression; RA symptoms that are causing a reduction in quality of life; and (3) the management of signs and/or symptoms is perceived as problematic by the rheumatologist and/or the patient., Conclusions: The proposed EULAR definition for difficult-to-treat RA can be used in clinical practice, clinical trials and can form a basis for future research., Competing Interests: Competing interests: All participants provided declaration of interest, the individual declarations are attached as online supplemental file 2., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The best approach for Helicobacter pylori management remains unclear. An audit process is essential to ensure clinical practice is aligned with best standards of care., Design: International multicentre prospective non-interventional registry starting in 2013 aimed to evaluate the decisions and outcomes in H. pylori management by European gastroenterologists. Patients were registered in an e-CRF by AEG-REDCap. Variables included demographics, previous eradication attempts, prescribed treatment, adverse events and outcomes. Data monitoring was performed to ensure data quality. Time-trend and geographical analyses were performed., Results: 30 394 patients from 27 European countries were evaluated and 21 533 (78%) first-line empirical H. pylori treatments were included for analysis. Pretreatment resistance rates were 23% to clarithromycin, 32% to metronidazole and 13% to both. Triple therapy with amoxicillin and clarithromycin was most commonly prescribed (39%), achieving 81.5% modified intention-to-treat eradication rate. Over 90% eradication was obtained only with 10-day bismuth quadruple or 14-day concomitant treatments. Longer treatment duration, higher acid inhibition and compliance were associated with higher eradication rates. Time-trend analysis showed a region-dependent shift in prescriptions including abandoning triple therapies, using higher acid-inhibition and longer treatments, which was associated with an overall effectiveness increase (84%-90%)., Conclusion: Management of H. pylori infection by European gastroenterologists is heterogeneous, suboptimal and discrepant with current recommendations. Only quadruple therapies lasting at least 10 days are able to achieve over 90% eradication rates. European recommendations are being slowly and heterogeneously incorporated into routine clinical practice, which was associated with a corresponding increase in effectiveness., Competing Interests: Competing interests: JPG has served as speaker, consultant and advisory member for or has received research funding from Mayoly, Allergan and Diasorin. OPN has received a research grant from Allergan. JM-I has served as a consultant for Casen Recordati and has received retribution from Allergan for formative actions. MC-F has received retribution from Allergan for formative actions. PB has served as speaker, consultant and advisory member for or has received research funding from Almirall, Allergan and Reckitt Benckiser. APA has received retribution from Allergan and Mylan for formative actions. DSB has served as lecturer for Astellas, AstraZeneca, KRKA and Abbott., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Since many patients with major depressive disorder (MDD) do not satisfactorily respond to initial antidepressant monotherapy, add-on treatment strategies with other psychiatric compounds are often established. The present European multicenter cross-sectional study comprising 1410 MDD in- and outpatients investigated the prescription pattern of benzodiazepines as add-on treatment in the psychopharmacotherapy of MDD. Analyses of variance, chi-squared tests, and logistic regression analyses were conducted to examine differences in socio-demographic, clinical, and treatment characteristics between benzodiazepine users and non-users. The prescription rate for adjunctive benzodiazepine treatment amounted to 31.35%. The most often administered benzodiazepines were lorazepam (11.13%), clonazepam (6.74%), and alprazolam (6.60%). Benzodiazepine users exhibited more severe depressive symptoms expressed by a higher mean Montgomery and Åsberg Depression Rating Scale total