Showing papers by "Maxime Dougados published in 2006"

Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy : Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks

Abstract: Objective To determine the efficacy and safety of treatment with rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to anti–tumor necrosis factor (anti-TNF) therapies and to explore the pharmacokinetics and pharmacodynamics of rituximab in this population. Methods We evaluated primary efficacy and safety at 24 weeks in patients enrolled in the Randomized Evaluation of Long-Term Efficacy of Rituximab in RA (REFLEX) Trial, a 2-year, multicenter, randomized, double-blind, placebo-controlled, phase III study of rituximab therapy. Patients with active RA and an inadequate response to 1 or more anti-TNF agents were randomized to receive intravenous rituximab (1 course, consisting of 2 infusions of 1,000 mg each) or placebo, both with background MTX. The primary efficacy end point was a response on the American College of Rheumatology 20% improvement criteria (ACR20) at 24 weeks. Secondary end points were responses on the ACR50 and ACR70 improvement criteria, the Disease Activity Score in 28 joints, and the European League against Rheumatism (EULAR) response criteria at 24 weeks. Additional end points included scores on the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F), Health Assessment Questionnaire (HAQ) Disability Index (DI), and Short Form 36 (SF-36) instruments, as well as Genant-modified Sharp radiographic scores at 24 weeks. Results Patients assigned to placebo (n = 209) and rituximab (n = 311) had active, longstanding RA. At week 24, significantly more (P < 0.0001) rituximab-treated patients than placebo-treated patients demonstrated ACR20 (51% versus 18%), ACR50 (27% versus 5%), and ACR70 (12% versus 1%) responses and moderate-to-good EULAR responses (65% versus 22%). All ACR response parameters were significantly improved in rituximab-treated patients, who also had clinically meaningful improvements in fatigue, disability, and health-related quality of life (demonstrated by FACIT-F, HAQ DI, and SF-36 scores, respectively) and showed a trend toward less progression in radiographic end points. Rituximab depleted peripheral CD20+ B cells, but the mean immunoglobulin levels (IgG, IgM, and IgA) remained within normal ranges. Most adverse events occurred with the first rituximab infusion and were of mild-to-moderate severity. The rate of serious infections was 5.2 per 100 patient-years in the rituximab group and 3.7 per 100 patient-years in the placebo group. Conclusion At 24 weeks, a single course of rituximab with concomitant MTX therapy provided significant and clinically meaningful improvements in disease activity in patients with active, longstanding RA who had an inadequate response to 1 or more anti-TNF therapies.

Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial.

Abstract: Objective To evaluate the safety and efficacy of adalimumab, a fully human recombinant IgG1 monoclonal antibody that specifically targets human tumor necrosis factor, in patients with active ankylosing spondylitis (AS). Methods This was a multicenter, randomized (2:1 ratio), double-blind, placebo-controlled study to evaluate a subcutaneous injection of adalimumab, 40 mg every other week, compared with placebo for 24 weeks. The primary efficacy end point was the percentage of patients with a 20% response according to the ASsessment in Ankylosing Spondylitis International Working Group criteria for improvement (ASAS20) at week 12. Secondary outcome measures included the ASAS20 at week 24 and multiple measures of disease activity, spinal mobility, and function, as well as ASAS partial remission. Results At week 12, 58.2% of adalimumab-treated patients (121 of 208) achieved an ASAS20 response, compared with 20.6% of placebo-treated patients (22 of 107) (P < 0.001). More patients in the adalimumab group (45.2% [94 of 208]) than in the placebo group (15.9% [17 of 107]) had at least a 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index at week 12 (P < 0.001). Significant improvements in the ASAS40 response and the response according to the ASAS5/6 criteria at weeks 12 and 24 were also demonstrated (P < 0.001). Partial remission was achieved by more adalimumab-treated patients than placebo-treated patients (22.1% versus 5.6%; P < 0.001). Adalimumab-treated patients reported more adverse events (75.0% versus 59.8% of placebo-treated patients; P < 0.05), but there was no statistically significant difference in the incidence of infections. Most adverse events were mild or moderate in severity. Conclusion Adalimumab was well-tolerated during the 24-week study period and was associated with a significant and sustained reduction in the signs and symptoms of active AS.

Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study.

