Effectiveness and safety of abatacept in elderly patients with rheumatoid arthritis enrolled in the French Society of Rheumatology's ORA registry.

OBJECTIVE: To study the effect of age on the risk-benefit balance of abatacept in RA. METHODS: Data from the French orencia and RA registry, including a 2-year follow-up, were used to compare the effectiveness and safety of abatacept according to age. RESULTS: Among the 1017 patients, 103 were very elderly (⩾75 years), 215 elderly (65-74), 406 intermediate aged (50-64) and 293 very young (<50). At baseline, elderly and very elderly patients had longer disease duration, higher CRP levels and higher disease activity. These age groups showed a lower incidence of previous anti-TNF therapy and less common concomitant use of DMARDs, but a similar use of corticosteroid therapy. After adjusting for disease duration, RF/ACPA positivity, use of DMARDs or corticosteroids and previous anti-TNF treatment, the EULAR response (good or moderate) and the remission rate were not significantly different between the four age groups. At 6 months, the very elderly had a significantly lower likelihood of a good response than the very young (odds ratio = 0.15, 95% CI: 0.03, 0.68). The decrease in DAS28-ESR over the 24-month follow-up period did not differ by age. Increasing age was associated with a higher rate of discontinuation for adverse events, especially severe infections (per 100 patient-years: 1.73 in very young, 4.65 in intermediates, 5.90 in elderly, 10.38 in very elderly; P < 0.001). CONCLUSION: The effectiveness of abatacept is not affected by age, but the increased rate of side effects, especially infections, in the elderly must be taken into account.

Early phase clinical and biological markers associated with subclinical atherosclerosis measured at 7 years of evolution in an early inflammatory arthritis cohort.

OBJECTIVES: Accelerated atherosclerosis has emerged as a critical issue in rheumatoid arthritis (RA). There is a need to better understand the link between RA and atherosclerosis. Our aim was to identify parameters associated with the development of subclinical atheroma in a very early arthritis (VErA) cohort. METHODS: VErA-cohort patients were prospectively recruited from 1998 to 2002. Arthritis treatment was standardised from onset. The clinical, biological and radiological parameters of all patients were collected from inclusion. Carotid intima-media thickness (cIMT) was measured 7 years after their first symptoms. RESULTS: Among 105 patients included, 82 developed RA (mean age at onset: 51.7±12.8 years). Mean carotid artery IMT at year 7 was 0.67±0.12 mm. Larger thickness defined by values above the median (0.66) was associated with inclusion age (p<10-6), swollen joint count (p=0.01), DAS44 (p=0.048) and hypertension (p=0.006). In contrast, anti-CCP positivity (>50 UA/ml) was associated with thinner cIMT (p=0.03). Baseline as well as cumulated values of markers reflecting systemic inflammation, lymphocyte activation, endothelial dysfunction and oxidative stress were not correlated with carotid subclinical atherosclerosis. Major independent atheroma risk factors retained by multivariate analyses were hypertension (OR 4.33 [1.59-11.73]; p=0.004) and swollen joint count at inclusion (OR 3.87 [1.54-9.72]; p=0.004), while methotrexate use was a protective marker (OR 0.27 [0.11-0.71]; p=0.007). CONCLUSIONS: This study conducted from the VErA vascular cohort of community-cases of RA confirm that cIMT is under the influence of classical CV risk (hypertension), disease marker (SJC) and methotrexate intake.

Identification of secreted phosphoprotein 1 gene as a new rheumatoid arthritis susceptibility gene.

OBJECTIVE: To evaluate the contribution of the SPP1 rs11439060 and rs9138 polymorphisms, previously reported as autoimmune risk variants, in the rheumatoid arthritis (RA) genetic background according to anti-citrullinated protein antibodies (ACPAs) status of RA individuals. METHODS: We analysed a total of 11,715 RA cases and 26,493 controls from nine independent cohorts; all individuals were genotyped or had imputed genotypes for SPP1 rs11439060 and rs9138. The effect of the SPP1 rs11439060 and rs9138 risk-allele combination on osteopontin (OPN) expression in macrophages and OPN serum levels was investigated. RESULTS: We provide evidence for a distinct contribution of SPP1 to RA susceptibility according to ACPA status: the combination of ≥3 SPP1 rs11439060 and rs9138 common alleles was associated mainly with ACPA negativity (p=1.29×10(-5), ORACPA-negative 1.257 (1.135 to 1.394)) and less with ACPA positivity (p=0.0148, ORACPA-positive 1.072 (1.014 to 1.134)). The ORs between these subgroups (ie, ACPA-positive and ACPA-negative) significantly differed (p=7.33×10(-3)). Expression quantitative trait locus analysis revealed an association of the SPP1 risk-allele combination with decreased SPP1 expression in peripheral macrophages from 599 individuals. To corroborate these findings, we found an association of the SPP1 risk-allele combination and low serum level of secreted OPN (p=0.0157), as well as serum level of secreted OPN correlated positively with ACPA production (p=0.005; r=0.483). CONCLUSIONS: We demonstrate a significant contribution of the combination of SPP1 rs11439060 and rs9138 frequent alleles to risk of RA, the magnitude of the association being greater in patients negative for ACPAs.

Pharmacokinetics and concentration-effect relationship of adalimumab in rheumatoid arthritis.

AIMS: This study aimed at describing adalimumab pharmacokinetics (PK) and the concentration-effect relationship of adalimumab using pharmacokinetic-pharmacodynamic (PK-PD) modelling in patients with rheumatoid arthritis (RA). METHODS: Adalimumab PK and PK-PD data were obtained from a multicentric observational study. Adalimumab (40 mg) was administered subcutaneously every other week, and its pharmacokinetics was described using a one-compartment model. The relationship between adalimumab concentration and C-reactive protein (CRP) concentration was described using an indirect response model with inhibition of CRP input, whereas the relationship between adalimumab concentration and disease activity score in 28 joints (DAS28) was described using a direct inhibition model. Dose regimens that included a loading dose of adalimumab were simulated. RESULTS: Thirty patients treated for RA were analysed. The following pharmacokinetic and PK-PD parameters were estimated (interidividual coefficient of variation): apparent volume of distribution (Vd /F) = 10.8 l (92%); apparent clearance (CL/F) = 0.32 l day(-1) (17%); first-order absorption rate (ka ) = 0.28 day(-1) ; CRP input (kin ) = 22.0 mg l(-1) day(-1) (65%); adalimumab concentration leading to a 50% decrease in kin (C50 ) = 3.6 mg l(-1) (88%); baseline DAS28 (DAS0 ) = 5.5 mg l(-1) (11%); and adalimumab concentration leading to 50% decrease of DAS0 (IC50 ) = 11.0 mg l(-1) (71%). Simulations showed that a 160 mg loading dose should reduce the time to reach efficacy in terms of both CRP and DAS28 after the first injection. CONCLUSIONS: This is the first study to describe adalimumab pharmacokinetics and the concentration-effect relationship in RA. A 160 mg loading dose may lead to an increased benefit from treatment in RA patients.

Evaluation of low-dose rituximab for the retreatment of patients with active rheumatoid arthritis: a non-inferiority randomised controlled trial.

BACKGROUND: The licensed dose of rituximab in rheumatoid arthritis (RA) is two doses of 1000 mg given 2 weeks apart. A lower dose has never been specifically studied in patients with an inadequate response to anti-tumour necrosis factor (TNF) agents. OBJECTIVE: To compare the efficacy and safety of rituximab repeat treatment with two doses (1000 mg×1 and 1000 mg×2) following initial treatment with 1000 mg×2. METHODS: We set up an open-label, prospective, multicentre, non-inferiority study comprising a non-controlled period (24 weeks) followed by a randomised controlled period (weeks 24-104) in patients with RA and an inadequate response to anti-TNF agents. All patients received one course of rituximab (1000 mg×2) with methotrexate. At week 24, patients achieving a EULAR response (moderate or good) were randomised to rituximab retreatment at 1000 mg×1 (Arm A) or 1000 mg×2 (Arm B). The primary objective measure was disease activity in 28 joints C-reactive protein (DAS28-CRP) area under the curve (AUC) over 104 weeks with a non-inferiority margin defined by 20% (444) of the mean DAS28-CRP AUC (mean±SD 2218±967) of the reference data. RESULTS: The intent-to-treat and per-protocol (PP) populations comprised 143 (A/B: 70/73) and 100 (A/B: 51/49) patients, respectively. The adjusted mean difference in DAS28-CRP AUC (PP) was 51.4 (95% CI -131.2 to 234), demonstrating non-inferiority between arms A and B. The overall rituximab safety profile was similar with both retreatment regimens. CONCLUSIONS: Following a clinical response to a first course of rituximab in RA at the licensed dose of 1000 mg×2, retreatment with rituximab at 1000 mg×1 results in efficacy outcomes that are non-inferior to those achieved with retreatment at 1000 mg×2. CLINICALTRIALSGOV REGISTRATION NUMBER: NCT01126541.

Influence of gender on response to rituximab in patients with rheumatoid arthritis: results from the Autoimmunity and Rituximab registry.

OBJECTIVE: The response rate to many therapies for RA is lower in women. The aim of this study was to analyse the influence of gender on the response to rituximab (RTX) in patients with RA. METHODS: A total of 1709 RA patients were included in the French Autoimmunity and Rituximab (AIR) registry. Disease activity assessed by the 28-joint DAS (DAS28) was recorded at baseline and at follow-up (6, 12, 18 and 24 months). Response criteria [European League Against Rheumatism (EULAR) remission defined as a DAS28 < 2.6 and EULAR response] were compared in both sexes. RESULTS: Seventy-seven per cent of the patients were female (age 61.4 years, disease duration 16 years). Approximately 78.6% of the patients were positive for RF and 75.8% for anti-CCP. Women had a longer disease duration (P < 0.001), less frequently had anti-CCP (P = 0.03) and had lower CRP levels at baseline (P < 0.001). Six months after RTX, 11% were in remission and 62% had a good to moderate EULAR response, irrespective of gender (P = 0.81 and P = 0.38, respectively). No differences were observed in terms of remission or EULAR response during the follow-up except at 12 months, when men achieved remission more frequently (18% vs 12%, P = 0.045). In the cases of anti-TNF failure, remission rates were higher in men than in women at 6, 12 and 18 months. Re-treatment delay between the first and second courses was similar in both genders (P = 0.26). CONCLUSION: In this large cohort of RA patients we found no significant differences in EULAR response to RTX between men and women during the 2-years of follow-up, but there was a previous anti-TNF exposure-dependent effect of gender on remission rate.

CCL19, a B cell chemokine, is related to the decrease of blood memory B cells and predicts the clinical response to rituximab in patients with rheumatoid arthritis.

OBJECTIVE: Migration of B cells from peripheral blood to the synovium in patients with rheumatoid arthritis (RA) may predict clinical response to rituximab (RTX). We undertook this study to investigate whether serum levels of chemokines involved in B cell trafficking are correlated with blood levels of memory B cells or serum levels of B cell activation biomarkers before B cell depletion and whether chemokine levels predict RTX responsiveness. METHODS: Blood B cell subsets were analyzed by flow cytometry (CD27, IgD), and serum B cell activation biomarkers (rheumatoid factor, anti-cyclic citrullinated peptide, free light chains, IgG, IgA, IgM, and BAFF) were measured in 208 RA patients and 70 control subjects. Serum CCL19, CXCL12, and CXCL13 chemokine levels in patients and controls were determined by enzyme-linked immunosorbent assay. The first course of RTX was administered to RA patients, and the response was evaluated at week 24 according to European League Against Rheumatism (EULAR) criteria. Results were expressed as the odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: Levels of all chemokines were increased in RA patients compared with controls, and levels were inversely correlated with CD27+ memory B cell frequency. CCL19 and CXCL13 levels correlated with levels of 6 serum B cell biomarkers and 4 serum B cell biomarkers, respectively. By univariate analysis, the CCL19 level was positively associated with EULAR response (OR 1.43 [95% CI 1.08-1.90], P = 0.01). By multivariate analysis, the CCL19 level was predictive of a response to RTX (OR 1.48 [95% CI 1.06-2.06], P = 0.02), but this did not persist after adjustment for autoantibody status. CONCLUSION: CXCL13 and CCL19 reflect blood B cell disturbances and their levels correlate with those of other serum B cell biomarkers. CXCL13 and CCL19 are, therefore, surrogate measures for serum B cell biomarkers in RA. Serum CCL19 measurement is a new hallmark of the B cell-mediated RA subtype and may predict clinical response to RTX.

Progression to rheumatoid arthritis in early inflammatory arthritis is associated with low IL-7 serum levels.

OBJECTIVE: Early diagnosis of rheumatoid arthritis (RA) remains a challenge. Interleukin (IL)-7 is a pleiotropic cytokine that plays a central role in the development and maintenance of T-cells and has been associated with T-cell dysfunction in RA. Serum levels of IL-7 are reduced in both early and established disease. The aim of this study was to determine whether serum IL-7 can identify patients with very early inflammatory joint symptoms who will progress to RA, and to examine whether IL-7 levels predict disease persistence and radiographic progression. METHODS: Patients with inflammatory joint symptoms<6 months followed over 5 years for progression to RA and 80 healthy controls were studied. Baseline IL-7 levels were measured by ELISA. RESULTS: Of 250 patients, 108 developed RA (ACR 1987- criteria). IL-7 at inclusion was reduced significantly in RA compared with non-RA patients (p=0.009). IL-7 was categorised using the lower limit of the healthy control distribution (10 pg/ml). In multivariate analysis, independent predictors of RA development were: antibodies against citrullinated peptides (ACPA) positivity (p=0.001), IL-7<10 pg/ml (p=0.003) and swollen joint count (p=0.050). In the ACPA-negative subgroup (n=199), the only predictors were: DAS-44 (p=0.001), IL-7<10 pg/ml (p=0.010) and radiographic erosions (p=0.050). At 1-year follow-up, remission (DAS<1.6) was only predicted by ACPA negativity (p=0.019) and IL-7>17 pg/ml at recruitment (p=0.013). CONCLUSION: These data demonstrate that low IL-7 levels in patients with recent onset of symptoms may have value as a diagnostic biomarker predicting the progression to RA, particularly in ACPA-negative disease, as well as being related to RA progression.

Association between -871C>T promoter polymorphism in the B-cell activating factor gene and the response to rituximab in rheumatoid arthritis patients.

OBJECTIVE: To determine whether a functional single-nucleotide polymorphism in the B-cell activating factor (BAFF) gene correlates with the response to treatment with rituximab (RTX) in RA. METHODS: SMART is a randomized open trial (NCT01126541) assessing two strategies of re-treatment in patients responding to 1-g infusion of RTX with MTX on days 1 and 15 after failure, intolerance or contraindication to TNF blockers. Among the 224 patients included, 115 provided informed consent, could be genotyped and were included in an ancillary study of SMART assessing European League Against Rheumatism (EULAR) response rate after the first course of RTX according to BAFF-871C>T polymorphism. Baseline clinical factors (patients and disease characteristics) and biologic factors (ESR, CRP, RF, anti-citrullinated peptide antibodies, serum immunoglobulins) were collected. Univariate analyses were performed to assess whether BAFF-871C>T polymorphism was associated with EULAR response at week 24. Results with P < 0.15 obtained in univariate analyses were then included in multivariate analysis adjusted on DAS28 level. RESULTS: Ninety-three patients (81%) were responders, of whom 31 (27%) were good responders. CC genotype was significantly associated with a higher response rate [92% of responders vs 64% for TT genotype, odds ratio (OR) = 6.9; 95% CI 1.6, 29.6; P = 0.03]. These results were also confirmed in RF-positive patients (96% vs 58%, P = 0.006). In multivariate analysis, C allele carriage was independently associated with response to RTX (OR = 4.1; 95% CI 1.3, 12.7; P = 0.017). CONCLUSION: The BAFF-871C>T polymorphism seems to influence the response to RTX in RA patients after failure or intolerance to TNF blockers.

Soluble VE-cadherin in rheumatoid arthritis patients correlates with disease activity: evidence for tumor necrosis factor α-induced VE-cadherin cleavage.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that principally attacks synovial joints. However, accelerated atherosclerosis and increased cardiovascular morbidity and mortality are major clinical consequences of endothelial dysfunction in RA patients. Tumor necrosis factor α (TNFα) is the major mediator of inflammation in RA, related to vascular injury by targeting VE-cadherin, an endothelium-specific adhesion molecule of vital importance for endothelium integrity and angiogenesis. We undertook this study to examine the mechanisms regulating VE-cadherin processing by TNFα and their occurrence in RA. METHODS: Human umbilical vein endothelial cells were used in primary culture and treated with recombinant TNFα to study VE-cadherin cleavage. Cell lysates and conditioned media were analyzed by Western blotting for VE-cadherin cytoplasmic domain and extracellular domain (VE-90) generation, respectively. VE-90 was analyzed at baseline and at the 1-year followup in sera from 63 RA patients (from the Very Early Rheumatoid Arthritis cohort) with disease duration of <6 months. RESULTS: TNFα induced a time-dependent shedding of VE-90 in cell media. This effect was prevented by tyrosine kinase inhibitors (genistein and PP2) or by knocking down Src kinase. In contrast, tyrosine phosphatase blockade enhanced VE-cadherin cleavage, confirming the requirement of tyrosine phosphorylation processes. In addition, using the matrix metalloproteinase (MMP) activator APMA and the MMP inhibitor GM6001, we demonstrated that MMPs are involved in TNFα-induced VE-cadherin cleavage. Of major importance, VE-90 was detected in sera from the 63 RA patients and was positively correlated with the Disease Activity Score at baseline and after 1-year followup. CONCLUSION: These findings provide the first evidence of VE-cadherin proteolysis upon TNFα stimulation and suggest potential clinical relevance of soluble VE-cadherin in management of RA.

A tool to identify recent or present rheumatoid arthritis flare from both patient and physician perspectives: the 'FLARE' instrument.

INTRODUCTION: There is a lack of consensus about the definition of flare of rheumatoid arthritis (RA) and a measurement tool. OBJECTIVES: To develop a self-administered tool integrating the perspectives of the patient and the rheumatologist, enabling the detection of present or recent-past RA flare. METHODS: The patient perspective was explored by semistructured individual interviews of patients with RA. Two health psychologists conducted a content analysis to extract items best describing flare from the interviews. The physician's perspective was explored through a Delphi exercise conducted among a panel of 13 rheumatologists. A comprehensive list of items produced in the first round was reduced in a four-round Delphi process to select items cited by at least 75% of the respondents. The identified elements were assembled in domains-each converted into a statement-to constitute the final self-administered Flare Assessment in Rheumatoid Arthritis (FLARE) questionnaire. RESULTS: The content of 99 patient interviews was analysed, and 10 domains were identified: joint swelling or pain, night pain, fatigue and different emotional consequences, as well as analgesic intake. The Delphi process for physicians identified eight domains related to objective RA symptoms and drug intake, of which only four were common to domains for patients. Finally, 13 domains were retained in the FLARE questionnaire, formulated as 13 statements with a Likert-scale response modality of six answers ranging from 'absolutely true' to 'completely untrue'. CONCLUSION: Two different methods, for patient and physician perspectives, were used to develop the FLARE self-administered questionnaire, which can identify past or present RA flare.

B cell activation biomarkers as predictive factors for the response to rituximab in rheumatoid arthritis: a six-month, national, multicenter, open-label study.

OBJECTIVE: To examine whether serum B cell markers can predict response to rituximab, a B cell-depleting monoclonal antibody, in patients with refractory rheumatoid arthritis (RA). METHODS: This rituximab re-treatment dose study (SMART [eSsai MAbthera sur la dose de Re-Traitement]) involved 208 patients with refractory RA. Serum markers of B cell activation (anti-cyclic citrullinated peptide [anti-CCP] antibodies, rheumatoid factor [RF], serum IgG, IgA, and IgM levels, serum κ and λ free light chains, and serum BAFF) were assessed before the first rituximab cycle (1,000 mg on days 1 and 15). Univariate and multivariate analyses were performed to identify factors associated with a European League Against Rheumatism (EULAR) response at 24 weeks. RESULTS: There were 149 responders (72%). Two baseline factors were associated with a EULAR response at 24 weeks in multivariate analysis: the presence of anti-CCP antibodies or RF (odds ratio 3.5 [95% confidence interval 1.6-7.6]) and a serum IgG concentration above normal (odds ratio 2.11 [95% confidence interval 1.02-4.33]), with synergy between them (odds ratio 6.0 [95% confidence interval 2.2-16.2]). CONCLUSION: The presence of RF or anti-CCP antibodies and elevated IgG are 2 simple biomarkers that can be used routinely before therapy to predict response to rituximab in patients with refractory RA.

Blood memory B cells are disturbed and predict the response to rituximab in patients with rheumatoid arthritis.

OBJECTIVE: To examine blood B cell subsets in patients with rheumatoid arthritis (RA) prior to B cell depletion therapy and to assess their potential as predictors of clinical response to rituximab (RTX). METHODS: Blood B cell subsets were assessed by flow cytometry in 208 RA patients included in an RTX retreatment study (assessed prior to RTX treatment) and in 47 age-matched controls. Expression of BAFF receptor (BAFF-R) on B cells and serum B cell biomarkers was also measured. B cell subsets and BAFF-R expression were compared between RA patient and control populations. Univariate and multivariate analyses were performed to identify baseline factors associated with a European League Against Rheumatism response 24 weeks after 1 cycle of RTX. RESULTS: Mean ± SD counts of both CD27- naive and CD27+ memory B cells were decreased in RA patients (188.6 ± 121.4/mm(3)) compared with controls (257.3 ± 154.1/mm(3)) (P = 0.001) and were partially restored in patients treated with methotrexate (MTX) plus anti-tumor necrosis factor compared with patients treated with MTX alone. Within the CD27+ memory B cells, the CD27+IgD- switched memory subtype was selectively decreased, irrespective of treatment. The frequency of CD27+ memory B cells correlated inversely with levels of several B cell activation biomarkers in RA. Serum BAFF level and BAFF-R expression was comparable in RA patients and controls. A low baseline CD27+ memory B cell frequency was associated with a greater clinical response to RTX (odds ratio 0.97 [95% confidence interval 0.95-0.99], P = 0.0015). CONCLUSION: In B cell depletion therapy-naive RA patients, a low frequency of CD27+ memory B cells correlated with levels of serum B cell activation biomarkers and may predict response to RTX. These results suggest that low memory B cell frequency may be indicative of a B cell-driven RA subtype that is more sensitive to B cell depletion therapy.

[Goals of therapy in rheumatoid arthritis]. / Objectifs thérapeutiques dans la polyarthrite rhumatoïde.

A better definition of goals of therapy has deeply changed the prognosis of rheumatoid arthritis. The main goal is the early control of joint inflammation reaching, if possible, remission in early arthritis and, in later cases, low disease activity. To target such a low activity, a tight control with therapeutic adjustment is necessary. The other goals derive from the control of inflammatory activity: reduction of progression and, if possible, stop of structural damage tightly linked to inflammation; control of functional consequences related mainly to the addition of inflammatory component and structural damage; control of cardio-vascular risk factors responsible of 30-50% of deaths and finally protection of bone.

