Drug Efficacy Related to Underlying Mechanism of Inflammation

Newswise — The effectiveness of TNF inhibitor therapy in treating rheumatoid arthritis is dependent, in part, on the level of TNF in each patient's tissues, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in Washington, DC.

TNF inhibitor therapy blocks the activity of the tumor necrosis factor that contributes to bone and cartilage damage in patients with rheumatoid arthritis. The ability to suppress this activity with infliximab, etanercept and adalimumab, and successfully reduce joint inflammation, has led to their widespread use. However, some 20 to 30% of patients do not respond to the medication.

To determine if potential success of the therapy could be predicted, researchers examined tissue samples from 143 patients with active rheumatoid arthritis. These samples, taken from the lining of the affected joints, were analyzed for the presence of the various cells and secretions that lead to inflammation and damage, most particularly the presence of TNF. The patients were then started on TNF inhibitor therapy.

At week 16, patients' level of improvement was evaluated. Those found to have higher levels of TNF-secreting cells responded significantly better to the medications than those with lower levels.

"As suspected, a TNF inhibitor's ability to reduce inflammation is going to be effective especially if the individual with rheumatoid arthritis is producing high levels of TNF," explains Professor Paul Peter Tak, MD, PhD, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, and the principal investigator in the study. "This means we can make some predictions as to the medication's probable effectiveness in each patient. However, there are still other mechanisms involved in the disease that preclude our being emphatic about the medication's potential success or failure."

The American College of Rheumatology is the professional organization for rheumatologists and health professionals who share a dedication to healing, preventing disability and curing arthritis and related rheumatic and musculoskeletal diseases. For more information on the ACR's annual meeting, see http://www.rheumatology.org/annual.

Presentation Number: L7

The Response To TNF-alpha Blockade In Rheumatoid Arthritis Is In Part Dependent On TNF-alpha Expression In The Synovium

Carla A. Wijbrandts1, Marcel G. Dijkgraaf1, Maarten C. Kraan2, Huib Dinant1, Koen Vos1, Willem F. Lems3, Gerrit J. Wolbink4, Dorine Sijpkens1, Ben A. C Dijkmans5, Paul P. Tak1. 1Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands; 2Schering Plough, New York, NY; 3Slotervaart Hospital/VUMC, Amsterdam, The Netherlands; 4Academic Medical Center/University of Amsterdam/Jan van Breemen instituut, Amsterdam, The Netherlands; 5VUMC, Amsterdam, The Netherlands

Background. It is at present unknown why some patients with rheumatoid arthritis (RA) exhibit a clinical response to TNF? blocking therapy, whereas others do not. Conceivably, this is related to TNF? expression at the site of inflammation.Objective. The aim of this study was to determine whether the heterogeneous clinical response to TNF? blocking therapy with infliximab in RA can be predicted by TNF? expression in the synovium before initiation of treatment.Methods. Prior to initiation of infliximab treatment (3mg/kg) synovial tissue (ST) biopsies were obtained from 143 patients with active RA. At week 16 clinical changes were evaluated by changes in Disease Activity Score (DAS28) compared to baseline. The synovial infiltrate was characterized by immunohistochemical staining to detect macrophages, B cells, T cells, plasma cells, cytokines, adhesion molecules, and growth factors. Stained sections were evaluated by sophisticated digital image analysis. Multivariate (MV) regression was used to identify the independent predictors of clinical response (?DAS28 ≥ 1.2) and the change in DAS28 (?DAS28).

Results. Synovial tissue analysis confirmed our hypothesis that the baseline level of TNF? expression is a significant predictor of response to TNF? blocking therapy. TNF? expression in the intimal lining layer and synovial sublining were significantly higher in responders than in non-responders (P < 0.05 and P = 0.005, respectively). Furthermore, the numbers of CD68+ macrophages, CD163+ macrophages, and CD3+ T cells in the synovial sublining (all able to produce TNF? in the synovium) were significantly higher in responders than in non-responders (P = 0.027, P = 0.017, and P = 0.037, respectively).

Conclusions. The results presented here show that the effects of TNF? blockade are dependent on TNF? expression and infiltration by inflammatory cells able to produce TNF? at the site of inflammation. Since the clinical response cannot be predicted completely, other mechanisms are involved as well.

Source of support. This study was funded by a Health Care Efficiency Research Programme grant from the Netherlands Organisation for Health Research and Development (ZonMw) in assignment of the Netherlands Organisation for Scientific Research (NWO) (grant number 945-02-029), the Dutch Arthritis Association, and the European Community's FP6 funding (Autocure).

Disclosure Block: C.A. Wijbrandts, None; M.G. Dijkgraaf, None; M.C. Kraan, None; H. Dinant, None; K. Vos, None; W.F. Lems, None; G.J. Wolbink, None; D. Sijpkens, None; B.A. Dijkmans, None; P.P. Tak, None.