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Early RA (early + ra)
Selected AbstractsDeveloping multidisciplinary guidelines for the management of early rheumatoid arthritisMUSCULOSKELETAL CARE, Issue 2 2008BA Hons, Sheena Hennell RGN Abstract Objective:,To develop an evidence based guideline, for the multidisciplinary management of early rheumatoid arthritis (RA). Methods:,Recommendations were developed using both an evidence-based approach and expert opinion. The scientific committee, composed of key members of the rheumatology multidisciplinary team used a Delphi approach to evaluate topics and standard statements, which formed the basis for developing recommendations for management of RA in the first 2 years of disease. Evidence taken from literature was used to support these recommendations. Results:,24 evidence based recommendations for the management of early RA, with a grade of recommendation from A to C, were developed. In addition an algorithm of care was designed to promote a clear multidisciplinary management pathway. A mechanism for audit was also identified. Conclusion:,Involvement of the multidisciplinary rheumatology team has enabled a holistic guideline to be developed for the management of patients presenting with early RA. This guideline is based around best practice that is supported by published literature. Whilst most statements in the guideline are based on strong evidence, others have been formulated by expert consensus in the absence of data and should serve as an opportunity to improve current practice through future research and audit. The development and implementation of such a guideline should improve the care of patients with early RA. Copyright © 2007 John Wiley & Sons, Ltd. [source] A functional RANKL polymorphism associated with younger age at onset of rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 10 2010Wenfeng Tan Objective We previously observed the association of the co-occurrence of the HLA,DRB1 shared epitope (SE) and RANKL single-nucleotide polymorphisms (SNPs) with younger age at the onset of rheumatoid arthritis (RA) in 182 rheumatoid factor (RF),positive European American patients with early-onset RA. The aim of this study was to fine-map the 48-kb RANKL region in the extended cohort of 210 European American RF-positive patients with early RA, to seek replication of RA-associated SNPs in additional RA cohorts of 501 European Americans and 298 African Americans, and to explore the functional consequences of RA-associated SNPs. Methods SNP genotyping was conducted using pyrosequencing or TaqMan polymerase chain reaction (PCR) assays. Associations of rs7984870 with RANKL expression in plasma, peripheral blood mononuclear cells, and isolated T cells were quantified using enzyme-linked immunosorbent assay and reverse transcription,PCR. Site-directed mutagenesis of rs7984870 within the 2-kb RANKL promoter was performed to drive the luciferase reporter gene in osteoblast and stromal cell lines. Interaction of DNA and protein was determined by electrophoretic mobility shift assay. Results A single promoter SNP, rs7984870, was consistently significantly associated with earlier age at the onset of RA in 3 independent seropositive (RF or anti,cyclic citrullinated peptide antibody) RA cohorts but not in seronegative RA patients. The C risk allele of rs7984870 conferred 2-fold higher plasma RANKL levels in RF-positive patients with RA, significantly elevated RANKL messenger RNA expression in activated normal T cells, and increased promoter activity after stimulation in vitro via differential binding to the transcription factor SOX5. Conclusion The RANKL promoter allele that increased transcription levels upon stimulation might promote interaction between activated T cells and dendritic cells, predisposing to a younger age at the onset of RA in seropositive European American and African American patients. [source] 1,25-dihydroxyvitamin D3 modulates Th17 polarization and interleukin-22 expression by memory T cells from patients with early rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 1 2010E. M. Colin Objective To examine the immunologic mechanism by which 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) may prevent corticosteroid-induced osteoporosis in patients with early rheumatoid arthritis (RA), with a focus on T cell biology. Methods Peripheral blood mononuclear cells (PBMCs) and CD4+CD45RO+ (memory) and CD4+CD45RO, (non-memory) T cells separated by fluorescence-activated cell sorting (FACS) from treatment-naive patients with early RA were stimulated with anti-CD3/anti-CD28 in the absence or presence of various concentrations