Jean-Francis Maillefert

Brief Report: Inhibition of interleukin-6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis†

OBJECTIVEnFrom an immunologic standpoint, the mechanisms by which treatment with tocilizumab (TCZ), a humanized anti-interleukin-6 (anti-IL-6) receptor antibody, results in improvement in rheumatoid arthritis (RA) patients are still not fully understood. In vitro studies and studies in mouse models have demonstrated the critical role of IL-6 in Th17 cell differentiation. Th17 lymphocytes have been shown to be strongly involved in RA pathogenesis, and the purpose of this study was to investigate the effect of IL-6 blockade on the balance between Th17 cells and Treg cells in patients with active RA.nnnMETHODSnPatients with active RA for whom TCZ had been prescribed by a rheumatologist were enrolled in this study. Phenotypic analyses of T cell populations were performed, and the Disease Activity Score in 28 joints (DAS28) was assessed. Serum cytokine levels and other parameters of inflammation were measured before the first infusion and after the third infusion of TCZ (8 mg/kg).nnnRESULTSnCompared to controls, levels of Th17 cells (CD4+IL-17+) were increased and Treg cells (CD4+CD25(high) FoxP3+) were decreased in the peripheral blood of patients with active RA. The suppressive function of circulating Treg cells was not impaired in patients with active RA. TCZ treatment induced a significant decrease in the DAS28 associated with a significant decrease in the percentage of Th17 cells (from a median of 0.9% to 0.45%; P = 0.009) and an increase in the percentage of Treg cells (from a median of 3.05% to 3.94%; P = 0.0039) in all patients.nnnCONCLUSIONnThis study demonstrates for the first time that inhibition of IL-6 function by TCZ corrects the imbalance between Th17 cells and Treg cells in patients with RA.

Gait analysis as a quantifiable outcome measure in hip or knee osteoarthritis: a systematic review.

OBJECTIVESnKinematic gait analysis consisting of measuring gait parameters (stride length, gait speed, dynamic joint angles) is a potential outcome measure in osteoarthritis (OA). The aim of this study was to evaluate its psychometric properties.nnnMETHODSnA systematic literature search was performed in PUBMED and the Cochrane database until January 2008 by selecting manuscripts assessing any psychometric property of gait analysis in knee or hip OA. Were assessed feasibility (cost, time and access); reliability; discriminant capacity by differences between OA and non-OA patients; construct validity by correlation between gait analysis and OA symptoms: pain or functional disability (Lequesne/WOMAC); and responsiveness by improvement of gait analysis after treatment of OA using effect size.nnnRESULTSnAmong the 252 articles identified, the final analysis included 30 reports (i.e., 781 knee OA patients and 343 hip OA patients). Gait analysis presents various feasibility issues and there was limited evidence regarding reliability (three studies, 67 patients). Discriminant capacity showed significant reduction of gait speed, stride length and knee flexion in OA patients compared to healthy subjects. Few data were available concerning construct validity (three studies, 79 patients). Responsiveness of gait speed was moderate to large with effect size ranging respectively from 0.33 to 0.89 for total knee replacement, and from 0.50 to 1.41 for total hip replacement.nnnCONCLUSIONnAvailable data concerning validity and reliability of kinematic gait analysis are insufficient to date to consider kinematic parameters as valuable outcome measures in OA. Further studies evaluating a large number of patients are needed.

