Remission in early rheumatoid arthritis defined by 28 joint counts: limited consequences of residual disease activity in the forefeet on outcome.

UNLABELLED: Introduction The new American College for Rheumatology (ACR)/European League Against Rheumatism (EULAR) remission criteria are based on the assessment of 28 joints. A study was undertaken to study the consequences of remission misclassification due to residual disease activity in the feet on physical function and joint damage in the subsequent year in an observational early disease cohort. METHODS: All patients with rheumatoid arthritis at inclusion or at 1-year follow-up in the early arthritis cohort of the Jan van Breemen Institute, The Netherlands were included. ACR/EULAR remission definitions for trials and clinical practice were calculated twice, once using a 28-joint count and once using a 38-joint count that included the 10 metatarsophalangeal joints. Disease stability was defined as stable x-ray scores over 1 year (change ≤ 0 in Sharp/van der Heijde scores) and stable and low scores on the Health Assessment Questionnaire (HAQ change ≤ 0 and HAQ score consistently ≤ 0.5), all during the second year after inclusion. Analyses comprised residual disease activity (swollen or tender joints >0) in the feet of patients who fulfilled the candidate remission criteria using a 28-joint count and likelihood ratios of remission definitions to predict disease stability. RESULTS: Of 421 patients, 9-15% reached remission at 1 year using a 28-joint count. Of these, 26-40% showed activity in the feet. Misclassification due to reduced joint counts was observed in 2-3%. A state of remission increased the likelihood of stability of both x-ray and HAQ, with similar likelihood ratios for definitions using 38-joint counts and those using 28-joint counts. CONCLUSION: The ability of remission definitions with 28-joint counts versus 38-joint counts to predict long-term good radiological and functional outcome is similar. This confirms that inclusion of ankles and forefeet in the assessment of remission is not required, although inclusion of these joints in the examination is recommended.

Physical disability in rheumatoid arthritis is associated with cartilage damage rather than bone destruction.

BACKGROUND: Joint destruction in rheumatoid arthritis is comprised of cartilage and bone damage, which can be evaluated radiographically separately by the joint space narrowing (JSN) and erosion (ERO) scores. It is currently unclear to which extent these components affect irreversible functional disability. The aim of the present work was to determine these contributions. METHODS: Data, kindly provided by the sponsors, was evaluated from several randomised controlled clinical trials on adalimumab, etanercept, infliximab and leflunomide. Patients who reached stringent remission according to the Simplified Disease Activity Index (SDAI≤3.3) were extracted to eliminate the activity related (ie, reversible) component of disability. In these patients, residual Health Assessment Questionnaire Disability Index (HAQ-DI) score at the time of remission (to reflect the level of 'irreversible' disability) was determined and related to baseline measures of ERO and JSN scores univariately, by stratification and in adjusted regression models. RESULTS: A total of 748 patients who achieved a state of remission were analysed (16.3% of the total pooled population of 4602 patients). In the univariate analyses, mean residual HAQ-DI values in remission were significantly larger in higher tertiles of JSN and ERO (ERO: 0.21, 0.25, 0.35; JSN: 0.19, 0.24, 0.39; p<0.001 for both). In stratified analyses, mean residual HAQ-DI scores were larger in higher tertiles of JSN within the first tertile of ERO (0.18, 0.25, 0.29; p=0.05), as well as the second (0.21, 0.24, 0.29; p=0.19) and the third (0.12, 0.23, 0.42; p<0.001). In contrast, there was no such trend across ERO tertiles within the first JSN tertile (0.18, 0.21, 0.12; p=0.99) and the second tertile (0.25, 0.24, 0.23; p=0.77), and only marginally within the third tertile of JSN (0.29, 0.29, 0.42; p=0.07). Adjusted multivariate regression models supported the significant association of JSN on residual disability. CONCLUSIONS: Cartilage damage appears to be the more clearly associated with irreversible physical disability than bony damage. These data suggest that particular attention should be given to therapeutic interference with cartilage destruction.

American College of Rheumatology/European League against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials.

