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1.  The effect on treatment response of fibromyalgic symptoms in early rheumatoid arthritis patients: results from the ESPOIR cohort 
Rheumatology (Oxford, England)  2015;54(12):2166-2170.
Objective. To evaluate whether patients with RA who belong to the spectrum of fibromyalgic RA (FRA) have an impaired response to treatment measured by traditional activity scores.
Methods. Patients from the ESPOIR cohort were analysed. This prospective cohort included 813 patients with early arthritis not initially receiving DMARDs. Among the 697 patients who met RA classification criteria, we studied two groups, one with and the other without FRA. The following endpoints were compared at 6, 12 and 18 months using a mixed linear regression model: 28-joint DAS (DAS28), Simple Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI) and HAQ. In addition, attainment of low disease activity (LDA; DAS28 <3.2) and remission (DAS28 <2.6, SDAI <3.3, CDAI <2.8) at these time points was analysed.
Results. Patients with FRA (n = 120) had higher DAS28, SDAI, CDAI and HAQ scores than patients with RA and no fibromyalgic characteristics (n = 548). DAS28 and other DASs started out higher in subjects with FRA, and while they improved to a similar extent to in the isolated RA group, they remained consistently higher among FRA patients. Achievement of LDA and remission was significantly less likely in subjects with FRA.
Conclusion. Patients with FRA and RA will have a similar response to treatment according to the decrease in indexes of disease activity, but may miss the target of remission or LDA.
PMCID: PMC4861641  PMID: 26175470
rheumatoid arthritis; therapy; outcome measures; disease activity scores; fibromyalgia; DMARDs; fibromyalgic RA; treat to target; early rheumatoid arthritis
2.  Improving inflammatory arthritis management through tighter monitoring of patients and the use of innovative electronic tools 
RMD Open  2016;2(2):e000302.
Treating to target by monitoring disease activity and adjusting therapy to attain remission or low disease activity has been shown to lead to improved outcomes in chronic rheumatic diseases such as rheumatoid arthritis and spondyloarthritis. Patient-reported outcomes, used in conjunction with clinical measures, add an important perspective of disease activity as perceived by the patient. Several validated PROs are available for inflammatory arthritis, and advances in electronic patient monitoring tools are helping patients with chronic diseases to self-monitor and assess their symptoms and health. Frequent patient monitoring could potentially lead to the early identification of disease flares or adverse events, early intervention for patients who may require treatment adaptation, and possibly reduced appointment frequency for those with stable disease. A literature search was conducted to evaluate the potential role of patient self-monitoring and innovative monitoring of tools in optimising disease control in inflammatory arthritis. Experience from the treatment of congestive heart failure, diabetes and hypertension shows improved outcomes with remote electronic self-monitoring by patients. In inflammatory arthritis, electronic self-monitoring has been shown to be feasible in patients despite manual disability and to be acceptable to older patients. Patients' self-assessment of disease activity using such methods correlates well with disease activity assessed by rheumatologists. This review also describes several remote monitoring tools that are being developed and used in inflammatory arthritis, offering the potential to improve disease management and reduce pressure on specialists.
PMCID: PMC5133416  PMID: 27933206
Rheumatoid Arthritis; Patient perspective; Disease Activity
3.  Certolizumab Pegol Efficacy Across Methotrexate Regimens: A Pre‐Specified Analysis of Two Phase III Trials 
Arthritis Care & Research  2016;68(3):299-307.
Anti–tumor necrosis factor (anti‐TNF) agents are frequently used in combination with methotrexate (MTX) to treat rheumatoid arthritis (RA). We investigated the effect of a background MTX dose, in combination with anti‐TNF certolizumab pegol (CZP), on treatment efficacy and safety in RA patients.
A pre‐specified subgroup analysis comparing 2 MTX dosage categories (<15 mg/week and ≥15 mg/week) was carried out using data pooled from phase III clinical trials, Rheumatoid Arthritis Prevention of Structural Damage 1 (RAPID 1) and RAPID 2, according to treatment group: CZP 200 mg, CZP 400 mg, or placebo, every 2 weeks. Inclusion criteria required MTX dosage ≥10 mg/week. Efficacy end points included week 24 American College of Rheumatology criteria for 20%, 50%, and 70% improvement (ACR20/50/70) responses analyzed by logistic regression, and changes from baseline in the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28‐ESR) and the modified Sharp/van der Heijde score (SHS) were analyzed by analysis of covariance. Incidence rates of treatment‐emergent adverse events (TEAEs) were categorized by baseline MTX dose. Post hoc sensitivity analysis investigated 3 MTX dose categories: ≤10 mg/week, >10 and ≤15 mg/week, and >15 mg/week.
A total of 638, 635, and 325 patients received CZP 200 mg, CZP 400 mg, and placebo, respectively. At week 24, treatment responses in both CZP groups were uninfluenced by baseline MTX dose category, and were superior to the placebo group for all investigated end points: ACR20/50/70, DAS28‐ESR, and SHS. TEAE incidence rates were higher in patients receiving MTX ≥15 mg/week for most TEAE types across treatment groups.
