Publications by authors named "Pascal Hilliquin"

26 Publications

  • Page 1 of 1

Real-World 1-Year Retention Rate of Subcutaneous Tocilizumab Treatment in Patients with Moderate to Severe Active Rheumatoid Arthritis: TANDEM Study.

Rheumatol Ther 2021 Mar 20;8(1):95-108. Epub 2020 Nov 20.

Rheumatology Department, CHU de Brest, Univ Brest, Inserm UMR1227, Lymphocytes B et Autoimmunité, Brest, France.

Introduction: Drug retention is particularly relevant to assess long-term treatments. This real-world study mainly aimed to describe 1-year retention rate (RR) of subcutaneously administered tocilizumab (TCZ-SC) in patients with moderate to severe active rheumatoid arthritis (RA).

Methods: This non-interventional, prospective, multicenter study (NCT02608112) was conducted in patients with RA initiating TCZ-SC treatment, with an 18-month follow-up. RR was estimated at month 12 in the overall population and baseline subgroups (combination with a conventional synthetic disease-modifying antirheumatic drug (csDMARD) or not, age, body mass index, methotrexate dose), using the Kaplan-Meier method. Patient compliance to TCZ-SC was described using the 5-item Compliance Questionnaire for Rheumatology (CQR5).

Results: At inclusion 75% of the 285 analyzed patients were women, mean RA duration was 9 ± 9 years, previous RA treatments included biological agents (63%) and/or csDMARDs (94%), mean Disease Activity Score 28 joints-Erythrocyte Sedimentation Rate (DAS28-ESR) was 4.8 ± 1.2. TCZ-SC RR at month 12 was estimated to be 64% (95% CI 58%-69%) with no statistical differences between subgroups. Clinical results improved with TCZ-SC; the proportion of patients treated with combined glucocorticoids decreased from 49% to 22% at month 12. At each follow-up time, at least 80% of patients were high adherers to TCZ-SC (at least 80% of theoretical injections). Among the 286 patients with at least one TCZ-SC injection, 25 patients (9%) experienced serious adverse events related to TCZ-SC with no differences according to patient age.

Conclusions: This real-world study corroborates the RR at month 12 previously shown in interventional studies on TCZ-SC. Our data suggest there are no differences according to patient's profile (age, BMI), methotrexate doses, and TCZ-SC use.

Trial Registration: NCT02608112.
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http://dx.doi.org/10.1007/s40744-020-00253-0DOI Listing
March 2021

Increased high molecular weight adiponectin and lean mass during tocilizumab treatment in patients with rheumatoid arthritis: a 12-month multicentre study.

Arthritis Res Ther 2020 09 29;22(1):224. Epub 2020 Sep 29.

Laboratoire de Biochimie Médicale, UF de Biochimie Endocrinienne et Métabolique, CHU de Besançon; EA 3920 Marqueurs pronostiques et facteurs de régulation des pathologies cardiaques et vasculaires, Université de Bourgogne Franche Comté, Besançon, France.

Background: Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular (CV) disease. Adiponectin is involved in the metabolism of glucose and lipids with favourable effects on CV disease, especially its high molecular weight (HMW) isoform. Body composition changes are described in RA with various phenotypes including obesity. The effects of tocilizumab on serum adiponectin and body composition, especially fat mass, in patients with RA are not well determined.

Methods: Patients with active RA despite previous csDMARDs and/or bDMARDs and who were tocilizumab naïve were enrolled in a multicentre open-label study. They were evaluated at baseline, 1, 3, 6 and 12 months. Clinical assessment included body mass index (BMI) and anthropometric measurements. Lipid and metabolic parameters, serum adiponectin (total and HMW), leptin, resistin and ghrelin were measured at each time point. Body composition (lean mass, fat mass, % fat, fat in the android and gynoid regions) was evaluated at baseline, 6 and 12 months.

Results: One hundred seven patients were included. Both total and HMW adiponectin significantly increased from baseline to month 3, peaking respectively at month 3 (p = 0.0105) and month 1 (p < 0.0001), then declining progressively until month 6 to 12 and returning to baseline values. Significant elevation in HMW adiponectin persisted at month 6 (p = 0.001). BMI and waist circumference significantly increased at month 6 and 12, as well as lean mass at month 6 (p = 0.0097). Fat mass, percentage fat and android fat did not change over the study period. Lipid parameters (total cholesterol and LDL cholesterol) increased while glycaemia, insulin and HOMA-IR remained stable. Serum leptin, resistin and ghrelin did not change during follow-up.

Conclusions: Tocilizumab treatment in RA patients was associated with a significant increase in total and HMW adiponectin, especially at the onset of the treatment. Tocilizumab also induced a significant gain in lean mass, while fat mass did not change. These variations in adiponectin levels during tocilizumab treatment could have positive effects on the CV risk of RA patients. In addition, tocilizumab may have an anabolic impact on lean mass/skeletal muscle.

Trial Registration: The ADIPRAT study was a phase IV open-label multicentre study retrospectively registered on ClinicalTrials.gov under the number NCT02843789 (date of registration: July 26, 2016).
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http://dx.doi.org/10.1186/s13075-020-02297-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523335PMC
September 2020

Two-year abatacept retention rate in clinical practice in the French ACTION cohort.

Joint Bone Spine 2019 11 25;86(6):753-759. Epub 2019 Jul 25.

