OMERACT consensus-based operational definition of contextual factors in rheumatology clinical trials: A mixed methods study.

OBJECTIVES: To develop an operational definition of contextual factors (CF) [1]. METHODS: 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. RESULTS: 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. CONCLUSION: Through consensus we developed an operational definition of CFs, which was well received by OMERACT members.

Harms reported by patients in rheumatology drug trials: a systematic review of randomized trials in the cochrane library from an OMERACT working group.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. REGISTRATION: PROSPERO: CRD42018108393.

Population characteristics as important contextual factors in rheumatological trials: an exploratory meta-epidemiological study from an OMERACT Working Group.

OBJECTIVES: To explore whether trial population characteristics modify treatment responses across various interventions, comparators and rheumatic conditions. METHODS: In this meta-epidemiological study, we included trials from systematic reviews available from the Cochrane Musculoskeletal Group published up to 23 April 2019 in Cochrane Library with meta-analyses of five or more randomised controlled trials (RCTs) published from year 2000. From trial reports, we extracted data on 20 population characteristics. For characteristics with sufficient data (ie, available for ≥2/3 of the trials), we performed multilevel meta-epidemiological analyses. RESULTS: We identified 19 eligible systematic reviews contributing 187 RCTs (212 comparisons). Only age and sex were explicitly reported in ≥2/3 of the trials. Using information about the country of the trials led to sufficient data for five further characteristics, that is, 7 out of 20 (35%) protocolised characteristics were analysed. The meta-regressions showed effect modification by economic status, place of residence, and, nearly, from healthcare system (explaining 4.8%, 0.9% and 1.5% of the between-trial variation, respectively). No effect modification was demonstrated from age, sex, patient education/health literacy or predominant religion. CONCLUSIONS: This study demonstrates the scarce reporting of most population characteristics, hampering investigation of their impact with meta-research. Our sparse results suggest that place of residence (ie, continent of the trial), economic status (based on World Bank classifications) and healthcare system (based on WHO index for health system performance) may be important in explaining the variation in treatment response across trials. There is an urgent need for consistent reporting of important population characteristics in trials. PROSPERO REGISTRATION NUMBER: CRD42019127642.

Rheumatology Common Toxicity Criteria (RCTC): An Update Reflecting Real-World Use.

INTRODUCTION: The Outcome Measures in Rheumatology Clinical Trials (OMERACT) Rheumatology Common Toxicity Criteria (RCTC) version 2.0 was published in 2007 by the OMERACT Drug Safety Working Group, building on limited experience with RCTC version 1.0, to facilitate standardization of assessment (grading) and reporting of adverse events (AEs) commonly seen in rheumatic disease clinical trials (Woodworth et al. in J Rheumatol 34:1401-1414, 2007). OBJECTIVES: The objectives of this study were to (1) report the real-world performance of RCTC 2.0; (2) report immediately correctable errors in RCTC 2.0, and provide a revised RCTC 2.1; and (3) begin to identify the need for a comprehensive revision of RCTC 2.0. METHODS: Safety data outputs for several large rheumatic/autoimmune disease clinical trials in which RCTC 2.0 was used were evaluated for accuracy of reporting and the ability to assess differences among treatments. We examined RCTC 2.0 tables for errors, as well as for omission of terms for AEs that commonly occur in more recent rheumatology clinical trials. We also considered recommendations from recent US Food and Drug Administration (FDA) and international initiatives such CDISC (Clinical Data Interchange Standards Consortium) to improve the consistency of safety data collection and interpretability of safety data analyses. RESULTS: RCTC 2.0 enabled comparisons of safety data across treatment groups, including grading. However, we discovered inaccuracies in laboratory results grading and omission of AE terms now recognized to occur in rheumatic disease clinical trials. CONCLUSION: The RCTC 2.0 performed as intended, although some inaccuracies and omissions were found. We provide a corrected version, RCTC 2.1, and also recommend further revision of the RCTC within OMERACT guidances to include AEs that have been reported in rheumatology clinical trials since RCTC 2.0 was published. Ideally, a revised RCTC 3.0 would not only facilitate standardized assessment and reporting of AEs, but would also expand and encourage accurate comparison of the safety profiles of treatments for rheumatic/autoimmune diseases.