Abstract: Objective Bisphosphonates have slowed the progression of osteoarthritis (OA) in animal models and have decreased pain in states of high bone turnover. The Knee OA Structural Arthritis (KOSTAR) study, which is the largest study to date investigating a potential structure-modifying OA drug, tested the efficacy of risedronate in providing symptom relief and slowing disease progression in patients with knee OA. Methods The study group comprised 2,483 patients with medial compartment knee OA and 2–4 mm of joint space width (JSW), as determined using fluoroscopically positioned, semiflexed-view radiography. Patients were enrolled in 2 parallel 2-year studies in North America and the European Union. These studies evaluated the efficacy of risedronate at dosages of 5 mg/day, 15 mg/day, 35 mg/week (in Europe), and 50 mg/week (in North America) compared with placebo in reducing signs and symptoms, as measured by the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and patient global assessment (PGA) scores, and in slowing radiographic progression. Results A reduction of ∼20% in signs and symptoms, as measured by WOMAC subscales and PGA scores, was observed in all groups, with no treatment effect of risedronate demonstrated. Risedronate did not significantly reduce radiographic progression as measured by decreased JSW or using a dichotomous definition of progression (joint space loss of ≥0.6 mm). Thirteen percent of patients receiving placebo demonstrated significant disease progression over 2 years. A dose-dependent reduction in the level of C-terminal crosslinking telopeptide of type II collagen, a cartilage degradation marker associated with progressive OA, was seen in patients who received risedronate. No increase in the number of adverse events was demonstrated for risedronate compared with placebo. Conclusion Although risedronate (compared with placebo) did not improve signs or symptoms of OA, nor did it alter progression of OA, a reduction in the level of a marker of cartilage degradation was observed. A sustained clinically relevant improvement in signs and symptoms was observed in all treatment and placebo groups.

First Update of the International ASAS Consensus Statement for the Use of Anti-TNF Agents in Patients with Ankylosing Spondylitis

Abstract: Objective: To update the international recommendations for use of anti-tumour necrosis factor (TNF) agents in the treatment of ankylosing spondylitis. Methods: The published recommendations on anti-TNF treatment in ankylosing spondylitis formed the basis of the update. A questionnaire was sent to the ASAS (assessment in ankylosing spondylitis) members before the final decisions were agreed upon at an international meeting of the ASAS working group. Results: Only minor changes to the original consensus statement were required. For the initiation of anti-TNF treatment, there should be: a diagnosis of definitive ankylosing spondylitis (normally based on modified New York criteria); active disease for at least four weeks, as defined by a sustained Bath ankylosing spondylitis disease activity index (BASDAI) of ⩾4 on a 0–10 scale and expert opinion based on clinical findings; refractory disease, defined by failure of at least two non-steroidal anti-inflammatory drugs during a three month period, failure of intra-articular steroids (if indicated), and failure of sulfasalazine in patients with predominantly peripheral arthritis; and application of the usual precautions and contraindications for biological treatment. For monitoring anti-TNF treatment: both the ASAS core set for clinical practice and the BASDAI should be followed after the initiation of treatment. Discontinuation of anti-TNF treatment in non-responders should be considered after 6–12 weeks. Response is defined by improvement of at least 50% or 2 units (on a 0–10 scale) of the BASDAI. Conclusions: This updated consensus statement is recommended in guiding clinical practice and as a basis for developing national guidelines. Evaluation and regular update of this consensus statement is subject to further research by the ASAS group.

Current evidence for the management of ankylosing spondylitis: a systematic literature review for the ASAS/EULAR management recommendations in ankylosing spondylitis

Abstract: Objective: To assess available management strategies in ankylosing spondylitis (AS) using a systematic approach, as a part of the development of evidence based recommendations for the management of AS. Methods: A systematic search of Medline, Embase, CINAHL, PEDro, and the Cochrane Library was performed to identify relevant interventions for the management of AS. Evidence for each intervention was categorised by study type, and outcome data for efficacy, adverse effects, and cost effectiveness were abstracted. The effect size, rate ratio, number needed to treat, and incremental cost effectiveness ratio were calculated for each intervention where possible. Results from randomised controlled trials were pooled where appropriate. Results: Both pharmacological and non-pharmacological interventions considered to be of interest to clinicians involved in the management of AS were identified. Good evidence (level Ib) exists supporting the use of non-steroidal anti-inflammatory drugs (NSAIDs) and coxibs for symptomatic treatment. Non-pharmacological treatments are also supported for maintaining function in AS. The use of conventional antirheumatoid arthritis drugs is not well supported by high level research evidence. Tumour necrosis factor inhibitors (infliximab and etanercept) have level Ib evidence supporting large treatment effects for spinal pain and function in AS over at least 6 months. Level IV evidence supports surgical interventions in specific patients. Conclusion: This extensive literature review forms the evidence base considered in the development of the new ASAS/EULAR recommendations for the management of AS.