CZP efficacy was not affected by background MTX dose category. It can be hypothesized that to minimize TEAEs, background MTX doses could be tailored to individual patient tolerance without affecting CZP efficacy.
PMCID: PMC5067694  PMID: 26238672
4.  Sustained improvements in MRI outcomes with abatacept following the withdrawal of all treatments in patients with early, progressive rheumatoid arthritis 
Annals of the Rheumatic Diseases  2016;75(8):1501-1505.
To assess structural damage progression with subcutaneous abatacept (ABA) in the Assessing Very Early Rheumatoid arthritis Treatment (AVERT) trial following abrupt withdrawal of all rheumatoid arthritis (RA) medication in patients achieving Disease Activity Score (DAS)-defined remission or low disease activity.
Patients with early, active RA were randomised to ABA plus methotrexate (ABA/MTX) 125 mg/week, ABA 125 mg/week or MTX for 12 months. All RA treatments were withdrawn after 12 months in patients with DAS28 (C reactive protein (CRP)) <3.2. Adjusted mean changes from baseline in MRI-based synovitis, osteitis and erosion were calculated for the intention-to-treat population.
351 patients were randomised and treated: ABA/MTX (n=119), ABA (n=116) or MTX (n=116). Synovitis and osteitis improved, and progression of erosion was statistically less with ABA/MTX versus MTX at month 12 (−2.35 vs −0.68, −2.58 vs −0.68, 0.19 vs 1.53, respectively; p<0.01 for each) and month 18 (−1.34 vs −0.49 −2.03 vs 0.34, 0.13 vs 2.0, respectively; p<0.01 for erosion); ABA benefits were numerically intermediate to those for ABA/MTX and MTX.
Structural benefits with ABA/MTX or ABA may be maintained 6 months after withdrawal of all treatments in patients who have achieved remission or low disease activity.
Trial registration number
NCT01142726; Results.
PMCID: PMC4975847  PMID: 26865601
Inflammation; Magnetic ResonaNce Imaging; Reactive arthritis
5.  Performance of matrices developed to identify patients with early rheumatoid arthritis with rapid radiographic progression despite methotrexate therapy: an external validation study based on the ESPOIR cohort data 
RMD Open  2016;2(1):e000245.
Use of prediction matrices of risk or rapid radiographic progression (RRP) for early rheumatoid arthritis (RA) in clinical practice could help to better rationalise the first line of treatment. Before use, they must be validated in populations that have not participated in their construction. The main objective is to use the ESPOIR cohort to validate the performance of 3 matrices (ASPIRE, BEST and SONORA) to predict patients at high risk of RRP at 1 year of disease despite initial treatment with methotrexate (MTX).
We selected from the ESPOIR cohort 370 patients receiving MTX or leflunomide (LEF) for ≥3 months within the first year of follow-up. Patients were assessed clinically every 6 months, and structural damage progression seen on radiography was measured by the van der Heijde-modified Sharp score (vSHS) at 1 year. RRP was defined as an increase in the vSHS≥5 points during the first year.
At 1 year, the mean vSHS score was 1.7±5.0 and 46 patients had RRP. The ASPIRE matrix had only moderate validity in the ESPOIR population, with area under the receiver operating characteristic curve (AUC) <0.7. The AUC for the BEST and SONORA matrices were 0.73 and 0.76. Presence of rheumatoid factor (RF)—or anti-citrullinated protein antibodies (ACPAs) and initial structural damage were always predictive of RRP at 1 year. Disease Activity Score in 28 joints (DAS28) and C reactive protein (ASPIRE threshold) were not associated with RRP.
Matrices to identify patients at risk of RRP tested in the ESPOIR cohort seem to perform moderately. There is no matrix that shows clearly superior performance.
PMCID: PMC4879338  PMID: 27252898
Rheumatoid Arthritis; Treatment; Early Rheumatoid Arthritis; Epidemiology
6.  Prediction of remission and low disease activity in disease-modifying anti-rheumatic drug-refractory patients with rheumatoid arthritis treated with golimumab 
Rheumatology (Oxford, England)  2016;55(8):1466-1476.
Objective. To create a tool to predict probability of remission and low disease activity (LDA) in patients with RA being considered for anti-TNF treatment in clinical practice.
Methods. We analysed data from GO-MORE, an open-label, multinational, prospective study in biologic-naïve patients with active RA (DAS28-ESR ⩾3.2) despite DMARD therapy. Patients received 50 mg s.c. golimumab (GLM) once monthly for 6 months. In secondary analyses, regression models were used to determine the best set of baseline factors to predict remission (DAS28-ESR <2.6) at month 6 and LDA (DAS28-ESR ⩽3.2) at month 1.
