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ID PMID Title PublicationDate abstract
19877072 Differential mechanism of NF-kappaB inhibition by two glucocorticoid receptor modulators i 2009 Nov OBJECTIVE: To investigate and compare the molecular mechanisms by which 2 glucocorticoid receptor (GR)-activating compounds, dexamethasone (DEX) and Compound A (CpdA), interfere with the NF-kappaB activation pathway in rheumatoid arthritis (RA) synovial cells. METHODS: Quantitative polymerase chain reaction was performed to detect the tumor necrosis factor alpha (TNFalpha)-induced cytokine gene expression of interleukin-1beta (IL-1beta) and to investigate the effects of DEX and CpdA in RA fibroblast-like synoviocytes (FLS) transfected with small interfering RNA (siRNA) against GR (siGR) compared with nontransfected cells. Immunofluorescence analysis was used to detect the subcellular distribution of NF-kappaB (p65) under the various treatment conditions, and active DNA-bound p65 was measured using a TransAM assay and by chromatin immunoprecipitation analysis of IL-1beta. Signaling pathways were studied via Western blotting of siGR-transfected cells, compared with nontransfected and nontargeting siRNA-transfected control cells, to detect the regulation of phospho-IKK, IkappaBalpha, phospho-p38, phospho-ERK, and phospho-JNK. RESULTS: Both DEX and CpdA efficiently inhibited IL-1beta gene expression in a GR-dependent manner. In addition, CpdA attenuated the TNFalpha-induced nuclear translocation and DNA binding of p65 in RA FLS, via the attenuation of IKK phosphorylation and subsequent IkappaBalpha degradation. CpdA also displayed profound effects on TNFalpha-induced MAPK activation. The effects of CpdA on TNFalpha-induced kinase activities occurred independently of the presence of GR. In sharp contrast, DEX did not affect TNFalpha-induced IKK phosphorylation, IkappaBalpha degradation, p65 nuclear translocation, or MAPK activation in RA FLS. CONCLUSION: DEX and CpdA display a dissimilar molecular mechanism of interaction with the NF-kappaB activation pathway ex vivo. A dual pathway, partially dependent and partially independent of GR (nongenomic), may explain the gene-inhibitory effects of CpdA in RA FLS.
20952478 Rheumatoid arthritis disease-modifying antirheumatic drug intervention and utilization stu 2011 Jan OBJECTIVE: to report the rates of serious adverse events (SAE), serious infectious events (SIE), and events of medical interest (EMI) in patients receiving etanercept; to identify the risk factors for SAE, SIE, and EMI; and to report time to switching from etanercept therapy, reasons for switching, and time to restarting treatment with etanercept in patients with rheumatoid arthritis (RA) in US clinical practice. METHODS: adults ≥ 18 years of age who fulfilled the 1987 American Rheumatism Association criteria for RA were eligible for enrollment in 2 prospective, 5-year, multicenter, observational registries. RADIUS 1 (Rheumatoid Arthritis DMARD Intervention and Utilization Study) enrolled patients with RA who required a change in treatment [either an addition or a switch of a biologic or nonbiologic disease-modifying antirheumatic drug (DMARD)]. In RADIUS 2, patients with RA were required to start etanercept therapy at entry. Patients were seen at a frequency determined by their rheumatologist. RADIUS 1 and RADIUS 2 were registered under the US National Institutes of Health ClinicalTrials.gov identifiers NCT00116714 and NCT00116727, respectively. RESULTS: in these patients, SAE, SIE, and EMI occurred at rates comparable to those seen in clinical trials. No unexpected safety signals were observed. Rates for SAE, SIE, and EMI in etanercept-treated patients were comparable to rates observed in patients receiving methotrexate monotherapy and did not increase with greater exposure to etanercept therapy. CONCLUSION: the RADIUS registries provide a better understanding of the safety of etanercept in patients with RA in the US practice setting.
