ANTI-TNF TREATMENT WITH INFLIXIMAB DECREASES PROCOAGULANT ACTIVITY AND FIBRINOLYSIS IN PATIENTS WITH RHEUMATOID ARTHRITIS

Background: There is an increasing evidence that patients with rheumatoid arthritis (RA) are at higher risk of cardiovascular events because of elevated plasma levels of some thrombotic variables including fibrinogen and up-regulated fibrinolytic system (1). This thrombogenic potential seems to be associated with cytokines involved in the pathogenesis of RA. Procoagulant activities of TNF-α, IL-1 and Il-6 have been documented in a number of studies (2). Thus TNF-α blocking therapy could influence the haemostatic balance in RA.Objectives: We performed an open study to evaluate the effects of anti-TNF-α therapy on thrombin formation, plasma fibrinogen levels and fibrinolytic system in patients with RAMethods: 20 patients with active RA (15 F., 5 M.) were treated with an anti-TNF-α monoclonal antibody (Infliximab, Schering-Plough) administered (i.v. infusion, 3mg/kg) on days 0, 14, 42 and continued at 8-week intervals. Before the treatment (day 0), and on days 3, 14, 16, 42 and 44, plasma concentrations of fibrinogen, TNF-α antigen, IL-6, plasmin-antiplasmin complexes (PAP), thrombin-antithrombin III complexes (TAT), tissue-type plasminogen activator antigen (t-PA) and its inhibitor - PAI-1, D-dimers, thrombomodulin and titer of C-reactive protein (CRP) were measured. Platelet counts, WBC and ESR were evaluated by routine methods.Results: 17 patients completed the 44-day study. Clinical improvement was accompanied by statistically significant down regulation of elevated acute -phase proteins (CRP, fibrinogen) together with the reduction of serum levels of Il-6 (Tab.1.), ESR and the decrease in platelet count within the first 16 days of treatment. On days 3, 14,16, 44, there was an almost parallel fall in plasma concentrations of TAT and PAP complexes (Tab.1.), indicating inhibition of both thrombin formation and fibrinolysis. Plasma levels of D-dimers showed even more marked reduction that persisted over the whole period of the study (Tab.). Alterations of t-PA antigen and thrombomodulin levels were not significant. We observed a significant fall of PAI-1 antigen level on day 14 with partial recovery by days 42 and 44. Day 0(mean ± SD) Day 3(mean ± SD) Day 14(mean ± SD) Day 16(mean ± SD) Day 42(mean ± SD) Day 44(mean ± SD) CRP(mg/L) 48,7 ± 48,2 21 ± 19,2* 8,8 ± 13,6* 9,4 ± 13* 19,1 ± 33,4* 14,2 ± 29,3* Il-6(pg/ml) 106,7 ± 124,5 6,5 ± 5,2* 9,1 ± 12,7* 8,4 ± 10,2* 38,2 ± 83* 5,4 ± 4,5* Fibrynogen(g/L) 5 ± 0,9 4,3 ± 1,1* 3,4 ± 0,8* 3,5 ± 1* 3,4 ± 0,8* 3,4 ± 1,1* TAT(ng/mL) 15,4 ± 16,9 12,3 ± 20,6 6,9 ± 7* 7,1 ± 9,4* 7,7 ± 11,2 8,5 ± 16,4 PAP(ng/mL) 706 ± 444 592,3 ± 307,3* 398,8 ± 173,8* 492,8 ± 363,5* 470 ± 447,8* 458,3 ± 359* D-dimers(ng/mL) 1360,1 ± 257,4* 1275,3 ± 285,1* 1010 ± 388,6* 1044,5 ± 398,8* 964,4 ± 526* 963,4 ± 440,2* * p < 0,05 * p < 0,05Conclusion: Down regulation of acute-phase response during the initial period of anti-TNF-α therapy in RA is accompanied by a significant impairment of plasma procoagulant and fibrinolytic activity.1. McEntegart A. et al. Cardiovascular risk factors, including thrombotic variables, in a population with rheumatoid arthritis. Rheumatol. 2001; 40: 640-644.2. Mulder A.B. et al. Augmented procoagulant activity in cancer patients treated with recombinant inerferon-gamma in addition to recombinant tumor necrosis factor-alpha and melphalan. Thromb. Haemost, 1996; 76: 897-901.1. McEntegart A. et al. Cardiovascular risk factors, including thrombotic variables, in a population with rheumatoid arthritis. Rheumatol. 2001; 40: 640-644.2. Mulder A.B. et al. Augmented procoagulant activity in cancer patients treated with recombinant inerferon-gamma in addition to recombinant tumor necrosis factor-alpha and melphalan. Thromb. Haemost, 1996; 76: 897-901.Citation: , volume , supplement , year 2002, page Session: Rheumatoid arthritis – Treatment 2