Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): A randomized, controlled trial. Arthritis Rheum 58(2 Suppl):S126-S135

VU University Amsterdam, Amsterdamo, North Holland, Netherlands
Arthritis & Rheumatology (Impact Factor: 7.76). 03/2008; 58(2 Suppl):S126-35. DOI: 10.1002/art.23364
Source: PubMed


Several treatment strategies have proven value in the amelioration of rheumatoid arthritis (RA), but the optimal strategy for preventing long-term joint damage and functional decline is unclear. We undertook this study to compare clinical and radiographic outcomes of 4 different treatment strategies, with intense monitoring in all patients.
In a multicenter, randomized clinical trial, 508 patients were allocated to 1 of 4 treatment strategies: sequential disease-modifying antirheumatic drug monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with tapered high-dose prednisone (group 3), and initial combination therapy with the tumor necrosis factor antagonist infliximab (group 4). Treatment adjustments were made every 3 months in an effort to obtain low disease activity (a Disease Activity Score in 44 joints of < or =2.4).
Initial combination therapy including either prednisone (group 3) or infliximab (group 4) resulted in earlier functional improvement than did sequential monotherapy (group 1) and step-up combination therapy (group 2), with mean scores at 3 months on the Dutch version of the Health Assessment Questionnaire (D-HAQ) of 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 (P < 0.001). After 1 year, mean D-HAQ scores were 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4 (P = 0.009). The median increases in total Sharp/Van der Heijde radiographic joint score were 2.0, 2.5, 1.0, and 0.5 in groups 1-4, respectively (P < 0.001). There were no significant differences in the number of adverse events and withdrawals between the groups.
In patients with early RA, initial combination therapy including either prednisone or infliximab resulted in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy.

