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1.  American College of Rheumatology/European League against Rheumatism Preliminary Definition of Remission in Rheumatoid Arthritis for Clinical Trials 
Arthritis and rheumatism  2011;63(3):573-586.
With remission in rheumatoid arthritis (RA) an increasingly attainable goal, there is no widely used definition of remission that is stringent but achievable and could be applied uniformly as an outcome in clinical trials.
A committee consisting of members of the American College of Rheumatology, the European League Against Rheumatism and the Outcome Measures in Rheumatology Initiative (OMERACT) met to guide the process and review prespecified analyses from clinical trials of patients with RA. The committee requested a stringent definition (little, if any, active disease) and decided to use core set measures to define remission including at least joint counts and an acute phase reactant. Members were surveyed to select the level of each core set measure consistent with remission. Candidate definitions of remission were tested including those that constituted a number of individual measures in 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 x-ray and functional outcomes.
Survey results for the definition of remission pointed to indexes at published thresholds and to a count of core set measures with each measure scored as 1 or less (e.g. tender and swollen joint counts, CRP and global assessments on 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 x-ray and functional outcomes, although DAS28 based measures of remission did not predict good radiographic outcomes as well as did the other candidate definitions. Given these and other considerations, we propose that a patient be defined as in remission based on one of two definitions : 1: When their scores on the following measures are all <1: tender joint count, swollen joint count, CRP (in mg/dL) and patient global assessment (0-10 scale), OR 2: when their score on the SDAI is < 3.3.
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 in each trial as an outcome and that the results on both be reported in each trial.
PMCID: PMC3115717  PMID: 21294106
2.  The incidence of rheumatoid arthritis in the UK: comparisons using the 2010 ACR/EULAR classification criteria and the 1987 ACR classification criteria. Results from the Norfolk Arthritis Register 
Annals of the Rheumatic Diseases  2012;72(8):1315-1320.
The development of new classification criteria for rheumatoid arthritis (RA) calls for a re-estimation of RA incidence rates. The objectives of this study were to estimate the age and sex-specific incidence rates (IR) of RA in Norfolk, England using the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism criteria, and to compare those with IRs estimated using the 1987 ACR criteria.
The Norfolk Arthritis Register (NOAR), a large primary care inception cohort of patients with inflammatory oligo- and polyarthritis (IP) aged ≥ 16.
All patients notified to NOAR from 1990-5 with symptom onset in 1990 were included. The former Norwich Health Authority population was the denominator. Age and sex specific IRs using 1987 and 2010 classification criteria were calculated at baseline visit, annually for the first 3 years and at 5 years.
260 patients were notified to NOAR with symptom onset in 1990 and without an alternative diagnosis. IRs applying the 2010 criteria at baseline were 54/100 000 for women and 25/100 000 for men. Age and sex-specific IRs using the 2010 classification criteria at baseline were similar to cumulative IRs applying the 1987 criteria up to 5 years. However, some patients only ever satisfied one set of criteria and a proportion of IA patients (20%) did not satisfy either criteria set over 5 years.
The 2010 criteria classify similar numbers of patients as having RA at baseline, as the 1987 criteria would have taken up to 5 years to identify.
PMCID: PMC3711368  PMID: 22945499
Early Rheumatoid Arthritis; Rheumatoid Arthritis; Epidemiology
3.  Performance of the 2010 Classification Criteria for Rheumatoid Arthritis: A Systematic Literature Review and a Meta-Analysis 
PLoS ONE  2013;8(2):e56528.
To evaluate the performance of the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 classification criteria for rheumatoid arthritis (RA) with a systematic literature review and a meta-analysis.
PubMed, Embase, Cochrane Library and the abstracts of the ACR and EULAR meetings (2010–2012) were searched for original articles or abstracts with the following inclusion criteria: 1) recent onset arthritis, with at least one swollen joint and no alternative diagnosis; 2) the ACR/EULAR 2010 criteria as index test; 3) the prescription of methotrexate (MTX) or disease modifying antirheumatic drugs (DMARDs) at any time during follow-up as reference standard. Data were pooled using the bivariate model. Three meta-analyses were performed with MTX (primary analysis), DMARDs or their combination (secondary analyses) as reference standard. Heterogeneity was formally tested and explored performing an influence analysis.
The search identified 1,277 references. Six full papers and 4 abstracts met the inclusion criteria. With MTX as reference standard, sensitivity (95% confidence interval, CI) was 0.80 (0.74,0.85), specificity 0.61 (0.56,0.67), positive likelihood ratio (LR) 2.11 (1.92,2.32), negative LR 0.31 (0.25,0.38) and the diagnostic odds ratio (DOR) was 6.74 (5.49,8.28). Using DMARDs as reference standard, sensitivity was 0.73 (0.64,0.80), specificity was 0.74 (0.68,0.79), LR+2.85 (2.53,3.22), LR− 0.35 (0.27,0.45) and DOR 8.03 (6.4,10.09). Using the combination of MTX and DMARDs as reference standard, intermediate results were obtained. The influence analysis detected one potentially influential study. However, its exclusion from the meta-analysis did not have a clinically relevant impact on the results.
The new classification criteria have good sensitivity, lower specificity and an overall moderate diagnostic accuracy. These results confirm that the criteria have classificative and not diagnostic function.
PMCID: PMC3577909  PMID: 23437156
4.  Performance of response criteria for assessing peripheral arthritis in patients with psoriatic arthritis: analysis of data from randomised controlled trials of two tumour necrosis factor inhibitors 
Annals of the Rheumatic Diseases  2006;65(10):1373-1378.