TNF alpha antagonist therapy and safety monitoring

OBJECTIVESnTo develop and/or update fact sheets about TNFα antagonists treatments, in order to assist physicians in the management of patients with inflammatory joint disease.nnnMETHODSn1. selection by a committee of rheumatology experts of the main topics of interest for which fact sheets were desirable; 2. identification and review of publications relevant to each topic; 3. development and/or update of fact sheets based on three levels of evidence: evidence-based medicine, official recommendations, and expert opinion. The experts were rheumatologists and invited specialists in other fields, and they had extensive experience with the management of chronic inflammatory diseases, such as rheumatoid. They were members of the CRI (Club Rhumatismes et Inflammation), a section of the Société Francaise de Rhumatologie. Each fact sheet was revised by several experts and the overall process was coordinated by three experts.nnnRESULTSnSeveral topics of major interest were selected: contraindications of TNFα antagonists treatments, the management of adverse effects and concomitant diseases that may develop during these therapies, and the management of everyday situations such as pregnancy, surgery, and immunizations. After a review of the literature and discussions among experts, a consensus was developed about the content of the fact sheets presented here. These fact sheets focus on several points: 1. in RA and SpA, initiation and monitoring of TNFα antagonists treatments, management of patients with specific past histories, and specific clinical situations such as pregnancy; 2. diseases other than RA, such as juvenile idiopathic arthritis; 3. models of letters for informing the rheumatologist and general practitioner; 4. and patient information.nnnCONCLUSIONnThese TNFα antagonists treatments fact sheets built on evidence-based medicine and expert opinion will serve as a practical tool for assisting physicians who manage patients on these therapies. They will be available continuously at www.cri-net.com and updated at appropriate intervals.

A tool to identify recent or present rheumatoid arthritis flare from both patient and physician perspectives: The ‘FLARE’ instrument

Introduction There is a lack of consensus about the definition of flare of rheumatoid arthritis (RA) and a measurement tool. Objectives To develop a self-administered tool integrating the perspectives of the patient and the rheumatologist, enabling the detection of present or recent-past RA flare. Methods The patient perspective was explored by semistructured individual interviews of patients with RA. Two health psychologists conducted a content analysis to extract items best describing flare from the interviews. The physicians perspective was explored through a Delphi exercise conducted among a panel of 13 rheumatologists. A comprehensive list of items produced in the first round was reduced in a four-round Delphi process to select items cited by at least 75% of the respondents. The identified elements were assembled in domains—each converted into a statement—to constitute the final self-administered Flare Assessment in Rheumatoid Arthritis (FLARE) questionnaire. Results The content of 99 patient interviews was analysed, and 10 domains were identified: joint swelling or pain, night pain, fatigue and different emotional consequences, as well as analgesic intake. The Delphi process for physicians identified eight domains related to objective RA symptoms and drug intake, of which only four were common to domains for patients. Finally, 13 domains were retained in the FLARE questionnaire, formulated as 13 statements with a Likert-scale response modality of six answers ranging from ‘absolutely true’ to ‘completely untrue’. Conclusion Two different methods, for patient and physician perspectives, were used to develop the FLARE self-administered questionnaire, which can identify past or present RA flare.

Long term structural effects of combination therapy in patients with early rheumatoid arthritis: five year follow up of a prospective double blind controlled study

Objective: To evaluate whether early combined therapy with methotrexate (MTX) and sulfasalazine (SSZ) during the first year in early rheumatoid arthritis (RA) induces long term beneficial effects, compared with monotherapy, when the further treatment strategy is a free choice. Methods: Study design: five year multicentre prospective longitudinal trial. Participants: 146/205 patients with RA previously included in a one year prospective randomised trial comparing the effects of treatment with MTX, SSZ, or a combination of both. Criteria for inclusion: patients with early RA (⩽1 year duration). Follow up: between the end of years 1 and 5, patients were followed up and treated by their own rheumatologist, who was allowed to indicate any treatment. Outcome measures: disease activity score (DAS), health assessment questionnaire (HAQ), and Sharp/van der Heijde radiological score at baseline and after five years of follow up. Analysis: comparison of the five year follow up DAS, HAQ, and radiological scores in patients given combined and single treatment during the first year. Results: At the end of the five years of follow up, the patients primarily receiving single or combined treatment had similar mean DAS, HAQ, and radiographic scores. Conclusion: Treatment of patients with early RA using combined therapy with MTX and SSZ during the first year did not influence the long term inflammatory status, or disability, or structural changes, compared with single disease modifying antirheumatic drug treatment.

