Bernard Mazières

Interleukin-1β, interleukin-1 receptor antagonist, interleukin-4, and interleukin-10 gene polymorphisms: Relationship to occurrence and severity of rheumatoid arthritis

OBJECTIVE To test if interleukin-1beta (IL-1beta), IL-1 receptor antagonist (IL-1Ra), IL-4, or IL-10 gene polymorphisms could be used as markers of susceptibility or severity in rheumatoid arthritis (RA). METHODS The study included 108 patients with early RA followed up for 2 years and 128 healthy controls. From genomic DNA, 6 polymorphisms in genes for IL-1beta, IL-1Ra, IL-10, and IL-4 were typed. Allelic frequencies and carriage rates were compared between RA patients and controls, between patients with erosive and nonerosive RA, and between patients with or without sustained remission. RESULTS The RP1 allele of the IL-4 gene was found with a significantly higher frequency in RA patients compared with controls. The combination of an RA-related HLA-DR allele expressing shared epitope and the presence of allele E2 in IL-1beta exon 5 was found to expose patients to an increased risk of erosive disease, with an odds ratio of 8.20 (95% confidence interval 2.59-25.84, P < 0.0001). No significant association was observed between polymorphisms and the occurrence of sustained remission. CONCLUSION This report, for the first time, indicates an association between RA and a polymorphic IL-4 gene sequence located in 5q31-33. In addition, the results show the prognostic value of a polymorphism in IL-1beta exon 5, which allowed prediction of erosive disease with a specificity of 91.8% in 42.1% of patients. Although these observations are very interesting, they have to be considered preliminary and will need to be confirmed.

Radiological progression of hip osteoarthritis: definition, risk factors and correlations with clinical status.

OBJECTIVES: To determine a cut off value for changes in radiological joint space width that allowed definition of radiological progression of hip osteoarthritis not related to measurement method errors and, thereafter, to determine factors predictive of radiological progression of hip osteoarthritis and to evaluate the correlations between clinical and radiological parameters. METHODS: A prospective, longitudinal (one year duration), multicentre study was made of patients with osteoarthritis of the hip (American College of Rheumatology criteria). Data on clinical activity (pain, functional impairment), demographic data (age, gender, body mass index), and femoral head migration (superolateral, superomedial, concentric) were collected when the patient entered the study; radiological grade (joint space width in millimetres at the narrowest point using a 0.1 mm graduated magnifying glass, evaluated by a single observer unaware of the chronology of the films) was recorded at the patients entry to the study and after one year. RESULTS: Analysis of the means of the differences between two analyses performed by a single observer of 30 pairs of radiographs (one performed after an interval of one year) (0.06 (SD 0.23)) suggested that a change of more than 0.56 mm (2 SD) after a one year follow up could define progression of osteoarthritis of the hip. Of the 508 patients recruited, 461 (91%) completed the one year follow up and radiological progression was observed in 102 (22%). The factors predictive of radiological progression that were identified in the multivariate analysis were: radiological joint space width at entry < or = 2 mm, superolateral migration of the femoral head, female gender, Lequesnes functional index > 10, age at entry > 65 years (odds ratios 2.11, 4.25, 2.51, 2.66, 1.90, respectively). The level of clinical parameters (pain, functional impairment) and the amount of symptomatic treatment required (non-steroidal anti-inflammatory drugs and analgesic intake) accounted for 20% (p < 0.0001) of the variability of the changes in radiological joint space width over the one year study period. CONCLUSION: These data suggest that radiological progression of hip osteoarthritis could be defined by a change in joint space width of at least 0.6 mm after a one year follow up period, is correlated with the changes in clinical status of the patients, and is related not only to demographic data (age, gender), but also to some specific characteristics of osteoarthritis (localisation, radiological severity, clinical activity).

Symptomatic efficacy of avocado/soybean unsaponifiables in the treatment of osteoarthritis of the knee and hip: A prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial with a six-month treatment period and a two-month followup demonstrating a persistent effect