Identifying Provisional Generic Contextual Factor Domains for Clinical Trials in Rheumatology: Results from an OMERACT Initiative.

OBJECTIVE: The Contextual Factors Working Group aims to provide guidance on addressing contextual factors in rheumatology trials within OMERACT. METHODS: During the Special Interest Group session at OMERACT 2018, preliminary results were presented from a case scenario survey and semistructured interviews, including contextual factors mentioned in these. A group-based exercise sought to identify and rank important generic contextual factors. RESULTS: A total of 79 candidate factors were listed. Across the 3 groups, gender/sex, comorbidities, and the healthcare system were ranked as most important. CONCLUSION: The identified important contextual factor domains may be considered a provisional list pending further research.

Ultra-low doses of rituximab for continued treatment of rheumatoid arthritis (REDO study): a randomised controlled non-inferiority trial.

BACKGROUND: Rituximab is an effective treatment for rheumatoid arthritis, given as either two doses of 1000 mg (2 weeks apart) every 6 months (the dose recommended by the US Food and Drug Administration and European Medicines Agency) or two doses of 500 mg (2 weeks apart) or one dose of 1000 mg (a standard low dose) every 6 months. Findings of several small uncontrolled studies suggest that doses lower than the recommended dose or standard low dose might be sufficient for maintenance treatment, potentially improving safety and reducing costs. Therefore, we aimed to compare the efficacy of ultra-low doses of rituximab (one dose of 500 mg or 200 mg) with a standard low dose of rituximab (one dose of 1000 mg) for patients with rheumatoid arthritis who respond to standard doses of rituximab. METHODS: The REDO study is a randomised, double-blind, non-inferiority trial done at five centres in the Netherlands. Adults (aged ≥18 years) with rheumatoid arthritis responding well to rituximab were randomly allocated (1:2:2) to receive intravenous rituximab as one dose of either 1000 mg, 500 mg, or 200 mg, respectively. Volumes of all doses were equal to achieve masking. Randomisation lists were computer-generated and stratified by rheumatoid factor or anti-citrullinated protein antibody status (positive or negative) and concomitant use of conventional synthetic disease modifying antirheumatic drugs (yes or no). The primary analysis was a per-protocol hierarchical testing procedure comparing ultra-low doses with a standard low dose (500 mg vs 1000 mg at 3 months, followed by 500 mg vs 1000 mg at 6 months, 200 mg vs 1000 mg at 3 months, and 200 mg vs 1000 mg at 6 months), using a non-inferiority margin of 0·60 on change from baseline in the 28-joint disease activity score based on C-reactive protein levels (DAS28-CRP). The study is registered at www.trialregister.nl, NTR6117. FINDINGS: Between Dec 15, 2016, and Sept 20, 2018, 142 patients were randomly allocated to either 1000 mg rituximab (n=29), 500 mg rituximab (n=58), or 200 mg rituximab (n=55). The 500 mg dose was non-inferior to 1000 mg at 3 months (mean change from baseline in DAS28-CRP, -0·07, 95% CI -0·41 to 0·27) but not at 6 months (0·29, -0·08 to 0·65). Because of the hierarchical testing procedure, non-inferiority could not be tested for the 200 mg dose. 13 patients had serious adverse events, three (10%) in the 1000 mg group, six (10%) in the 500 mg group, and four (7%) in the 200 mg group. The most frequently reported serious adverse events were cardiovascular. No deaths occurred during the study. A significantly lower incidence of infections was seen in the ultra-low-dose groups compared with the standard dose group (1·10 infections per patient-year with the 1000 mg dose vs 0·52 per patient-year with the 500 mg dose and 0·51 per patient-year with the 200 mg dose; rate ratio 0·47, 95% CI 0·21-0·83; p=0·013 for 500 mg vs 1000 mg; 0·44, 0·22-0·88; p=0·019 for 200 mg vs 1000 mg). INTERPRETATION: Our study did not show non-inferiority of ultra-low doses of rituximab for continued treatment of patients with rheumatoid arthritis. Nonetheless, in clinical practice, a strategy with an ultra-low dose of rituximab might be considered after evaluation of risks and benefits, although further studies are needed to establish non-inferiority. Further analyses and a 2-year observational extension are ongoing and should provide further insight into efficacy and safety. FUNDING: Menzis and Centraal Ziekenfonds.