of 1,25(OH)2D3, dexamethasone (DEX), and 1,25(OH)2D3 and DEX combined. Levels of T cell cytokines were determined by enzyme-linked immunosorbent assay and flow cytometry. Results The presence of 1,25(OH)2D3 reduced interleukin-17A (IL-17A) and interferon-, levels and increased IL-4 levels in stimulated PBMCs from treatment-naive patients with early RA. In addition, 1,25(OH)2D3 had favorable effects on tumor necrosis factor , (TNF,):IL-4 and IL-17A:IL-4 ratios and prevented the unfavorable effects of DEX on these ratios. Enhanced percentages of IL-17A, and IL-22,expressing CD4+ T cells and IL-17A,expressing memory T cells were observed in PBMCs from treatment-naive patients with early RA as compared with healthy controls. Of note, we found no difference in the percentage of CD45RO+ and CD45RO, cells between these 2 groups. Interestingly, 1,25(OH)2D3, in contrast to DEX, directly modulated human Th17 polarization, accompanied by suppression of IL-17A, IL-17F, TNF,, and IL-22 production by memory T cells sorted by FACS from patients with early RA. Conclusion These data indicate that 1,25(OH)2D3 may contribute its bone-sparing effects in RA patients taking corticosteroids by the modulation of Th17 polarization, inhibition of Th17 cytokines, and stimulation of IL-4. [source] The good initial response to therapy with a combination of traditional disease-modifying antirheumatic drugs is sustained over time: The eleven-year results of the Finnish rheumatoid arthritis combination therapy trialARTHRITIS & RHEUMATISM, Issue 5 2009Vappu Rantalaiho Objective To evaluate the evolution of functional and clinical outcomes over 11 years in patients with early rheumatoid arthritis (RA) initially treated with a combination of 3 disease-modifying antirheumatic drugs (DMARDs) or with a single DMARD. Methods A cohort of 199 patients with early active RA were initially randomized to receive treatment with a combination of methotrexate, sulfasalazine, and hydroxychloroquine with prednisolone or treatment with a single DMARD (initially, sulfasalazine) with or without prednisolone. After 2 years, the drug treatment strategy became unrestricted, but still targeted remission. At 11 years, function was assessed with the Health Assessment Questionnaire (HAQ), and clinical outcomes were assessed with the modified Minimal Disease Activity (MDA) measure and the American College of Rheumatology (ACR) criteria for remission. Results At 11 years, 138 patients were assessed (68 in the combination-DMARD group and 70 in the single-DMARD group). The mean ± SD HAQ scores were 0.34 ± 0.54 in the combination-DMARD group and 0.38 ± 0.58 in the single-DMARD group (P = 0.88). Modified MDA was achieved by 63% (95% confidence interval [95% CI] 51, 77) and by 43% (95% CI 32, 55) (P = 0.016) of the combination-DMARD group and the single-DMARD group, respectively, and ACR remission by 37% (95% CI 26, 49) and by 19% (95% CI 11, 29) (P = 0.017), respectively. Conclusion Initial therapy with a combination of DMARDs in early RA results in higher rates of patients achieving modified MDA and strict ACR remission even over the long term than initial single-DMARD therapy. Targeting remission with tight clinical controls results in good functional and clinical outcomes in most RA patients. [source] Rheumatoid arthritis joint progression in sustained remission is determined by disease activity levels preceding the period of radiographic assessmentARTHRITIS & RHEUMATISM, Issue 5 2009D. Aletaha Objective Joint damage is related to disease activity in rheumatoid arthritis (RA), but the degree of its progression and the temporal associations between disease activity and joint damage are unclear. The aim of this study was to evaluate whether there is a latency in the effect of disease activity on radiographic progression in patients with RA. Methods Data were obtained from the PREMIER trial, a 2-year randomized, controlled clinical trial of adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in early RA. Radiographic progression of joint damage was calculated using the modified total Sharp score in a subset of patients whose disease was in remission (Simplified Disease Activity Index ,3.3) in the second year of the trial. The progression of damage in the second year was compared between groups of patients whose disease was already in remission for an additional period of 3, 6, or 9 months during the first year. Analysis of variance was used to test for a linear trend. Results Among 794 patients with early RA, 119 (15%) achieved sustained remission during the second year, with no difference in radiographic progression across the 3 treatment