Centre de rhumatologie, hôpital Pierre-Paul-Riquet, CHU de Toulouse, place du Dr Baylac, TSA 40 031, 31059 Toulouse cedex 9, France; CPTP, Inserm UMR 1043, CHU Purpan, BP 3028, 31024 Toulouse cedex 3, France.

Objectives: Abatacept retention rates were evaluated in the French cohort in the prospective ACTION study (2010-2013), which included patients with moderate-to-severe rheumatoid arthritis managed in everyday clinical practice and started on intravenous abatacept therapy.

Methods: Two-year abatacept retention rates were evaluated in 455 patients classified according to treatment line, body mass index (BMI), and status for rheumatoid factor (RF) and anti-citrullinated peptide antibody (ACPA).

Results: After 2 years, the overall abatacept retention rate was 44%. The retention rate was non-significantly higher in the patients with vs. without a history of unresponsiveness to at least one biologic (48.1% vs. 41.8%, respectively). No significant retention rate differences were found across BMI categories (444 patients; <25, 45.5%; ≥25 to <30, 48.9%; and ≥30, 36.6%). Neither were any significant differences demonstrated according to RF and ACPA status (RF+ and ACPA+, 45.7%; RF+ or ACPA+, 43.8%; and FR- and ACPA-, 39.1%).

Conclusion: The 44% 2-year retention rate in the French ACTION cohort supports the usefulness of abatacept therapy. In this study, retention was not associated with treatment line, BMI, or antibody status.
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http://dx.doi.org/10.1016/j.jbspin.2019.07.006DOI Listing
November 2019

Rachialgie.

Rev Prat 2016 Dec;66(10):e471-e478

Service de rhumatologie, Centre hospitalier sud-francilien, Corbeil-Essonnes, France.

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December 2016

Rachialgie : un motif fréquent de consultation.

Rev Prat 2016 Dec;66(10):e470

Service de rhumatologie, Centre hospitalier sud-francilien, Corbeil-Essonnes, France.

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December 2016

[What's new in rheumatology].

Rev Prat 2016 Oct;66(8):869-873

Service de rhumatologie, centre hospitalier Sud-Francilien, Corbeil-Essonnes, France.

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October 2016

Glucocorticoid-sparing in patients suffering from rheumatoid arthritis and treated with tocilizumab: the SPARE-1 study.

Clin Exp Rheumatol 2016 Mar-Apr;34(2):303-10. Epub 2016 Mar 3.

Rheumatology, Purpan Hospital, Toulouse, France.

Objectives: To describe steroid-sparing in rheumatoid arthritis (RA) patients treated with tocilizumab (TCZ).

Methods: To evaluate the proportion of RA patients treated with more than 5 mg of prednisone (or equivalent)/day and starting TCZ who can receive less than 5 mg/day after 12 months without intensification of disease-modifying anti-rheumatic drugs (DMARDs), we conducted a non-interventional, multicentre, prospective study from 2011 to 2013. We included patients with moderate-to-severe RA, >18 years old, starting TCZ and receiving corticosteroids (GCs) at a dose greater than 5 mg/day of prednisone for at least 3 months.

Results: Amongst the 307 analysed patients (78% women, median RA duration: 8 years, mean DAS28-ESR: 5.1±1.3), 40% (95%CI=[35-46]) reached the targeted daily prednisone dose at M12, without conventional synthetic (cs)DMARD intensification. Predictive factors were RA duration of 5 years or less (OR=2.60, p=0.01), daily prednisone dose of 7.5 mg or less (OR=2.12, p=0.03), and low ESR value before the first TCZ infusion (OR=0.86, p=0.047). The proportion of patients with no more GCs increased up to 20% at M12. Disease activity improved over the 1-year period (DAS28-ESR LDA and remission in 41% and 33% of patients at M12, respectively). Amongst the 314 patients analysed for safety, at least one AE and at least one SAE were reported in 211 patients (67%) and in 48 patients (15%), respectively. No unexplained safety signal arose with TCZ.

Conclusions: A biological DMARD as TCZ allows reducing both GCs dose and disease activity in RA patients. Nevertheless, corticosteroid spare in real life is probably lower.
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July 2016

Onset of action of etanercept in rheumatoid arthritis based on patient-reported outcomes.

Clin Exp Rheumatol 2012 Mar-Apr;30(2):266-8. Epub 2012 Apr 13.

Department of Rheumatology, Cochin Hospital, Paris, France.

Background: Onset of action is considered to be a key characteristic of the treatment of rheumatoid arthritis. The efficacy of TNF blockers is usually evaluated after 2 to 4 weeks of therapy. EULAR-RAID is a valid patient-reported outcome composite index.

Objectives: To evaluate the onset of action of etanercept in rheumatoid arthritis patients according to the EULAR-RAID score.

Methods: An open-label, single-arm (etanercept 50 mg/week), 12-week study was carried out in patients with active rheumatoid arthritis. Patients were asked to fill in the RAID score questionnaire each day for the first 14 days of the study and at the 4-week and 12-week visits. Onset of action was evaluated by considering: a) changes over time of the EULAR-RAID score; b) the percentage of patients achieving an 'acceptable' condition according to the EULAR-RAID score (e.g. a score ≤3.00).