Scleroderma renal crisis and renal involvement in systemic sclerosis.

This corrects the article DOI: 10.1038/nrneph.2016.124.

Content and Construct Validity, Reliability, and Responsiveness of the Rheumatoid Arthritis Flare Questionnaire: OMERACT 2016 Workshop Report.

OBJECTIVE: The Outcome Measures in Rheumatology (OMERACT) Rheumatoid Arthritis (RA) Flare Group was established to develop a reliable way to identify and measure RA flares in randomized controlled trials (RCT). Here, we summarized the development and field testing of the RA Flare Questionnaire (RA-FQ), and the voting results at OMERACT 2016. METHODS: Classic and modern psychometric methods were used to assess reliability, validity, sensitivity, factor structure, scoring, and thresholds. Interviews with patients and clinicians also assessed content validity, utility, and meaningfulness of RA-FQ scores. RESULTS: People with RA in observational trials in Canada (n = 896) and France (n = 138), and an RCT in the Netherlands (n = 178) completed 5 items (11-point numerical rating scale) representing RA Flare core domains. There was moderate to high evidence of reliability, content and construct validity, and responsiveness. Factor analysis supported unidimensionality. Rasch analysis showed acceptable fit to the Rasch model, with items and people covering a broad measurement continuum and evidence of appropriate targeting of items to people, ordered thresholds, minimal differential item functioning by language, sex, or age. A summative score across items is defensible, yielding an interval score (0-50) where higher scores reflect worsening flare. The RA-FQ received endorsement from 88% of attendees that it passed the OMERACT Filter 2.0 "Eyeball Test" for instrument selection. CONCLUSION: The RA-FQ has been developed to identify and measure RA flares. Its review through OMERACT Filter 2.0 shows evidence of reliability, content and construct validity, and responsiveness. These properties merit its further validation as an outcome for clinical trials.

An OMERACT Initiative Toward Consensus to Identify and Characterize Candidate Contextual Factors: Report from the Contextual Factors Working Group.

OBJECTIVE: The importance of contextual factors (CF) for appropriate patient-specific care is widely acknowledged. However, evidence in clinical trials on how CF influence outcomes remains sparse. The 2014 Outcome Measures in Rheumatology (OMERACT) Handbook introduced the role of CF in outcome assessment and defined them as "potential confounders and/or effect modifiers of outcomes in randomized controlled trials." Subsequently, the CF Methods Group (CFMG) was formed to develop guidance on how to address CF in clinical trials. METHODS: First, the CFMG conducted an e-mail survey of OMERACT working groups (WG) to analyze how they had addressed CF in outcome measurement so far. The results facilitated an informed discussion at the OMERACT 2016 CFMG Special Interest Group (SIG) session, with the aim of gaining preliminary consensus regarding an operational definition of CF and to make a first selection of potentially relevant CF. RESULTS: The survey revealed that the WG had mostly used the OMERACT Handbook and/or the International Classification of Functioning, Disability and Health (ICF) definition. However, significant heterogeneity was found in the methods used to identify, refine, and categorize CF candidates. The SIG participants agreed on using the ICF as a framework along with the OMERACT Handbook definition. A list with 28 variables was collected including person-related factors and physical and social environments. Recommendations from the SIG guided the CFMG to formulate 3 preliminary projects on how to identify and analyze CF. CONCLUSION: New methods are urgently needed to assist researchers to identify and characterize CF that significantly influence the interpretation of results in clinical trials. The CFMG defined first steps to develop further guidance.

