Abstract:
INTRODUCTION:Since current treatment options for patients suffering from active rheumatoid arthritis (RA) remain inadequate, especially for those unresponsive to disease-modifying antirheumatic drugs (DMARDs), new and improved medication is needed. This study evaluates the safety and efficacy of masitinib (AB1010), a potent and selective protein tyrosine kinase inhibitor of c-KIT, in the monotherapy treatment of DMARD-refractory RA. METHODS:This was a multicentre, uncontrolled, open-label, randomised, dose-ranging, phase 2a trial. Masitinib was administered orally to 43 patients who had inadequate response to DMARDs, at initial randomised dosing levels of 3 and 6 mg/kg per day over a 12-week period. Dose adjustment was permitted based upon tolerability and response criteria. Efficacy was assessed via American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70) responses, disease activity score using 28 joint counts (DAS28), index of improvement in RA (ACRn) and C-reactive protein (CRP) improvement, relative to baseline at week 12. RESULTS:Improvement was observed in all efficacy endpoints, including ACR20/50/70 scores of 54%, 26% and 8%, respectively, and a reduction in CRP level by greater than 50% for approximately half the population. This improvement was sustainable throughout an extension phase (> 84 weeks) and was also independent of initial DMARD resistance (anti-tumour necrosis factor-alpha and/or methotrexate). A relatively high patient withdrawal rate (37%) required the use of last observation carried forward (LOCF) data imputation. Incidence of adverse events was high (95%), although the majority were of mild or moderate severity with a considerable decline in frequency observed after 12 weeks of treatment. Two nonfatal serious adverse events were reported. Dose-response analyses tentatively indicate that an initial dosing level of 6.0 mg/kg per day administered orally in two daily intakes is the most appropriate, based upon potency and tolerability trends. CONCLUSIONS:Treatment with masitinib improved DMARD-refractory active RA. Following an initial high incidence of mostly mild to moderate side effects during the first 12 weeks of treatment, masitinib appears to be generally well tolerated. This, together with evidence of a sustainable efficacy response, suggests that masitinib is suitable for long-term treatment regimens. Since this was the first study of masitinib in a nononcologic pathology, the relatively high patient withdrawal rate observed can be partly attributed to a highly cautious response to adverse events. There is sufficient compelling evidence to warrant further placebo-controlled investigation. TRIAL REGISTRATION:ClinicalTrials.gov NCT00831922.
journal_name
Arthritis Res Therjournal_title
Arthritis research & therapyauthors
Tebib J,Mariette X,Bourgeois P,Flipo RM,Gaudin P,Le Loët X,Gineste P,Guy L,Mansfield CD,Moussy A,Dubreuil P,Hermine O,Sibilia Jdoi
10.1186/ar2740subject
Has Abstractpub_date
2009-01-01 00:00:00pages
R95issue
3eissn
1478-6354issn
1478-6362pii
ar2740journal_volume
11pub_type
杂志文章,多中心研究,随机对照试验abstract:BACKGROUND:Although the short-term effects of tumor necrosis factor alpha (TNF-α) and interleukin-17A (IL-17A) inhibition on the structural changes in psoriatic arthritis (PsA) using high-resolution peripheral quantitative computed tomography (HR-pQCT) have been reported, no studies have investigated the long-term stru...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-019-2043-3
更新日期:2019-12-04 00:00:00
abstract:BACKGROUND:The purpose of this study was to examine the effect of aldosterone receptor blockade on the immunopathogenesis and progression of nephritis in the (NZB x NZW) F1 murine lupus model. METHODS:Female NZB/W F1 mice (11 weeks old) were treated daily with 25 or 50 mg/kg oral spironolactone or vehicle. Proteinuria...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar2353
更新日期:2008-01-01 00:00:00
abstract::Abnormalities in lymphocyte signaling cascades are thought to play an important role in the development of autoimmune disease. However, the large amount of cellular material needed for standard biochemical assessment of signaling status has made it difficult to evaluate putative abnormalities completely using primary ...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar1155
更新日期:2004-01-01 00:00:00
abstract:BACKGROUND:Differential diagnosis among psoriatic arthritis (PsA) and seronegative rheumatoid arthritis (Abneg RA) can be challenging particularly in the clinical setting of peripheral phenotype and autoantibodies seronegativity. The aim of the study was to identify synovial tissue (ST) biomarkers differentially expres...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-019-1898-7
更新日期:2019-05-09 00:00:00
abstract::Treatment of Sjögren's syndrome is almost entirely symptomatic. A lack of true understanding of the underlying immunological pathology of the disease prevents directed therapy. Interleukin-21 (IL-21) is elevated in the serum of patients with this disease and is expressed by the lymphocytes infiltrating the salivary gl...
