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To develop a set of detailed definitions for foundational domains commonly used in OMERACT (Outcome Measures in Rheumatology) core domain sets. We identified candidate domain definitions from prior OMERACT publications and websites and publications of major organizations involved in outcomes research for six domains commonly used in OMERACT Core Domain Sets: pain intensity, pain interference, physical function, fatigue, patient global assessment, and health-related quality of life. We conducted a two-round survey of OMERACT working groups, patient research partners, and then the OMERACT Technical Advisory Group to establish their preferred domain definitions. Results were presented at the OMERACT 2023 Methodology Workshop, where participants discussed their relevant lived experience and identified potential sources of variability giving the needed detail in our domain definitions. One-hundred four people responded to both rounds of the survey, and a preferred definition was established for each of the domains except for patient global assessment for which no agreement was reached. Seventy-five participants at the OMERACT 2023 Methodology Workshop provided lived experience examples, which were used to contextualise domain definition reports for each of the five domains. Using a consensus-based approach, we have created a detailed definition for five of the foundational domains in OMERACT core domain sets; patient global assessment requires further research. These definitions, although not mandatory for working groups to use, may facilitate the initial domain-match assessment step of instrument selection, and reduce the time and resources required by future OMERACT groups when developing core outcome sets. [ABSTRACT FROM AUTHOR]

Core outcome sets are critically important outcomes that should be measured in clinical trials. Their absence in atopic dermatitis is a form of research waste and impedes combining evidence to inform patient care. Here, we articulate the rationale for core outcome sets in atopic dermatitis and review the work of the international Harmonising Outcome Measures for Eczema group from its inception in Munich, 2010. We describe core domain determination (what should be measured), to instrument selection (how domains should be measured), culminating in the complete core outcome measurement set in Tokyo, 2019. Using a "road map," Harmonising Outcome Measures for Eczema includes diverse research methods including Delphi and nominal group techniques informed by systematic reviews of properties of candidate instruments. The 4 domains and recommended instruments for including in all clinical trials of atopic dermatitis are patient symptoms, measured by Patient-Oriented Eczema Measure and peak Numerical Rating Scale 11 for itch intensity over 24 hours, clinical signs measured using the Eczema Area and Severity Index, quality of life measured by the Dermatology Life Quality Index series for adults, children, and infants, and long-term control measured by either Recap of atopic eczema or Atopic Dermatitis Control Tool. [ABSTRACT FROM AUTHOR]

To generate candidates for contextual factors (CFs) for each CF type (i.e., Effect Modifying Contextual Factors (EM-CFs), Outcome Influencing Contextual Factors (OI-CFs), and Measurement Affecting Contextual Factors (MA-CFs)) considered important within rheumatology. We surveyed OMERACT working groups and conducted a Special Interest Group (SIG) session at the OMERACT 2023 meeting, where the results were reviewed, and additional CFs suggested. The working groups suggested 44, 49, and 21 generic EM-CFs, OI-CFs, and MA-CFs, respectively. SIG participants added 49, 44, and 55 factors, respectively. Candidate CFs were identified, next step is a consensus-based set of endorsed (important) CFs. [ABSTRACT FROM AUTHOR]

OMERACT uses an evidence-based framework known as the 'OMERACT Filter Instrument Selection Algorithm' (OFISA) to guide decisions in the assessment of outcome measurement instruments for inclusion in a core outcome set for interventional and observational clinical trials. A group of OMERACT imaging and patient-centered outcome methodologists worked with imaging outcome groups to facilitate the selection of imaging outcome measurement instruments using the OFISA approach. The lessons learned from this work influenced the evolution to Filter 2.2 and necessitated changes to OMERACT's documentation and processes. OMERACT has revised documentation and processes to incorporate the evolution of instrument selection to Filter 2.2. These revisions include creation of a template for detailed definitions of the target domain which is a necessary first step for instrument selection, modifications to the Summary of Measurement Properties (SOMP) table to account for sources of variability, and development of standardized reporting tables for each measurement property. OMERACT Filter 2.2 represents additional modifications of the OMERACT guide for working groups in their rigorous assessment of measurement properties of instruments of various types, including imaging outcome measurement instruments. Enhanced reporting aims to increase the transparency of the evidence base leading to judgements for the endorsement of instruments in core outcome sets. [ABSTRACT FROM AUTHOR]

• Clear definition of the domain we want to measure is a necessary prerequisite to the selection of a good instrument. • Measurement instruments, whatever the domain they strive to measure, are always the result of the interaction between the instrument (technique+ application + scoring system) and a domain of interest, and it is always the score that is used to represent the domain. • Imaging outcome measurement instruments for research are not the imaging techniques themselves (i.e. ultrasound or X-ray), but the result of a formalized interpretation (through a scale or score) • Clear identification of the sources of variability that can directly influence the instrument and therefore the measurement of the domain of interest should be clearly identified before endorsing any outcome measurement instrument Imaging is one of the most rapidly evolving fields in medicine. Unfortunately, many imaging technologies have been applied as measurement instruments without rigorous evaluation of the evidence supporting their truth, discriminatory capability and feasibility for that context of use. The Outcome Measures in Rheumatology (OMERACT) Filter 2.1 Instrument Selection Algorithm (OFISA) is used to evaluate such evidence for use of an instrument in a research setting. The objectives of this work are to: [1] define and describe the key conceptual aspects that are essential for the evaluation of imaging as an outcome measurement instrument and [2] describe how these aspects can be assessed through OFISA. Experts in imaging and/or methodology met to formalize concepts and define key steps. These concepts were discussed with a team of patient research partners with interest in imaging to refine technical and methodological aspects into comprehensible information. A workshop was held at OMERACT2020 and feedback was incorporated into existing OMERACT process for domain and instrument selection. Three key lessons were identified: (1) a clear definition of the domain we want to measure is a necessary prerequisite to the selection of a good instrument, (2) the sources of variability that can directly influence the instrument should be clearly identified, (3) incorporating these first two lessons into OFISA improves the quality of every instrument selection process. The incorporation of these lessons in the updated OMERACT Filter (now 2.2) will improve the quality of the selection process for all types of outcome measurement instruments. [ABSTRACT FROM AUTHOR]