In recent clinical trials in patients with psoriatic arthritis (PsA), the response criteria and disease activity measures that have been used were those developed for rheumatoid arthritis. However, these have not yet been validated in PsA.
To compare the responsiveness and discriminative capacity of the psoriatic arthritis response criteria (PsARC), American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response criteria and the Disease Activity Score (DAS) and core‐set measures in patients with PsA and peripheral arthritis, using the data from two randomised placebo‐controlled trials of tumour necrosis factor inhibitors.
In an infliximab trial, 104 patients with active PsA were randomised to receive placebo or infliximab for 16 weeks. In an etanercept trial, 60 patients with active PsA were randomised to receive placebo or etanercept for 12 weeks. Data from baseline and the end of the intervention phase were used from each study. Responsiveness was assessed using the standardised response mean and effect size. Capacity to discriminate between the active drug and placebo was assessed using t values or a χ2 test. Measures were ranked in order of their t value or χ2 value.
The EULAR criteria performed better in discriminating the active drug from placebo than the ACR20 improvement criteria, which in turn performed better than the PsARC. It was also found that the pooled indices (DAS and DAS28) were generally more responsive, and performed better in discriminating active drug from placebo, than the single core‐set measures.
Response criteria and pooled indices developed for rheumatoid arthritis are useful for the assessment of arthritis in PsA clinical trials.
PMCID: PMC1798317  PMID: 16644783
5.  Utility of the new rheumatoid arthritis 2010 ACR/EULAR classification criteria in routine clinical care 
BMJ Open  2012;2(5):e001117.
The new 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria for rheumatoid arthritis (RA) have been designed to classify early onset RA, but has not been studied to identify RA in patients with arthritis seen in routine clinical care where correct ‘classification’ of patients, when they are not selected for having RA would be important.
Prospective, consecutive patients cohort.
Outpatient clinic of a university rheumatology centre.
A total of 126 patients with joint symptoms were consecutively recruited.
The ACR/EULAR RA criteria were applied, with questions followed by a targeted musculoskeletal exam. The gold standard for the diagnosis of RA was the primary rheumatologist's diagnosis.
Primary outcome measure
Number of patients with non-RA diagnosis who were classified as having RA by the new classification criteria.
The sensitivity and specificity of the 2010 criteria in classifying RA were 97% and 55%, respectively, compared with the 1987 RA criteria which were 93% and 76%, respectively. The 2010 criteria as applied to this group of patients had a poorer positive predictive (44% vs 61%) and a similar negative predictive value (98% vs 97%) compared with the 1987 criteria. More specifically, 66.7% of systemic lupus erythematosus patients, 50% of osteoarthritis, 37.5% of psoriatic arthritis and 27.2% of others fulfilled the new criteria and could have been classified as RA.
In this, we believe, the first study to examine the new 2010 ACR/EULAR RA criteria among consecutive patients seen in routine care, we found the criteria to have low specificity, and therefore incorrectly label those as having RA when, in fact, they may have a different type of inflammatory arthritis. Physicians need to be aware of this when applying the new criteria for classifying their patients for any purpose.
PMCID: PMC3488748  PMID: 23035013
Rheumatology; rheumatoid arthritis; diagnosis
6.  Bone Mineral Density Changes in Patients with Recent-Onset Rheumatoid Arthritis 
Osteoporosis and related fragility fractures are one of the most common complications seen in patients with rheumatoid arthritis (RA) and dramatically affect quality of life.
To evaluate changes in bone mineral density in patients with recent onset rheumatoid arthritis (<1 year) and its correlation if any with a modified DAS-28 score and simple erosion narrowing score (SENS).
This study included 30 patients with recent-onset rheumatoid arthritis fulfilling the new American College of Rheumatology/European League Against Rheumatism diagnostic criteria for rheumatoid arthritis and 20 healthy volunteers as controls. All were subjected to a complete blood count, erythrocyte sedimentation rate, C-reactive protein, liver function tests, renal function tests, rheumatoid factor, and plain x-rays of the hands and feet. Dual-energy x-ray absorptiometry DEXA was used to measure bone mineral density (BMD) of the left proximal femur, lumbar spine (L1–L4), and lower distal radius at the time of recruitment.
In the RA patients, 13.3% had osteoporosis, 50% had osteopenia, and 36.7% had normal BMD. The most common site of osteoporosis was the lumbar spine (four patients, 13.3%) followed by the femur (two patients, 6.6%), and forearm (only one patient, 3.3%). There was a significantly higher percentage of osteoporosis among RA males than females and the difference was statistically significant (P = 0.009). Osteoporosis was more common in patients treated with corticosteroids and disease modifying antirheumatic drugs (DMARDs) than in patients treated with only nonsteroidal anti-inflammatory drugs (P = 0.004). Higher disease activity (DAS-28) was found in RA patients with osteoporosis compared to RA patients with normal BMD or osteopenia, but the difference was not statistically significant. Osteoporotic RA patients were found to have a higher SENS score for radiological damage than nonosteoporotic ones.
BMD changes do occur in patients with early RA, and are not necessarily correlated with disease activity (DAS-28). However, a significant negative correlation was found between BMD and the score of radiological damage (SENS). Dual energy x-ray absorptiometry is an important investigation to assess BMD in early RA patients.
PMCID: PMC3201106  PMID: 22084606
BMD; recent onset; rheumatoid arthritis
7.  Application of the 2010 ACR/EULAR classification criteria in patients with very early inflammatory arthritis: analysis of sensitivity, specificity and predictive values in the SAVE study cohort 
Annals of the Rheumatic Diseases  2012;72(8):1335-1341.