groups. Radiographic progression in the second year was significantly different between patients with 3, 6, or 9 additional months of remission during year 1 (mean change in the modified Sharp score 1.19 in those with 3 additional months of remission versus 0.20 in those with 6 additional months of remission and ,0.32 in those with 9 additional months of remission; P < 0.05). The results were supported by similar findings in a series of sensitivity analyses. Conclusion These data indicate that the level of disease activity as well as the duration of remission affect subsequent progression of radiographic damage in RA. This latency between disease activity and its effects on radiographic progression should be considered when evaluating radiographic outcomes in trials of RA. [source] Antibodies against citrullinated vimentin in rheumatoid arthritis: Higher sensitivity and extended prognostic value concerning future radiographic progression as compared with antibodies against cyclic citrullinated peptides,ARTHRITIS & RHEUMATISM, Issue 1 2008Linda Mathsson Objective The Sa autoantigen can be found in inflamed synovium of patients with rheumatoid arthritis (RA), and at least part of the humoral RA-specific anti-Sa response is directed against citrullinated vimentin. This study was undertaken to evaluate the sensitivity, specificity, and prognostic value of determination of levels of antibodies against modified citrullinated vimentin (anti-MCV) as compared with antibodies against cyclic citrullinated peptides (anti-CCP) in an inception cohort of patients with early RA. Methods Clinical data, radiographs, and measurements of levels of anti-MCV and anti-CCP antibodies were obtained in 273 patients with early RA at baseline, after 3 months, and after 1, 2, 3, and 5 years. Autoantibodies were also analyzed in 100 healthy controls. Results Of the 273 patients, 193 (70.7%) were anti-MCV positive and 158 (57.9%) were anti-CCP positive at the time of diagnosis, with nearly equal specificities (95% and 96%, respectively). Forty (14.7%) were anti-MCV positive only, and 5 (1.8%) were anti-CCP positive only. Anti-MCV,positive and anti-MCV,negative patients had similar disease activity at baseline, but presence of anti-MCV was predictive of subsequent high disease activity and continued radiographic progression. Changes in anti-MCV level showed stronger correlation with changes in clinical parameters than did changes in anti-CCP level. The subgroup of patients who were anti-MCV positive and anti-CCP negative showed a higher rate of radiographic destruction than did patients who were negative for both anti-MCV and anti-CCP. Conclusion These findings show that when patients with early RA are compared with healthy controls, analysis of anti-MCV yields greater sensitivity and unchanged specificity as compared with analysis of anti-CCP. Anti-MCV also appears to perform better than anti-CCP in identifying poor radiographic prognosis in patients with early RA. [source] Treatment of early rheumatoid arthritis: A randomized magnetic resonance imaging study comparing the effects of methotrexate alone, methotrexate in combination with infliximab, and methotrexate in combination with intravenous pulse methylprednisolone,ARTHRITIS & RHEUMATISM, Issue 12 2007Patrick Durez Objective To compare the effects of methotrexate (MTX), alone or in combination with intravenous (IV) methylprednisolone (MP) or infliximab, on magnetic resonance imaging (MRI),detected synovitis, bone edema, and erosive changes in patients with early rheumatoid arthritis (RA). Methods Forty-four patients with early RA were randomized to receive MTX alone (MTX group), MTX plus IV MP (IV MP group), or MTX plus infliximab (infliximab group), infused on day 0 and weeks 2, 6, 14, 22, 30, 38, and 46. Gadolinium-enhanced MRI scans of the metacarpophalangeal joints, wrists, and metatarsophalangeal joints were performed at baseline, week 18, and week 52. Results Scores for MRI-detected synovitis and bone edema improved over time in the 3 groups, with significantly lower synovitis scores in the infliximab group compared with the MTX group and significantly lower bone edema scores in the infliximab group compared with the MTX and the IV MP groups. Scores for MRI-detected erosion significantly increased over time in all groups. There were no differences in erosion scores between the MTX group and the other groups. It is of note that patients treated with IV MP showed more significant progression in MRI-detected erosions compared with patients treated with infliximab. At week 22, response rates according to the American College of Rheumatology 20% improvement criteria (ACR20), the ACR50, and the ACR70 were significantly higher in both the IV MP group and the infliximab group compared with the MTX group. At week 52, remission was achieved in 40% of patients in the MTX group and in 70% of patients in the IV MP and infliximab groups. Health Assessment Questionnaire scores improved significantly over time in all groups, with patients receiving IV MP experiencing significantly more improvement compared with patients treated with MTX alone. No severe side effects were observed, except 1 case of MTX-related pneumonitis. Conclusion The combination of MTX and infliximab is superior to MTX alone for reducing MRI-detected signs of synovitis and bone edema in patients with early RA. Progression of MRI-detected erosion was greater in patients treated with MTX plus IV MP compared with that in patients who received MTX plus infliximab. [source] The ratio of circulating osteoprotegerin to RANKL in early rheumatoid arthritis predicts later joint destructionARTHRITIS & RHEUMATISM, Issue 6 2006P. P. Geusens Objective Rheumatoid arthritis (RA) is a chronic inflammatory disease that may result in debilitating joint deformities with destruction of bone and cartilage. Inflammation is still considered the pivotal inducer of both components of joint damage. Results of recent animal studies suggested a prominent contribution of osteoclastic bone resorption that could be dissociated from inflammation. RANKL and its natural decoy receptor, osteoprotegerin (OPG), play key roles in osteoclast activation. In a group of patients with early RA not treated with disease-modifying drugs, we tested the hypothesis that osteoclast activation, reflected by the serum OPG:RANKL ratio at baseline, is negatively associated with progression of bone damage, independent of inflammation. Methods OPG and RANKL levels, together with a parameter of inflammation (first-year time-averaged erythrocyte sedimentation rate [tESR]), were measured in 92 patients with newly diagnosed early active RA who were participants in a randomized study. The tESR and the OPG:RANKL ratio were evaluated for the ability to predict 5-year radiographic progression of joint damage. Results The first-year tESR and the OPG:RANKL ratio, as measured at baseline, independently predicted 5-year radiographic progression of joint damage (both P , 0.001). Progression of radiographic damage was greatest in patients with a high tESR and a low OPG:RANKL ratio and was lowest in patients with a low tESR and a high OPG:RANKL ratio. Conclusion This study in patients with early untreated RA is the first to confirm the findings in animal models of arthritis, that radiographic progression of the bone component of joint destruction is dependent on both inflammation (tESR) and osteoclast activation (the OPG:RANKL ratio). [source] Peripheral blood T lymphocytes from patients with early rheumatoid arthritis express RANKL and interleukin-15 on the cell surface and promote osteoclastogenesis in autologous monocytesARTHRITIS & RHEUMATISM, Issue 4 2006María-Eugenia Miranda-Carús Objective To investigate the osteoclastogenic potential of T cells from the peripheral blood (PB) and synovial fluid (SF) of patients with rheumatoid arthritis (RA) on autologous monocytes, and to study the cytokines implicated in this process. Methods T cells and monocytes were isolated from the PB of 20 healthy subjects and 20 patients with early RA, and from the SF of 20 patients with established RA. Autologous T cell/monocyte cocultures were established in the absence of exogenous cytokines or growth factors in order to examine spontaneous ex vivo osteoclast differentiation by tartrate-resistant acid phosphatase staining and calcified matrix resorption activity. Results Surface RANKL was expressed on freshly isolated T cells from the PB of patients with early RA and the SF of patients with established RA. In addition, surface interleukin-15 (IL-15) was detected on freshly isolated T cells and monocytes from the PB of patients with early RA and the SF of patients with established RA. Autologous T cell/monocyte cocultures derived from the SF of patients with established RA and from the PB of patients with early RA, but not from the PB of healthy controls, resulted in osteoclast differentiation that was significantly inhibited by osteoprotegerin (OPG) and by neutralizing monoclonal antibodies to IL-15, IL-17, tumor necrosis factor , (TNF,), and IL-1,. OPG, anti-TNF,, and anti,IL-1, demonstrated a cooperative inhibitory effect. At 1-year followup, surface RANKL and IL-15 and ex vivo osteoclastogenesis were no longer observed on PB T cells or monocytes from patients with early