Our primary objective was to develop an Outcome Measures in Rheumatology (OMERACT) core domain set to capture the impact of glucocorticoids (GC), both positive and negative, on patients with Rheumatic conditions. The OMERACT Filter 2.1 was used to guide core domain selection. Systematic literature reviews, qualitative studies and quantitative surveys were conducted by the OMERACT GC Impact working group to identify candidate domains for a core domain set. A summary of prior work and Delphi exercise were presented at the OMERACT 2020 virtual GC workshop. A proposed GC Impact core domain set derived from this work was presented for discussion in facilitated breakout groups. Participants voted on the proposed GC Impact core domain set. 113 people, including 23 patient research partners, participated in two virtual workshops conducted at different times on the same day. The proposed mandatory domains to be evaluated in clinical trials involving GCs were: infection, bone fragility, hypertension, diabetes, weight, fatigue, mood disturbance and death. In addition, collection of disease specific outcomes was included in the core domain set as "mandatory in specific circumstances". The proposed core domain set was endorsed by 100% (23/23) of the patient research partners and 92% (83/90) of the remaining participants, including clinicians, researchers and industry stakeholders. A GC Impact core domain set was endorsed at the OMERACT 2020 virtual workshop. The OMERACT GC Impact working group will now progress to identify, develop and validate measurement tools to best address these domains in clinical trials. [ABSTRACT FROM AUTHOR]

To develop an operational definition of contextual factors (CF) [1]. Based on previously conducted interviews, we presented three CF types in a Delphi survey; Effect Modifying -, Outcome Influencing - and Measurement Affecting CFs. Subsequently, a virtual Special Interest Group (SIG) session was held for in depth discussion of Effect Modifying CFs. Of 161 Delphi participants, 129 (80%) completed both rounds. After two rounds, we reached consensus (≥70% agreeing) for all but two statements. The 45 SIG participants were broadly supportive. Through consensus we developed an operational definition of CFs, which was well received by OMERACT members. [ABSTRACT FROM AUTHOR]

Underreporting of harms in randomized controlled trials (RCTs) may lead to incomplete or erroneous assessments of the perceived benefit-to-harm profile of an intervention. To compare benefit with harm in clinical practice and future clinical studies, adverse event (AE) profiles including severity need to be understood. Even though patients report harm symptoms earlier and more frequently than clinicians, rheumatology RCTs currently do not provide a reporting framework from the patient's perspective regarding harms. Our objective for this meta-research project was to identify AEs in order to determine harm clusters and whether these could be self-reported by patients. Our other objective was to examine reported severity grading of the reported harms. We considered primary publications of RCTs eligible if they were published between 2008 and 2018 evaluating pharmacological interventions in patients with a rheumatic or musculoskeletal condition and if they were included in Cochrane reviews. We extracted data on harms such as reported AE terms together with severity (if described), and categorized AE- and severity-terms into overall groups. We deemed all AEs with felt components appropriate for patient self-reporting. The literature search identified 187 possible Cochrane reviews, of which 94 were eligible for evaluation, comprising 1,297 articles on individual RCTs. Of these RCTs, 93 pharmacological trials met our inclusion criteria (including 31,023 patients; representing 20,844 accumulated patient years), which reported a total of 21,498 AEs, corresponding to 693 unique reported terms for AEs. We further sub-categorized these terms into 280 harm clusters (i.e., themes). AEs appropriate for patient self-reporting accounted for 58% of the AEs reported. Among the reported AEs, we identified medical terms for all of the 117 harm clusters appropriate for patient reporting and lay language terms for 86%. We intended to include severity grades of the reported AEs, but there was no evidence for systematic reporting of clinician- or patient-reported severity in the primary articles of the 93 trials. However, we identified 33 terms suggesting severity, but severity grading was discernible in only 9%, precluding a breakdown by severity in this systematic review. Our results support the need for a standardized framework for patients' reporting of harms in rheumatology trials. Reporting of AEs with severity should be included in future reporting of harms, both from the patients' and investigators' perspectives. PROSPERO: CRD42018108393 [ABSTRACT FROM AUTHOR]

• International, up to 10-year observational safety study in patients with RA. • Five data sources were used across Europe and North America. • Data sources included registries and healthcare claims databases. • Similar risk of hospitalized infection with abatacept compared with DMARDs. • The incidence of opportunistic infections, including tuberculosis, was low. To evaluate risk of infections requiring hospitalization and opportunistic infections, including tuberculosis, in patients with rheumatoid arthritis (RA) treated with abatacept versus conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) and other biologic/targeted synthetic (b/ts) DMARDs. Five international observational data sources were used: two biologic registries (Sweden, Germany), a disease registry (USA) and two healthcare claims databases (Canada, USA). Crude incidence rates (IRs) per 1000 patient-years, with 95 % CIs, were used to estimate rate ratios (RRs) comparing abatacept versus csDMARDs or other b/tsDMARDs. RRs were adjusted for demographic factors, comorbidities, and other potential confounders and then pooled across data sources using a random effects model (REM). The data sources included 6450 abatacept users, 136,636 csDMARD users and 54,378 other b/tsDMARD users, with a mean follow-up range of 2.2–6.2 years. Across data sources, the IRs for infections requiring hospitalization ranged from 16 to 56 for abatacept, 19–46 for csDMARDs, and 18–40 for other b/tsDMARDs. IRs for opportunistic infections were 0.4–7.8, 0.3–4.3, and 0.5–3.8; IRs for tuberculosis were 0.0–8.4, 0.0–6.0, and 0.0–6.3, respectively. The pooled adjusted RR (95 % CI), only reported for infections requiring hospitalization, was 1.2 (0.6–2.2) for abatacept versus csDMARDs and 0.9 (0.6–1.3) versus other b/tsDMARDs. Data from this international, observational study showed similar hospitalized infection risk for abatacept versus csDMARDs or other b/tsDMARDs. IRs for opportunistic infections, including tuberculosis, were low. These data are consistent with the known safety profile of abatacept. [ABSTRACT FROM AUTHOR]

