Rheumatoid Arthritis: Ravaud P

Fautrel B, Pham T, Mouterde G, Le Loët X, Goupille P, Guillemin F, Ravaud P, Cantagrel A, Dougados M, Puéchal X, Sibilia J, Soubrier M, Mariette X, Combe B, Anonymous00061, Anonymous00062. · Pierre and Marie Curie University - Paris VI, UFR de Médecine, France. · Joint Bone Spine. · Pubmed #18037319 No free full text.

Abstract: OBJECTIVES: To update French Society for Rheumatology guidelines regarding the use of TNFalpha antagonists for treating patients with rheumatoid arthritis (RA). METHODS: Existing guidelines were updated using the AGREE instrument. Items that required updating were selected by a task force, the relevant literature was critically appraised, and new wording was suggested by a limited committee of experts then validated by the task force and subsequently by a panel of external reviewers. The three-topic structure of the recommendations (indication, initiation, and adjustment) and the final algorithm format were maintained. RESULTS: Of the 12 items, five were selected for updating; one pertained to the indication for treatment with TNFalpha antagonists, two to treatment initiation, and two to treatment adjustment. Of the four initially recommended criteria for determining that TNFalpha antagonist therapy is indicated, the first three were left unchanged (confirmed diagnosis of RA; active disease for more than 1month with objective evidence of inflammation or progressive structural damage, or dependency on glucocorticoid therapy, or progressive radiographic damage; and failure to respond adequately to methotrexate - or another agent when methotrexate is contraindicated - in the optimal tolerated dosage). The fourth and last criterion was modified as follows: co-morbidities should be evaluated in order to distinguish absolute contraindications from relative contraindications that require referral to a specialist. Of the four initial recommendations about TNFalpha antagonist initiation, the first and fourth were left unchanged (a workup should be performed prior to treatment initiation, and the patient should receive regular standardized follow-up); the second and third recommendations were modified as follows: there is no evidence that one TNFalpha antagonist is more effective than the others, and concomitant methotrexate therapy is generally advisable, regardless of the TNFalpha antagonist used. Of the four recommendations about treatment adjustment, the first two were modified as follows: the goal of treatment is to achieve the EULAR response criteria or better; and in non-responders, the dosage or dosing interval can be modified when infliximab is used, methotrexate should be added when the TNFalpha antagonist is used alone, and in all other situations the patient should be switched to a different TNFalpha antagonist. The other two recommendations about treatment adjustment were left unchanged (patients who fail to tolerate one TNFalpha antagonist can be switched to another TNFalpha antagonist if allowed by the nature of the adverse event; and when a remission is achieved, reduction or discontinuation of symptomatic drugs - most notably glucocorticoids - is appropriate, followed in the event of a prolonged remission by changes in the dosage and/or dosing interval of the TNFalpha antagonist or concomitant disease-modifying drug). CONCLUSION: These recommendations are designed to help practitioners optimize the use of TNFalpha antagonists in patients with RA seen in everyday practice. They do not constitute regulations.

Gossec L, Tubach F, Dougados M, Ravaud P. · AP-HP, Rheumatology B Department, Cochin Hospital, 27 rue du faubourg St Jacques, Paris 5 University, Paris, France. · Am J Med Sci. · Pubmed #18030180 No free full text.

Abstract: BACKGROUND: International recommendations such as the CONSORT and International Conference on Harmonisation statements recognize patient adherence to prescribed treatment as an important aspect of a treatment's evaluation, but this issue is little assessed. OBJECTIVES: To evaluate how medication adherence was assessed and reported in recently published randomized controlled trials (RCTs). MATERIAL AND METHODS: All publications of RCTs assessing pharmacological treatments in 6 major chronic diseases published in high-impact-factor journals in 2003 and 2004 were selected from the Medline database. Two investigators analyzed how medication adherence was assessed and reported. RESULTS: A total of 192 publications were analyzed: 71 in HIV infection, 48 diabetes mellitus, 24 rheumatoid arthritis, 23 asthma, 15 hypertension, 7 osteoporosis, and 4 about 2 of these diseases. The assessment of medication adherence was documented in 69 (35.9%) publications, by counting pill intake in half of these. Results of adherence were reported in 64 (33.3%) publications. Adherence was reported as a quantitative measure: Proportion of the treatment prescribed in 27 articles and as a qualitative measure (adherent patient, yes/no) in 41 (in 4 reports both techniques were used). When reported, the median intake of prescribed medication was 93%, and the median proportion of "nonadherent" patients was 6.2%. CONCLUSIONS: There is important variability in the assessment and reporting of medication adherence in published RCTs of pharmacological treatments of selected chronic diseases, for a given disease and across diseases. Standardization is advisable to allow for comparisons among studies.

Miceli-Richard C, Comets E, Verstuyft C, Tamouza R, Loiseau P, Ravaud P, Kupper H, Becquemont L, Charron D, Mariette X. · Rhumatologie, Institut Pour la Santé et la Recherche Médicale U 802, Université Paris-Sud 11, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France. · Ann Rheum Dis. · Pubmed #17673491 No free full text.

Abstract: OBJECTIVE: To determine whether tumour necrosis factor (TNF) gene polymorphisms and/or the shared epitope are genetic predictors of the 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 = 388) treated with ADA plus methotrexate (MTX) (n = 182), ADA plus any other DMARD (n = 98) or ADA alone (n = 108). The primary outcome was ACR50 at 12 weeks. Patients underwent genotyping for HLA-DRB1 and three TNF gene polymorphisms (-238A/G,-308A/G and-857C/T). Extended haplotypes involving HLA-DRB1 and TNF loci were reconstructed using the PHASE program. RESULTS: A total of 151 patients (40%) had an ACR50 response at week 12. Neither the number of HLA-DRB1 shared epitope copies nor presence of the three TNF polymorphisms tested separately was significantly associated with ACR50 response at week 12. However, haplotype reconstruction of the TNF locus revealed that the GGC haplotype (-238G/-308G/-857C) in a homozygous form (i.e. present in more than half of the patients) was significantly associated with a lower ACR50 response to ADA at 12 weeks (34% vs. 50% in patients without the haplotype) (p = 0.003; pa = 0.015). This effect was more important in the subgroup of patients concomitantly treated with MTX. CONCLUSION: This large pharmacogenetic study provides preliminary data indicating that a single TNF locus haplotype (-238G/-308G/-857C), present on both chromosomes is associated with a lower response to ADA, mainly in patients treated with ADA and MTX.