OBJECTIVE To assess the efficacy and safety of avocado/soybean unsaponifiables (ASU) in the treatment of patients with symptomatic osteoarthritis (OA) of the knee or hip, as well as the potential residual effects of ASU after stopping treatment, to determine whether ASU might be a symptomatic slow-acting drug for the treatment of OA. METHODS One hundred sixty-four patients with regular, painful, primary OA of the knee (n = 114) or hip (n = 50) entered a prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial with a 6-month treatment period and a 2-month posttreatment followup. A 15-day washout period for nonsteroidal antiinflammatory drugs (NSAIDs) preceded the study. Efficacy was judged according to 1) Lequesnes functional index (LFI) and 2) pain on Huskissons visual analog scale (VAS; 100-mm scale), intake of NSAIDs/analgesics, and overall disability score (by 100-mm VAS). RESULTS Eighty-five patients received ASU; 79 received placebo. One hundred forty-four patients were evaluable at month 6 (75 taking ASU; 69 taking placebo). The mean +/- SEM LFI score decreased from 9.7 +/- 0.3 to 6.8 +/- 0.4 in the ASU group and from 9.4 +/- 0.3 to 8.9 +/- 0.4 in the placebo group (P < 0.001 for intergroup difference at month 6). Pain decreased from 56.1 +/- 1.6 mm to 35.3 +/- 2.3 in the ASU group and from 56.1 +/- 1.8 mm to 45.7 +/- 2.6 in the placebo group (P = 0.003 at month 6). NSAID consumption was slightly lower in the ASU group. Fewer patients in the ASU group required NSAIDs (48%, versus 63% in the placebo group; P = 0.054). The success rate was 39% in the ASU group and 18% in the placebo group. Overall functional disability was significantly reduced in the ASU group. Improvement appeared more marked in patients with hip OA. A residual effect was observed at month 8. Tolerance was good to excellent for most patients. CONCLUSION ASU treatment showed significant symptomatic efficacy over placebo in the treatment of OA, acting from month 2 and showing a persistent effect after the end of treatment.

Antiinflammatory and immunoregulatory action of methotrexate in the treatment of rheumatoid arthritis: Evidence of increased interleukin‐4 and interleukin‐10 gene expression demonstrated in vitro by competitive reverse transcriptase‐polymerase chain reaction

OBJECTIVE To look for in vitro modulation of the main immunoregulatory and antiinflammatory cytokines by methotrexate (MTX) during the course of rheumatoid arthritis (RA). METHODS We quantified interleukin-2 (IL-2), IL-4, IL-10, and interferon-gamma (IFNgamma) gene expression by peripheral blood mononuclear cells ex vivo under basal conditions and in vitro after stimulation with phytohemagglutinin (PHA) or PHA plus MTX, by competitive reverse transcriptase-polymerase chain reaction (RT-PCR), in 12 patients with untreated active RA (group 1), 10 patients with MTX-treated disease in partial remission (group 2), and 11 healthy control subjects. Simultaneously, under the same experimental conditions, we quantified cytokine production by specific enzyme-linked immunosorbent assays (ELISAs). RESULTS Under basal conditions, we found no differences in IL-2, IL-10, and IFNgamma gene expression in the 3 groups, while IL-4 gene expression was significantly decreased in RA patient group 1 compared with the control group. In vitro, under the action of MTX, IL-10 gene expression was significantly increased in the 3 groups, IL-4 gene expression was significantly increased in RA group 1 and in the control group, and IL-2 and IFNgamma gene expression was significantly decreased in RA group 1. Cytokine gene expression assessed by RT-PCR and cytokine production assessed by specific ELISAs were highly correlated. CONCLUSION In vitro modulation of the cytokine network by MTX, increasing Th2 cytokines and decreasing Th1 cytokines, could explain its antiinflammatory and immunoregulatory actions in vivo during the treatment of RA.

Molecular markers of cartilage breakdown and synovitis at baseline as predictors of structural progression of hip osteoarthritis. The ECHODIAH* Cohort

Objective: To determine whether systemic markers of bone, cartilage, and synovium can predict structural progression of osteoarthritis (OA). Methods: Patients with painful hip OA were treated with diacerein or placebo in a multicentre, prospective, double blind, 3 year follow up trial. The following information was collected at entry: demographics, characteristics of hip OA, and 10 markers: N-propeptides of collagen types I and III, cartilage oligomeric matrix protein, YKL-40, hyaluronan (sHA), matrix metalloproteinases-1 and -3, C reactive protein, C-terminal crosslinking telopeptides of collagen types I and II (uCTX-II). Radiographs were obtained at entry and every year. Structural progression was defined as a joint space decrease ⩾0.5 mm or requirement for total hip replacement. Grouped survival analysis was performed with time to structural progression as dependent variable, and clinical data, radiographic findings, treatment groups (diacerein versus placebo), and markers as explanatory measures. Results: In the 333 patients in whom all markers were measured, high functional impairment, a joint space width <2 mm, and lateral migration of the femoral head at baseline increased the risk of progression, but diacerein had a protective effect (relative risk = 0.75; 95% confidence interval (CI) 0.54 to 0.96). In addition, patients in whom uCTX-II and sHA were in the upper tertile had a relative risk of progression of 3.73 (95% CI 2.48 to 5.61) compared with patients with markers in the two lower tertiles. Conclusion: In this large cohort, combined measurements of uCTX-II and sHA were a new predictor of the structural progression of hip OA.

