Development and preliminary validation of the Sjögren's Tool for Assessing Response (STAR): a consensual composite score for assessing treatment effect in primary Sjögren's syndrome.

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.

Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis.

Importance: Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm. Objective: To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes. Data Sources: Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts. Study Selection: Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria. Data Extraction and Synthesis: In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality. Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days. Results: A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16). Conclusions and Relevance: In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality. Trial Registration: PROSPERO Identifier: CRD42021230155.

Correction to: Three randomized controlled trials evaluating the impact of "spin" in health news stories reporting studies of pharmacologic treatments on patients'/caregivers' interpretation of treatment benefit.

Figure 3 in the original article [1] is incorrect; labels for secondary outcomes have been shifted and do not correspond to the numbers reported in the table (Additional file 8). The corrected version can be seen ahead. This figure should be used over the figure 3 seen in the original article. This error does not affect the results, interpretation, or conclusion.

Three randomized controlled trials evaluating the impact of "spin" in health news stories reporting studies of pharmacologic treatments on patients'/caregivers' interpretation of treatment benefit.

BACKGROUND: News stories represent an important source of information. We aimed to evaluate the impact of "spin" (i.e., misrepresentation of study results) in health news stories reporting studies of pharmacologic treatments on patients'/caregivers' interpretation of treatment benefit. METHODS: We conducted three two-arm, parallel-group, Internet-based randomized trials (RCTs) comparing the interpretation of news stories reported with or without spin. Each RCT considered news stories reporting a different type of study: (1) pre-clinical study, (2) phase I/II non-RCT, and (3) phase III/IV RCT. For each type of study, we identified news stories reported with spin that had earned mention in the press. Two versions of the news stories were used: the version with spin and a version rewritten without spin. Participants were patients/caregivers involved in Inspire, a large online community of more than one million patients/caregivers. The primary outcome was participants' interpretation assessed by one specific question "What do you think is the probability that 'treatment X' would be beneficial to patients?" (scale, 0 [very unlikely] to 10 [very likely]). RESULTS: For each RCT, 300 participants were randomly assigned to assess a news story with spin (n = 150) or without spin (n = 150), and 900 participants assessed a news story. Participants were more likely to consider that the treatment would be beneficial to patients when the news story was reported with spin. The mean (SD) score for the primary outcome for abstracts reported with and without spin for pre-clinical studies was 7.5 (2.2) versus 5.8 (2.8) (mean difference [95% CI] 1.7 [1.0-2.3], p < 0.001); for phase I/II non-randomized trials, 7.6 (2.2) versus 5.8 (2.7) (mean difference 1.8 [1.0-2.5], p < 0.001); and for phase III/IV RCTs, 7.2 (2.3) versus 4.9 (2.8) (mean difference 2.3 [1.4-3.2], p < 0.001). CONCLUSIONS: Spin in health news stories reporting studies of pharmacologic treatments affects patients'/caregivers' interpretation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03094078 , NCT03094104 , NCT03095586.

Accuracy in detecting inadequate research reporting by early career peer reviewers using an online CONSORT-based peer-review tool (COBPeer) versus the usual peer-review process: a cross-sectional diagnostic study.

