Importance:As health care systems face greater strain due to the increasing prevalence of long-term conditions (LTCs) and workforce shortages, optimizing remote care could help maintain access to timely follow-up care while alleviating pressure on in-person services. Objectives:To assess the availability and use of 3 remote modalities by patients with LTCs for interacting with their referring physician; their preference for in-person vs remote consultation for different situations; and their willingness to trade an in-person consultation with their referring physician in 20 days for an earlier remote consultation with a nonreferring physician. Design, Setting, and Participants:This survey study was conducted from April 1 to August 28, 2024, in France. Adult patients with at least 1 LTC participating in a nationwide e-cohort were recruited to complete an online survey. To obtain estimates representative of patients with LTCs in France, analyses were performed on a weighted dataset with calibration on margins from the 2021 Santé Publique France Survey. Exposures:Each patient was presented with 1 of 5 randomly assigned situations regarding worsening symptoms, new symptoms, annual checkup, medication renewal, and results discussion. Main Outcomes and Measures:Responses were assessed for (1) availability and use of remote modalities (video consultation, telephone contact, and asynchronous message exchange) for interacting with the referring physician; (2) patient preference for in-person or remote modalities when interacting with the referring physician depending on the situation; and (3) patient willingness to trade an in-person consultation with their physician in 20 days for an earlier direct-to-consumer (DTC) remote consultation with a nonreferring physician. Results:Among 1995 participants (mean [SD] age, 55 [17] years; 56% women), 47% reported that no remote modalities for communicating with their referring physician were available. (All percentages presented are weighted.) Up to 55% preferred remote over in-person consultation to interact with their referring physician, with higher proportions for results discussion (43%) and medication renewal (55%) than for worsening symptoms (36%), new symptoms (25%), and annual checkup (26%). Up to 51% of patients were willing to trade an in-person consultation with their referring physician in 20 days for a DTC remote consultation within 5 days with a nonreferring physician. Conclusions and Relevance:This survey study showed that patients with LTCs had limited access to remote modalities to interact with their referring physician for follow-up care, and patients considered replacing an in-person with a remote consultation even with another physician depending on the situation and the length of delay. Further research is needed to investigate the effective integration of remote care into the health care system in ways that maintain patient-centered care and improve patient outcomes.

BACKGROUND AND OBJECTIVES:Target trial emulation, i.e., the analysis of observational data by explicitly emulating the design components of a randomized controlled trial (RCT), has gained attention in recent years as an approach to estimate causal effects of pharmacological or nonpharmacological interventions that are, on average, similar to those of RCTs. METHODS:This article addresses 2 objectives. First, we examine factors that may explain discrepancies in treatment effect estimates between RCTs and their target trial emulations, beyond issues related to bias or imperfect replication of the original trial. Second, we outline 11 practical considerations for the design and planning of a target trial emulation. RESULTS:Treatment effect estimates from RCTs and their target trial emulations may differ because of differences in the underlying populations (beyond formal eligibility criteria), the definition of interventions, the measurement and definition of outcomes, and the causal estimand being targeted. To improve the validity of target trial emulations, several design elements should be considered. For example, control and intervention groups should be concomitant and geographically comparable, and temporal changes in clinical practice should be accounted for. Also, when grace periods are used, they should reflect logistical delays in treatment initiation while maintaining assignment at time zero. Finally, emulations necessitate adequate sample size and sufficiently rich data to address imbalances in prognostic factors. CONCLUSION:This article provides key elements to consider when planning a target trial emulation.

Importance:Retractions are rising in the scientific literature, increasing the risk of reusing unreliable results. Objectives:To identify reports of systematic reviews that included retracted studies in their meta-analyses, and to assess the impact of these retracted studies on the results. Design, Setting, and Participants:In this systematic review and meta-analysis the Feet of Clay Detector tool was searched to identify all systematic reviews that reported at least 1 meta-analysis including at least 1 retracted study and were published in the 25 highest impact factor journals in medicine, general and internal, from January 2013 to April 2024. All effect estimates where the retracted study contributed to the analysis were identified. For each meta-analysis, the summary effect, including all studies and excluding retracted studies was calculated. The search was conducted on April 8, 2024. Results:Overall, 61 systematic reviews were identified that included retracted studies in their meta-analyses. Of these, 11 (18%) have been republished, retracted, or withdrawn. Data were extracted from 50 systematic reviews that included a total of 62 retracted studies. Retraction occurred after the publication in 37 systematic reviews (74%). Overall, 173 meta-analyses including the retracted study were identified; 70 of them (40%) were primary outcomes. One-hundred sixty-six meta-analyses were recalculated. Overall, 160 (96%) of the 166 recalculated effect estimates were within the CIs of the original effect. After exclusion of the retracted study, the statistical significance of the results changed in 18 meta-analyses (11%). The rate of evolution between effect estimates with and without retracted studies for 163 meta-analyses overall were calculated, including 64 addressing the primary outcomes of the systematic reviews. For primary outcomes (n = 64), the recalculated effect estimates changed by at least 10% in 27 meta-analyses (42%), 30% in 16 (25%), and 50% in 12 (19%). Overall (n = 163), effect estimates changed by at least 10% in 57 meta-analyses (35%), 30% in 31 (19%), and 50% in 23 (14%). Conclusions and Relevance:This study found that retracted studies have been included in systematic reviews and meta-analyses, with retractions occurring mainly after the publication of the systematic review. The inclusion of retracted studies can impact the results and interpretation of reviews. Quality control measures should be implemented to prevent the dissemination of unreliable data in scientific literature.