OBJECTIVE: Remission in rheumatoid arthritis (RA) is an increasingly attainable goal, but there is no widely used definition of remission that is stringent but achievable and could be applied uniformly as an outcome measure in clinical trials. This work was undertaken to develop such a definition. METHODS: A committee consisting of members of the American College of Rheumatology, the European League Against Rheumatism, and the Outcome Measures in Rheumatology Initiative met to guide the process and review prespecified analyses from RA clinical trials. The committee requested a stringent definition (little, if any, active disease) and decided to use core set measures including, as a minimum, joint counts and levels of an acute-phase reactant to define remission. Members were surveyed to select the level of each core set measure that would be consistent with remission. Candidate definitions of remission were tested, including those that constituted a number of individual measures of remission (Boolean approach) as well as definitions using disease activity indexes. To select a definition of remission, trial data were analysed to examine the added contribution of patient-reported outcomes and the ability of candidate measures to predict later good radiographic and functional outcomes. RESULTS: Survey results for the definition of remission suggested indexes at published thresholds and a count of core set measures, with each measure scored as 1 or less (eg, tender and swollen joint counts, C reactive protein (CRP) level, and global assessments on a 0-10 scale). Analyses suggested the need to include a patient-reported measure. Examination of 2-year follow-up data suggested that many candidate definitions performed comparably in terms of predicting later good radiographic and functional outcomes, although 28-joint Disease Activity Score-based measures of remission did not predict good radiographic outcomes as well as the other candidate definitions did. Given these and other considerations, we propose that a patient's RA can be defined as being in remission based on one of two definitions: (1) when scores on the tender joint count, swollen joint count, CRP (in mg/dl), and patient global assessment (0-10 scale) are all ≤1, or (2) when the score on the Simplified Disease Activity Index is ≤3.3. CONCLUSION: We propose two new definitions of remission, both of which can be uniformly applied and widely used in RA clinical trials. The authors recommend that one of these be selected as an outcome measure in each trial and that the results on both be reported for each trial.

American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials.

OBJECTIVE: Remission in rheumatoid arthritis (RA) is an increasingly attainable goal, but there is no widely used definition of remission that is stringent but achievable and could be applied uniformly as an outcome measure in clinical trials. This work was undertaken to develop such a definition. METHODS: A committee consisting of members of the American College of Rheumatology, the European League Against Rheumatism, and the Outcome Measures in Rheumatology Initiative met to guide the process and review prespecified analyses from RA clinical trials. The committee requested a stringent definition (little, if any, active disease) and decided to use core set measures including, as a minimum, joint counts and levels of an acute-phase reactant to define remission. Members were surveyed to select the level of each core set measure that would be consistent with remission. Candidate definitions of remission were tested, including those that constituted a number of individual measures of remission (Boolean approach) as well as definitions using disease activity indexes. To select a definition of remission, trial data were analyzed to examine the added contribution of patient-reported outcomes and the ability of candidate measures to predict later good radiographic and functional outcomes. RESULTS: Survey results for the definition of remission suggested indexes at published thresholds and a count of core set measures, with each measure scored as 1 or less (e.g., tender and swollen joint counts, C-reactive protein [CRP] level, and global assessments on a 0-10 scale). Analyses suggested the need to include a patient-reported measure. Examination of 2-year followup data suggested that many candidate definitions performed comparably in terms of predicting later good radiographic and functional outcomes, although 28-joint Disease Activity Score-based measures of remission did not predict good radiographic outcomes as well as the other candidate definitions did. Given these and other considerations, we propose that a patient's RA can be defined as being in remission based on one of two definitions: (a) when scores on the tender joint count, swollen joint count, CRP (in mg/dl), and patient global assessment (0-10 scale) are all ≤ 1, or (b) when the score on the Simplified Disease Activity Index is ≤ 3.3. CONCLUSION: We propose two new definitions of remission, both of which can be uniformly applied and widely used in RA clinical trials. We recommend that one of these be selected as an outcome measure in each trial and that the results on both be reported for each trial.

2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.

OBJECTIVE: The 1987 American College of Rheumatology (ACR; formerly, the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticized for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA. METHODS: A joint working group from the ACR and the European League Against Rheumatism developed, in 3 phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease--this being the appropriate current paradigm underlying the disease construct "rheumatoid arthritis." RESULTS: In the new criteria set, classification as "definite RA" is based on the confirmed presence of synovitis in at least 1 joint, absence of an alternative diagnosis that better explains the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in 4 domains: number and site of involved joints (score range 0-5), serologic abnormality (score range 0-3), elevated acute-phase response (score range 0-1), and symptom duration (2 levels; range 0-1). CONCLUSION: This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimize the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct "rheumatoid arthritis."

2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.

