Genetic Variants in Toll-Like Receptors Are Not Associated with Rheumatoid Arthritis Susceptibility or Anti-Tumour Necrosis Factor Treatment Outcome

Coenen, Marieke J. H.; Enevold, Christian; Barrera, Pilar; Schijvenaars, Mascha M.V.A.P.; Toonen, Erik J. M.; Scheffer, Hans; Padyukov, Leonid; Kastbom, Alf; Klareskog, Lars; Barton, Anne; Kievit, Wietske; Rood, M. J.; Jansen, Tim L.; Swinkels, Dorine W.; Riel, P.L.C.M. van; Franke, Barbara; Bendtzen, Klaus; Radstake, Timothy R. D. J.

doi:10.1371/journal.pone.0014326

Cited by 26 publications

(25 citation statements)

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“…While monitoring can help to identify non-responders early and allow switching to another treatment, the causes of non-response or loss of response remain, in most cases, elusive. Although it is possible that the clinical manifestations of RA may be driven by different pathways in different subjects, the multifactorial nature of the disease has made identification of robust biomarkers challenging, thus highlighting a significant unmet need 33–35. In this small phase I study, mavrilimumab demonstrated an adequate safety profile when administered as a single, escalating intravenous dose of 0.01–10.0 mg/kg in subjects with RA.…”

Section: Discussionmentioning

confidence: 90%

Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor- , in subjects with rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase I, first-in-human study

Burmester

Feist

Sleeman³

et al. 2011

Annals of the Rheumatic Diseases

115

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ObjectiveTo evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic profiles of mavrilimumab, a human monoclonal antibody targeting the granulocyte-macrophage colony-stimulating factor receptor-α, in subjects with rheumatoid arthritis (RA).MethodsA randomised, double-blind, placebo-controlled, dose-escalating phase I study in subjects with RA who received stable methotrexate treatment for ≥3 months before enrolment. Subjects received single intravenous escalating doses of mavrilimumab (0.01–10.0 mg/kg) or placebo.Results32 subjects were enrolled in this study (1 unblinded subject at 0.01 mg/kg and another at 0.03 mg/kg were followed by five sequential double-blinded cohorts, n=6 each, treated with 0.1, 0.3, 1.0, 3.0 and 10.0 mg/kg, respectively). Adverse events were mild or moderate and were reported with similar frequency across all treatment cohorts. One subject (10.0 mg/kg) experienced moderate face and neck urticaria during infusion that resolved with symptomatic treatment. Systemic clearance of mavrilimumab approached that of endogenous IgG at doses >1.0 mg/kg; pharmacodynamic activity was confirmed in the 1.0 and 3.0 mg/kg cohorts by suppression of suppressor of cytokine signalling 3 mRNA transcripts. In exploratory analyses, reductions of acute phase reactants were observed in subjects with elevated C-reactive protein (>5 mg/l) and erythrocyte sedimentation rate (≥20.0 mm/h) at baseline. No significant change in Disease Activity Score 28-joint assessment (DAS28) was seen in any of the cohorts. In mavrilimumab-treated subjects (n=15) with baseline DAS28 >3.2, mean disease activity (DAS28) was significantly reduced at 4 weeks.ConclusionIn this first-in-human study, mavrilimumab showed preliminary evidence of pharmacodynamic activity. Importantly, the safety and pharmacokinetic profiles of mavrilimumab support further clinical studies in RA.Trial registration number: NCT00771420.

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Section: Discussionmentioning

confidence: 90%

Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor- , in subjects with rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase I, first-in-human study

Burmester

Feist

Sleeman³

et al. 2011

Annals of the Rheumatic Diseases

115

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“…The results somewhat vary from region to region. The TLR9 SNP rs187084 allele variant TT may increase RA susceptibility in the Turkish RA population, although it was not associated in studies of Dutch or French cohorts [100][101][102]. Furthermore, the SNP rs5741883 of TLR8 has been reavealed to have association with rheumatoid factor autoantibody positivity in a cohort study on 319 European individuals [103].…”

Section: Rheumatoid Arthritismentioning

confidence: 99%

Toll-Like Receptor Pathways in Autoimmune Diseases

Chen

Szodoray

Zeher

2015

Clinic Rev Allerg Immunol

242

177

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Autoimmune diseases are a family of chronic systemic inflammatory disorders, characterized by the dysregulation of the immune system which finally results in the break of tolerance to self-antigen.Several studies suggest that Toll-like receptors (TLRs) play an essential role in the pathogenesis of autoimmune diseases. TLRs belong to the family of pattern recognition receptors (PRRs) that recognize a wide range of pathogen-associated molecular patterns (PAMPs). TLRs are type I transmembrane proteins and located on various cellular membranes. Two main groups have been classified based on their location；the extracelluar group referred to the ones located on the plasma membrane while the intracellular group all located in endosomal compartments responsible for the recognition of nucleic acids. They are released by the host cells and trigger various intracellular pathways which results in the production of proinflammatory cytokines, chemokines, as well as the expression of co-stimulatory molecules to protect against invading microorganisms. Particular, TLR pathway-associated proteins, such as IRAK, TRAF, and SOCS are often dysregulated in this group of diseases. TLR-associated gene expression profile analysis together with single nucleotide polymorphism (SNP) assessment could be important to explain the pathomechanism driving autoimmune diseases. In this review, we summarize recent findings on TLR pathways regulation in various autoimmune diseases, including Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), systemic sclerosis (SSc), and psoriasis. KEYWORDS:Toll-like receptors (TLRs); autoimmune disease; IL-1 receptor associated kinase (IRAK); TNF receptor associated factor (TRAF); Suppressor of cytokine signaling (SOCS) 3 Autoimmune diseases are characterized by the dysregulation of the immune system which finally results in the break of tolerance to self-antigen. Even though the accurate etiology and pathogenesis of the majority of these diseases are still not clear, complex elements, including genetic, environmental, hormonal factors may provoke the autoimmune processes leading to the development of the disease.Concerning the role of derailed immune responses in the pathogenesis, aberrant processes both in the innate and adaptive immune system have been shown to participate in the disease initiation and perpetuation [1]. Within these processes, numerous studies have been demonstrated that Toll-like receptors (TLRs) have an essential role in various autoimmune diseases, including Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), systemic sclerosis (SSc), and psoriasis. [2,3]. Toll-like receptorsThe innate immune system is the first line of host defense mechanisms against invading microorganisms and forms the basis of the development of adaptive immunity. Host cells express diverse pattern recognition receptors (PRRs) include toll-like receptors (TLRs), C-type lectin-like receptors (CL...

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“…Ahmad-Nejad et al, 2004;Alvarez-Rodriguez et al, 2011;Brand et al, 2005;Britton et al, 2001;Coenen et al, 2010;Feldmann et al, 2002;Gazouli et al, 2005;Hoffman et al, 2001Hoffman et al, , 2003Neven et al, 2004;Pontillo et al, 2011;Schoultz et al, 2009;Shen et al, 2010;Snelgrove et al, 2007;Villani et al, 2009;Yang et al, 2011)…”

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