BACKGROUND AND OBJECTIVES:Randomized controlled trials (RCTs) are more likely to be included in evidence syntheses of health interventions due to their methodological rigor. However, the integration of nonrandomized studies (NRSs) may be necessary, as was seen during the COVID-19 pandemic due to the emergence of variants of concern. We aimed to examine the body of evidence, randomized and nonrandomized, on COVID-19 vaccine effectiveness (VE) during the emergence of the Delta variant and to share lessons learned from including nonrandomized evidence alongside randomized evidence in the COVID-NMA living systematic review. STUDY DESIGN AND SETTING:The COVID-NMA initiative is an international, living systematic review and meta-analysis that continually synthesized evidence on COVID-19 interventions. For this study, we identified all RCTs and comparative NRSs reporting on VE against the Delta variant from December 2020 (its initial detection) through November 2021 (date of last COVID-NMA NRS search). We conducted two parallel systematic reviews: one focusing on RCTs and the other on NRSs to compare available evidence on VE against the Delta variant. We also compared the publication timelines of the included studies with the global prevalence of the Delta variant, and documented the specific methodological challenges and solutions when including NRSs in living systematic reviews. RESULTS:From December 2020 to November 2021, only one RCT reported vaccine efficacy against Delta in a subgroup of 6325 participants, while, during the same period, 52 NRSs including 68,010,961 participants reported VE against this variant. Nevertheless, including NRSs in our living systematic review posed several challenges. We faced difficulties in identifying eligible studies, encountered overlapping studies (ie, NRSs using the same database), and inconsistent definitions of Delta variant cases. Moreover, multiple analyses and metrics for the same outcome were reported without a pre-specified primary analysis in a registry or protocol. In addition, assessing the risk of bias required expertise, standardization, and training. CONCLUSION:To remain responsive during public health emergencies, living systematic reviews should implement processes that enable the timely identification, evaluation, and integration of both randomized and nonrandomized evidence where appropriate. PLAIN LANGUAGE SUMMARY:When new health treatments are tested, the best way to see how well they work is through randomized controlled trials (RCTs). These are carefully designed studies that help reduce bias. However, during the COVID-19 pandemic, scientists also had to rely on other types of studies called nonrandomized studies (NRS) based on real-world data because the virus was changing quickly and required urgent action. Our living systematic review examined how effective COVID-19 vaccines were against the Delta variant, which spread widely from late 2020 to 2021. We wanted to understand what both RCTs and NRSs revealed about vaccine protection at that time. We also aimed to learn about the benefits and challenges of including different kinds of studies. From December 2020 to November 2021, we found that only one RCT reported results specifically for the Delta variant, including just over 6000 people. However, during the same period, 52 NRSs, involving over 68 million people, shared results about vaccine effectiveness against Delta in real-world settings. Including these NRSs were important for answering questions quickly, but it also created challenges. For instance, it was sometimes unclear how studies should be included, as many used the same data sources. Different studies defined "Delta cases" in various ways and often reported several kinds of results without stating which one was most significant. Evaluating the quality of these studies was complex and required special training. We developed rules to handle each of these challenges. In this study, we found that while RCTs remain the gold standard, NRSs provided crucial information during a fast-moving public health emergency. To help patients, doctors, and policymakers get timely answers in the future, living systematic reviews should be designed to include both types of evidence when appropriate, using clear methods to address challenges.

Objectives Real world evidence based on observational data from cohorts, registries, and health-care databases are increasingly used to assess the effectiveness of therapeutic interventions, often using the target trial emulation framework. One challenge when analyzing observational data are risks of biases due to misalignment of times of eligibility, start of follow-up, and treatment assignment. We aimed to describe the methods used to generate alignment or to account for misalignment in studies explicitly aimed at emulating target trials, and to estimate the proportion of studies for which a low-cost change would limit the risk of biases associated with misalignment of the times. Study Design and Setting We analyzed 199 studies explicitly aiming at emulating a target trial identified in a previous systematic review from Hansford et al. Two reviewers extracted the times of eligibility, start of follow-up, and treatment assignment and the methods used by authors to generate alignment or to account for misalignment of time points. Results Out of the 199 studies, 181 (91%) reported the times of eligibility, start of follow-up, and treatment assignment. All time points were aligned for 93/181 (51%), with 73 using no specific method, 18 emulating a sequence of target trials, and 2 using other methods to generate alignment. In contrast, 88/181 (49%) studies had misalignment of time points, of which 29 used a method to correct for misalignment during analysis (24 studies used a cloning, censoring, and weighting approach; 4 randomly allocated patients with early events; and 1 randomly allocated all participants to the study groups with subsequent censoring when they deviated from the allocated intervention). Out of 59/88 (67%) studies that did not use any method to address nonalignment, 46/59 (78%) could have applied low-cost changes to account for misalignment. Conclusion Approximately, half of the studies explicitly aiming to emulate a target trial had alignment of times of eligibility, start of follow-up, and treatment assignment, either by design or using a method generating alignment. Among studies with misalignment, about 67% did not account for it in the analysis among which 78% could have applied low-cost changes to reduce bias. Plain Language Summary Researchers increasingly use real-world evidence from sources like routinely collected or claims data to assess the efficacy and safety of therapeutic interventions (medications, surgery, physiotherapy, etc). To prevent design errors when analyzing these data, researchers follow a framework called “target trial emulation”. A crucial aspect of this framework is to ensure that three key time points of the study are aligned during analysis: the times at which 1) participants in the database are assessed for eligibility in the study (ie, when do we choose to include them or not in the analysis), 2) their follow-up begin, and 3) they are assigned to a treatment group. If these time points are misaligned, the study results can be biased. Here, we reviewed 199 published studies that explicitly aimed to emulate a target trial identified in a previous systematic review by Hansford et al. We found that about half of them had alignment between of times of eligibility, treatment assignment, and follow-up. In the other half, there was misalignment but one-third used specific methods to correct for this problem. Many studies that aim to emulate a trial may have issues in alignment of key time points, which can compromise the validity of their findings. Most of these issues could be corrected with straightforward adjustments.