score at study entry (26.92 ± 11.07 vs 23.55 ± 11.23, p<.0001) and at the beginning of the current major depressive episode (35.74 ± 8.08 vs 33.31 ± 7.40, p<.0001). Furthermore, they were characterized by a higher proportion of patients receiving additional augmentation/combination medications with antidepressants (40.95% vs 24.28%, p<.0001), antipsychotics (41.63% vs 18.39%, p<.0001), and low-potency antipsychotics (10.18% vs 4.75%, p<.0001). Moreover, benzodiazepine prescription was associated with older age, unemployment, inpatient treatment, suicide risk, psychotic and melancholic features, comorbid panic disorder, agoraphobia, social phobia, and obsessive-compulsive disorder. Taken together, our findings indicate that benzodiazepine augmentation in MDD is first of all established in severe/difficult-to-treat conditions and serves as predictor for the use of additional augmentation/combination treatment strategies., Competing Interests: Conflict of Interest All other authors declare that they have no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

Objectives: The aim of the study was to assess clinical presentation, endoscopic findings, antibiotic susceptibility and treatment success of Helicobacter pylori (H. pylori) infected pediatric patients., Methods: Between 2013 and 2016, 23 pediatric hospitals from 17 countries prospectively submitted data on consecutive H. pylori-infected (culture positive) patients to the EuroPedHP-Registry., Results: Of 1333 patients recruited (55.1% girls, median age 12.6 years), 1168 (87.6%) were therapy naïve (group A) and 165 (12.4%) had failed treatment (group B). Patients resided in North/Western (29.6%), Southern (34.1%) and Eastern Europe (23.0%), or Israel/Turkey (13.4%). Main indications for endoscopy were abdominal pain or dyspepsia (81.2%, 1078/1328). Antral nodularity was reported in 77.8% (1031/1326) of patients, gastric or duodenal ulcers and erosions in 5.1% and 12.8%, respectively. Primary resistance to clarithromycin (CLA) and metronidazole (MET) occurred in 25% and 21%, respectively, and increased after failed therapy. Bacterial strains were fully susceptible in 60.5% of group A, but in only 27.4% of group B. Primary CLA resistance was higher in Southern and Eastern Europe (adjusted odds ratio [ORadj] = 3.44, 95% confidence interval [CI] 2.22-5.32, P < 0.001 and 2.62, 95% CI: 1.63-4.22, P < 0.001, respectively) compared with Northern/Western Europe. Children born outside Europe showed higher primary MET resistance (ORadj = 3.81, 95% CI: 2.25-6.45, P < 0.001). Treatment success in group A reached only 79.8% (568/712) with 7 to 14 days triple therapy tailored to antibiotic susceptibility., Conclusions: Peptic ulcers are rare in dyspeptic H. pylori-infected children. Primary resistance to CLA and MET is markedly dependent on geographical regions of birth and residence. The ongoing survey will show whether implementation of the updated ESPGHAN/NASPGHAN guidelines will improve the eradication success.

Background: Genotype 1b is the most common HCV genotype worldwide, accounting for the largest proportion of infections in Europe, Russia, Latin America and Asia. Reducing treatment duration can improve adherence, reduce drug exposure and cost. Accordingly, we evaluated the efficacy of 8 weeks fixed-dose combination of grazoprevir-elbasvir in treatment-naïve patients, with non-severe fibrosis., Methods: HCV mono-infected and treatment naïve patients with non-severe fibrosis (Fibroscan ® <9.5 kPa and Fibrotest ®  < 0.59) were enrolled in a study which included 117 patients. Genotyping by sequencing identified five patients with non-1b genotype (two GT1a, one GT1h, one GT1e and one GT1l). Thus, we included in the final analysis 112 GT1b patients. The primary end point was the proportion of patients with HCVRNA below the lower limit of quantification 12 weeks after treatment (SVR12)., Findings: Mean age was 54 ± 13 years, 31% were men and viral load was higher than 800.000 IU/mL in 70 of 112 patients (63%). Using Fibroscan ® , 100 had F0-1 fibrosis score. FIB-4 lower than 1.45 and APRI less than 1 was found in 74/112 (66%) and 107/112 (95%) patients respectively. Relapse occurred in