Baron G, Boutron I, Giraudeau B, Ravaud P. · Département d'Epidémiologie Biostatistique et Recherche Clinique, INSERM, U738, Groupe Hospitalier Bichat-Claude Bernard, 46 rue Henri Huchard, 75018 Paris, France. · Ann Rheum Dis. · Pubmed #17158823 links to  free full text

Abstract: BACKGROUND: Because an increasing number of clinical trials evaluating disease-modifying antirheumatic drugs in rheumatoid arthritis (RA) emphasise radiographic outcomes as a primary outcome, using a reproducible radiographic measure should be placed at a premium. AIM: To evaluate the reporting of radiographic methods in randomised trials assessing radiographic outcomes in RA. METHODS: Medline was searched for randomised controlled trials assessing radiographic outcomes published between January 1994 and December 2005 in general medical and specialty journals with a high impact factor. One reader extracted data (radiographic acquisition, assessment and reproducibility) using a standardised form. RESULTS: A total of 46 reports were included in the analysis. The mean (SD) methodological quality scores on the Jadad scale (range 0-5) and the Delphi list (0-9) were 2.9 (1.2) and 6.4 (1.3), respectively. Use of a standardised procedure for the acquisition of the radiographs was reported in 2 (4.3%) articles. 2 (4.3%) reports indicated that the quality of the radiographs was evaluated. In 65.2% of the reports, > or = 2 radiographic scores were used. Reporting of radiographic assessment was well detailed for number of readers (91.3%), information on readers (71.7%), blinding (91.4%) and how films were viewed (74.0%). The reproducibility of the reading was reported in 39.1% of the articles. CONCLUSION: The reporting of results of randomised controlled trials of radiographic outcomes in RA shows great variability in radiographic scores used. Reporting of radiographic methods could be improved upon, especially the acquisition procedure and the reproducibility of the reading.

Schaeverbeke T, Vicaut E, Cohen A, Ravaud P. · Service de Rhumatologie, CHU Pellegrin, Bordeaux 33000. · Presse Med. · Pubmed #17078593 No free full text.

Abstract: The cardiovascular impact of the non-steroidal anti-inflammatory drugs and the higher cardiovascular mortality during treatment of inflammatory rheumatism impose a rigorous evaluation of the cardiovascular risk of rheumatic patients. Large epidemiological studies have identified risk factors for cardiovascular diseases such as the age, male gender, family history (infarct, stroke), tobacco consumption, systolic arterial pressure, renal insufficiency, hypercholesterolemia, diabetes mellitis, sedentariness, obesity and "electric" ventricular hypertrophy. Some equations make it possible to evaluate the absolute cardiovascular risk at the individual level, which corresponds to the onset risk of a stroke in the 10 years to come in a subject according to the number and importance of each of his risk factors. It has been demonstrated that the correction of one or more risk factors reduce the overall cardiovascular risk justifying the strategies for evaluating this risk to define therapeutic intervention thresholds. The impact of a long-term anti-inflammatory treatment or an inflammatory disease such as rheumatoid arthritis has not been the subject of specific epidemiological study allowing these elements to be included in an equation of the estimation of the cardiovascular risk. However, the introduction of on anti-inflammatory treatment, likely to increase the cardiovascular risk of a patient, certainly justifies an evaluation of the absolute cardiovascular risk.

Tubach F, Wells GA, Ravaud P, Dougados M. · Département d'Epidémiologie, Biostatistique et Recherche Clinique, Groupe Hospitalier Bichat-Claude Bernard (AP-HP), INSERM U738, Faculté Xavier Bichat (Université Paris 7), Paris, France. · J Rheumatol. · Pubmed #16206363 No free full text.

Abstract: The importance of determining a minimal clinically important difference (MCID) and a low disease activity state (LDAS) as treatment targets in clinical trials no longer needs to be demonstrated. However, many methodological issues remain: whether these thresholds should be defined for each criterion or for composite criteria, whether there is a difference between the LDAS and patient acceptable symptom state (PASS), how to determine these thresholds (i.e., the wording of the questions and the statistical approach), and whether there are confounding factors in their evaluation. We consider these methodological issues and discuss their impact. Methods to determine the thresholds must be standardized, and recommendations could be endorsed by an OMERACT module. Threshold values for the MCID and LDAS should be determined according to data-driven and experts' opinions and approaches.

Chopin F, Garnero P, le Henanff A, Debiais F, Daragon A, Roux C, Sany J, Wendling D, Zarnitsky C, Ravaud P, Thomas T. · INSERM U890, Rheumatology Department, University Hospital of St-Etienne, France. · Ann Rheum Dis. · Pubmed #17644538 No free full text.

