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Volume 3 Supplement 2

21st European Workshop for Rheumatology Research

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Altered migratory capacity of polymorphonuclear leucocytes as an effect of TNF-alpha blockade in patients with rheumatoid arthritis

Rheumatoid Arthritis (RA) is associated with progressive joint destruction, functional disability and decreased life expectancy. Althought the underlying cause of RA is unknown, TNF-alpha, a proinflammatory cytokine, contributes to the pathogenesis of synovitis and joint destruction. Anti-TNF-biological response modifiers, such as Etanercept a recombinant human TNF receptor fusion protein, suggest that TNF-alpha-inhibition is a viable approach to control disease activity in RA.

Considering the pivotal role TNF alpha plays in the first line defense against bacterial and fungal infections by polymorphonuclear leucocytes (PMN) it seems important to focus on the PMN function in RA patients, treated with Etanercept. Since a 29% increase in infections of the upper respiratory tract under TNF-alpha blockade has been reported, we investigated inflammatory parameters related to PMN-activity in 6 RA-patients, before and after 3-months of Etanercept treatment without altering their methotrexate and/or glucocorti-coid-medication. The migration of the neutrophils was measured with a standardized whole blood membrane filter assay with and without stimulation by the chemoattractant fMLP. The percentage of migrating PMN (total migration index,TMI) and the relative penetration depth into the filters (distribution characteristics, DC) served to characterize the migratory behaviour of neutrophils. To estimate in vivo granulocyte activation, neutrophil elastase was measured in plasma from RA patients. In addition, PMN-blood count and C-reactive protein as a marker of disease activity, were analysed. TNF-alpha blockade significantly (p < 0,03) reduced the spontaneous and fMLP stimulated median TMI (15.2 vs. 10.9 and 16.5 vs. 11,4, respectively). Moreover the spontaneous and the fMLP-stimulated median DC was reduced under Etanercept-treatment (21.1 vs. 5.9, P < 0.03 and 20.5 vs. 6.6, P < 0.06 respectively). Interestingly, these values were still within the normal range of migratory activity. Furthermore, TNF blockade significantly reduced the median plasma elastase levels (252 vs. 108, p <0,04), as well as the median C reactive protein levels (21 vs. 7 P < 0,035) and the median number of polymorphonuclear leucocytes (7.73 vs. 4.58, P < 0.0001). Of note, plama elastase levels as a sign of systemic PMN-activation were still above the normal range. During the observed treatment period all patients showed an improvement in the inflammatory symptoms of RA (2 had a 70% ACR-response, 3 a 50% and 1 a 20% ACR response). No patients had signs of bacterial or fungal infections. In conclusions, TNF alpha blockade did not suppress PMN migratory activities to levels that are assosciated with higher incidences of infections.

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Mitterhammer, H., Hermann, J., Tilz, G. et al. Altered migratory capacity of polymorphonuclear leucocytes as an effect of TNF-alpha blockade in patients with rheumatoid arthritis. Arthritis Res Ther 3 (Suppl 2), P090 (2001).

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