• International, up to 10-year observational safety study in patients with RA. • No significant increased risk of overall malignancy with abatacept vs cs/b/tsDMARDs. • No increased risk of breast cancer with abatacept compared with cs/b/tsDMARDs. • No increased risk of lung cancer with abatacept compared with cs/b/tsDMARDs. • ARTIS showed significantly increased risk of lymphoma with abatacept vs b/tsDMARDs. To evaluate the risk of malignancy (overall, breast, lung, and lymphoma) in patients with rheumatoid arthritis treated with abatacept, conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs), and other biologic/targeted synthetic (b/ts)DMARDs in clinical practice. Four international observational data sources were included: ARTIS (Sweden), RABBIT (Germany), FORWARD (USA), and BC (Canada). Crude incidence rates (IRs) per 1000 patient-years of exposure with 95% confidence intervals (CIs) for a malignancy event were calculated; rate ratios (RRs) were estimated and adjusted for demographics, comorbidities, and other potential confounders. RRs were then pooled in a random-effects model. Across data sources, mean follow-up for patients treated with abatacept (n = 5182), csDMARDs (n = 73,755), and other b/tsDMARDs (n = 37,195) was 3.0–3.7, 2.9–6.2, and 3.1–4.7 years, respectively. IRs per 1000 patient-years for overall malignancy ranged from 7.6–11.4 (abatacept), 8.6–13.2 (csDMARDs), and 5.0–11.8 (other b/tsDMARDs). IRs ranged from: 0–4.4, 0–3.3, and 0–2.5 (breast cancer); 0.1–2.8, 0–3.7, and 0.2–2.9 (lung cancer); and 0–1.1, 0–0.9, and 0–0.6 (lymphoma), respectively, for the three treatment groups. The numbers of individual cancers (breast, lung, and lymphoma) in some registries were low; RRs were not available. There were a few cases of lymphoma in some of the registries; ARTIS observed an RR of 2.8 (95% CI 1.1–6.8) with abatacept versus csDMARDs. The pooled RRs (95% CIs) for overall malignancy with abatacept were 1.1 (0.8–1.5) versus csDMARDs and 1.0 (0.8–1.3) versus b/tsDMARDs. This international, post-marketing observational safety study did not find any statistically significant increase in the risk of overall malignancies in pooled data in patients treated with abatacept compared with csDMARDs or with other b/tsDMARDs. Assessment of larger populations is needed to further evaluate the risks for individual cancers, especially lymphoma. [ABSTRACT FROM AUTHOR]

To develop an understanding of the concept of safety/harms experienced by patients involved in clinical trials for their rheumatic and musculoskeletal diseases (RMDs) and to seek input from the OMERACT community before moving forward to developing or selecting an outcome measurement instrument. OMERACT 2023 presented and discussed interview results from 34 patients indicating that up to 171 items might be important for patients' harm-reporting. Domain was defined in detail and supported by qualitative work. Participants in the Special-Interest-Group endorsed (96 %) that enough qualitative data are available to start Delphi survey(s). We present a definition of safety/harms that represents the patient voice (i.e., patients' perception of safety) evaluating the symptomatic treatment-related adverse events for people with RMDs enrolled in clinical trials. [ABSTRACT FROM AUTHOR]

In the ULTIMATE study with an open label extension, we assessed the long-term effect of secukinumab at tissue level on synovitis and enthesitis, and across all psoriatic arthritis (PsA) manifestations, using both clinical evaluations and power Doppler ultrasonography (PDUS). This randomised, placebo-controlled, Phase 3 study (ULTIMATE) included biologic-naïve patients with PsA with active PDUS synovitis and clinical enthesitis, and inadequate response to conventional synthetic disease-modifying antirheumatic drugs. The study consisted of 3 treatment periods; in the first period (baseline to week 12) patients were randomised to receive subcutaneous secukinumab (150 mg or 300 mg according to severity of skin psoriasis) or placebo every week until week 4 and once every 4 weeks up to week 12. In the second period (weeks 12–24) all patients received open-label secukinumab with placebo patients switching to secukinumab (150 mg or 300 mg). The third period (weeks 24–52) was an extended open-label treatment period. The long-term responsiveness of the Global EULAR-OMERACT Synovitis Score (GLOESS), clinical enthesitis and global PDUS-detected enthesitis score (using two candidate definitions of activity) at patient level, together with clinical efficacy across key manifestations of PsA and safety were assessed. Of the 166 patients enrolled, 144 completed week 52. A significant reduction in GLOESS was demonstrated in the secukinumab group vs placebo at week 12, followed by a stable reduction of synovitis until week 52 in the secukinumab group while placebo switchers from week 12 reached a similar level of reduction at week 24 with stability thereafter. Likewise, a significant reduction in the Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis index was shown in the secukinumab group vs placebo at week 12 with sustained improvement to week 52. Global OMERACT PDUS enthesitis scores were numerically lower in secukinumab vs placebo switchers in the first two treatment periods, with some stability in the third period in both groups. Improvements in clinical responses were also observed across all key domains of PsA up to week 52 in both treatment groups with no new or unexpected safety signals. ULTIMATE showed consistent improvements in clinically and ultrasound-assessed synovitis and enthesitis and sustained clinical efficacy through week 52 in patients with PsA treated with secukinumab and placebo switched to secukinumab. [ABSTRACT FROM AUTHOR]

Randomized controlled trials (RCTs) are considered the gold standard in clinical research due to credible causality. Their results, however, may not be generalizable to real-world populations. While glucocorticoids (GCs) remain a mainstay of rheumatoid arthritis (RA) treatment, it is unclear whether the results of GC-RCTs are generalizable to current real-world RA patients. MEDLINE was searched for RCTs and, as comparators, cohort studies (CSs) in RA evaluating systemic GCs. Random-effects meta-analyses were performed for descriptive baseline characteristics (including general demographics, comorbidities, and disease activity) that have been shown to be able to modify the benefit-risk-ratio of various RA therapeutics. These meta-analyses were stratified by study type (RCT and CS). Stratified estimates were subsequently compared. Further sensitivity analyses were performed stratifying by disease duration. 56 RCTs (7053 participants) and 10 CSs (14,688 participants) were included. 12 characteristics were reported frequently enough to allow for comparative analysis. In 10/12 characteristics (83%), RCT estimates did not appear to differ from CS estimates. However, RCT participants were younger (-4.7 years [95% CI -7.2 to -2.1]; p < 0.001) and had higher erythrocyte sedimentation rates (11.8 mm/h [5.7 to 17.8]; p < 0.001) than CS participants. Comorbidities could not be assessed due to insufficient reporting. Our findings suggest that evidence from GC trials in RA is of acceptable generalizability to current real-world patients – especially compared to findings from biologic agents in RA. However, RCT participants were younger than real-world patients, potentially limiting the generalizability of trial results to elderly patients. PROSPERO (CRD42019134675) [ABSTRACT FROM AUTHOR]

