Rheumatoid Arthritis: Combe B

Aletaha D, Landewe R, Karonitsch T, Bathon J, Boers M, Bombardier C, Bombardieri S, Choi H, Combe B, Dougados M, Emery P, Gomez-Reino J, Keystone E, Koch G, Kvien TK, Martin-Mola E, Matucci-Cerinic M, Michaud K, O'Dell J, Paulus H, Pincus T, Richards P, Simon L, Siegel J, Smolen JS, Sokka T, Strand V, Tugwell P, van der Heijde D, van Riel P, Vlad S, van Vollenhoven R, Ward M, Weinblatt M, Wells G, White B, Wolfe F, Zhang B, Zink A, Felson D, Anonymous00358, Anonymous00359. · Medical University of Vienna, Vienna, Austria. · Arthritis Rheum. · Pubmed #18821648 No free full text.

Abstract: OBJECTIVE: To make recommendations on how to report disease activity in clinical trials of rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: The project followed the EULAR standardized operating procedures, which use a three-step approach: 1) expert-based definition of relevant research questions (November 2006); 2) systematic literature search (November 2006 to May 2007); and 3) expert consensus on recommendations based on the literature search results (May 2007). In addition, since this is the first joint EULAR/ACR publication on recommendations, an extra step included a meeting with an ACR panel to approve the recommendations elaborated by the expert group (August 2007). RESULTS: Eleven relevant questions were identified for the literature search. Based on the evidence from the literature, the expert panel recommended that each trial should report the following items: 1) disease activity response and disease activity states; 2) appropriate descriptive statistics of the baseline, the endpoints and change of the single variables included in the core set; 3) baseline disease activity levels (in general); 4) the percentage of patients achieving a low disease activity state and remission; 5) time to onset of the primary outcome; 6) sustainability of the primary outcome; 7) fatigue. CONCLUSION: These recommendations endorsed by EULAR and ACR will help harmonize the presentations of results from clinical trials. Adherence to these recommendations will provide the readership of clinical trials with more details of important outcomes, while the higher level of homogeneity may facilitate the comparison of outcomes across different trials and pooling of trial results, such as in meta-analyses.

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.

Combe B, Landewe R, Lukas C, Bolosiu HD, Breedveld F, Dougados M, Emery P, Ferraccioli G, Hazes JM, Klareskog L, Machold K, Martin-Mola E, Nielsen H, Silman A, Smolen J, Yazici H. · Immuno-Rhumatologie, Lapeyronie Hosp, Montpellier, France. · Ann Rheum Dis. · Pubmed #16396980 No free full text.

Abstract: OBJECTIVE: To formulate EULAR recommendations for the management of early arthritis. METHODS: In accordance with EULAR's "standardised operating procedures", the task force pursued an evidence based approach and an approach based on expert opinion. A steering group comprised of 14 rheumatologists representing 10 European countries. The group defined the focus of the process, the target population, and formulated an operational definition of "management". Each participant was invited to propose issues of interest regarding the management of early arthritis or early rheumatoid arthritis. Fifteen issues for further research were selected by use of a modified Delphi technique. A systematic literature search was carried out. Evidence was categorised according to usual guidelines. A set of draft recommendations was proposed on the basis of the research questions and the results of the literature search.. The strength of the recommendations was based on the category of evidence and expert opinion. RESULTS: 15 research questions, covering the entire spectrum of "management of early arthritis", were formulated for further research; and 284 studies were identified and evaluated. Twelve recommendations for the management of early arthritis were selected and presented with short sentences. The selected statements included recognition of arthritis, referral, diagnosis, prognosis, classification, and treatment of early arthritis (information, education, non-pharmacological interventions, pharmacological treatments, and monitoring of the disease process). On the basis of expert opinion, 11 items were identified as being important for future research. CONCLUSIONS: 12 key recommendations for the management of early arthritis or early rheumatoid arthritis were developed, based on evidence in the literature and expert consensus.