20821185 [Rehabilitation in rheumatology]. 2010 Oct Rehabilitation in rheumatology focuses on prevention of functional disorders of the musculoskeletal system, maintenance of working ability and prevention of care dependency. Drug treatment alone rarely results in long-term remission, therefore rehabilitative measures must be integrated into rheumatic care. Rehabilitative therapy in rheumatology includes physiotherapy, patient education and occupational therapy. Positive effects of physical therapy methods have been proven by various studies. Patient education and occupational therapy are important tools for stabilizing the course of the disease. To maintain positive rehabilitative results patients have to be involved in the selection of treatment measures and should take an active part in the long-term treatment process. Despite proven efficacy of physical measures there is evidence for a lack of utilization of rehabilitative therapy due to increasing cost pressure in the health care system which will further increase over time.
20429644 Serum cytokine and periodontal profiles in relation to disease activity of rheumatoid arth 2010 May BACKGROUND: Rheumatoid arthritis (RA) and periodontitis are common chronic inflammatory conditions and share many pathologic features. A similar profile of cytokines is involved in the pathogenesis of the two diseases. The relationship between the disease activity of RA and the periodontal condition remains unclear. This study examines whether the disease activity of RA affects serum cytokine and periodontal profiles. METHODS: The study subjects consisted of 84 Japanese adults with RA and 22 race-matched control individuals. After periodontal and rheumatologic examination, the disease activity of RA was determined with the Disease Activity Score including 28 joints using C-reactive protein (DAS28-CRP). Serum levels of cytokines including interleukin (IL)-1beta, IL-6, IL-12, IL-12 p40, IL-18, and tumor necrosis factor-alpha (TNF-alpha) were determined by an enzyme-linked immunosorbent assay. High-sensitive CRP was also measured with a latex particle-enhanced nephelometric method. RESULTS: Of 84 patients with RA, 28 and 56 patients exhibited low and moderate to high disease activity, respectively. Serum levels of IL-6, TNF-alpha, and CRP were significantly different between the two groups (P <0.05). Additionally, a significant correlation was observed between DAS28-CRP and percentage of sites with bleeding on probing (BOP) (P = 0.008) and between serum TNF-alpha levels and percentage of sites with BOP (P = 0.01) in 56 patients with RA with moderate to high activity. CONCLUSION: These results suggest that the disease activity of RA correlated with serum levels of IL-6, TNF-alpha, and CRP, and it might influence BOP in the patients with moderate to high disease activity.
19938361 [Persisting pain after open articulosynovectomy--gossypiboma]. 2009 Sep We report about a 44-year-old woman who presented at our Orthopaedic Department suffering from persisting pain and a tumor of the right knee after open articulosynovectomy. MRI did not clarify the entity at all. The X-ray examination could identify an inlying compress after a synovectomy in 1999. The intra-articular foreign body could be removed by open revision surgery.
19407827 The pleiotropic effect of TRAIL on tumor-like synovial fibroblasts from rheumatoid arthrit 2009 Sep The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has gained much attention as a possible therapeutic reagent for the treatment of tumors, as TRAIL was originally described to induce apoptosis specifically in cancer cells, but not in normal cells. Fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) patients exhibit tumor-like features and we have described earlier that TRAIL induces apoptosis only in a subset of RA FLS, but an induction of proliferation in the surviving cells. This observation corresponds to the pleiotropic effects of TRAIL observed on primary human tumor cells. Here, we describe that the PI3 kinase/Akt-signaling pathway, but not that of the MAP kinases ERK and p38, protects RA FLS from TRAIL-induced apoptosis by modulating the expression of the cell survival regulators p21, XIAP, Mcl-1 and RIP. Moreover, we found that not only TRAIL-induced apoptosis, but also TRAIL-triggered proliferation in RA FLS is mediated by caspases with a crucial role for caspase 8. TRAIL was found to induce degradation of p21 and p27 that was caspase-dependent, but independent of the ERK, p38 and PI3 kinase/Akt-signaling pathways. The finding that TRAIL-triggered proliferation and apoptosis share intracellular routes has to be taken in consideration in defining therapeutic strategies on the basis of the administration of TRAIL.