BACKGROUND: The peer review process has been questioned as it may fail to allow the publication of high-quality articles. This study aimed to evaluate the accuracy in identifying inadequate reporting in RCT reports by early career researchers (ECRs) using an online CONSORT-based peer-review tool (COBPeer) versus the usual peer-review process. METHODS: We performed a cross-sectional diagnostic study of 119 manuscripts, from BMC series medical journals, BMJ, BMJ Open, and Annals of Emergency Medicine reporting the results of two-arm parallel-group RCTs. One hundred and nineteen ECRs who had never reviewed an RCT manuscript were recruited from December 2017 to January 2018. Each ECR assessed one manuscript. To assess accuracy in identifying inadequate reporting, we used two tests: (1) ECRs assessing a manuscript using the COBPeer tool (after completing an online training module) and (2) the usual peer-review process. The reference standard was the assessment of the manuscript by two systematic reviewers. Inadequate reporting was defined as incomplete reporting or a switch in primary outcome and considered nine domains: the eight most important CONSORT domains and a switch in primary outcome(s). The primary outcome was the mean number of domains accurately classified (scale from 0 to 9). RESULTS: The mean (SD) number of domains (0 to 9) accurately classified per manuscript was 6.39 (1.49) for ECRs using COBPeer versus 5.03 (1.84) for the journal's usual peer-review process, with a mean difference [95% CI] of 1.36 [0.88-1.84] (p < 0.001). Concerning secondary outcomes, the sensitivity of ECRs using COBPeer versus the usual peer-review process in detecting incompletely reported CONSORT items was 86% [95% CI 82-89] versus 20% [16-24] and in identifying a switch in primary outcome 61% [44-77] versus 11% [3-26]. The specificity of ECRs using COBPeer versus the usual process to detect incompletely reported CONSORT domains was 61% [57-65] versus 77% [74-81] and to identify a switch in primary outcome 77% [67-86] versus 98% [92-100]. CONCLUSIONS: Trained ECRs using the COBPeer tool were more likely to detect inadequate reporting in RCTs than the usual peer review processes used by journals. Implementing a two-step peer-review process could help improve the quality of reporting. TRIAL REGISTRATION: Clinical.Trials.gov NCT03119376 (Registered April, 18, 2017).

Non-severe eosinophilic granulomatosis with polyangiitis: long-term outcomes after remission-induction trial.

OBJECTIVE: In a previous controlled trial, 1-year adjunction of AZA to glucocorticoids (GC) for patients with non-severe, newly diagnosed eosinophilic granulomatosis with polyangiitis (EGPA) failed to lower remission failure, vasculitis relapse and isolated asthma/rhinosinus exacerbation rates, or cumulative GC use at month (M) 24. The aim of this study was to analyse longer-term outcomes to determine whether subsequent vasculitis relapse or isolated asthma/rhinosinus exacerbation (IARE) rates differed. METHODS: After M24, patients were followed prospectively, being treated based on physicians' best judgment. Flares and reasons for increased GC dose or immunosuppressant use were recorded, and reviewed according to randomization group to distinguish vasculitis relapses from IAREs according to EGPA Task Force recommendations. RESULTS: Fifty EGPA trial participants were followed for a median (interquartile range) of 6.3 (5.4-7.6) years; two (4%) died 11 months post-inclusion. By M24, vasculitis had relapsed in 21/49 (43%) patients and 14/50 (28%) had IAREs. Another patient died 4.8 years post-inclusion (infection). Among nine patients with subsequent vasculitis relapses, three had a major relapse and three had their first relapse after M24; among 25 patients with later IAREs, 17 occurred after M24. At 5 years, respective vasculitis relapse and IARE rates were 48% (95% CI 34.0, 62.6) and 56% (95% CI 41.7, 70.8), with no between-arm differences (P = 0.32 and 0.13). No entry clinical or biological parameter was associated with these outcomes during follow-up. CONCLUSION: These results confirmed that 1-year AZA and GC induction obtained good overall survival but no long-term benefit for non-severe EGPA patients. Vasculitis relapses, occurring mostly during the first 2 years, and IAREs, occurring throughout follow-up, require other preventive treatments. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT00647166.

Post-marketing research and its outcome for novel anticancer agents approved by both the FDA and EMA between 2005 and 2010: A cross-sectional study.