Results: Of the 120 screened patients, 108 (female: 75%), age 54±13 years, disease duration 8±7 years) were enrolled. At baseline, patients had active rheumatoid arthritis (DAS: 5.4±0.8; CRP: 18.±30mg/l). Eleven patients dropped out of the study. A statistically significant decrease in the EULAR-RAID score was observed by day 1 of therapy. Kaplan-Meier estimates of the proportion of patients achieving an acceptable RAID score were 29.8 [% 95% C.I. 23.8-X42.6], 50 % [95% C.I. 41-60.9], 51.9% [95% C.I. 43.8-63.7], 56% [95% C.I. 49.5-69.1, after 1, 2, 4 and 12 weeks of therapy respectively. The median time to achieve an acceptable EULAR-RAID score was 14.5 days.

Conclusions: This open-label study suggests that patients can perceive a clinically relevant improvement by the first week of etanercept therapy.
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July 2012

Early effect of hyaluronic acid intra-articular injections on serum and urine biomarkers in patients with knee osteoarthritis: An open-label observational prospective study.

J Orthop Res 2012 May 24;30(5):679-85. Epub 2011 Oct 24.

Rheumatology, Pavillon 2B, Centre Hospitalier Lyon Sud, 165 chemin du grand revoyet 69495, Pierre-Bénite cedex, France.

The aim of the study was to investigate the effect of hyaluronic acid (HA) intra articular injections (IA) on osteoarthritis (OA) biomarkers in patients with knee OA. Prospective open label study. Fifty-one patients with unilateral symptomatic K-OA received IA injections of 2mL of HA on days (D) 1, 7, 14 and were followed 3 months. At D-15 patients were examined and X-rays performed, to exclude patients with bilateral K-OA, or those with more than three symptomatic OA joints. From 15 days (D-15) before the first injection to D90 concomitant therapies were unchanged. Walking pain (WP) on VAS was obtained at each visit. Urine (U) and serum (S) samples were obtained at D-15, D1, D30, and D90. S-C2C, S-Cartilage oligomeric matrix protein, S-HA, S-CS 846 epitope, S-type II collagen propeptide, and U-type II collagen C telopeptide (U-CTX II/creatinin) were assayed. Predictive factors of response were analyzed using logistic regression. Correlations between variables were obtained using Spearman test. Forty-five patients were analyzed. Between D-15 and D1 there was no difference for any biomarkers At D1, WP (SD) was correlated with U-CTX II/creat (p = 0.006). Between D1 and D90: U-CTX II/creat decreased significantly. After adjustment for confounding variables there was a significant correlation between clinical response and U-CTX II/creat variation. U-CTX II and S-HA at baseline were independently predictive of clinical response. This study showed that 90 days after HA IA injections, U-CTX II levels significantly decrease compared to baseline, suggesting a slowdown of type II collagen degradation.
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http://dx.doi.org/10.1002/jor.21580DOI Listing
May 2012

The influence of the definition of patient global assessment in assessment of disease activity according to the Disease Activity Score (DAS28) in rheumatoid arthritis.

J Rheumatol 2011 Nov 1;38(11):2326-8. Epub 2011 Oct 1.

Department of Rheumatology B, Cochin Hospital, Paris; Pfizer SAS France, Paris. France.

Objective: Patient global assessment (PGA) is one of the 4 items included in the Disease Activity Score (DAS28) for evaluation of activity of rheumatoid arthritis (RA). We studied the influence of the use of 3 different techniques of PGA on the assessment of disease activity.

Methods: We evaluated 3 different DAS28 according to the technique of PGA in 108 patients with active RA before and after 12 weeks of etanercept therapy.

Results: The reliability (intraclass coefficient of correlation) between screening and baseline was very high and similar for the 3 DAS28. The percentage of patients in the different states of disease (from remission to higher disease activity) and the sensitivity to change across the 3 DAS28 scales were very similar.

Conclusion: The different techniques of collection of PGA to be included in the DAS calculation yield similar results. However, an accepted, unequivocal technique should be encouraged in order to reduce heterogeneity in scoring DAS among patients with RA.
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http://dx.doi.org/10.3899/jrheum.110487DOI Listing
November 2011

Comparison of general practitioners and rheumatologists' prescription patterns for patients with knee osteoarthritis.

BMC Musculoskelet Disord 2011 Apr 12;12:72. Epub 2011 Apr 12.

Univ Paris Diderot, Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, Fédération de Rhumatologie, 75010, Paris, France.

Background: To compare the prescription modalities of general practitioners (GPs) and rheumatologists (RHs) for symptomatic knee osteoarthritis (OA) and to determine correlates with prescription of low-dose NSAIDs.

Methods: This observational, prospective, national survey was carried out among a national representative sample of GPs (n = 808) and RHs (n = 134). Each physician completed a medical questionnaire for the 2 most recent patients fulfilling the ACR criteria for knee OA.

Results: GPs and RHs included 1,570 and 251 patients, respectively. Mean pain level of the knee (on a VAS, 0-100 mm) was greater for GP patients than for RH patients (49.8 ± 16.3 vs. 46.2 ± 17.1 mm, respectively; p < 0.01). As compared with patients of RHs, those of GPs more frequently had another joint affected by OA: 71.2% vs. 63.7% (p < 0.0001) and more often had hypertension and diabetes mellitus (p < 0.05). As compared with RHs, GPs more frequently prescribed low-dose NSAIDs (p < 0.0001), oral NSAIDs (p < 0.05), and topical NSAIDs (p < 0.0001) but less frequently symptomatic slow-acting drugs for OA (p < 0.01). Moreover, GPs more frequently recommended rehabilitation (p < 0.01) and loss of weight (p < 0.0001). Logistic regression analysis revealed an association of low-dose NSAIDs prescription and prescription by GPs, prescription of topical NSAIDs, no prescription of oral NSAIDs or coxibs and no intra-articular injection of steroids.

