Low levels of apoptosis and high FLIP expression in early rheumatoid arthritis synovium

Objectives

To define synovial apoptosis with respect to disease duration, inflammatory cell type, FLIP (FLICE like inhibitory protein) and cytokines expression in patients with rheumatoid arthritis (RA).

Methods

Synovial biopsy specimens from eleven patients with longstanding RA (median disease duration 21 years) and eight with early RA (median disease duration 5 months) have been investigated. We evaluated apoptosis (TUNEL method combined with morphologic analysis), cell surface markers (CD3, CD68), cytokines (IL-1α, IL-1β, TNF-α and IL-6) and FLIP expression. Computer-assisted image analysis was used for quantification.

Results

Apoptosis level in RA synovium was significantly higher in the group of patients with long standing RA than in the patients with early RA (8.8% versus 0.6%, P = 0.001), while number of macrophages and FLIP expression were higher in the early as compared with long standing RA group (16.2% versus 8.3%, P = 0.02 and 31.1% versus 0.2%, P = 0.001 respectively). All three markers significantly correlate with disease duration (r = -0.7, P < 0.001 for FLIP, r = 0.6, P = 0.001 for apoptosis and r = -0.5, P < 0.05 for CD68). Cytokine expression and T cell scores were not significantly different in early RA compared to longstanding RA. We did not observe differences between corticosteroids treated versus corticosteroids non-treated patients or between DMARD treated versus non-treated patients.

Conclusions

Our findings suggest that RA synovial macrophages are resistant to apoptosis in early RA and express high levels of FLIP. During natural or drug modified disease progression the apoptotic mechanism may be restored with a specific increase of synovial apoptosis in patients with long standing arthritis.