Post-marketing research in oncology has rarely been described. We aimed to characterize post-marketing trials for a consistent set of anticancer agents over a long period. We performed a cross-sectional analysis of post-marketing trials registered at ClinicalTrials.gov through September 2014 for novel anticancer agents approved by both the US Food and Drug Administration and the European Medicines Agency between 2005 and 2010. All relevant post-marketing trials were classified according to indication, primary outcome, starting date, sponsors, and planned enrollment. Supplemental indications were retrieved from regulatory documents and publication rate was assessed by two different methods. Ten novel anticancer agents were eligible: five were indicated for hematologic malignancies and the remaining five for solid cancers (three for kidney cancer). We identified 2,345 post-marketing trials; 1,362 (58.1%) targeted an indication other than the originally approved one. We observed extreme variations among drugs in both number of post-marketing trials (range 8-530) and overall population to be enrolled per trial (1-8,381). Post-marketing trials assessed almost all types of cancers, the three most frequently studied cancers being leukemia, kidney cancer and myeloma. In all, 6.6% of post-marketing trials had a clinical endpoint as a primary outcome, and 35.9% and 54.1% had a safety or surrogate endpoint, respectively, as a primary outcome. Nine drugs obtained approval for supplemental indications. The publication rate at 10 years was 12.3 to 26.1% depending on the analysis method. In conclusion, we found that post-marketing research in oncology is highly heterogeneous and the publication rate of launched trials is low.

Designs of trials assessing interventions to improve the peer review process: a vignette-based survey.

BACKGROUND: We aimed to determine the best study designs for assessing interventions to improve the peer review process according to experts' opinions. Furthermore, for interventions previously evaluated, we determined whether the study designs actually used were rated as the best study designs. METHODS: Study design: A series of six vignette-based surveys exploring the best study designs for six different interventions (training peer reviewers, adding an expert to the peer review process, use of reporting guidelines checklists, blinding peer reviewers to the results (i.e., results-free peer review), giving incentives to peer reviewers, and post-publication peer review). Vignette construction: Vignettes were case scenarios of trials assessing interventions aimed at improving the quality of peer review. For each intervention, the vignette included the study type (e.g., randomized controlled trial [RCT]), setting (e.g., single biomedical journal), and type of manuscript assessed (e.g., actual manuscripts received by the journal); each of these three features varied between vignettes. PARTICIPANTS: Researchers with expertise in peer review or methodology of clinical trials. OUTCOME: Participants were proposed two vignettes describing two different study designs to assess the same intervention and had to indicate which study design they preferred on a scale, from - 5 (preference for study A) to 5 (preference for study B), 0 indicating no preference between the suggested designs (primary outcome). Secondary outcomes were trust in the results and feasibility of the designs. RESULTS: A total of 204 experts assessed 1044 paired comparisons. The preferred study type was RCTs with randomization of manuscripts for four interventions (adding an expert, use of reporting guidelines checklist, results-free peer review, post-publication peer review) and RCTs with randomization of peer reviewers for two interventions (training peer reviewers and using incentives). The preferred setting was mainly several biomedical journals from different publishers, and the preferred type of manuscript was actual manuscripts submitted to journals. However, the most feasible designs were often cluster RCTs and interrupted time series analysis set in a single biomedical journal, with the assessment of a fabricated manuscript. Three interventions were previously assessed: none used the design rated first in preference by experts. CONCLUSION: The vignette-based survey allowed us to identify the best study designs for assessing different interventions to improve peer review according to experts' opinion. There is gap between the preferred study designs and the designs actually used.

Intradiscal Glucocorticoid Injection for Patients With Chronic Low Back Pain Associated With Active Discopathy: A Randomized Trial.

BACKGROUND: Active discopathy is associated with a specific phenotype of chronic low back pain (LBP). Local inflammation has a role in active discopathy-associated symptoms. OBJECTIVE: To assess the efficacy of a single glucocorticoid intradiscal injection (GC IDI) in patients with chronic LBP with active discopathy. DESIGN: Prospective, parallel-group, double-blind, randomized, controlled study. (ClinicalTrials.gov: NCT00804531). SETTING: 3 tertiary care centers in France. PATIENTS: 135 patients with chronic LBP with active discopathy on magnetic resonance imaging (MRI). INTERVENTION: A single GC IDI (25 mg prednisolone acetate) during discography (n = 67) or discography alone (n = 68). MEASUREMENTS: The primary outcome was the percentage of patients with LBP intensity less than 40 on an 11-point numerical rating scale (0 [no pain] to 100 [maximum pain] in 10-point increments) in the previous 48 hours at 1 month after the intervention. The main secondary outcomes were LBP intensity and persistent active discopathy on MRI at 12 months and spine-specific limitations in activities, health-related quality of life, anxiety and depression, employment status, and use of analgesics and nonsteroidal anti-inflammatory drugs at 1 and 12 months. RESULTS: All randomly assigned patients were included in the primary efficacy analysis. At 1 month after the intervention, the percentage of responders (LBP intensity <40) was higher in the GC IDI group (36 of 65 [55.4%]) than the control group (21 of 63 [33.3%]) (absolute risk difference, 22.1 percentage points [95% CI, 5.5 to 38.7 percentage points]; P = 0.009). The groups did not differ in LBP intensity at 12 months and in most secondary outcomes at 1 and 12 months. LIMITATION: Tertiary care setting. CONCLUSION: In chronic LBP associated with active discopathy, a single GC IDI reduces LBP at 1 month but not at 12 months. PRIMARY FUNDING SOURCE: French Ministry of Health.

Risk factors of serious infections in patients with rheumatoid arthritis treated with tocilizumab in the French Registry REGATE.

Objectives: Observational studies have already reported the risk of serious infections in RA treated with tocilizumab, but in limited samples. The aim of this study was to investigate the predictive risk factors for serious infections in the largest European registry of patients treated with tocilizumab for RA. Methods: A total of 1491 RA patients included in the French REGistry-RoAcTEmra were analysed to calculate the incidence rate of first serious infections rate after initiation of tocilizumab. To identify independent factors associated with serious infections, a Cox model was performed. Results: Among the 1491 patients, average age 56.6 (13.6) years, 125 serious infections occurred in 122 patients (incidence rate of serious infection: 4.7/100 patient-years). Univariate analysis identified initial ACPA positivity as the only factor associated with a lower risk of serious infection [hazard ratio (HR) = 0.56, 95% CI: 0.36, 0.88]. Other factors significantly associated with a higher risk of serious infections were DAS28, concomitant Leflunomide (LEF) treatment, and absolute neutrophil count (ANC) at baseline. Initial ANC above 5.0 × 109/l (HR = 1.94, 95% CI: 1.32, 2.85; P < 0.001), negative ACPA (HR = 1.79, 95% CI: 1.15, 2.78; P = 0.012) at baseline and concomitant LEF treatment (LEF alone vs no treatment, HR = 2.18, 95% CI: 1.22, 3.88; P = 0.009) remained significantly associated with first serious infections in multivariate analysis after imputation for missing data. Conclusion: The rate of first serious infections in current practice is similar to that reported in clinical trials. High ANC (above 5.0 × 109 at baseline), negative ACPA and concomitant therapy with LEF are predictive factors of serious infection, requiring in this case a tighter surveillance.

Patients' preferences in transplantation from marginal donors: results of a discrete choice experiment.

To increase the donor pool, the strategy of transplantation from "marginal" donors was developed though patients' preferences about these donors were insufficiently known. The preferences of patients registered on the waiting list or already transplanted in eight transplant teams covering four main organs (i.e., kidney, liver, heart, and lung) were evaluated using the discrete choice experiment method. In each left during 2 days, patients were interviewed on four scenarios. Of 178 eligible patients, 167 were interviewed; 40% accepted marginal graft in their own situation and 89% at least in one of the scenarios. Imagining urgent situations or rare profiles with difficult access to transplantation, respectively, 86% and 71% accepted these grafts. Most (76%) preferred to be informed about these grafts and 43% preferred to be involved in decision. The emergency [OR = 1.24; 95% CI: (1.06-1.45)] and the hazardousness [OR = 0.88; 95% CI: (0.78-0.99)] of the transplantation were factors independently associated with marginal graft acceptance. Most patients preferred to be informed and to be involved in the decision. Marginal grafts could be more accepted by patients in critical medical situations or perceiving their situation as critical. Physicians' practices in transplantation should be reconsidered taking into account individual preferences. This study was performed in a single country and thus reflects the cultural bias and practice thereof.