19722791 Anti-tumor necrosis factor-alpha therapy and periodontal parameters in patients with rheum 2009 Sep BACKGROUND: The aim of this study was to evaluate the influence of anti-tumor necrosis factor-alpha (TNF-alpha) therapy on the clinical and immunologic parameters of the periodontium. METHODS: Ten patients with rheumatoid arthritis (RA) who routinely received infusions of infliximab, 200 mg (RA+), 10 patients with RA without anti-TNF-alpha therapy (RA-), and 10 healthy controls (C) were included. Clinical parameters, including the plaque index (PI), gingival index (GI), probing depth (PD), clinical attachment loss (AL), and bleeding on probing (BOP), were assessed, and total gingival crevicular fluid (GCF) TNF-alpha level was determined using enzyme-linked immunosorbent assay. Analysis of variance with Scheffe modification and the Pearson correlation test were used for statistical analysis. RESULTS: The ages of the patients ranged from 22 to 76 years (mean, 50.73 +/- 9.1 years). The mean PI was similar among the groups. However, mean inflammatory parameters in the three groups varied significantly; GI was greater in the RA- group compared to RA+ and C groups (P = 0.0042). The RA+ group exhibited less BOP than RA- and C groups (21.1% +/- 3.0%, 45.9% +/- 6.2%, and 39.1% +/- 7.2%, respectively; P = 0.0146). The mean PD in the RA+ group was shallower than in RA- and C groups (3.22 +/- 0.13 mm, 3.85 +/- 0.22 mm, and 3.77 +/- 0.20 mm, respectively; P = 0.055). Clinical AL in the RA+ group was lower than in RA- and C groups (3.68 +/- 0.11 mm, 4.52 +/- 0.26 mm, and 4.35 +/- 0.24 mm, respectively; P = 0.0273). TNF-alpha levels in the GCF of the RA+ group were the lowest compared to RA- and C groups (0.663, 1.23, and 0.949 ng/site, respectively; P = 0.0401). A significant positive correlation was found between TNF-alpha levels in the GCF and clinical AL (r = 0.448; P = 0.0283). CONCLUSIONS: Patients with RA receiving anti-TNF-alpha medication had lower periodontal indices and GCF TNF-alpha levels. Thus, suppression of proinflammatory cytokines might prove beneficial in suppressing periodontal diseases.
19541595 Cytokine production from stimulated whole blood cultures in rheumatoid arthritis patients 2009 Jun Infectious complications are not rare in rheumatoid arthritis (RA), and the susceptibility to infections is increased during treatment with TNF blocking agents. As a possible mechanism contributing to that, we assessed the modulation of cytokine production induced by TNF neutralization. METHODS: Whole blood cultures from six healthy volunteers and 13 RA patients starting therapy with either adalimumab (n = 7) or etanercept (n = 6) were stimulated with heat-killed Salmonella typhimurium, Staphylococcus aureus or with S. typhimurium lipopolysaccharide (LPS). The production of interleukin (IL)-1beta, IL-6, IL10, IL-17, TNF, IL-8 and IFN-gamma was measured by specific immunoassays. RESULTS: Stimulation with Salmonella LPS resulted in a significantly lower production of IL-1beta, TNF and a trend towards lower IL-6 and IFN-gamma production in RA patients compared to healthy volunteers. Therapy with either of the agents did not significantly alter cytokine production capacity, with the exception of a lower IFN-gamma and IL-8 production in patients treated with adalimumab and stimulated with heat-killed S. aureus. CONCLUSION: The results of our study suggest that the detrimental effects of anti-TNF agents on the immune response can vary quite widely, from very serious to limited effects, as reported here for etanercept and adalimumab. Because anti-TNF therapy can affect the cellular integrity of tuberculous granuloma, recruitment of new cells at the granuloma site becomes crucial. In line with this, an impaired chemokine production induced by anti-TNF agents may ultimately result in the reactivation of tuberculosis, as previously reported. Therefore, caution should be constantly exercised in order to prevent the development of severe infections and reactivation of tuberculosis whenever therapy with anti-TNF is initiated.