Effect of chondroitin sulphate in symptomatic knee osteoarthritis: a multicentre, randomised, double-blind, placebo-controlled study

Objective: To evaluate the efficacy and tolerability of chondroitin sulphate (chondroitin sulphate) in knee osteoarthritis. Patients and methods: A 24-week, randomised placebo-controlled trial of chondroitin sulphate (1 g/day) in patients with symptomatic knee osteoarthritis as measured on a visual analgue scale. Pain on daily activities and Lequesne’s Index were the primary efficacy criteria. Secondary outcomes included the rate of responders according to the outcome measures in rheumatoid arthritis clinical trials of the Osteoarthritis Research Society International (OMERACT-OARSI) criteria, quality of life, patient’s/physician’s global assessments and carry-over effect after treatment. Biochemical markers of bone (CTX-I), cartilage (CTX-II) and synovium (hyaluronic acid) metabolism were also measured. Safety was assessed by recording adverse events (AEs). Statistical analysis was performed on the inter-group differences in the intention-to-treat population. Results: 307 patients were included in the study. 28 (9%) patients discontinued the study because of lack of efficacy or AEs. At the end of treatment, the decrease in pain was −26.2 (24.9) and −19.9 (23.5) mm and improved function was −2.4 (3.4) (−25%) and −1.7 (3.3) (−17%) in the chondroitin sulphate and placebo groups, respectively (p = 0.029 and 0.109). The OMERACT-OARSI responder rate was 68% in the chondroitin sulphate and 56% in the placebo group (p = 0.03). The investigator’s assessments and short form 12 (SF-12) physical component reported improvement more frequently in the chondroitin sulphate than in the placebo group (p = 0.044 and 0.021, respectively). No significant difference was observed between treatment groups for changes in biomarkers over 24 weeks. However, there was a significant difference between non-responders and responders according to the OARSI criteria for 24-week changes of CTX-I (p = 0.018) and CTX-II (p = 0.014). Tolerance was considered to be satisfactory. Conclusion: This study failed to show an efficacy of chondroitin sulphate on the two primary criteria considered together, although chondroitin sulphate was slightly more effective than placebo on pain, OMERACT-OARSI response rate, investigator’s assessment and quality of life.

Effect of Hyaluronic Acid in Symptomatic Hip Osteoarthritis : A Multicenter, Randomized, Placebo-Controlled Trial

OBJECTIVE To evaluate the efficacy and tolerability of a single intraarticular (IA) injection of hyaluronic acid (HA) for the treatment of hip osteoarthritis (OA). METHODS A multicenter, randomized, parallel-group, placebo-controlled trial was conducted over 3 months. Patients (older than 30 years) with symptomatic hip OA (pain score of >40 mm on a visual analog scale [VAS]) and a Kellgren/Lawrence grade of 2 or 3 were randomly assigned to receive 1 fluoroscopically guided IA injection of HA (2.5 ml) or placebo (2.5 ml). Patients were followed up for 3 months. The main outcome measure was pain score on a VAS (100 mm) at month 3 compared with baseline. Secondary outcome measures were the proportion of responders defined by Osteoarthritis Research Society International criteria; Western Ontario and McMaster Universities Osteoarthritis Index subscores for pain, stiffness, and disability; and patient and physician global assessment. Randomization was computer generated. HA and placebo preparations were placed in numbered identical containers, and syringes were covered with masking tape. Physicians assessing outcomes were blinded with regard to group assignment. RESULTS Eighty-five patients were randomized to the HA group (n = 42) or placebo group (n = 43). Baseline characteristics were similar between the 2 groups. At 3 months, the decrease in pain score did not differ between the HA and placebo groups in the intent-to-treat analysis (mean +/- SD decrease 7.8 +/- 24.9 mm with HA versus 9.1 +/- 27.4 mm with placebo; P = 0.98). The responder rates were 33.3% and 32.6% in the HA and placebo groups, respectively (P = 0.94). Other secondary end points did not differ between the groups, nor did use of rescue medication or frequency of adverse events. CONCLUSION Our findings indicate that a single IA injection of HA is no more effective than placebo in treating the symptoms of hip OA.