ObjectiveTo compare the long-term efficacy and safety of azathioprine (AZA), 18-month fixed-schedule rituximab (RTX), 18-month tailored RTX and 36-month RTX in preventing relapses in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis who achieved a complete remission after induction therapy. Patients treated with 36-month RTX received either a fixed or a tailored regimen for the first 18 months and a fixed regimen for the last 18 months (36-month fixed/fixed RTX and 36-month tailored/fixed RTX, respectively).MethodsThe Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN) trials sequentially compared: 18-month fixed-schedule RTX versus AZA (MAINRITSAN); 18-month fixed-schedule RTX versus 18-month tailored-RTX (MAINRITSAN2); and extended therapy to 36 months with four additional RTX infusions after MAINRITSAN2 versus placebo (MAINRITSAN3). Patients were then followed prospectively through month 84 and their data were pooled to analyse relapses and adverse events. The primary endpoint was relapse-free survival at month 84.Results277 patients were enrolled and divided in 5 groups: AZA (n=58), 18-month fixed-schedule RTX (n=97), 18-month tailored-RTX (n=40), 36-month tailored/fixed RTX (n=42), 36-month fixed/fixed RTX (n=41). After adjustment for prognostic factors, 18-month fixed-schedule RTX was superior to AZA in preventing major relapses at month 84 (HR 0.38, 95% CI 0.20 to 0.71). The 18-month tailored-RTX regimen was associated with an increased risk of major relapse compared with fixed-schedule regimen (HR 2.92, 95% CI 1.43 to 5.96). The risk of major relapse was similar between 36-month fixed/fixed and 18-month fixed-RTX (HR 0.69, 95% CI 0.38 to 1.25).ConclusionsAccording to these results, it appears that the 84-month remission rate is higher with an 18-month fixed RTX regimen compared with AZA and 18-month tailored RTX. Also, extending RTX to 36 months does not appear to reduce the long-term relapse rate compared with the 18-month fixed RTX regimen. However, as this study was underpowered to make this comparison, further prospective studies are needed to determine the potential long-term benefits of extending treatment in these patients.

Background: ANCA-associated vasculitis (AAV) is a frequently relapsing disease for which a meta-analysis concluded that an increase or persistence of ANCA during remission is only moderately predictive of future disease relapse and that serial ANCA measurements during remission are of limited use in guiding treatment decisions for individual patients. However, this analysis used heterogeneous ANCA assays and combined different subgroups of AAV patients or PR3 and MPO-AAV patients, whereas granulomatosis with polyangiitis (GPA) and PR3-AAV have a higher risk of relapse. Objectives: We investigated whether serial ANCA testing with a uniform ELISA assay could be of interest in predicting the relapse risk in a cohort of GPA patients. Methods: To be included, patients had to have GPA follow-up at the Cochin National Referral Centre, at least two measurements of ANCA titer by ELISA, one less than 12 months apart during inactive disease, with a follow-up visit and assessment of disease activity within 12 months of the second ANCA titer measurement. The primary objective was to evaluate the association of an increase in ANCA titer at the time of inactive disease with any relapse within the following 12 months of follow-up. The secondary objective was to evaluate the association of ANCA titer increase with major relapses. The primary endpoint was the cumulative incidence of relapse within the following 12 months. The secondary endpoint was the cumulative incidence of major relapse. We estimated 12-month adjusted restricted mean survival times (RMST) for patients with an increase in ANCA levels compared with those without an increase. To obtain confounder-adjusted relapse-free survival curves for each group, we used direct standardisation (G-computation) using a Cox regression model with potential confounders. The difference in RMST between the two groups and its 95% confidence interval were calculated. Results were analysed globally in patients with an increase in ANCA titer (Increase group) versus those without an increase (No increase group) and in a subgroup focused on ANCA PR3 positive patients. In a sensitivity analysis, we compared patients with doubling of ANCA versus no doubling. Results: 121 GPA patients were analysed in the primary analysis (PR3-ANCA+: 101; MPO-ANCA+: 20) for a total of 357 countable periods. We observed 52 relapses, 5 in the Increase group (unadjusted relapse rate: 18.8%) vs. 47 in the No increase group (unadjusted relapse rate: 13.0%). The adjusted relapse rate was 13.3% (3.2 to 32.0) in 23 patient-periods vs. 13.0% (8.9 to 17.5) in 334 patient-periods. Of the patients with increasing ANCA levels (23 periods), 18 did not relapse during the one-year observation period and 5 relapsed. In PR3-ANCA positive patients (101 patients, 297 periods), the corresponding relapse rate was 15.6% (3.8 to 36.7) vs. 14.5% (9.7 to 19.8) (Figure 1). When restricted to patients with a doubling of the ANCA titer, the relapse rate was 18.0% (4.4 to 41.2) in 18 patient-periods vs. 12.7 (8.7 to 17.1) in 339 patient-periods (Figure 2). Similarly, the RMST in the adjusted analysis was 342.4 (307.8 to 359.9) vs. 343.0 (334.3 to 350.8) days in the two groups for a difference of -0.6 (-35.8 to 18.9) days. The difference in RMST was -1.8 (-39.0 to 19.8) and -9.6 (-53.8 to 13.9) days in patients with PR3-ANCA positivity and a doubling of the ANCA titer, respectively, compared to those without. In the secondary analysis, the adjusted risk of major relapse was 10.6% (1.2 to 29.4) vs. 8.1% (5.2 to 11.7), with a difference in RMST of -4.3 days (-36.3 to 13.5) in the Increase vs. No increase group. Conclusion: Despite using the same ELISA test consistently over time in a homogeneous population of GPA patients followed at a reference centre, the predictive value of an increase in ANCA, a doubling of ANCA or an increase in PR3-ANCA alone is not sufficient to predict relapse at one year to consider escalating treatment on an individual basis. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: Xavier Puéchal GSK, investigator in academic studies of ANCA-associated vasculitis for which rituximab was provided by Roche Pharma., Michele Iudici: None declared, Elodie Perrodeau: None declared, Claire Goulvestre: None declared, Pascal Cohen investigator in academic studies of ANCA-associated vasculitis for which rituximab was provided by Roche Pharma, Alexis Régent investigator in academic studies of ANCA-associated vasculitis for which rituximab was provided by Roche Pharma., Luc Mouthon investigator in academic studies of ANCA-associated vasculitis for which rituximab was provided by Roche Pharma., Loïc Guillevin investigator in academic studies of ANCA-associated vasculitis for which rituximab was provided by Roche Pharma., Raphaël Porcher: None declared, Benjamin Terrier investigator in academic studies of ANCA-associated vasculitis for which rituximab was provided by Roche Pharma.Figure 1Adjusted relapse rate for the subset of GPA patients restricted to PR3-ANCA patients Figure 2Adjusted relapse rate for the subgroup of GPA patients with doubling of ANCA titer