Abstract: BACKGROUND: Rheumatoid arthritis (RA) is associated with systemic bone loss, subchondral bone erosion and cartilage degradation under the control of pro-inflammatory cytokines, including tumour necrosis factor alpha (TNFalpha). Therefore, we tested the hypothesis that administration of infliximab, an anti-TNFalpha drug in the treatment of RA, would modulate systemic and local bone resorption and reduce cartilage degradation. METHODS: We performed a prospective study of a multicentric cohort of 48 women, mean (SD) age 54.2 (12.1) years old, with severe RA for 11.4 (7.8) years, who started infliximab after failure of other disease-modifying antirheumatic drugs. At baseline and 6, 22 and 54 weeks after initiating Infliximab therapy we measured the following biochemical markers: pro-collagen serum type I N-terminal propeptide (PINP), a marker of bone formation; serum C-terminal cross-linked telopeptide of type I collagen (CTX-I), a marker of cathepsin K-mediated bone collagen degradation believed to reflect systemic bone resorption; serum C-terminal cross-linked telopeptide of type I collagen (ICTP), an index of matrix metalloprotease (MMP) mediated type I collagen degradation reflecting preferential joint metabolism; and urinary CTX-II a biochemical markers of cartilage degradation. Total hip and lumbar spine bone mineral density (BMD) was assessed at baseline, and after 6 and 12 months by dual-energy x-ray absorptiometry (DXA). No patient received bisphosphonates while 77% were under oral glucocorticoids. RESULTS: BMD remained stable over 1 year. Serum CTX-I levels rapidly decreased by 19% and 28% at week 6 and week 22, respectively (analysis of variance (ANOVA) p = 0.032) values returning to pre-treatment level at week 54. By contrast, ICTP levels progressively declined with a maximal 25% decrease at week 54 (ANOVA p = 0.028). By contrast, PINP levels remained stable over time, which led to a 30 to 40% improvement in bone remodelling balance, as assessed by the ratios PINP/CTX and PINP/ICTP (p<0.05). There was no significant change of urinary CTX-II in the whole population, but a slight decrease (ANOVA p = 0.041) in those with pre-treatment levels above the upper limit of normal range. CONCLUSIONS: In summary, the improvement in the formation/resorption marker ratio suggests beneficial systemic and local bone effects of infliximab in patients with RA.

Mariette X, Ravaud P, Steinfeld S, Baron G, Goetz J, Hachulla E, Combe B, Puéchal X, Pennec Y, Sauvezie B, Perdriger A, Hayem G, Janin A, Sibilia J. · Service de Rhumatologie, Hôpital de Bicêtre AP-HP, and Université Paris-Sud, Le Kremlin Bicêtre, France. · Arthritis Rheum. · Pubmed #15077311 links to  free full text

Abstract: OBJECTIVE: There is no effective treatment for patients with primary Sjögren's syndrome (SS). Since tumor necrosis factor alpha (TNF alpha) could be a key element in the pathogenesis of primary SS, we conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the effect of infliximab in primary SS. METHODS: A total of 103 patients with primary SS were randomly assigned to receive infliximab infusions (5 mg/kg) or placebo at weeks 0, 2, and 6 and were followed up for 22 weeks. All patients fulfilled the new American-European Consensus Group criteria for SS and had active disease as assessed by values >50 mm on 2 of 3 visual analog scales (VAS) (0-100 mm) that evaluated joint pain, fatigue, and buccal, ocular, skin, vaginal, or bronchial dryness. A favorable overall response was defined as the patient having > or =30% improvement between weeks 0 and 10 in the values on 2 of the 3 VAS. Secondary end points were values on each VAS separately, the number of tender and swollen joints, the basal salivary flow rate, results of the Schirmer test for lacrimal gland function, the focus score on labial salivary gland biopsy, the level of C-reactive protein, and the erythrocyte sedimentation rate evaluated at weeks 0, 10, and 22, as well as quality of life evaluated by use of the generic Short Form 36 questionnaire administered at weeks 0, 10, and 22. RESULTS: At week 10, 26.5% of patients receiving placebo and 27.8% of patients treated with infliximab had a favorable overall response (P = 0.89), and at week 22, 20.4% of the placebo group and 16.7% of the infliximab group had a favorable response (P = 0.62). In addition, the 2 groups did not differ in any of the secondary end points over the 22 weeks of the trial. Severe adverse events reported in the infliximab group did not differ from those observed in previous studies. CONCLUSION: This randomized, double-blind, placebo-controlled study of an anti-TNF agent did not show any evidence of efficacy of infliximab in primary SS.

Tubach F, Salmon D, Ravaud P, Allanore Y, Goupille P, Bréban M, Pallot-Prades B, Pouplin S, Sacchi A, Chichemanian RM, Bretagne S, Emilie D, Lemann M, Lorthololary O, Mariette X, Anonymous00120. · Université Paris 7 Denis Diderot; INSERM U738; Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Bichat, Biostatistique et Recherche Clinique, Paris, France. · Arthritis Rheum. · Pubmed #19565495 No free full text.

Abstract: OBJECTIVE: Tuberculosis (TB) is associated with anti-tumor necrosis factor (anti-TNF) monoclonal antibody (mAb) therapy, but whether this association is drug-specific remains a concern. Our objective was to describe cases of TB associated with anti-TNF mAb therapy, identify risk factors, and estimate the incidence. METHODS: We conducted an incidence study and a case-control analysis to investigate the risk of newly diagnosed TB associated with the use of anti-TNF agents. As part of the French Research Axed on Tolerance of Biotherapies (RATIO) registry, for 3 years we collected cases of TB among French patients receiving anti-TNF mAb therapy for any indication; for each case, 2 patients treated with anti-TNF agents served as control subjects. RESULTS: We collected 69 cases of TB in patients treated for rheumatoid arthritis (n = 40), spondylarthritides (n = 18), inflammatory colitis (n = 9), psoriasis (n = 1) and Behçet's disease (n = 1) with infliximab (n = 36), adalimumab (n = 28), and etanercept (n = 5). None of the patients had received correct chemoprophylactic treatment. The sex- and age-adjusted incidence rate of TB was 116.7 per 100,000 patient-years. The standardized incidence ratio (SIR) was 12.2 (95% confidence interval [95% CI] 9.7-15.5) and was higher for therapy with infliximab and adalimumab than for therapy with etanercept (SIR 18.6 [95% CI 13.4-25.8] and SIR 29.3 [95% CI 20.3-42.4] versus SIR 1.8 [95% CI 0.7-4.3], respectively). In the case-control analysis, exposure to infliximab or adalimumab versus etanercept was an independent risk factor for TB (odds ratio [OR] 13.3 [95% CI 2.6-69.0] and OR 17.1 [95% CI 3.6-80.6], respectively). Other risk factors were age, the first year of anti-TNF mAb treatment, and being born in an endemic area. CONCLUSION: The risk of TB is higher for patients receiving anti-TNF mAb therapy than for those receiving soluble TNF receptor therapy. The increased risk with early anti-TNF treatment and the absence of correct chemoprophylactic treatment favor the reactivation of latent TB.

