Update on the use of etanercept across a spectrum of rheumatoid disorders

Etanercept is a soluble TNF receptor p75 fusion protein which is approved for subcutaneous use (50 mg weekly) in the treatment of patients with active rheumatoid arthritis (RA), juvenile RA, ankylosing spondylitis, and psoriatic arthritis. Etanercept binds to both TNFα and lymphotoxin and has quite a short mean half-life (70 hours). Numerous randomized clinical trials have demonstrated its efficacy to improve signs and symptoms in early and established RA and other inflammatory arthritis. Furthermore, etanercept has shown its ability to prevent radiographic progression and to improve health-related quality of life in patients with RA and psoriatic arthritis. A combination of etanercept plus methotrexate was more efficacious than etanercept monotherapy in RA patients but there is currently no evidence that such rheumatic combination is better than monotherapy in other disorders. Etanercept was generally well tolerated both in controlled trials with withdrawal rates being similar to the comparator groups and in large observational studies. Infections and injection-site reactions were the most frequently reported events. Serious infections were slightly increased but the occurrence of tuberculosis seemed less frequent than with anti-TNF monoclonal antibodies (infliximab and adalimumab). The benefit-risk ratio of etanercept appeared to be very positive, and this drug has now emerged as a major therapy in patients with active inflammatory arthritis. Furthermore, it is more frequently considered as an emerging and valuable option in patients with early disease

Lymphotoxin α revisited: general features and implications in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting synovial joints. Therapies blocking tumor necrosis factor-alpha (TNFα) are now routinely used in the management of RA. However, a significant number of patients with RA do not respond or develop resistance to anti-TNF therapies, and the participation of other cytokines in RA pathogenesis has been reported as well. Lymphotoxin alpha (LTα) is the closest homolog to TNFα and has been implicated in inflammation and autoimmunity since its original description in 1968. In spite of that, little is known about the role of LTα in RA or the potential of blocking this cytokine as an alternative therapeutic approach. In this review, we aim to summarize the general features of LTα and what is currently known about its participation in RA

Apoptosis is not the major death mechanism induced by celecoxib on rheumatoid arthritis synovial fibroblasts

Synovial hyperplasia in rheumatoid arthritis (RA) has been associated with apoptosis deficiency of RA fibroblast-like synoviocytes (FLSs). Celecoxib is a non-steroidal anti-inflammatory drug that has been demonstrated to induce apoptosis in some cellular systems. We have therefore examined the dose- and time-dependent effects of celecoxib on RA FLS viability. Treatment of RA FLSs with celecoxib for 24 hours reduced their viability in a dose-dependent manner. Analysis of celecoxib-treated RA FLSs for their content of apoptotic and necrotic cells by Annexin V staining and TO-PRO-3 uptake displayed only few apoptotic cells. Caspase 3, a key mediator of apoptosis, was not activated in celecoxib-treated RA FLSs, and the presence of specific caspase 3 or pan-caspase inhibitors did not affect celecoxib-induced cell death. Moreover, we could not detect other signs of apoptosis, such as cleavage of poly(ADP-ribose) polymerase, caspase 8 or 9, or DNA fragmentation. We therefore conclude that apoptosis is not the major death pathway in celecoxib-treated RA FLSs

Performance of matrices developed to identify patients with early rheumatoid arthritis with rapid radiographic progression despite methotrexate therapy: an external validation study based on the ESPOIR cohort data

International audienceIntroduction Use of prediction matrices of risk or rapid radiographic progression (RRP) for early rheumatoid arthritis (RA) in clinical practice could help to better rationalise the first line of treatment. Before use, they must be validated in populations that have not participated in their construction. The main objective is to use the ESPOIR cohort to validate the performance of 3 matrices (ASPIRE, BEST and SONORA) to predict patients at high risk of RRP at 1 year of disease despite initial treatment with methotrexate (MTX).Methods We selected from the ESPOIR cohort 370 patients receiving MTX or leflunomide (LEF) for ≥3 months within the first year of follow-up. Patients were assessed clinically every 6 months, and structural damage progression seen on radiography was measured by the van der Heijde-modified Sharp score (vSHS) at 1 year. RRP was defined as an increase in the vSHS≥5 points during the first year.Results At 1 year, the mean vSHS score was 1.7±5.0 and 46 patients had RRP. The ASPIRE matrix had only moderate validity in the ESPOIR population, with area under the receiver operating characteristic curve (AUC) <0.7. The AUC for the BEST and SONORA matrices were 0.73 and 0.76. Presence of rheumatoid factor (RF)—or anti-citrullinated protein antibodies (ACPAs) and initial structural damage were always predictive of RRP at 1 year. Disease Activity Score in 28 joints (DAS28) and C reactive protein (ASPIRE threshold) were not associated with RRP.Conclusions Matrices to identify patients at risk of RRP tested in the ESPOIR cohort seem to perform moderately. There is no matrix that shows clearly superior performance

