Abatacept for rheumatoid arthritis

Institute of Population Health, University of Ottawa, 1 Stewart Street, Ottawa, Ontario, Canada, K1N 6N5.
Cochrane database of systematic reviews (Online) (Impact Factor: 6.03). 10/2009; DOI: 10.1002/14651858.CD007277.pub2
Source: PubMed

ABSTRACT Abatacept inhibits the co-stimulation of T cells and disrupts the inflammatory chain of events that leads to joint inflammation, pain, and damage in rheumatoid arthritis.
To assess the efficacy and safety of abatacept in reducing disease activity, pain, and improving function in people with rheumatoid arthritis.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 1), MEDLINE (from 1966), EMBASE (from 1980), ACP Journal Club (from 2000), and Biosis Previews (from 1990) in March 2007 and December 2008. We contacted authors of included studies and the abatacept manufacturer.
Randomized controlled trials comparing abatacept alone, or in combination with disease-modifying anti-rheumatic drugs (DMARDs) or biologics, to placebo or other DMARDs or biologics in patients with moderate to severe rheumatoid arthritis.
Two authors independently assessed search results and risk of bias, and extracted data. We obtained adverse event data from trials, long-term extension studies, and regulatory agencies.
Seven trials with 2908 patients were included. Compared with placebo, patients in the abatacept group were 2.2 times more likely to achieve an ACR 50 response at one year (RR 2.21, 95% confidence interval (CI) 1.73 to 2.82) with a 21% (95% CI 16% to 27%) absolute risk difference between groups. The number needed to treat to achieve an ACR 50 response was 5 (95% CI 4 to 7). Significant improvements in physical function and a reduction in disease activity and pain were found in abatacept-treated patients compared to placebo. One RCT found abatacept significantly slowed the radiographic progression of joint damage at 12 months compared to placebo, although it is not clear what the clinical relevance of this difference may be. There may be a risk of attrition bias. Total adverse events were greater in the abatacept group (RR 1.05, 95% CI 1.01 to 1.08). Other harm outcomes were not significant with the exception of a greater number of serious infections at 12 months in the abatacept group (Peto odds ratio 1.91 (95% CI 1.07 to 3.42). Serious adverse events were increased when abatacept was given in combination with other biologics (RR 2.30, 95% CI 1.15 to 4.62).
There is moderate-level evidence that abatacept is efficacious and safe in the treatment of rheumatoid arthritis. Abatacept should not be used in combination with other biologics to treat rheumatoid arthritis. The withdrawal and toxicity profile appears acceptable at the present time but further long-term studies and post-marketing surveillance are required to assess harms and sustained efficacy.