Combe B. · No affiliation provided · Joint Bone Spine. · Pubmed #17071123 No free full text.

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Combe B. · No affiliation provided · Joint Bone Spine. · Pubmed #15182784 No free full text.

This publication has no abstract.

Combe B. · Immuno-Rhumatologie, Hopital Lapeyronie, CHU de Montpellier, Montpellier I University, Montpellier, France. · Best Pract Res Clin Rheumatol. · Pubmed #19233046 No free full text.

Abstract: Rheumatoid arthritis (RA) is a very heterogeneous disease, the outcome of which is difficult to predict. The vast majority of the patients will have disease progression with bone erosions and cartilage breakdown resulting in joint destruction, functional impairment, and increased mortality. The management of RA to prevent and control disease progression has changed considerably in the past few years. The treatment goal should now be to achieve clinical remission in order to prevent structural damage and long-term disability. A very early use of effective disease-modifying anti-rheumatic drugs (DMARDs) is a key point in patients at risk of developing persistent and erosive arthritis. Intensive treatment such as combination DMARDs plus steroids or mainly biological therapies can induce high rates of remission and control of radiological progression, and can provide better outcomes than DMARD monotherapy in early RA, and should be considered very early in at-risk patients. In addition, close monitoring of disease activity and radiographic progression is mandatory in order to adapt DMARD therapy and strategy if necessary.

Combe B. · Immuno-Rhumatologie Hôpital Lapeyronie, CHU de Montpellier, University Montpellier I, 371, Avenue du Doyen Gaston Giraud 34295 Montpellier cedex 5, France. · Best Pract Res Clin Rheumatol. · Pubmed #17350542 No free full text.

Abstract: The treatment of rheumatoid arthritis (RA) has changed considerably in the past few years since new tools and new concepts have been developed and validated highlighting the need for guidelines focused on early RA. The treatment goal should now be to achieve clinical remission, in order to prevent structural damage and long-term disability. A very early use of effective disease-modifying anti-rheumatic drugs (DMARDs) is a key point in patients at risk of developing persistent and erosive arthritis. Intensive treatment such as combination DMARDs plus steroids or biological therapies can induce a high rate of remission, control of radiological progression and provide better outcome than DMARD monotherapy in early RA and should be considered in at risk patients. Regarding the risk:benefit ratio and the cost-effectiveness of these strategies, a reasonable course of action in early RA should be initial DMARD monotherapy such as methotrexate. However, a close monitoring of disease activity and radiographic progression is mandatory in order to change DMARD therapy and strategy if necessary. Systemic glucocorticoids are effective in the short-term relief of pain and swelling and should be considered, but mainly as a temporary therapy part of the DMARD strategy. Information and education for patients, as well as some non-pharmacological interventions, can be proposed as treatment adjuncts. Finally, the reduction or stopping of smoking, which could prevent the development and progression of early RA, is the only prevention tool currently available.

Thomas T, Noël E, Goupille P, Duquesnoy B, Combe B, Anonymous00114. · Rheumatology Department, St-Etienne University Hospital, Boulevard Pasteur, 42055 Saint-Etienne cedex 02, France. · Joint Bone Spine. · Pubmed #16213772 No free full text.

Abstract: Shoulder involvement is usually inconspicuous in patients with rheumatoid arthritis, and the clinical manifestations are nonspecific. Nevertheless, shoulder involvement should be sought routinely and detected early. Range of motion at the shoulder should be evaluated. Although normal radiographic findings do not rule out shoulder involvement, radiographs are crucial for detecting micro- and macro-geodes during follow-up. The development of glenohumeral joint space narrowing is a turning point that indicates a risk of rapid joint destruction. Magnetic resonance imaging is useful for assessing the lesions and guiding the treatment strategy. Stepwise use of local interventions as indicated by imaging findings is recommended. Joint replacement should not be left too late, and surgical procedures on the shoulder should be built into the overall treatment plan.