Efficacy of tumour necrosis factor blockers in reducing uveitis flares in patients with spondylarthropathy: a retrospective study

Abstract: Objective: To evaluate the efficacy of anti-tumour necrosis factor (TNF) treatments (given for rheumatological manifestations) in reducing uveitis flares in patients with spondylarthropathy in daily practice. Methods: A retrospective observational study of all patients with spondylarthropathy with at least one uveitis flare treated with anti-TNF in one centre (December 1997–December 2004). The number of uveitis flares per 100 patient-years was compared before and during anti-TNF treatment; each patient was his or her own control. The relative risk (RR) and the number needed to treat (NNT) were calculated. Results: 46 patients with spondylarthropathy treated with anti-TNF drugs had at least one uveitis flare (33 treated with anti-TNF antibodies, infliximab or adalimumab, and 13 with soluble TNF receptor, etanercept). The mean age at first symptoms was 26 years, 71% were men. Patients were followed for 15.2 years (mean) before anti-TNF versus 1.2 years during anti-TNF treatment. The number of uveitis flares per 100 patient-years before and during anti-TNF were, respectively: for all anti-TNF treatments,—51.8 v 21.4 (p = 0.03), RR = 2.4, NNT = 3 (95% confidence interval (CI) 2 to 5); for soluble TNF receptor—54.6 v 58.5 (p = 0.92), RR = 0.9; and for anti-TNF antibodies—50.6 v 6.8 (p = 0.001), RR = 7.4, NNT = 2 (95% CI 2 to 5). Conclusion: Anti-TNF treatments were efficacious in decreasing the number of uveitis flares in patients with spondylarthropathy. Anti-TNF antibodies decreased the rate of uveitis flares, whereas soluble TNF receptor did not seem to decrease this rate. These results could have consequences for the choice of anti-TNF treatment in certain patients.

Development of classification and response criteria for rheumatic diseases.

Abstract: RELEVANCE TO THE CLINICIAN: Clinicians already know that not all patients who are diagnosed with rheumatic diseases really have them. Moreover, determining which patients have improved and by how much is also difficult. Classification criteria allow clinical researchers to recruit patients with similar diseases (e.g., rheumatoid arthritis or systemic lupus erythematosus) into studies. Response criteria help to determine whether treatments really work, i.e., whether they actually produce clinically important improvement. As the science of clinical research advances, we must update our standards for considering classification and response criteria. In this editorial, members of the American College of Rheumatology (ACR) Subcommittee on Classification and Response Criteria describe the purpose of criteria sets, their development and validation, and the role of the ACR in adopting them.

Infections during tumour necrosis factor-α blocker therapy for rheumatic diseases in daily practice: a systematic retrospective study of 709 patients

Abstract: Objective. To evaluate the rate of infections in rheumatic patients treated with tumour necrosis factor (TNF)-� blockers in daily practice and to determine potential risk factors of infections. Methods. Systematic retrospective study was conducted in a tertiary-referral centre of all patients receiving at least one TNF-�blocker, between 1997 and December 2004. Serious infections were defined as life-threatening, requiring hospitalization or sequelae. The incidence of infections during the first TNF-� blocker course was compared with the incidence during the period just before such therapy, in the same patients and a number needed to harm was calculated. Univariate and multivariate analysis between patients who suffered from at least one infection during treatment or not, was conducted in order to determine potential associated risk factors. Results. Among the 709 patients treated with at least one TNF-� blocker, 57.7% had rheumatoid arthritis; a total of 275 infectious events in 245 patients (34.5%) were reported during all treatment courses. Among these infections, 47 infections in 44 patients (6.2%) fulfilled the definition of serious infections. The incidence rate of serious infections was 3.4 � 38.7 per 100 patient-yrs before TNF-� blocker therapy vs 10.5 � 86.9 during the first TNF-� blocker course (P ¼ 0.03, number needed to harm ¼ 14). The single risk factor picked up by multivariate analysis to explain infections was previous joint surgery [odds ratio (OR) ¼ 2.07, 95% confidence interval (CI) ¼ (1.43–2.98), P < 0.0001] and, if surgery was taken out of the model, the cumulative dose of steroids [OR ¼ 1.28 (1.04–1.59), P ¼ 0.02]. Conclusion. The rate of serious infections during TNF-� blocker treatment observed in daily practice conditions was much higher than in phase III trials evaluating TNF-� blockers. Serious infections are frequent in daily practice and close monitoring is required.