Performance of the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) criteria was analysed in an internationally recruited early arthritis cohort (≤16 weeks symptom duration) enrolled in the ‘Stop-Arthritis-Very-Early’ trial. This sample includes patients with a variety of diseases diagnosed during follow-up.
Two endpoints were defined: Investigators’ diagnosis and disease-modifying antirheumatic drug (DMARD) treatment start during the 12-month follow-up. The 2010 criteria were applied to score Patients’ baseline data. Sensitivity, specificity, predictive values and areas under the receiver operating curves of this scoring with respect to both endpoints were calculated and compared to the 1987 criteria. The optimum level of agreement between the endpoints and the 2010 classification score ways estimated by Cohen’s ϰ coefficients.
303 patients had 12-months follow-up. Positive predictive values of the 2010 criteria were 0.68 and 0.71 for RA-diagnosis and DMARD-start, respectively. Sensitivity for RA-diagnosis was 0.85, for DMARD-start 0.8, whereas the 1987 criteria’s sensitivities were 0.65 and 0.55. The areas under the receiver operating curves of the 2010 criteria for RA-diagnosis and DMARD-start were 0.83 and 0.78. Analysis of inter-rater-agreement using Cohen’s ϰ demonstrated the highest ϰ values (0.5 for RA-diagnosis and 0.43 for DMARD-start) for the score of 6.
In this international very early arthritis cohort predictive and discriminative abilities of the 2010 ACR/EULAR classification criteria were satisfactory and substantially superior to the ‘old’ 1987 classification criteria. This easier classification of RA in early stages will allow targeting truly early disease stages with appropriate therapy.
PMCID: PMC3711367  PMID: 22984174
Arthritis; Early Rheumatoid Arthritis; Outcomes research; Rheumatoid Arthritis; Treatment
8.  Adalimumab alone and in combination with disease‐modifying antirheumatic drugs for the treatment of rheumatoid arthritis in clinical practice: the Research in Active Rheumatoid Arthritis (ReAct) trial 
Annals of the Rheumatic Diseases  2007;66(6):732-739.
To evaluate the safety and effectiveness of adalimumab alone or in combination with standard disease‐modifying antirheumatic drugs (DMARDs) for the treatment of rheumatoid arthritis (RA).
Patients with active RA despite treatment with DMARDs or prior treatment with a tumour necrosis factor antagonist participated in a multicentre, open‐label clinical study of adalimumab 40 mg every other week for 12 weeks with an optional extension phase. Patients were allowed to continue with pre‐existing traditional DMARDs. Long‐term safety results are reported for all patients (4210 patient‐years (PYs) of adalimumab exposure). The observed effectiveness results at week 12 are reported using American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response criteria.
Among the 6610 treated patients, adalimumab was generally well tolerated. Serious infections occurred in 3.1% of patients (5.5/100 PYs, including active tuberculosis, 0.5/100 PYs). Demyelinating disease (0.06%) and systemic lupus erythematosus (0.03%) were rare serious adverse events. The standardised incidence ratio of malignancy was 0.71 (95% CI 0.49 to 1.01). The standardised mortality ratio was 1.07 (95% CI 0.75 to 1.49). At week 12, 69% of patients achieved an ACR20 response, 83% a moderate, and 33% a good EULAR response. Adalimumab was effective in combination with a variety of DMARDs. The addition of adalimumab to antimalarials was comparably effective to the combination of adalimumab and methotrexate.
Considering the limitations of an open‐label study, adalimumab alone or in combination with standard DMARDs appeared to be well tolerated and effective in 6610 difficult‐to‐treat patients with active RA treated in clinical practice.
PMCID: PMC1954645  PMID: 17329305
adalimumab; rheumatoid arthritis; tumour necrosis factor; monoclonal antibody; antirheumatic agents
9.  Tools for monitoring remission in rheumatoid arthritis: any will do, let's just pick one and start measuring 
Rheumatoid arthritis treatment has seen major changes in the last decade, one of which is the concept of treating to target. Various composite outcome measures have been developed, and the latest is the new American College of Rheumatology/European League Against Rheumatism remission criteria. Zhang and colleagues test the predictive validity of the new criteria in an observational cohort and show that they work as well as other definitions of remission. Our main challenge remains getting rheumatologists to use one of the outcome measures rather than developing new measures that are basically no different from already available measures in predicting functional and radiographic changes, the two most important long-term outcomes of rheumatoid arthritis.
PMCID: PMC3672754  PMID: 23374997
10.  Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative 
Annals of the Rheumatic Diseases  2008;68(7):1086-1093.
To develop evidence-based recommendations for the use of methotrexate in daily clinical practice in rheumatic disorders.
751 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2007–8 consisting of three separate rounds of discussions and Delphi votes. Ten clinical questions concerning the use of methotrexate in rheumatic disorders were formulated. A systematic literature search in Medline, Embase, Cochrane Library and 2005–7 American College of Rheumatology/European League Against Rheumatism meeting abstracts was conducted. Selected articles were systematically reviewed and the evidence was appraised according to the Oxford levels of evidence. Each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed.
A total of 16 979 references was identified, of which 304 articles were included in the systematic reviews. Ten multinational key recommendations on the use of methotrexate were formulated. Nine recommendations were specific for rheumatoid arthritis (RA), including the work-up before initiating methotrexate, optimal dosage and route, use of folic acid, monitoring, management of hepatotoxicity, long-term safety, mono versus combination therapy and management in the perioperative period and before/during pregnancy. One recommendation concerned methotrexate as a steroid-sparing agent in other rheumatic diseases.