three patients by week 12. These three patients had a viral load higher than 6 million IU/mL and NS5A Y93H RAS (resistance-associated substitution). Then, modified intention-to-treat SVR12 for patients with genotype 1b was 109/112 (97%). By week 24; five relapses were observed and all had the Y93H RAS at relapse. SVR12 was achieved in 100% of patients with a baseline viral load below 6 million and decreased to 98% (98/100) by follow-up week 24., Interpretation: Naïve patients with genotype 1b and non-severe fibrosis can achieve an SVR12 of 97% and an SVR24 of 95%. Then, these patients can be treated with grazoprevir-elbasvir for 8 weeks., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: In Europe, increases in HCV infection have been observed over the last two decades in MSM, making them a key population for recently acquired HCV. Alternative combinations of direct-acting antiviral agents against early HCV infection need to be assessed., Patients and Methods: In this pilot trial, MSM with recently acquired genotype 1 or 4 HCV infection were prospectively included and received 8 weeks of oral grazoprevir 100 mg and elbasvir 50 mg in a fixed-dose combination administered once daily. The primary endpoint was sustained virological response evaluated 12 weeks after the end of treatment (EOT) (SVR12). Secondary endpoints were the virological characterization of failures, the quality of life before, during and after treatment and the rate of reinfection., Results: In a 15 month period, 30 patients were enrolled, all of whom were MSM. Of the 29 patients completing follow-up, 28 (96%, 95% CI = 82%-99%) achieved SVR12. One patient interrupted follow-up (suicide) but had undetectable plasma HCV RNA at EOT. One patient with suboptimal adherence confirmed by plasma drug monitoring relapsed and developed NS3, NS5A and NS5B resistance-associated substitutions (V36M, M28V and S556G). The most common adverse events related to study drug were diarrhoea (n = 4, 13%), insomnia (n = 2, 7%) and fatigue (n = 2, 7%), although no patient discontinued treatment. No HIV RNA breakthrough was reported in the 28 patients with HIV coinfection. At Week 48, reinfection was diagnosed in three patients., Conclusions: Our data support the use of grazoprevir/elbasvir for immediate treatment against HCV in order to reduce HCV transmission in MSM., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Patients infected with the novel coronavirus (SARS-CoV-2) are being treated empirically with oseltamivir, but there is little evidence from randomised controlled trials to support the treatment of coronavirus infections with oseltamivir., Aim: To determine whether adding oseltamivir to usual care reduces time to recovery in symptomatic patients who have tested positive for coronavirus (not including SARS-CoV-2)., Design and Setting: Exploratory analysis of data from an open-label, pragmatic, randomised controlled trial during three influenza seasons, from 2016 to 2018, in primary care research networks, in 15 European countries., Method: Patients aged ≥1 year presenting to primary care with influenza-like illness (ILI), and who tested positive for coronavirus (not including SARS-CoV-2), were randomised to usual care or usual care plus oseltamivir. The primary outcome was time to recovery defined as a return to usual activities, with minor or absent fever, headache, and muscle ache., Results: Coronaviruses (CoV-229E, CoV-OC43, CoV-KU1 and CoV-NL63) were identified in 308 (9%) out of 3266 randomised participants in the trial; 153 of these were allocated to usual care and 155 to usual care plus oseltamivir; the primary outcome was ascertained in 136 and 147 participants, respectively. The median time to recovery was shorter in patients randomised to oseltamivir: 4 days (interquartile range [IQR] 3-6) versus 5 days (IQR 3-8; hazard ratio 1.31; 95% confidence interval = 1.03 to 1.66; P = 0.026)., Conclusion: Primary care patients with ILI testing positive for coronavirus (not including SARS-CoV-2) recovered sooner when oseltamivir was added to usual care compared with usual care alone. This may be of relevance to the primary care management of COVID-19., (©The Authors.)

