A. K. Brown

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 patients 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.

An explanation for the apparent dissociation between clinical remission and continued structural deterioration in rheumatoid arthritis

OBJECTIVE Achieving remission is the aim of treatment in rheumatoid arthritis (RA). This should represent minimal arthritis activity and ensure optimal disease outcome. However, we have previously demonstrated a high prevalence of imaging-detected synovial inflammation in RA patients who were in clinical remission. The purpose of this study was to evaluate the long-term significance of subclinical synovitis and its relationship to structural outcome. METHODS We studied 102 RA patients receiving conventional treatment who had been judged by their consultant rheumatologist to be in remission, as well as 17 normal control subjects. Subjects underwent clinical, laboratory, functional, and quality of life assessments over 12 months. In addition to standard radiography of the hands and feet, imaging of the hands and wrists was performed with musculoskeletal ultrasonography (US) and conventional 1.5 T magnetic resonance imaging (MRI) at baseline and 12 months, using validated acquisition and scoring techniques. RESULTS Despite their being in clinical remission, 19% of the patients displayed deterioration in radiographic joint damage over the study period. Scores on musculoskeletal US synovial hypertrophy, power Doppler (PD), and MRI synovitis assessments in individual joints at baseline were significantly associated with progressive radiographic damage (P=0.032, P<0.001, and P=0.002, respectively). Furthermore, there was a significant association between the musculoskeletal US PD score at baseline and structural progression over 12 months in totally asymptomatic metacarpophalangeal joints (P=0.004) and 12 times higher odds of deterioration in joints with increased PD signal (odds ratio 12.21, P<0.001). CONCLUSION Subclinical joint inflammation detected by imaging techniques explains the structural deterioration in RA patients in clinical remission who are receiving conventional therapy. Our findings reinforce the utility of imaging for the accurate evaluation of disease status and the prediction of structural outcome.

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 patients 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.

Should imaging be a component of rheumatoid arthritis remission criteria? A comparison between traditional and modified composite remission scores and imaging assessments

Objectives Patients can fulfil clinical criteria for remission, yet still have evidence of synovitis detectable clinically and by ultrasound, and this is associated with structural damage. Stricter remission criteria may more accurately reflect true remission (no synovitis). This hypothesis was examined by studying patients using more stringent thresholds for clinical remission and determining their levels of ultrasound synovitis. Methods Rheumatoid arthritis patients with a disease activity score in 28 joints (DAS28) ≤2.6 for at least 6 months were classified using standard and more stringent DAS28 and simplified disease activity index (SDAI) remission thresholds and the corresponding clinical and ultrasound imaging measures of synovitis recorded. Results 128 patients (all DAS28 <2.6, median DAS28 1.70) receiving either disease-modifying antirheumatic drugs alone (n=66) or with a tumour necrosis factor blocker (n=62) were recruited. Of the 640 imaged joints, 5% had moderate or severe power Doppler (PD) activity, 8% were clinically swollen and 1% tender. In patients fulfilling DAS28, American College of Rheumatology or SDAI remission criteria, moderate or severe PD activity was present in 21%, 15% and 19%, respectively. More stringent DAS28 and SDAI criteria reduced the mean number of swollen and tender joints (p<0.001) but not the percentage of patients with PD activity: 32 patients had a DAS28 <1.17 but eight (25%) had significant PD activity. Conclusion Using more stringent remission criteria resulted in reduced signs and symptoms of inflammation, but the percentage of joints with PD activity was not reduced, even in those without signs or symptoms. These data suggest that clinical criteria are sufficiently insensitive to detect low but clinically relevant levels of inflammation accurately.

Disease remission state in patients treated with the combination of tumor necrosis factor blockade and methotrexate or with disease-modifying antirheumatic drugs: A clinical and imaging comparative study.