OBJECTIVES:Some therapeutic strategy questions in oncology could be answered with studies using observational data. Target trial emulation is the application of design principles from randomized controlled trials (RCTs) to the analysis of observational data, to reduce design-induced biases. Our objective was to determine which type of study physicians would preferably plan to answer a comparative effectiveness question lacking evidence in oncology. METHODS:We launched an online survey among physicians specialized in oncology. We constructed a vignette-based inquiry where vignettes described study scenarios which could be conducted to answer the predefined question. We designed six vignettes described by study design (RCT or observational study with a trial emulation framework), main study characteristics, probability of the study succeeding and anticipated delay before results availability. Participants randomly assessed five pair-wise comparisons of the vignettes and were asked which study they would preferably plan by using a Likert scale ranging from -5 to 5. The main outcome was the evaluation of clinicians' preferences for each pairwise comparison. Mean and median preference scores were calculated. RESULTS:Two hundred thirteen participants, specialized in many tumor types, assessed at least one comparison with 82% reporting France as their country of affiliation. The interquartile range was -4 to 4 across pairwise comparisons. The median preference score was in disfavor of the monocentric RCT for the five comparisons where it appeared. The median preference score was strongly in favor of the multicentric national emulated trial when compared to the monocentric emulated trial 4 [IQR 2.5-4]. The mean preference score was the highest for the large European observational study 1.14 (SD 3.33), while the mean preference score was the lowest for the monocentric RCT -1.86 (SD 2.93). CONCLUSION:No study design was strongly preferred, but the monocentric RCT was the least favored study in pair-wise comparisons. The planification of the new research is a compromise between scientific soundness, feasibility, cost, and time before obtaining results. We need to have the right answers to the right questions at the right time.

ObjectiveTo evaluate the effect of covid-19 vaccination on the severity of symptoms in patients with long covid.DesignTarget trial emulation based on ComPaRe e-cohort.Data sourceComPaRe long covid cohort, a nationwide e-cohort (ie, a cohort where recruitment and follow-up are performed online) of patients with long covid, in France.MethodsAdult patients (aged ≥18 years) enrolled in the ComPaRe cohort before 1 May 2021 were included in the study if they reported a confirmed or suspected SARS-CoV-2 infection, symptoms persistent for >3 weeks after onset, and at least one symptom attributable to long covid at baseline. Patients who received a first covid-19 vaccine injection were matched with an unvaccinated control group in a 1:1 ratio according to their propensity scores. Number of long covid symptoms, rate of complete remission of long covid, and proportion of patients reporting an unacceptable symptom state at 120 days were recorded.Results910 patients were included in the analyses (455 in the vaccinated group and 455 in the control group). By 120 days, vaccination had reduced the number of long covid symptoms (mean 13.0 (standard deviation 9.4) in the vaccinated groupv14.8 (9.8) in the control group; mean difference −1.8, 95% confidence interval −3.0 to −0.5) and doubled the rate of patients in remission (16.6%v7.5%, hazard ratio 1.93, 95% confidence interval 1.18 to 3.14). Vaccination reduced the effect of long covid on patients' lives (mean score on the impact tool 24.3 (standard deviation 16.7)v27.6 (16.7); mean difference −3.3, 95% confidence interval −5.7 to −1.0) and the proportion of patients with an unacceptable symptom state (38.9%v46.4%, risk difference −7.4%, 95% confidence interval −14.5% to −0.3%). In the vaccinated group, two (0.4%) patients reported serious adverse events requiring admission to hospital.ConclusionIn this study, covid-19 vaccination reduced the severity of symptoms and the effect of long covid on patients' social, professional, and family lives at 120 days in those with persistent symptoms of infection.