Benhamou M, Rincheval N, Roy C, Foltz V, Rozenberg S, Sibilia J, Schaeverbeke T, Bourgeois P, Ravaud P, Fautrel B. · Department of Rheumatology, University of Paris VI, Pitie Salpetriere Hospital, Paris, France. · J Rheumatol. · Pubmed #19286850 No free full text.

Abstract: OBJECTIVE: To compare rheumatologists' prescription for first disease modifying antirheumatic drug (DMARD) in early rheumatoid arthritis (RA) in real-life settings with 2 clinical practice guidelines (CPG), the French Society of Rheumatology/STPR 2004 and EULAR/ESCISIT 2007, and thus assess the gap between practices and guidelines. Method. ESPOIR was a French multicenter cohort study of 813 patients with early arthritis between 2002 and 2005. "Definite" and "probable" RA were defined according to ACR criteria and the level of diagnostic certainty. The objectives were to assess conformity between the observed first-line DMARD prescribed for those patients and the DMARD recommended in the guidelines; and to conduct a mail survey of patients' usual rheumatologists to investigate the reasons for their nonconformity with guidelines. RESULTS: In total 627 patients with definite or probable RA were identified. Conformity rates were 58% for STPR guidelines and 54% for EULAR guidelines. At 6 months, 83 (34%) patients with early RA did not receive any DMARD. Main determinants associated with conformity to guidelines were disease activity and presence of severity-predictive factors. The main reason leading to a discrepancy between guidelines and daily practice appeared to be diagnostic uncertainty, i.e., the difficulty to reliably assess RA diagnosis as early as the first visits to the rheumatologist. CONCLUSION: There is a substantial gap between CPG and rheumatologists' daily practice concerning the first DMARD to prescribe in early RA. This is explained mainly by diagnostic uncertainty. More attention should be paid in future guidelines to the diagnostic difficulties of early RA.

Baron G, Ravaud P, Samson A, Giraudeau B. · AP-HP, Hôpital Bichat, Biostatistique et Recherche Clinique, INSERM, U738, and Université Paris, France. · Arthritis Rheum. · Pubmed #18163406 links to  free full text

Abstract: OBJECTIVE: To assess the impact, in terms of statistical power and bias of treatment effect, of approaches to dealing with missing data in randomized controlled trials of rheumatoid arthritis with radiographic outcomes. METHODS: We performed a simulation study. The missingness mechanisms we investigated copied the process of withdrawal from trials due to lack of efficacy. We compared 3 methods of managing missing data: all available data (case-complete), last observation carried forward (LOCF), and multiple imputation. Data were then analyzed by classic t-test (comparing the mean absolute change between baseline and final visit) or F test (estimation of treatment effect with repeated measurements by a linear mixed-effects model). RESULTS: With a missing data rate close to 15%, the treatment effect was underestimated by 18% as estimated by a linear mixed-effects model with a multiple imputation approach to missing data. This bias was lower than that obtained with the case-complete approach (-25%) or LOCF approach (-35%). This statistical approach (combination of multiple imputation and mixed-effects analysis) was moreover associated with a power of 70% (for a 90% nominal level), whereas LOCF was associated with a power of 55% and a case-complete power of 58%. Analysis with the t-test gave qualitatively equivalent but poorer quality results, except when multiple imputation was applied. CONCLUSION: Our simulation study demonstrated multiple imputation, offering the smallest bias in treatment effect and the highest power. These results can help in planning trials, especially in choosing methods of imputation and data analysis.

Mayoux-Benhamou A, Giraudet-Le Quintrec JS, Ravaud P, Champion K, Dernis E, Zerkak D, Roy C, Kahan A, Revel M, Dougados M. · Department of Rehabilitation, Cochin Hospital, 27 Rue du Faubourg Saint Jacques, 75679 Paris Cedex 14, France. · J Rheumatol. · Pubmed #18085742 No free full text.

Abstract: OBJECTIVE: To determine the effect of education on the exercise habits of patients with rheumatoid arthritis (RA) after 6 and 12 months. METHODS: We studied 208 outpatients recruited between June 2001 and December 2002. This was a prospective controlled randomized trial. The active group received a multidisciplinary education program, including training in home-based exercises and guidelines for leisure physical activity (PA). The control group received a booklet added to usual medical care. Compliance with home-based exercises was defined as a practice rate >or= 30% of the prescribed training. Compliance with leisure PA was defined as >or= 20% increase in Baecke questionnaire score. Additional assessments involved possible predictors of compliance and changes with regard to the compliance. RESULTS: At 6-month followup, home-based exercise and leisure PA compliance were significantly higher [13.5% vs 1%, respectively (p = 0.001); and 28.2% vs 13.8% (p = 0.02)], but were not at 12 months. Predictors of leisure PA compliance at 6 months included participating in the active group (odds ratio 2.74, 95% CI 1.17 to 6.38) and previous low leisure PA (OR 6.01, 95% CI 2.47 to 14.61), with decreased fatigue (FACIT-F mean -2.94 +/- 8.04 vs -0.1 +/- 7.25 for noncompliant subjects; p = 0.04) and improved psychological status (Arthritis Impact Measurement Scale mean -1.25 +/- 3.12 vs 0.11 +/- 3.39; p = 0.03). CONCLUSION: Education of patients with RA may increase compliance especially with leisure PA, particularly when it is poor at baseline, but these effects are limited and short-term.