Public availability of results of observational studies evaluating an intervention registered at ClinicalTrials.gov.

BACKGROUND: Observational studies are essential for assessing safety. The aims of this study were to evaluate whether results of observational studies evaluating an intervention with safety outcome(s) registered at ClinicalTrials.gov were published and, if not, whether they were available through posting on ClinicalTrials.gov or the sponsor website. METHODS: We identified a cohort of observational studies with safety outcome(s) registered on ClinicalTrials.gov after October 1, 2007, and completed between October 1, 2007, and December 31, 2011. We systematically searched PubMed for a publication, as well as ClinicalTrials.gov and the sponsor website for results. The main outcomes were the time to the first publication in journals and to the first public availability of the study results (i.e. published or posted on ClinicalTrials.gov or the sponsor website). For all studies with results publicly available, we evaluated the completeness of reporting (i.e. reported with the number of events per arm) of safety outcomes. RESULTS: We identified 489 studies; 334 (68%) were partially or completely funded by industry. Results for only 189 (39%, i.e. 65% of the total target number of participants) were published at least 30 months after the study completion. When searching other data sources, we obtained the results for 53% (n = 158; i.e. 93% of the total target number of participants) of unpublished studies; 31% (n = 94) were posted on ClinicalTrials.gov and 21% (n = 64) on the sponsor website. As compared with non-industry-funded studies, industry-funded study results were less likely to be published but not less likely to be publicly available. Of the 242 studies with a primary outcome recorded as a safety issue, all these outcomes were adequately reported in 86% (114/133) when available in a publication, 91% (62/68) when available on ClinicalTrials.gov, and 80% (33/41) when available on the sponsor website. CONCLUSIONS: Only 39% of observational studies evaluating an intervention with safety outcome(s) registered at ClinicalTrials.gov had their results published at least 30 months after study completion. The registration of these observational studies allowed searching other sources (results posted at ClinicalTrials.gov and sponsor website) and obtaining results for half of unpublished studies and 93% of the total target number of participants.

Development of the ClinESSDAI: a clinical score without biological domain. A tool for biological studies.

OBJECTIVE: To develop and validate ClinESSDAI (Clinical European League Against Rheumatism Sjögren's Syndrome Disease Activity Index), ie, ESSDAI without the biological domain. PATIENTS AND METHODS: The 702 fictive vignettes derived from 96 real cases of primary Sjögren's syndrome of the ESSDAI development study were used. As for ESSDAI development, the physician assessment of disease activity (0-10 scale) was used as the 'gold standard' in a multivariate model for weighting domains, after removing the biological domain. The reliability, assessed by intraclass correlation coefficient (ICC) between ClinESSDAI and ESSDAI, explored if ClinESSDAI was equivalent to ESSDAI. Its psychometric (ie, measurement) properties were compared with that of ESSDAI in an independent cohort. Also, its use was evaluated on data of two clinical trials. RESULTS: In multivariate modelling, all 11 domains remained significantly associated with disease activity, with slight modifications of some domain weights. Reliability between clinESSDAI and ESSDAI was excellent (ICC=0.98 and 0.99). Psychometric properties of clinESSDAI, disease activity levels and minimal clinically important improvement thresholds and its ability to detect change over time in clinical trials were very close to that of ESSDAI. CONCLUSIONS: ClinESSDAI appears valid and very close to the original ESSDAI. This score provides an accurate evaluation of disease activity independent of B-cell biomarkers. It could be used in various circumstances: (i) in biological/clinical studies to avoid data collinearity, (ii) in clinical trials, as secondary endpoint, to detect change independent of biological effect of the drug, (iii) in clinical practice to assess disease activity for visits where immunological tests have not been done.