Feeling good rather than feeling better matters more to patients.

Abstract: Objective To determine the most appropriate means to assess the response to treatment in terms of pain and functional impairment in a chronic rheumatic condition (knee osteoarthritis [OA]) and an acute rheumatic condition (rotator cuff syndrome [RCS]). Methods Two prospective studies were conducted consisting of 1,019 outpatients with knee OA and 271 patients with acute RCS. The minimal clinically important improvement and the patient acceptable symptom state were determined for knee OA pain using a visual analog scale, and for knee OA function using the Western Ontario and McMaster Universities Osteoarthritis Index function subscale; for acute RCS pain, a numeral rating scale was used, and the Neer function subscale was used for RCS function. Results The minimal clinically important improvement was shown to be the change required to achieve the patient acceptable symptom state, whatever the baseline level of symptom, the outcome (pain or function), or type of condition (chronic or acute). This acceptable state for pain was higher for chronic (27.0–36.4 across the baseline score) than acute (16.7–24.1) conditions. The level of functional impairment considered satisfactory by patients with knee OA was higher for more disabled patients (43.1) than for less disabled patients (20.4). Conclusion Patients consider that they experienced an important improvement only if this improvement allowed them to achieve a state they consider satisfactory. The most appropriate means to assess the response to therapy seems to be to assess whether patients feel good (i.e., achieve the patient acceptable symptom state).

Etanercept 50 mg once weekly is as effective as 25 mg twice weekly in patients with ankylosing spondylitis

Abstract: Objective: To compare the efficacy, pharmacokinetics and safety of etanercept 50 mg once weekly with 25 mg twice weekly and placebo in patients with ankylosing spondylitis. Methods: A 12-week, double-blind, placebo-controlled study compared the effects of etanercept 50 mg once weekly, etanercept 25 mg twice weekly and placebo in 356 patients with active ankylosing spondylitis (3:3:1 randomisation, respectively). The primary end point was the proportion of patients achieving a response at week 12 based on the Assessment in Ankylosing Spondylitis Working Group criteria (ASAS 20). The pharmacokinetics of etanercept 50 mg once weekly and 25 mg twice weekly were analysed. Results: Baseline characteristics and disease activity were similar among the three groups: etanercept 50 mg once weekly, etanercept 25 mg twice weekly and placebo. The percentage of patients discontinuing therapy was 9.0%, 9.3% and 13.7% for the three respective groups. ASAS 20 response at 12 weeks was achieved by 74.2% of patients with etanercept 50 mg once weekly and 71.3% of those with etanercept 25 mg twice weekly, both significantly higher than the percentage of patients taking placebo (37.3%, p Conclusions: Patients with ankylosing spondylitis can expect a comparable significant improvement in clinical outcomes with similar safety when treated with etanercept 50 mg once weekly or with 25 mg twice weekly.

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

Abstract: 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 Conclusion: In this large cohort, combined measurements of uCTX-II and sHA were a new predictor of the structural progression of hip OA.

Serial determination of cyclic citrullinated peptide autoantibodies predicted five-year radiological outcomes in a prospective cohort of patients with early rheumatoid arthritis