Kalden JR, Antoni C, Alvaro-Gracia JM, Combe B, Emery P, Kremer JM, Strand CV, Van Riel P, Smolen JS. · Medizinische Klinik III, Institute for Clinical Immunology, Erlangen, Germany. · J Rheumatol. · Pubmed #16078347 No free full text.

Abstract: An Expert Panel Meeting was held in May 2004 to assess experience with combination therapy with leflunomide and biological agents in the treatment of rheumatoid arthritis (RA), to identify both optimal use of such combinations and precautions for use. Eleven published prospective or retrospective studies were reviewed, principally evaluating combination of leflunomide with infliximab, as well as patient registry data. Available data suggest that combination therapies are more efficacious than monotherapies, reflecting the complementarity of mechanisms of action. Information on side effects remains contradictory, and tolerability of these combinations may vary between different patient groups. In some studies, tolerability is equivalent to that seen with monotherapy; in others a high rate of adverse events has led to frequent treatment discontinuation. Dermatological reactions may be a specific side effect of these combination therapies. Combination therapy is considered justified for treatment of patients diagnosed early who are at risk for rapid progression and for patients who fail to respond to monotherapy. The majority of participants favored adding biological agents to a previously established leflunomide monotherapy rather than starting both treatments simultaneously. On the other hand, combination therapy should be considered with caution in patients with a history of treatment failure, with hepatic comorbidity, or with other autoimmune disease, and in immunocompromised patients. When considering initiation of combination therapy, it is important to provide full information to the patient on the potential benefits and risks of such treatment and to integrate patients as far as possible into the decision-making process.

Fautrel B, Pham T, Gossec L, Combe B, Flipo RM, Goupille P, Le Loët X, Mariette X, Puéchal X, Wendling D, Schaeverbeke T, Sibilia J, Sany J, Dougados M. · Service de rhumatologie, groupe hospitalier Pitié-Salpêtrière, Paris, France. · Joint Bone Spine. · Pubmed #15797498 No free full text.

Abstract: OBJECTIVES: To develop recommendations for the information and education of patients with rheumatoid arthritis (RA) seen in everyday practice, using evidence from the literature, supplemented with expert opinion when needed. METHODS: A scientific committee developed eight questions using the Delphi consensus procedure. A task force reviewed the literature for answers to these questions, using the PubMed Medline database (1980-2004) and the 2002-2004 databases of the annual meetings held by the French Society for Rheumatology (SFR), the European League Against Rheumatism (EULAR), and the American College of Rheumatology (ACR); the indexing terms for the search were rheumatoid, arthritis, patient, education, information, knowledge, general practitioner, family doctor, and continuing medical education. Only articles in French or English were included. A panel of rheumatologists used the evidence thus compiled to develop recommendations for each question; gaps in evidence were filled by calling on the panelists' expert opinion. For each recommendation, the level of evidence and extent of agreement among panelists were specified. RESULTS: There were four general questions about the objectives, supports, and mode of delivery (group or one-on-one) of patient information and education, as well as on evaluating knowledge, and four specific questions on program content. The search identified 1235 articles; 144 were selected on the title and 118 of those on the abstract. Three abstracts presented at meetings were also kept. The evidence from the literature was presented to the panelists during interactive workshops. The panelists then developed eight recommendations, all of which were grade D because no published studies specifically addressed everyday clinical practice. Agreement among panelists ranged across recommendations from 85.7% to 100%. CONCLUSION: Recommendations about educating and informing patients with RA in everyday practice were developed. They should increase practice uniformity and ultimately optimize the management of patients with RA.

Combe B. · Immuno-Rheumatology Department, Lapeyronie Teaching Hospital, 31, avenue du Doyen Gaston Giraud, 34295 Montpellier 5, France. · Joint Bone Spine. · Pubmed #15589426 No free full text.