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    • "Timely recognition of RA will allow for earlier start of therapy preventing more severe expansion of the disease. Moreover, several studies have shown that tight control as a treatment strategy in individual RA patients seems promising in achieving predefined level of low disease activity or preferably remission within a reasonable period of time [3] [4]. To this end, noninvasive imaging modalities may serve as sensitive and accurate tools for assessment and monitoring of disease activity during therapy to evaluate therapeutic efficacy. "
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    ABSTRACT: To widen the therapeutic window for PET guided evaluation of novel anti-RA agents, modifications were made in a rat model of rheumatoid arthritis (RA). Arthritis was induced in the right knee of Wistar rats with repeated boosting to prolong articular inflammation. The contralateral knee served as control. After immunization with methylated bovine serum albumin (mBSA) in complete Freund's adjuvant and custom Bordetella pertussis antigen, one or more intra-articular (i.a.) mBSA injections were given over time in the right knee. Serum anti-mBSA antibodies, DTH response, knee thickness, motion, and synovial macrophages were analyzed and [18F]FDG(-general inflammation) and (R)-[11C]PK11195 (macrophages-)PET was performed followed by ex vivo tissue distribution. Significant anti-mBSA levels, DTH, swelling of arthritic knee, and sustained and prolonged macrophage infiltration in synovial tissue were found, especially using multiple i.a. injections. Increased [18F]FDG and (R)-[11C]PK11195 accumulation was demonstrated in arthritic knees as compared to contralateral knees, which was confirmed in ex vivo tissue distribution studies. Boosting proved advantageous for achieving a chronic model without remission. The model will offer excellent opportunities for repeated PET studies to monitor progression of disease and efficacy of novel therapeutic agents for RA in the same animal.
    Full-text · Article · Oct 2014 · BioMed Research International
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    • "Three trials [3], [28], [29] of the 39 trials contributed with treatment arms to three combination treatment groups (TNFi, Double and Triple). Pairwise consistency analyses of the SMD effects obtained in the trials directly comparing combination treatments versus the SMD effects obtained by means of the exclusively indirect comparisons were performed to explore possible differences between the direct and the indirect comparisons. "
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    ABSTRACT: Background Despite significant cost differences, the comparative effect of combination treatments of disease modifying anti-rheumatic drugs (DMARDs) with and without biologic agents has rarely been examined. Thus we performed a network meta-analysis on the effect of combination therapies on progression of radiographic joint erosions in patients with rheumatoid arthritis (RA). Methods and Findings The following combination drug therapies compared versus single DMARD were investigated: Double DMARD: 2 DMARDs (methotrexate, sulfasalazine, leflunomide, injectable gold, cyclosporine, chloroquine, azathioprin, penicillamin) or 1 DMARD plus low dose glucocorticoid (LDGC); triple DMARD: 3 DMARDs or 2 DMARDs plus LDGC; biologic combination: 1 DMARD plus biologic agent (tumor necrosis factor α inhibitor (TNFi) or abatacept or tocilizumab or CD20 inhibitor (CD20i)). Randomized controlled trials were identified in a search of electronic archives of biomedical literature and included in a star-shaped network meta-analysis and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement protocol. Effects are reported as standardized mean differences (SMD). The effects of data from 39 trials published in the period 1989–2012 were as follows: Double DMARD: −0.32 SMD (CI: −0.42, −0.22); triple DMARD: −0.46 SMD (CI: −0.60, −0.31); 1 DMARD plus TNFi: −0.30 SMD (CI: −0.36, −0.25); 1 DMARD plus abatacept: −0.20 SMD (CI: −0.33, −0.07); 1 DMARD plus tocilizumab: −0.34 SMD (CI: −0.48, −0.20); 1 DMARD plus CD20i: −0.32 SMD (CI: −0.40, −0.24). The indirect comparisons showed similar effects between combination treatments apart from triple DMARD being significantly better than abatacept plus methotrexate (−0.26 SMD (CI: −0.45, −0.07)) and TNFi plus methotrexate (−0.16 SMD (CI: −0.31, −0.01)). Conclusion Combination treatment of a biologic agent with 1 DMARD is not superior to 2–3 DMARDs including or excluding LDGC in preventing structural joint damage. Future randomized studies of biologic agents should be compared versus a combination of DMARDs.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "Cohort B comprised 40 patients with established RA at the year 3 time point of the Behandel Strategieën (BeSt) study [22]. The patients’ mean age (SD) was 50.9 years (12.2), and 30 (75%) of the patients were female. "
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    ABSTRACT: The aim of this study was to investigate whether 14-3-3eta, a specific isoform of a family of proteins regulating processes such as cellular signaling, activates cell-signaling pathways and induces factors known to contribute to the pathophysiology of rheumatoid arthritis (RA). We also investigated whether 14-3-3eta is associated with more severe disease in both early and established RA. We investigated the effect of 14-3-3eta on the activation of RA-relevant signaling cascades and induction of pro-inflammatory mediators that contribute to the joint damage process. 14-3-3eta titres were measured in serum from 33 patients with early RA (mean duration 1.8 months) and 40 patients with established RA from the 3-year time point of the Behandel Strategieen (BeSt) cohort. The relationship between 14-3-3eta titres and standard clinical variables was investigated by correlation analysis. The association with radiographic damage and radiographic progression over at least two years was investigated using univariate and multivariate regression analyses. 14-3-3eta activated selective members of the mitogen-activated protein kinase (MAPK) family, mainly extracellular regulated kinase (ERK) 1/2 and c-jun kinase (JNK) but not p38MAPK. Activation by 14-3-3eta, using levels spanning the concentration range found in RA patient serum, resulted in the induction of inflammatory transcripts such as IL-1 and IL-6 and factors linked to the joint damage process, such as receptor activator of nuclear factor kappa-B ligand (RANKL) and matrix metalloproteinase-1 (MMP-1). Serum 14-3-3eta correlated significantly with rheumatoid factor (RF) (r=0.43) and anti-citrullinated protein antibodies, (ACPA) (r=0.31) in only the early RA cohort but not with C-reactive protein (CRP) or Disease Activity Score 28 in either cohort. Serum 14-3-3eta concentrations were significantly higher in patients with radiographically assessed joint damage and in those who had radiographic progression. Through multivariate analysis, 14-3-3eta was shown to complement markers such as CRP, RF, and ACPA in informing radiographic status and/or progression. Extracellular 14-3-3eta activates key signaling cascades and induces factors associated with the pathogenesis of RA at concentrations found in patients with RA and its expression is higher in patients with radiographic damage and who demonstrate progression.
    Full-text · Article · Apr 2014 · Arthritis research & therapy
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