Defining disease activity states and clinically meaningful improvement in primary Sjögren's syndrome with EULAR primary Sjögren's syndrome disease activity (ESSDAI) and patient-reported indexes (ESSPRI).

OBJECTIVES: To define disease activity levels, minimal clinically important improvement (MCII) and patient-acceptable symptom state (PASS) with the primary Sjögren's syndrome (SS) disease activity indexes: European League Against Rheumatism (EULAR) SS disease activity index (ESSDAI) and EULAR SS patient-reported index (ESSPRI). METHODS: For 790 patients from two large prospective cohorts, ESSDAI, physician evaluation of disease activity, ESSPRI and patients' satisfaction with their current health status were recorded. Receiver operating characteristic curve analyses and anchoring methods were used to estimate disease activity levels of ESSDAI and the PASS of ESSPRI. At follow-up visit, patients and physicians assessed, respectively, whether symptoms and disease activity have improved or not. An anchoring method based on this evaluation was used to estimate MCII of ESSDAI and ESSPRI. RESULTS: Low-activity (ESSDAI<5), moderate-activity (5≤ESSDAI≤13) and high-activity (ESSDAI≥14) levels were defined. MCII of ESSDAI was defined as an improvement of at least three points. The PASS estimate was defined as an ESSPRI<5 points and MCII as a decrease of at least one point or 15%. CONCLUSIONS: This study determined disease activity levels, PASS and MCII of ESSDAI and ESSPRI. These results will help designing future clinical trials in SS. For evaluating systemic complications, the proposal is to include patients with moderate activity (ESSDAI≥5) and define response to treatment as an improvement of ESSDAI at least three points. For addressing patient-reported outcomes, inclusion of patients with unsatisfactory symptom state (ESSPRI≥5) and defining response as an improvement of ESSPRI at least one point or 15% seems reasonable.

Performance of principal scores to estimate the marginal compliers causal effect of an intervention.

We examine the properties of principal scores methods to estimate the causal marginal odds ratio of an intervention for compliers in the context of a randomized controlled trial with non-compliers. The two-stage estimation approach has been proposed for a linear model by Jo and Stuart (Statistics in Medicine 2009; 28:2857-2875) under a principal ignorability (PI) assumption. Using a Monte Carlo simulation study, we compared the performance of several strategies to build and use principal score models and the robustness of the method to violations of underlying assumptions, in particular PI. Results showed that the principal score approach yielded unbiased estimates of the causal marginal log odds ratio under PI but that the method was sensitive to violations of PI, which occurs in particular when confounders are omitted from the analysis. For principal score analysis, probability weighting performed slightly better than full matching or 1:1 matching. Concerning the variables to be included in principal score models, the lowest mean squared error was generally obtained when using the true confounders. Using variables associated with the outcome only but not compliance however yielded very similar performance.

MRI and serum biomarkers correlate with radiographic features in painful hand osteoarthritis.

OBJECTIVES: To explore the relationship between clinical findings, biologic biomarkers, conventional radiography and MRI in patients with painful hand OA. METHODS: The following patient baseline data from the DORA study (evaluating anti-TNF-α agents against painful hand OA) were used: clinical assessment (pain, swelling, stiffness and function: Dreiser functional hand index [FIHOA] and Cochin hand functional scale [CHFS]); measurement of biomarkers (cartilage oligomeric matrix protein (COMP), type IIA collagen N-propeptid (PIINP), hyaluronic acid (HA), ultrasensitive C-reactive protein (usCRP), tumour necrosis factor (TNF), interleukin (IL)-6, IL-1ß and urinary CTXII); radiological staging (Verbruggen, Kallman, Kellgren-Lawrence); anatomical evaluation by contrast-enhanced MRI of proximal and distal interphalangeal joints of dominant hand. Associations between clinical, biomarker and imaging findings were assessed using the Spearman correlation coefficient and test. RESULTS: 18 patients were recruited, and 144 joints studied. A correlation was found between clinical features (pain, FIHOA, CHFS) and the Verbruggen score (respectively: p=0.05, r=0.47; p=0.05, r=0.48; p=0.05, r=0.48). Serum IL-1 level was strongly associated with loss of function (FIHOA: p=0.02, r=-0.73; CHFS: p=0.01, r=-0.76) and radiological erosions (p=0.03, r=0.7) as with urinary CTX2. A significant association was found between MRI osteophytes and usCRP (p=0.0026). MRI and radiological features were significantly correlated except for synovitis and bone marrow lesions. CONCLUSIONS: MRI synovitis was not correlated with radiological scores, clinical or biologic markers of inflammation. There was a strong correlation between other MRI features and radiological scores. Serum IL-1 level was associated with structural damage and function.