OBJECTIVE: The 1987 American College of Rheumatology (ACR; formerly the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticised for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA. METHODS: A joint working group from the ACR and the European League Against Rheumatism developed, in three phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease--this being the appropriate current paradigm underlying the disease construct 'RA'. RESULTS: In the new criteria set, classification as 'definite RA' is based on the confirmed presence of synovitis in at least one joint, absence of an alternative diagnosis better explaining the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in four domains: number and site of involved joints (range 0-5), serological abnormality (range 0-3), elevated acute-phase response (range 0-1) and symptom duration (two levels; range 0-1). CONCLUSION: This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimise the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct 'RA'.

The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: methodological report phase I.

OBJECTIVE: To apply a data-driven approach to investigate, in patients newly presenting with undifferentiated inflammatory synovitis, key variables that discriminate the subset of patients at sufficiently high risk of persistent or erosive disease for the purpose of developing new criteria for rheumatoid arthritis (RA). METHODS: In this first phase of the collaborative effort of the American College of Rheumatology and European League Against Rheumatism to develop new criteria for RA, a pooled analysis of early arthritis cohorts made available by the respective investigators is presented. All the variables associated with the gold standard of treatment with methotrexate during the first year after enrolment were first identified. Principal component analysis was then used to identify among the significant variables those sets that represent similar domains. In a final step, from each domain one representative variable was extracted, all of which were then tested for their independent effects in a multivariate regression model. From the OR in that final model, the relative weight of each variable was estimated. RESULTS: The final domains and variables identified by this process (and their relative weights) were: swelling of a metacarpophalangeal joint (MCP; 1.5), swelling of a proximal interphalangeal joint (PIP; 1.5), swelling of the wrist (1.5), tenderness of the hand (ie, MCP, PIP or wrist (2)), acute phase reaction (ie, C reactive protein or erythrocyte sedimentation rate and weights for moderate or high elevations of either one (1 for moderate, 2 for high elevation)) and serological abnormalities (ie, rheumatoid factors or anti-citrullinated protein antibodies, again with separate weights for moderate or high elevations (2 and 4, respectively)). CONCLUSION: The results of this first phase were subsequently used in the second phase of the project, which is reported in a separate methodological paper, and for derivation of the final set of criteria.

Progress toward the development of a new definition of remission in rheumatoid arthritis.

The first definition of remission in rheumatoid arthritis was proposed by Pinals and colleagues in 1981. Although its development process was of high quality, the definition proved unfeasible and was not often applied. Subsequently many other definitions appeared, either as variations or as cutpoints of disease activity indices. The American College of Rheumatology, together with the European League Against Rheumatism and the Initiative for Outcome Measures in Rheumatology (OMERACT) decided to develop a new definition that would meet the OMERACT Filter of Truth, discrimination and Feasibility. This article summarizes the development process to date. The new definition is expected to be launched in 2010.

Application of the DAREA/DAPSA score for assessment of disease activity in psoriatic arthritis.

BACKGROUND AND OBJECTIVES: Instruments for measuring disease activity in psoriatic arthritis (PsA) are not yet firmly established, and most of the currently employed ones have been derived for rheumatoid arthritis. Some of these instruments are based on 28 joint counts, which do not capture joints frequently affected in PsA. Therefore, the reliability and validity of DAREA (for 'Disease Activity index for REactive Arthritis'), which was originally developed for reactive arthritis and employs a 66/68 joint count, was tested in patients with PsA. METHODS: Trial data from the Infliximab Multinational Psoriatic Arthritis Controlled Trial were analysed. Results were then independently validated using an observational data set. DAREA was compared to other composite indices regarding correlations with core set variables, sensitivity to change and criterion validity. RESULTS: Good correlation of the DAREA with single items of disease activity, other composite scores (r=0.6-0.9) and physical function (Health Assessment Questionnaire; r=0.5) was found. Likewise, DAREA was at least as sensitive to change as the other indices and more so in patients with distal interphalangeal joint involvement. Additionally, DAREA correlated well with radiographic changes. CONCLUSION: The analyses of this study provide evidence of the utility and validity of the DAREA for PsA disease activity assessment. A second name should therefore be assigned to this score: DAPSA (for 'Disease Activity index for PSoriatic Arthritis').

Response of elderly patients with rheumatoid arthritis to methotrexate or TNF inhibitors compared with younger patients.

