Remission definitions guiding immunosuppressive therapy in rheumatoid arthritis: which is best fitted for the purpose?

Objective: To assess which definition of remission best predicts good radiographic outcome (GRO) and good functional outcome (GFO) in rheumatoid arthritis, focusing the updated American College of Rheumatology/European Alliance of Associations for Rheumatology criteria. / Material and methods: Meta-analyses of individual patient data (IPD) from randomised controlled trials (RCTs). Six definitions of remission were considered: (1) Boolean with Patient Global Assessment (PGA)≤1 (Boolean); (2) Simplified Disease Activity Index (SDAI)≤3.3; (3) Clinical Disease Activity Index (CDAI)≤2.8; (4) Boolean with PGA≤2 (Updated-Boolean); (5) Boolean with Physician Global Assessment (PhGA≤1) replacing PGA (Boolean-PhGA) and (6) Boolean excluding PGA (3VBoolean). GRO was defined as a worsening ≤0.5 units in radiographic score and GFO as a no worsening in Health Assessment Questionnaire (HAQ), that is, ∆HAQ-DI≤0.0 units. Relationships between each remission definition at 6 and/or 12 months and GRO and GFO during the second year were analysed. Pooled probabilities for each outcome for each definition and their predictive accuracy were estimated. / Results: IPD from eight RCTs (n=4423) were analysed. Boolean, SDAI, CDAI, Updated-Boolean, Boolean-PhGA and 3VBoolean were achieved by 24%, 27%, 28%, 32%, 33% and 43% of all patients, respectively. GRO among patients achieving remission ranged from 82.4% (3VBoolean) to 83.9% (SDAI). 3VBoolean showed the highest predictive accuracy for GRO: 51.1% versus 38.8% (Boolean) and 44.1% (Updated-Boolean). The relative risk of GFO ranged from 1.16 (Boolean) to 1.05 (3VBoolean). However, the proportion of GFO correctly predicted was highest for the 3VBoolean (50.3%) and lowest for the Boolean (43.8%). / Conclusion: 3VBoolean definition provided the most accurate prediction of GRO and GFO, avoiding the risk of overtreatment in a substantial proportion of patients without increment in radiographic damage progression, supporting the proposal that 3VBoolean remission is preferable to guide immunosuppressive treatment. The patient’s perspective, which must remain central, is best served by an additional patient-oriented target: a dual-target approach

Revisiting the use of remission criteria for rheumatoid arthritis by excluding patient global assessment: an individual meta-analysis of 5792 patients

Objectives: To determine the impact of excluding patient global assessment (PGA) from the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Boolean remission criteria, on prediction of radiographic and functional outcome of rheumatoid arthritis (RA). Methods: Meta-analyses using individual patient data from randomised controlled trials testing the efficacy of biological agents on radiographic and functional outcomes at ≥2 years. Remission states were defined by 4 variants of the ACR/EULAR Boolean definition: (i) tender and swollen 28-joint counts (TJC28/SJC28), C reactive protein (CRP, mg/dL) and PGA (0–10=worst) all ≤1 (4V-remission); (ii) the same, except PGA >1 (4V-near-remission); (iii) 3V-remission (i and ii combined; similar to 4V, but without PGA); (iv) non-remission (TJC28 >1 and/or SJC28 >1 and/or CRP >1). The most stringent class achieved at 6 or 12 months was considered. Good radiographic (GRO) and functional outcome (GFO) were defined as no worsening (ie, change in modified total Sharp score (ΔmTSS) ≤0.5 units and ≤0.0 Health Assessment Questionnaire–Disability Index points, respectively, during the second year). The pooled probabilities of GRO and GFO for the different definitions of remission were estimated and compared. Results: Individual patient data (n=5792) from 11 trials were analysed. 4V-remission was achieved by 23% of patients and 4V-near-remission by 19%. The probability of GRO in the 4V-near-remission group was numerically, but non-significantly, lower than that in the 4V-remission (78 vs 81%) and significantly higher than that for non-remission (72%; difference=6%, 95% CI 2% to 10%). Applying 3V-remission could have prevented therapy escalation in 19% of all participants, at the cost of an additional 6.1%, 4.0% and 0.7% of patients having ΔmTSS >0.0, >0.5 and >5 units over 2 years, respectively. The probability of GFO (assessed in 8 trials) in 4V-near-remission (67%, 95% CI 63% to 71%) was significantly lower than in 4V-remission (78%, 74% to 81%) and similar to non-remission (69%, 66% to 72%). Conclusion: 4V-near-remission and 3V-remission have similar validity as the original 4V-remission definition in predicting GRO, despite expected worse prediction of GFO, while potentially reducing the risk of overtreatment. This supports further exploration of 3V-remission as the target for immunosuppressive therapy complemented by patient-oriented targets