journal_title:Arthritis research & therapy
pub_type: 评论,社论
doi:10.1186/ar3518
更新日期:2011-01-01 00:00:00
abstract:INTRODUCTION:Patients with rheumatoid arthritis (RA) are at an increased risk for cardiovascular disease (CVD). One of the earliest manifestations of CVD is endothelial dysfunction (ED), which can lead to functional and morphological vascular abnormalities. Several non-invasive assessments of vascular function and morp...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar4287
更新日期:2013-01-01 00:00:00
abstract::Mammalian immune responses are intended to eradicate microbial pathogens and thus protect individuals from the harmful effects of such infections. However, unresolved inflammation can be devastating to the host and cause tissue damage and organ malfunction. Immune responses can even mistakenly target self-antigens and...
journal_title:Arthritis research & therapy
pub_type: 杂志文章,评审
doi:10.1186/ar4131
更新日期:2013-01-25 00:00:00
abstract::Behçet's disease is characterized by recurrent aphthous stomatitis, uveitis, genital ulcers, and skin lesions. The role of the HLA-B*51 gene has been confirmed in recent years, although its contribution to the overall genetic susceptibility to Behçet's disease was estimated to be only 19%. The production of a variety ...
journal_title:Arthritis research & therapy
pub_type: 杂志文章,评审
doi:10.1186/ar757
更新日期:2003-01-01 00:00:00
abstract:BACKGROUND:The long-term outcome of rheumatoid arthritis (RA) patients who in clinical practice exhibit persistent moderate disease activity (pMDA) despite treatment with biologics has not been adequately studied. Herein, we analyzed the 5-year outcome of the pMDA group and assessed for within-group heterogeneity. MET...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-020-02313-w
更新日期:2020-09-29 00:00:00
abstract::The characteristic of a biomarker that makes it a useful surrogate is the ability to identify a high risk of clinically important benefits or harms occurring in the future. A number of definitions or descriptions of surrogate definition have been put forward. Most recently the Institute of Medicine of the National Aca...
journal_title:Arthritis research & therapy
pub_type: 杂志文章,评审
doi:10.1186/ar4176
更新日期:2013-01-01 00:00:00
abstract::First identified by the Egyptians in 2640 BC, podagra (acute gout occurring in the first metatarsophalangeal joint) was later recognized by Hippocrates in the fifth century BC, who referred to it as 'the unwalkable disease'. The term is derived from the Latin word gutta (or 'drop'), and referred to the prevailing medi...
journal_title:Arthritis research & therapy
pub_type: 历史文章,杂志文章,评审
doi:10.1186/ar1906
更新日期:2006-01-01 00:00:00
abstract:INTRODUCTION:The longitudinal degradation mechanism of extracellular matrix (ECM) in the interbertebral disc remains unclear. Our objective was to elucidate catabolic and anabolic gene expression profiles and their balances in intervertebral disc degeneration using a static compression model. METHODS:Forty-eight 12-we...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar3764
更新日期:2012-03-06 00:00:00
abstract:INTRODUCTION:The purpose of this study was to evaluate and compare the serum levels and local expression of resistin in patients with idiopathic inflammatory myopathies to controls, and to determine the relationship between resistin levels, inflammation and disease activity. METHODS:Serum resistin levels were determin...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar3836
更新日期:2012-05-11 00:00:00
abstract:INTRODUCTION:We previously demonstrated that a single-chain fragment variable (scFv) specific to collagen type II (CII) posttranslationally modified by reactive oxygen species (ROS) can be used to target anti-inflammatory therapeutics specifically to inflamed arthritic joints. The objective of the present study was to ...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar4613
更新日期:2014-07-16 00:00:00
abstract:INTRODUCTION:An adjuvanted pandemic H1N1 influenza (pH1N1) vaccine (Pandemrix) was reported as highly immunogenic resulting in seroconversion in 77 to 94% of adults after administration of a single dose. The aim of the study was to investigate the impact of different anti-rheumatic treatments on antibody response to pH...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar4427
更新日期:2014-01-02 00:00:00
abstract:BACKGROUND:Porphyromonas gingivalis (Pg) infection causes periodontal disease and exacerbates rheumatoid arthritis (RA). It is reported that inoculation of periodontopathogenic bacteria (i.e., Pg) can alter gut microbiota composition in the animal models. Gut microbiota dysbiosis in human has shown strong associations ...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-020-02348-z
更新日期:2020-10-19 00:00:00
abstract:INTRODUCTION:Studies investigating genetic risk factors for susceptibility to rheumatoid arthritis (RA) studied anti-citrullinated peptide antibody (CCP)-positive RA more frequently than anti-CCP-negative RA. One of the reasons for this is the perception that anti-CCP-negative RA may include patients that fulfilled cri...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar3505
更新日期:2011-01-01 00:00:00
abstract:BACKGROUND:Some abnormalities in nailfold videocapillaroscopy (NVC), such as the presence of micro-haemorrhages (MHEs), micro-thromboses (MTs), giant capillaries (GCs) and reduction in the number of capillaries (nCs), suggest a disease activity (DA) phase in systemic sclerosis (SSc). In a previous paper, we showed that...