The most important tasks for peer reviewers evaluating a randomized controlled trial are not congruent with the tasks most often requested by journal editors.

BACKGROUND: The peer review process is a cornerstone of biomedical research publications. However, it may fail to allow the publication of high-quality articles. We aimed to identify and sort, according to their importance, all tasks that are expected from peer reviewers when evaluating a manuscript reporting the results of a randomized controlled trial (RCT) and to determine which of these tasks are clearly requested by editors in their recommendations to peer reviewers. METHODS: We identified the tasks expected of peer reviewers from 1) a systematic review of the published literature and 2) recommendations to peer reviewers for 171 journals (i.e., 10 journals with the highest impact factor for 14 different medical areas and all journals indexed in PubMed that published more than 15 RCTs over 3 months regardless of the medical area). Participants who had peer-reviewed at least one report of an RCT had to classify the importance of each task relative to other tasks using a Q-sort technique. Finally, we evaluated editors' recommendations to authors to determine which tasks were clearly requested by editors in their recommendations to peer reviewers. RESULTS: The Q-sort survey was completed by 203 participants, 93 (46 %) with clinical expertise, 72 (36 %) with methodological/statistical expertise, 17 (8 %) with expertise in both areas, and 21 (10 %) with other expertise. The task rated most important by participants (evaluating the risk of bias) was clearly requested by only 5 % of editors. In contrast, the task most frequently requested by editors (provide recommendations for publication), was rated in the first tertile only by 21 % of all participants. CONCLUSIONS: The most important tasks for peer reviewers were not congruent with the tasks most often requested by journal editors in their guidelines to reviewers.

Efficacy and safety of belimumab in primary Sjögren's syndrome: results of the BELISS open-label phase II study.

BACKGROUND: Increased expression of B cell activating factor (BAFF or B lymphocyte stimulator) may explain the B cell activation characteristic of primary Sjögren's syndrome (pSS). OBJECTIVES: To evaluate the efficacy and safety of belimumab, targeting BAFF, in patients with pSS. METHODS: Patients were included in this bi-centric prospective 1-year open-label trial if they fulfilled American European Consensus group criteria, were anti-Sjögren's syndrome A-positive and had current systemic complications or salivary gland enlargement, or early disease (<5 years), or biomarkers of B cell activation. They received belimumab, 10 mg/kg, at weeks 0, 2 and 4 and then every 4 weeks to week 24. The primary end-point, assessed at week 28, was improvement in two of five items: reduction in ≥30% in dryness score on a visual analogue scale (VAS), ≥30% in fatigue VAS score, ≥30% in VAS pain score, ≥30% in systemic activity VAS assessed by the physician and/or >25% improvement in any B cell activation biomarker values. RESULTS: Among 30 patients included, the primary end-point was achieved in 18 (60%). The mean (SD) European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index decreased from 8.8 (7.4) to 6.3 (6.6) (p=0.0015) and EULAR) Sjögren's Syndrome Patient Reported Index from 6.4 (1.1) to 5.6 (2.0) (p=0.0174). The mean dryness, fatigue and pain VAS varied from 7.8 (1.8) to 6.2 (2.9) (p=0.0021), 6.9 (1.8) to 6.0 (2.2) (p=0.0606) and 4.6 (2.6) to 4.7 (2.4) (p=0.89), respectively. Salivary flow and Schirmer's test did not change. CONCLUSIONS: These encouraging results justify future randomised controlled trials of belimumab in a selected target population of pSS patients most likely to benefit from treatment.