Results. In 3280 efficacy-evaluable patients, of 12 factors included in initial regression models predicting remission or LDA, six were retained in final multivariable models. Greater likelihood of LDA and remission was associated with being male; younger age; lower HAQ, ESR (or CRP) and tender joint count (or swollen joint count) scores; and absence of comorbidities. In models predicting 1-, 3- and 6-month LDA or remission, area under the receiver operating curve was 0.648–0.809 (R2 = 0.0397–0.1078). The models also predicted 6-month HAQ and EuroQoL-5-dimension scores. A series of matrices were developed to easily show predicted rates of remission and LDA.
Conclusion. A matrix tool was developed to show predicted GLM treatment outcomes in patients with RA, based on a combination of six baseline characteristics. The tool could help provide practical guidance in selection of candidates for anti-TNF therapy.
PMCID: PMC4957672  PMID: 27114562
rheumatoid arthritis; predictors of response; remission; tumour necrosis factor; biologic
7.  Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force 
Reaching the therapeutic target of remission or low-disease activity has improved outcomes in patients with rheumatoid arthritis (RA) significantly. The treat-to-target recommendations, formulated in 2010, have provided a basis for implementation of a strategic approach towards this therapeutic goal in routine clinical practice, but these recommendations need to be re-evaluated for appropriateness and practicability in the light of new insights.
To update the 2010 treat-to-target recommendations based on systematic literature reviews (SLR) and expert opinion.
A task force of rheumatologists, patients and a nurse specialist assessed the SLR results and evaluated the individual items of the 2010 recommendations accordingly, reformulating many of the items. These were subsequently discussed, amended and voted upon by >40 experts, including 5 patients, from various regions of the world. Levels of evidence, strengths of recommendations and levels of agreement were derived.
The update resulted in 4 overarching principles and 10 recommendations. The previous recommendations were partly adapted and their order changed as deemed appropriate in terms of importance in the view of the experts. The SLR had now provided also data for the effectiveness of targeting low-disease activity or remission in established rather than only early disease. The role of comorbidities, including their potential to preclude treatment intensification, was highlighted more strongly than before. The treatment aim was again defined as remission with low-disease activity being an alternative goal especially in patients with long-standing disease. Regular follow-up (every 1–3 months during active disease) with according therapeutic adaptations to reach the desired state was recommended. Follow-up examinations ought to employ composite measures of disease activity that include joint counts. Additional items provide further details for particular aspects of the disease, especially comorbidity and shared decision-making with the patient. Levels of evidence had increased for many items compared with the 2010 recommendations, and levels of agreement were very high for most of the individual recommendations (≥9/10).
The 4 overarching principles and 10 recommendations are based on stronger evidence than before and are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA.
PMCID: PMC4717393  PMID: 25969430
Rheumatoid Arthritis; Outcomes research; Treatment; Early Rheumatoid Arthritis; Disease Activity
8.  Diagnostic value of ultrasound in calcium pyrophosphate deposition disease: a systematic review and meta-analysis 
RMD Open  2015;1(1):e000118.
A systematic review and meta-analysis of data from cohort studies to analyse the diagnostic performances (ie, sensitivity and specificity) of ultrasound (US) for diagnosis of calcium pyrophosphate deposition (CPPD) disease with microscopic crystal detection used as a gold standard.
We performed a systematic review of articles published up to December 2014 using EMBASE, MEDLINE and Cochrane databases and abstracts from the past two EULAR and ACR annual meetings. Only studies reporting the performance of US for diagnosis of CPPD disease were selected. A meta-analysis involved the inverse variance method to evaluate global sensitivity and specificity of US. Statistical heterogeneity was assessed by the Cochran Q-test and I2 values.
The search resulted in 85 articles and 11 abstracts; 17 and 4, respectively, were selected for the systematic review. A total of 262 patients with CPPD disease and 335 controls from 4 original articles and 4 abstracts were included in the meta-analysis. The US diagnostic patterns most frequently recorded were thin hyperechoic bands in the hyaline cartilage (8 articles); hyperechoic spots in fibrous cartilage or in tendons (7 articles); and homogeneous hyperechoic nodules localised in bursa or articular recesses (4 articles). The meta-analysis revealed a heterogeneity of the data, with a sensitivity of 87.9% (95% CI 80.9% to 94.9%) and specificity of 91.5% (95% CI 85.5% to 97.5%) using a random model.
This meta-analysis confirmed that US has high sensitivity and specificity for the diagnosis of CPPD and may be a promising tool for the diagnosis and management of CPPD.
PMCID: PMC4623362  PMID: 26535143
Ultrasonography; Chondrocalcinosis; Synovial fluid
9.  Cardiovascular and selected comorbidities in early arthritis and early spondyloarthritis, a comparative study: results from the ESPOIR and DESIR cohorts 
RMD Open  2015;1(1):e000128.
To investigate the prevalence of comorbidities in early rheumatoid arthritis (ERA) and early axial spondyloarthritis (ESpA) versus the general population.