journal_title:Arthritis research & therapy
pub_type: 杂志文章,多中心研究
doi:10.1186/s13075-017-1354-5
更新日期:2017-06-13 00:00:00
abstract:INTRODUCTION:Antibodies against citrullinated peptides (anti-CCP) and increased levels of cytokines precede the development of rheumatoid arthritis (RA) by several years. Recently, the proteins survivin and Fms-like tyrosine kinase 3 ligand (Flt3L) have been identified as biomarkers of RA associated with joint destruct...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar4474
更新日期:2014-02-05 00:00:00
abstract:INTRODUCTION:The pleiotropic cytokine interleukin-6 (IL-6) plays an important role in the pathogenesis of different diseases, including rheumatoid arthritis (RA). ALX-0061 is a bispecific Nanobody® with a high affinity and potency for IL-6 receptor (IL-6R), combined with an extended half-life by targeting human serum a...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-015-0651-0
更新日期:2015-05-20 00:00:00
abstract::Lupus nephritis is a major contributor to morbidity and mortality in systemic lupus erythematosus, but little is known about the pathogenic processes that underlie the progressive decay in renal function. A common finding in lupus nephritis is thickening of glomerular basement membranes associated with immune complex ...
journal_title:Arthritis research & therapy
pub_type: 杂志文章,评审
doi:10.1186/ar2532
更新日期:2008-01-01 00:00:00
abstract::We investigated the therapeutic potential and mechanism of action of IFN-beta protein for the treatment of rheumatoid arthritis (RA). Collagen-induced arthritis was induced in DBA/1 mice. At the first clinical sign of disease, mice were given daily injections of recombinant mouse IFN-beta or saline for 7 days. Disease...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar1165
更新日期:2004-01-01 00:00:00
abstract:BACKGROUND:Rheumatoid arthritis (RA) has been known to be associated with increased risk of cardiovascular disease (CVD). The aim of this study was to investigate the effects of Tai Chi exercise on CVD risk in elderly women with RA. METHOD:In total, 56 female patients with RA were assigned to either a Tai Chi exercise...
journal_title:Arthritis research & therapy
pub_type: 临床试验,杂志文章
doi:10.1186/s13075-015-0893-x
更新日期:2015-12-24 00:00:00
abstract:BACKGROUND:Fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA-FLS) contribute to joint inflammation and damage characteristic of the disease. RA-FLS express KCa1.1 (BK, Slo1, MaxiK, KCNMA1) as their major plasma membrane potassium channel. Blocking KCa1.1 reduces the invasive phenotype of RA-FLS and attenua...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-016-1003-4
更新日期:2016-05-10 00:00:00
abstract:BACKGROUND:Osteoarthritis (OA) is characterized by the formation and deposition of calcium-containing crystals in joint tissues, but the underlying mechanisms are poorly understood. The gasotransmitter hydrogen sulfide (H2S) has been implicated in mineralization but has never been studied in OA. Here, we investigated t...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/s13075-020-02147-6
更新日期:2020-03-17 00:00:00
abstract::Although it is generally accepted that osteoarthritis is a degenerative condition of the cartilage, other tissues such as synovium in which immunological and inflammatory reactions occur contribute to the development of joint pathology. This sheds new light on the potential mechanism of action of mesenchymal stem cell...
journal_title:Arthritis research & therapy
pub_type: 社论
doi:10.1186/ar4190
更新日期:2013-03-20 00:00:00
abstract::T-helper (Th) lymphocytes contribute to arthritis pathogenesis by helping B cells to produce antibodies, by producing cytokines that activate effector cells involved in the destruction of cartilage and bone, and by contributing to osteoclast differentiation. There are murine models of arthritis, most notably collagen-...
journal_title:Arthritis research & therapy
pub_type: 评论,社论
doi:10.1186/ar3008
更新日期:2010-01-01 00:00:00
abstract:INTRODUCTION:IL-10 is a very important anti-inflammatory cytokine. However, the role of this cytokine in T cells in the pathogenesis of collagen-induced arthritis is unclear. The purpose of this study was to define the role of IL-10 signaling in T cells in the pathogenesis of collagen-induced arthritis. METHODS:IL-10 ...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
doi:10.1186/ar3545
更新日期:2011-01-01 00:00:00
abstract:INTRODUCTION: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 we...
journal_title:Arthritis research & therapy
pub_type: 杂志文章,多中心研究
doi:10.1186/ar2773
更新日期:2009-01-01 00:00:00
abstract::The past 10 years have seen the description of families of receptors that drive proinflammatory cytokine production in infection and tissue injury. Two major classes have been examined in the context of inflammatory joint disease--the Toll-like receptors (TLRs) and NOD-like receptors (NLRs). TLRs such as TLR2 and TLR4...
journal_title:Arthritis research & therapy
pub_type: 杂志文章,评审
doi:10.1186/ar2729
更新日期:2009-01-01 00:00:00