20374331 Clinical and high resolution computed tomography characteristics of patients with rheumato 2009 Jul INTRODUCTION: Rheumatoid arthritis (RA) is a systemic disease of unknown cause. A variety of pulmonary disorders have been described in association with RA. Among the most common are interstitial lung disease (ILD) and bronchiectasis. OBJECTIVES: This study aims to determine the characteristics of RA patients with lung disease in relation to clinical characteristics, pulmonary function test (PFT) and high resolution computed tomography (HRCT) thorax. METHOD: This is a 6-months cross-sectional study involving 63 consecutive RA patients in an outpatient rheumatology clinic. Patients had a mean disease duration of 5 years and above. Disease activity and severity was assessed by Disease Activity Score 28 (DAS28), Health Assessment Questionnaire (HAQ) and Rheumatoid Arthritis Articular Damage (RAAD) score. Full pulmonary function test (PFT) and HRCT of thorax were performed. CONCLUSIONS: The prevalence of RA-ILD is 44% and 67% of patients are asymptomatic. There was significant higher proportion (68%) in patients of Chinese ethnicity who have ILD. Diffusion capacity of carbon monoxide was abnormal in all patients and forced expiratory flow (FEF)(25-75%) was low in 16%. Restrictive pattern was 66.7% by PFT. The most common HRCT findings were reticulation (46%) followed by ground glass opacities (38.1%) and bronchiectasis (28.6%). There was no association between ILD and male gender, duration of the disease, smoking, rheumatoid factor, extra-articular manifestations, disease activity or severity.
20139792 Assessing physical activity in persons with rheumatoid arthritis using accelerometry. 2010 Aug PURPOSE: To investigate empirically if the nonwear threshold and the "valid day" definition for accelerometer data from the general adult US population are appropriate for accelerometer data from persons with rheumatoid arthritis (RA). METHODS: This study analyzed data from 107 persons with RA participating in the baseline (2006-2008) accelerometer assessment from two studies with common inclusion/exclusion criteria. We examined candidate nonwear thresholds ranging from 20 to 300 min of zero activity count. The effect of the selected nonwear threshold is examined in regard to 1) mean daily activity counts, 2) activity counts per wear hour, 3) mean daily minutes of moderate to vigorous physical activity (MVPA) according to count thresholds that occur in 10-min bouts, and 4) MVPA bout minutes per wear hour. The effect of ranging the definition of a valid day of accelerometer data from 8 h of wear time to 12 h on data retention was also examined. RESULTS: In 737 d of accelerometer data analyzed, the average daily wear hours increased with length of nonwear threshold of allowed continuous zero activity count minutes. The mean number of nonzero activity count minutes increased with the chosen nonwear threshold until it stabilized at 478 min.d of activity, which corresponded to the 90-min nonwear threshold. Choosing this threshold and requiring at least 10 h of wear time to constitute a valid day were associated with 92.8% of days of collected data defined as "valid." CONCLUSIONS: Data supported increasing the allowed nonwear threshold in this RA subpopulation from 60 to 90 min, while retaining the 10-h day as the measure of the "valid day."