Importance:Multidisciplinary prehabilitation before total knee replacement (TKR) for osteoarthritis may improve outcomes in the postoperative period. Objective:To compare multidisciplinary prehabilitation with usual care before TKR for osteoarthritis in terms of functional independence and activity limitations after surgery. Design, Setting, and Participants:This prospective, open-label randomized clinical trial recruited participants 50 to 85 years of age with knee osteoarthritis according to the American College of Rheumatology criteria for whom a TKR was scheduled at 3 French tertiary care centers. Recruitment started on October 4, 2012, with follow-up completed on November 29, 2017. Statistical analyses were conducted from March 29, 2018, to March 6, 2019. Interventions:Four supervised sessions of multidisciplinary rehabilitation and education (2 sessions per week, at least 2 months before TKR, delivered to groups of 4-6 participants at each investigating center; session duration was 90 minutes and included 30 minutes of education followed by 60 minutes of exercise therapy) or usual care (information booklet and standard advice by the orthopedic surgeon) before TKR. Main Outcomes and Measures:The short-term primary end point was the proportion of participants achieving functional independence a mean (SD) of 4 (1) days after surgery defined as level 3 on the 4 functional tests. The midterm primary end point was activity limitations within 6 months after TKR assessed by the area under the receiver operating characteristic curve of the self-administered Western Ontario Questionnaire and McMaster Universities Osteoarthritis Index function subscale. Results:A total of 262 patients (mean [SD] age, 68.6 [8.0] years; 178 women [68%]) were randomized (131 to each group). A mean (SD) of 4 (1) days after surgery, 34 of 101 (34%) in the experimental group vs 26 of 95 (27%) in the control group achieved functional independence (risk ratio, 1.4; 97.5% CI, 0.9-2.1; P = .15). At 6 months, the mean (SD) area under the curve for the Western Ontario Questionnaire and McMaster Universities Osteoarthritis Index function subscale was 38.1 (16.5) mm2 in the experimental group vs 40.6 (17.8) mm2 in the control group (absolute difference, -2.8 mm2; 97.5% CI, -7.8 to 2.3; P = .31 after multiple imputation). No differences were found in secondary outcomes. Conclusions and Relevance:This randomized clinical trial found no evidence that multidisciplinary prehabilitation before TKR for osteoarthritis improves short-term functional independence or reduces midterm activity limitations after surgery. Trial registration:ClinicalTrials.gov Identifier: NCT01671917.