Conclusions: This study identified speciality-related variability in some aspects of the management of knee OA. The clinical profile of patients with knee OA differed between GPs and RHs.
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http://dx.doi.org/10.1186/1471-2474-12-72DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094262PMC
April 2011

Management recommendations for knee osteoarthritis: how usable are they?

Joint Bone Spine 2010 Oct 18;77(5):458-65. Epub 2010 Sep 18.

School of Rehabilitation, University of Ottawa, Ottawa, Canada.

Objectives: Despite the availability of practice guidelines for the management of knee osteoarthritis, inadequacies in practices of clinicians and patients have been found, leading to suboptimal outcomes. Literature has shown that simply disseminating management recommendations does not lead to adherence. Research suggests that barriers to use should be identified and addressed to improve adherence. The objective of this study was to identify barriers to use of conservative management recommendations for knee osteoarthritis by patients, general practitioners and physiotherapists.

Methods: Following systematic reviews of evidence and guidelines, 12 key management recommendations were elaborated on four themes: medication, exercise, self-management and occupation. Focus groups were separately done with patients with knee osteoarthritis, general practitioners and physiotherapists to assess barriers to the use of recommendations.

Results: Patients and general practitioners appeared generally fatalistic with regards to knee osteoarthritis, with physiotherapists being more positive regarding long-term improvement of knee osteoarthritis. For medication, discrepancies were found between recommendations and views of clinicians. Both patients and general practitioners appeared ambivalent towards exercise and activity, recognizing its usefulness but identifying it at the same time as a cause of knee osteoarthritis. Patients and general practitioners appeared to consider weight loss particularly difficult.

Discussion/conclusions: Barriers specific to each knee osteoarthritis management recommendation and stakeholder group were identified. Recommendations to address these barriers were elaborated. Results of this study can be used to develop implementation strategies to overcome identified barriers, with the goal of facilitating the use of guideline recommendations and improving outcomes.
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http://dx.doi.org/10.1016/j.jbspin.2010.08.001DOI Listing
October 2010

Transcriptome analysis describing new immunity and defense genes in peripheral blood mononuclear cells of rheumatoid arthritis patients.

PLoS One 2009 Aug 27;4(8):e6803. Epub 2009 Aug 27.

GenHotel-EA3886, Evry University, Paris 7 University Medical School, AutoCure European Consortium member, Evry, France.

Background: Large-scale gene expression profiling of peripheral blood mononuclear cells from Rheumatoid Arthritis (RA) patients could provide a molecular description that reflects the contribution of diverse cellular responses associated with this disease. The aim of our study was to identify peripheral blood gene expression profiles for RA patients, using Illumina technology, to gain insights into RA molecular mechanisms.

Methodology/principal Findings: The Illumina Human-6v2 Expression BeadChips were used for a complete genome-wide transcript profiling of peripheral blood mononuclear cells (PBMCs) from 18 RA patients and 15 controls. Differential analysis per gene was performed with one-way analysis of variance (ANOVA) and P values were adjusted to control the False Discovery Rate (FDR<5%). Genes differentially expressed at significant level between patients and controls were analyzed using Gene Ontology (GO) in the PANTHER database to identify biological processes. A differentially expression of 339 Reference Sequence genes (238 down-regulated and 101 up-regulated) between the two groups was observed. We identified a remarkably elevated expression of a spectrum of genes involved in Immunity and Defense in PBMCs of RA patients compared to controls. This result is confirmed by GO analysis, suggesting that these genes could be activated systemically in RA. No significant down-regulated ontology groups were found. Microarray data were validated by real time PCR in a set of nine genes showing a high degree of correlation.

Conclusions/significance: Our study highlighted several new genes that could contribute in the identification of innovative clinical biomarkers for diagnostic procedures and therapeutic interventions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0006803PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2729373PMC
August 2009

Validation of the KOFUS (Knee Osteoarthritis Flare-Ups Score).

Joint Bone Spine 2009 May 17;76(3):268-72. Epub 2009 Mar 17.

Service de Rhumatologie, Centre hospitalier Henri Mondor, Créteil 94010, France.

Objective: To develop a diagnostic score for knee osteoarthritis flare-ups and to evaluate its sensitivity and specificity.

Methods: We used two epidemiological databases built using the same methodology. One database was from a general-practice study and served to develop the score, whereas the other was from a rheumatology study and served to validate the score. Physicians determined the flare-up status of each patient. The rheumatologist diagnosis was the reference standard. Logistic regression was performed to identify factors significantly associated with having a flare-up.

Results: Of the 6085 patients in the general-practice database, 52.3% had a knee osteoarthritis flare-up. The score was built by assigning points to features that were present, with a weighting system based on the odds ratio of each feature for having a flare-up (0, feature absent; 1, morning stiffness for longer than 20 min; 2, pain causing nocturnal awakenings and knee effusion; 3, limping, joint swelling, and increased warmth over the knee). The score could range from 0 to 14. The receiver-operating characteristic curve showed that 7 was the best cutoff for diagnosing a flare-up. In the rheumatologist database, the numbers of patients having a flare-up were 274 (46.4%) based on the score and 270 (45.7%) based on the rheumatologist diagnosis. Sensitivity of the score was 87.0%, specificity 87.9%, positive predictive value 85.8%, and negative predictive value 89.0%. The Youden index was 0.75.