Denis B, Lefort A, Flipo RM, Tubach F, Lemann M, Ravaud P, Salmon D, Mariette X, Lortholary O, Anonymous00380. · Université Paris V, Hôpital Necker-Enfants Malades, Service des Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker-Pasteur, Paris, France. · Clin Microbiol Infect. · Pubmed #18076664 No free full text.

Abstract: This study investigated the long-term outcome of patients with tuberculosis (TB) as a complication of tumour necrosis factor (TNF)-alpha blocker therapy. All TB cases (n = 21) complicating TNF-alpha blocker therapy from French university hospitals were collated between January 2000 and September 2002. Outcome was assessed via a postal questionnaire during September 2005. The mortality rate after 4 years was 4.8%, and one patient had relapsed and six (29%) patients had recommenced TNF-alpha antagonist treatment, after appropriate anti-TB therapy, without reactivation. These data support the concept that TNF-alpha antagonists can be restarted in TB patients provided that adequate anti-TB treatment has been completed.

Combe B, Benessiano J, Berenbaum F, Cantagrel A, Daurès JP, Dougados M, Fardellone P, Fautrel B, Flipo RM, Goupille P, Guillemin F, Le Loet X, Logeart I, Mariette X, Meyer O, Ravaud P, Rincheval N, Saraux A, Schaeverbeke T, Sibilia J. · University Hospital, Montpellier, France. · Joint Bone Spine. · Pubmed #17905631 No free full text.

Abstract: OBJECTIVES: The French Society of Rheumatology initiated a large national multicenter, longitudinal and prospective cohort, the so-called "ESPOIR cohort study" in order to set up databases to allow various investigations on diagnosis, prognostic markers, epidemiology, pathogenesis and medico-economic factors in the field of early arthritis and rheumatoid arthritis. METHODS: Patients were recruited if they had undifferentiated arthritis or rheumatoid arthritis, of less than 6 months disease duration and if they were DMARD and steroids naïve. Patients have then to be followed every 6 months during the first 2 years then every year during at least 10 years. Clinical, biological, radiographic and medico-economic databases have been constituted to fit in the different objectives of the project and more than 20 scientific studies have already been accepted by the scientific committee. RESULTS: 813 patients were included (76.75% were female). The mean age was 48.07+/-12.55 years. The mean delay from the onset of symptoms to referral to the rheumatologist was 74.8+/-76.6 days. Baseline swollen and tender joint counts were 7.19+/-5.37 and 8.43+/-7.01; DAS28 score was 5.11+/-1.31. CRP was abnormal in 38.9% of the patients; 44.2%, 45.8% and 38.8% had respectively IgM rheumatoid factor (RF), IgA RF and anti-CCP antibodies. HLA DRB1*01 or 04 genes were found in 56.7% of them. Finally, 22% of these patients had erosions on hand or feet at baseline.

Giraudet-Le Quintrec JS, Mayoux-Benhamou A, Ravaud P, Champion K, Dernis E, Zerkak D, Ouslimani A, Courpied JP, Revel M, Kahan A, Dougados M. · AP-HP, Hôpital Cochin, Université René-Descartes, Faculté de Médecine, Paris, France. · J Rheumatol. · Pubmed #17610321 No free full text.

Abstract: OBJECTIVE: To evaluate the effect on health and functional status of an 8-week group-education program for rheumatoid arthritis (RA) in addition to usual medical care. METHODS: All consecutive inpatients and outpatients with RA (ACR criteria) were asked to participate in this randomized, prospective, controlled trial. The educational intervention consisted of 8 weekly ambulatory sessions, each lasting 6 hours. Followup was undertaken after 1 year. The primary criterion for judging effectiveness was the Health Assessment Questionnaire (HAQ) score; secondary criteria consisted of coping, medical knowledge, patient global satisfaction, and quality of life scores before the intervention and after 1 year. RESULTS: We asked 1242 inpatients and outpatients to participate in the study: 208 (16.75%) agreed (104 in each group). At baseline, there was no statistically significant difference between the 2 groups. After 1 year, no statistically significant difference was observed between the 2 groups in change in HAQ score: -0.04 +/- 0.46 (education group) vs -0.06 +/- 0.47 (control group) (p = 0.79). Statistically significant differences were found in 3 domains: patient coping (-1.22 +/- 5.55 vs -0.22 +/- 3.81; p = 0.03), knowledge (3.42 +/- 4.73 vs 0.73 +/- 3.78; p < 0.0001), and satisfaction (10.07 +/- 11.70 vs 5.72 +/- 13.77; p = 0.02), all of which were better for the group attending the education sessions. CONCLUSION: Despite improvements in patient coping, knowledge, and satisfaction, the education program was not found to be effective at 1 year. There may have been methodological problems relating to the sensitivity of questionnaires and patient selection, and tailored educational interventions should be considered.

Nguyen M, Kabir M, Ravaud P. · René Descartes University, Institute of Rheumatology, Cochin Hospital, Paris, France. · Clin Drug Investig. · Pubmed #17516696 No free full text.