Adalimumab for steroid sparing in patients with giant-cell arteritis: results of a multicentre randomised controlled trial.

OBJECTIVES: To evaluate the effect of adding a 10-week treatment of adalimumab to a standardised treatment with corticosteroids on the ability to taper more rapidly corticosteroid doses in patients with newly diagnosed giant cell arteritis (GCA). METHODS: Patients included in this double-blind, multicentre controlled trial were randomly assigned to receive a 10-week subcutaneous treatment of adalimumab 40 mg every other week or placebo in addition to a standard prednisone regimen (starting dose 0.7 mg/kg per day). The primary endpoint was the percentage of patients in remission on less than 0.1 mg/kg of prednisone at week 26. Analysis was performed by intention to treat (ITT). RESULTS: Among the 70 patients enrolled (adalimumab, n=34; placebo, n=36), 10 patients did not receive the scheduled treatment, seven in the adalimumab and three in the placebo group. By ITT, the number of patients achieving the primary endpoint was 20 (58.9%) and 18 (50.0%) in the adalimumab and placebo arm, respectively (p=0.46). The decrease in prednisone dose and the proportion of patients who were relapse free did not differ between the two groups. Serious adverse events occurred in five (14.7%) patients on adalimumab and 17 (47.2%) on placebo, including serious infections in three patients on adalimumab and five on placebo. Two patients died in the placebo arm (septic shock and cancer) and one in the adalimumab group (pneumonia). CONCLUSIONS: In patients with newly diagnosed GCA, adding a 10-week treatment of adalimumab to prednisone did not increase the number of patients in remission on less than 0.1 mg/kg of corticosteroids at 6 months. CLINICAL TRIAL REGISTRATION NUMBER: NCT00305539.

Impact of adding a limitations section to abstracts of systematic reviews on readers' interpretation: a randomized controlled trial.

BACKGROUND: To allow an accurate evaluation of abstracts of systematic reviews, the PRISMA Statement recommends that the limitations of the evidence (e.g., risk of bias, publication bias, inconsistency, imprecision) should be described in the abstract. We aimed to evaluate the impact of adding such limitations sections on reader's interpretation. METHOD: We performed a two-arm parallel group randomized controlled trial (RCT) using a sample of 30 abstracts of systematic reviews evaluating the effects of healthcare intervention with conclusions favoring the beneficial effect of the experimental treatments. Two formats of these abstracts were derived: one reported without and one with a standardized limitations section written according to the PRISMA statement for abstracts. The primary outcome was readers' confidence in the results of the systematic review as stated in the abstract assessed by a Likert scale from 0, not at all confident, to 10, very confident. In total, 300 participants (corresponding authors of RCT reports indexed in PubMed) were randomized by a web-based randomization procedure to interpret one abstract with a limitations section (n = 150) or without a limitations section (n = 150). Participants were blinded to the study hypothesis. RESULTS: Adding a limitations section did not modify readers' interpretation of findings in terms of confidence in the results (mean difference [95% confidence interval] 0.19 [-0.37-0.74], p = 0.50), confidence in the validity of the conclusions (0.07 [-0.49-0.62], p = 0.80), or benefit of the experimental intervention (0.12 [-0.42-0.44], p = 0.65).This study is limited because the participants were expert-readers and are not representative of all systematic review readers. CONCLUSION: Adding a limitations section to abstracts of systematic reviews did not affect readers' interpretation of the abstract results. Other studies are needed to confirm the results and explore the impact of a limitations section on a less expert panel of participants. TRIAL REGISTRATION: ClinicalTrial.gov (NCT01848782).