Baseline data of 689 patients with ERA from the Etude et Suivi des Polyarthrites Indifférenciées Récentes (ESPOIR) cohort (age 48.2±12.1 years, symptoms duration 14.2±14.5 weeks) and 645 patients with ESpA from Devenir des Spondylarthropathies Indifférenciées Récentes (DESIR; age 32.8±8.4 years, axial symptoms duration 79.0±45.7 weeks) were analysed. Metabolic and cardiovascular diseases (CVD), infections and neoplasia were determined in each cohort. The prevalence (95% CI) of several comorbidities was compared with that in the French general population. For patients without CVD, the 10-year risk of developing CVD was calculated using the Framingham and SCORE equations. The heart age was calculated using the 2008 Framingham points system.
42% of patients with ERA and 20.3% of patients with ESpA had at least 1 comorbidity; the most common were arterial hypertension (AHT) and dyslipidaemia. AHT prevalence (95% CI) in ERA (18.2% (15.5% to 21.3%)), but not in ESpA (5.08% (3.57% to 7.14%)), was significantly increased (p<0.05) compared with the general population (7.58%). Prevalence of tuberculosis history was higher in ERA (4.7% (3.3% to 6.6%)), and ESpA (0.99% (0.4% to 2.3%)) than in the general population (0.02%; both p<0.05). No differences were observed in malignancies, coronary heart disease or diabetes. In ERA, among patients without a history of CVD, an intermediate to high CVD risk was found. The heart age exceeded the real age by 4.1±9.6 years in ERA and by 2.1±7.0 years in ESpA (p<0.001).
We found an increased prevalence of AHT and tuberculosis history in ERA and ESpA, and an increased CVD risk. These results should prompt rheumatologists to check these comorbidities early in the disease.
PMCID: PMC4623372  PMID: 26535145
Rheumatoid Factor; Spondyloarthritis; Cardiovascular Disease; Tuberculosis
10.  Efficacy and safety of tabalumab, an anti-BAFF monoclonal antibody, in patients with moderate-to-severe rheumatoid arthritis and inadequate response to TNF inhibitors: results of a randomised, double-blind, placebo-controlled, phase 3 study 
RMD Open  2015;1(1):e000037.
Tabalumab is a human monoclonal antibody that neutralises B-cell activating factor.
To evaluate tabalumab efficacy and safety in patients with rheumatoid arthritis (RA).
This phase 3, randomised, double-blind, placebo-controlled study evaluated 456 patients with active RA after 24-week treatment with subcutaneous tabalumab (120 mg every 4 weeks (120/Q4W) or 90 mg every 2 weeks (90/Q2W)) versus placebo, with loading doses (240 or 180 mg) at week 0. Patients were allowed background disease-modifying antirheumatic drugs and previously discontinued ≥1 tumour necrosis factor α inhibitors for lack of efficacy/intolerance. Primary end point was American College of Rheumatology 20% (ACR20) response at 24 weeks. This study was terminated early due to futility.
Most patients had moderate-to-high baseline disease activity. There was no significant difference in week 24 ACR20 responses between 120/Q4W, 90/Q2W, and placebo (17.6%, 24.3%, 20%) per non-responder imputation analysis. Mean percent changes in CD20+ B-cell count (−10.8%, −9.6%, +10.9%) demonstrated expected pharmacodynamic effects. Treatment-emergent adverse events (AEs) were similar (59.5%, 51.7%, 52.6%), as were AE discontinuations (2.6%, 2.7%, 2.6%), serious AEs (4.6%, 4.1%, 3.9%), serious infectious events (1.3%, 0, 0) and events of interest: infections (23.5%, 25.9%, 24%), injection site reactions (13.1%, 25.8%, 11%) and allergy/hypersensitivity (3.9%, 4.1%, 3.9%) reports. Incidence of treatment-emergent antidrug antibodies was similar to placebo (3.9%, 4.8%, 3.9%). No deaths or new/unexpected safety findings were reported.
Tabalumab did not demonstrate clinical efficacy in patients with RA in this phase 3 study, despite evidence of biological activity. There were no notable differences in safety parameters between tabalumab treatment groups and placebo.
Trial registration number:
PMCID: PMC4623366  PMID: 26535134
Autoimmunity; B cells; Rheumatoid Arthritis
11.  Osteoprotegerin and tumor necrosis factor-related apoptosis-inducing ligand as prognostic factors in rheumatoid arthritis: results from the ESPOIR cohort 
We previously reported that low ratio of osteoprotegerin (OPG) to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was associated with Disease Activity Score in 28 joints (DAS28) remission at 6 months in patients with early rheumatoid arthritis (RA). Here, we aimed to evaluate the value of baseline OPG/TRAIL ratio in predicting clinical and radiological outcomes in patients with early RA in the ESPOIR cohort.
