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Long term anti-tumour necrosis factor monotherapy in rheumatoid arthritis: effect on radiological course and prognostic value of markers of cartilage turnover and endothelial activation

¹ Department of Rheumatology, University Medical Centre Nijmegen, the Netherlands
² Departments of Rheumatology and Cell and Molecular Biology University Hospital Lund, Sweden
³ Gelterkinden, Germany
⁴ Management Immunology Programme, Organon, Oss, The Netherlands
⁵ Department of Surgery, University of Maastricht, The Netherlands

Correspondence to:
Correspondence to:
Dr A A den Broeder, Department of Rheumatology, University Medical Centre Nijmegen, PO box 9101, 6500 HB Nijmegen, The Netherlands;
A.denbroeder{at}aig.azn.nl

Objectives: To investigate the effect of prolonged neutralisation of tumour necrosis factor (TNF) on the radiological course in rheumatoid arthritis (RA). To assess whether the radiological course can be predicted by clinical variables or biological markers of cartilage and synovium turnover and of endothelial activation.

Patients and methods: Forty seven patients with active RA enrolled at our centre in monotherapy trials with adalimumab (D2E7), a fully human anti-TNF monoclonal antibody, were studied for two years. Radiographs of hands and feet obtained at baseline and after one and two years were scored in chronological order by a single, blinded observer using the modified Sharp method. Radiological course was classified as stable or progressive using the smallest detectable difference as cut off point. The relation between radiological course and serum markers of cartilage and synovium turnover (metalloproteinases (MMP-1 and MMP-3), cartilage oligomeric matrix protein (COMP), human cartilage glycoprotein-39 (HC gp-39)), endothelial activation (soluble E-selectin and intercellular adhesion molecule (ICAM-1)), and integrated measures of disease activity were assessed using univariate and multivariate analysis.

Results: Radiological evaluation was performed in 36 patients with paired sets of radiographs at baseline and two years. After two years a total of 15/36 (42%) presented no radiological progression. More patients with stable radiological course were still receiving anti-TNF treatment after two years (13/15 (87%) v 11/21 (52%); p=0.03) and had lower baseline COMP and sICAM-1 levels (p=0.01 and 0.04, respectively) than those in the group with progressive disease. In a logistic regression model the combination of sustained TNF neutralisation and baseline COMP and sICAM-1 levels was predictive for radiological outcome (p=0.03). C reactive protein and disease activity score area under the curve were significantly correlated with changes in radiological scores after two years (r=0.40 and 0.37, p<0.05). Long term TNF neutralisation decreased the levels of COMP, sICAM, MMPs, and HC gp-39, but not sE-selectin.

Conclusion: The results suggest that long term monotherapy with anti-TNF has a positive effect on radiological outcome and modulates cartilage and synovium turnover as measured by biological markers. Baseline serum sICAM-1 levels and COMP levels may be helpful to identify patients with progressive or non-progressive radiological outcome.

Keywords: rheumatoid arthritis; tumour necrosis factor blocking agents; radiological course; biological markers

Abbreviations: COMP, cartilage oligomeric matrix protein; CRP, C reactive protein; DAS, disease activity score; DMARD, disease modifying antirheumatic drug; ELISA, enzyme linked immunosorbent assay; FCS, fetal calf serum; HC gp-39, human cartilage glycoprotein-39; ICAM-1, intercellular adhesion molecule-1; mAb, monoclonal antibody; MMP, matrix metalloproteinase; PBS, phosphate buffered saline; PBST, PBS-Tris; RA, rheumatoid arthritis; RF, rheumatoid factor; SDD, smallest detectable difference; TNF, tumour necrosis factor

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