Examining the validity of the rheumatoid arthritis magnetic resonance imaging score according to the OMERACT filter-a systematic literature review.

Objective: To examine whether the RA MRI score (RAMRIS) for RA of the wrist/hand meets the OMERACT filter criteria-truth (validity), discrimination and feasibility. Methods: We conducted a systematic literature review in PubMed and Scopus, from 1970 through June 2014, focused on MRI measures of synovitis, osteitis/bone marrow oedema, erosions and/or joint space narrowing in RA randomized controlled trials and observational studies with cohort size ⩾10. Strength of evidence was assessed using the Cochrane Handbook criteria. Results: Of 634 MRI titles/abstracts, 202 met the review criteria, with 92 providing at least 1 type of validity. Four articles provided criterion validity, and 26 articles utilized RAMRIS to assess 1.5 T MRI images. Histopathology data showed inflammation corresponding to MRI of synovitis and osteitis. MRI erosions corresponded to those identified with CT. Content and construct validity for RAMRIS synovitis, osteitis and erosions were documented by correlations with clinical, laboratory and/or radiographic data. Each measure was sensitive to change and responsive to therapy. RAMRIS synovitis and osteitis were able to discriminate between the efficacy of treatments vs placebo in 12-week studies, whereas RAMRIS erosions required studies of ⩾24 weeks. Conclusion: RAMRIS synovitis, osteitis and erosions imaged with 1.5 T MRI are valid and useful for evaluating joint inflammation and damage for RA of the wrist/hand, according to the OMERACT filter.

Scleroderma renal crisis and renal involvement in systemic sclerosis.

Scleroderma renal crisis (SRC) is a rare, potentially life-threatening complication that affects 2-15% of patients with systemic sclerosis (SSc, also known as scleroderma). SRC typically presents in patients with early, rapidly progressive, diffuse cutaneous SSc within the first 3-5 years after the onset of a non-Raynaud sign or symptom. SRC is characterized by an acute, usually symptomatic increase in blood pressure, a rise in serum creatinine levels, oliguria and thrombotic microangiopathy in about 50% of patients. The prognosis of SRC substantially improved in the 1980s with the introduction of angiotensin-converting-enzyme inhibitors for rapid blood pressure control, with additional antihypertensive agents as required. However, the survival of patients with SRC can still be improved. Current patient survival is 70-82% at 1 year, but decreases to 50-60% at 5 years despite dialysis support. Patients with SRC who show no signs of renal functional recovery despite timely blood pressure control are candidates for transplantation. In this Review, we discuss progress made in the identification and proactive management of patients at risk of SRC and make recommendations aimed at optimizing management for those who progress to chronic kidney failure.

Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial.