20304962 Synoviocyte-derived angiopoietin-like protein 2 contributes to synovial chronic inflammati 2010 May Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by symmetrical polyarticular synovitis of the diarthrodial joints. Several proinflammatory cytokines derived from both infiltrating inflammatory cells and activated resident cells within the RA joint play a fundamental role in the processes that cause inflammation. However, anticytokine treatment is beneficial but not curative, the effects are only partial, and nonresponses are common. Therefore, an effort has been made to identify other key regulators of inflammation in articular structures to develop new therapies to suppress synovial inflammation and joint destruction in RA. Adipose tissue-derived angiopoietin-like protein 2 (Angptl2) activates an inflammatory cascade in endothelial cells and induces chemotaxis of monocytes/macrophages in obesity, resulting in initiation and propagation of inflammation within adipose tissues and obesity-related metabolic diseases. Angptl2 mRNA and protein are abundantly expressed in hyperplastic rheumatoid synovium of RA patients, especially in fibroblast-like and macrophage-like synoviocytes, but not in B and T lymphocytes. Angptl2 concentration in joints of RA patients was also significantly increased in comparison with patients with osteoarthritis, which in comparison with RA represents a significantly lower inflammatory grade form of arthritis. Notably, Angptl2 promoted increased chemotactic activities of CD14+CD16- monocytes from synovial fluid of RA patients. Therefore, Angptl2 acts as an important rheumatoid synovium-derived inflammatory mediator in RA pathogenesis.
19836037 [Cancer of the cheek in a patient under etanercept]. 2009 Nov INTRODUCTION: Etanercept (Enbrel) is a TNF-alpha inhibitor effective in rheumatoid polyarthritis, psoriatic rheumatism, ankylosing spondyloarthritis, chronic plaque psoriasis, and juvenile idiopathic arthritis. Several cases of tumours have been described in patients under etanercept. However, no case of association with oral carcinoma had ever been described. The aim of this study was to report a case of carcinoma of the cheek mucosa in a patient treated with etanercept for rheumatoid polyarthritis. OBSERVATION: An 82-year-old female patient, non smoker, consulted for a tumour of the oral cavity. History revealed that this lesion had appeared soon after the initiation of etanercept treatment for severe and resistant rheumatoid polyarthritis. Clinical observation revealed a tumour of the right cheek mucosa 5 by 3 cm. The lesion was superficially infiltrative, budding in spots, and verrucous. The clinical observation was otherwise normal. The histological examination of the surgical piece revealed a micro-infiltrative and non-invasive orthoplastic epidermoid carcinoma. DISCUSSION: The possible development of an oral cavity carcinoma should be taken into account when following a patient under TNF-alpha inhibitor treatment. Anti-TNF treatment has improved the management of patients with severe chronic inflammatory diseases. They allow for a better quality of life. Nevertheless, their immunosuppressive effect should be taken into account when prescribed and during follow-up.
20506224 The programmed death 1/programmed death ligand 1 inhibitory pathway is up-regulated in rhe 2010 Jul OBJECTIVE: T cells play a major role in the pathogenesis of rheumatoid arthritis (RA). The programmed death 1 (PD-1)/programmed death ligand 1 (PDL-1) pathway is involved in peripheral tolerance through inhibition of T cells at the level of synovial tissue. The aim of this study was to examine the role of PD-1/PDL-1 in the regulation of human and murine RA. METHODS: In synovial tissue and synovial fluid (SF) mononuclear cells from patients with RA, expression of PD-1/PDL-1 was examined by immunohistochemistry and flow cytometry, while PD-1 function was assessed in RA peripheral blood (PB) T cells after stimulation of the cells with anti-CD3 and PDL-1.Fc to crosslink PD-1. Collagen-induced arthritis (CIA) was induced in PD-1(-/-) C57BL/6 mice, and recombinant PDL-1.Fc was injected intraperitoneally to activate PD-1 in vivo. RESULTS: RA synovium and RA SF were enriched with PD-1+ T cells (mean +/- SEM 24 +/- 5% versus 4 +/- 1% in osteoarthritis samples; P = 0.003) and enriched with PDL-1+ monocyte/macrophages. PD-1 crosslinking inhibited both T cell proliferation and production of interferon-gamma (IFNgamma) in RA patients; PB T cells incubated with RA SF, as well as SF T cells from patients with active RA, exhibited reduced PD-1-mediated inhibition of T cell proliferation at suboptimal, but not optimal, concentrations of PDL-1.Fc. PD-1(-/-) mice demonstrated increased incidence of CIA (73% versus 36% in wild-type mice; P < 0.05) and greater severity of CIA (mean maximum arthritis score 5.0 versus 2.3 in wild-type mice; P = 0.040), and this was associated with enhanced T cell proliferation and increased production of cytokines (IFNgamma and interleukin-17) in response to type II collagen. PDL-1.Fc treatment ameliorated the severity of CIA and reduced T cell responses. CONCLUSION: The negative costimulatory PD-1/PDL-1 pathway regulates peripheral T cell responses in both human and murine RA. PD-1/PDL-1 in rheumatoid synovium may represent an additional target for immunomodulatory therapy in RA.