Abstract: The objective of this study was to evaluate the potential of serially determined anti-cyclic citrullinated peptide (CCP) antibodies for predicting structural joint damage in patients with early rheumatoid arthritis (RA), compared to a single baseline determination. Ninety-nine RA patients with disease durations of less than one year and no history of disease-modifying antirheumatic drug therapy were followed prospectively for at least five years. Anti-CCP2 concentrations were measured using a second-generation ELISA. Sharp scores as modified by van der Heijde were determined on hand and foot radiographs. Anti-CCP2 antibodies were detected in 55.5% of patients at baseline and 63.6% at any time during the first three years. Presence of anti-CCP2 at any time during the first three years was associated with radiographic damage at baseline (odds ratio (OR), 3.66; 95% confidence interval (95% CI) 0.99–13.54) and with five year progression of the total Sharp score (OR, 3.17; 95% CI, 1.3–7.7), erosion score (OR, 5.3; 95% CI, 1.4–19.2) and joint space narrowing score (OR, 2.8; 95% CI, 1.15–6.8). The presence of anti-CCP2 or IgM RF at baseline did not predict these outcomes. Patients with negative anti-CCP2 tests throughout follow-up had less radiographic progression than patients with increasing anti-CCP2 concentrations; they did not differ from patients with decreasing anti-CCP2 antibody levels. HLADRB1* typing showed that progression of the mean modified Sharp score was not correlated with the presence of the shared epitope alleles. In conclusion, serially determined anti-CCP2 antibodies during the first three years of follow-up performs better than baseline determination for predicting radiographic progression in patients with early RA.

A long-term, open-label trial of the safety and efficacy of etanercept (Enbrel) in patients with rheumatoid arthritis not treated with other disease-modifying antirheumatic drugs

Abstract: Objective: To evaluate the long-term safety and efficacy of etanercept in patients with rheumatoid arthritis. Methods: 549 patients entered this 5-year, open-label extension study and received etanercept 25 mg twice weekly. All patients showed inadequate responses to disease-modifying antirheumatic drugs before entry into the double-blind studies. Safety assessments were carried out at regular intervals. Primary efficacy end points were the numbers of painful and swollen joints; secondary variables included American College of Rheumatology (ACR) response rate, Disease Activity Score and acute-phase reactants. Efficacy was analysed using the last-observation-carried-forward approach. Results: Of the 549 patients enrolled in the open-label trial, 467 (85%), 414 (75%) and 371 (68%) completed 1, 2 and 3 years, respectively; 363 (66%) remained in the study at the time of this analysis. A total exposure of 1498 patient-years, including the double-blind study, was accrued. In the open-label trial, withdrawals for efficacy-related and safety-related reasons were 11% and 13%, respectively. Frequent adverse events included upper respiratory infections, flu syndrome, rash and injection-site reactions. Rates of serious infections and malignancies remained unchanged over the course of the study; there were no reports of patients with central demyelinating disease or serious blood dyscrasias. After 3 years, ACR20, ACR50 and ACR70 response rates were 78%, 51% and 27%, respectively. The Disease Activity Score score was reduced to 3.0 at 3 months and 2.6 at 3 years from 5.1. A sustained improvement was found in Health Assessment Questionnaire scores throughout the 3-year time period. Conclusion: After 3 years of treatment, etanercept showed sustained efficacy and a favourable safety profile.

Determinants of hyperkyphosis in patients with ankylosing spondylitis

Abstract: Objective: To determine clinical and radiographic determinants of hyperkyphosis in patients with ankylosing spondylitis. Methods: Spinal hyperkyphosis was assessed by occiput to wall distance (OWD) in 135 patients participating in the OASIS cohort and defined as OWD >0. Disease activity was assessed by the Bath ankylosing spondylitis disease activity index (BASDAI). Wedging of the vertebrae was calculated as the Ha/Hp ratio. Structural damage of the spine was assessed by the modified Stoke ankylosing spondylitis spine score (mSASSS). Hip involvement was assessed by the Bath ankylosing spondylitis radiology index (BASRI) and defined as a score >2. Data were analysed by multiple regression analysis on van der Waerden-normal OWD values, with mean Ha/Hp ratio, mSASSS, hip involvement, and BASDAI as explanatory variables, and age, sex, and disease duration after diagnosis as covariates. Results: 61 patients (45.2%) had an OWD >0 cm. Of these, 81% were male, v 57% in the group with normal OWD (p r = −0.45, p = 0.01), mSASSS ( r = 0.56, p = 0.01), and hip involvement ( r = 0.2, p = 0.05). Multivariate analysis showed that mSASSS (standardised β (stβ) = 0.52; p Conclusions: Radiological damage of the cervical and lumbar spine, thoracic wedging, and disease activity are determinants of hyperkyphosis in patients with ankylosing spondylitis. These findings could be important in determining treatment goals in this disease.

Retention rates of tumor necrosis factor blockers in daily practice in 770 rheumatic patients.