Conclusion: A score equal to or greater than 7 points correlated well with a rheumatologist diagnosis of flare-up. Our score may constitute a valid objective criterion for standardizing the diagnosis of knee osteoarthritis flare-up, most notably when screening patients for inclusion in therapeutic trials.
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http://dx.doi.org/10.1016/j.jbspin.2008.07.018DOI Listing
May 2009

Genetic and expression analysis of CASP7 gene in a European Caucasian population with rheumatoid arthritis.

J Rheumatol 2008 Oct 1;35(10):1912-8. Epub 2008 Sep 1.

GenHotel-EA3886, Evry-Paris VII Universities, Evry-Genopole, France.

Objective: To study the possible role of the caspase 7 (CASP7) gene in susceptibility to rheumatoid arthritis (RA) in a European Caucasian population.

Methods: CASP7 rs2227309 single nucleotide polymorphism (SNP) was genotyped in 197 French RA trio families and in 252 European RA families available for replication using Taqman allelic discrimination assay. Relative quantification of caspase 7 isoforms alpha and beta mRNA expression was performed from whole blood in 25 unrelated patients with RA and in 15 healthy controls by real-time quantitative reverse transcription-polymerase chain reaction. The genetic analyses for association and linkage were performed using the comparison of allelic frequencies, the transmission disequilibrium test, and the genotype relative risk.

Results: We observed, in the first sample, a significant association of rs2227309-AA genotype with RA [p=0.03, odds ratio (OR) 2.11 (95% CI 1.0-4.6)]. The second sample did not show any significant association of the AA genotype with RA [p=0.6, OR 0.87 (95% CI 0.4-1.8)]. When the 2 samples were combined, no significant association of the AA genotype [p=0.3, OR 1.32 (95% CI 0.8-2.2)] was observed. CASP7 isoforms alpha and beta mRNA were expressed in patients with RA at lower level than in healthy controls (-89%, p=0.003 and -47%, p=0.01; respectively).

Conclusion: CASP7 rs2227309 SNP was not associated with RA in a European Caucasian population. Nevertheless, CASP7 isoforms alpha and beta could have an involvement in the apoptosis process in RA.
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October 2008

A critical appraisal of guidelines for the management of knee osteoarthritis using Appraisal of Guidelines Research and Evaluation criteria.

Arthritis Res Ther 2007 ;9(6):R126

Département d'épidémiologie, biostatistiques et de santé au travail, Université McGill, Montréal, Canada.

Clinical practice guidelines have been elaborated to summarize evidence related to the management of knee osteoarthritis and to facilitate uptake of evidence-based knowledge by clinicians. The objectives of the present review were summarizing the recommendations of existing guidelines on knee osteoarthritis, and assessing the quality of the guidelines using a standardized and validated instrument--the Appraisal of Guidelines Research and Evaluation (AGREE) tool. Internet medical literature databases from 2001 to 2006 were searched for guidelines, with six guidelines being identified. Thirteen clinician researchers participated in the review. Each reviewer was trained in the AGREE instrument. The guidelines were distributed to four groups of three or four reviewers, each group reviewing one guideline with the exception of one group that reviewed two guidelines. One independent evaluator reviewed all guidelines. All guidelines effectively addressed only a minority of AGREE domains. Clarity/presentation was effectively addressed in three out of six guidelines, scope/purpose and rigour of development in two guidelines, editorial independence in one guideline, and stakeholder involvement and applicability in none. The clinical management recommendation tended to be similar among guidelines, although interventions addressed varied. Acetaminophen was recommended for initial pain treatment, combined with exercise and education. Nonsteroidal anti-inflammatory drugs were recommended if acetaminophen failed to control pain, but cautiously because of gastrointestinal risks. Surgery was recommended in the presence of persistent pain and disability. Education and activity management interventions were superficially addressed in most guidelines. Guideline creators should use the AGREE criteria when developing guidelines. Innovative and effective methods of knowledge translation to health professionals are needed.
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http://dx.doi.org/10.1186/ar2339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2246248PMC
March 2008

Association and expression study of PRKCH gene in a French Caucasian population with rheumatoid arthritis.

J Clin Immunol 2008 Mar 24;28(2):115-21. Epub 2007 Oct 24.

GenHotel-EA3886, Evry-Paris VII Universities, Evry-Genopole, France.

We study the association between three protein kinase C, eta gene polymorphisms (+8134C/T, rs912620, rs959728), and susceptibility to rheumatoid arthritis. One hundred French Caucasian rheumatoid arthritis trio families were genotyped. Relative quantification of protein kinase C, eta mRNA expression was performed from whole blood in 24 unrelated rheumatoid arthritis patients and in 16 healthy controls. Our results showed no significant association or linkage between the protein kinase C, eta polymorphisms, and rheumatoid arthritis. The protein kinase C, eta mRNA was expressed at lower level in rheumatoid arthritis unrelated patients than in healthy controls. This study shows that protein kinase C, eta gene is not a Rheumatoid Arthritis major susceptibility genetic factor in the French Caucasian population. Furthermore, the lower expression of this gene in rheumatoid arthritis patients comparing to healthy controls suggests that protein kinase C, eta could be associated with the patho-physiologic mechanism of rheumatoid arthritis.
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http://dx.doi.org/10.1007/s10875-007-9143-6DOI Listing
March 2008

HSPD1 is not a major susceptibility gene for rheumatoid arthritis in the French Caucasian population.

