Synovial tissue and serum biomarkers of disease activity, therapeutic response and radiographic progression: analysis of a proof-of-concept randomised clinical trial of cytokine blockade.
Veale, Douglas J
AffiliationDepartment of Rheumatology, St Vincent's University Hospital, Dublin 4, Ireland. , firstname.lastname@example.org
MeSHAntirheumatic Agents/adverse effects/*therapeutic use
Arthritis, Rheumatoid/*drug therapy/immunology/radiography
Drug Therapy, Combination
Interleukin 1 Receptor Antagonist Protein/adverse effects/therapeutic use
Polyethylene Glycols/adverse effects/therapeutic use
Receptors, Tumor Necrosis Factor, Type I/adverse effects/therapeutic use
Tumor Necrosis Factor-alpha/antagonists & inhibitors
MetadataShow full item record
CitationAnn Rheum Dis. 2010 Apr;69(4):706-14. Epub 2009 May 20.
JournalAnnals of the rheumatic diseases
AbstractOBJECTIVES: To evaluate synovial tissue and serum biomarkers of disease activity, therapeutic response and radiographic progression during biological therapy for rheumatoid arthritis (RA). METHODS: Patients with active RA entered a randomised study of anakinra 100 mg/day, administered as monotherapy or in combination with pegsunercept 800 microg/kg twice a week. Arthroscopic synovial tissue biopsies were obtained at baseline and two further time points. Following immunohistochemical staining, selected mediators of RA pathophysiology were quantified using digital image analysis. Selected mediators were also measured in the serum. RESULTS: Twenty-two patients were randomly assigned: 11 received monotherapy and 11 combination therapy. American College of Rheumatology 20, 50 and 70 response rates were 64%, 64% and 46% with combination therapy and 36%, 9% and 0% with monotherapy, respectively. In synovial tissue, T-cell infiltration, vascularity and transforming growth factor beta (TGFbeta) expression demonstrated significant utility as biomarkers of disease activity and therapeutic response. In serum, interleukin 6 (IL-6), matrix metalloproteinase (MMP) 1, MMP-3 and tissue inhibitor of metalloproteinase 1 (TIMP-1) were most useful in this regard. An early decrease in serum levels of TIMP-1 was predictive of the later therapeutic outcome. Pretreatment tissue levels of T-cell infiltration and the growth factors vascular endothelial growth factor/TGFbeta, and serum levels of IL-6, IL-8, MMP-1, TIMP-1, soluble tumour necrosis factor receptor types I and II and IL-18 correlated with radiographic progression. CONCLUSIONS: Synovial tissue analysis identified biomarkers of disease activity, therapeutic response and radiographic progression. Biomarker expression in tissue was independent of the levels measured in the serum.
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