OPG and TRAIL serum concentrations were assessed in the ESPOIR cohort patients. Patients with definite RA were included in this study. Patients were excluded if they had high erosion score at baseline (>90th percentile) or received biological therapy during the first 2 years of follow-up. Data were analyzed by univariate analysis and multivariate logistic regression to predict 1-year DAS28 remission and 2-year radiographic disease progression.
On univariate analysis of 399 patients, OPG/TRAIL ratio at baseline was significantly lower in patients with than without remission at 1 year (p = 0.015). On multivariate logistic regression including age, gender, body mass index and DAS28, low OPG/TRAIL ratio was independently associated with remission at 1 year (odds ratio 1.68 [95 % confidence interval 1.01–2.79]). On univariate analysis, high OPG/TRAIL ratio at baseline was associated with rapid progression of erosion at 2 years (p = 0.041), and on multivariate logistic regression including age, anti-citrullinated protein antibody positivity and C-reactive protein level, OPG/TRAIL ratio independently predicted rapid progression of erosion at 2 years.
OPG/TRAIL ratio at baseline was an independent predictor of 1-year remission and 2-year rapid progression of erosion for patients with early rheumatoid arthritis. Thus, OPG/TRAIL ratio could be included in matrix prediction scores to predict rapid radiographic progression. Further confirmation in an independent cohort is warranted.
PMCID: PMC4518710  PMID: 26220665
12.  Development of EULAR recommendations for the reporting of clinical trial extension studies in rheumatology 
Annals of the Rheumatic Diseases  2014;74(6):963-969.
Our initiative aimed to produce recommendations on post-randomised controlled trial (RCT) trial extension studies (TES) reporting using European League Against Rheumatism (EULAR) standard operating procedures in order to achieve more meaningful output and standardisation of reports.
We formed a task force of 22 participants comprising RCT experts, clinical epidemiologists and patient representatives. A two-stage Delphi survey was conducted to discuss the domains of evaluation of a TES and definitions. A ‘0–10’ agreement scale assessed each domain and definition. The resulting set of recommendations was further refined and a final vote taken for task force acceptance.
Seven key domains and individual components were evaluated and led to agreed recommendations including definition of a TES (100% agreement), minimal data necessary (100% agreement), method of data analysis (agreement mean (SD) scores ranging between 7.9 (0.84) and 9.0 (2.16)) and reporting of results as well as ethical issues. Key recommendations included reporting of absolute numbers at each stage from the RCT to TES with reasons given for drop-out at each stage, and inclusion of a flowchart detailing change in numbers at each stage and focus (mean (SD) agreement 9.9 (0.36)). A final vote accepted the set of recommendations.
This EULAR task force provides recommendations for implementation in future TES to ensure a standardised approach to reporting. Use of this document should provide the rheumatology community with a more accurate and meaningful output from future TES, enabling better understanding and more confident application in clinical practice towards improving patient outcomes.
PMCID: PMC4431343  PMID: 24827533
Rheumatoid Arthritis; DMARDs (biologic); Epidemiology
13.  Evaluation of the nonsteroidal anti-inflammatory drug-sparing effect of etanercept in axial spondyloarthritis: results of the multicenter, randomized, double-blind, placebo-controlled SPARSE study 
In clinical practice, nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly discontinued after response to biologic therapy is achieved in patients with axial spondyloarthritis (axSpA), but the impact of NSAID discontinuation has not been assessed in prospective controlled trials. The aim of the SPARSE study was to evaluate the effects of the anti-tumor necrosis factor agent etanercept on NSAID intake and conventional clinical outcomes in axSpA patients.
In the double-blind, placebo-controlled period, patients with active (mini Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4) axSpA despite optimal NSAID intake were randomized to receive etanercept 50 mg or placebo once weekly for 8 weeks. All patients were advised to taper/discontinue their NSAID intake during the treatment period. NSAID intake was self-reported by diary and Assessment of SpondyloArthritis International Society (ASAS)-NSAID scores calculated based on ASAS recommendations. The primary endpoint was change from baseline to week 8 in ASAS-NSAID score (analysis of covariance).
In 90 randomized patients at baseline, mean age (standard deviation) was 38.9 (11.8) years; disease duration, 5.7 (8.1) years; 59/90 (66%) were human leukocyte antigen-B27 positive; 51/90 (57%) had radiographic sacroiliitis; and 45/90 (50%) were magnetic resonance imaging sacroiliitis-positive. Mean ASAS-NSAID scores were similar between etanercept and placebo groups at baseline (98.2 (39.0) versus 93.0 (23.4)), as were BASDAI (6.0 (1.7) versus 5.9 (1.5)), and Bath Ankylosing Spondylitis Functional Index (5.2 (2.1) versus 5.1 (2.2)). Mean changes (SE) in ASAS-NSAID score from baseline to week 8 were –63.9 (6.1) and –36.6 (5.9) in the etanercept and placebo groups (between-group difference, –27.3; P = 0.002). Significantly higher proportions of patients receiving etanercept versus placebo had an ASAS-NSAID score <10 (46% versus 17%; P = 0.008) and ASAS-NSAID score of 0 (41% versus 14%; P = 0.013) at this time point. Significantly more patients in the etanercept versus placebo group achieved BASDAI50 (39% versus 18%; P = 0.032) and ASAS40 (44% versus 21%; P = 0.028) at week 8.