Ten recommendations for the use of methotrexate in daily clinical practice focussed on RA were developed, which are evidence based and supported by a large panel of rheumatologists, enhancing their validity and practical use.
PMCID: PMC2689523  PMID: 19033291
11.  A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study 
Annals of the Rheumatic Diseases  2013;72(10):1613-1620.
To compare the efficacy and safety of innovator infliximab (INX) and CT-P13, an INX biosimilar, in active rheumatoid arthritis patients with inadequate response to methotrexate (MTX) treatment.
Phase III randomised, double-blind, multicentre, multinational, parallel-group study. Patients with active disease despite MTX (12.5–25 mg/week) were randomised to receive 3 mg/kg of CT-P13 (n=302) or INX (n=304) with MTX and folic acid. The primary endpoint was the American College of Rheumatology 20% (ACR20) response at week 30. Therapeutic equivalence of clinical response according to ACR20 criteria was concluded if the 95% CI for the treatment difference was within ±15%. Secondary endpoints included ACR response criteria, European League Against Rheumatism (EULAR) response criteria, change in Disease Activity Score 28 (DAS28), Medical Outcomes Study Short-Form Health Survey (SF-36), Simplified Disease Activity Index, Clinical Disease Activity Index, as well as pharmacokinetic (PK) and pharmacodynamic (PD) parameters, safety and immunogenicity.
At week 30, ACR20 responses were 60.9% for CT-P13 and 58.6% for INX (95% CI −6% to 10%) in the intention-to-treat population. The proportions in CT-P13 and INX groups achieving good or moderate EULAR responses (C reactive protein (CRP)) at week 30 were 85.8% and 87.1%, respectively. Low disease activity or remission according to DAS28–CRP, ACR–EULAR remission rates, ACR50/ACR70 responses and all other PK and PD endpoints were highly similar at week 30. Incidence of drug-related adverse events (35.2% vs 35.9%) and detection of antidrug antibodies (48.4% vs 48.2%) were highly similar for CT-P13 and INX, respectively.
CT-P13 demonstrated equivalent efficacy to INX at week 30, with a comparable PK profile and immunogenicity. CT-P13 was well tolerated, with a safety profile comparable with that of INX. Identifier
PMCID: PMC3786641  PMID: 23687260
12.  Selective involvement of ERK and JNK mitogen-activated protein kinases in early rheumatoid arthritis (1987 ACR criteria compared to 2010 ACR/EULAR criteria): a prospective study aimed at identification of diagnostic and prognostic biomarkers as well as therapeutic targets 
Annals of the Rheumatic Diseases  2011;71(3):415-423.
To investigate the expression and activation of mitogen-activated protein kinases in patients with early arthritis who are disease-modifying antirheumatic drug (DMARD) naïve.
A total of 50 patients with early arthritis who were DMARD naïve (disease duration <1 year) were prospectively followed and diagnosed at baseline and after 2 years for undifferentiated arthritis (UA), rheumatoid arthritis (RA) (1987 American College of Rheumatology (ACR) and 2010 ACR/European League Against Rheumatism (EULAR) criteria), or spondyloarthritis (SpA). Synovial biopsies obtained at baseline were examined for expression and phosphorylation of p38, extracellular signal regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) by immunohistochemistry and digital analysis. Synovial tissue mRNA expression was measured by quantitative PCR (qPCR).
ERK and JNK activation was enhanced at inclusion in patients meeting RA criteria compared to other diagnoses. JNK activation was enhanced in patients diagnosed as having UA at baseline who eventually fulfilled 1987 ACR RA criteria compared to those who remained UA, and in patients with RA fulfilling 2010 ACR/EULAR criteria at baseline. ERK and JNK activation was enhanced in patients with RA developing progressive joint destruction. JNK activation in UA predicted 1987 ACR RA classification criteria fulfilment (R2=0.59, p=0.02) after follow-up, and disease progression in early arthritis (R2=0.16, p<0.05). Enhanced JNK activation in patients with persistent disease was associated with altered synovial expression of extracellular matrix components and CD44.
JNK activation is elevated in RA before 1987 ACR RA classification criteria are met and predicts development of erosive disease in early arthritis, suggesting JNK may represent an attractive target in treating RA early in the disease process.
PMCID: PMC3277721  PMID: 21953337
13.  Effectiveness and safety of the interleukin 6-receptor antagonist tocilizumab after 4 and 24 weeks in patients with active rheumatoid arthritis: the first phase IIIb real-life study (TAMARA) 
Annals of the Rheumatic Diseases  2010;70(5):755-759.
To confirm the effectiveness and safety of the interleukin 6-receptor antagonist tocilizumab in patients with rheumatoid arthritis (RA) in a setting close to real-life medical care in Germany.
A multicentre open-label phase IIIb study was undertaken. Patients with active RA with a 28-joint Disease Activity Score (DAS28) >3.2 despite previous disease-modifying antirheumatic drugs (DMARDs) were treated with tocilizumab 8 mg/kg every 4 weeks. The primary end point was the proportion of patients achieving LDAS ≤3.2 at week 24; secondary end points included American College of Rheumatology (ACR), European League Against Rheumatism (EULAR) or Clinical Disease Activity Index (CDAI) responses and decrease in acute phase. Analyses in subgroups such as rheumatoid factor (RF)-positive versus RF-negative patients and patients with an inadequate response to treatment with DMARDs (DMARD-IR) versus those with an inadequate response to tumour necrosis factor (TNF) antagonists (TNF antagonist-IR) were performed. Safety was assessed by adverse event documentation.