Background Today, there are still no DMARDs licensed for primary Sjögren Syndrome (pSS) patients. Among the explanations, are the limitations of current outcome measures used as primary endpoints: e.g; high placebo response rate, evaluation of either symptoms or systemic activity, and important features not being assessed. The NECESSITY consortium ( https://www.necessity-h2020.eu/ ), including pSS experts from academia, pharmaceutical industry and patient groups formed to develop a new composite responder index, the Sjögren’s Tool for Assessing Response (STAR) that solve the issues of current outcome measures in pSS and is intended for use in clinical trials as an efficacy endpoint. Objectives To develop a composite responder index in primary Sjögren’s syndrome (pSS): the STAR. Methods To develop the STAR, the NECESSITY consortium used data-driven methods, based on 9 randomized controlled trials (RCTs), and consensus techniques, involving 78 experts and 20 patients. Based on reanalysis of rituximab trials (TRACTISS and TEARS) and literature review, the Delphi panel identified a core set of domains to include in the STAR, with their respective outcome measures. STAR options combining these domains were designed and proposed to the panel to select and improve them. For each STAR option, sensitivity to change was estimated by the C-index (derived from Effect size) in all 9 RCTs. Delphi rounds were run for selecting STAR among these options. The Delphi panel also voted to classify trials as positive, negative or “in between” in regards to primary but also key secondary endpoints. For the options remaining before the final vote, meta-analyses of the RCTs were performed separately for positive and “in between” trials together, and for negative trials. Results The Delphi panel identified 5 core domains (systemic activity, patient symptoms, lachrymal gland function, salivary gland function and biological parameters), and 227 STAR options, combining these domains, were selected to be tested for sensitivity to change. After two Delphi rounds, meta-analyses of the 20 remaining options were performed. The candidate STAR was selected by a final vote based on metrological properties and clinical relevance. In positive/in between trials, candidate STAR detected a difference between arms (OR 3.29, 95%-CI [2.07;5.22], whereas it did not in negative trials (OR 1.53, 95%-CI [0.81;2.91]). Conclusion The candidate STAR is a composite responder index, including in a single tool all main disease features, and is designed for use as a primary endpoint in pSS RCTs. Its rigorous and consensual development process ensures its face and content validity. The candidate STAR showed good sensitivity and specificity to change. The candidate STAR will be prospectively validated in a dedicated three arms RCT of the NECESSITY consortium that will evaluate combination of synthetic DMARDs (hydroxychloroquine + lefunomide or hydroxychloroquine + mycophenolate vs placebo). We encourage the use of STAR in any ongoing and future trials. Table 1. Candidate STAR Domain Point Definition of response Systemic activity 3 Decrease of clinESSDAI ≥ 3 Patient reported outcome 3 Decrease of ESSPRI ≥ 1 point or ≥ 15% Lachrymal gland function 1 Schirmer: If abnormal score at baseline: increase ≥ 5 mm from baseline If normal score at baseline: no change to abnormal Or Ocular Staining Score: If abnormal score at baseline: decrease ≥ 2 points from baseline If normal score at baseline: no change to abnormal Salivary gland function 1 Unstimulated Whole Salivary Flow: If score > 0 at baseline: increase ≥ 25% from baseline If score is 0 at baseline: any increase from baseline or Ultrasound: Decrease ≥ 25% in total Hocevar score from baseline Biological 1 Serum IgG levels: decrease ≥ 10% or Rheumatoid Factor levels: decrease ≥ 25% Candidate STAR responder ≥ 5 points ESSDAI: EULAR Sjögren syndrome disease activity index; ESSPRI: EULAR Sjögren syndrome patient reported index; IgG: Immunoglobulin G; Acknowledgements NECESSITY WP5 STAR development participants: Suzanne Arends (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Francesca Barone (Centre for Translational Inflammation Research, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK), Albin Björk (Division of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden), Coralie Bouillot (Association Française du Gougerot Sjögren et des Syndromes Secs, France), Guillermo Carvajal Alegria (University of Brest, Inserm, CHU de Brest, LBAI, UMR1227, Brest, France; Service de Rhumatologie, Centre de Référence Maladies Autoimmunes Rares CERAINO, CHU Cavale Blanche, Brest, France), Wen-Hung Chen (GlaxoSmithKline, Research Triangle Park, North Carolina, USA), Kenneth Clark (GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom), Konstantina Delli (Department of Oral and Maxillofacial Surgery, University Medical Center Groningen (UMCG), University of Groningen, The Netherlands), Salvatore de Vita (Rheumatology Clinic, University Hospital of Udine, Italy), Liseth de Wolff (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Jennifer Evans (Novartis Pharmaceuticals corporation USA), Stéphanie Galtier (Institut de Recherches Internationales Servier (IRIS), Suresnes Cedex, France), Saviana Gandolfo (Rheumatology Clinic, Department of Medical area, University of Udine, ASUFC, 33100 Udine, Italy), Mickael Guedj (Institut de Recherches Internationales Servier (IRIS), Suresnes Cedex, France), Dewi Guellec (CHU de Brest, Service de Rhumatologie, Inserm, CIC 1412, Brest, France), Safae Hamkour (Center of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht 3584 GA, Netherlands), Dominik Hartl (Novartis Institutes for BioMedical Research, Basel, Switzerland), Malin Jonsson (Section for Oral and Maxillofacial Radiology, Department of Clinical Dentistry, Faculty of Medicine and Dentistry, University of Bergen, Norway), Roland Jonsson (Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Department of Rheumatology, Haukeland University Hospital, Bergen, Norway), Frans Kroese (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Aike Albert Kruize (University Medical Center Utrecht, Department Rheumatology and Clinical Immunology, Utrecht, Netherlands), Laurence Laigle (Institut de Recherches Internationales Servier (IRIS), Suresnes Cedex, France), Véronique Le Guern (AP-HP, Hôpital Cochin, Centre de référence maladies auto-immunes et systémiques rares, service de médecine interne, Paris, France), Wen-Lin Luo (Department of Biometrics and Statistical Science, Novartis Pharmaceuticals, East Hanover, New Jersey), Esther Mossel (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Wan-Fai Ng (Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK), Gaëtane Nocturne (Department of Rheumatology, Université Paris-Saclay, INSERM U1184: Centre for Immunology of Viral Infections and Autoimmune Diseases, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, Paris, France), Marleen Nys (Global Biometric Sciences, Bristol Myers Squibb, Braine L’Alleud, Belgium), Roald Omdal (Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, PO Box 8100, 4068, Stavanger, Norway), Jacques-Olivier Pers (LBAI, UMR1227, University of Brest, Inserm, Brest, France and CHU de Brest, Brest, France), Maggy Pincemin (Association Française du Gougerot Sjögren et des Syndromes Secs, France), Manel Ramos-Casals (Department of Autoimmune Diseases, Hospital Clinic de Barcelona Institut Clinic de Medicinai Dermatologia, Barcelona, Catalunya, Spain), Philippe Ravaud (Centre d’Epidémiologie Clinique, Hôpital Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Paris, France), Neelanjana Ray (Global Drug Development - Immunology, Bristol Myers Squibb Company, Princeton, New Jersey, USA), Alain Saraux (HU de Brest, Service de Rhumatologie, Univ Brest, Inserm, UMR1227, Lymphocytes B et Autoimmunité, Univ Brest, Inserm, LabEx IGO, Brest, France), Athanasios Tzioufas (Rheumatology Clinic, Department of Medical area, University of Udine, ASUFC, 33100 Udine, Italy), Gwenny Verstappen (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Arjan Vissink, Marie Wahren-Herlenius (Division of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden). We thank the following experts: Esen Karamursel Akpek, Alan Baer, Chiara Baldini, Elena Bartoloni, Marí-Alfonso Begona, Johan Brun, Vatinee Bunya, Laurent Chiche, Troy Daniels, Paul Emery, Robert Fox, Roberto Giacomelli, John Gonzales, John Greenspan, Robert Moots, Susumu Nishiyama, Elizabeth Price, Christophe Richez, Caroline Shiboski, Roser Solans Laque, Muthiah Srinivasan, Peter Olsson, Tsutomu Takeuchi, Frederick Vivino, Paraskevi Voulgari, Daniel Wallace, Ava Wu, Wen Zhang. We thank the anonymous patients from the NECESSITY Patient Advisory Group and the Sjögren Foundation for their valuable contribution to the Delphi process. We thank EW StClair and AN Baer who generated the baminercept data and made them publicly available. Disclosure of Interests Raphaèle Seror Consultant of: GlaxoSmithKline, Boehringer, Janssen and Novartis, Grant/research support from: GlaxoSmithKline and Amgen, Gabriel Baron: None declared, Marine Camus: None declared, Divi Cornec Consultant of: GlaxoSmithKline, Bristol Myers Squibb, Janssen, Amgen, Pfizer and Roche, Elodie Perrodeau: None declared, Simon J. Bowman Consultant of: Abbvie, Astra Zeneca, Galapagos and Novartis Pharmaceuticals, Michele Bombardieri Consultant of: UCB, Amgen/Medimmune, Janssen, and GlaxoSmithKline, Grant/research support from: Amgen/Medimmune, Janssen, and GlaxoSmithKline, Hendrika Bootsma: None declared, Jacques-Eric Gottenberg Consultant of: AbbVie, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Pfizer, Roche, Sanofi, Novartis, MSD, CSL-Behring and Genzyme, Grant/research support from: Bristol Myers Squibb, Benjamin Fisher Speakers bureau: Bristol Myers Squibb and Novartis, Consultant of: Novartis, Bristol Myers Squibb, Janssen and Servier, Grant/research support from: Servier, Galapagos and Janssen, Wolfgang Hueber Shareholder of: Novartis Pharma, Employee of: Novartis Pharma, Joel van Roon: None declared, Valerie Devauchelle-Pensec: None declared, Peter Gergely Shareholder of: Novartis Pharma, Employee of: Novartis Pharma, Xavier Mariette Consultant of: Bristol Myers Squibb, Galapagos, GlaxoSmithKline, Janssen, Novartis, Pfizer and UCB, Grant/research support from: Ose Pharmaceuticals, Raphaël Porcher: None declared