20465316 Understanding the relationship between the EQ-5D, SF-6D, HAQ and disease activity in infla 2010 BACKGROUND: The growth of economic analyses and in particular cost-utility analyses (CUA), which use the QALY as a measure of outcome, has heightened the interest in the methodologies used to calculate the QALY. The EQ-5D has produced quite different utility values from that of the SF-6D. This article seeks to understand these differences using a cohort of patients with inflammatory arthritis. OBJECTIVE: To examine the relationship between the disease-specific measure, Health Assessment Questionnaire (HAQ) disability index (DI) and the preference-based measures, SF-6D, EQ-5D and European League Against Arthritis (EULAR) Disease Activity Score (DAS) in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA). METHODS: Patients with RA and PsA (n = 504) attending a tertiary rheumatology referral centre completed the HAQ, SF-6D and the EQ-5D before starting biological therapy and again 12 months later. The SF-36 was converted into a utility using the preference-based SF-6D. Clinical outcomes such as the DAS, joint counts and laboratory measures were also recorded. We calculated single index utility scores from the preference-based instruments using UK population norms. We used regression analysis to derive a mapping function and calculated utility scores from the HAQDI and the DAS 28. RESULTS: The mean utility observed at baseline for RA was 0.43 for the EQ-5D and 0.54 for the SF-6D and for PsA was 0.49 for the EQ-5D and 0.57 for the SF-6D. The utility gain demonstrated by the EQ-5D was over twice that of the SF-6D. The EQ-5D scored 17% of the RA group as less than 0 (state defined as worse than death); 7% of this group remained less than 0 at follow-up. The distribution of the utility estimates was similar for both RA and PsA. CONCLUSIONS: Our findings draw attention to the impact of states worse than death on the overall distribution for the EQ-5D derived utilities and how these impact on its use in practice. EQ-5D-derived QALY changes are over twice that of the SF-6D. The implication of this for decision makers is that cost-effectiveness evaluations for treatments in this disease class are likely to be very sensitive to the choice of utility measure.
19681313 Comparison of early and delayed failed total shoulder arthroplasty. 2009 Jun The purpose of the present study is to determine what factors contribute to early failure after total shoulder arthroplasty (TSA). Implants were retrieved from 69 patients after failed TSA and were retrospectively assigned to two cohorts based on time of failure: Early, less than 2 years (N = 34); and Delayed, longer than 2 years (N = 35). The clinical information, intraoperative information, most recent radiographs, and damage mapping were collected for all patients. Patients in the Early failure group were significantly older (63.9 +/- 9.5 years) than those in the Delayed group (49.9 +/- 12.8 years) by an average of 14 years. The proportion of osteoarthritis cases was significantly higher for the Early group compared to the Delayed group (62% vs. 40%). The Delayed group had higher damage scores for several damage modalities. Elderly age and osteoarthritis were significant factors that were associated with early failures after TSA.
