Immunomodulatory effects of etanercept on peripheral joint synovitis in the spondylarthropathies

Objective. Because different tumor necrosis factor alpha (TNF alpha) blockers may have distinct immunomodulatory effects on specific disease manifestations, the present study was carried out to investigate the immunomodulating effects of etanercept on peripheral synovitis in the spondylarthropathies (SpA). Methods. Peripheral joint disease was assessed clinically, histologically, and radiologically in a prospective 2-year study of 20 patients with SpA treated with etanercept. Synovial tissue biopsy samples obtained at weeks 0,12, and 52 were analyzed by histology and immunohistochemistry for the extent of inflammation, changes to tissue architecture, and matrix degradation. Serum levels of myeloid-related protein 8 (MRP-8)/MRP-14, matrix metalloproteinase 3 (MMP-3), and cartilage oligomeric matrix protein (COMP) were determined by enzyme-linked immunosorbent assay. Results. Etanercept induced a rapid and sustained clinical improvement of peripheral joint disease. Histologic synovitis was down-regulated, with a profound reduction in global cellular infiltration and T lymphocytes, but not B lymphocytes. The most prominent change in markers of inflammation was a reduction in the different macrophage subsets (CD68, CD163, MRP-8, and MRP-14), but this was not paralleled by a decrease in serum MRP-8/MRP-14. Structural changes included normalization of lining layer hyperplasia and a moderate reduction in vascularity. However, no effect on the microarchitecture of lymphoid aggregates was observed. In terms of an effect on matrix degradation, the synovial expression of MMP-3 and MMP-9 was down-modulated in correlation with a rapid and profound decrease in serum MMP-3. At week 52, serum COMP levels were also reduced. No significant radiologic disease progression was observed in these patients over a 2-year period. Conclusion. Use of etanercept effectively down-modulated the immunopathologic processes of SpA synovitis, both in the short term and in the long term.