High levels of memory B cells are associated with response to a first tumor necrosis factor inhibitor in patients with rheumatoid arthritis in a longitudinal prospective study

Tumor necrosis factor inhibitor (TNFi) therapy is effective for rheumatoid arthritis (RA). Some reports suggested that the therapy affects B-cell homeostasis. We studied the effect of TNFi therapy on the distribution of peripheral B-cell subsets and elucidated B-cell-related biomarkers to predict the TNFi response. Peripheral B cells were analyzed for expression of CD19, CD27, CD38, and IgD in 31 healthy donors and 96 RA patients, including 21 who were followed 3 months after TNFi introduction. Treatment with steroids significantly altered the distribution of B-cell subsets. After adjustment for age, gender and steroid dose, patients with RA had similar B-cell subset proportions as controls. B-cell subset distribution did not differ by use of TNFi at baseline or before and after TNFi introduction. TNFi responders (according to European League Against Rheumatism criteria) at 3 months had significantly higher proportion of CD27+ memory B cells at baseline, and >= 26% CD27+ cells at inclusion was associated with a relative risk of 4.9 (1.3 to 18.6) of responding to TNFi treatment. CD27+ cells produced 3 times more TNFalpha than did naive B cells, and were correlated with interferon-gamma produced from CD4+ cells in patients without TNFi treatment. In patients with RA, high levels of baseline memory B cells were associated with response to TNFi, which may be related to TNFalpha-dependent activation of the T helper cell type 1 pathwa

Markers of B-lymphocyte activation are elevated in patients with early rheumatoid arthritis and correlated with disease activity in the ESPOIR cohort

International audienceINTRODUCTION: Little is known about systemic B-cell activation in early rheumatoid arthritis (RA). We therefore evaluated the serum levels of markers of B-cell activation in patients included in the ESPOIR early arthritis cohort. METHODS: In the ESPOIR early arthritis cohort (at least 2 swollen joints for more than 6 weeks but less than 6 months), 710 patients were assessed at 1 year and either met the 1987 American College of Rheumatology criteria for RA (n = 578) or had undifferentiated arthritis (n = 132). Baseline serum samples of patients naïve to corticosteroid and disease-modifying antirheumatic drug treatment were assessed for beta2-microglobulin, IgG, IgA, IgM, immunoglobulin free light chains of immunoglobulins, and B-cell activating factor of the tumor necrosis factor family (BAFF). The BAFF gene 871T>C polymorphism was genotyped in all patients. RESULTS: All markers of B-cell activation except BAFF and IgM were significantly higher in patients with early RA than those with undifferentiated arthritis. Anti-cyclic citrullinated peptide (anti-CCP) and beta2-microglobulin were associated with a diagnosis of early RA in the multivariate analysis. Markers of B-cell activation, except BAFF, were associated with disease activity, rheumatoid factor and anti-CCP secretion. The BAFF gene polymorphism was not associated with early RA. CONCLUSIONS: Markers of B-cell activation are elevated in patients with early RA, compared with undifferentiated arthritis, independently of any systemic increase in BAFF secretion, and correlate with disease activity. This study sheds new light on the early pathogenic role of B-lymphocytes in RA and suggests that targeting them might be a useful therapeutic strategy in early RA

Myths and lessons of liberal intervention: The British campaign for the abolition of the Atlantic slave trade to Brazil