J Hum Genet 2007 11;52(12):1036-1039. Epub 2007 Oct 11.

GenHotel-EA3886, Evry-Paris VII Universities, 2 rue Gaston Crémieux, 91057, Evry-Genopole cedex, France.

The heat shock 60-kDa protein 1 (HSP60) is involved in immune and inflammatory reactions, which are hallmarks of rheumatoid arthritis (RA). HSP60 is encoded by the HSPD1 gene located on 2q33, one of the suggested RA susceptibility loci in the French Caucasian population. Our aim was to test whether HSPD1 is a major susceptibility gene by studing families from the French Caucasian population. Three single nucleotide polymorphisms (SNPs) were studied in 100 RA trio families, and 100 other families were used for replication. Genetic analyses were performed by comparing allelic frequencies, by applying the transmission disequilibrium test, and by assessing the genotype relative risk. We observed a significant RA association for the C/C genotype of rs2340690 in the first sample. However, this association was not confirmed when the second sample was added. The two other SNPs and the haplotype analysis did not give any significant results. We conclude that HSPD1 is not a major RA susceptibility gene in the French Caucasian population.
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http://dx.doi.org/10.1007/s10038-007-0201-yDOI Listing
February 2008

Characterisation of patients with postmenopausal osteoporosis in French primary healthcare.

Drugs Aging 2007 ;24(7):603-14

Rheumatology Department, Montpellier University Hospital, Montpellier, France.

Background: The public health burden of osteoporosis is high, principally because of increased risk of fractures and associated morbidity, handicap and mortality. Osteoporotic fracture prevention is therefore an important public health goal. General practitioners (GPs) play a key role in the management of osteoporosis, both in ensuring timely diagnosis and in providing treatment. Little information is available on standards of care for postmenopausal women with osteoporosis in general practice.

Objectives: The primary objective of this study was to describe risk factors and treatment in postmenopausal women with osteoporosis. Secondary objectives were to evaluate treatment compliance and to assess the impact of osteoporosis on quality of life.

Methods: This observational, cross-sectional, pharmacoepidemiological study was performed in a primary-care setting in France. A random sample of GPs recruited postmenopausal women with a diagnosis of osteoporosis who had been followed by the investigator for at least 2 years. At inclusion, investigators completed a questionnaire providing information on patient age, osteoporosis duration, risk factors and treatment history. The first three patients recruited by each investigator completed a questionnaire providing information on sociodemographic features, osteoporosis treatments and quality of life. Treatment compliance was quantified using the Test d'Evaluation de l'Observance and quality of life evaluated using the 12-item Short Form Health Survey (SF-12).

Results: Overall, 389 physicians included 3,097 patients, of whom 1,053 completed the patient questionnaire. Risk factors for osteoporotic fracture were identified in 2,148 patients (69.4%), most frequently personal or maternal antecedents of osteoporotic fracture and a low body mass index. Of these, 946 (44.0%) presented more than one risk factor. At the time of diagnosis, 629 patients (59.7%) presented fractures, which involved the vertebrae in 51.7% of cases, the wrist in 40.5% and the hip in 5.4%. Older patients were more likely to have fractures at the time of diagnosis and to have multiple fractures. After diagnosis, at least one new fracture occurred in 201 patients (19.2%). Multivariate logistic regression analysis identified age >70 years, diagnosis at least 10 years previously, diagnosis based on the presence of a fracture, biochemical and haematological evaluation at the time of diagnosis, and a change in osteoporosis treatment in the previous 2 years as being significantly associated with incident fracture risk. At inclusion, 1,019 patients (97.4%) were receiving treatment for osteoporosis, most frequently weekly bisphosphonates (71.6% of treatments). Most patients (81.0%) had been treated for at least 1 year. Treatment compliance was high in 61% of patients and low in <5%. Patient variables associated with high compliance were being retired, prescription of bisphosphonates and, among the bisphosphonate users, prescription of weekly formulations. SF-12 quality-of-life scores were low, ranging from 38.6 (energy/vitality) to 65.1 (social functioning) out of a possible maximum score of 100. Baseline variables associated with SF-12 physical component summary scores included age, height loss since menopause, diagnosis following a fracture, fracture incidence since diagnosis, time since diagnosis and treatment with bisphosphonates.

Conclusions: In this study of postmenopausal osteoporosis in the French primary healthcare setting, many women with osteoporosis were diagnosed following a fracture. Although most were treated with bone-consolidating drugs, compliance was suboptimal in a significant minority. Osteoporotic fracture was associated with reduced quality of life.
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http://dx.doi.org/10.2165/00002512-200724070-00007DOI Listing
October 2007

The ITGAV rs3738919-C allele is associated with rheumatoid arthritis in the European Caucasian population: a family-based study.

Arthritis Res Ther 2007 ;9(4):R63

GenHotel-EA3886, Evry-Paris VII Universities, 91057 Evry-Genopole cedex, France.