In patients with axSpA, etanercept was associated with clinically relevant NSAID-sparing effects in addition to significant improvements in conventional clinical outcomes.
Trial registration NCT01298531. Registered 16 February 2011.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-014-0481-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4282738  PMID: 25428762
14.  High levels of memory B cells are associated with response to a first tumor necrosis factor inhibitor in patients with rheumatoid arthritis in a longitudinal prospective study 
Tumor necrosis factor inhibitor (TNFi) therapy is effective for rheumatoid arthritis (RA). Some researchers have suggested that TNFi therapy affects B-cell homeostasis. We studied the effect of TNFi therapy on the distribution of peripheral B-cell subsets to elucidate B-cell–related biomarkers to predict the TNFi response.
Peripheral B cells were analyzed for expression of CD19, CD27, CD38 and immunoglobulin D in 31 healthy donors and 96 RA patients, including 21 patients who were followed 3 months after TNFi initiation.
Treatment with steroids significantly altered the distribution of B-cell subsets. After we adjusted for age, sex and steroid dose, we found that patients with RA had B-cell subset proportions similar to controls. B-cell subset distributions did not differ upon use of TNFi at baseline or before or after TNFi introduction. TNFi responders (according to European League Against Rheumatism criteria) at 3 months had significantly higher proportions of CD27+ memory B cells at baseline, and ≥26% CD27+ cells at inclusion was associated with a relative risk of 4.9 (1.3 to 18.6) for response to TNFi treatment. CD27+ cells produced three times more TNFα than did TNFi-naïve B cells and were correlated with interferon γ produced from CD4+ cells in patients without TNFi treatment.
In patients with RA, high levels of baseline memory B cells were associated with response to TNFi, which may be related to TNFα-dependent activation of the T helper type 1 cell pathway.
PMCID: PMC4060280  PMID: 24735586
15.  EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update 
Annals of the Rheumatic Diseases  2013;73(3):492-509.
In this article, the 2010 European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs (sDMARDs and bDMARDs, respectively) have been updated. The 2013 update has been developed by an international task force, which based its decisions mostly on evidence from three systematic literature reviews (one each on sDMARDs, including glucocorticoids, bDMARDs and safety aspects of DMARD therapy); treatment strategies were also covered by the searches. The evidence presented was discussed and summarised by the experts in the course of a consensus finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) were determined. Fourteen recommendations were developed (instead of 15 in 2010). Some of the 2010 recommendations were deleted, and others were amended or split. The recommendations cover general aspects, such as attainment of remission or low disease activity using a treat-to-target approach, and the need for shared decision-making between rheumatologists and patients. The more specific items relate to starting DMARD therapy using a conventional sDMARD (csDMARD) strategy in combination with glucocorticoids, followed by the addition of a bDMARD or another csDMARD strategy (after stratification by presence or absence of adverse risk factors) if the treatment target is not reached within 6 months (or improvement not seen at 3 months). Tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, biosimilars), abatacept, tocilizumab and, under certain circumstances, rituximab are essentially considered to have similar efficacy and safety. If the first bDMARD strategy fails, any other bDMARD may be used. The recommendations also address tofacitinib as a targeted sDMARD (tsDMARD), which is recommended, where licensed, after use of at least one bDMARD. Biosimilars are also addressed. These recommendations are intended to inform rheumatologists, patients, national rheumatology societies and other stakeholders about EULAR's most recent consensus on the management of RA with sDMARDs, glucocorticoids and bDMARDs. They are based on evidence and expert opinion and intended to improve outcome in patients with RA.
PMCID: PMC3933074  PMID: 24161836
Rheumatoid Arthritis; DMARDs (synthetic); DMARDs (biologic); Treatment; Early Rheumatoid Arthritis
16.  GUEPARD treat-to-target strategy is significantly more efficacious than ESPOIR routine care in early rheumatoid arthritis according to patient-reported outcomes and physician global estimate 
Rheumatology (Oxford, England)  2013;52(10):1890-1897.
Objective. To analyse seven RA Core Data Set measures and three indices for their capacity to distinguish treatment results in early RA in the GUEPARD treat-to-target clinical trial vs ESPOIR routine care.
Methods. Post hoc analyses compared 65 GUEPARD and 130 matched control ESPOIR patients over 6 and 12 months for mean changes in measures, relative efficiencies and standardized response means (SRM). Three indices—28-joint disease activity score (DAS28), clinical disease activity index (CDAI) and routine assessment of patient index data (RAPID3)—were compared for mean changes and numbers of patients with high, moderate or low activity or remission using κ values.