Prevalence of hepatitis C virus infection in patients with rheumatoid arthritis

Backround: Various viruses have been implicated in the cause and pathogenesis of rheumatoid arthritis (RA). Hepatitis C virus (HCV) infection, which has been recognised as a cause of some autoimmune diseases, and which has been described as sometimes presenting with rheumatic manifestations indistinguishable from RA, might be a candidate. Objective: To evaluate the prevalence of HCV infection in patients with RA. Methods: Consecutive patients with RA admitted to hospital in two departments of rheumatology were prospectively studied. Patients serum samples were screened for the presence of anti-HCV antibodies. Patients with positive serology were further evaluated for the presence of HCV ribonucleic acid by reverse transcriptase polymerase chain reaction (RT-PCR). Results: 309 patients (232 women, 77 men, mean age (SD) 54.1 (14.8) years) were studied. Their mean (SD) disease duration was 74.1 (91) months. Tests for rheumatoid factors and antinuclear antibodies were positive in 213 (69%) and 114 (37%) of the patients respectively. Systemic vasculitis was found in 12 (4%) of the patients. Mean erythrocyte sedimentation rate was 36.4 (SD 30.5) mm at the first hour (normal <10 mm) and C reactive protein was 36.8 (SD 45.8) mg/l (normal range <5 mg/l), respectively, with 181(58.6%) of patients considered as having active disease. Aspartate transaminases were increased in 14 (4%) patients, and alkaline phosphatase in 14 (4%). A positive anti-HCV serology was found in two (0.65%) patients, including one with a previously diagnosed HCV infection. HCV RNA was positive by RT-PCR in one of those two patients. Conclusion: A 0.65% prevalence of past or active HCV infection was found in patients with RA, which did not differ from the prevalence of HCV in the general French population. This result does not support the participation of HCV infection in the pathogenesis of RA.

Use of glucocorticoids in rheumatoid arthritis – Pratical modalities of glucocorticoid therapy: Recommendations for clinical practice based on data from the literature and expert opinion

OBJECTIVEnTo develop recommendations about the use of glucocorticoids in patients with established rheumatoid arthritis (RA) managed in everyday practice, using the evidence-based approach and expert opinion.nnnMETHODSnA three-step procedure was used: a scientific committee used a Delphi procedure to select five questions, which formed the basis for developing the recommendations; a systematic literature review was conducted by searching the Medline and Embase databases and the abstracts of meetings held by the Société Française de Rhumatologie (SFR), American College of Rheumatology (ACR), and European League Against Rheumatism (EULAR); and recommendations were developed and validated by a panel of experts based on the data from the literature review and on their experience. For each recommendation, the level of evidence and extent of agreement among experts were determined.nnnRESULTSnThe five questions pertained to the use of glucocorticoids in RA patients: role for intravenous glucocorticoid bolus therapy, role for intraarticular injections, and practical modalities of glucocorticoid administration and discontinuation. From the literature search, 93 articles were selected based on their titles and abstracts. Of these, 50 were selected for the literature review. Eight recommendations about the use of glucocorticoid therapy in everyday practice in patients with established RA were validated by a vote among all participating experts: bolus glucocorticoid therapy should be reserved for highly selected situations; triamcinolone hexacetonide is the preferred glucocorticoid for intraarticular therapy, and the joint should be rested for about 24h after the injection; for oral glucocorticoid therapy, agents with a short half-life taken once daily should be preferred; and when discontinuing glucocorticoid therapy, the patient and usual physician should be informed of the risk of adrenal insufficiency.

Indications of glucocorticoids in early arthritis and rheumatoid arthritis: recommendations for clinical practice based on data from the literature and expert opinion.