Abstract: The diagnostic and therapeutic management of rheumatoid arthritis has benefited considerably in recent years not only from the introduction of new treatments (including new disease-modifying antirheumatic drugs, new combinations of these drugs, and TNF inhibitors), but also from the development of new concepts. Important new concepts include the use of novel diagnostic approaches, very early management within the first 3-6 months of symptom onset, periodic assessments of clinical disease activity based on objective clinical criteria and radiographic progression, and earlier use of aggressive treatments. The goal is to induce a clinical remission, thereby preventing radiographic deterioration. These concepts are firmly supported by sound scientific data. At present, patients at risk for progression to severe rheumatoid arthritis must be identified early on, and disease activity and progression must be monitored closely. This should enable patients with highly progressive disease to receive aggressive treatment (e.g., a combination of disease-modifying antirheumatic drugs or biological therapy) very early on with the goal of minimizing joint destruction and subsequent functional impairments.

Morel J, Combe B. · Department of Immunorheumatology, Hospital Lapeyronie, 34295 Montpellier Cedex 5 and Inserm Unit 454, France. · Best Pract Res Clin Rheumatol. · Pubmed #15588975 No free full text.

Abstract: In early rheumatoid arthritis (RA), the objectives of therapeutic strategies are to obtain remission and prevent joint destruction as early as possible. These goals may be reached with conventional disease-modifying antirheumatic drugs (DMARDs) or with biological agents. In clinical practice, initial treatments are usually chosen according to the degree of disease activity at baseline, and adapted according to a step-up strategy. A more elegant therapeutic approach would be to choose the most appropriate treatment based on the prognosis of RA. Therefore, prognostic stratification could improve the relative roles and benefits of initial DMARD or biological therapy for early RA. For RA with a severe prognosis, a combination of DMARDs or biologicals could be initiated as the first-line therapy. However, we need to know how to predict outcome in early RA for this type of strategy. This review attempts to answer this question by reporting the most reliable prognostic factors and some predictive models proposed for classification into benign, mild and severe RA.

Combe B. · Service d'Immuno-Rhumatologie, Hôpital Lapeyronie, 34295 Montpellier, France. · Clin Exp Rheumatol. · Pubmed #14969063 No free full text.

Abstract: This report is focused on two French multicenter cohorts of patients with early rheumatoid arthritis (RA). The first one is a community-based study which was started in 1993. It was mainly designed to identify prognostic factors of joint destruction, disability and remission in patients with early RA. The 3-year and 5-year results have been recently reported. Briefly, progression of joint damage was best predicted at baseline by radiographic scores, ESR, CRP, rheumatoid factor and DRB1*04 genes, and disability by disease activity including the HAQ score. Recently, the French Society of Rheumatology initiated a large national multicenter registry (800 patients), the "ESPOIR cohort study", that could serve as a database to allow investigations not only on diagnostic and prognostic markers, but also on etiologic, pathogenic and medico-economic factors among patients with early inflammatory arthritis who could later develop RA. The objectives, design and organization of this early arthritis registry are described.

Combe B. · Rheumatology Federation, Hôpital Lapeyronie, Montpellier, France. · Joint Bone Spine. · Pubmed #11809002 No free full text.

Abstract: Thalidomide, which was developed as a nonbarbiturate sedative agent, was taken off the market in 1961 after it was linked to a spate of major birth defects. Gradually, thalidomide was reintroduced for the treatment of a few skin diseases including leprous erythema nodosum, severe mucosal ulcers (e.g., associated with HIV infection or Behçet's disease), lymphocytic skin infiltrations, cutaneous lupus erythematosus, and chronic graft-versus-host disease. Recent reports of original pharmacological properties including modulation of cytokine production (mainly reduced TNF-alpha production) and inhibition of angiogenesis have led to the suggestion that thalidomide may be useful in some inflammatory and neoplastic conditions. Several open-label studies and case reports have described the effects of thalidomide in Crohn's disease, rheumatoid arthritis, ankylosing spondylarthritis, systemic sclerosis, and a few other systemic disorders. In these indications, minor but dose-limiting side effects were apparently common. Thalidomide analogs with better acceptability profiles are under evaluation. The anti-angiogenic effects of thalidomide may make this compound valuable as single-drug therapy or as an adjunct to chemotherapy in patients with cancer, particularly those with metastases or multiple myeloma. This possibility requires further evaluation.