Abstract: OBJECTIVE: To determine the efficacy and safety profile of 6-month treatment with leflunomide 20mg daily in patients with acute rheumatoid arthritis (RA) receiving treatment from 197 office-based rheumatologists in France. METHODS: This open-label, prospective, multicentre study included 378 ambulatory RA patients who received leflunomide at a loading dose of 100mg daily on days 1-3, followed by 20mg daily for 6 months. The primary efficacy endpoint was a >/=20% response according to the American College of Rheumatology criteria (ACR 20) after 6 months. Secondary efficacy criteria were a >/=50% response (ACR 50) and a >/=70% response (ACR 70), as well as disease activity score (DAS28) responses. RESULTS: Among the 407 selected patients, 378 patients were included in the study, all of whom were treated with leflunomide. Female patients made up 78.6% of the study population; the mean age was 57.7 +/- 12.0 years, and the mean disease duration was 9.7 +/- 8.5 years. At 6 months, the ACR 20 response rate was 48.2% (95% confidence interval [CI] 43-53%). ACR 50 and 70 response rates were 25.3% (95% CI 21.0-30.1) and 11.7% (95% CI 8.6-15.4%), respectively. According to the DAS28, 21.8% of patients had a good response, 39.9% a moderate response, and 38.2% were non-responders. The DAS28 response rate was thus 61.8% (95% CI 56.5-66.9%). Mean improvements in tender joint count were -5.6 +/- 7.4 (from baseline of 12.2 +/- 6.7), in swollen joint count were -4.2 +/- 5.7 (from baseline of 9.8 +/- 5.8), and in investigator's global assessment of RA disease activity were -20.2 +/- 25.1 (from baseline of 51.6 +/- 17.1). Treatment-related adverse events caused 15.9% of patients to discontinue the study prematurely. Serious adverse events possibly related to therapy were reported in 2.4% of patients. CONCLUSIONS: This 6-month study carried out under daily routine practice conditions in a typical sample of RA patients showed a favourable efficacy and safety profile for leflunomide 20mg daily. The study confirms the findings of the earlier phase II and III study programme in more selected patient samples.

Tubach F, Ravaud P, Salmon-Céron D, Petitpain N, Brocq O, Grados F, Guillaume JC, Leport J, Roudaut A, Solau-Gervais E, Lemann M, Mariette X, Lortholary O, Anonymous00158. · Université Paris 7, Faculté de Medecine, Paris, France. · Clin Infect Dis. · Pubmed #17051484 No free full text.

Abstract: BACKGROUND: Patients treated with tumor necrosis factor-alpha (TNF-alpha) antagonists have an increased risk of infection, but infection due to Legionella pneumophila has rarely been described in patients receiving such therapy. METHODS: A registry involving 486 clinical departments in France was designed by a multidisciplinary group (Recherche Axée sur la Tolérance des Biothérapies [RATIO]) to collect data on opportunistic and severe infections occurring in patients treated with TNF-alpha antagonists. All cases are reported to RATIO in accordance with national health authorities and validated by infectious disease experts. The legionellosis rate among patients treated with TNF-alpha antagonists was compared with the rate in France overall. RESULTS: We report a 1-year consecutive series of 10 cases of L. pneumophila pneumonia in France in 2004, including 6 cases treated with adalimumab, 2 treated with etanercept, and 2 treated with infliximab. The median patient age was 51 years (range, 40-69 years). Eight patients were treated for rheumatoid arthritis, 1 was treated for cutaneous psoriasis, and 1 was treated for pyoderma gangrenosum. The median duration of TNF-alpha antagonist treatment at onset of infection was 38.5 weeks (range, 3-73 weeks). Eight patients were receiving concomitant treatment with corticosteroids, and 6 were receiving treatment with methotrexate. The relative risk of legionellosis when receiving treatment with a TNF-alpha antagonist, compared with the relative risk in France overall, was estimated to be between 16.5 and 21.0. We also report a second episode of confirmed legionellosis following the reintroduction of infliximab therapy. CONCLUSIONS: L. pneumophila pneumonia is a potentially severe but curable infection that might complicate anti-TNF-alpha therapy. In patients receiving anti-TNF-alpha who develop pneumonia, legionellosis should be systematically investigated, and first-line antibiotic therapy should be efficient against L. pneumophila.

Fautrel B, Constantin A, Morel J, Vittecoq O, Cantagrel A, Combe B, Dougados M, Le Loët X, Mariette X, Pham T, Puéchal X, Sibilia J, Soubrier M, Ravaud P, Anonymous00369. · Service de Rhumatologie, Groupe Hospitalier Pitié-Salpêtrière, UFR de Médecine, Université Pierre et Marie-Curie-Paris-VI, 83, Boulevard de l'Hôpital, 75651 Paris cedex 13, France. · Joint Bone Spine. · Pubmed #16798046 No free full text.

Abstract: OBJECTIVES: To develop recommendations for TNFalpha-antagonist therapy in patients with rheumatoid arthritis (RA) seen in everyday practice, under the aegis of the French Society for Rheumatology. METHOD: We used the methods recommended by the French Agency for Healthcare Accreditation and Evaluation, the AGREE collaboration, and the European League against Rheumatism (EULAR). The recommendations focus on patient selection, monitoring, and treatment adjustments. RESULTS: Criteria for selecting patients eligible for TNFalpha-antagonist treatment of RA include: 1) a definitive diagnosis of RA; 2) disease activity for longer than 1 month, including presence of objective signs of inflammation; or radiographic progression; 3) previous failure of methotrexate in the highest tolerated dosage or of another disease-modifying antirheumatic drug in patients with contraindications to methotrexate; 4) absence of contraindications to TNFalpha-antagonist therapy. When starting TNFalpha-antagonist therapy 1) a thorough baseline evaluation should be conducted; 2) any of the three available agents can be used, as no differences in efficacy have been identified in patient populations; 3) concomitant methotrexate therapy is recommended regardless of the TNFalpha antagonist used; and 4) patients should receive standardized follow-up at regular intervals. Treatment adjustments should be based on the following: 1) the treatment objective is achievement of a EULAR response; 2) when such a response is not achieved, the dosage or dosing interval can be changed, or the patient can be switched to another TNFalpha antagonist; 3) in patients who experience intolerance to a TNFalpha antagonist, another TNFalpha antagonist may be tried, depending on the nature of the adverse event; 4) occurrence of a remission should lead to a reduction in symptomatic medications, most notably glucocorticoids where used; in the event of a prolonged remission, either the TNFalpha antagonist or the concomitant disease-modifying antirheumatic drug may be reduced. CONCLUSION: These recommendations are intended to help physicians use TNFalpha antagonists in their everyday practice with RA patients. They do not constitute regulations.