Results. Greater improvement was seen for GUEPARD vs ESPOIR, statistically significant for physician and patient global estimates and pain and health assessment questionnaire physical function (HAQ-FN), but not joint counts and laboratory tests. Relative efficiencies with tender joint count as the referent measure indicated that pain (2.57) and global estimates by patient (3.13) and physician (2.31) were most efficient in distinguishing GUEPARD from ESPOIR. Mean improvements in GUEPARD vs ESPOIR were −3.4 vs −2.6 for DAS28 (0–10) (24%), −29.8 vs −23.1 for CDAI (0–76) (23%) and −13.0 vs −7.8 for RAPID3 (0–30) (40%) (all P < 0.01); agreement was moderate between CDAI vs DAS28 (κ = 0.56) and vs RAPID3 (κ = 0.48), and fair between DAS28 vs RAPID3 (κ = 0.26).
Conclusion. Patient and global measures indicate greater efficacy than joint counts or laboratory measures in detecting difference between GUEPARD treat-to-target and ESPOIR routine care. A RAPID3 of only patient measures may help guide treat-to-target in busy clinical settings.
PMCID: PMC3775294  PMID: 23864169
treat-to-target; patient-reported outcomes; assessment; rheumatoid arthritis; patient questionnaires
17.  Matrix to predict rapid radiographic progression of early rheumatoid arthritis patients from the community treated with methotrexate or leflunomide: results from the ESPOIR cohort 
Arthritis Research & Therapy  2012;14(6):R249.
Early rheumatoid arthritis (RA) patients may show rapid radiographic progression (RRP) despite rapid initiation of synthetic disease-modifying anti-rheumatic drugs (DMARDs). The present study aimed to develop a matrix to predict risk of RRP despite early DMARD initiation in real life settings.
The ESPOIR cohort included 813 patients from the community with early arthritis for < 6 months; 370 patients had early RA and had received methotrexate or leflunomide during the first year of follow-up. RRP was defined as an increase in the van der Heijde-modified Sharp score (vSHS) ≥ 5 points at 1 year. Determinants of RRP were examined first by bivariate analysis, then multivariate stepwise logistic regression analysis. A visual matrix model was then developed to predict RRP in terms of patient baseline characteristics.
We analyzed data for 370 patients. The mean Disease Activity Score in 28 joints was 5.4 ± 1.2, 18.1% of patients had typical RA erosion on radiographs and 86.4% satisfied the 2010 criteria of the American College of Rheumatology/European League Against Rheumatism. During the first year, mean change in vSHS was 1.6 ± 5.5, and 41 patients (11.1%) showed RRP. A multivariate logistic regression model enabled the development of a matrix predicting RRP in terms of baseline swollen joint count, C-reactive protein level, anti-citrullinated peptide antibodies status, and erosions seen on radiography for patients with early RA who received DMARDs.
The ESPOIR matrix may be a useful clinical practice tool to identify patients with early RA at high risk of RRP despite early DMARD initiation.
PMCID: PMC3674616  PMID: 23164197
18.  Rheumatoid arthritis and sexuality: A patient survey in France 
The objective of this study was to evaluate the impact of rheumatoid arthritis (RA) on patients’ sexuality and identify disease and other factors such as fatigue that most influence sexual relationships.
A specific pretested questionnaire was sent to all members of a French patient association (ANDAR). Questions related to demographics, disease status, quality of life (utility, EQ-5D), pain, psychological status (mood), fatigue and emotional and sexual relationships. To isolate the impact of RA, an attempt was made to include a matched sample from the general population.
The analysis included 1271 patients, but only 70 controls agreed to participate and comparisons should therefore be considered with caution. The two groups were similar in terms of age, gender distribution, living conditions and diseases other than RA. However, patients scored worse for global health, mood, fatigue, had a lower utility (0.55 versus 0.65). Controls were more active sexually (69% versus 63%), in particular women (71% versus 60%). Age, gender, living alone, physical function and mood were significant predictors for being sexually active for patients; for controls, age and overall quality of life (utility) were significant predictors.
While it is known that RA has a negative impact on patients’ sexuality, there have been few attempts to quantify the problem. Our study highlights the negative impact of RA on patients’ sexuality, and triggers the question how to include this aspect into care.
PMCID: PMC3493389  PMID: 22963081
Rheumatoid arthritis; Fatigue; Quality of life; Sexuality
19.  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
20.  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
21.  Lymphotoxin α revisited: general features and implications in rheumatoid arthritis 
Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting synovial joints. Therapies blocking tumor necrosis factor-alpha (TNFα) are now routinely used in the management of RA. However, a significant number of patients with RA do not respond or develop resistance to anti-TNF therapies, and the participation of other cytokines in RA pathogenesis has been reported as well. Lymphotoxin alpha (LTα) is the closest homolog to TNFα and has been implicated in inflammation and autoimmunity since its original description in 1968. In spite of that, little is known about the role of LTα in RA or the potential of blocking this cytokine as an alternative therapeutic approach. In this review, we aim to summarize the general features of LTα and what is currently known about its participation in RA.