Objective: To update the 2012 EULAR/ERA-EDTA recommendations for the management of lupus nephritis (LN)., Methods: Following the EULAR standardised operating procedures, a systematic literature review was performed. Members of a multidisciplinary Task Force voted independently on their level of agreeement with the formed statements., Results: The changes include recommendations for treatment targets, use of glucocorticoids and calcineurin inhibitors (CNIs) and management of end-stage kidney disease (ESKD). The target of therapy is complete response (proteinuria <0.5-0.7 g/24 hours with (near-)normal glomerular filtration rate) by 12 months, but this can be extended in patients with baseline nephrotic-range proteinuria. Hydroxychloroquine is recommended with regular ophthalmological monitoring. In active proliferative LN, initial (induction) treatment with mycophenolate mofetil (MMF 2-3 g/day or mycophenolic acid (MPA) at equivalent dose) or low-dose intravenous cyclophosphamide (CY; 500 mg × 6 biweekly doses), both combined with glucocorticoids (pulses of intravenous methylprednisolone, then oral prednisone 0.3-0.5 mg/kg/day) is recommended. MMF/CNI (especially tacrolimus) combination and high-dose CY are alternatives, for patients with nephrotic-range proteinuria and adverse prognostic factors. Subsequent long-term maintenance treatment with MMF or azathioprine should follow, with no or low-dose (<7.5 mg/day) glucocorticoids. The choice of agent depends on the initial regimen and plans for pregnancy. In non-responding disease, switch of induction regimens or rituximab are recommended. In pure membranous LN with nephrotic-range proteinuria or proteinuria >1 g/24 hours despite renin-angiotensin-aldosterone blockade, MMF in combination with glucocorticoids is preferred. Assessment for kidney and extra-renal disease activity, and management of comorbidities is lifelong with repeat kidney biopsy in cases of incomplete response or nephritic flares. In ESKD, transplantation is the preferred kidney replacement option with immunosuppression guided by transplant protocols and/or extra-renal manifestations. Treatment of LN in children follows the same principles as adult disease., Conclusions: We have updated the EULAR recommendations for the management of LN to facilitate homogenization of patient care., Competing Interests: Competing interests: AF reports personal fees from GSK, Abbvie, Amgen, Enorasis, Roche and Genesis Pharma, outside the submitted work. HJA reports personal fees from GSK, Astra Zeneca and Janssen, during the conduct of the study; personal fees from Secarna, Inositec, Previpharma and Noxxon, outside the submitted work. MA reports honoraria fees from GSK and Roche, outside the submitted work; FH reports honoraria fees from GSL, outside the submitted work. MP reports personal fees from Otsuka, grants and personal fees from Alexion, personal fees from Retrophin, outside the submitted work. YKOT reports grants from GSK, personal fees from Aurinia Pharmaceuticals, personal fees from Novartis, during the conduct of the study. MT reports grants from Abbvie, BMS, Novartis, Pfize and Roche and honoraria fees from Novartis, outside the submitted work. DJ reports personal fees from Astra-Zeneca, Aurinia, Boehringer-Ingelheim, grants and personal fees from Chemocentryx, GSK, Roche/Genentech, and Sanofi-Genzyme, personal fees and other from Vifor, outside the submitted work., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To provide an update of the European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) management recommendations to account for the most recent developments in the field., Methods: An international task force considered new evidence