Ethgen M, Boutron I, Baron G, Giraudeau B, Sibilia J, Ravaud P. · Centre Hospitalier Universitaire de Hautepierre, Strasbourg, France. · Ann Intern Med. · Pubmed #15998751 links to  free full text

Abstract: BACKGROUND: Reports of clinical trials usually emphasize benefits and give less attention to harms. PURPOSE: To compare the reporting of harm in trials of pharmacologic and nonpharmacologic treatment. DATA SOURCES: MEDLINE and the Cochrane Central Register of Controlled Trials. STUDY SELECTION: Reports of randomized, controlled trials assessing treatment of rheumatic disease that were published between January 1999 and January 2005. DATA EXTRACTION: A standardized abstraction form was used to extract data. DATA SYNTHESIS: 193 articles were analyzed. After adjustment for medical area, sample size, funding source, and multicenter trials, data on harm were more often described in pharmacologic treatment reports than in nonpharmacologic treatment reports in reporting adverse events (odds ratio, 5.2 [95% CI, 2.1 to 12.9]), reporting withdrawals due to adverse events (odds ratio, 4.6 [CI, 2.0 to 10.9]), reporting severity (odds ratio, 3.7 [CI, 1.5 to 9.1]), and allocating space for describing harm (odds ratio, 1.6 [CI, 1.2 to 2.3]). LIMITATIONS: Extrapolating results to trials in areas other than rheumatic disease is questionable. CONCLUSIONS: The lack of reporting harm in trials assessing nonpharmacologic treatment in rheumatic disease is an important barrier to evaluating the benefit-harm balance of nonpharmacologic treatments.

Baron G, Boutron I, Giraudeau B, Ravaud P. · INSERM U 738, Groupe Hospitalier Bichat-Claude Bernard, Assistance Publique Hôpitaux de Paris, Paris, France. · Arthritis Rheum. · Pubmed #15934058 links to  free full text

Abstract: OBJECTIVE: To evaluate the methodologic quality of and identify methodologic issues in superiority trials assessing structural outcomes in rheumatic diseases. METHODS: We searched Medline and the Cochrane Central Register of Controlled Trials for reports of randomized controlled trials assessing structural outcomes in osteoarthritis (OA), rheumatoid arthritis (RA), and osteoporosis (OP) published between January 1994 and December 2003 in high-impact factor general medical and specialty journals. One reader extracted data (quality assessment, intent-to-treat analysis [ITT analysis], rate of missing data, and methods of handling missing data), using a standardized form. RESULTS: A total of 81 reports were included in the analysis (37 on OP, 34 on RA, and 10 on OA). The mean +/- SD methodologic quality scores on the Jadad scale (possible range 0-5) and the Delphi list (possible range 0-9) were 2.9 +/- 1.2 and 6.4 +/- 1.3, respectively. Although it was reported in 54 articles (66.7%) that the analysis was done on an ITT basis, full ITT analysis was performed in only 6 of the studies (7.4%), modified ITT analysis in 11 (13.6%), and case-complete analysis in 48 (59.3%); the analysis was unclear in 16 articles (19.8%). The rate of missing data on structural outcomes could be determined in only 63 articles (77.8%) and was >20% in approximately one-third of these reports. Methods for handling missing data on structural outcomes were described in 19 articles (23.5%) and were, in general, inappropriate. CONCLUSION: Lack of ITT analysis and a high rate of missing data in superiority trials assessing structural outcomes may bias results from such trials. Our recommendations for improving these shortcomings may help researchers plan, analyze, and report the results of such trials.

d'Agostino MA, Ayral X, Baron G, Ravaud P, Breban M, Dougados M. · Cochin Hospital, and Université René Descartes, Paris, France. · Arthritis Rheum. · Pubmed #15818652 links to  free full text

Abstract: OBJECTIVE: To assess the impact of ultrasonography (US) on local corticosteroid (CS) injections of painful ankle, hindfoot, and midfoot in chronic inflammatory diseases. METHODS: Consecutive patients with chronic rheumatic diseases admitted to the hospital for local CS injections of painful ankle, hindfoot, or midfoot were enrolled in this study. Clinical and radiographic evaluation was performed by the physician in charge of CS injections, and US examination was performed by an independent examiner blinded to the clinical and radiologic findings. According to a randomized weekly-periods design, the physician planned CS injections either aware (G1 group) or unaware (G2 group) of US results. In the latter case, he was nonetheless informed of US results after he had performed the injections. Impact of this information on the treatment planning was assessed in all cases. Prognostic impact of US was also evaluated by comparing the change in global assessment of efficacy of CS injections, in activity of the disease, and in the Western Ontario and McMaster Universities (WOMAC) subscales after 1 and 3 months, between G1 and G2 groups. RESULTS: The knowledge of US findings led the physician to change his decision of local CS injections in 56 (82%) of 68 patients studied. Among 1,131 assessed sites, by clinical, radiographic, and US evaluation, injection was cancelled in 37 (15%) of 242 proposed sites, whereas it was decided in 74 (8%) additional sites. After 1 month, there was an improvement in G1 as compared with G2 groups. The mean +/- SD change in WOMAC physical function subscale was 15.6 +/- 17.5 in G1 versus 8 +/- 13 in G2 (P = 0.0305). After 3 months, only the global assessment of efficacy of CS injections was statistically greater in G1 than in G2 group (P = 0.0170). CONCLUSION: US frequently led the physician to change his diagnosis of inflammatory lesions in painful foot, and consequently his planning of CS injections. Moreover, US could improve the response to local treatment.