286 patients were treated and 83.6% completed the study. 41.6% had previously been treated with TNF antagonists. 57% of the intention-to-treat patients achieved the primary end point of LDAS, 47.6% achieved DAS remission <2.6 and a EULAR ‘good response’ was achieved by 54.9%; ACR50/70 response rates at week 24 were 50.7% and 33.9%, respectively. The mean±SD decrease in CDAI from baseline to week 24 was 71±29%. C reactive protein levels normalised rapidly within 1 week. Major improvements in fatigue, pain and morning stiffness were observed in the first 4 weeks and further improved until week 24. DAS28, EULAR and ACR responses at week 24 did not differ between RF-positive and RF-negative patients. TNF antagonist-naive patients responded better than patients who had previously failed on TNF antagonists. The safety profile of tocilizumab was comparable to that previously observed in the phase III trial programme. Serious infections were observed in 3.1% of patients.
Tocilizumab is highly effective in a setting close to real-life medical care with a rapid and sustained improvement in signs and symptoms of RA. A manageable safety profile was seen over the 24-week study period.
PMCID: PMC3070275  PMID: 21187298
14.  Long-term safety and efficacy of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis (the STREAM study): evidence of safety and efficacy in a 5-year extension study 
Annals of the Rheumatic Diseases  2008;68(10):1580-1584.
To evaluate the safety and efficacy of 5-year, long-term tocilizumab monotherapy for patients with rheumatoid arthritis.
In an open-label, long-term extension trial following an initial 3-month randomised phase II trial, 143 of the 163 patients who participated in the initial blinded study received tocilizumab monotherapy (8 mg/kg) every 4 weeks. Concomitant therapy with non-steroidal anti-inflammatory drugs and/or oral prednisolone (10 mg daily maximum) was permitted. All patients were evaluated with American College of Rheumatology (ACR) improvement criteria, disease activity score (DAS) in 28 joints, and the European League Against Rheumatism response, as well as for safety issues.
143 patients were enrolled in the open-label, long-term extension trial and 94 (66%) patients had completed 5 years as of March 2007. 32 patients (22%) withdrew from the study due to adverse events and one patient (0.7%) due to unsatisfactory response. 14 patients withdrew because of the patient’s request or other reasons. The serious adverse event rate was 27.5 events per 100 patient-years, with 5.7 serious infections per 100 patient-years, based on a total tocilizumab exposure of 612 patient-years. Of the 88 patients receiving corticosteroids at baseline, 78 (88.6%) were able to decrease their corticosteroid dose and 28 (31.8%) discontinued corticosteroids. At 5 years, 79/94 (84.0%), 65/94 (69.1%) and 41/94 (43.6%) of the patients achieved ACR20, ACR50, and ACR70 improvement criteria, respectively. Remission defined as DAS28 less than 2.6 was achieved in 52/94 (55.3%) of the patients.
In this 5-year extension study, tocilizumab demonstrated sustained long-term efficacy and a generally good safety profile.
PMCID: PMC2732899  PMID: 19019888
15.  Utility of ultrasound joint counts in the prediction of rheumatoid arthritis in patients with very early synovitis 
Annals of the Rheumatic Diseases  2010;70(3):500-507.
Early therapy improves outcomes in rheumatoid arthritis (RA). It is therefore important to improve predictive algorithms for RA in early disease. This study evaluated musculoskeletal ultrasound, a sensitive tool for the detection of synovitis and erosions, as a predictor of outcome in very early synovitis.
58 patients with clinically apparent synovitis of at least one joint and symptom duration of ≤3 months underwent clinical, laboratory, radiographic and 38 joint ultrasound assessments and were followed prospectively for 18 months, determining outcome by 1987 American College of Rheumatology (ACR) and 2010 ACR/European League Against Rheumatism criteria. Sensitivity and specificity for 1987 RA criteria were determined for ultrasound variables and logistic regression models were then fitted to evaluate predictive ability over and above the Leiden rule.
16 patients resolved, 13 developed non-RA persistent disease and 29 developed RA by 1987 criteria. Ultrasound demonstrated subclinical wrist, elbow, knee, ankle and metatarsophalangeal joint involvement in patients developing RA. Large joint and proximal interphalangeal joint ultrasound variables had poor predictive ability, whereas ultrasound erosions lacked specificity. Regression analysis demonstrated that greyscale wrist and metacarpophalangeal joint involvement, and power Doppler involvement of metatarsophalangeal joints provided independently predictive data. Global ultrasound counts were inferior to minimal power Doppler counts, which significantly improved area under the curve values from 0.905 to 0.962 combined with the Leiden rule.
In a longitudinal study, extended ultrasound joint evaluation significantly increased detection of joint involvement in all regions and outcome groups. Greyscale and power Doppler scanning of metacarpophalangeal joints, wrists and metatarsophalangeal joints provides the optimum minimal ultrasound data to improve on clinical predictive models for RA.
PMCID: PMC3033529  PMID: 21115552
16.  Validation of ACR/EULAR definition of remission in rheumatoid arthritis from RA practice: the ESPOIR cohort 
Arthritis Research & Therapy  2012;14(3):R156.
In development of the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) remission definitions using clinical trials data, one criterion used to compare different remission definitions was whether, compared with those not in remission, those in remission had evidence of later disease stability defined by x-ray and functional status. Validation of the RA remission criteria using observational study data is necessary before recommending their use in practice.
Using data from those who met RA criteria in the ESPOIR cohort, we matched each person in remission with a person not in remission and then carried out analyses comparing later stability of x-ray and health assessment questionnaire (HAQ) between the two groups. We compared the predictive validity of the same candidate definitions of remission evaluated in the ACR/EULAR process. To minimize potential bias and produce more stable results, we used a bootstrap resampling approach to select those not in remission, repeating the sample matching analysis process 500 times.