Smolen JS, Breedveld FC, Burmester GR, Combe B, Emery P, Kalden JR, Klareskog L, Maini RN, Numo R, van De Putte LB, van Riel PL, Rodriguez-Valverde V. · University of Vienna, Berlin. · Ann Rheum Dis. · Pubmed #10873957 links to  free full text

This publication has no abstract.

Keystone E, Heijde D, Mason D, Landewé R, Vollenhoven RV, Combe B, Emery P, Strand V, Mease P, Desai C, Pavelka K. · University of Toronto, Toronto, Ontario, Canada. · Arthritis Rheum. · Pubmed #18975346 No free full text.

Abstract: OBJECTIVE: To evaluate the efficacy and safety of 2 dosage regimens of lyophilized certolizumab pegol (a novel PEGylated anti-tumor necrosis factor agent) as adjunctive therapy to methotrexate (MTX) in patients with active rheumatoid arthritis (RA) with an inadequate response to MTX therapy alone. METHODS: In this 52-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial, 982 patients were randomized 2:2:1 to receive treatment with subcutaneous certolizumab pegol at an initial dosage of 400 mg given at weeks 0, 2, and 4, with a subsequent dosage of 200 mg or 400 mg given every 2 weeks, plus MTX, or placebo plus MTX. Co-primary end points were the response rate at week 24 according to the American College of Rheumatology 20% criteria for improvement (ACR20) and the mean change from baseline in the modified total Sharp score at week 52. RESULTS: At week 24, ACR20 response rates using nonresponder imputation for the certolizumab pegol 200-mg and 400-mg groups were 58.8% and 60.8%, respectively, as compared with 13.6% for the placebo group. Differences in ACR20 response rates versus placebo were significant at week 1 and were sustained to week 52 (P < 0.001). At week 52, mean radiographic progression from baseline was reduced in patients treated with certolizumab pegol 200 mg (0.4 Sharp units) or 400 mg (0.2 Sharp units) as compared with that in placebo-treated patients (2.8 Sharp units) (P < 0.001 by rank analysis). Improvements in all ACR core set of disease activity measures, including physical function, were observed by week 1 with both certolizumab pegol dosage regimens. Most adverse events were mild or moderate. CONCLUSION: Treatment with certolizumab pegol 200 or 400 mg plus MTX resulted in a rapid and sustained reduction in RA signs and symptoms, inhibited the progression of structural joint damage, and improved physical function as compared with placebo plus MTX treatment in RA patients with an incomplete response to MTX.

Courvoisier N, Dougados M, Cantagrel A, Goupille P, Meyer O, Sibilia J, Daures JP, Combe B. · Service de Rhumatologie, Hôpital Saint Antoine, 184 rue du Faubourg Saint Antoine, Paris, 75012, France. · Arthritis Res Ther. · Pubmed #18771585 links to  free full text