Do we need bone mineral density to estimate osteoporotic fracture risk? A 10-year prospective multicentre validation study

Objective Evaluate the performance of FRAX®, with and without bone mineral densitometry (BMD), in predicting the occurrence of fragility fractures over 10 years. Methods Participants aged ≥40 years at baseline, with a complete set of data and a minimum of 8.5 years of follow-up were identified from three cohorts (n=2626). Ten-year fracture risk at baseline were estimated with FRAX® and assessed by comparison with observed fractures and receiver operating characteristic analysis. Results During a mean (SD) follow-up of 9.12 (1.5) years, 178 participants suffered a major osteoporotic (MOP) fracture and 28 sustained a hip fracture. The predictive performance of FRAX® was superior to that of BMD alone for both MOP and hip fractures. The area under the curve (AUC) of FRAX® without BMD was 0.76 (95% CI 0.72 to 0.79) for MOP fractures and 0.78 (95% CI 0.69 to 0.86) for hip fractures. No significant improvements were found when BMD was added to clinical variables to predict either MOP (0.78, 95% CI 0.74 to 0.82, p=0.25) or hip fractures (0.79, 95% CI 0.69 to 0.89, p=0.72). AUCs for FRAX® (with and without BMD) were greater for men than for women. FRAX®, with and without BMD, tended to underestimate the number of MOP fractures and to overestimate the number of hip fractures in females. In men, the number of observed fractures were within the 95% CI of the number predicted, both with and without BMD. Conclusion FRAX® without BMD provided good fracture prediction. Adding BMD to FRAX® did not improve the performance of the tool in the general population.This study was supported by unrestricted grants from the Direção Geral da Saúde and Amgen, which had no role in the design of the study, the writing or review of the paper

The impact of patient global assessment in the definition of remission as a predictor of long-term radiographic damage in patients with rheumatoid arthritis: protocol for an individual patient data meta-analysis

BACKGROUND: Remission is the target for management of rheumatoid arthritis (RA) and intensification of immunosuppressive therapy is recommended for those that do not achieve this status. Patient global assessment (PGA) is the single patient reported outcome considered in the American College of Rheumatology/European League Against Rheumatism remission criteria, but its use as target has been questioned. The primary aim of this study is to assess whether excluding PGA from the definition of disease remission changes the association of disease remission with long-term radiographic damage and physical function in patients with RA. METHODS: Individual Patient Data Meta-analysis using data from randomized controlled trials of biological and targeted synthetic agents, identified through ClinicalTrials.gov and PubMed. Different remission states will be defined: (i) 4v-remission [tender (TJC28) and swollen 28-joint counts (SJC28) both≤1, C-reactive protein (CRP)≤1 (mg/dl), and PGA≤1 (0-10 scale)], (ii) 4v-near-remission (TJC28≤1, SJC28≤1, CRP≤1, and PGA>1), (iii) non-remission (TJC28>1 or SJC28>1 or CRP>1), all mutually exclusive, and (iv) 3v-remission (TJC28≤1, SJC28≤1, CRP≤1). Likelihood ratios will be used to descriptively compare whether meeting the 3v and 4v-remission criteria in a single visit (at 6 or 12 months) predicts good outcome in the second year (1-2y). Differences in the predictive value of PGA in the definition of remission will be assessed by comparing the three mutually exclusive disease states using logistic regression analysis. Good outcome is defined primarily by radiographic damage (no deterioration in radiographic scores, whatever the instrument used in each trial), and secondarily by functional disability (Health Assessment Questionnaire consistently ≤0.5 and no deterioration), and their combination ("overall good outcome"). Additional analyses will consider longer periods over which to (concurrently) define remission status and outcome (between 1-5y and 1-10y), different cut-offs to define good radiographic outcome (change ≤0.5, ≤3 and ≤5 in radiographic score), sustained remission and the influence of treatment and other clinical factors. DISCUSSION: If 4v-remission and 4v-near-remission are associated with a similar probability of good outcomes, particularly regarding structural damage, the 3v-remission (excluding PGA) could be adopted as the target for immunosuppressive therapy. Patients' perspectives would remain essential, but assessed separately from disease activity, using instruments adequate to guide adjunctive therapies. Systematic review registration: PROSPERO, CRD42017057099