IntroductionLa non-infériorité du rituximab (RTX) par rapport au cyclophosphamide (CYC), en traitement d’induction des vascularites associées aux ANCA, a été montrée dans des essais thérapeutiques, sans avantage spécifique d’un des deux traitements pour la granulomatose avec polyangéite (GPA, Wegener). Cependant, une analyse post-hoc a suggéré que le RTX pourrait être plus efficace que le CYC pour induire une rémission chez les patients ayant des ANCA dirigés contre la protéinase-3 (PR3).Patients et méthodesL’objectif de cette étude est de comparer le RTX au CYC pour l’obtention d’une rémission au sein d’une large cohorte multicentrique de patients non sélectionnés atteints de GPA active, répondant aux critères de classification de l’ACR ou de la nomenclature révisée de Chapel Hill. Cet essai thérapeutique émulé a utilisé les données observationnelles du registre du Groupe français d’étude des vascularites. Les patients inclus avaient reçu au moins une perfusion de CYC ou de RTX entre avril 2008 et avril 2018. Les groupes ont été déterminés selon le traitement reçu, sans intervention de la part des investigateurs. Une pondération de la probabilité inverse de traitement a été utilisée pour corriger les déséquilibres de base entre les groupes. Les données manquantes ont été traitées par imputations multiples. Le critère principal d’efficacité était le taux de mise en rémission à 6±2 mois, définie par un Birmingham Vasculitis Activity Score (BVAS)=0 et une posologie de prednisone ≤ 10mg/j. Des analyses en sous-groupes ont étudié le critère principal d’efficacité chez les patients avec GPA nouvellement diagnostiquée et chez les patients avec ANCA dirigés contre la myéloperoxidase (MPO).RésultatsParmi 194 patients inclus avec une GPA active (âge moyen 54 ans, 110 [57 %] hommes, 165 [85 %] GPA nouvellement diagnostiquée, [81 %] ANCA-PR3+), 61 ont reçu du RTX et 133 du CYC en traitement d’induction. Dans l’analyse pondérée, le critère principal d’évaluation a été atteint chez 69,8 % vs 39,8 % des patients ayant reçu le RTX vs CYC, respectivement (risque relatif : 1,75 [95 % CI : 1,19 ; 2,57] ; différence de risque +30,0 % [95 % CI : 8,0 ; 52,0], E-value 2,90). Des résultats comparables ont été observés dans le sous-groupe des patients avec GPA nouvellement diagnostiquée. Parmi les 27 patients avec GPA ANCA-MPO+, 8/10 et 8/17 patients ayant reçu le RTX ou le CYC ont atteint respectivement le critère principal d’évaluation (risque relatif non pondéré 1,74 [95 % CI : 0,96 ; 3,18]).ConclusionCet essai thérapeutique émulé, à partir de données de vie réelle, a montré qu’un traitement d’induction par le RTX était plus souvent associé à une mise en rémission que par le CYC dans une large population de GPA. Ces résultats éclairent la prise de décision clinique concernant le choix du traitement d’induction pour ce sous-groupe de patients atteints de vascularite associée aux ANCA.

Background: In moderate-to-severe COVID-19 pneumonia, dexamethasone (DEX) and tocilizumab (TCZ) reduce the occurrence of death and ventilatory support. The efficacy and safety of combining the two drugs remains to be investigated.Methods: Patients with moderate-to-severe COVID-19 pneumonia (WHO class 5) requiring oxygen (>3 L/min) were randomly assigned to receive DEX (10mg/d 5 days tapering up to 10 days) alone or combined with TCZ (8mg/kg IV) at day 1 possibly repeated with a fixed dose of 400 mg i.v at day 3. The primary outcome was time from randomization to mechanical ventilation support or death up to day 14, analyzed on an intent-to-treat basis using a Bayesian approach.Findings: A total of 453 patients were randomized, 3 withdrew consent, 450 were analyzed of whom 226 and 224 patients were assigned to receive DEX or TCZ+DEX, respectively. At day 14, mechanical ventilation or death occurred in 32/226 (14%) and 27/224 (12%) in the DEX and TCZ+DEX arms, respectively (Hazard ratio (HR) [90% credible interval (CrI)], 0.85 [0.55-1.31]). At day 14, WHO CPS scale was significantly improved in the TCZ+DEX arm (OR 0.69, (95% CrI, 0.49 to 0.97). On day 90, 24 deaths (11%) were observed in the DEX arm and 18 (8%) in the TCZ+DEX arm (HR 0.77, 95% CI 0.42-1.41). Patients with at least one serious adverse event were observed in 25 and 21% in DEX and TCZ+DEX arms, respectively.Interpretation: Mechanical ventilation need and mortality were not improved with combination of TCZ and DEX compared with DEX alone. The safety of both treatments was similar. However, given the wide confidence intervals for the estimate of effect, the findings do not allow for a definitive interpretation.Trial Registration: ClinicalTrials.gov number, NCT04476979.Funding: Funded by PHRCDeclaration of Interest: None to declare. Ethical Approval: The CORIMUNO Cohort and all embedded trials (i.e. trials using data collected in the CORIMUNO cohort) were approved by an ethics committee (CPP Île-de-France VI) and relevant authorities.

