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

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

Treatment of rheumatoid arthritis: a global perspective on the use of antirheumatic drugs

Modern therapy for rheumatoid arthritis (RA) is based on knowledge of the severity of the natural history of the disease. RA patients are approached with early and aggressive treatment strategies, methotrexate as an anchor drug, biological targeted therapies in those with inadequate response to methotrexate, and “tight control,” aiming for remission and low disease activity according to quantitative monitoring. This chapter presents a rationale for current treatment strategies for RA with antirheumatic drugs, a review of published reports concerning treatments in clinical cohorts outside of clinical trials, and current treatments at 61 sites in 21 countries in the QUEST-RA database

Clusters within a wide spectrum of biochemical markers for osteoarthritis: data from CHECK, a large cohort of individuals with very early symptomatic osteoarthritis

Objective: To assess a wide spectrum of biochemical markers (biomarkers) in a large cohort of individuals with (very) early symptomatic knee and/or hip osteoarthritis (OA). Secondly, to investigate associations between biomarkers and between biomarkers and demographics to demonstrate validity of the obtained dataset and further investigate the involvement and/or role of these biomarkers in OA. Design: Fourteen biomarkers (uCTX-II, uCTX-I, uNTX-I, sCOMP, sPIIANP, 5CS846, sC1,2C, sOC, sPINP, sHA, sPIIINP, pLeptin, pAdiponectin, pResistin) were assessed by ELISA or RIA in CHECK (Cohort Hip and Cohort Knee), a 10-year prospective cohort of 1,002 individuals with early symptomatic knee and/or hip OA. Results: Quality controls revealed that gathered data were technically reliable. The majority of biomarkers showed relevant associations with demographic variables, which were expectedly different between genders and/or menopausal status for some. Principal component analysis enabled identification of five clusters, consecutively designated as 'bone-CTX-II', 'inflammation', 'synovium', 'C1,2C-adipokines', and 'cartilage synthesis' cluster. Notably, uCTX-II clustered with biomarkers of bone metab Conclusions: The identified clusters extended knowledge on individual biomarkers from mostly smaller studies as did the observed associations between biomarker levels and demographics, from which validity of our data was deduced. uCTX-II may not only reflect articular cartilage but also bone metabolism and sCOMP may reflect synovial rather than cartilage metabolism. Major involvement of adipokines in joint metabolism was not identified. (C) 2012 Osteoarthritis Research Society International. Pu

The ability of systemic biochemical markers to reflect presence, incidence, and progression of early-stage radiographic knee and hip osteoarthritis: data from CHECK

Objective: To relate systemic biochemical markers of joint metabolism to presence, incidence, and progression of early-stage radiographic knee and/or hip osteoarthritis (OA). Method: The cartilage markers uCTX-II, sCOMP, sPIIANP, and sCS846, bone markers uCTX-I, uNTX-I, sPINP, and sOC, and synovial markers sHA and sPIIINP were assessed by enzyme-linked immunosorbent assay or radioactive immunoassay in baseline samples of CHECK (Cohort Hip and Cohort Knee), a cohort study of early-stage symptomatic knee and/or hip OA. Knee and hip radiographs were obtained at baseline and 5-year follow-up. Presence of OA at baseline was defined as Kellgren and Lawrence (K&L) = 1 (maximum observed). Incidence of OA was defined as K&L = 0 at baseline and K&L = 1 at 5-year follow-up. Progression of OA was defined as K&L = 1 at baseline and K&L >= 2 at 5-year follow-up. Results: Data were available for 801 subjects at baseline and for 723 subjects at both baseline and 5-year follow-up. Multiple cartilage and synovial markers showed positive associations with presence and progression of knee and hip OA and with incidence of hip OA, except for negative associations of uCTX-II and sCOMP with incidence of knee OA. uCTX-II and sCOMP showed multiple interactions with other biomarkers in their associations with knee and hip OA. Bone markers were positively associated with presence of radiographic knee OA, but negatively associated with progression of radiographic hip OA. Conclusion: Especially metabolism in cartilage and synovial matrix appear to be of relevance in knee and hip OA. The role of bone metabolism appears to differ between knee and hip OA. (C) 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved

Skin pentosidine in very early hip/knee osteoarthritis (CHECK) is not a strong independent predictor of radiographic progression over 5 years follow-up

SummaryObjectivesAge-related changes in articular cartilage are likely to play a role in the etiology of osteoarthritis (OA). One of the major age-related changes in cartilage is the accumulation of advanced glycation end products (AGEs). The present study evaluates whether pentosidine can predict radiographic progression and/or burden over 5 years follow-up in a cohort of early knee and/or hip OA.DesignThe 5 years follow-up data of 300 patients from cohort hip & cohort knee (CHECK) were used. Radiographic progression and burden were assessed by X-rays of both knees and hips (Kellgren and Lawrence (K&L) and Altman scores). Baseline pentosidine levels (and urinary CTXII as a comparator) were measured by high-performance-liquid-chromatography (HPLC) and enzyme linked immunosorbent assay (ELISA). Univariable and multivariable associations including baseline radiographic damage, age, gender, body mass index (BMI) and kidney function were performed.ResultsBoth pentosidine and urinary C-terminal telopeptide of type II collagen (uCTXII) correlated with radiographic progression and burden. In general pentosidine did not have an added predictive value to uCTXII for progression nor burden of the disease. The best prediction was obtained for burden of radiographic damage (R2 = 0.60–0.88), bus this was predominantly determined by baseline radiographic damage (without this parameter R2 = 0.07–0.17). Interestingly, pentosidine significantly added to prediction of osteophyte formation, whereas uCTXII significantly added to prediction of JSN in multivariable analysis.ConclusionPentosidine adds to prediction of radiographic progression and burden of osteophyte formation and uCTXII to radiographic progression and burden of JSN, but overall skin pentosidine did not perform better that uCTXII in predicting radiographic progression or burden. Burden of damage over 5 years is mainly determined by radiographic joint damage at baseline

Evaluation of separate quantitative radiographic features adds to the prediction of incident radiographic osteoarthritis in individuals with recent onset of knee pain: 5-year follow-up in the CHECK cohort

Objective: Detailed radiographic evaluation might enable the identification of osteoarthritis (OA) earlier in the disease. This study evaluated whether and which separate quantitative features on knee radiographs of individuals with recent onset knee pain are associated with incidence of radiographic OA and persistence and/or progression of clinical OA during 5-year follow-up. Method: From the Cohort Hip & Cohort Knee study participants with knee pain at baseline were evaluated. Radiographic OA development was defined as Kellgren & Lawrence (K&L) grade >= II at 5-year follow-up. Clinical OA was defined as persistent knee pain and as progression of Westen Ontario & McMaster Universities Osteoarthritis index (WOMAC) pain and function score during follow-up. At baseline radiographic damage was determined by quantitative measurement of separate features using Knee Images Results: Measuring osteophyte area [odds ratio (OR) = 7.0] and minimum joint space width (OR = 0.7), in addition to demographic and clinical characteristics, improved the prediction of radiographic OA 5 years later [area under curve receiver operating characteristic = 0.74 vs 0.64 without radiographic features]. When the predictive score (based on multivariate regression coefficients) was larger than the cut-off for optimal specificity, the chance of incident radiographic OA was 54% instead of t Conclusion: In individuals with onset knee pain, radiographic characteristics added to the prediction of radiographic OA development 5 years later. Quantitative radiographic evaluation in individuals with suspected OA is worthwhile when determining treatment strategies and designing clinical trials. (C) 2012 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved