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1.  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.
doi:10.1136/annrheumdis-2013-204573
PMCID: PMC3933074  PMID: 24161836
Rheumatoid Arthritis; DMARDs (synthetic); DMARDs (biologic); Treatment; Early Rheumatoid Arthritis
2.  Integration of Sequence Data from a Consanguineous Family with Genetic Data from an Outbred Population Identifies PLB1 as a Candidate Rheumatoid Arthritis Risk Gene 
PLoS ONE  2014;9(2):e87645.
Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2×10−6). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted.
doi:10.1371/journal.pone.0087645
PMCID: PMC3919745  PMID: 24520335
3.  Safety and effectiveness of adalimumab in patients with rheumatoid arthritis over 5 years of therapy in a phase 3b and subsequent postmarketing observational study 
Introduction
Patients with active rheumatoid arthritis who had failed at least one disease-modifying anti-rheumatic drug (DMARD) were treated with adalimumab (ADA) in the ReAct study with the option to continue treatment for 5 years in ReAlise. The purpose of this study was to evaluate the long-term safety and effectiveness of ADA as prescribed from the first injection in ReAct to the last observation in ReAlise.
Methods
Patients received ADA alone or in combination with DMARDs according to usual clinical care practices. Adverse events (AEs) were tabulated by five time windows after the first ADA injection. Effectiveness measures included achievement of low disease activity (LDA), defined as Simplified Disease Activity Index (SDAI) ≤11, or remission, (REM), defined as SDAI ≤3.3.
Results
Of the 6,610 ReAct patients, 3,435 (52%) continued in ReAlise. At baseline in ReAct, mean age was 54 years, mean DAS28 was 6.0 and mean HAQ DI was 1.64. The mean treatment duration was 1,016 days, representing 18,272 patient-years (PYs) of ADA exposure. Overall incidence rates of serious AEs and serious infections were 13.8 and 2.8 events (E)/100 PYs, respectively. Serious AEs occurred most frequently in the first 6 months and deceased thereafter. Standardised mortality ratio was 0.71 (95% CI 0.57 to 0.87) and standardised incidence ratio for malignancies was 0.64 (95% CI 0.53 to 0.76). LDA was achieved by 50% and REM by 21% of patients at last observation.
Conclusions
Results of this large observational study of ADA in routine clinical practice were consistent with controlled trials, with no new safety concerns during a follow-up of more than 5 years. Effectiveness of ADA was maintained during long-term observation.
Trial registration
NCT00448383, NCT00234884
doi:10.1186/ar4452
PMCID: PMC3979145  PMID: 24460746
4.  Serum Levels of Beta2-Microglobulin and Free Light Chains of Immunoglobulins Are Associated with Systemic Disease Activity in Primary Sjögren’s Syndrome. Data at Enrollment in the Prospective ASSESS Cohort 
PLoS ONE  2013;8(5):e59868.
Objectives
To analyze the clinical and immunological characteristics at enrollment in a large prospective cohort of patients with primary Sjögren's syndrome (pSS) and to investigate the association between serum BAFF, beta2-microglobulin and free light chains of immunoglobulins and systemic disease activity at enrollment.
Methods
Three hundred and ninety five patients with pSS according to American-European Consensus Criteria were included from fifteen centers of Rheumatology and Internal Medicine in the “Assessment of Systemic Signs and Evolution of Sjögren's Syndrome” (ASSESS) 5-year prospective cohort. At enrollment, serum markers were assessed as well as activity of the disease measured with the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI).
Results
Patient median age was 58 (25th–75th: 51–67) and median disease duration was 5 (2–9) years. Median ESSDAI at enrollment was 2 (0–7) with 30.9% of patients having features of systemic involvement. Patients with elevated BAFF, beta2-microglobulin and kappa, lambda FLCS had higher ESSDAI scores at enrollment (4 [2]–[11] vs 2 [0–7], P = 0.03; 4 [1]–[11] vs 2 [0–7], P< 0.0001); 4 [2]–[10] vs 2 [0–6.6], P< 0.0001 and 4 [2–8.2] vs 2 [0–7.0], P = 0.02, respectively). In multivariate analysis, increased beta2-microglobulin, kappa and lambda FLCs were associated with a higher ESSDAI score. Median BAFF and beta2-microglobulin were higher in the 16 patients with history of lymphoma (1173.3(873.1–3665.5) vs 898.9 (715.9–1187.2) pg/ml, P = 0.01 and 2.6 (2.2–2.9) vs 2.1 (1.8–2.6) mg/l, P = 0.04, respectively).
Conclusion
In pSS, higher levels of beta2-microglobulin and free light chains of immunoglobulins are associated with increased systemic disease activity.
doi:10.1371/journal.pone.0059868
PMCID: PMC3663789  PMID: 23717383
5.  The ability of synovitis to predict structural damage in rheumatoid arthritis: a comparative study between clinical examination and ultrasound 
Annals of the Rheumatic Diseases  2012;72(5):665-671.
Objectives
To evaluate synovitis (clinical vs ultrasound (US)) to predict structural progression in rheumatoid arthritis (RA).
Methods
Patients with RA.
Study design
Prospective, 2-year follow-up.
Data collected
Synovitis (32 joints (2 wrists, 10 metacarpophalangeal, 10 proximal interphalangeal, 10 metatarsophalangeal)) at baseline and after 4 months of therapy by clinical, US grey scale (GS-US) and power doppler (PD-US); x-rays at baseline and at year 2.
Analysis
Measures of association (OR) were tested between structural deterioration and the presence of baseline synovitis, or its persistence, after 4 months of therapy using generalised estimating equation analysis.
Results
Structural deterioration was observed in 9% of the 1888 evaluated joints in 59 patients. Baseline synovitis increased the risk of structural progression: OR=2.01 (1.36–2.98) p<0.001 versus 1.61 (1.06–2.45) p=0.026 versus 1.75 (1.18–2.58) p=0.005 for the clinical versus US-GS versus US-PD evaluation, respectively. In the joints with normal baseline examination (clinical or US), an increased probability for structural progression in the presence of synovitis for the other modality was also observed (OR=2.16 (1.16–4.02) p=0.015 and 3.50 (1.77–6.95) p<0.001 for US-GS and US-PD and 2.79 (1.35–5.76) p=0.002) for clinical examination. Persistent (vs disappearance) synovitis after 4 months of therapy was also predictive of subsequent structural progression.
Conclusions
This study confirms the validity of synovitis for predicting subsequent structural deterioration irrespective of the modality of examination of joints, but also suggests that both clinical and ultrasonographic examinations may be relevant to optimally evaluate the risk of subsequent structural deterioration.
doi:10.1136/annrheumdis-2012-201469
PMCID: PMC3618684  PMID: 22679298
6.  How does BAFF activate B cells in patients with autoimmune diseases? 
In a study in a recent issue of Arthritis Research & Therapy, Yoshimoto and colleagues demonstrate that peripheral monocytes from patients with Sjögren's syndrome (SS) produce significantly higher amounts of B cell-activating factor (BAFF) and interleukin-6 (IL-6) in comparison with normal monocytes. This difference exists at baseline and is amplified after stimulation with interferon-gamma. Increased IL-6 secretion is partially suppressed by an anti-BAFF antibody, suggesting that signal transduction pathways mediated by BAFF are implicated in the regulation of IL-6 production by monocytes. The origin and pathways involved in this higher susceptibility to BAFF-driven IL-6 induction by monocytes of patients with SS are still unknown.
doi:10.1186/ar3729
PMCID: PMC3392821  PMID: 22360881
7.  Association of an IRF5 gene functional polymorphism with Sjögren's syndrome 
Arthritis and Rheumatism  2007;56(12):3989-3994.
Objective
Interferon (IFN) regulatory factor 5 (IRF-5) is a transcription factor involved in the regulation of host defense. Previous reports have demonstrated a significant association of various IRF-5 polymorphisms with systemic lupus erythematosus (SLE), among Caucasians. This case-control study aimed to investigate whether IRF-5 polymorphisms were involved in the genetic predisposition to primary Sjögren Syndrome (pSS), an autoimmune disease closely related to SLE.
Methods
We analyzed IRF-5 rs2004640, rs2070197, rs10954213, and rs2280714 polymorphisms in a cohort of 212 pSS patients and 162 controls, all of Caucasian origin. The four studied polymorphisms were genotyped by competitive allele specific polymerase chain reaction (PCR) using FRET technology.
Results
The IRF-5 rs2004640 GT or TT genotypes (T allele carriers) were found among 87% of pSS patients compared with 77% in controls (P=0.01; OR1.93, 95%IC [1.15–3.42]). Likewise, IRF-5 rs2004640 T allele was found on 59% of chromosomes in pSS patients compared with 52% in controls (P=0.04; OR 1.36, 95% CI [1.01–1.83]). No significant association was evidenced with rs2070197, rs10954213, and rs2280714 when analyzed independently. Nevertheless, haplotype reconstructions based on the four studied polymorphisms suggest that various allele combinations of rs2004640 and rs2070197 could define susceptibility or protective haplotypes.
Conclusion
We demonstrated for the first time a significant association of IRF-5 rs2004640 T allele with pSS. These results, which require further replication on larger sample sized populations suggest that, beside association with identical major histocompatibility complex (MHC) gene polymorphisms, pSS and SLE also share IRF-5 polymorphism as a common genetic susceptibility factor.
doi:10.1002/art.23142
PMCID: PMC3184606  PMID: 18050197
Alleles; Case-Control Studies; Genetic Predisposition to Disease; genetics; Genotype; Haplotypes; Humans; Interferon Regulatory Factors; genetics; Lupus Erythematosus, Systemic; genetics; Polymorphism, Single Nucleotide; genetics; Sjogren's Syndrome; genetics; IRF-5; Sjögren's syndrome; genetic polymorphism; haplotype
8.  Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis 
Annals of the Rheumatic Diseases  2011;70(6):909-920.
Background
Since initial approval for the treatment of rheumatoid arthritis (RA), rituximab has been evaluated in clinical trials involving various populations with RA. Information has also been gathered from registries. This report therefore updates the 2007 consensus document on the use of rituximab in the treatment of RA.
Methods
Preparation of this new document involved many international experts experienced in the treatment of RA. Following a meeting to agree upon the core agenda, a systematic literature review was undertaken to identify all relevant data. Data were then interrogated by a drafting committee, with subsequent review and discussion by a wider expert committee leading to the formulation of an updated consensus statement. These committees also included patients with RA.
Results
The new statement covers wide-ranging issues including the use of rituximab in earlier RA and impact on structural progression, and aspects particularly pertinent to rituximab such as co-medication, optimal dosage regimens, repeat treatment cycles and how to manage non-response. Biological therapy following rituximab usage is also addressed, and safety concerns including appropriate screening for hepatitis, immunoglobulin levels and infection risk. This consensus statement will support clinicians and inform patients when using B-cell depletion in the management of RA, providing up-to-date information and highlighting areas for further research.
Conclusion
New therapeutic strategies and treatment options for RA, a chronic destructive and disabling disease, have expanded over recent years. These have been summarised in general strategic suggestions and specific management recommendations, emphasising the importance of expedient disease-modifying antirheumatic drug implementation and tight disease control. This consensus statement is in line with these fundamental principles of management.
doi:10.1136/ard.2010.144998
PMCID: PMC3086093  PMID: 21378402
9.  Tumour necrosis factor receptor 2 (TNFRSF1B) association study in Sjögren's syndrome 
Annals of the Rheumatic Diseases  2007;66(12):1684-1685.
doi:10.1136/ard.2007.071167
PMCID: PMC2095302  PMID: 17998218
Sjögren syndrome; tumour necrosis factor receptor 2; association
10.  Comparison of in vitro‐specific blood tests with tuberculin skin test for diagnosis of latent tuberculosis before anti‐TNF therapy 
Annals of the Rheumatic Diseases  2007;66(12):1610-1615.
Introduction
Latent tuberculosis infection (LTBI) is detected with the tuberculin skin test (TST) before anti‐TNF therapy. We aimed to investigate in vitro blood assays with TB‐specific antigens (CFP‐10, ESAT‐6), in immune‐mediated inflammatory diseases (IMID) for LTBI screening.
Patients and methods
Sixty‐eight IMID patients with (n = 35) or without (n = 33) LTBI according to clinico‐radiographic findings or TST results (10 mm cutoff value) underwent cell proliferation assessed by thymidine incorporation and PKH‐26 dilution assays, and IFNγ‐release enzyme‐linked immunosorbent spot (ELISPOT) assays with TB‐specific antigens.
Results
In vitro blood assays gave higher positive results in patients with LTBI than without (p<0.05), with some variations between tests. Among the 13 patients with LTBI diagnosed independently of TST results, 5 had a negative TST (38.5%) and only 2 a negative blood assays result (15.4%). The 5 LTBI patients with negative TST results all had positive blood assays results. Ten patients without LTBI but with intermediate TST results (6–10 mm) had no different result than patients with TST result ⩽5 mm (p>0.3) and lower results than those with LTBI (p<0.05) on CFP‐10+ESAT‐6 ELISPOT and CFP‐10 proliferation assays.
Conclusion
Anti‐TB blood assays are beneficial for LTBI diagnosis in IMID. Compared with TST, they show a better sensitivity, as seen by positive results in 5 patients with certain LTBI and negative TST, and better specificity, as seen by negative results in most patients with intermediate TST as the only criteria of LTBI. In the absence of clinico‐radiographic findings for LTBI, blood assays could replace TST for antibiotherapy decision before anti‐TNF.
doi:10.1136/ard.2007.069799
PMCID: PMC2095326  PMID: 17456528
11.  EULAR Sjogren's syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjogren's syndrome 
Annals of the Rheumatic Diseases  2009;69(6):1103-1109.
Objective
To develop a disease activity index for patients with primary Sjögren’s syndrome (SS): the European League Against Rheumatism (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI).
Methods
Thirty-nine SS experts participated in an international collaboration, promoted by EULAR, to develop the ESSDAI. Experts identified 12 organ-specific “domains” contributing to disease activity. For each domain, features of disease activity were classified in 3 or 4 levels according to their severity. Data abstracted from 96 patients with systemic complications of primary SS were used to generate 702 realistic vignettes for which all possible systemic complications were represented. Using the 0–10 physician global assessment (PhGA) scale, each expert scored the disease activity of 5 patient profiles and 20 realistic vignettes. Multiple regression modelling, with PhGA used as the dependent variable, was used to estimate the weight of each domain.
Results
All 12 domains were significantly associated with disease activity in the multivariate model, domain weights ranged from 1 to 6. The ESSDAI scores varied from 2 to 47 and were significantly correlated with PhGA for both real patient profiles and realistic vignettes (r=0.61 and r=0.58, respectively, p<0.0001). Compared to 57 (59.4%) of the real patient profiles, 468 (66.7%) of the realistic vignettes were considered likely or very likely to be true.
Conclusion
The ESSDAI is a clinical index designed to measure disease activity in patients with primary SS. Once validated, such a standardized evaluation of primary SS should facilitate clinical research and should be helpful as an outcome measure in clinical trials.
doi:10.1136/ard.2009.110619
PMCID: PMC2937022  PMID: 19561361
primary Sjogren's syndrome; outcome assessment; systemic features; activity index; clinical vignettes; disease activity
12.  Lymphoma in patients treated with anti-TNF: results of the 3-year prospective French RATIO registry 
Annals of the Rheumatic Diseases  2009;69(2):400-408.
Objective
To describe cases of lymphoma associated with anti-TNF therapy, identify risk factors, estimate the incidence and compare risks for different anti-TNF agents.
Methods
We designed a national prospective registry (RATIO) from 2004 to 2006, for collecting all cases of lymphoma in French patients receiving anti-TNF therapy, whatever the indication. We conducted a case-control analysis including two controls treated with anti-TNF per case and an incidence study of lymphoma with the French population used as reference..
Results
We collected 38 cases of lymphoma, 31 non-Hodgkin’s lymphoma (NHL) (26 B-cell and 5 T-cell), 5 Hodgkin’s lymphoma (HL) and 2 Hodgkin’s-like lymphoma. Epstein-Barr virus (EBV) was detected in 2 of 2 Hodgkin’s-like lymphoma, 3 of 5 HL and one NHL. Patients receiving adalimumab or infliximab had a higher risk than those treated with etanercept: SIR = 4.1 (2.3–7.1) and 3.6 (2.3–5.6) versus 0.9 (0.4– 1.8). The exposure to adalimumab or infliximab versus etanercept was an independent risk factor for lymphoma in the case-control study: odds ratio=4.7 (1.3– 17.7) and 4.1 (1.4–12.5), respectively. The sex and age- adjusted incidence rate of lymphoma was 42.1 per 100,000 patient-years. The standardized incidence ratio (SIR) was 2.4 (95% confidence interval [CI] 1.7–3.2).
Conclusion
Some lymphomas associated with immunosuppression may occur in patients receiving anti TNF therapy, and the risk of lymphoma is higher with monoclonal-antibody therapy than with soluble-receptor therapy.
doi:10.1136/ard.2009.117762
PMCID: PMC2925048  PMID: 19828563
Aged; Antirheumatic Agents; adverse effects; therapeutic use; Arthritis; drug therapy; Epidemiologic Methods; Female; France; epidemiology; Humans; Immunocompromised Host; Immunosuppressive Agents; adverse effects; therapeutic use; Lymphoma; chemically induced; epidemiology; immunology; Male; Middle Aged; Registries; Tumor Necrosis Factor-alpha; antagonists & inhibitors; Anti-TNF; Lymphoma; Safety; Rheumatoid arthritis; Spondylarthropathies
13.  Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: The three-year prospective French Research Axed on Tolerance of Biotherapies registry 
Arthritis and Rheumatism  2009;60(7):1884-1894.
Background
Tuberculosis (TB) is associated with anti-tumour necrosis factor (TNF) therapy but whether it is drug-specific remains a concern. Our objective was to describe cases of tuberculosis associated with anti-TNF therapy, identify risk factors and estimate the incidence.
Methods
An incidence study with the French population as reference and a case-control analysis. We collected, for 3 years, cases of TB among French patients receiving anti-TNF therapy, whatever the indication, with two controls treated with anti-TNF agents per case.
Results
We collected 69 cases of TB in patients treated for rheumatoid arthritis (n=40), spondylarthropathies (n=18), inflammatory colitis (n=9), psoriasis (n=1) and Behçet’s disease (n=1) treated with infliximab (n=36), adalimumab (n=28) and etanercept (n=5). None of the cases had received correct chemoprophylaxis treatment. The sex and age-adjusted incidence rate of TB was 116.7 per 100,000 patient-years. The SIR was 12.2 (95% confidence interval 9.7–15.5) and was higher for therapy with infliximab and adalimumab than for that with etanercept: 18.6 (13.4–25.8) and 29.3 (20.2–42.4) versus 1.8 (0.7–4.3), respectively. In the case-control analysis, the exposure to infliximab or adalimumab versus etanercept was an independent risk factor for TB: odds ratio=13.3 (2.6–69.0) and 17.1 (3.6–80.6), respectively. Other risk factors were age, the first year of anti-TNF treatment, and being born in an endemic area.
Conclusions
The risk of TB is higher for patients receiving monoclonal-antibody than soluble-receptor anti-TNF therapy. The increased risk with early anti-TNF treatment and the absence of correct chemoprophylaxis treatment favours the reactivation of latent TB.
doi:10.1002/art.24632
PMCID: PMC2921546  PMID: 19565495
Adult; Aged; Antibodies, Monoclonal; adverse effects; therapeutic use; Arthritis, Rheumatoid; drug therapy; Behcet Syndrome; drug therapy; Case-Control Studies; Colitis; drug therapy; Female; France; Humans; Immunoglobulin G; adverse effects; therapeutic use; Male; Middle Aged; Prospective Studies; Receptors, Tumor Necrosis Factor; therapeutic use; Registries; Risk Factors; Spondylarthritis; drug therapy; Treatment Outcome; Tuberculosis; chemically induced; drug therapy; epidemiology; Tumor Necrosis Factor-alpha; immunology; anti-TNF-alpha; tuberculosis; safety; rheumatoid arthritis; inflammatory chronic diseases
14.  Risk factors for total joint arthroplasty infection in patients receiving tumor necrosis factor α-blockers: a case-control study 
Arthritis Research & Therapy  2010;12(4):R145.
Introduction
The objective of this study was to assess natural microbial agents, history and risk factors for total joint arthroplasty (TJA) infections in patients receiving tumor necrosis factor (TNF)α-blockers, through the French RATIO registry and a case-control study.
Methods
Cases were TJA infections during TNFα-blocker treatments. Each case was compared to two controls (with TJA and TNFα-blocker therapy, but without TJA infection) matched on age (±15 years), TJA localization, type of rheumatic disorder and disease duration (±15 years). Statistical analyses included univariate and multivariate analyses with conditional logistic regression.
Results
In the 20 cases (18 rheumatoid arthritis), TJA infection concerned principally the knee (n = 12, 60%) and the hip (n = 5, 25%). Staphylococcus was the more frequent microorganism involved (n = 15, 75%). Four patients (20%) were hospitalized in an intensive care unit and two died from infection. Eight cases (40%) versus 5 controls (13%) had undergone primary TJA or TJA revision for the joint subsequently infected during the last year (P = 0.03). Of these procedures, 5 cases versus 1 control were performed without withdrawing TNFα-blockers (P = 0.08). In multivariate analysis, predictors of infection were primary TJA or TJA revision for the joint subsequently infected within the last year (odds ratio, OR = 88.3; 95%CI 1.1-7,071.6; P = 0.04) and increased daily steroid intake (OR = 5.0 per 5 mg/d increase; 1.1-21.6; P = 0.03). Case-control comparisons showed similar distribution between TNFα-blockers (P = 0.70).
Conclusions
In patients receiving TNFα-blockers, TJA infection is rare but potentially severe. Important risk factors are primary TJA or TJA revision within the last year, particularly when TNFα-blockers are not interrupted before surgery, and the daily steroid intake.
doi:10.1186/ar3087
PMCID: PMC2945039  PMID: 20637100
15.  Adalimumab alone and in combination with disease‐modifying antirheumatic drugs for the treatment of rheumatoid arthritis in clinical practice: the Research in Active Rheumatoid Arthritis (ReAct) trial 
Annals of the Rheumatic Diseases  2007;66(6):732-739.
Objective
To evaluate the safety and effectiveness of adalimumab alone or in combination with standard disease‐modifying antirheumatic drugs (DMARDs) for the treatment of rheumatoid arthritis (RA).
Methods
Patients with active RA despite treatment with DMARDs or prior treatment with a tumour necrosis factor antagonist participated in a multicentre, open‐label clinical study of adalimumab 40 mg every other week for 12 weeks with an optional extension phase. Patients were allowed to continue with pre‐existing traditional DMARDs. Long‐term safety results are reported for all patients (4210 patient‐years (PYs) of adalimumab exposure). The observed effectiveness results at week 12 are reported using American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response criteria.
Results
Among the 6610 treated patients, adalimumab was generally well tolerated. Serious infections occurred in 3.1% of patients (5.5/100 PYs, including active tuberculosis, 0.5/100 PYs). Demyelinating disease (0.06%) and systemic lupus erythematosus (0.03%) were rare serious adverse events. The standardised incidence ratio of malignancy was 0.71 (95% CI 0.49 to 1.01). The standardised mortality ratio was 1.07 (95% CI 0.75 to 1.49). At week 12, 69% of patients achieved an ACR20 response, 83% a moderate, and 33% a good EULAR response. Adalimumab was effective in combination with a variety of DMARDs. The addition of adalimumab to antimalarials was comparably effective to the combination of adalimumab and methotrexate.
Conclusions
Considering the limitations of an open‐label study, adalimumab alone or in combination with standard DMARDs appeared to be well tolerated and effective in 6610 difficult‐to‐treat patients with active RA treated in clinical practice.
doi:10.1136/ard.2006.066761
PMCID: PMC1954645  PMID: 17329305
adalimumab; rheumatoid arthritis; tumour necrosis factor; monoclonal antibody; antirheumatic agents
16.  Increase of B cell‐activating factor of the TNF family (BAFF) after rituximab treatment: insights into a new regulating system of BAFF production 
Annals of the Rheumatic Diseases  2006;66(5):700-703.
Background
The cytokine B cell‐activating factor of the TNF family (BAFF) is involved in the pathogenesis of autoimmune diseases.
Objective
To access changes in serum protein and mRNA levels of BAFF after rituximab treatment.
Methods
Serum and peripheral blood mononuclear cells (PBMCs) were isolated from five patients (two with lupus, two with Sjögren's syndrome, one with rheumatoid arthritis) before and 12 weeks (range 7–17) after a first course of rituximab infusion. Monocytes and B cells were selected from healthy controls and cocultured for 72 h. BAFF protein and mRNA levels were assessed by ELISA and real‐time PCR, respectively.
Results
After rituximab treatment, median serum BAFF protein level and BAFF to actin mRNA ratio in PBMCs significantly increased. In monocytes cocultured with autologous B cells, BAFF protein level decreased, whereas the mRNA level was stable. In one closely monitored patient, the mRNA ratio of BAFF to actin in PBMCs increased later than the BAFF serum level.
Conclusions
Two distinct mechanisms are probably involved in the increase in BAFF level after B cell depletion: (1) the decrease in its receptors leading to a release of BAFF; (2) a delayed regulation of BAFF mRNA transcription. This could favour the re‐emergence of autoreactive B cells.
doi:10.1136/ard.2006.060772
PMCID: PMC1954605  PMID: 17040963
17.  Increased levels of circulating microparticles in primary Sjögren's syndrome, systemic lupus erythematosus and rheumatoid arthritis and relation with disease activity 
Arthritis Research & Therapy  2009;11(5):R156.
Introduction
Cell stimulation leads to the shedding of phosphatidylserine (PS)-rich microparticles (MPs). Because autoimmune diseases (AIDs) are characterized by cell activation, we investigated level of circulating MPs as a possible biomarker in primary Sjögren's syndrome (pSS), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).
Methods
We measured plasma levels of total, platelet and leukocyte MPs by prothrombinase capture assay and flow cytometry in 43 patients with pSS, 20 with SLE and 24 with RA and in 44 healthy controls (HCs). Secretory phospholipase A2 (sPLA2) activity was assessed by fluorometry. Soluble CD40 ligand (sCD40L) and soluble P-selectin (sCD62P), reflecting platelet activation, were measured by ELISA.
Results
Patients with pSS showed increased plasma level of total MPs (mean ± SEM 8.49 ± 1.14 nM PS equivalent (Eq), P < 0.0001), as did patients with RA (7.23 ± 1.05 n PS Eq, P = 0.004) and SLE (7.3 ± 1.25 nM PS Eq, P = 0.0004), as compared with HCs (4.13 ± 0.2 nM PS Eq). Patients with AIDs all showed increased level of platelet MPs (P < 0.0001), but only those with pSS showed increased level of leukocyte MPs (P < 0.0001). Results by capture assay and flow cytometry were correlated. In patients with high disease activity according to extra-glandular complications (pSS), DAS28 (RA) or SLEDAI (SLE) compared with low-activity patients, the MP level was only slightly increased in comparison with those having a low disease activity. Platelet MP level was inversely correlated with anti-DNA antibody level in SLE (r = -0.65; P = 0.003) and serum β2 microglobulin level in pSS (r = -0.37; P < 0.03). The levels of total and platelet MPs were inversely correlated with sPLA2 activity (r = -0.37, P = 0.0007; r = -0.36, P = 0.002, respectively). sCD40L and sCD62P concentrations were significantly higher in pSS than in HC (P ≤ 0.006).
Conclusions
Plasma MP level is elevated in pSS, as well as in SLE and RA, and could be used as a biomarker reflecting systemic cell activation. Level of leukocyte-derived MPs is increased in pSS only. The MP level is low in case of more severe AID, probably because of high secretory phospholipase A2 (sPLA2) activity, which leads to consumption of MPs. Increase of platelet-derived MPs, sCD40L and sCD62P, highlights platelet activation in pSS.
doi:10.1186/ar2833
PMCID: PMC2787287  PMID: 19832990
18.  A single tumour necrosis factor haplotype influences the response to adalimumab in rheumatoid arthritis 
Annals of the Rheumatic Diseases  2007;67(4):478-484.
Objective
To determine whether tumor necrosis factor (TNF) gene polymorphisms and/or the shared epitope are genetic predictors of response to adalimumab (ADA) in rheumatoid arthritis (RA).
Methods
This ancillary study to the Research in Active Rheumatoid Arthritis (ReAct) Phase IIIb study included a large cohort of Caucasian patients with RA from France (N=380) treated with ADA plus methotrexate (MTX) (n=182), ADA plus any other DMARD (N=96) or ADA alone (N=102). The primary outcome was ACR50 at 12 weeks. Patients underwent genotyping for HLA-DRB1 and 3 TNFα gene polymorphisms (-238A/G, -308A/G and -857C/T). Extended haplotypes involving HLA-DRB1 and TNFα loci were reconstructed by use of the PHASE program.
Results
A total of 152 patients (40%) had an ACR50 response at week 12. Neither the number of HLA-DRB1 SE copies nor presence of the 3 TNFα polymorphisms tested separately was significantly associated with ACR50 response at week 12. However, haplotype reconstruction of the TNFα locus revealed the GGC haplotype (-238G/-308G/–857C) in a homozygous form, present in more than half of the patients, significantly associated with a lower ACR50 response at 12 weeks (34% vs. 50% in patients without the haplotype) on treatment with ADA concomitant with MTX (P=0.0041; Pc=0.02). This effect was restricted to the subgroup of patients concomitantly treated with MTX.
Conclusion
This large pharmacogenetic study provides robust data indicating that a single TNFα locus haplotype (-238G/-308G/-857C), present on both chromosomes is associated with a lower response to ADA and MTX therapy in RA patients homozygous for this haplotype.
doi:10.1136/ard.2007.074104
PMCID: PMC2750008  PMID: 17673491
Adult; Aged; Antibodies, Monoclonal; therapeutic use; Antirheumatic Agents; therapeutic use; Arthritis, Rheumatoid; drug therapy; genetics; Drug Therapy, Combination; Female; Genotype; HLA-DR Antigens; genetics; Haplotypes; Humans; Male; Methotrexate; therapeutic use; Middle Aged; Polymorphism, Single Nucleotide; Treatment Outcome; Tumor Necrosis Factor-alpha; genetics; TNF-alpha; adalimumab; rheumatoid arthritis; genetic polymorphism; haplotype
19.  Effect of response format for clinical vignettes on reporting quality of physician practice 
Background
Clinical vignettes have been used widely to compare quality of clinical care and to assess variation in practice, but the effect of different response formats has not been extensively evaluated. Our objective was to compare three clinical vignette-based survey response formats – open-ended questionnaire (A), closed-ended (multiple-choice) questionnaire with deceptive response items mixed with correct items (B), and closed-ended questionnaire with only correct items (C) – in rheumatologists' pre-treatment assessment for tumor-necrosis-factor (TNF) blocker therapy.
Methods
Study design: Prospective randomized study. Setting: Rheumatologists attending the 2004 French Society of Rheumatology meeting. Physicians were given a vignette describing the history of a fictitious woman with active rheumatoid arthritis, who was a candidate for therapy with TNF blocking agents, and then were randomized to receive questionnaire A, B, or C, each containing the same four questions but with different response formats, that asked about their pretreatment assessment. Measurements: Long (recommended items) and short (mandatory items) checklists were developed for pretreatment assessment for TNF-blocker therapy, and scores were expressed on the basis of responses to questionnaires A, B, and C as the percentage of respondents correctly choosing explicit items on these checklists. Statistical analysis: Comparison of the selected items using pairwise Chi-square tests with Bonferonni correction for variables with statistically significant differences.
Results
Data for all surveys distributed (114 As, 118 Bs, and 118 Cs) were complete and available for analysis. The percentage of questionnaire A, B, and C respondents for whom data was correctly complete for the short checklist was 50.4%, 84.0% and 95.0%, respectively, and was 0%, 5.0% and 5.9%, respectively, for the long version. As an example, 65.8%, 85.7% and 95.8% of the respondents of A, B, and C questionnaires, respectively, correctly identified the need for tuberculin skin test (p < 0.0001).
Conclusion
In evaluating clinical practice with use of a clinical vignette, a multiple-choice format rather than an open-ended format overestimates physician performance. The insertion of deceptive response items mixed with correct items in closed-ended (multiple-choice) questionnaire failed to avoid this overestimation.
doi:10.1186/1472-6963-9-128
PMCID: PMC3224732  PMID: 19638231
20.  Markers of B-lymphocyte activation are elevated in patients with early rheumatoid arthritis and correlated with disease activity in the ESPOIR cohort 
Arthritis Research & Therapy  2009;11(4):R114.
Introduction
Little is known about systemic B-cell activation in early rheumatoid arthritis (RA). We therefore evaluated the serum levels of markers of B-cell activation in patients included in the ESPOIR early arthritis cohort.
Methods
In the ESPOIR early arthritis cohort (at least 2 swollen joints for more than 6 weeks but less than 6 months), 710 patients were assessed at 1 year and either met the 1987 American College of Rheumatology criteria for RA (n = 578) or had undifferentiated arthritis (n = 132). Baseline serum samples of patients naïve to corticosteroid and disease-modifying antirheumatic drug treatment were assessed for beta2-microglobulin, IgG, IgA, IgM, immunoglobulin free light chains of immunoglobulins, and B-cell activating factor of the tumor necrosis factor family (BAFF). The BAFF gene 871T>C polymorphism was genotyped in all patients.
Results
All markers of B-cell activation except BAFF and IgM were significantly higher in patients with early RA than those with undifferentiated arthritis. Anti-cyclic citrullinated peptide (anti-CCP) and beta2-microglobulin were associated with a diagnosis of early RA in the multivariate analysis. Markers of B-cell activation, except BAFF, were associated with disease activity, rheumatoid factor and anti-CCP secretion. The BAFF gene polymorphism was not associated with early RA.
Conclusions
Markers of B-cell activation are elevated in patients with early RA, compared with undifferentiated arthritis, independently of any systemic increase in BAFF secretion, and correlate with disease activity. This study sheds new light on the early pathogenic role of B-lymphocytes in RA and suggests that targeting them might be a useful therapeutic strategy in early RA.
doi:10.1186/ar2773
PMCID: PMC2745796  PMID: 19627580
21.  Masitinib in the treatment of active rheumatoid arthritis: results of a multicentre, open-label, dose-ranging, phase 2a study 
Introduction
Since current treatment options for patients suffering from active rheumatoid arthritis (RA) remain inadequate, especially for those unresponsive to disease-modifying antirheumatic drugs (DMARDs), new and improved medication is needed. This study evaluates the safety and efficacy of masitinib (AB1010), a potent and selective protein tyrosine kinase inhibitor of c-KIT, in the monotherapy treatment of DMARD-refractory RA.
Methods
This was a multicentre, uncontrolled, open-label, randomised, dose-ranging, phase 2a trial. Masitinib was administered orally to 43 patients who had inadequate response to DMARDs, at initial randomised dosing levels of 3 and 6 mg/kg per day over a 12-week period. Dose adjustment was permitted based upon tolerability and response criteria. Efficacy was assessed via American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70) responses, disease activity score using 28 joint counts (DAS28), index of improvement in RA (ACRn) and C-reactive protein (CRP) improvement, relative to baseline at week 12.
Results
Improvement was observed in all efficacy endpoints, including ACR20/50/70 scores of 54%, 26% and 8%, respectively, and a reduction in CRP level by greater than 50% for approximately half the population. This improvement was sustainable throughout an extension phase (> 84 weeks) and was also independent of initial DMARD resistance (anti-tumour necrosis factor-alpha and/or methotrexate). A relatively high patient withdrawal rate (37%) required the use of last observation carried forward (LOCF) data imputation. Incidence of adverse events was high (95%), although the majority were of mild or moderate severity with a considerable decline in frequency observed after 12 weeks of treatment. Two nonfatal serious adverse events were reported. Dose-response analyses tentatively indicate that an initial dosing level of 6.0 mg/kg per day administered orally in two daily intakes is the most appropriate, based upon potency and tolerability trends.
Conclusions
Treatment with masitinib improved DMARD-refractory active RA. Following an initial high incidence of mostly mild to moderate side effects during the first 12 weeks of treatment, masitinib appears to be generally well tolerated. This, together with evidence of a sustainable efficacy response, suggests that masitinib is suitable for long-term treatment regimens. Since this was the first study of masitinib in a nononcologic pathology, the relatively high patient withdrawal rate observed can be partly attributed to a highly cautious response to adverse events. There is sufficient compelling evidence to warrant further placebo-controlled investigation.
Trial registration
ClinicalTrials.gov NCT00831922.
doi:10.1186/ar2740
PMCID: PMC2714151  PMID: 19549290
22.  Effect of methotrexate and anti-TNF on Epstein-Barr virus T-cell response and viral load in patients with rheumatoid arthritis or spondylarthropathies 
Introduction
There is a suspicion of increased risk of Epstein-Barr virus (EBV)-associated lymphoproliferations in patients with inflammatory arthritides receiving immunosuppressive drugs. We investigated the EBV load and EBV-specific T-cell response in patients treated with methotrexate (MTX) or anti-TNF therapy.
Methods
Data for patients with rheumatoid arthritis (RA) (n = 58) or spondylarthropathy (SpA) (n = 28) were analyzed at baseline in comparison with controls (n = 22) and after 3 months of MTX or anti-TNF therapy for EBV load and EBV-specific IFNγ-producing T cells in response to EBV latent-cycle and lytic-cycle peptides.