Abstract: INTRODUCTION: The objectives of this study were to determine the predictive factors of long-term radiographic outcome of rheumatoid arthritis (RA) and to describe the relationship between joint damage and disability over the course of the disease. METHODS: A cohort of 191 patients with early RA referred from primary care physicians were prospectively followed for 10 years. To determine the predictive factors of radiographic outcome, univariate analysis of the relationship between baseline values and outcome measures was undertaken using a chi-squared or Fisher's exact test. Stepwise multiple logistic regression was also performed to select independent prognostic factors. RESULTS: From data available for 112 patients, univariate analysis revealed a total Sharp score at 10 years that was significantly correlated with erythrocyte sedimentation rate (ESR), presence and level of IgA rheumatoid factor, presence of an anti-citrullinated protein antibody (ACPA), serum level of matrix metalloproteinase-3 and radiographic score at baseline. Logistic regression identified the baseline erosion score to be the most important baseline parameter as an independent prognostic factor of total radiographic score at 10 years (odds ratio = 5.64; 95% confidence interval = 1.78 to 17.86). After excluding radiographic scores from the entry parameters, the presence of ACPA and ESR were also predictive of the final total Sharp score. The Health Assessment Questionnaire (HAQ) score was strongly correlated with disease activity parameters, such as disease activity score and pain, at baseline and at three, five and 10 years. No correlation was found between total radiographic Sharp score and HAQ score throughout the study. CONCLUSIONS: In this prospective study, baseline radiographic score, ESR and ACPA were the best predictive factors of 10-year radiographic outcome in early RA. HAQ disability was associated with disease activity throughout the 10-year follow-up but not with joint damage. This discrepancy with previous reports may be due in part to the early start of therapy with disease-modifying anti-rheumatic drugs.

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.

Maillefert JF, Combe B, Goupille P, Cantagrel A, Dougados M. · Centre Hospitalier Universitaire Dijon, and INSERM/ERIT-M 0207, University of Burgundy, Dijon, France. · Ann Rheum Dis. · Pubmed #12860733 links to  free full text

Abstract: 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 (< or =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.

Combe B, Vélicitat P, Garzón N, Bluhmki E. · Fédération de Rhumatologie, H pital Lapeyronie 371, Montpellier, France. · Inflamm Res. · Pubmed #11339515 No free full text.

Abstract: OBJECTIVE: This double-blind, double-dummy, two-way comparative trial evaluated the overall efficacy and tolerability of intramuscular (im) vs oral meloxicam. SUBJECTS: 346 patients with rheumatoid arthritis (RA). TREATMENT AND METHODS: 173 patients in each group were randomised to receive either im meloxicam (15 mg) plus a placebo tablet, or oral meloxicam (15 mg) plus a placebo injection for 7 days. RESULTS: Significant (p < 0.001) improvements in overall pain and disease activity were observed by patients treated with im and oral meloxicam, with no significant difference between treatments. The im formulation was better than the oral tablet in terms of rapidity of action (p=0.012), global efficacy (p=0.030) and duration of morning stiffness (p=0.026). Local tolerability of im meloxicam was very good and comparable with placebo injections. CONCLUSION: Oral and im meloxicam (15 mg) were both effective and well-tolerated for acute exacerbations of RA. The im formulation had some advantages, such as a faster onset of action.

Bressolle F, Kinowski JM, Morel J, Pouly B, Sany J, Combe B. · Laboratoire de Pharmacocinétique, Faculté de Pharmacie, CHU Lapeyronie, Montpellier, France. · J Rheumatol. · Pubmed #10990220 No free full text.

Abstract: OBJECTIVE: To evaluate the effects of repeated doses of folic acid on the pharmacokinetics of methotrexate (MTX) in patients with rheumatoid arthritis. METHODS: We studied 20 patients (ages 30-78 years) who received MTX intramuscularly (10 mm/week). MTX was administered alone or after treatment with folic acid (5 mg tablet once daily) for 13 days. Plasma samples were collected 2 and 8 h after dose intake. MTX concentrations in plasma and ultrafiltrate samples were measured by fluorescence polarization immunoassay. A Bayesian approach was used to determine individual MTX pharmacokinetic variables to minimize the number of samples collected. RESULTS: Folic acid supplementation led to reduced plasma MTX levels 2 and 8 h after MTX administration and reduced area under the plasma MTX concentration versus time curve (AUC) (about 20%; p < 0.02). Total clearance of MTX and Vd were higher when patients were also receiving folic acid than when they were taking MTX alone (p < 0.02). The plasma protein binding of MTX remains unchanged. CONCLUSION: The lower plasma MTX concentrations in patients taking folic acid supplements could be interpreted as increased cellular uptake of MTX; the folic acid supplements would promote the sequestering of MTX intracellularly. The decrease of MTX concentrations leads to reduced AUC; it is also possible that there are reduced AUC combined with increased intracellular folate levels. These results reopen the question of whether folic acid should be used immediately in all patients when MTX is begun.