BACKGROUND: For patients with newly diagnosed rheumatoid arthritis, treatment aim is early, rapid, and sustained remission. We compared the efficacy and safety of strategies initiating the interleukin-6 receptor-blocking monoclonal antibody tocilizumab with or without methotrexate (a conventional synthetic disease-modifying antirheumatic drug [DMARD]), versus initiation of methotrexate monotherapy in line with international guidelines. METHODS: We did a 2-year, multicentre, randomised, double-blind, double-dummy, strategy study at 21 rheumatology outpatient departments in the Netherlands. We included patients who had been diagnosed with rheumatoid arthritis within 1 year before inclusion, were DMARD-naive, aged 18 years or older, met current rheumatoid arthritis classification criteria, and had a disease activity score assessing 28 joints (DAS28) of at least 2·6. We randomly assigned patients (1:1:1) to start tocilizumab plus methotrexate (the tocilizumab plus methotrexate arm), or tocilizumab plus placebo-methotrexate (the tocilizumab arm), or methotrexate plus placebo-tocilizumab (the methotrexate arm). Tocilizumab was given at 8 mg/kg intravenously every 4 weeks with a maximum of 800 mg per dose. Methotrexate was started at 10 mg per week orally and increased stepwise every 4 weeks by 5 mg to a maximum of 30 mg per week, until remission or dose-limiting toxicity. We did the randomisation using an interactive web response system. Masking was achieved with placebos that were similar in appearance to the active drug; the study physicians, pharmacists, monitors, and patients remained masked during the study, and all assessments were done by masked assessors. Patients not achieving remission on their initial regimen switched from placebo to active treatments; patients in the tocilizumab plus methotrexate arm switched to standard of care therapy (typically methotrexate combined with a tumour necrosis factor inhibitor). When sustained remission was achieved, methotrexate (and placebo-methotrexate) was tapered and stopped, then tocilizumab (and placebo-tocilizumab) was also tapered and stopped. The primary endpoint was the proportion of patients achieving sustained remission (defined as DAS28 <2·6 with a swollen joint count ≤four, persisting for at least 24 weeks) on the initial regimen and during the entire study duration, compared between groups with a two-sided Cochran-Mantel-Haenszel test. Analysis was based on an intention-to-treat method. This trial was registered at ClinicalTrials.gov, number NCT01034137. FINDINGS: Between Jan 13, 2010, and July 30, 2012, we recruited and assigned 317 eligible patients to treatment (106 to the tocilizumab plus methotrexate arm, 103 to the tocilizumab arm, and 108 to the methotrexate arm). The study was completed by a similar proportion of patients in the three groups (range 72-78%). The most frequent reasons for dropout were adverse events or intercurrent illness: 27 (34%) of dropouts, and insufficient response: 26 (33%) of dropouts. 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm achieved sustained remission on the initial regimen, compared with 86 (84%) of 103 in the tocilizumab arm, and 48 (44%) of 108 in the methotrexate arm (relative risk [RR] 2·00, 95% CI 1·59-2·51 for tocilizumab plus methotrexate vs methotrexate, and 1·86, 1·48-2·32 for tocilizumab vs methotrexate, p<0·0001 for both comparisons). For the entire study, 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm, 91 (88%) of 103 in the tocilizumab arm, and 83 (77%) of 108 in the methotrexate arm achieved sustained remission (RR 1·13, 95% CI 1·00-1·29, p=0·06 for tocilizumab plus methotrexate vs methotrexate, 1·14, 1·01-1·29, p=0·0356 for tocilizumab vs methotrexate, and p=0·59 for tocilizumab plus methotrexate vs tocilizumab). Nasopharyngitis was the most common adverse event in all three treatment groups, occurring in 38 (36%) of 106 patients in the tocilizumab plus methotrexate arm, 40 (39%) of 103 in the tocilizumab arm, and 37 (34%) of 108 in the methotrexate arm. The occurrence of serious adverse events did not differ between the treatment groups (17 [16%] of 106 patients in the tocilizumab plus methotrexate arm vs 19 [18%] of 103 in the tocilizumab arm and 13 [12%] of 108 in the methotrexate arm), and no deaths occurred during the study. INTERPRETATION: For patients with newly diagnosed rheumatoid arthritis, strategies aimed at sustained remission by immediate initiation of tocilizumab with or without methotrexate are more effective, and with a similar safety profile, compared with initiation of methotrexate in line with current standards. FUNDING: Roche Nederland BV.

Treating to target in established rheumatoid arthritis: Challenges and opportunities in an era of novel targeted therapies and biosimilars.