Results
The EBV load and the number of IFNγ-producing T-cells after peptide stimulation were not significantly different between groups at baseline (P = 0.61 and P = 0.89, respectively). The EBV load was not significantly modified by treatment, for RA with MTX (P = 0.74) or anti-TNF therapy (P = 0.94) or for SpA with anti-TNF therapy (P = 1.00). The number of EBV-specific T cells was not significantly modified by treatment, for RA with MTX (P = 0.58) or anti-TNF drugs (P = 0.19) or for SpA with anti-TNF therapy (P = 0.39). For all patients, the EBV load and EBV-specific T cells were significantly correlated (P = 0.017; R = 0.21). For most patients, short-term exposure (3 months) to MTX or anti-TNF did not alter the EBV load or EBV-specific T-cell response but two patients had discordant evolution.
Conclusions
These data are reassuring and suggest there is no short-term defect in EBV-immune surveillance in patients receiving MTX or anti-TNF drugs. However, in these patients, long term follow-up of EBV-specific T-cell response is necessary and the role of non-EBV-related mechanisms of lymphomagenesis is not excluded.
doi:10.1186/ar2708
PMCID: PMC2714125  PMID: 19470150
24.  CTLA-4 +49A/G and CT60 gene polymorphisms in primary Sjögren syndrome 
CTLA-4 encodes cytotoxic T lymphocyte-associated antigen-4, a cell-surface molecule providing a negative signal for T-cell activation. CTLA-4 gene polymorphisms have been widely studied in connection with genetic susceptibility to various autoimmune diseases, but studies have led to contradictory results in different populations. This case-control study sought to investigate whether CTLA-4 CT60 and/or +49A/G polymorphisms were involved in the genetic predisposition to primary Sjögren syndrome (pSS). We analysed CTLA-4 CT60 and +49A/G polymorphisms in a first cohort of 142 patients with pSS (cohort 1) and 241 controls, all of Caucasian origin. A replication study was performed on a second cohort of 139 patients with pSS (cohort 2). In cohort 1, the CTLA-4 +49A/G*A allele was found on 73% of chromosomes in patients with pSS, compared with 66% in controls (p = 0.036; odds ratio (OR) 1.41, 95% confidence interval (CI) 1.02 to 1.95). No difference in CTLA-4 CT60 allelic or genotypic distribution was observed between patients (n = 142) and controls (n = 241). In the replication cohort, the CTLA-4 +49A/G*A allele was found on 62% of chromosomes in patients with pSS, compared with 66% in controls (p = 0.30; OR 0.85, 95% CI 0.63 to 1.16). Thus, the CTLA-4 +49A/G*A allele excess among patients from cohort 1 was counterbalanced by its under-representation in cohort 2. When the results from the patients in both cohorts were pooled (n = 281), there was no difference in CTLA-4 +49A/G allelic or genotypic distribution in comparison with controls. Our results demonstrate a lack of association between CTLA-4 CT60 or +49A/G polymorphisms and pSS. Premature conclusions might have been made if a replication study had not been performed. These results illustrate the importance of case-control studies performed on a large number of patients. In fact, sampling bias may account for some contradictory results previously reported for CTLA-4 association studies in autoimmune diseases.
doi:10.1186/ar2136
PMCID: PMC1906800  PMID: 17341301
25.  Inhibition of anti-tuberculosis T-lymphocyte function with tumour necrosis factor antagonists 
Reactivation of latent Mycobacterium tuberculosis (Mtb) infection is a major complication of anti-tumour necrosis factor (TNF)-α treatment, but its mechanism is not fully understood. We evaluated the effect of the TNF antagonists infliximab (Ifx), adalimumab (Ada) and etanercept (Eta) on anti-mycobacterial immune responses in two conditions: with ex vivo studies from patients treated with TNF antagonists and with the in vitro addition of TNF antagonists to cells stimulated with mycobacterial antigens. In both cases, we analysed the response of CD4+ T lymphocytes to purified protein derivative (PPD) and to culture filtrate protein (CFP)-10, an antigen restricted to Mtb. The tests performed were lymphoproliferation and immediate production of interferon (IFN)-γ. In the 68 patients with inflammatory diseases (rheumatoid arthritis, spondylarthropathy or Crohn's disease), including 31 patients with a previous or latent tuberculosis (TB), 14 weeks of anti-TNF-α treatment had no effect on the proliferation of CD4+ T lymphocytes. In contrast, the number of IFN-γ-releasing CD4+ T lymphocytes decreased for PPD (p < 0.005) and CFP-10 (p < 0.01) in patients with previous TB and for PPD (p < 0.05) in other patients (all vaccinated with Bacille Calmette-Guérin). Treatments with Ifx and with Eta affected IFN-γ release to a similar extent. In vitro addition of TNF antagonists to CD4+ T lymphocytes stimulated with mycobacterial antigens inhibited their proliferation and their expression of membrane-bound TNF (mTNF). These effects occurred late in cultures, suggesting a direct effect of TNF antagonists on activated mTNF+ CD4+ T lymphocytes, and Ifx and Ada were more efficient than Eta. Therefore, TNF antagonists have a dual action on anti-mycobacterial CD4+ T lymphocytes. Administered in vivo, they decrease the frequency of the subpopulation of memory CD4+ T lymphocytes rapidly releasing IFN-γ upon challenge with mycobacterial antigens. Added in vitro, they inhibit the activation of CD4+ T lymphocytes by mycobacterial antigens. Such a dual effect may explain the increased incidence of TB in patients treated with TNF antagonists as well as possible differences between TNF antagonists for the incidence and the clinical presentation of TB reactivation.
doi:10.1186/ar1994
PMCID: PMC1779425  PMID: 16859506

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