To compare dimensionality, item-level characteristics, scale-level reliability, and construct validity of PROMIS Physical Function short forms (PROMIS-PF) and 24-item Roland Morris Disability Questionnaire (RMDQ-24) in patients with chronic low back pain (LBP). Cross-sectional study. Secondary care center for rehabilitation and rheumatology. Patients with nonspecific LBP ≥3 months (N=768). Mean age was 49±13 years, 77% were female, and 54% displayed pain for more than 5 years. Not applicable. Dutch versions of the 4-, 6-, 8-, 10-, and 20-item PROMIS-PF and of the RMDQ-24. PROMIS-PF-6, PROMIS-PF-8, and RMDQ-24 exhibited sufficient unidimensionality (confirmatory factor analysis: comparative fit index>0.950, Tucker-Lewis index>0.950, root means square error of approximation<0.060), whereas the other instruments did not. All instruments were free of local dependence except PROMIS-PF-20 with 4 item pairs with clear residual correlations. Mokken scale analysis found 1 nonmonotone item for PROMIS-PF-20 and 8 for RMDQ-24 (ie, the probability of endorsing these items was not increasing with increasing level on the underlying construct). PROMIS-PF-20 displayed 2 misfitting items (S-χ2 P value>.001). Two-parameter item response theory models found 2 items with low discrimination for RMDQ-24. All other instruments had adequate fit statistics and item parameters. PROMIS-PF-20 displayed the best scale-level reliability. Construct validity was sufficient for all instruments as all hypotheses on expected correlations with other instruments and differences between relevant subgroups were met. PROMIS-PF-6, PROMIS-PF-8, and RMDQ-24 exhibited better unidimensionality, whereas PROMIS-PF-4, PROMIS-PF-6, PROMIS-PF-8, and PROMIS-PF-10 showed superior item-level characteristics. PROMIS-PF-20 was the instrument with the best scale-level reliability. This study warrants assessment of other measurement properties of PROMIS-PF short forms in comparison with disease-specific physical functioning instruments in LBP. [ABSTRACT FROM AUTHOR]

The distribution of progression scores in rheumatoid arthritis is highly skewed, requiring advanced statistical analysis techniques, with different techniques resulting in different outcomes. Three databases were searched to identify rheumatoid arthritis clinical trials and observational studies that described radiographic analysis techniques, comparing at least two groups. Of 5980 identified papers, 225 were eligible for data extraction. Parametric techniques (t-tests, ANOVA or linear regression) were used in 39 studies, of which 18% took the skewed distribution into account. In 53 studies, continuous data was categorized and analyzed with binomial or ordinal methods (chi-square tests or logistic regression). Two studies treated the outcome as a 'count' outcome variable (applying a Poisson). There is large heterogeneity in the analysis strategy of radiographic progression in recent rheumatoid arthritis clinical trials and observational studies, with the majority of studies applying simple, suboptimal or inappropriate methods. [ABSTRACT FROM AUTHOR]

To evaluate whether elderly people and women are adequately represented in randomized controlled trials (RCT) in rheumatoid arthritis (RA) and osteoarthritis (OA). Four systematic searches in MEDLINE yielded RCT in RA and OA on any intervention published in 2016 and 2017 and population-based studies (PBS) in RA and OA published between 2013 and 2017. Random effects meta-analyses estimated the pooled proportion of elderly people (defined as being ≥ 65 years old), the mean age, its standard deviation (SD), and the proportion of women stratified by disease (RA and OA) and study type (RCT and PBS). Stratified estimates were subsequently compared. 265 RCT comprising 51,240 participants and 53 PBS comprising 523,630 participants were included. In both RA and OA, RCT included lower proportions of elderly people than PBS: RA –0.18 (95% confidence interval –0.22 to –0.13); OA –0.20 (–0.30 to –0.09); had lower mean ages: RA –5.2 years (–6.8 to –3.5); OA –4.7 years (–7.5 to –2.0); and smaller SD: RA –1.9 years (–2.6 to –1.3); OA –2.7 years (–4.2 to –1.2); (all comparisons: p ≤ 0.001). Proportions of women were comparable in RCT compared to PBS in both RA and OA. While women are adequately represented in RA and OA trials, the elderly are underrepresented, probably limiting applicability of current evidence to this growing subgroup. It is urgent to improve the inclusion of elderly people in clinical trials and study age as a determinant for outcome. [ABSTRACT FROM AUTHOR]

The Visual Analogue Scale (VAS), Numeric Rating Scale (NRS), and Pain Severity subscale of the Brief Pain Inventory (BPI-PS) are the most frequently used instruments to measure pain intensity in low back pain. However, their measurement properties in this population have not been reviewed systematically. The goal of this study was to provide such systematic evidence synthesis. Six electronic sources (MEDLINE, EMBASE, CINAHL, PsycINFO, SportDiscus, Google Scholar) were searched (July 2017). Studies assessing any measurement property in patients with nonspecific low back pain were included. Two reviewers independently screened articles and assessed risk of bias using the COSMIN checklist. For each measurement property, evidence quality was rated as high, moderate, low, or very low (GRADE approach) and results were classified as sufficient, insufficient, or inconsistent. Ten studies assessed the VAS, 13 the NRS, 4 the BPI-PS. The 3 instruments displayed low or very low quality evidence for content validity. High-quality evidence was only available for NRS insufficient measurement error. Moderate evidence was available for NRS inconsistent responsiveness, BPI-PS sufficient structural validity and internal consistency, and BPI-PS inconsistent construct validity. All VAS measurement properties were underpinned by no, low, or very low quality evidence; likewise, the other measurement properties of NRS and BPI-PS. PERSPECTIVES: Despite their broad use, there is no evidence clearly suggesting that one among VAS, NRS, and BPI-PS has superior measurement properties in low back pain. Future adequate quality head-to-head comparisons are needed and priority should be given to assessing content validity, test-retest reliability, measurement error, and responsiveness. [ABSTRACT FROM AUTHOR]