Computational case-based redesign for people with ability impairment: Rethinking, reuse and redesign learning for home modification practice

Home modification practice for people with impairments of ability involves redesigning existing residential environments as distinct from the creation of a new dwelling. A redesigner alters existing structures, fittings and fixtures to better meet the occupant's ability requirements. While research on case-based design reasoning and healthcare informatics are well documented, the reasoning and process of redesign and its integration with individual human functional abilities remains poorly understood. Developing a means of capturing redesign knowledge in the form of case documentation online provides a means for integrating and learning from individual case-based redesign episodes where assessment and interventions are naturally linked. A key aim of the research outlined in this thesis was to gain a better understanding of the redesign of spaces for individual human ability with the view to computational modelling. Consequently, the foundational knowledge underpinning the model development includes design, redesign, case-based building design and human functional ability. Case-based redesign as proposed within the thesis, is a method for capturing the redesign context, the residential environment, the modification and the transformational knowledge involved in the redesign. Computational simulation methods are traditionally field dependent. Consequently, part of the research undertaken within this thesis involved the development of a framework for analysing cases within an online case-studies library to validate redesign for individuals and a method of acquiring reuse information so as to be able to estimate the redesign needs of a given population based on either their environment or ability profile. As home modification for people with functional impairments was a novel application field, an explorative action-based methodological approach using computational modelling was needed to underpin a case-based reasoning method. The action-based method involved a process of articulating and examining existing knowledge, suggesting new case-based computational practices, and evaluating the results. This cyclic process led to an improvement cycle that included theory, computational tool development and practical application. The rapid explosion of protocols and online redesign communities that utilise Web technologies meant that a web-based prototype capable of acquiring cases directly from home modification practitioners online and in context was both desirable and achievable. The first online version in 1998-99, encoded home modification redesigns using static WebPages and hyperlinks. This motivated the full-scale more dynamic and robust HMMinfo casestudies prototype whose action-based development is detailed within this thesis. The home modification casestudies library results from the development and integration of a novel case-based redesign model in combination with a Human- Activity-Space computational ontology. These two models are then integrated into a relational database design to enable online case acquisition, browsing, case reuse and redesign learning. The application of the redesign ontology illustrates case reuse and learning, and presents some of the implementation issues and their resolution. Original contributions resulting from this work include: extending case-based design theory to encompass redesign and redesign models, distinguishing the importance of human ability in redesign and the development of the Human-Activity-Space ontology. Additionally all data models were combined and their associated inter-relationships evaluated within a prototype made available to redesign practitioners. v Reflective and practitioner based evaluation contributed enhanced understanding of redesign case contribution dynamics in an online environment. Feedback from redesign practitioners indicated that gaining informed consent to share cases from consumers of home modification and maintenance services, in combination with the additional time required to document a case online, and reticence to go public for fear of critical feedback, all contributed to a less than expected case library growth. This is despite considerable interest in the HMMinfo casestudies website as evidenced by web usage statistics. Additionally the redesign model described in this thesis has practical implications for all design practitioners and educators who seek to create new work by reinterpreting, reconstructing and redesigning spaces