OBJECTIVE For patients with rheumatoid arthritis (RA) in remission who are receiving disease-modifying antirheumatic drugs (DMARDs), radiographic progression correlates with imaging-detected synovitis as measured by power Doppler activity. In contrast, patients with disease in remission who are receiving the combination of tumor necrosis factor (TNF) blockade with methotrexate (MTX) (combination treatment) have reduced radiographic damage for the equivalent clinical state. We undertook this study to determine whether the difference in radiographic outcome is a result of more complete suppression of imaging-detected synovitis. METHODS One hundred patients with RA in remission (Disease Activity Score in 28 joints [DAS28] <2.6) for at least 6 months while receiving either combination treatment (n = 50) or DMARDs (n = 50) were matched for clinical variables. Ultrasound of metacarpophalangeal joints 1-5 and the wrist joints was performed. Remission according to imaging results was defined as a score of 0 for both grey scale synovitis and power Doppler activity. RESULTS In patients receiving combination treatment or DMARDs (median DAS28 1.65 versus 1.78, median disease duration 120 months versus 90 months, and median duration of remission 13 months versus 18 months), the proportion with remission according to imaging results was not significantly different (10% versus 16%, respectively). The combination treatment group had more grey scale synovitis (P < 0.001) but similar power Doppler activity (48% versus 60%, respectively; P = 0.229) in any joint as compared with the DMARD group. Results were not affected by stratification for duration of disease or remission. CONCLUSION In RA patients with disease in remission, imaging-detected synovitis persists, with power Doppler activity seen in >or=48% of the patients regardless of therapy. These results suggest that superior radiographic outcomes in patients treated with the combination of TNF blockade and MTX may not be due to complete suppression of imaging-detected synovitis.

Contemporary treatment principles for early rheumatoid arthritis: a consensus statement

OBJECTIVE RA has a substantial impact on both patients and healthcare systems. Our objective is to advance the understanding of modern management principles in light of recent evidence concerning the conditions diagnosis and treatment. METHODS A group of practicing UK rheumatologists formulated contemporary management principles and clinical practice recommendations concerning both diagnosis and treatment. Areas of clinical uncertainty were documented, leading to research recommendations. RESULTS A fundamental concept governing treatment of RA is minimization of cumulative inflammation, referred to as the inflammation-time area under the curve (AUC). To achieve this, four core principles of management were identified: (i) detect and refer patients early, even if the diagnosis is uncertain: patients should be referred at the first suspicion of persistent inflammatory polyarthritis and rheumatology departments should provide rapid access to a diagnostic and prognostic service; (ii) treat RA immediately: optimizing outcomes with conventional DMARDs and biologics requires that effective treatment be started early-ideally within 3 months of symptom onset; (iii) tight control of inflammation in RA improves outcome: frequent assessments and an objective protocol should be used to make treatment changes that maintain low-disease activity/remission at an agreed target; (iv) consider the risk-benefit ratio and tailor treatment to each patient: differing patient, disease and drug characteristics require long-term monitoring of risks and benefits with adaptations of treatments to suit individual circumstances. CONCLUSION These principles focus on effective control of the inflammatory process in RA, but optimal uptake may require changes in service provision to accommodate appropriate care pathways.

Determining a Magnetic Resonance Imaging Inflammatory Activity Acceptable State Without Subsequent Radiographic Progression in Rheumatoid Arthritis: Results from a Followup MRI Study of 254 Patients in Clinical Remission or Low Disease Activity