Objectives To summarize and compare the benefits and harms of biological agents used as monotherapy for rheumatoid arthritis (RA) in order to inform decisions for patients who are intolerant to conventional DMARD therapy. Methods We searched MEDLINE, EMBASE, CENTRAL, and other sources for randomised trials that compared biological monotherapy with methotrexate, placebo, or other biological monotherapies. Primary outcomes were ACR50 and the number of patients who discontinued due to adverse events. Our network meta-analysis was based on mixed-effects logistic regression, including both direct and indirect comparisons of the treatment effects, while preserving the randomised comparisons within each trial. PROSPERO identifier: CRD42012002800. Results The analysis comprises 28 trials (8602 patients), including all nine biological agents approved for RA. Eight trials included “DMARD-naïve”, and 20 “DMARD-Inadequate responder” (DMARD-IR) patients. All agents except anakinra and infliximab were superior ( p < 0.05) to placebo (i.e., no DMARD treatment) with regard to ACR50. Etanercept and rituximab were superior to anakinra ( p = 0.018 and p = 0.049, respectively). Tocilizumab was superior to adalimumab ( p = 0.0082), anakinra ( p = 0.0083), certolizumab ( p = 0.037), and golimumab ( p = 0.049). No differences among etanercept, tocilizumab, and rituximab were found ( p > 0.52). However, because rituximab was evaluated in just 40 patients, our confidence in the estimates is limited. When including only DMARD-IR trials, the same statistical pattern emerged; in addition etanercept and tocilizumab were superior to abatacept. At recommended doses, both etanercept and tocilizumab were superior to adalimumab and certolizumab. No statistically significant differences among biological agents were found with respect to discontinuation due to adverse events ( p > 0.068). Conclusions Evidence from randomised trials suggests that most biological agents are effective as monotherapy. Although our confidence in the estimates is limited, etanercept or tocilizumab may be the optimal choice for most patients who need treatment with biological monotherapy. However, given our limited confidence in the estimates including possibility of bias, it is appropriate to strongly weight patients׳ preferences and values in the final treatment choice. [ABSTRACT FROM AUTHOR]

To internally and externally validate our diagnostic criteria of early stage knee osteoarthritis (OA) in the CHECK and OAI cohorts. We applied two previously developed diagnostic models to all knees in CHECK and OAI cohorts to calculate probabilities of early stage knee OA at baseline. Knees were categorized into three groups based on probability: 'no OA' (probability ≤ 30%), 'uncertain' (probability between 30% and 70%) and 'early stage OA' (probability ≥ 70%). To validate the diagnosis, we obtained OA related outcome measures at 10-year follow-up in the CHECK cohort, and at 8-9-year follow-up in the OAI cohort. We compared outcome measures between 'no OA' and 'early stage OA' knees, and between 'no OA' and 'uncertain' knees using generalized estimating equations. In CHECK (n = 1042 knees) both models showed 'early stage OA' knees presented with significant and clinically relevant higher WOMAC scores, higher Kellgren & Lawrence (KL) grade, and higher rates of joint space narrowing (JSN) progression after 10 years, compared to 'no OA' knees. In OAI (n = 2937 knees) both models showed 'early stage OA' knees presented with significant and clinically relevant higher WOMAC scores, higher KL grade, and higher rates of KL and JSN progression after 8-9 years, compared to 'no OA' knees. Smaller, but still significant differences between 'uncertain' and 'no OA' knees were observed in both cohorts. These results support internal and external validity of the two sets of diagnostic criteria for early stage knee OA. [ABSTRACT FROM AUTHOR]

Background General recommendations for a reference case for economic studies in rheumatic diseases were published in 2002 in an initiative to improve the comparability of cost-effectiveness studies in the field. Since then, economic evaluations in osteoarthritis (OA) continue to show considerable heterogeneity in methodological approach. Objectives To develop a reference case specific for economic studies in OA, including the standard optimal care, with which to judge new pharmacologic and non-pharmacologic interventions. Methods Four subgroups of an ESCEO expert working group on economic assessments (13 experts representing diverse aspects of clinical research and/or economic evaluations) were charged with producing lists of recommendations that would potentially improve the comparability of economic analyses in OA: outcome measures, comparators, costs and methodology. These proposals were discussed and refined during a face-to-face meeting in 2013. They are presented here in the format of the recommendations of the recently published Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement, so that an initiative on economic analysis methodology might be consolidated with an initiative on reporting standards. Results Overall, three distinct reference cases are proposed, one for each hand, knee and hip OA; with diagnostic variations in the first two, giving rise to different treatment options: interphalangeal or thumb-based disease for hand OA and the presence or absence of joint malalignment for knee OA. A set of management strategies is proposed, which should be further evaluated to help establish a consensus on the “standard optimal care” in each proposed reference case. The recommendations on outcome measures, cost itemisation and methodological approaches are also provided. Conclusions The ESCEO group proposes a set of disease-specific recommendations on the conduct and reporting of economic evaluations in OA that could help the standardisation and comparability of studies that evaluate therapeutic strategies of OA in terms of costs and effectiveness. [ABSTRACT FROM AUTHOR]