This is the Pre-print version of the Article. The official published version can be accessed from the link below - Copyright @ 2012 Martinus NijhoffThis article takes issue with recent references to the British nineteenth century campaign for the abolition of the trans-Atlantic slave trade to Brazil that serve to bolster interventionist or imperialist agendas. In particular, such accounts reproduce two and a half myths about the campaign: that it can serve as a model for the present age; that the success of the campaign can be explained through the actions of the intervening party alone (with a corresponding neglect of those of the ‘target’ state); and the half-myth that the campaign’s success was due to military action (at the expense of institutional (legal) and normative factors and the capacity of the target state). I argue instead that this case – and interventions more generally – would benefit from an analysis that considers the role of force in relation to a series of residual institutional and cultural constraints within the liberal state and to political conditions in the target state. In light of the complexities and contingencies that these factors present the underlying lesson is that military force should be used sparingly, if at all

Serial determination of cyclic citrullinated peptide autoantibodies predicted five-year radiological outcomes in a prospective cohort of patients with early rheumatoid arthritis

The objective of this study was to evaluate the potential of serially determined anti-cyclic citrullinated peptide (CCP) antibodies for predicting structural joint damage in patients with early rheumatoid arthritis (RA), compared to a single baseline determination. Ninety-nine RA patients with disease durations of less than one year and no history of disease-modifying antirheumatic drug therapy were followed prospectively for at least five years. Anti-CCP2 concentrations were measured using a second-generation ELISA. Sharp scores as modified by van der Heijde were determined on hand and foot radiographs. Anti-CCP2 antibodies were detected in 55.5% of patients at baseline and 63.6% at any time during the first three years. Presence of anti-CCP2 at any time during the first three years was associated with radiographic damage at baseline (odds ratio (OR), 3.66; 95% confidence interval (95% CI) 0.99–13.54) and with five year progression of the total Sharp score (OR, 3.17; 95% CI, 1.3–7.7), erosion score (OR, 5.3; 95% CI, 1.4–19.2) and joint space narrowing score (OR, 2.8; 95% CI, 1.15–6.8). The presence of anti-CCP2 or IgM RF at baseline did not predict these outcomes. Patients with negative anti-CCP2 tests throughout follow-up had less radiographic progression than patients with increasing anti-CCP2 concentrations; they did not differ from patients with decreasing anti-CCP2 antibody levels. HLADRB1* typing showed that progression of the mean modified Sharp score was not correlated with the presence of the shared epitope alleles. In conclusion, serially determined anti-CCP2 antibodies during the first three years of follow-up performs better than baseline determination for predicting radiographic progression in patients with early RA

Intra-operative intra-peritoneal chemotherapy with cisplatin in patients with peritoneal carcinomatosis of ovarian cancer

International audienceBACKGROUND: Intra-peritoneal (i.p.) chemotherapy is an encouraging treatment option for ovarian cancer with peritoneum involvement in addition with intravenous (i.v.) chemotherapy. Intra-operative i.p. chemotherapy is an interesting method of administration by enhancing the diffusion of chemotherapy. This study had assessed the feasibility of intra-operative i.p. chemotherapy in patients with peritoneal carcinoma of ovarian cancer. METHODS: From January 2003 to February 2006, 47 patients with stage III ovarian cancer were treated with standard paclitaxel carboplatin intravenous chemotherapy and debulking surgery with intra-operative i.p. chemotherapy. After optimal cytoreductive surgery, defined by no unresectable residual disease > 1 cm, i.p. chemotherapy was performed during surgery. The peritoneal cavity was filled by 3 litres of isotonic saline pre-heated at 37 degrees and 90 mg of cisplatin. The sequence was repeated twice during 2 hours based on previous published studies which optimized the cisplatin dosage and exposure duration. Optimal diffusion was obtained by stirring by hands during the 2 hours. RESULTS: Median age was 59.6 years. No severe haematological or non-haematological toxicity induced by intra operative i.p. chemotherapy was reported. No patient died due to the complications of surgery or the i.p. chemotherapy. No neurotoxicity occurred, and one patients had renal impairment. CONCLUSION: This study demonstrates the feasibility of intra-operative i.p. chemotherapy with cisplatin after optimal resection of peritoneal tumor nodules. Further randomized trials are planned to investigate the clinical benefit of this therapeutic modality