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Available from: Jasvinder A Singh, Sep 26, 2015
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    • "Abatacept is believed to work by blocking CD28 costimulation and thereby interfering with T cell-APC interaction and limiting T cell activation. Use of abatacept is associated with reduction in joint inflammation, pain and joint damage in patients with active RA [10]. Recently it has been reported that abatacept shows a better clinical response in ACPA-positive as compared to ACPA-negative patients [11]. "
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    ABSTRACT: Rheumatoid arthritis is a chronic inflammatory disease with a strong MHC class II component and where many patients develop characteristic autoantibodies towards the noncoding amino acid citrulline. Such anti-citrullinated protein antibodies (ACPA) have recently been put forward as an independent predictive factor for treatment response by co-stimulation blockade by CTLA4-Ig (abatacept). We have performed a mechanism of action study to dissect T cell functionality in RA patients with long-standing disease undergoing abatacept treatment and the influence of ACPA status. Peripheral blood samples were collected from RA patients as they started CTLA4-Ig treatment and 3 and 6 months later. A general decrease of regulatory T cell subsets was observed in the cohort. Additionally within the ACPA-positive group significant down-regulation of all key T cell effector subsets including Th1, Th2, and Th17 was observed by analyzing cytokines by intracellular flow cytometry and in cell culture supernatants.RA synovial fluid samples were cultured in vitro in the presence or absence of CTLA4-Ig (abatacept). T cell cytokine production was diminished, but without increasing the functional capacity of CD4+CD25hi regulatory T cells as previously demonstrated in the context of TNF-blockade and anti-IL6R therapy. Our immunological study of T cell functionality in RA patients, both ACPA-positive and ACPA-negative starting biological therapy with the co-stimulation blockade abatacept (CTLA4-Ig) supports the recently published registry study implicating ACPA seropositivity as an independent predictive factor to treatment response as we observed the most striking effect on T cell subset modulation in ACPA-positive patients. These data further support the notion of RA as a disease with several sub-entities, where the ACPA-positive fraction represents a classical HLA-associated autoimmune disorder while ACPA-negative patients may have other driving forces apart from classical adaptive immune responses.
    BMC Immunology 08/2013; 14(1):34. DOI:10.1186/1471-2172-14-34 · 2.48 Impact Factor
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    • "This is suggested by its association with certain MHC II loci, especially HLA-DRB1, and PTPN22, which is relevant for T cell function [8]. The therapeutic effects of blockade of T cell costimulation by abatacept provides more direct evidence [9]. "
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    ABSTRACT: CD4+ T cells express K(2P)5.1 (TWIK-related acid-sensitive potassium channel 2 (TASK2); KCNK5), a member of the two-pore domain potassium channel family, which has been shown to influence T cell effector functions. Recently, it was shown that K(2P)5.1 is upregulated upon (autoimmune) T cell stimulation. The aim of this study was to correlate expression levels of K(2P)5.1 on T cells from patients with rheumatoid arthritis (RA) to disease activity in these patients. Expression levels of K(2P)5.1 were measured by RT-PCR in the peripheral blood of 58 patients with RA and correlated with disease activity parameters (C-reactive protein levels, erythrocyte sedimentation rates, disease activity score (DAS28) scores). Twenty patients undergoing therapy change were followed-up for six months. Additionally, synovial fluid and synovial biopsies were investigated for T lymphocytes expressing K(2P)5.1. K(2P)5.1 expression levels in CD4+ T cells show a strong correlation to DAS28 scores in RA patients. Similar correlations were found for serological inflammatory parameters (erythrocyte sedimentation rate, C-reactive protein). In addition, K(2P)5.1 expression levels of synovial fluid-derived T cells are higher compared to peripheral blood T cells. Prospective data in individual patients show a parallel behaviour of K(2P)5.1 expression to disease activity parameters during a longitudinal follow-up for six months. Disease activity in RA patients correlates strongly with K(2P)5.1 expression levels in CD4+ T lymphocytes in the peripheral blood in cross-sectional as well as in longitudinal observations. Further studies are needed to investigate the exact pathophysiological mechanisms and to evaluate the possible use of K(2P)5.1 as a potential biomarker for disease activity and differential diagnosis.
    Arthritis research & therapy 02/2011; 13(1):R21. DOI:10.1186/ar3245 · 3.75 Impact Factor
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    • "This interaction provides a co-stimulatory signal necessary for full activation of T-lymphocytes.84–86 Abatacept has been shown to be effective in treating RA and is indicated in the treatment of moderate to severe RA and active polyarticular juvenile idiopathic arthritis.84–86 "
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    ABSTRACT: Rheumatoid arthritis (RA) is a chronic heterogeneous autoimmune disorder of unknown etiology resulting in inflammation in the synovium, cartilage, and bone. Genetic factors play an important role in susceptibility to RA as the heritability of RA is between 50% and 60%, with the human leukocyte antigen (HLA) locus accounting for at least 30% of overall genetic risk. Outside the major histocompatibility complex (MHC) region, six additional risk loci have been identified and validated including PTPN22, STAT4, PADI4, CTLA4, TNFAIP3-OLIG3, and TRAF1/C5. Genetic factors are also important in RA pharmacotherapy due to the gene-dependent activity of enzymes involved in the pharmacokinetics and/or pharmacodynamics of RA medications. Indeed, there is great variability in drug efficacy as well as adverse events associated with any anti-rheumatic therapy and genetics is thought to contribute significantly to this inter-individual variability in response. This review will summarize the genetic factors that have been implicated in the pathogenesis of RA, and how these determinants may factor into the potential pharmacogenetics of this disease. We will also review the therapeutic agents that are currently being utilized or presently being evaluated in the treatment of RA, along with potential pharmacogenetic markers that have been proposed for such medications.
    Pharmacogenomics and Personalized Medicine 03/2010; 3(1):15-31. DOI:10.2147/PGPM.S5012
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