Background: Lack of standardization of outcome measures limits the usefulness of clinical trial evidence to inform health care decisions. This can be addressed by agreeing on a minimum core set of outcome measures per health condition, containing measures relevant to patients and decision makers. Since 1992, the Outcome Measures in Rheumatology (OMERACT) consensus initiative has successfully developed core sets for many rheumatologic conditions, actively involving patients since 2002. Its expanding scope required an explicit formulation of its underlying conceptual framework and process. Methods: Literature searches and iterative consensus process (surveys and group meetings) of stakeholders including patients, health professionals, and methodologists within and outside rheumatology. Results: To comprehensively sample patient-centered and intervention-specific outcomes, a framework emerged that comprises three core ''Areas,'' namely Death, Life Impact, and Pathophysiological Manifestations; and one strongly recommended Resource Use. Through literature review and consensus process, core set development for any specific health condition starts by identifying at least one core ''Domain'' within each of the Areas to formulate the ''Core Domain Set.'' Next, at least one applicable measurement instrument for each core Domain is identified to formulate a ''Core Outcome Measurement Set.'' Each instrument must prove to be truthful (valid), discriminative, and feasible. In 2012, 96% of the voting participants (n5125) at the OMERACT 11 consensus conference endorsed this model and process. Conclusion: The OMERACT Filter 2.0 explicitly describes a comprehensive conceptual framework and a recommended process to develop core outcome measurement sets for rheumatology likely to be useful as a template in other areas of health care. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: There is an important need to evaluate therapeutic approaches for osteoarthritis (OA) in terms of cost-effectiveness as well as efficacy. Methods: The ESCEO expert working group met to discuss the epidemiological and economic evidence that justifies the increasing concern of the impact of this disease and reviewed the current state-of-the-art in health economic studies in this field. Results: OA is a debilitating disease; it is increasing in frequency and is associated with a substantial and growing burden on society, in terms of both burden of illness and cost of illness. Economic evaluations in this field are relatively rare, and those that do exist, show considerable heterogeneity of methodological approach (such as indicated population, comparator, decision context and perspective, time horizon, modeling and outcome measures used). This heterogeneity makes comparisons between studies problematic. Conclusions: Better adherence to guidelines for economic evaluations is needed. There was strong support for the definition of a reference case and for what might constitute “standard optimal care” in terms of best clinical practice, for the control arms of interventional studies. [Copyright &y& Elsevier]

The article offers information on a data collection methodology involving the Short Form-36 questionnaire (SF-36) in medical care and discusses an article published in the periodical which suggests using radar graphs also called spydergrams for plotting result of the questionnaire. It informs that spydergraph graphically depicts the data in two dimensions on a flat surface and analyzes its difficulties in quantitative interpretation.

Abstract: Background: In the setting of multiple remission and relapse periods of a chronic disease, simple endpoint analysis does not fully capture all relevant information, and we need methods to additionally describe both the duration of remission as well as the interruptions in this desired state. Probably the two-state continuous Markov process model comprises the best mathematical approach to data analysis. However, this approach is complex and not intuitive to clinicians. In this paper we propose a simple scoring system and a graph that can enhance the information about the remission experience in a trial or cohort study. Methods: The continuity rewarded (‘ConRew’) score sums up periods in remission, and rewards extended periods by placing more value on uninterrupted periods than on interrupted periods. The ‘patient vector graph’ attempts to plot each patient''s remission experience over time as a horizontal line (the ‘vector’) that is visible when the patient is in remission, but interrupted whenever relapse occurs. In this way a pattern is formed that conveys the number of patients experiencing remission, their individual total duration and interruptions, and time when these occur. Results: In a dataset of a randomized trial in early rheumatoid arthritis, the graph clearly showed both early and late benefit of one group over the other. The scoring system demonstrated the main benefit was in the number of remission periods, not in their ‘uninterruptedness’. Conclusion: Both approaches proved feasible and added extra information. [Copyright &y& Elsevier]

Abstract: Objective: To develop a simple system to assess benefit and harm of treatment on a single scale. Harm and benefit signals from trials need to be placed in the proper perspective to decide on the value of a treatment. Several systems have been developed for assessment, but few attempt to incorporate both benefit and risk in the same metric while retaining enough simplicity to aid patients and clinicians in their decision making. Study Design and Setting: We designed a very simple 3×3 table (Outcome Measures in Rheumatology [OMERACT] 3×3) that comprises three ranks for both beneficial and harm outcomes: for benefit, these are “none,” “substantial,” and “(near) remission”; for harm, these are “none,” “severe,” and “(near) death.” Patients are ranked both for benefit and harm and subsequently counted in a 3×3 table. Results: The system was feasible when applied to one trial dataset (patient-level information) and a meta-analysis. To become applicable as a tool, several issues need to be resolved in further development, especially the definitions and cutoffs for the ranks. Conclusion: A simple 3×3 table to rank both benefit and harm outcomes is feasible. For rheumatology this will be further developed in the context of the OMERACT initiative. [Copyright &y& Elsevier]

Objectives: To compare the patterns of American College of Rheumatology (ACR) response between tocilizumab and other biologic agents in patients with rheumatoid arthritis who have inadequate response to disease-modifying antirheumatic drugs (DMARD-IR). Methods: Systematic literature review identified similarly designed double-blind, randomized, placebo-controlled trials over an 18-year period that investigated the effectiveness of abatacept (2), rituximab (2), and TNF-α inhibitors etanercept, infliximab, and adalimumab (11) in DMARD-IR patients; data from 3 placebo-controlled, phase 3 trials for tocilizumab, a newly developed IL-6 inhibitor, were included. The endpoint of interest was ACR20/50/70 response criteria at 24 to 30 weeks. Results were analyzed simultaneously using Bayesian mixed-treatment comparison techniques. Nonoverlapping ACR response rates (ACR70) for each agent were compared among treatments to identify differences in ACR response pattern. Separate analyses of overlapping ACR20/50/70 responses were conducted to identify the source of any differences. Results were expressed as relative risk of ACR20/50/70 response and associated 95% credible interval (CrI). Results: Patterns across nonoverlapping ACR response levels varied significantly across treatments. In subsequent analyses, the effectiveness of tocilizumab appeared to be comparable to that of other biologic agents for ACR20 and ACR50 responses but greater for ACR70. Specifically, tocilizumab had greater ACR70 responses than both TNF-α inhibitors (relative risk = 1.8; CrI = 1.2, 2.6) and abatacept (relative risk = 2.0; CrI = 1.3, 3.1). Conclusions: Among DMARD-IR patients, tocilizumab shows a pattern of response that differs from that of other biologic agents. Post-hoc analyses suggest that the difference lies in a higher likelihood of ACR70 response with tocilizumab. [Copyright &y& Elsevier]