D'Agostino MA, Maillefert JF, Said-Nahal R, Breban M, Ravaud P, Dougados M. · Service de Rhumatologie B, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, 75014 Paris, France. · Ann Rheum Dis. · Pubmed #15361388 links to  free full text

Abstract: BACKGROUND: Ultrasonography allows assessment of soft tissue structures and has become a valued tool for diagnosing synovitis. OBJECTIVE: To assess the learning curve for ultrasonography in evaluating synovitis of the small joints in rheumatoid arthritis. METHODS: Metacarpophalangeal (MCP), metatarsophalangeal (MTP), and proximal interphalangeal (PIP) joints were evaluated using ultrasonography (Esaote AU 5 Epi, linear probe 10-13 MHz) by four rheumatologists, the first being experienced (senior), the others having no (fellows 1 and 2) or little (fellow 3) experience in ultrasonography. For each fellow, the learning curve was divided into blocks. In each block the fellow examined five consecutive patients with the senior; then, blinded to the senior's results, two further patients alone (seven patients examined per block). For each evaluation, the MCP, PIP, and MTP joints were individually tagged as having synovitis or not. The ultrasonography results were compared between fellow and senior for the two last patients of each block, using proportions of agreement and kappa statistics. RESULTS: 70 patients were evaluated (seven practice patients, followed by nine blocks). For fellows 1 and 2, the proportions of agreement were respectively 42% and 47% (kappa = 0 and 0) at the first evaluation, and rose progressively to 82% and 82% (kappa = 0.63 and 0.62) at the ninth evaluation. For fellow 3, initially good results were followed by decreased accuracy. CONCLUSIONS: Detecting synovitis of the MCP, PIP, and MTP joints using ultrasonography can be done accurately by rheumatologists initially not experienced in this technique. At least 70 examinations were necessary to develop competence.

Fautrel B, Fermand JP, Sibilia J, Nochy D, Rousselin B, Ravaud P. · Rheumatology Institute, Hĵpital Cochin, Paris, France. · J Rheumatol. · Pubmed #12136908 No free full text.

Abstract: OBJECTIVE: Primary amyloidosis is classical in the course of multiple myeloma (MM), but peripheral amyloid arthropathy is unusual. We evaluated the frequency and effect of amyloid arthropathy in a single center series of patients with MM. METHODS: Retrospective analysis of cases of peripheral joint amyloidosis in a cohort of patients with MM. RESULTS: Between 1978 and 1996, 11 patients (6 women, 5 men, mean age 59 yrs) were diagnosed with biopsy proven amyloid arthropathy in a cohort of 311 patients with MM. Arthritis was the first symptom of amyloidosis in all patients and occurred within the 6 months after MM diagnosis in most patients (7/11). Nine patients had light chain MM and X light chain was more common than kappa (6 vs 5). Shoulder hypertrophic arthropathy and rheumatoid arthritis-like polyarthritis were the 2 most common involved sites. In most cases, joint involvement was responsible for major limitations in activities of daily living. Amyloid deposits were clearly visible on magnetic resonance images (MRI), which also showed inflammatory synovitis in some cases. Control of MM was often associated with improvement of amyloid arthropathy, but additional rheumatological treatment--oral low dose prednisone or joint steroid injection--was often needed to achieve more complete relief. Amyloid arthropathy was not associated with decreased survival, except for patients with concomitant cardiac involvement. CONCLUSION: This series provides reliable information on amyloid arthropathy, especially regarding functional effects, anatomical lesions on MRI, and therapeutic options.

Witko-Sarsat V, Lesavre P, Lopez S, Bessou G, Hieblot C, Prum B, Noël LH, Guillevin L, Ravaud P, Sermet-Gaudelus I, Timsit J, Grünfeld JP, Halbwachs-Mecarelli L. · Institut National de la Santé et de la Recherche Médicale U507 and Department of Nephrology, Necker Hospital, Paris, France. · J Am Soc Nephrol. · Pubmed #10361860 links to  free full text

Abstract: It has been shown previously that proteinase 3 (PR3), a neutrophil intracellular protease that is the main antigen of antineutrophil cytoplasm (ANCA) autoantibodies, is present on the plasma membrane of a subset of freshly isolated neutrophils. This study shows that the size of this subset of membrane PR3-positive (mPR3+) neutrophils is a stable feature of a given individual, most likely genetically controlled. It ranges from 0 to 100% of neutrophils and allows us to define a new polymorphism in the healthy population, with three discrete phenotypes corresponding respectively to less than 20% mPR3 + neutrophils (mPR3low) or to a mean percentage of 47% (mPR3intermediate) and 71.5% (mPR3high) mPR3+ neutrophils. The frequency of the mPR3high phenotype was significantly increased in patients with ANCA-associated vasculitis (85% versus 55% in healthy subjects). The percentage of mPR3+ neutrophils was not affected by disease activity, relapses, or therapy, and did not reflect in vivo cell activation. In addition, mPR3+ phenotypes were normally distributed in cystic fibrosis patients, indicating that infection and/or inflammation per se do not lead to a high percentage of mPR3+ neutrophils. The frequency of the mPR3high phenotype was not related to anti-PR3 autoimmunization, since it was increased in vasculitic patients regardless of the ANCA specificity (anti-PR3, anti-myeloperoxidase, or unknown). Interestingly, the frequency of the mPR3high phenotype was also increased in patients with rheumatoid arthritis. It was normal in type I-diabetes, a T cell-dependent autoimmune disease. It is proposed here that a high proportion of membrane PR3-positive neutrophils could favor the occurrence or the progression of chronic inflammatory diseases.

Giraudeau B, Ravaud P. · No affiliation provided · Arthritis Rheum. · Pubmed #10403291 links to  free full text

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