OBJECTIVEnTo develop clinical practice guidelines about the indications of glucocorticoid therapy in early arthritis and established rheumatoid arthritis, based on previously published data and on the opinions of rheumatology experts.nnnMETHODSnWe used a three-step procedure. (a) A scientific committee used a Delphi procedure to select three questions about glucocorticoid indications: what is the role for glucocorticoid therapy in early arthritis? What is the role for long-term glucocorticoid therapy in established rheumatoid arthritis? What is the role for systemic glucocorticoid therapy in flares of rheumatoid arthritis? (b) Evidence providing answers to the three questions was sought in Pubmed, Embase, Cochrane, and abstracts from the annual meetings of the ACR and EULAR. (c) Based on this evidence, recommendations were developed and validated by a panel of experts. The strength of each recommendation was determined based on the level of the underlying evidence. The level of agreement among experts regarding each recommendation was measured.nnnRESULTSnThe literature search retrieved 2851 publications, of which 36 were selected based on the titles and abstracts then on the full-length articles. These 36 studies were presented to the experts as a basis for discussion. Six recommendations rated A to D were developed and validated by the experts. They dealt with the appropriateness of low- or moderate-dose glucocorticoid therapy for a limited period in early polyarthritis after advice from a specialist and in the event of active disease, in combination with disease-modifying antirheumatic drug (DMARD) therapy; the appropriateness of low-dose glucocorticoid therapy (no more than 0.1mg/kg/day) in RA if needed to achieve symptom control; and the appropriateness of oral glucocorticoid therapy (no more than 0.5mg/kg/day) for 1 to 2 weeks in polyarticular flares of RA.nnnCONCLUSIONnThe six recommendations for everyday practice presented here should help to standardize and to optimize clinical practice, thereby improving the management of patients with early arthritis or RA.

Response to tocilizumab in rheumatoid arthritis is not influenced by the body mass index of the patient.

Objective. To assess the relationship between the body mass index (BMI) and the efficacy of tocilizumab (TCZ) in patients with rheumatoid arthritis (RA). Methods. We conducted a retrospective study in 222 patients with RA followed by 5 centers. The European League Against Rheumatism response was evaluated at 6 months. Univariate and multivariate logistic regressions were performed. Results. No significant association between the BMI and the response to TCZ at 6 months was found after adjustment for potential confounding factors (adjusted OR 0.45, 95% CI 0.16–1.24, p = 0.13 and OR 1.19, 95% CI 0.31–4.48, p = 0.78 for BMI 25–30 kg/m2 and BMI > 30 kg/m2, respectively, compared to BMI < 25 kg/m2). Conclusion. Response to TCZ in patients with RA is not influenced by the baseline BMI, in contrast to anti-tumor necrosis factor drugs.

Three-dimensional kinematics of the lower limbs in hip osteoarthritis during walking

OBJECTIVEnTo describe the kinematic adaptations of all lower limb joints in hip osteoarthritis patients during walking.nnnMETHODSnPatients with unilateral primary hip OA, without associated joint disorders were included. Normal subjects were included as controls. Gait analysis, using a 3-dimensional computerised gait analysis system was used to evaluate the usual spatiotemporal parameters, the peak motion of the hips, knees, and ankles during walking, and the intersegmental coordination of the lower limbs.nnnRESULTSnEleven patients, mean age =60.5 ± 7 years and nine controls, mean age=60.3 ± 7 years, were included. The gait of hip OA patients was characterised as follows: a reduced stride length, a reduced maximal flexion and extension in the OA hip, a reduced maximal contralateral hip range of motion, an increased ipsi- and contralateral ankle dorsal flexion, a decreased ipsilateral relative temporal phase between the thighs and shanks segments and an increased ipsilateral relative phase between the shanks and foot segments.nnnCONCLUSIONnThe present results suggest that hip OA patients use shorter stride length, less contra lateral and especially ipsilateral hip motion, modify ankles motion, and have a different intra-limb coordination pattern compared to control subjects.