19517338 [Bony pathologies of the metacarpophalangeal joints in early rheumatoid arthritis: compari 2009 Sep AIM: Comparison of MRI with a newly developed high-resolution multi-pinhole single photon emission computed tomography (MPH-SPECT) regarding the detection of bony pathologies of the metacarpophalangeal (MCP) joints in patients with early rheumatoid arthritis (ERA). MATERIALS AND METHODS: The clinically dominant hand of 15 patients with ERA (disease duration 6 months) was examined using MRI and MPH-SPECT. The evaluation of MRI was achieved according to RAMRIS criteria and for the MPH SPECT regarding pathological tracer uptake and distribution. Image fusions of MRI and MPH-SPECT were provided and the two methods were compared. RESULTS: In MRI 12 of 15 patients showed arthritic joint pathologies, while 8 patients exhibited soft tissue and bony changes. 4 patients had only soft tissue inflammation (synovitis) with a normal bone signal. In MPH-SPECT 10 of 15 patients showed pathologically increased bone metabolism. The fusion images presented a high agreement of the pathological changes in both methods, while areas with increased bone metabolism were not only present in the case of erosions, but also in the case of bone edema. In 2 patients increased bone metabolism was detectable in areas of MR tomographic normal bone, while a clear surrounding synovitis was present in each case here. CONCLUSION: The comparison of MPH-SPECT with MRI proves that the latter is a sensitive procedure for the detection of bony pathologies of MCP joints in ERA. A normal bone signal in MRI does not exclude early changes in bone metabolism in cases of severe synovialitis.
21169343 Outcome in rheumatoid arthritis patients with continued conventional therapy for moderate 2011 May OBJECTIVE: To report from early RA network (ERAN) on Years 2 and 3 28-joint DAS (DAS-28) and HAQ outcomes in newly diagnosed RA patients treated with DMARD therapies stratified to DAS-28 status after 1 year. METHODS: ERAN is a prospective observational cohort of newly diagnosed RA patients, monitored and treated according to local practice. Standardized case report forms are completed at first presentation, 3-6 months, 1 year and annually thereafter. RESULTS: A total of 418 newly diagnosed RA patients with 2 years and 302 with 3 years follow-up were identified in 22 ERAN centres from 2002 to 2008. Within their first year from registration, 67% of patients received monotherapy DMARDs, and 26% combination DMARDs including 2% were on anti-TNF therapies. Between Years 1 and 3, 60% received DMARD monotherapy, 34% combination DMARD therapy including 8% on anti-TNF therapies. Seventy-four per cent of patients with Year 1 DAS-28 < 3.2 and 27% with DAS-28 3.2-5.1 achieved a DAS-28 < 3.2 outcome at Year 2 [odds ratio (OR) 7.64; 95% CI 4.6, 12.6], and 71 and 35%, respectively, at Year 3 (OR 4.49; 95% CI 2.5, 7.9). Seventy-nine per cent of patients with a Year 1 DAS-28 < 3.2 and 52% with DAS-28 3.2-5.1 achieved an HAQ < 1.25 at Year 2 (OR 3.47; 95% CI 2.1, 5.6), and 81 and 47%, respectively, at Year 3 (OR 4.92; 95% CI 2.6, 9.0). CONCLUSIONS: In RA patients with a DAS-28 3.2-5.1 at 1 year, the likelihood of achieving a target low DAS-28 < 3.2, or a low HAQ, at Years 2 or 3 is poor in a routine care setting using conventional DMARDs according to current practice.