Comparison of the efficacy of sonography, magnetic resonance imaging and conventional radiography for the detection of bone erosions in rheumatoid arthritis patients: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the reproducibility of US and to compare its efficacy with that of MRI and conventional radiography (CR) for the detection of bone erosion in RA patients. METHODS: A systematic literature search was performed in the Medline, Embase and Cochrane databases up to August 2009. Trials evaluating the reproducibility of US for bone erosion detection or comparing the number of erosions detected by the three imaging methods at patient and/or joint level were included. This last parameter was assessed using the odds ratio (OR) and 95% CI with the Mantel-Haenszel method (OR < 1 favours US). We explored the heterogeneity between the studies by subgroup analysis. RESULTS: Twenty-one studies including 913 patients were included in this meta-analysis. Intraobserver and interobserver reproducibility of US for erosion detection was good. US and MRI efficacies were comparable at both joint (OR = 1.19, P = 0.45; seven studies, 869 joints) and patient (OR = 1.76, P = 0.22; nine studies, 338 patients) levels. US detected significantly more erosion than CR at both joint (OR = 0.30, P < 0.00001; 4047 joints studied) and patient (OR = 0.31, P < 0.00001; 592 studied patients) levels. The number of patients to screen in order to detect an additional patient with an erosion in comparison with CR was 4, 95% CI (2.4, 5.9). CONCLUSION: US is more effective for erosion detection than CR and has a comparable efficacy to MRI with good reproducibility.

Number and phenotype of rheumatoid arthritis patients' CD4+CD25hi regulatory T cells are not affected by adalimumab or etanercept.

OBJECTIVE: To analyse the therapeutic effects of etanercept (ETA) or adalimumab (ADA) on the numbers and phenotypes of CD4+CD25hi Tregs in RA patients. METHODS: RA patients received ADA (n = 28) or ETA (n = 20) and stable-dose MTX or LEF. Therapeutic responses were assessed with the 28-joint DAS (DAS-28) criteria after 12 weeks of treatment. Treg numbers and phenotypes, determined by flow cytometry using different gating strategies, were compared between responders and non-responders before and after 6 and 12 weeks of treatment. RESULTS: The percentages of good, moderate and non-responders among patients given ADA or ETA, respectively, were 46.5, 35.7 and 17.8% or 30, 20 and 50%, with respective mean (s.d.) pre-treatment CD4+CD25hi Treg percentages of 5.5 (0.04)% or 4.95 (0.02)%. Overall, for patients with active RA given ADA or ETA, neither TNF-α-blocking agent had an effect on Tregs percentage and absolute number. Moreover, CD4+CD25hi Treg counts remained unaffected in RA responders to ADA or ETA, compared with RA non-responders. Furthermore, the CD4+CD25hiCD45RA+, CD4+CD25hiCD45RO+ and CD4+CD25hiCD62L+ cell populations were unchanged by TNF-α-blocking agents. CONCLUSION: Neither ADA nor ETA modified the percentages or absolute numbers of circulating CD4+CD25hi Tregs and their phenotypes after being administered for 6 and 12 weeks to RA patients. TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00234234.

Combining anti-cyclic citrullinated peptide with the American College of Rheumatology 1987 criteria failed to improve early rheumatoid arthritis diagnosis in the community-based very early arthritis cohort.

OBJECTIVES: To test the performances of combining anti-CCP second generation (CCP2) with ACR 1987 classification criteria and to diagnose early RA in a community-based very early arthritis (VErA) patient cohort. METHODS: The VErA cohort comprised 310 patients (median age 52 years; 68.1% women; median symptom duration 4.2 months; glucocorticoid- and DMARD naïve) conservatively treated during the first 2 years. At 6 years of follow-up, a three-expert committee classified the patients into three groups: RA, other classified arthritis (OCA) or unclassified arthritis (UA). We calculated the performances of the different sets, including anti-CCP2 positivity, while retaining or deleting RF and rheumatoid nodule components with ACR 1987 criteria for early RA diagnosis. Models were subjected to receiver operating characteristics curve and logistic regression analyses to try to identify relevant sets able to classify very early RA. RESULTS: At 6 years, 149 patients were diagnosed as RA and 119 as non-RA (95 OCA and 24 UA). The original ACR 1987 criteria had 77.9% sensitivity and 64.7% specificity for the RA diagnosis at 6 years. The modified set excluding rheumatoid nodules, including anti-CCP2 positivity and retaining RF performed significantly better than ACR 1987 criteria, with 79.9% sensitivity and 64.7% specificity and with a larger area under the curve. However, in the zone of interest, i.e., ≥4/7 criteria, the curves for these sets were superimposed. CONCLUSIONS: Adding anti-CCP2 positivity and deleting rheumatoid nodules failed to improve the performances of ACR 1987 classification criteria for the diagnosis of early RA.