Abstract: OBJECTIVE: Tumor necrosis factor (TNF) blockers are efficacious in clinical trials in rheumatic diseases. However, their efficacy in daily practice, depending on the specific diagnosis or the use of concomitant therapy, remains to be confirmed. Our objective was to evaluate TNF blocker retention rates and their predisposing factors in daily practice. METHODS: Retrospective evaluation of all TNF blocker therapies in one center. Retention rate was evaluated using a Kaplan-Meier survival data analysis technique in which the event was discontinuation of the drug due to inefficacy or toxicity with log-rank tests and a Cox proportional-hazards regression model. RESULTS: From 1997 to 2004, 770 patients with inflammatory rheumatism received at least one TNF blocker; 142 received more than one agent (975 treatment courses: 493 etanercept, 335 infliximab, 147 adalimumab). The underlying disease was mainly rheumatoid arthritis (RA), found in 57.1% of patients, and spondyloarthropathies (SpA) in 37.7%. The percentage of patients receiving the same treatment at Month 12, 24, and 36 was 64.0%, 50.3%, and 39.4%, respectively. No difference between the 3 TNF blockers was found (p = 0.48). The retention rate was longer for the first treatment course [hazard ratio (HR) 2.17, 95% confidence interval (95% CI) 1.82-2.58, p < 0.0001]; longer for patients with SpA (HR 1.60, 95% CI 1.20-2.13, p = 0.001); and longer without concomitant DMARD (HR 0.70, 95% CI 0.51-0.97, p = 0.03). CONCLUSION: Our results indicate a lower retention rate of TNF blockers in daily practice compared with clinical trials, with no difference between the 3 currently available agents. Moreover, results suggest greater benefit in SpA. The role of concomitant DMARD remains to be confirmed.

Characterization and functional consequences of underexpression of clusterin in rheumatoid arthritis.

Abstract: We previously compared by microarray analysis gene expression in rheumatoid arthritis (RA) and osteoarthritis (OA) tissues. Among the set of genes identified as a molecular signature of RA, clusterin (clu) was one of the most differentially expressed. In the present study we sought to assess the expression and the role of CLU (mRNA and protein) in the affected joints and in cultured fibroblast-like synoviocytes (FLS) and to determine its functional role. Quantitative RT-PCR, Northern blot, in situ hybridization, immunohistochemistry, and Western blot were used to specify and quantify the expression of CLU in ex vivo synovial tissue. In synovial tissue, the protein was predominantly expressed by synoviocytes and it was detected in synovial fluids. Both full-length and spliced isoform CLU mRNA levels of expression were lower in RA tissues compared with OA and healthy synovium. In synovium and in cultured FLS, the overexpression of CLU concerned all protein isoforms in OA whereas in RA, the intracellular forms of the protein were barely detectable. Transgenic overexpression of CLU in RA FLS promoted apoptosis within 24 h. We observed that CLU knockdown with small interfering RNA promoted IL-6 and IL-8 production. CLU interacted with phosphorylated IκBα. Differential expression of CLU by OA and RA FLS appeared to be an intrinsic property of the cells. Expression of intracellular isoforms of CLU is differentially regulated between OA and RA. We propose that in RA joints, high levels of extracellular CLU and low expression of intracellular CLU may enhance NF-κB activation and survival of the synoviocytes.

Stability of the patient acceptable symptomatic state over time in outcome criteria in ankylosing spondylitis

Abstract: Objective The Patient Acceptable Symptomatic State (PASS) is the highest level of symptoms beyond which patients consider themselves well. It provides clinically meaningful information to interpret results from scales or questionnaires. Our goal was to determine the PASS in main outcome criteria when assessing patients with ankylosing spondylitis (AS) and to evaluate whether the PASS is stable over time. Methods We used data from a randomized controlled trial of 330 patients with AS. The PASS was estimated at weeks 2, 6, and 12 for the following patient-reported outcomes: global pain (measured on a visual analog scale [VAS]), nocturnal pain (VAS), patient's global assessment of disease activity (VAS), disease activity (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]), and functional impairment (Bath Ankylosing Spondylitis Functional Index [BASFI]). We used an anchoring method based on patients answering yes or no to, “Is your current condition satisfactory, when you take your general functioning and your current pain into consideration?” The PASS was defined as the 75th percentile of the score for patients who considered their state satisfactory. All patients were considered together in the analysis. Results The values (95% confidence interval) of PASS were 33.5 (29.2–38.6) for pain, 28.0 (23.1–34.1) for night pain, 35.7 (31.3–41.1) for patient's global disease assessment, 31.4 (26.9–37.0) for BASFI, and 34.5 (30.9–38.9) for BASDAI. The PASS estimates were stable over time for all criteria during followup. Conclusion This study provides cutoff values for the PASS for the main outcome measures in AS and shows that PASS values are stable over time.