Objective. To assess the predictive value of magnetic resonance imaging (MRI)-detected subclinical inflammation for subsequent radiographic progression in a longitudinal study of patients with rheumatoid arthritis (RA) in clinical remission or low disease activity (LDA), and to determine cutoffs for an MRI inflammatory activity acceptable state in RA in which radiographic progression rarely occurs. Methods. Patients with RA in clinical remission [28-joint Disease Activity Score-C-reactive protein (DAS28-CRP) < 2.6, n = 185] or LDA state (2.6 ≤ DAS28-CRP < 3.2, n = 69) with longitudinal MRI and radiographic data were included from 5 cohorts (4 international centers). MRI were assessed according to the Outcome Measures in Rheumatology (OMERACT) RA MRI scoring system (RAMRIS). Statistical analyses included an underlying conditional logistic regression model stratified per cohort, with radiographic progression as dependent variable. Results. A total of 254 patients were included in the multivariate analyses. At baseline, synovitis was observed in 95% and osteitis in 49% of patients. Radiographic progression was observed in 60 patients (24%). RAMRIS synovitis was the only independent predictive factor in multivariate analysis. ROC analysis identified a cutoff value for baseline RAMRIS synovitis score of 5 (maximum possible score 21). Rheumatoid factor (RF) status yielded a significant interaction with synovitis (p value = 0.044). RF-positive patients with a RAMRIS synovitis score of > 5 vs ≤ 5, had an OR of 4.4 (95% CI 1.72–11.4) for radiographic progression. Conclusion. High MRI synovitis score predicts radiographic progression in patients in clinical remission/LDA. A cutoff point for determining an MRI inflammatory activity acceptable state based on the RAMRIS synovitis score was established. Incorporating MRI in future remission criteria should be considered.

Long-term efficacy and toxicity of ciclosporin A in combination with methotrexate in poor prognosis rheumatoid arthritis

Whereas the optimum therapy for early rheumatoid arthritis (RA) has not been established, there is still interest in combination therapy with existing disease-modifying antirheumatic drugs, due to the cost and toxicity of biological agents. We previously reported a 24-month open-label, randomised study comparing a methotrexate and ciclosporin A combination with sulfasalazine monotherapy in 82 early, poor-prognosis RA patients (n  =  40 combination, n  =  42 sulfasalazine).1 In the combination arm, first ciclosporin A then methotrexate doses were optimised. After 24 months all patients were treated according to standard clinical care. The aim of this report is to present long-term efficacy and toxicity data. At 12 months there was no difference in …

Extremity magnetic resonance imaging assessment of synovitis (without contrast) in rheumatoid arthritis may be less accurate than power Doppler ultrasound

Although synovitis detection is optimal with contrast-enhanced, high field magnetic resonance imaging (MRI), the increased accessibility of power Doppler ultrasound (PDUS) has meant that it is more frequently utilised in the clinical setting. However, with the advent of low field extremity MRI (eMRI) and its practical advantages,1 there is a need to understand what is the most sensitive tool for routine clinical use. eMRI has been evaluated with respect to its ability to assess rheumatoid arthritis erosions in comparison with both high field MRI and radiography.2–4 There is relatively little published work, however, on eMRI’s ability to assess synovitis in comparison with high field MRI,4–7 and three of these reports used intravenous contrast, which further limits feasibility. Only one group have published …

Utility and feasibility of musculoskeletal ultrasonography (MSK US) in rheumatology practice in Canada: needs assessment

The utility of musculoskeletal ultrasound (MSK US) is being extensively explored and evaluated amongst European rheumatologists. However, utilization of MSK US by rheumatologists in Canada is much less common. This study aimed to evaluate the current use of MSK US in Canadian rheumatology practice, to determine beliefs and attitudes towards MSK US, and to determine factors that may encourage or limit its use. A 13-question needs assessment questionnaire was developed. All Canadian rheumatologists were invited via e-mail to participate in the survey. The overall response rate was 156/470 (33%). Fifty-one percent of participants used MSK US in their clinical practice. Lack of training appeared to be the main obstacle to its current use. Eighty-three percent believed that MSK US should be performed by rheumatologists and expressed a willingness to learn the technique. Skills offering greatest clinical utility were the assessment of inflammatory arthritis in small joints (i.e., hands (metacarpophalyngeal and proximal interphalangeal joints), wrists, feet (metatarsophalyngeal), shoulders, and ankles. Limited available time, equipment costs, and difficulties with billing were the main obstacles to MSK US utilization in the clinical setting. There is a great level of interest in learning and applying MSK US in Canadian rheumatology practice. The balance between added clinical value and lack of remuneration, equipment associated costs, and time to complete training is the major limiting factor influencing rheumatologists’ willingness to take on MSK US. Training programs must be relevant to rheumatologists’ needs before MSK US will be adopted into routine clinical practice in Canada.