OBJECTIVE: To compare the efficacy of MTX and MTX+TNF inhibitors (TNFis) in elderly patients with RA with that in patients of younger age. METHODS: Data from two large, randomized, controlled, double-blind trials in patients with early RA using adalimumab or infliximab+MTX or MTX alone were obtained and pooled. Composite disease activity indices were calculated at baseline and 1 year of treatment, and compared in groups of patients classified by quartiles of age with the highest age group comprising 61-82 years using analysis of variance or Kruskal-Wallis test. RESULTS: Across all age quartiles, improvement on MTX was similar with respect to changes of composite disease activity indices, assessment of physical function and X-ray progression. Likewise, TNFi+MTX had similar effects across all age groups, but the effects of the combination were more profound than those of MTX monotherapy. Also in 10% of the patients with the highest age, primarily septuagenarians, improvement was seen to a similar degree as in the younger ones. CONCLUSIONS: Responsiveness of elderly patients with RA to MTX or TNFi+MTX is similar to that observed in patients of younger age.

The importance of reporting disease activity states in rheumatoid arthritis clinical trials.

OBJECTIVE: To compare the value of reporting treatment effects in rheumatoid arthritis (RA) as relative change from baseline (e.g., American College of Rheumatology [ACR] responder status) with the value of evaluating absolute disease activity states (e.g., remission). METHODS: We pooled data from several recent RA clinical trials and evaluated patients who had completed a 1-year treatment period (n = 629). We compared levels of functional impairment and radiographic progression among patients meeting the ACR 50% or 70% improvement criteria (ACR50 and ACR70 responders, respectively) who attained remission of disease, low disease activity, or moderate disease activity after 1 year, as assessed by the Simplified Disease Activity Index and the Disease Activity Score in 28 joints. RESULTS: Within the ACR50 and ACR70 responder groups, functional disability and radiographic progression were lowest in patients who had attained disease remission at 1 year, compared with those who had attained low or moderate disease activity. When patients attained the same disease activity category, physical function and radiographic progression did not differ significantly with different response states. CONCLUSION: Functional and radiographic outcomes are different in patients depending on the disease activity category they attain, even if the same level of response (change from baseline) is achieved. Among patients who attain the same disease activity category, the degree of response they experience does not seem to matter. Assessing actual disease activity as well as disease activity states should constitute an integral part of clinical trial data reporting.

Disease activity early in the course of treatment predicts response to therapy after one year in rheumatoid arthritis patients.

OBJECTIVE: To assess whether disease activity levels at treatment initiation or during the first 3 months of therapy predict disease activity at 1 year after treatment initiation. METHODS: Pooled patient data from early rheumatoid arthritis (RA) clinical trials (n = 1,342) of methotrexate (MTX), tumor necrosis factor (TNF) inhibitor monotherapy (adalimumab and etanercept), and the combination of the two (adalimumab or infliximab plus MTX) were used for the primary analyses. Pooled data from clinical trials of MTX and of TNF inhibitor plus MTX in late RA (n = 712) were used for validation of the results. Disease activity was primarily assessed using the Simplified Disease Activity Index (SDAI); in addition, we calculated the Disease Activity Score 28-joint assessment (DAS28) and the Clinical Disease Activity Index (CDAI). Associations of disease activity measures at baseline and at 1, 2, 3, and 6 months with disease activity values or disease activity states at 1 year were performed using Spearman's rank correlation, analysis of variance, and diagnostic testing procedures, including receiver operating characteristic (ROC) curve analyses, and probit analysis. RESULTS: Correlations with SDAI values at end point were significant (P < 0.0001) at baseline, and increased to r = approximately 0.6 at 3 months. The area under the ROC curve indicated a high diagnostic test yield with respect to the 1-year outcome (area under the ROC curve approximately 0.8). At all time points, including baseline, the group of patients who achieved remission at 1 year had lower average SDAI values than did those whose disease activity was high at 1 year. The groups achieving low or moderate disease activities at 1 year had SDAI values lying between. Baseline disease activity was less associated with disease activity at the end point for treatment with TNF inhibitor plus MTX, indicating its effectiveness over a broader range of baseline disease activity, but the association with end point disease activity was similar to that in the MTX treatment group at 1 month after treatment initiation. The data were similar when scores on the DAS28 and CDAI were used and were fully validated in the independent cohort of patients with late RA. CONCLUSION: The level of disease activity at baseline and especially during the first 3 months of treatment is significantly related to the level of disease activity at 1 year. Patients who reach a moderate or low disease activity status after 3-6 months of therapy may require switching to alternative therapies. Our findings indicate that intensive and dynamic treatment strategies that include a closer look at disease activity at 3 months in patients with early and late RA is warranted.