Results were similar to those of clinical trials analyzed for the ACR/EULAR remission criteria. Specifically, the ACR/EULAR remission definitions using either an simple disease activity index (SDAI) ≤ 3.3, clinical disease activity index (CDAI) ≤ 2.8 or a definition of remission requiring tender joint count, swollen joint count, patient global assessment all ≤ 1 performed as well or better than other candidate definitions of remission in terms of predicting later x-ray and function stability.
ACR/EULAR definitions of remission developed for trials are similarly valid in observational studies in RA and could be used in practice.
PMCID: PMC3446542  PMID: 22747951
17.  Comparison of remission criteria in a tumour necrosis factor inhibitor treated rheumatoid arthritis longitudinal cohort: patient global health is a confounder 
Arthritis Research & Therapy  2013;15(6):R221.
Our objectives were to assess the frequency and sustainability of American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) and Disease Activity Score (DAS)28(4v)–C-reactive protein (CRP) remission 12 months after the initiation of tumour necrosis factor inhibitor (TNFi) therapy in a rheumatoid arthritis (RA) cohort.
Data were collected of 273 biologic naive RA patients at baseline, then 3, 6 and 12 months post-TNFi therapy. Remission status was calculated using DAS28(4v)-CRP <2.6 and ACR/EULAR Boolean criteria. Response was scored using EULAR criteria.
Mean (range) patient age was 59.9 (7.2-85.4) years with disease duration of 13.4 (1.0-52.0) years. Responder status maintained from 3–12 months (86%, 82.4%), laboratory/clinical parameters (erythrocyte sedimentation rate (ESR), CRP, patient global health (PGH), DAS28(4v)-CRP) also showed sustained improvement (P < 0.05). DAS28 remission was reached by 102 subjects at 1 year, 27 patients were in Boolean remission, but 75 missed it from the DAS28 remission group. Patients in remission were younger (P = 0.041) with lower baseline tender joint count (TJC)28 and PGH than those not in remission (P = 0.001, P = 0.047). DAS28 remission patients were older (P = 0.026) with higher 12 months PGH and subsequently higher DAS28 than Boolean remission patients (P < 0.0001). Patients not achieving Boolean remission due to missing one subcriteria most frequently missed PGH ≤1 criteria (79.8%).
Only 10% of this TNFi treated cohort achieved remission according to the new ACR/EULAR criteria, which requires lower disease activity. More stringent criteria may ensure further resolution of disease activity and better longterm radiographic outcome, which supports earlier intervention with biologic therapy in RA.
PMCID: PMC3978469  PMID: 24365061
18.  Management of rheumatoid arthritis: consensus recommendations from the Hong Kong Society of Rheumatology 
Clinical Rheumatology  2010;30(3):303-312.
Given the recent availability of novel biologic agents for the treatment of rheumatoid arthritis (RA), the Hong Kong Society of Rheumatology has developed consensus recommendations on the management of RA, which aim at providing guidance to local physicians on appropriate, literature-based management of this condition, specifically on the indications and monitoring of the biologic disease-modifying anti-rheumatic drugs (DMARDs). The recommendations were developed using the European League Against Rheumatism (EULAR) recommendations for the management of early arthritis as a guide, along with local expert opinion. As significant joint damage occurs early in the course of RA, initiating therapy early is key to minimizing further damage and disability. Patients with serious disease or poor prognosis should receive early, aggressive therapy. Because of its good efficacy and safety profile, methotrexate is considered the standard first-line DMARD for most treatment-naïve RA patients. Patients with a suboptimal response to methotrexate monotherapy should receive step-up (combination) therapy with either the synthetic or biologic DMARDs. In recent years, combinations of methotrexate with tocilizumab, abatacept, or rituximab have emerged as effective therapies in patients who are unresponsive to traditional DMARDs or the anti-tumor necrosis factor (TNF)-α agents. As biologic agents can increase the risk of infections such as tuberculosis and reactivation of viral hepatitis, screening for the presence of latent tuberculosis and chronic viral hepatitis carrier state is recommended before initiating therapy.
PMCID: PMC3052444  PMID: 21046421
Hong Kong; Management; Recommendations; Rheumatoid arthritis
19.  TNF Antagonist Responsiveness in a United States Rheumatoid Arthritis Cohort 
The American journal of medicine  2008;121(6):532-538.
To investigate responsiveness according to whether patients satisfy eligibility criteria from randomized controlled trials of tumor necrosis factor (TNF) antagonists in a multi-centered United States cohort
Biologic-naïve rheumatoid arthritis patients prescribed TNF antagonists (n=465) in the Consortium of Rheumatology Researchers of North America registry were included. Patients were stratified by whether they met eligibility criteria from 3 major TNF antagonist trials. Two cohorts were examined: cohort A (n=336) included patients with complete American College of Rheumatology response criteria except acute phase reactants; and cohort B (n=129) with the complete response criteria. Study outcomes included modified American College of Rheumatology 20% and 50% improvement responses (Cohort A) and standard American College of Rheumatology improvement (Cohort B).
A minority of patients (5.4% to 19.4%) prescribed TNF antagonists met trial eligibility criteria, and predominantly had high disease activity (78.5% to 100%). In cohort A for patients who met eligibility criteria, rates of 20% improvement (52.3% to 63.6%) and 50% improvement (30.8% to 45.5%) were achieved. Among patients failing to meet eligibility criteria, rates of 20% improvement (16.2% to 20.4%) and 50% improvement (8.9% to 10.8%) were consistently inferior (p<0.05 all comparisons). For cohort B, similar differences were observed.