supporting or contradicting previous recommendations and novel therapies and strategic insights based on two systematic literature searches on efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) since the last update (2016) until 2019. A predefined voting process was applied, current levels of evidence and strengths of recommendation were assigned and participants ultimately voted independently on their level of agreement with each of the items., Results: The task force agreed on 5 overarching principles and 12 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GCs); biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, sarilumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (the Janus kinase (JAK) inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib). Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering on sustained clinical remission is provided. Cost and sequencing of b/tsDMARDs are addressed. Initially, MTX plus GCs and upon insufficient response to this therapy within 3 to 6 months, stratification according to risk factors is recommended. With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD or JAK inhibitor should be added to the csDMARD. If this fails, any other bDMARD (from another or the same class) or tsDMARD is recommended. On sustained remission, DMARDs may be tapered, but not be stopped. Levels of evidence and levels of agreement were mostly high., Conclusions: These updated EULAR recommendations provide consensus on the management of RA with respect to benefit, safety, preferences and cost., Competing Interests: Competing interests: DA: grants from Abbvie, Novartis, Roche and honoraria from Abbvie, Amgen, Celgene, Lilly, Medac, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi/Genzyme; MA: honoraria from AbbVie, Astra Zeneca, BMS, Boehringer Ingelheim, Chugai, HEXAL, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, UCB; JA: grants from Abbvie, BMS, Lilly, Merck, Pfizer, Roche, Samsung Bioepis, UCB; AB: grants from Pfizer, Bristol-Myers Squibb and honoraria from Pfizer, Roche, AbbVie, Bristol-Myers Squibb, UCB, MSD, Novartis, Sanofi, Biogen, Sandoz, Celltrion, Nordic, Gilead; JWJB: honoraria from Lilly, Roche, Sanofi; MB: honoraria from BMS, Teva, Novartis, Pfizer, GSK; AdB: grants from Abbvie, Biogen, Celltrion and honoraria from Abbvie, Biogen, Boehringer-Ingelheim, Celgene, Fresenius, MSD, Roche.MHB has received grants from Pfizer, Roche and UCB and consulting fees from Abbvie, Eli-Lilly, Merck.Serono, Pfizer, Sandoz, Sanofi; GB: grants from Abbvie, Pfizer, Sanofi, UCB and honoraria from Abbvie, Celgene, Gilead, Lilly, MSD, Novartis, Pfizer, Sanofi, Roche. FB: grants from Abbvie, BMS, Horizon, Medac, Pfizer, Roche, Lilly, Sanofi and honoraria from Abbvie, Galapagos, Horizon, Medac, Pfizer, Roche, Sanofi, Janssen, BMS, MSD, Lilly; RC: honoraria from Abbvie, BMS, Celgene, Celltrion, Gilead, Janssen, Lilly MSD, Mundipharma, Novartis-Sandoz, Pfizer, Roche, Sanofi and UCB; MC; honoraria from Abbvie, Astellas, BMS, Lilly, Pfizer and Roche; DDC: no conflict; CC: honoraria from AbbVie, Accord Healthcare, Alfasigma, Berlin Chemie, Egis, Eli Lilly, Ewopharma, Genesis, MSD, Mylan, Novartis, Pfizer, Roche, Sandoz, UCB; MD: grants from Pfizer, Abbvie, UCB, Janssen, Novartis and honoraria from Pfizer, Abbvie, UCB, Janssen, MSD, Novartis, BMS, Celgene, Biogen, Sandoz; CJE: grants from Abbvie, Biogen and honoraria from Abbvie, BMS, Biogen, Celgene, Fresenius, Gilead, Janssen, Lilly, Mundipharma, Pfizer, MSD, Novartis, Roche, Samsung, Sanofi, UCB; PE: grants from AbbVie, Novartis, Samsung, Lilly and honoraria from AbbVie, Novartis, BMS, Gilead, Samsung, Lilly; AF: grants from BMS, Pfizer and honoraria from AB2 