Objective To develop a composite responder index in primary Sjögren’s syndrome (pSS): the Sjögren’s Tool for Assessing Response (STAR). Methods To develop STAR, the NECESSITY (New clinical endpoints in primary Sjögren’s syndrome: an interventional trial based on stratifying patients) consortium used data-driven methods based on nine randomised controlled trials (RCTs) and consensus techniques involving 78 experts and 20 patients. Based on reanalysis of rituximab trials and the literature, the Delphi panel identified a core set of domains with their respective outcome measures. STAR options combining these domains were proposed to the panel for selection and improvement. For each STAR option, sensitivity to change was estimated by the C-index in nine RCTs. Delphi rounds were run for selecting STAR. For the options remaining before the final vote, a meta-analysis of the RCTs was performed. Results The Delphi panel identified five core domains (systemic activity, patient symptoms, lachrymal gland function, salivary gland function and biological parameters), and 227 STAR options combining these domains were selected to be tested for sensitivity to change. After two Delphi rounds, a meta-analysis of the 20 remaining options was performed. The candidate STAR was then selected by a final vote based on metrological properties and clinical relevance. Conclusion The candidate STAR is a composite responder index that includes all main disease features in a single tool and is designed for use as a primary endpoint in pSS RCTs. The rigorous and consensual development process ensures its face and content validity. The candidate STAR showed good sensitivity to change and will be prospectively validated by the NECESSITY consortium in a dedicated RCT.

We used data from 910 adult patients included the ComPaRe long COVID cohort to emulate a target trial evaluating the effect of vaccination on the symptoms of patients who already had long COVID. We used propensity score matching to compare the outcomes, at 120 days, of patients who received a first COVID-19 vaccine injection (n=455) and those who did not (n=455). Vaccination reduced the number of long COVID symptoms (mean difference: -1.8, 95% CI -3.0 to -0.5), the proportion of patients with an unacceptable symptom state (risk difference -7.5%, 95% CI -14.4 to -0.5), and doubled the remission rate (16.6% vs 7.5%, HR: 1.97, 95% CI 1.23 to 3.15). In the vaccination group, two (0.4%) patients reported serious adverse events leading to hospitalisation. Vaccination lowered the severity and life impact of long COVID, at 120 days, among patients with persistent symptoms.

Background Listeriosis is caused by the foodborne pathogen Listeria monocytogenes. It can present as a maternal-neonatal infection. We implemented a nationwide prospective cohort and analyzed the features of neonatal listeriosis. Methods We studied all neonates born alive from mothers with microbiologically proven maternal-neonatal listeriosis enrolled from November 2009 to December 2017. We analyzed presentation, neonatal outcome at discharge, and predictors of severe presentation and outcome. Results We studied 189 infants; 133 of 189 (70%) had abnormal clinical status at birth, including acute respiratory distress in 106 of 189 (56%). There were 132 of 189 (70%) infants who developed early-onset listeriosis and 12 of 189 (6%) who developed late-onset listeriosis; all presented with acute meningitis. There were 17 of 189 (9%) infants who had major adverse outcomes: 3%, (5 of 189) death; 6% (12 of 189), severe brain injury; and 2% (3 of 189), severe bronchopulmonary dysplasia. Fifteen of 17 infants were born <34 weeks of gestation (P<.0001 vs infants born >= 34 weeks of gestation). Maternal antimicrobial treatment >= 1 day before delivery was associated with a significant decrease in presentation severity for the infant, resulting in significantly fewer inotropic drugs, fluid resuscitation, and mechanical ventilation requirement (odds ratio, 0.23; 95% confidence interval, 0.09-0.51; P<.0001). Conclusions Antenatal maternal antimicrobial treatment is associated with reduced neonatal listeriosis severity, justifying the prescription of preemptive maternal antimicrobial therapy when maternal-fetal listeriosis is suspected. Neonatal outcome is better than reported earlier, and its major determinant is gestational age at birth. Clinical Trials Registration NCT01520597. We prospectively assessed the presentation and outcome of neonatal listeriosis and evidenced that maternal antibiotic treatment administered at least 1 day before delivery is associated with a significant reduction in presentation severity of the neonate.

Key Points Question Is rituximab more effective than cyclophosphamide for treatment of granulomatosis with polyangiitis (GPA)? Findings In this comparativeness effectiveness study based on clinical data from 194 patients with GPA, rituximab as induction therapy was associated with significantly more achievement of remission with a prednisone dose of 10 mg/d or less compared with cyclophosphamide. Rare disease registries and comparative effectiveness studies enable hitherto poorly addressed treatment comparisons for such entities. Meaning These findings may inform clinical decision-making regarding the choice of remission-inducing regimen for patients with GPA.