There is increasing consensus that periodic monitoring of disease activity status in rheumatoid arthritis (RA) patients to achieve and maintain remission, or at least low disease activity (LDA), the so-called treat to target (T2T) improves outcomes regardless of the duration of disease. Based on systematic literature reviews (SLRs) of clinical trials and registries, International Recommendations published in 2015 represent expert opinion describing efficacy and safety of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologic DMARDs (bDMARDs). A total of 10 recommendations are detailed from four "Overarching Principles": (1) treatment decisions are shared between patient and rheumatologist; (2) the primary goalv is to maximize long-term quality of life by controlling the symptoms, preventing joint damage, and by normalizing the function and social and work participation; (3) abrogation (not just control) of inflammation is the most effective method to achieve this goal; (4) T2T by measuring disease activity regularly and adjusting therapy to achieve remission/LDA optimizes outcomes in RA. The SLRs provide solid evidence that methotrexate is the "anchor" of csDMARD and that step-up therapy by adding/substituting other csDMARDs, such as sulfasalazine (SSZ), hydroxychloroquine (HCQ), or/and leflunomide (LEF) is as effective as combination therapy to initiate. Tofacitinib, a recently marketed csDMARD, may be more effective in comparison to MTX, and can be used in combination. Rapid disease control can be achieved by "bridging" with various regimens of glucocorticoids (GCs), but tapering to doses ≤7.5 mg/day is critical to limit side effects. In practice settings, use of bDMARDs is influenced by reimbursement. Tumor necrosis factor inhibitors (TNFi) are highly used, but as more data emerge, there appear to be no major differences to more recently available targeted bDMARD monoclonal antibodies such as abatacept (co-stimulation blockade), rituximab (B cell depleting), tocilizumab (TCZ) (interleukin (IL)-6 receptor blockade). Rituximab appears to be most effective for seropositive patients, and tocilizumab may be more effective as a monotherapy in patients intolerant to csDMARDs. Besides T2T, attention to managing treatment and optimizing outcomes should take into account potential adverse effects, such as risk of serious infection, as well as potential morbidity/mortality related to cardiovascular events, pulmonary disease, osteoporosis, diabetes, and fibromyalgia which often influence some measures, such as the Health Assessment Questionnaire (HAQ).

Feasibility and Domain Validation of Rheumatoid Arthritis (RA) Flare Core Domain Set: Report of the OMERACT 2014 RA Flare Group Plenary.

OBJECTIVE: The Outcome Measures in Rheumatology (OMERACT) Rheumatoid Arthritis (RA) Flare Group was established to develop an approach to identify and measure RA flares. An overview of our OMERACT 2014 plenary is provided. METHODS: Feasibility and validity of flare domains endorsed at OMERACT 11 (2012) were described based on initial data from 3 international studies collected using a common set of questions specific to RA flare. Mean flare frequency, severity, and duration data were presented, and domain scores were compared by flare status to examine known-groups validity. Breakout groups provided input for stiffness, self-management, contextual factors, and measurement considerations. RESULTS: Flare data from 501 patients in an observational study indicated 39% were in flare, with mean (SD) severity of 6.0 (2.6) and 55% lasting > 14 days. Pain, physical function, fatigue, participation, and stiffness scores averaged ≥ 2 times higher (2 of 11 points) in flaring individuals. Correlations between flare domains and corresponding legacy instruments were obtained: r = 0.46 to 0.93. A combined definition (patient report of flare and 28-joint Disease Activity Score increase) was evaluated in 2 other trials, with similar results. Breakout groups debated specific measurement issues. CONCLUSION: These data contribute initial evidence of feasibility and content validation of the OMERACT RA Flare Core Domain Set. Our research agenda for OMERACT 2016 includes establishing duration/intensity criteria and developing criteria to identify RA flares using existing disease activity measures. Ongoing work will also address discordance between patient and physician ratings, facilitate application of flare criteria to clinical care, elucidate the role of self-management, and finalize recommendations for RA flare measurement.

Safety and feasibility of umbilical cord mesenchymal stem cells in treatment-refractory systemic lupus erythematosus nephritis: time for a double-blind placebo-controlled trial to determine efficacy.