Dougados M, Combe B, Cantagrel A, Goupille P, Olive P, Schattenkirchner M, Meusser S, Paimela L, Rau R, Zeidler H, Leirisalo-Repo M, Peldan K. · Institut de Rhumatologie, Hardy B, Hôpital Cochin, Paris, France. · Ann Rheum Dis. · Pubmed #10364900 links to  free full text

Abstract: OBJECTIVES: To investigate the potential clinical benefit of a combination therapy. METHODS: 205 patients fulfilling the ACR criteria for rheumatoid arthritis (RA), not treated with disease modifying antirheumatoid drugs previously, with an early (< or = 1 year duration), active (Disease Activity Score (DAS) > 3.0), rheumatoid factor and/or HLA DR 1/4 positive disease were randomised between sulphasalazine (SASP) 2000 (maximum 3000) mg daily (n = 68), or methotrexate (MTX) 7.5 (maximum 15) mg weekly (n = 69) or the combination (SASP + MTX) of both (n = 68). RESULTS: The mean changes in the DAS during the one year follow up of the study was -1.15, -0.87, -1.26 in the SASP, MTX, and SASP + MTX group respectively (p = 0.019). However, there was no statistically significant difference in terms of either EULAR good responders 34%, 38%, 38% or ACR criteria responders 59%, 59%, 65% in the SASP, MTX, and SASP + MTX group respectively. Radiological progression evaluated by the modified Sharp score was very modest in the three groups: mean changes in erosion score: +2.4, +2.4, +1.9, in narrowing score: +2.3, +2.1, +1.6 and in total damage score: +4.6, +4.5, +3.5, in the SASP, MTX, and SASP + MTX groups respectively. Adverse events occurred more frequently in the SASP + MTX group 91% versus 75% in the SASP and MTX group (p = 0.025). Nausea was the most frequent side effect: 32%, 23%, 49% in the SASP, MTX, and SASP + MTX groups respectively (p = 0.007). CONCLUSION: This study suggests that an early initiation therapy of disease modifying drug seems to be of benefit. However, this study was unable to demonstrate a clinically relevant superiority of the combination therapy although several outcomes were in favour of this observation. The tolerability of the three treatment modalities seems acceptable.

Maravic M, Bologna C, Daures JP, Jorgensen C, Combe B, Sany J. · Service d'Immuno-Rhumatologie, CHU Montpellier, Unité INSERM U475, France. · J Rheumatol. · Pubmed #9972956 No free full text.

Abstract: OBJECTIVE: To evaluate radiologic progression in patients with early rheumatoid arthritis (RA) receiving methotrexate (MTX) as the first slow acting drug. METHODS: An open, prospective study of 29 patients with RA (21 F, 8 M, mean age 48.5+/-15.4 yrs). The mean duration of RA was 6.6 (2-60) months; and rheumatoid factor was present in 11 cases. Clinical, biological, and radiographic evaluations were done before the start of MTX treatment and after 13+/-3.8 months. Radiographs of hands and wrists were blindly studied by 2 physicians, using Larsen's and modified Sharp's methods. There was a significant correlation for the scores of the 2 physicians evaluated by kappa coefficient. Radiographic evolution was defined as an increase of 15 points in the radiologic score by each method used. RESULTS: Patients showed significant clinical improvement after one year of MTX treatment. Despite clinical and biological improvement, significant mean radiographic progression was noted, with Larsen's method (p = 0.001) and Sharp's method (p = 0.034), without reaching the maximum score. However, using the definition of radiographic progression, the radiologic scores indicated stabilization in 23 patients with Larsen's method and in 24 patients with Sharp's method. CONCLUSION: This study revealed mild radiographic progression in early RA patients treated with MTX for one year. Further controlled studies are needed.