An international study on starting tumour necrosis factor-blocking agents in ankylosing spondylitis

Abstract: Objectives: To determine the type and proportion of patients with ankylosing spondylitis who rheumatologists consider to be candidates for treatment with tumour necrosis factor (TNF)-blocking agents, and to what extent this is in agreement with the ASsessment in Ankylosing Spondylitis (ASAS) international working group recommendations on initiation of treatment with anti-TNF agents. Methods: Participants were rheumatologists from 10 different countries, who were considered to be experts in treating patients with ankylosing spondylitis and in the use of anti-TNF treatment, but were unaware of the ASAS recommendations (unpublished at the time of study in 2003). The first 10 consecutive patients with ankylosing spondylitis seen by the rheumatologist were evaluated as to whether the patient was a candidate for anti-TNF treatment. Thereafter, a metrologist assessed the patient for disease activity and severity, and collected data on demographics and treatment. Results: Complete data were available for 1207 of the 1284 patients and were used for analysis. Overall, the rheumatologists indicated that they would initiate TNF-blocking agents in 49.3% of patients, ranging from 37.2% patients in Canada to 78.3% in Australia. These candidates had higher disease activity, higher levels of acute-phase reactants, worse spinal mobility, worse function, more often hip involvement and a higher prevalence of sick leave. Of all patients considered to be candidates, 40% did not fulfil ASAS recommendations with respect to previous use of non-steroidal anti-inflammatory drugs (NSAIDs; at least two NSAIDs) or Bath Ankylosing Spondylitis Disease Activity Index (⩾4). Conversely, 36% of patients who did not fulfil the NSAID or BASDAI recommendations were still considered to be candidates for TNF-blocking treatment. Objective variables, such as C reactive protein, erythrocyte sedimentation rate or magnetic resonance activity, were considered less important than disease activity in the decision on starting TNF-blocking drugs. The only important objective criterion was rapid radiographic progression. Conclusion: Rheumatologists wanted to initiate TNF-blocking drugs in roughly half of the patients with ankylosing spondylitis. However, there was a wide variation across countries and doctors. Rheumatologists considered both disease activity and severity to be determinants of starting TNF blockers, but their decision was often in disagreement with ASAS recommendations.

Which variables best predict change in rheumatoid arthritis therapy in daily clinical practice

Abstract: OBJECTIVE:To determine in clinical practice which clinical status variables for rheumatoid arthritis (RA) are most closely associated with a change in disease modifying antirheumatic drug (DMARD) therapy. METHODS: A prospective monocenter study was conducted in 204 consecutive patients with RA. Rheumatologists recorded patient characteristics, treatments, and disease activity data [tender and swollen joint count (28), morning stiffness, visual analog scale (VAS) for pain (0-100 mm), patient global assessment and physician global assessment, Westergren erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP)]. The rheumatologists decided whether or not to initiate or change treatment but were not informed that their decisions were part of the investigation. Logistic regression analysis was performed to evaluate which study variables best predict change in therapy. ROC analysis was used to obtain the cutoff value of the different composite indices (DAS28(ESR), DAS28(CRP), SDAI) for treatment change, as well as sensitivity and specificity. RESULTS: The variables that were predictive for a change in treatment were (in descending order): swollen joint count, morning stiffness, CRP, tender joint count, and patient global assessment. Composite index values associated with a decision to modify DMARD therapy were: DAS28(ESR) 4.2 (sensitivity 87%, specificity 70%); DAS28(CRP) 3.6 (sensitivity 86%, specificity 78%); and SDAI 15 (sensitivity 90%, specificity 86%). The discriminative ability of SDAI was better than that of DAS28(CRP) or DAS28(ESR). CONCLUSION: In our study, swollen joint count was the variable with the greatest weight, which explains the observed better performance of SDAI.