As translational clinical researchers familiar with the risk-benefit of hematopoietic stem cell transplantation in autoimmune diseases, we are intrigued by the recent report of umbilical cord mesenchymal stem cell (UC-MSC) transplantation in treatment-refractory systemic lupus erythematosus nephritis by Wang and colleagues. They report the results of an open-label single-arm multicenter phase I/II study. This stimulated us to examine whether collective data from this group provide sufficient evidence for the feasibility, safety, dose rationale, and potential efficacy of UC-MSCs to conduct a randomized controlled trial in such patients. Results, though confounded by variable baseline prednisone and immuno-suppressive treatment, appear to indicate near-term response rates of approximately 50%, which are comparable to those seen with hematopoietic stem cell transplantation but with less morbidity and mortality.

Validation of OMERACT preliminary rheumatoid arthritis flare domains in the NOR-DMARD study.

OBJECTIVE: Domains identified as a result of qualitative research and Delphi exercises to assess rheumatoid arthritis (RA) flare include pain, function, swollen and tender joints, patient and physician global, laboratory measures, participation, stiffness, self-management and fatigue. Here we examine aspects of construct and content validity of these domains in a longitudinal observational study. METHODS: A total of 1195 patients with RA treated with non-biological disease-modifying antirheumatic drugs (DMARDs) or biologics were eligible for the analyses. Working definitions of 'flare' included patient-reported worsening between 3 and 6 months (primary) and treatment change at 6 months (DMARDs and/or systemic corticosteroids) (secondary). Available outcome measures were mapped to the flare domains. Changes between 3 and 6 months were compared between patients with and without 'flare'. Convergent and divergent construct validity and content validity were assessed by correlation analyses and logistic regression analysis, respectively. RESULTS: Applying the flare working definition based on patient-reported worsening, standardised mean differences (SMDs) were >0.5 for the majority of outcomes. The largest SMDs were observed for Pain visual analogue scale (1.30), SF-36 Bodily pain (1.24), Patient global (1.20) and morning stiffness intensity (1.17). The flare working definition based on treatment change yielded lower SMDs (<0.5 for most variables). Consistently stronger intradomain than corresponding interdomain correlations supported convergent and divergent validity of the domains. CONCLUSIONS: Probing a flare definition via outcome measures, the identified flare domains discriminated well between patients with and without worsening. Interdomain and intradomain correlation and logistic regression analyses provide further support for construct and content validity of the identified flare domains.

Identifying core domains to assess flare in rheumatoid arthritis: an OMERACT international patient and provider combined Delphi consensus.

OBJECTIVE: For rheumatoid arthritis (RA), there is no consensus on how to define and assess flare. Variability in flare definitions impairs understanding of findings across studies and limits ability to pool results. The OMERACT RA Flare Group sought to identify domains to define RA flares from patient and healthcare professional (HCP) perspectives. METHODS: Flare was described as a worsening of disease activity of sufficient intensity and duration to consider a change in therapy. International patients and HCPs participated in separate and combined rounds of Delphi exercises to rate candidate flare domains previously generated in patient focus groups. Core domains were defined as those with ≥70% ratings of being 'essential' according to the third/final Delphi exercise. RESULTS: The final Delphi included 125 RA patients from 10 countries and 108 HCPs from 23 countries who rated 14 domains. Patients had a mean (±SD) age of 56±12 years and disease duration of 18±12 years. HCPs included physicians from clinical practice/research and industry, allied health providers and researchers with 17±11 years experience. Core domains comprised: pain (93%), function (89%), swollen joints (84%), tender joints (81%), participation (81%), stiffness (79%), patient global assessment (76%) and self-management (75%). Fatigue (68%), which did not reach group consensus, will receive additional consideration. CONCLUSIONS: As part of the process to develop a measure for RA flare, patients and HCPs agreed on eight core domains. Next steps include identifying items to assess domains and conducting studies to validate and refine a new measure.