PMCID: PMC3239340  PMID: 21861866
22.  The 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Rheumatoid Arthritis 
Arthritis and rheumatism  2010;62(9):2582-2591.
The American College of Rheumatology and the European League Against Rheumatism have developed new classification criteria for rheumatoid arthritis (RA). The aim of Phase 2 of the development process was to achieve expert consensus on the clinical and laboratory variables that should contribute to the final criteria set.
Twenty-four expert RA clinicians (12 from Europe and 12 from North America) participated in Phase 2. A consensus-based decision analysis approach was used to identify factors (and their relative weights) that influence the probability of “developing RA,” complemented by data from the Phase 1 study. Patient case scenarios were used to identify and reach consensus on factors important in determining the probability of RA development. Decision analytic software was used to derive the relative weights for each of the factors and their categories, using choice-based conjoint analysis.
The expert panel agreed that the new classification criteria should be applied to individuals with undifferentiated inflammatory arthritis in whom at least 1 joint is deemed by an expert assessor to be swollen, indicating definite synovitis. In this clinical setting, they identified 4 additional criteria as being important: number of joints involved and site of involvement, serologic abnormality, acute-phase response, and duration of symptoms in the involved joints. These criteria were consistent with those identified in the Phase 1 data-driven approach.
The consensus-based, decision analysis approach used in Phase 2 complemented the Phase 1 efforts. The 4 criteria and their relative weights form the basis of the final criteria set.
PMCID: PMC3077961  PMID: 20872596
23.  Understanding emerging treatment paradigms in rheumatoid arthritis 
Arthritis Research & Therapy  2011;13(Suppl 1):S3.
Treatment strategies for rheumatoid arthritis (RA) will continue to evolve as new drugs are developed, as new data become available, and as our potential to achieve greater and more consistent outcomes becomes more routine. Many patients will find both symptom relief and modest control of their disease with disease-modifying antirheumatic drugs (DMARDs), yet this course of therapy is clearly not effective in all patients. In fact, despite strong evidence that intensive treatment in the early stages of RA can slow or stop disease progression and may prevent disability, many patients continue to be managed in a stepwise manner and are treated with an ongoing monotherapy regimen with DMARDs. There is now a large body of evidence demonstrating the success of treating RA patients with anti-TNF therapy, usually in combination with methotrexate. As a result of the increased use of anti-TNF therapy, treatment paradigms have changed – and our practice is beginning to reflect this change. In the present review, we summarize the salient points of several recently proposed and emerging treatment paradigms with an emphasis on how these strategies may impact future practice.
PMCID: PMC3123964  PMID: 21624182
24.  EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs 
Annals of the Rheumatic Diseases  2010;69(6):964-975.
Treatment of rheumatoid arthritis (RA) may differ among rheumatologists and currently, clear and consensual international recommendations on RA treatment are not available. In this paper recommendations for the treatment of RA with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects, are described. The recommendations are based on evidence from five systematic literature reviews (SLRs) performed for synthetic DMARDs, biological DMARDs, GCs, treatment strategies and economic issues. The SLR-derived evidence was discussed and summarised as an expert opinion in the course of a Delphi-like process. Levels of evidence, strength of recommendations and levels of agreement were derived. Fifteen recommendations were developed covering an area from general aspects such as remission/low disease activity as treatment aim via the preference for methotrexate monotherapy with or without GCs vis-à-vis combination of synthetic DMARDs to the use of biological agents mainly in patients for whom synthetic DMARDs and tumour necrosis factor inhibitors had failed. Cost effectiveness of the treatments was additionally examined. These recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA, based on evidence and expert opinion.
PMCID: PMC2935329  PMID: 20444750
25.  Evidence for treating rheumatoid arthritis to target: results of a systematic literature search 
Annals of the Rheumatic Diseases  2010;69(4):638-643.
To summarise existing evidence on a target oriented approach for rheumatoid arthritis (RA) treatment.
We conducted a systematic literature search including all clinical trials testing clinical, functional, or structural values of a targeted treatment approach. Our search covered Medline, Embase and Cochrane databases until December 2008 and also conference abstracts (2007, 2008).
The primary search yielded 5881 citations; after the selection process, 76 papers underwent detailed review. Of these, only seven strategic clinical trials were extracted: four studies randomised patients to routine or targeted treatment, two compared two different randomised targets and one compared targeted treatment to a historical control group. Five trials dealt with early RA patients. All identified studies showed significantly better clinical outcomes of targeted approaches than routine approaches. Disability was reported in two studies with no difference between groups. Four studies compared radiographic outcomes, two showing significant benefit of the targeted approach.
Only few studies employed randomised controlled settings to test the value of treatment to a specific target. However, they provided unanimous evidence for benefits of targeted approaches. Nevertheless, more data on radiographic and functional outcomes and on patients with established RA are needed.
PMCID: PMC3015093  PMID: 20237123

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