Conventional graphs often include error bars around the group means. Regardless of what these bars depict, they are uninformative as to whether a difference between the groups is statistically significant.This article suggests plotting the null bar or null zone: that is, the range or area in which the means of the two groups fall if the null hypothesis of no difference cannot be rejected. The bar and zone are simply derived from the confidence interval around the difference, obtained from the t-test. [Copyright &y& Elsevier]

Background Up to 50% of curative surgery for suspected non-small-cell lung cancer is unsuccessful. Accuracy of positron emission tomography (PET) with 18-fluorodeoxyglucose (18FDG) is thought to be better than conventional staging for diagnosis of this malignancy. Up to now however, there has been no evidence that PET leads to improved management of patients in routine clinical practice. We did a randomised controlled trial in patients with suspected non-small-cell lung cancer, who were scheduled for surgery after conventional workup, to test whether PET with 18FDG reduces number of futile thoracotomies.Methods Before surgery (mediastinoscopy or thoracotomy), 188 patients from nine hospitals were randomly assigned to either conventional workup (CWU) or conventional workup and PET (CWU+PET). Patients were followed up for 1 year. Thoracotomy was regarded as futile if the patient had benign disease, explorative thoracotomy, pathological stage IIIA–N2/IIIB, or postoperative relapse or death within 12 months of randomisation. The primary outcome measure was futile thoracotomy. Analysis was by intention to treat.Findings 96 patients were randomly assigned CWU and 92 CWU+PET. Two patients in the CWU+PET group did not undergo PET. 18 patients in the CWU group and 32 in the CWU+PET group did not have thoracotomy. In the CWU group, 39 (41%) patients had a futile thoracotomy, compared with 19 (21%) in the CWU+PET group (relative reduction 51%, 95% CI 32–80%; p=0·003). Interpretation Addition of PET to conventional workup prevented unnecessary surgery in one out of five patients with suspected non-small-cell lung cancer. [Copyright &y& Elsevier]

Every year, 3000 women in the Netherlands are treated with in-vitro fertilisation (IVF), and results from studies suggest that the offspring of these women do not have a heightened risk of cancer. Between November, 2000, and February, 2002, we diagnosed retinoblastoma in five patients born after IVF. To calculate the relative risk of the disease, we assumed that the proportion of children conceived by IVF in the Netherlands is between 1·0 and 1·5%, and that the five patients who we diagnosed with the disease represent all new cases in the Netherlands during that period. Relative risks for retinoblastoma were significantly raised (7·2 [95% CI 2·4–17·0], and 4·9 [1·6–11·3], for 1% and 1·5% rates, respectively). This possible association of an increased risk of retinoblastoma in a population-based study needs to be established. [Copyright &y& Elsevier]

Objective: To test the reliability of two radiologic scoring methods in rheumatoid arthritis (RA)—the Sharp/van der Heijde (SvH) and the Larsen/Scott (LS)—with generalizability analyses.Study design and setting: Films of 51 patients representing the spectrum of early RA were read by two raters for each method. The discriminative ability and responsiveness were expressed as: intraclass correlation coefficients (ICCs), two types of smallest detectable difference (SDD), and two types of smallest detectable change (SDC); reflecting measurement error when discriminating between or detecting changes within (1) individuals or (2) groups. They were calculated for (average) scores of one to three raters.Results: The discriminative capacity (0.85–0.97) and responsiveness (0.91–0.97) were good when expressed by ICC. On the group level the SDDs and SDCs ranged between 0.6–3.3% of the max. obtainable score. On the individual level, the scores showed better reliability measured with the SvH (SDDs 2.0–3.4%) than with the LS (SDDs 5.3–9.2%). The SvH also assessed changes in scores in individuals with less measurement error (SDCs 1.3–2.2%) than the LS (SDCs 2.3–3.9%).Conclusion: For early RA patients, the SvH seems preferable if analyses on individual level are included. [Copyright &y& Elsevier]

Background: This masterclass introduces the topic of core outcome sets, describing rationale and methods for developing them, and providing some examples that are relevant for clinical research and practice. Method: A core outcome set is a minimum consensus-based set of outcomes that should be measured and reported in all clinical trials for a specific health condition and/or intervention. Issues surrounding outcome assessment, such as selective reporting and inconsistency across studies, can be addressed by the development of a core set. As suggested by key initiatives in this field (i.e. OMERACT and COMET), the development requires achieving consensus on: (1) core outcome domains and (2) core outcome measurement instruments. Different methods can be used to reach consensus, including: literature systematic reviews to inform the process, qualitative research with clinicians and patients, group discussions (e.g. nominal group technique), and structured surveys (e.g. Delphi technique). Various stakeholders should be involved in the process, with particular attention to patients. Results and conclusions: Several COSs have been developed for musculoskeletal conditions including a longstanding one for low back pain, IMMPACT recommendations on outcomes for chronic pain, and OMERACT COSs for hip, knee and hand osteoarthritis. There is a lack of COSs for neurological, geriatric, cardio-respiratory and pediatric conditions, therefore, future research could determine the value of developing COSs for these conditions. [ABSTRACT FROM AUTHOR]