RA in whom clinical remission had been achieved with treatment. Conclusion T cells are important contributors to the pathogenesis of bone erosions in RA through interaction with osteoclast precursors of the monocyte/macrophage lineage. [source] A new classification of HLA,DRB1 alleles differentiates predisposing and protective alleles for rheumatoid arthritis structural severityARTHRITIS & RHEUMATISM, Issue 2 2006Pierre-Antoine Gourraud Objective A new classification of HLA,DRB1 alleles supporting the shared epitope hypothesis of rheumatoid arthritis (RA) susceptibility was recently introduced. We investigated the relevance of this classification in terms of the structural severity of RA. Methods The study group comprised 144 patients who were included in a prospective longitudinal cohort of French Caucasoid patients with early RA. Progression of the total radiographic damage score (Sharp/van der Heijde method) was used to quantify the structural severity of RA after 4 years of followup. HLA,DRB1 typing and subtyping were performed by polymerase chain reaction, using a panel of sequence-specific oligonucleotide probes. HLA,DRB1 alleles were classified according to the above-mentioned new system. The association between the HLA,DRB1 allele groups (S1, S2, S3P, S3D, and X) and the structural severity of RA was analyzed with nonparametric statistical tests. Results The presence of S2 alleles (HLA,DRB1*0401 and HLA,DRB1*1303) was associated with severe forms of RA (P = 0.004); a significant dose effect was observed (P = 0.01). The presence of S3D alleles (HLA,DRB1*11001, HLA,DRB1*1104, HLA,DRB1*12, and HLA,DRB1*16) was associated with benign forms of RA (P < 0.0001), and a significant dose effect was observed (P < 0.01). Conclusion The studied classification of HLA,DRB1 alleles is relevant in terms of RA outcomes. Compared with a previously described classification system, this system differentiates predisposing (S2) and protective (S3D) alleles for RA structural severity, which, respectively, correspond to KRRAA and DRRAA amino acid patterns at position 70,74 of the third hypervariable region of the HLA,DR, chain. [source] COBRA combination therapy in patients with early rheumatoid arthritis: Long-term structural benefits of a brief interventionARTHRITIS & RHEUMATISM, Issue 2 2002Robert B. M. Landewé Objective The Combinatietherapie Bij Reumatoide Artritis (COBRA) trial demonstrated that step-down combination therapy with prednisolone, methotrexate, and sulfasalazine (SSZ) was superior to SSZ monotherapy for suppressing disease activity and radiologic progression of rheumatoid arthritis (RA). The current study was conducted to investigate whether the benefits of COBRA therapy were sustained over time, and to determine which baseline factors could predict outcome. Methods All patients had participated in the 56-week COBRA trial. During followup, they were seen by their own rheumatologists and were also assessed regularly by study nurses; no treatment protocol was specified. Disease activity, radiologic damage, and functional ability were the primary outcome domains. Two independent assessors scored radiographs in sequence according to the Sharp/van der Heijde method. Outcomes were analyzed by generalized estimating equations on the basis of intent-to-treat, starting with data obtained at the last visit of the COBRA trial (56 weeks after baseline). Results At the beginning of followup, patients in the COBRA group had a significantly lower mean time-averaged 28-joint disease activity score (DAS28) and a significantly lower median radiologic damage (Sharp) score compared with those in the SSZ monotherapy group. The functional ability score (Health Assessment Questionnaire [HAQ]) was similar in both groups. During the 4,5 year followup period, the time-averaged DAS28 decreased 0.17 points per year in the SSZ group and 0.07 in the COBRA group. The Sharp progression rate was 8.6 points per year in the SSZ group and 5.6 in the COBRA group. After adjustment for differences in treatment and disease activity during followup, the between-group difference in the rate of radiologic progression was 3.7 points per year. The HAQ score did not change significantly over time. Independent baseline predictors of radiologic progression over time (apart from treatment allocation) were rheumatoid factor positivity, Sharp score, and DAS28. Conclusion An initial 6-month cycle of intensive combination treatment that includes high-dose corticosteroids results in sustained suppression of the rate of radiologic progression in patients with early RA, independent of subsequent antirheumatic therapy. [source] | ||||||||||