The integrin alpha(v)beta3, whose alpha(v) subunit is encoded by the ITGAV gene, plays a key role in angiogenesis. Hyperangiogenesis is involved in rheumatoid arthritis (RA) and the ITGAV gene is located in 2q31, one of the suggested RA susceptibility loci. Our aim was to test the ITGAV gene for association and linkage to RA in a family-based study from the European Caucasian population. Two single nucleotide polymorphisms were genotyped by PCR-restriction fragment length polymorphism in 100 French Caucasian RA trio families (one RA patient and both parents), 100 other French families and 265 European families available for replication. The genetic analyses for association and linkage were performed using the comparison of allelic frequencies (affected family-based controls), the transmission disequilibrium test, and the genotype relative risk.We observed a significant RA association for the C allele of rs3738919 in the first sample (affected family-based controls, RA index cases 66.5% versus controls 56.7%; P = 0.04). The second sample showed the same trend, and the third sample again showed a significant RA association. When all sets were combined, the association was confirmed (affected family-based controls, RA index cases 64.6% versus controls 58.1%; P = 0.005). The rs3738919-C allele was also linked to RA (transmission disequilibrium test, 56.5% versus 50% of transmission; P = 0.009) and the C-allele-containing genotype was more frequent in RA index cases than in controls (RA index cases 372 versus controls 339; P = 0.002, odds ratio = 1.94, 95% confidence interval = 1.3-2.9). The rs3738919-C allele of the ITGAV gene is associated with RA in the European Caucasian population, suggesting ITGAV as a new minor RA susceptibility gene.
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http://dx.doi.org/10.1186/ar2221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2206364PMC
April 2008

Paget's disease of bone in the French population: novel SQSTM1 mutations, functional analysis, and genotype-phenotype correlations.

J Bone Miner Res 2007 Feb;22(2):310-7

Hôpital Lariboisière, Paris, France.

Unlabelled: Mutation screening of the SQSTM1 gene in 94 French patients with PDB revealed two novel point-mutations (A381V and L413F) and two new compound heterozygous genotypes (P392L/A381V and P392L/A390X). Functional analysis showed an increased level of SQSTM1/p62 protein in PDB patients and truncated forms of the protein encoded by the A390X allele. Clinical data indicate that PDB patients with SQSTM1 mutation are younger at PDB diagnosis and have more extensive bone lesions.

Introduction: Paget's disease of bone (PDB) is a common chronic disease of the skeleton, with a strong genetic component. A recurrent mutation (P392L) was first identified on chromosome 5, in the Sequestosome 1 (SQSTM1) gene. Several other mutations of the SQSTM1 gene have been described in PDB patients, affecting the ubiquitin-associated domain (UBA) of the SQSTM1/p62 protein. The objectives of this study were to evaluate the frequency of the SQSTM1 mutations in French PBD patients, to study the expression of the SQSTM1/p62 protein, and to search for genotype-phenotype correlations.

Materials And Methods: Blood was obtained from 94 unrelated French PDB patients and 100 controls for mutation screening of exons 7 and 8, encoding for the UBA domain of SQSTM1. Epstein-Barr virus (EBV)-immortalized B-cell lymphocytes were established from 13 patients, giving access to functional analysis of the gene and the SQSTM1/p62 expressions using real-time PCR and Western blot.

Results: Mutations of the SQSTM1 gene were identified in 12 of the 94 PDB patients (13%). Eight patients carried P392L. Two novel missense mutations were identified: L413F and A381V. This A381V mutation and A390X were found in distinct patients already carriers of P392L. The SQSTM1/p62 protein expression in PDB patients increased when zero, one, or two mutations were present, and SQSTM1 truncated forms were associated with the A390X mutation. The mean age of PDB diagnosis was younger in patients with the SQSTM1 mutation. PDB was more extensive in patients who carried a SQSTM1 mutation.

Conclusions: Mutations of SQSTM1 are present in the French population. PDB patients with and without the SQSTM1 mutation have an increased level of SQSTM1/p62, caused by overproduction of the protein, probably involved in the pathophysiology of PDB. The presence of the SQSTM1 mutation may be a worsening factor for PDB.
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http://dx.doi.org/10.1359/jbmr.061106DOI Listing
February 2007

Osteoarthritis of the knee and hip and activity: a systematic international review and synthesis (OASIS).

Joint Bone Spine 2006 Jul 6;73(4):442-55. Epub 2006 May 6.

Université Claude-Bernard, Lyon, France.

Unlabelled: The goal of this study was to determine which activities in four domains, daily life, exercises, sports and occupational activities, should be recommended, in favor or against, for the patient suffering from knee or hip OA.

Methods: Scientific literature was searched in Medline, Embase and Cochrane databases for articles in French or English, reporting original data. The articles were evaluated with standardized epidemiological criteria. Seventy-two articles were retained. Recommendations were graded according to the level of scientific evidence (A high, B moderate, C clinical consensus) and were formulated for primary care.