18753157 The safety of anti-tumour necrosis factor treatments in rheumatoid arthritis: meta and exp 2009 Jul OBJECTIVE: To evaluate the safety of biological treatments for rheumatoid arthritis (RA) using results from randomised controlled trials (RCT). METHODS: The literature was searched to December 2007 for RCT evaluating inhibitors of tumour necrosis factor alpha (anti-TNF) for RA. Safety data were abstracted and risk estimates were calculated using three approaches, meta-analysis with and without adjustment for exposure and simple exposure-adjusted pooling. RESULTS: Eighteen randomised trials involving 8808 RA subjects were included. Treatment with recommended doses of anti-TNF found no increase in the odds of death (odds ratio (OR) 1.39; 95% CI 0.74 to 2.62), serious adverse events (OR 1.11; 95% CI 0.94 to 1.32), serious infection (OR 1.21; 95% CI 0.89 to 1.63), lymphoma (OR 1.26; 95% CI 0.52 to 3.06), non-melanoma skin cancers (OR 1.27; 95% CI 0.67 to 2.42) or the composite endpoint of non-cutaneous cancers plus melanomas (OR 1.31; 95% CI 0.69 to 2.48) when evaluated using the unadjusted meta-analytic method. Risk estimates were similar with the other methods. For subjects who received two to three times the recommended doses of anti-TNF the risk of serious infection was increased with the unadjusted meta-analytic and pooled analysis, (OR 2.07; 95% CI 1.31 to 3.26) and (risk ratio (RR) 1.83; 95% CI 1.18 to 2.85), respectively, but not increased in the exposure-adjusted meta-analysis (RR 1.99; 95% CI 0.90 to 4.37). Meta-regression identified that the risk of serious infection with anti-TNF therapy decreases with increasing trial duration (p = 0.035). CONCLUSION: Meta-analytic and exposure-adjusted pooled analyses on over 8800 RA subjects in RCT treated over an average of 0.8 years did not identify an increased risk of serious adverse events with recommended doses. High-dose anti-TNF therapy was associated with a twofold increase in the risk of serious infections.
20561984 Study of chromosomal region 5p13.1 in Crohn's disease, ulcerative colitis, and rheumatoid 2010 Aug Chromosomal region 5p13 includes regulatory elements of the prostaglandin receptor EP4 (PTGER4) gene and is associated with inflammatory bowel disease (IBD) susceptibility. We aimed at corroborating the association of the PTGER4 risk variant in IBD. Given the proinflammatory activity of prostaglandin E(2) in rheumatoid arthritis (RA), the reduction in incidence and severity of collagen-induced arthritis observed in mice deficient in the prostaglandin receptor EP4, and a modest signal of association found in an RA genome-wide scan, we proposed to extend the investigation of this locus to RA patients. A total of 709 Crohn's disease (CD) patients, 662 ulcerative colitis (UC) patients, and 1369 control subjects were genotyped for rs17234657. This polymorphism was also analyzed in 605 RA patients, and rs6871834 was studied in the RA patient group. Replication of the previous finding in CD was achieved in our independent collections, although with a milder effect (odds ratios = 1.23) than that originally described. No further association of the previously mentioned polymorphisms was detected with either UC or RA patients. We validated this 5p13 signal as a genuine susceptibility factor for CD in Caucasian populations. Our data seem to rule out a major influence of these polymorphisms on UC or RA predisposition.
20082770 Application of thiophilic chromatography to deplete serum immunoglobulins in sample prepar 2010 Jan 18 Serum is a typical sample for non-invasive studies in clinical research. Its proteome characterization is challenging, since requires extensive protein depletion. Methods used nowadays for removal of high-abundance proteins are expensive or show quite often a low loading capacity, which has strong repercussions on the number of samples and replicates per analysis. In order to deplete immunoglobulins (Igs) and albumin (HSA) from 1 mL serum samples, we have developed a protocol based on a combination of thiophilic chromatography, not previously used in clinical proteomics, and a HSA-specific resin. Ig/HSA-depleted samples, immunoglobulinome and albuminone were analyzed by 2-DE. Thiophilic chromatography, coupled with HSA-depletion, allows a good 2-DE resolution as well as the visualization of new spots. Moreover, it yields enough protein to evaluate technical variability and facilitate subsequent protein identification. To validate the protocol, we carried out a preliminary comparative study between triplicate Igs/HSA-depleted serum samples from healthy control individuals and recently diagnosed/untreated rheumatoid arthritis (RA) patients. RA patients showed several acute phase proteins, as well as additional serum proteins, differentially and significantly regulated. Therefore, thiophilic chromatography can be used as an efficient and economical method in 2-DE to deplete immunoglobulins from large human serum samples before a more extensive fractioning.