BIO, Abbvie, BMS, Lilly, MSD, Pfizer, Roche, Sanofi; LG: grants from Abbvie, BMS, Lilly, UCB and honoraria from Abbvie, Biogen, Celgene, Janssen, Lilly, Novartis, Pfizer, Sanofi-Aventis, UCB; J-EG: grants from BMS, Pfizer and honoraria from Abbvie, BMS, Lilly, Sanofi-Genzyme, Roche, UCB; MLH: grants from Abbvie, Biogen, BMS, Celltrion, MSD, Novartis, Orion, Pfizer, Samsung, UCB; TH: grants from Lilly, Merck, UCB, BMS, Janssen, Pfizer, Sanofi-Aventis, Galapagos, Boeringher and honoraria from Abblynx, BMS, Janssen, Pfizer, Sanofi-Aventis, Crescendo Bioscience, Galapagos, Lilly; AK: honoraria from BMS, Pfizer, Celgene, MSD; MK: no conflicts of interest; RBML: honoraria from AbbVie, BMS, Celgene, Eli-Lilly, Jansen Pharmaceuticals, Galapagos, Novartis, MSD, Pfizer, UCB and Director of Rheumatology Consultancy BV; XM: honoraria from BMS, Gilead, Pfizer, Samsung, UCB; IBM: grants from Astra Zeneca, UCB, BMS, Janssen, GSK, Compugen, Boehringer, Celgene and honoraria from Abbvie, BMS, Janssen, Novartis, UCB, Astra Zeneca, Celgene, Causeway, Lilly, Leo, Novimmune; EM: grants from Pfizer, Lilly, BMS, AbbVie, GSK, Astra and honoraria from Pfizer, BMS, Roche, Lilly, AbbVie, Gemma, Sanofi; TWJH: grants from Eli Lilly, Merck, UCB, BMS, Janssen, Pfizer, Sanofi-Aventis, Galapagos, Boehringer and honoraria from Abblynx, Abbvie, BMS, Boehringer, Crescendo-Bioscience, Epirus, Galapagos, Janssen, Lilly, Merck, Novartis, Nycomed, Pfizer, Roche, Sanofi-Aventis, Takeda, UCB; ZL: no conflicts of interest; UM-L: honoraria from Abbvie, BMS, MSD, Chugai, Roche, Pfizer, Sanofi, Boehringer, Actelion, Medac, Lilly; GP: no conflicts of interest; JP: grants from BMS, Merck, UCB and honoraria from AbbVie, Actelion, Amgen, BMS, Bayer, GSK, Lilly, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, UCB; AR-R: honoraria from Abbvie, Chugai, BMS, Sanofi, Roche, Lilly, Janssen, Novartis, Celgene, MSD, UCB; AR-W: grants from Pfizer, Abbvie and honoraria from Abbvie, Amgen, BMS, Janssen, Lilly, Medac, Nordic Pharma, Novartis, Pfizer, Roche-Chugai, Sanofi, UCB; KS: grants from Amgen, Ironwood/AstraZeneca, Horizon, SOBI, Takeda and honoraria from AbbVie, Amgen, Ironwood/AstraZeneca, Bayer, Gilead, Horizon, Kowa, Radius, Roche/Genentech, SOBI, Takeda, Teijin; MSV: no conflicts of interest. AS: honoraria from Novartis; JSS: grants from Abbvie, AstraZeneca, Janssen, Lilly, Novartis, Roche and honoraria from Abbvie, Amgen, AstraZeneca, Astro, BMS, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Lilly, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB; AS: grants from AbbVie, Bristol-Myers Squibb, Celltrion, Hexal AG Lilly, MSD Sharp & Dome, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, UCB and honoraria from AbbVie, BMS, MSD, Pfizer, Roche; TT: grants from AbbVie, Asahikasei, Astellas, AYUMI, Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, Nipponkayaku, Novartis, Pfizer, Takeda and honoraria from AbbVie, Astellas, Astra Zeneca, BMS, Chugai, Diaichi Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Janssen, Mitsubishi Tanabe, Nipponkayaku, Novartis, Pfizer, Sanofi, Teijin, Taiho Pharmaceutical, Taisho Pharmaceutical, Takeda, UCB; DvdH: grants from UCB and honoraria from AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi, Eli-Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB and Director Imaging Rheumatology BV; YvE-H: honoraria from Celgene; RFvV: grants from BMS, GSK, Lilly, UCB and honoraria from AbbVie, AstraZeneca, Biotest, BMS, Celgene, GSK, Janssen, Lilly, Novartis, Pfizer, Roche, UCB; RW: grants from Roche, BMS and honoraria from Celltrion, Galapagos-Gilead; MdW: honoraria from 'Stichting Tools', Janssen-Cilag., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)