Conclusions And Recommendations: For activity of daily life (ADL), the OASIS group states with a moderate level of scientific evidence, that ADL are a risk factor for knee OA and that risk increases with intensity and duration of activity. The group concludes that healthy subjects as well as OA patients in general can pursue a high level of physical activity, provided the activity is not painful and does not predispose to trauma (grade B). Radiographic or clinical OA is not a contraindication to promoting activity in patients who have a sedentary lifestyle (grade C). For exercises and other structured activities pursued with a goal of health improvement, the group states with a high level of scientific evidence that they have a favourable effect on pain and function in the sedentary knee OA patient. The OASIS group recommends the practice of exercises and other structured activities for the sedentary patient with knee OA (grade A). Static exercises are not favored over dynamic exercises, availability, preference and tolerance being the criteria for the choice of an exercise (grade A). As results deteriorate when exercises are stopped, they should be performed at a frequency of between one and three times per week (grade B). Professional assistance can be useful in improving initial compliance and perseverance (grade B). There is no scientific argument to support halting exercise in case of an OA flare-up (grade C). For sports and recreational activity, the group states with a high degree of scientific evidence, that these activities are a risk factor for knee and hip OA and that the risk correlates with intensity and duration of exposure. The group also states, with a high degree of scientific evidence, that the risk of OA associated with sport is lesser than that associated with a history of trauma and overweight. No firm conclusion could be drawn about the possible protective role of sports such as cycling, swimming or golf. The OASIS group recommends that athletes should be informed that joint trauma is a greater risk factor than the practice of sport (Grade A). The high level athlete should be informed that the risk of OA is associated with the duration and intensity of exposure (Grade B). The OA patient can continue to engage regularly in recreational sports as long as the activity does not cause pain (Grade C). The OA patient who practices a sport at risk for joint trauma should be encouraged to change sport (Grade C). For occupational activity, the OASIS group states with a high level of scientific evidence that there is a relationship between occupational activity and OA of the knee and hip. The precise nature of biomechanical stresses leading to OA remains unclear but factors such as high loads on the joint, unnatural body position, heavy lifting, climbing and jumping may contribute to knee and hip OA. The group recommends that taking an occupational history should always be part of managing the OA patient (Grade B). In the knee or hip OA patient, work-related activity that produces or maintains pain should be avoided (Grade B). Physicians should be alerted by the early knee and hip signs and symptoms in workers exposed to stresses that are known or supposed to favour knee or hip OA (Grade C).
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http://dx.doi.org/10.1016/j.jbspin.2006.03.001DOI Listing
July 2006

Impact of osteoarthritis: results of a nationwide survey of 10,000 patients consulting for OA.

Joint Bone Spine 2005 May;72(3):235-40

Department of Rheumatology, Hospital Pitié-Salpêtrière, Paris, France.

Unlabelled: The clinical burden of osteoarthritis (OA) is difficult to assess because of the substantial variability between patients.

Objective: Evaluate the human consequences of OA in patients.

Methods: In 2000, a nationwide survey was conducted among a sample of more than 5000 physicians (90.3% general practitioners and 9.7% rheumatologists), representative of French physicians. Each recruited the first two patients consulting for hip, knee, or hand OA after the survey began. The functional limitation rates were compared with those for age- and sex-matched controls obtained from the 1999 population-based national survey on disability (HID survey).

Results: Clinical and demographic information was obtained for 10,412 OA patients (mean-age 66.2 years, sex ratio F:M 1.96). The OA diagnosis was based on both clinical and radiographic findings for 84.5%. More than 80% of all patients reported limitations in their activities of daily living, either for basic tasks, leisure activities, or work. OA patients were substantially more limited than controls: the standardised limitation rate ratios (SLRR) were 6.0 (95% confidence interval: 5.9:6.1) for mobility outside the home, 2.1 (2.0:2.1) for house cleaning, 1.6 (1.5:1.8) for dressing oneself, and 1.6 (1.5:1.8) for sports. Of the 17.6% of OA patients and 17.5% of the controls still working, 64.4% and 14.3%, respectively, were limited in their job duties, for a SLRR of 4.5 (4.3:4.7).

Conclusion: This study shows that OA-related disability has a significant impact on the retired as well as on those still involved in the labour market.
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http://dx.doi.org/10.1016/j.jbspin.2004.08.009DOI Listing
May 2005

Inhibition of inducible NO synthase by TH2 cytokines and TGF beta in rheumatoid arthritic synoviocytes: effects on nitrosothiol production.

Nitric Oxide 2002 May;6(3):271-82

Laboratoire de Biochimie A, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris V, 27 rue du fg St Jacques, 75014 Paris, France.

The aim of this study was to compare the effects on NO production of IL-4, IL-10, and IL-13 with those of TGF-beta. RA synovial cells were stimulated for 24 h with IL-1 beta (1 ng/ml), TNF-alpha (500 pg/ml), IFN-gamma (10(-4)IU/ml) alone or in combination. Nitrite was determined by the Griess reaction, S-nitrosothiols by fluorescence, and inducible NO synthase (iNOS) by immunofluorescence and fluorescence activated cell sorter analysis (FACS). In other experiments, IL-4, IL-10, IL-13, and TGF beta were used at various concentrations and were added in combination with proinflammatory cytokines. The addition of IL-1 beta, TNF-alpha, and IFN-gamma together increased nitrite production: 257.5 +/- 35.8 % and S-nitrosothiol production : 413 +/- 29%, P < 0.001. None of these cytokines added alone had any significant effect. iNOS synthesis increased with NO production. IL-4, IL-10, IL-13, and TGF beta strongly decreased the NO production caused by the combination of IL-1 beta, TNF-alpha, and IFN-gamma. These results demonstrate that stimulated RA synoviocytes produce S-nitrosothiols, bioactive NO* compounds, in similar quantities to nitrite. IL-4, IL-10, IL-13, and TGF-beta decrease NO production by RA synovial cells. The anti-inflammatory properties of these cytokines may thus be due at least in part to their effect on NO metabolism.
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http://dx.doi.org/10.1006/niox.2001.0418DOI Listing
May 2002