Adherence to, and results of, physical therapy programs in patients with hip or knee osteoarthritis. Development of French clinical practice guidelines.

OBJECTIVE To develop recommendations regarding adherence to physical therapy programs by patients with hip or knee osteoarthritis. METHODS We used the method recommended by the French Society for Physical and Rehabilitation Therapy (SOFMER), which combines a systematic literature review, a practice survey, and validation by a multidisciplinary panel of experts. RESULTS When setting up exercise programs for patients with lower limb osteoarthritis, measures should be taken to increase effectiveness by optimizing adherence. Patient selection is among these measures, as exercise programs are more likely to succeed in patients with a history of being physically active, a positive view of the suggested program, and/or favorable social and material conditions. Regardless of the type of exercise, the program should be tailored to exercise capacity and pain level (professional consensus). Patient adherence can be improved by explaining the expected results to the patient, asking the patient to keep a self-evaluation diary, conducting long-term evaluations (by phone or mail), and providing follow-up visits. CONCLUSION Studies of adherence according to the type of exercise are needed. The relevance of widely used incentives in patients with hip or knee osteoarthritis should be evaluated in new therapeutic trials.

Screening for hip and knee osteoarthritis in the general population: predictive value of a questionnaire and prevalence estimates

Objective: To study the feasibility and validity of a two-step telephone screening procedure for symptomatic knee and hip osteoarthritis (OA) in the general population. Method: The screening questionnaire was based on signs and symptoms, previous diagnosis of OA and validated OA criteria. A random sample of telephone numbers was obtained and, at each number, one person aged 40–75 years was included. A physical examination and knee or hip radiographs were offered when the screen was positive. A sample of subjects with negative screens was also examined. The diagnosis of hip/knee OA was based on the American College of Rheumatology criteria for signs and symptoms and Kellgren–Lawrence radiographic stage 2 or greater. Prevalence rates were estimated with correction for the performance of the screening procedure. Results: Of 1380 subjects, 479 had positive screens, among whom 109 were evaluated; symptomatic radiographic OA was found in 50 subjects, at the knee (n = 35) or hip (n = 20). Corrected prevalence estimates of symptomatic OA were 7.6% (6.4%–8.8%) for the knee and 5% (3.9%–6.1%) for the hip. The screening procedure had 87% (95% CI 79% to 95%) sensitivity and 92% (95% CI 91% to 93%) specificity for detecting knee OA and respectively 93% (95% CI 86% to 100%) and 93% (95% CI 92% to 94%) for hip OA. Conclusion: This study establishes the feasibility of telephone screening for symptomatic knee/hip OA, which could be used for a nationwide prevalence study. Pain and previous OA diagnosis were the best items for detecting symptomatic OA.

Rituximab treatment for spondyloarthritis. A nationwide series: data from the AIR registry of the French Society of Rheumatology.

Objective. To evaluate the efficacy and safety of rituximab (RTX) in several subsets of spondyloarthritis (SpA) using the data of the AIR (Autoimmunity and Rituximab) registry. Methods. All patients receiving RTX for SpA, and prospectively included in the AIR registry from September 2005 to September 2010, were retrospectively analyzed. The response to treatment was evaluated by the Bath Ankylosing Spondylitis Disease Activity Index for axial disease, joint count for peripheral disease, and C-reactive protein reduction. Results. Among the 595 patients included in the AIR registry, 26 patients with SpA from 13 centers were reported: ankylosing spondylitis (10), undifferentiated SpA (7), and psoriatic arthritis (9). Mean disease duration was 8.8 years (range 1−40). The extraarticular features found were psoriasis, 12 cases; uveitis, 4 cases; and Crohn’s disease, 3 cases. The mean number of disease-modifying antirheumatic drugs before RTX was 2.4; previous anti-tumor necrosis factor (TNF) agents were taken in 23 cases. The mean number of RTX courses was 1.5 (range 1−5), with a total of 35.6 patient-years. Efficacy was noted in 11/23 cases: 3 out of 3 anti-TNF-naive patients and 8 out of 20 anti-TNF nonresponder patients. No predictive factors of response could be identified, particularly in diagnosis subsets or clinical presentation (axial or peripheral). Conclusion. In this nationwide study of several subsets of SpA, RTX had only a moderate efficacy that was more marked in patients who were anti-TNF-naive.