This multi-centered U.S. cohort study demonstrates that the majority of patients receiving TNF antagonists would not meet trial eligibility criteria and achieve lower clinical responses. These findings highlight the tradeoff between defining treatment responsive populations and achieving results that can be generalized for broader patient populations.
PMCID: PMC2587326  PMID: 18501236
TNF antagonist; rheumatoid arthritis; trial eligibility
20.  A Korean rheumatic diseases screening questionnaire. 
Journal of Korean Medical Science  2003;18(2):171-178.
The aim of our study was to develop a Korean rheumatic diseases-screening questionnaire. The questionnaire was constructed based on American College of Rheumatology criteria for rheumatic diseases and a connective tissue diseases screening questionnaire. Two groups of patients were selected and completed the questionnaire: (i) those with osteoarthritis (n=46), rheumatoid arthritis (n=52), systemic lupus erythematosus (n=50), scleroderma (n=8), polymyositis or dermatomyositis (n=7), Sjogren's disease (n=4), and mixed connective-tissue disease (n=9) as case subjects; and (ii) those with fibromyalgia (n=8) and general disease without evidence of any rheumatic disease (n=72) as controls. Laboratory results were analyzed for correlation with actual data using kappa (kappa) statistics. Test-retest reliability was performed in 12 patients, and showed strong agreement between the first and second interviews (kappa=0.91). The sensitivity of the questionnaire ranged from 77.8 to 100%, and specificity ranged from 68.8 to 95.0%. Negative predictive values were very high in the general population, from 98.4 to 99.99%. The kappa statistic for agreement between laboratory items was 0.22-0.56, except for rheumatoid factor, antinuclear antibody test, and muscle enzyme level. We have developed a simple and sensitive Korean rheumatic diseases-screening questionnaire for the epidemiologic study of rheumatic diseases in Korea.
PMCID: PMC3055029  PMID: 12692412
21.  The Role of Bone Scintigraphy in the Diagnosis of Rheumatoid Arthritis According to the 2010 ACR/EULAR Classification Criteria 
Journal of Korean Medical Science  2014;29(2):204-209.
We aimed to investigate the role of bone scintigraphy (BS) in the diagnosis of rheumatoid arthritis (RA) as a supplement to the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria. A total of 156 patients who underwent BS with screening laboratory to confirm RA were enrolled. We divided them into two groups according to the presence of arthritis upon the first physical examination, and evaluated the diagnostic validity of BS as an independent (BS only) or assistant diagnostic tool using the 2010 criteria (BS-assisted). Seventy-five patients had active arthritis (Group I), while the remaining 81 patients did not (Group II). Among them, 56 patients in group I and 5 patients in group II were finally classified as RA. In the group I patients who were eligible for application of the 2010 criteria, the sensitivity of the BS only and BS-assisted diagnosis was not superior to that of the 2010 criteria. However, BS-assisted diagnosis showed high positive prediction values in group I patients with 2010 criteria score < 6 and group II patients. Therefore, BS is still helpful to detect RA even after the introduction of the 2010 criteria, especially among patients who do not satisfy the 2010 criteria as well as those who are ineligible for the 2010 criteria due to dubitable arthritis at clinical presentation.
Graphical Abstract
PMCID: PMC3923998  PMID: 24550646
Arthritis, Rheumatoid; 2010 ACR/EULAR Classification Criteria; Bone Scintigraphy
22.  Pain persists in DAS28 rheumatoid arthritis remission but not in ACR/EULAR remission: a longitudinal observational study 
Disease remission has become a feasible goal for most rheumatoid arthritis (RA) patients; however, patient-reported symptoms, such as pain, may persist despite remission. We assessed the prevalence of pain in RA patients in remission according to the Disease Activity Score (DAS28-CRP4) and the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission criteria.
Data were analyzed from RA patients in the Brigham Rheumatoid Arthritis Sequential Study with data at baseline and 1 year. DAS28 remission was defined as DAS28-CRP4 <2.6. The ACR/EULAR remission criteria included (a) one or more swollen joints, (b) one or more tender joints, (c) C-reactive protein ≤1 mg/dl, and (d) patient global assessment score ≤1. Pain severity was measured by using the pain score from the Multi-Dimensional Health Assessment Questionnaire (MDHAQ). The associations between baseline clinical predictors and MDHAQ pain at baseline and 1 year were assessed by using multivariable linear regression.
Among the 865 patients with data at baseline and 1 year, 157 (18.2%) met DAS28-CRP4 remission criteria at both time points. Thirty-seven (4.3%) met the ACR/EULAR remission criteria at baseline and 1 year. The prevalence of clinically significant pain (MDHAQ pain ≥4) at baseline ranged from 11.9% among patients meeting DAS28-CRP4 remission criteria to none among patients meeting ACR/EULAR remission criteria. Patient global assessment, MDHAQ function, MDHAQ fatigue, MDHAQ sleep, and arthritis self-efficacy were significantly associated with MDHAQ pain in cross-sectional (P ≤ 0.0005) and longitudinal analyses (P ≤ 0.03). Low swollen-joint counts were associated with high MDHAQ pain in longitudinal analyses (P = 0.02) but not cross-sectional analyses. Other measures of inflammatory disease activity and joint damage were not significantly associated with MDHAQ pain at baseline or at 1 year.