Gene profiling predicts rheumatoid arthritis responsiveness to IL-1Ra (anakinra).

OBJECTIVES: The overall non-response rate to biologics remains 30-40% for patients with RA resistant to MTX. The objective of this study was to predict responsiveness to the anakinra-MTX combination by peripheral blood mononuclear cell gene profiling in order to optimize treatment choice. METHODS: Thirty-two patients treated with anakinra (100 mg/day s.c.) and MTX were categorized as responders when their 28-joint DAS (DAS-28) had decreased by ≥1.2 at 3 months. Pre-treatment blood samples had been drawn. RESULTS: For seven responders and seven non-responders, 52 microarray-identified mRNAs were expressed as a function of the response to treatment, and unsupervised hierarchical clustering correctly separated responders from non-responders. The levels of seven of these 52 transcripts, as assessed by real-time, quantitative RT-PCR, were able to accurately classify 15 of 18 other patients (8 responders and 10 non-responders), with 87.5% specificity and 77.8% negative-predictive value for responders. Among the 52 genes, 56% were associated with IL-1ß. CONCLUSION: This predictive gene expression profile was obtained with a non-invasive procedure. After further validation in other cohorts of patients, it could be proposed and used on a large scale to select likely RA responders to combined anakinra-MTX. Trial registration. Clinical Trials; NCT00213538 (http://www.clinicaltrials.gov).

Anti-Carbamylated Fibrinogen Antibodies Might Be Associated With a Specific Rheumatoid Phenotype and Include a Subset Recognizing In Vivo Epitopes of Its γ Chain One of Which Is Not Cross Reactive With Anti-Citrullinated Protein Antibodies.

To identify the targets recognized by anti-carbamylated protein antibodies (anti-CarP) in patients with early Rheumatoid Arthritis (RA), to study the cross-reactivity between anti-CarP and anti-citrullinated protein antibodies (ACPA) and to evaluate their prognostic value. 331 patients (184 RA and 147 other rheumatisms) from the Very Early Arthritis (VErA) French cohort were analyzed. We performed mass spectrometry analysis of RA sera displaying anti-CarP activity and epitope mapping of the carbamylated fibrinogen γ chain to identify immunodominant peptides. The specificity of these targets was studied using competition assays with the major antigens recognized by ACPA. The prognostic value of anti-carbamylated fibrinogen IgG antibodies (ACa-Fib IgG) was compared to that of anti-cyclic citrullinated peptide antibodies (anti-CCP) and anti-CarP using an in-house ELISA. Besides the α chain, the γ chain of fibrinogen, particularly one immunodominant epitope that has a specific reactivity, was identified as a circulating carbamylated target in sera. The prevalence of ACa-Fib was 37% at baseline and 10.9% for anti-CCP-negative RA. In anti-CCP-negative patients, ACa-Fib positivity was associated with a more inflammatory and erosive disease at baseline but not with rapid radiological progression, which remains strongly related to anti-CCP antibodies. Fibrinogen seems to be one of the antigens recognized in vivo by the anti-CarP response, particularly 2 epitopes of the γ chain, one of which is not cross reactive with ACPA. This specificity might be associated with a distinct clinical phenotype since ACa-Fib IgG were shown to be linked to systemic inflammation in very early RA but not to rapid radiological progression.