Reproducibility and sensitivity to change of four scoring methods for the radiological assessment of osteoarthritis of the hand

Abstract: Background: Osteoarthritis (OA) of the hand could be a relevant model to study the progression of OA in structure-modification trials Various methods are proposed to assess hand OA and its progression radiologically Objective: To compare intra-reader and inter-reader precision and sensitivity to change of four radiological scoring methods proposed in hand OA Methods: 2 trained readers scored separately 105 pairs of radiographs (baseline; year 1), selected from patients enrolled in a randomised controlled trial, for inter-reader reliability and sensitivity to change They scored twice 60 pairs among the 105 for cross-sectional and longitudinal intra-reader reliability Radiological hand OA assessment used: global, Kellgren–Lawrence (KL), Kallman and Verbruggen scoring methods Inter- and intra-reader reliabilities were studied using intraclass coefficient (ICC) and the Bland–Altman method Sensitivity to change was compared by calculating the standardised response means Results: Transversal intra-reader reproducibility ICCs ranged from 0922 to 0999 Verbruggen ranked the highest, followed by the KL and Kallman methods Inter-rater reliability was higher for the Verbruggen scores, followed by the KL, global and Kallman scores (ICC 0706–0999) Longitudinal intra-reader reliability (baseline; year 1) was better using the Kallman and KL (ICC 0986 and 0990), followed by the Verbruggen (0941) or global methods (0939) Standardised response means ranged from 024 (KL) to 029 (Kallman) Conclusion: All four methods compared well with respect to reliabilities However, the Verbruggen and Kallman methods performed better The method most sensitive to change was the Kallman method, followed by Verbruggen and global scores This study also suggests that structural changes could be detected in hand OA over a 1-year period

Health assessment questionnaire score is the best predictor of 5-year quality of life in early rheumatoid arthritis.

Abstract: OBJECTIVE: To evaluate and determine prognostic factors of 5-year quality of life in patients with early rheumatoid arthritis (RA). METHODS: A cohort of 191 patients with RA and disease duration

Leflunomide in clinical practice.

Abstract: Leflunomide (LEF) is a prodrug that is rapidly converted to its active metabolite A77 1726, that inhibits the novo pyrimidine nucleotide biosynthesis, mediated especially by the dihydroorotate dehidrogenase (DHODH). DMARD properties were documented in rheumatoid arthritis with efficacy, safety and limiting of radiological progression demonstrated in multiple studies. LEF has been also used in other autoimmune diseases, like Psoriatic Arthritis, Wegener granulomatosis, Systemic Lupus Erythematosus, Sarcoidosis and others. This article reviews the place of LEF in clinical practice and outlines its potential applications beyond the officially recognized indication: rheumatoid arthritis (RA).

Psoriatic arthritis: one or more diseases?

Abstract: Psoriatic arthritis (PsA) is a common, debilitating auto-immune disease with diverse clinical features. In this paper, published evidence is examined, which addresses the issues that (a) PsA exists; and (b) PsA can or cannot be viewed as a distinct rheumatic disease from other spondyloarthritides. Evidence derived from epidemiological, clinical, genetic and immunohistological studies is included. Summarizing the evidence, it is clear that PsA does indeed exist, with the prevalence of rheumatic disease in patients with psoriasis (Ps) higher than would be expected. Certain clinical features also occur more commonly in PsA, although none can differentiate consistently from other arthropathies. Both genetic and immunohistological studies suggest that PsA, both oligo- and polyarticular disease, can be clearly separated from rheumatoid arthritis and that it belongs to the family of spondyloarthritides. The presence of Ps may confer a more severe clinical phenotype with poor radiological outcome. It may be that, with time, a specific genetic marker or diagnostic feature will emerge; additional, more detailed pathogenic studies are required. In the meanwhile, particularly with new treatments being evaluated, it is important to continue to develop specific classification or diagnostic criteria and to define both clinical and laboratory-based outcome measures.

Indications for lowering LDL cholesterol in rheumatoid arthritis: an unrecognized problem.

Abstract: OBJECTIVE: To evaluate the prevalence of patients with rheumatoid arthritis (RA) in whom lowering low density lipoprotein cholesterol (LDL-C) should be considered in accord with the ATPIII guidelines. The treatment goals are based on the number of risk factors (RF) other than LDL-C. The goal for 0-1 RF is