Fautrel B, Guillemin F, Meyer O, de Bandt M, Berthelot JM, Flipo RM, Lioté F, Maillefert JF, Wendling D, Saraux A, Combe B, Le Loët X, Anonymous00044, Anonymous00045, Anonymous00046. · Department of Rheumatology, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. · Arthritis Rheum. · Pubmed #19333993 No free full text.

Abstract: OBJECTIVE: To survey rheumatologists' preferences for the choice of a second-line disease-modifying antirheumatic drug (DMARD) after inadequate response with methotrexate (MTX) therapy in rheumatoid arthritis (RA). METHODS: Thirty-six rheumatologists stated their preferences for RA treatment after inadequate response with MTX therapy (optimal dose at least 6 months). From the initial scenario, we derived 54 vignettes varying by rheumatoid factor or anti-cyclic citrullinated peptide antibody presence, swollen joint count, Disease Activity Score in 28 joints, and structural damage. Respondents stated their preference among 5 therapeutic options: MTX continuation, switch to another conventional DMARD, addition of another conventional DMARD, addition of anakinra, or addition of a tumor necrosis factor (TNF) blocker. Presentation by pairs yielded 10 combinations of strategies for each variant, totaling 540 vignettes; participants evaluated a random sample of 180 vignettes. Determinants of each top-ranked option were analyzed by logistic regression. The compilation of these data served to define a therapeutic algorithm. RESULTS: The responses of 33 rheumatologists were analyzable. Therapeutic preferences corresponded to the top-ranked options. For patients with mild or moderately active RA, either a switch or step-up strategy to another conventional DMARD was top ranked. TNF blockers were preferred for RA patients with high disease activity or progressive structural damage. On the basis of these preferences, we developed a simple decision tree for use in daily clinical practice. CONCLUSION: Our simple, easy-to-use decision tree developed from rheumatologists' preferences for therapy after failure of MTX therapy in RA treatment may guide rheumatologists in daily practice to choose a second-line DMARD.

Lukas C, Guillemin F, Landewé R, van der Heijde D, Logeart I, Fautrel B, Daures JP, Combe B, Anonymous00090. · Immuno-Rhumatologie, Hôpital Lapeyronie, Montpellier, France. · Clin Exp Rheumatol. · Pubmed #19327234 No free full text.

Abstract: BACKGROUND: To describe the rate and timing of DMARD start in patients with early inflammatory arthritis in France, and to determine the factors leading to this treatment start. METHODS: The ESPOIR cohort study collects data on patients presenting with early arthritis. Baseline characteristics were assessed, and Cox regression analysis was performed to estimate the likelihood of starting DMARD treatment over time, adjusting for patient-, disease- and physician characteristics. RESULTS: Of the 775 analysed patients, 598 (77.2%) received at least 1 DMARD during the follow-up period, after a median time of 4.0 months. In general, a higher tender joint count, involvement of the hands, involvement of more than 3 joint groups, presence of abnormal CRP-levels or CCP-antibodies significantly increased the likelihood of being treated (p<0.01 for all determinants), as well as a positive result on the bilateral foot-squeeze test (p<0.04). In addition, a significant hetero-geneity in therapeutic strategy across the 14 tested French regions was found: adjusted hazard ratios for DMARD start ranged from 1 to 2.15 (p<0.01), depending on the region where a patient was followed. For anti-CCP test and swollen joint count we demonstrated a statistically significant interaction with geographic region, implying that these tests are interpreted differently across regions. The same factors that increased the likelihood to start a DMARD were related to an earlier start. CONCLUSION: Rate and timing of treatment start with DMARDs in patients with early inflammatory arthritis in France is determined by well known clinical and biochemical variables. Apart from these variables, however, unknown and intangible factors that seem to cluster geographically are responsible for important variations in practice performance.