Clinically significant pain continues among a substantial proportion of patients in DAS28 remission but not among those in ACR/EULAR remission. Among patients in DAS28 remission, patient global assessment, disability, fatigue, sleep problems, and self-efficacy are strongly associated with pain severity at baseline and 1 year, whereas inflammatory disease activity and joint damage are not significantly associated with elevated pain severity at either baseline or 1 year.
PMCID: PMC3218896  PMID: 21651807
23.  Sustained rheumatoid arthritis remission is uncommon in clinical practice 
Remission is an important goal of therapy in rheumatoid arthritis (RA), but data on duration of remission are lacking. Our objective was to describe the duration of remission in RA, assessed by different criteria.
We evaluated patients from the Brigham and Women's Rheumatoid Arthritis Sequential Study (BRASS) not in remission at baseline with at least 2 years of follow-up. Remission was assessed according to the Disease Activity Score 28-C-reactive protein (DAS28-CRP4), Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) scores, and the recently proposed American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) criteria for remission. Analyses were performed by using Kaplan-Meier survival curves.
We identified 871 subjects with ≥2 years of follow-up. Of these subjects, 394 were in remission at one or more time-points and not in remission at baseline, according to at least one of the following criteria: DAS28-CRP < 2.6 (n = 309), DAS28-CRP < 2.3 (n = 275), SDAI (n = 168), CDAI (n = 170), and 2010 ACR/EULAR (n = 158). The median age for the 394 subjects at entrance to BRASS was 56 years; median disease duration was 8 years; 81% were female patients; and 72% were seropositive. Survival analysis performed separately for each remission criterion demonstrated that < 50% of subjects remained in remission 1 year later. Median remission survival time was 1 year. Kaplan-Meier curves of the various remission criteria did not significantly differ (P = 0.29 according to the log-rank test).
This study shows that in clinical practice, a minority of RA patients are in sustained remission.
PMCID: PMC3446437  PMID: 22429277
24.  Responsiveness of the core set, response criteria, and utilities in early rheumatoid arthritis 
Annals of the Rheumatic Diseases  2000;59(12):966-974.
OBJECTIVE—Validation of responsiveness and discriminative power of the World Health Organisation/International League of Associations for Rheumatology (WHO/ILAR) core set, the American College of Rheumatology (ACR), and European League for Rheumatology (EULAR) criteria for improvement/response, and other single and combined measures (indices) in a trial in patients with early rheumatoid arthritis (RA).
METHODS—Ranking of measures by response (standardised response means and effect sizes) and between-group discrimination (unpaired t test and χ2 values) at two time points in the COBRA study. This study included 155 patients with early RA randomly allocated to two treatment groups with distinct levels of expected response: combined treatment, high response; sulfasalazine treatment, moderate response.
RESULTS—At week 16, standardised response means of core set measures ranged between 0.8 and 3.5 for combined treatment and between 0.4 and 1.2 for sulfasalazine treatment (95% confidence interval ±0.25). Performance of patient oriented measures (for example, pain, global assessment) was best when the questions were focused on the disease. The most responsive single measure was the patient's assessment of change in disease activity, at 3.5. Patient utility, a generic health status measure, was moderately (rating scale) to poorly (standard gamble) responsive. Response means of most indices (combined measures) exceeded 2.0, the simple count of core set measures improved by 20% was most responsive at 4.1. Discrimination performance yielded similar but not identical results: best discrimination between treatment groups was achieved by the EULAR response and ACR improvement criteria (at 20% and other percentage levels), the pooled index, and the disease activity score (DAS), but also by the Health Assessment Questionnaire (HAQ) and grip strength.
CONCLUSIONS—Responsiveness and discrimination between levels of response are not identical concepts, and need separate study. The WHO/ILAR core set comprises responsive measures that discriminate well between different levels of response in early RA. However, the performance of patient oriented measures is highly dependent on their format. The excellent performance of indices such as the ACR improvement and EULAR response criteria confirms that they are the preferred primary end point in RA clinical trials.

PMCID: PMC1753042  PMID: 11087700
25.  Response criteria for rheumatoid arthritis in clinical practice: how useful are they? 
Annals of the Rheumatic Diseases  2005;64(8):1186-1189.
Objective: To compare the performance of the American College of Rheumatology (ACR), European League Against Rheumatism (EULAR), and simple disease activity index (SDAI) response criteria for rheumatoid arthritis at the individual level in an observational cohort.
Methods: 184 outpatients were followed using a structured protocol. For each patient, the responses according to ACR 20% and 50%, EULAR moderate and good, and SDAI minor and major responses were calculated. For comparison, improvements in health assessment questionnaire (HAQ) score of 0.22 and 0.5 were calculated. The numbers of individuals fulfilling the criteria at each level were compared, and the numbers fulfilling any two sets of response criteria calculated. The EULAR "moderate" and "good" responses were grouped together as "overall," and SDAI "minor" and "major" were merged into SDAI "overall".
Results: All 94 ACR 20 responders were found in the EULAR and SDAI "overall" response groups, and 118 of 124 SDAI "overall" responders were found in the EULAR "overall" group. In contrast, of 53 ACR 50 responders, only 34 were found in the EULAR "good" or SDAI "major" group. Among the 56 patients in the EULAR "good" response group, only 26 met the SDAI "major" response. Improvement in HAQ score performed similarly to the other response criteria sets at the group levels.
Conclusions: For individual patients, agreement is good at the level of ACR 20 response, when EULAR overall, SDAI overall, or HAQ 0.22 criteria are applied. Agreement between ACR 50, EULAR good, SDAI major, and HAQ 0.5 response is poor. This should be considered when response criteria are used for clinical decisions.
PMCID: PMC1755621  PMID: 15760931

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