Purpose The purpose of this study is to evaluate the efficacy of 18 F-FDG-PET as first-line diagnostic investigation, prior to performing a direct laryngoscopy with biopsy under general anesthesia, in patients suspected of recurrent laryngeal carcinoma after radiotherapy. Patients and methods 150 patients suspected of recurrent T2–4 laryngeal carcinoma at least two months after prior (chemo)radiotherapy with curative intent for resectable disease were randomized to direct laryngoscopy (CWU: conventional workup strategy) or to 18 F-FDG-PET only followed by direct laryngoscopy if PET was assessed ‘positive’ or ‘equivocal’ (PWU: PET based workup strategy), to compare the effectiveness of these strategies. Primary endpoint was the number of indications for direct laryngoscopies classified as unnecessary based on absence of recurrence, both on direct laryngoscopy and on six month follow up. Safety endpoints comprised resectability of recurrent lesions and completeness of surgical margins following salvage laryngectomy. Results Intention-to-treat analyses were performed on all randomized patients (CWU: n = 74, PWU: n = 76). Tumor recurrence was similar in both groups: 45 patients (30%; 21 CWU, 24 PWU) within six months. In 53 patients in the CWU arm (72%, 95% CI: 60–81) unnecessary direct laryngoscopies were performed compared to 22 in the PWU arm (29%, 95% CI: 19–40) ( p < 0·0001). The percentage of salvage laryngectomies (resectability) and positive surgical margins were similar between CWU and PWU (81%, 63% respectively, p = 0·17, and 29%, 7%, respectively, p = 0.20). The prevalence of the combination of local unresectability and positive margins is in the CWU group 24% and in the PWU group 8%. No difference ( p = 0.32) in disease specific survival between both groups was found. Conclusion In patients with suspected laryngeal carcinoma after radiotherapy, PET as the first diagnostic procedure can reduce the need for direct laryngoscopy by more than 50% without jeopardizing quality of treatment. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To compare statistical models for the analysis of two-state disease processes. Study Design and Setting: A two-armed randomized trial of patients with early rheumatoid arthritis (RA) treated by either combination therapy (sulfasazaline, methotrextate, prednisolone) or monotherapy (sulfasazaline). Disease activity (remission or relapse) was analyzed with the logistic regression model, the proportional hazards regression model, and the continuous-time Markov process model for panel data. The dependence among the switching times was studied by (1) including correlated normal random patient effects for the relapse–remission and remission–relapse switching probabilities; (2) assuming the population to be a mixture of patients responsive and nonresponsive to therapy; (3) including separate parameters for the first and subsequent relapse–remission switch; and (4) combining (1) and (3). The four approaches were compared using parametric bootstrap checks. Results: The logistic regression model, the proportional hazards regression model, and the continuous-time Markov process model for panel data yielded similar combination therapy effects. The inclusion of random patient effects (approaches 1 and 4) gave the best fit to the observed disease activity pattern. Conclusion: Models with correlated random effects can provide a satisfactory fit to two-state disease patterns. [Copyright &y& Elsevier]

Abstract: Objective: Our purpose was to measure the agreement, reliability, construct validity, and feasibility of a measurement tool to assess systematic reviews (AMSTAR). Study Design and Setting: We randomly selected 30 systematic reviews from a database. Each was assessed by two reviewers using: (1) the enhanced quality assessment questionnaire (Overview of Quality Assessment Questionnaire [OQAQ]); (2) Sacks'' instrument; and (3) our newly developed measurement tool (AMSTAR). We report on reliability (interobserver kappas of the 11 AMSTAR items), intraclass correlation coefficients (ICCs) of the sum scores, construct validity (ICCs of the sum scores of AMSTAR compared with those of other instruments), and completion times. Results: The interrater agreement of the individual items of AMSTAR was substantial with a mean kappa of 0.70 (95% confidence interval [CI]: 0.57, 0.83) (range: 0.38–1.0). Kappas recorded for the other instruments were 0.63 (95% CI: 0.38, 0.78) for enhanced OQAQ and 0.40 (95% CI: 0.29, 0.50) for the Sacks'' instrument. The ICC of the total score for AMSTAR was 0.84 (95% CI: 0.65, 0.92) compared with 0.91 (95% CI: 0.82, 0.96) for OQAQ and 0.86 (95% CI: 0.71, 0.94) for the Sacks'' instrument. AMSTAR proved easy to apply, each review taking about 15 minutes to complete. Conclusions: AMSTAR has good agreement, reliability, construct validity, and feasibility. These findings need confirmation by a broader range of assessors and a more diverse range of reviews. [Copyright &y& Elsevier]

Abstract: The RELAPS study (REcurrent LAryngeal carcinoma PET Study) was designed to determine whether FDG–PET is of value in the selection of patients for direct laryngoscopy under general anesthesia in patients with suspicion of recurrent laryngeal carcinoma after radiotherapy. In a randomized controlled clinical trial the current diagnostic practice, i.e. all patients undergo direct laryngoscopy, will be compared to a strategy in which FDG–PET selects the patients for laryngoscopy. All eight head and neck cancer centers of the Dutch Head and Neck Oncology Cooperative Group NWHHT will participate in this multicenter trial. The study population consists of patients with clinical suspicion of recurrent T2–T4 laryngeal carcinoma after radiotherapy (without obvious signs of tumor) in whom a direct laryngoscopy under general anesthesia with taking of biopsies is indicated by the local physician. The primary efficacy endpoint is the difference in the number of futile indications for direct laryngoscopy between the conventional diagnostic arm and the FDG–PET based diagnostic arm. An indication for laryngoscopy is classified as futile if this laryngoscopy was negative and no recurrence was diagnosed within 6 months follow-up (gold standard). The FDG–PET based strategy may increase the risk of missing recurrent tumor compared to current practice. Safety endpoints include survival and morbidity due to laryngoscopy with taking of biopsies. Survival rates of both groups will have to be collected outside the time frame of the funded trial. Resectability of recurrent tumor and tumor negative surgical margins after total laryngectomy will be used as proxy endpoints. The trial will also compare quality of life and direct medical costs between both arms. [Copyright &y& Elsevier]

Abstract: Objective: To investigate areas of consensus and disagreement among Dutch physiatrists concerning prescription of therapeutic footwear for the neuropathic foot and to develop a research agenda. Study Design and Setting: Forty participants were physiatrists and experts in the field of orthopedic shoe techniques. Four postal Delphi rounds were followed by a final plenary session. Results: Forty of the 44 invited experts participated in all postal Delphi rounds, with an overall response of 100%. They achieved consensus on the following. 1. (Dutch) Terminology for two sets of domains and dimensions for the various features of the neuropathic foot and for the shoe characteristics. 2. Application of specific shoe components: insole, shaft, outsole, tongue, and heel. In most features of the neuropathic foot, shaft and outsole domains were linked in the flexibility dimension. 3. Shoe prescriptions for various features of the neuropathic foot in at least four technical domains. Experts disagreed on application of rocker bar and shaft height. In a final conference, 31 experts agreed on a prioritized research agenda. Conclusion: An intensive Delphi process yielded consensus on terminology, and determined areas of consensus and disagreement for future research for the various features of the neuropathic foot and the shoe characteristics. [Copyright &y& Elsevier]