Etanercept exerts beneficial effects on articular cartilage biomarkers of degradation and turnover in patients with ankylosing spondylitis

Abstract

Objective: Anti-tumor necrosis factor-alpha (TNF-alpha) therapies are not only beneficial for reducing symptoms in rheumatoid arthritis (RA) but also for structural damage visible on plain radiographs and serological biomarkers of articular cartilage damage. It is not known if these therapies also prevent structural damage in ankylosing spondylitis (AS). The low sensitivity to change over time of plain radiographic instruments mandates a search for the effects of these therapies on possible biomarkers of cartilage damage.

Methods: We studied 2 populations of patients with AS: (1) patients recruited to a placebo controlled trial of etanercept in AS for 16 weeks; (2) an observational cohort receiving infliximab for disease refractory to conventional therapy. Clinical (morning stiffness, nocturnal pain, Bath AS Disease Activity Index) and laboratory [erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)] assessments of disease activity were performed at baseline and at either 16 weeks (clinical trial cohort) or at 14 weeks (observational cohort). We measured serum matrix metalloproteinase-1 (MMP-1), MMP-3, human cartilage glycoprotein-39 (YKL-40), and cartilage oligomeric matrix protein by ELISA at the same timepoints. We also measured serum concentrations of 2 novel biomarker epitopes, C2C and 846, by competitive ELISA. The C2C assay detects a neoepitope at the carboxy terminus of the long three-quarter amino-terminal fragment generated following cleavage of type II collagen by collagenases. Aggrecan 846 epitope is a chondroitin sulfate epitope present on intact aggrecan molecules. Both these assays would detect products originating from both hyaline cartilages and intervertebral discs.

Results: There was a significant reduction in levels of C2C (p = 0.005) and a significant increase in the 846 epitope (p = 0.01) in patients who received etanercept compared to placebo controls. Changes in C2C correlated significantly with changes in ESR (r = 0.51, p = 0.04) and CRP (r = 0.48, p = 0.048). Significant changes in C2C were not evident in the infliximab observational cohort, although significant reductions were noted in levels of MMP-3 (p = 0.04) and MMP-1 (p = 0.02) at 14 weeks that were not observed in the etanercept group. Analysis of all baseline samples showed a significant correlation between levels of MMP-3 with CRP (r = 0.73, p < 0.0001), and YKL-40 (r = 0.71, p < 0.0001). No correlation was evident at baseline between levels of C2C or 846 epitope and either acute phase reactants or other biomarkers.

Conclusion: Our data suggest that an anti-TNF-alpha agent, etanercept, may modify cartilage turnover. These include decreased degradation of type II collagen and increased turnover of aggrecan. Additional therapeutic properties of some anti-TNF-alpha agents in AS, such as infliximab, may be related to decreased expression of MMP. Additional studies in larger populations are therefore warranted.