Caroline Aalbers1, Danielle Gerlag2, Koen Vos3, Margriet Vervoordeldonk4, Robert Landewé5, Paul Peter Tak6. 1. Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; Arthrogen B.V., Meibergdreef 45, 1105 BA Amsterdam, The Netherlands. Electronic address: c.j.aalbers@amc.uva.nl. 2. Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. 3. Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; Department of rheumatology, Flevoziekenhuis, Hospitaalweg 1, 1315 RA Almere, The Netherlands. 4. Arthrogen B.V., Meibergdreef 45, 1105 BA Amsterdam, The Netherlands. 5. Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; Department of Rheumatology, Atrium Medical Center, Postbus 4446, 6401 CX Heerlen, The Netherlands. 6. Arthrogen B.V., Meibergdreef 45, 1105 BA Amsterdam, The Netherlands; GlaxoSmithKline, Stevenage, UK; University of Cambridge, Cambridge, UK; Ghent University, Ghent, Belgium.
Abstract
OBJECTIVE: There is an increased interest in developing gene therapy approaches for local delivery of therapeutic genes in patients with arthritis. Intra-articular (i.a.) gene delivery, using an adeno-associated virus encoding a TNF soluble receptor, resulted in reduced paw swelling in an arthritis animal model, but i.a. treatment with a similar vector did not induce robust clinical improvement in patients. It is unclear whether this can be explained by for instance insufficient transduction efficiency or the fact that TNF is not a good therapeutic target for i.a treatment. The objective of this study was to explore the effects of i.a TNF blockade. METHODS:Thirty-one patients with rheumatoid or psoriatic arthritis were assigned to a single i.a. injection of 25mg etanercept or placebo in a double-blind randomised controlled clinical trial. The primary end point was target joint improvement, determined by a composite change index. RESULTS: Twenty-two patients received etanercept and 9 received placebo. Treatment was generally well tolerated. Treatment with etanercept resulted in a prompt and statistically significant improvement of the index (P<0.001) in comparison with placebo. As expected in light of the half-life of etanercept, the beneficial effect was transient and only statistically significant at week 1 and 2 after i.a. injection. CONCLUSION: The results support the development of novel approaches for long-term inhibition of TNF at the site of inflammation, such as gene therapy. TRIAL REGISTRATION: The Netherlands National Trial Register (NTR), www.trialregister.nl, NTR-1210.
RCT Entities:
OBJECTIVE: There is an increased interest in developing gene therapy approaches for local delivery of therapeutic genes in patients with arthritis. Intra-articular (i.a.) gene delivery, using an adeno-associated virus encoding a TNF soluble receptor, resulted in reduced paw swelling in an arthritis animal model, but i.a. treatment with a similar vector did not induce robust clinical improvement in patients. It is unclear whether this can be explained by for instance insufficient transduction efficiency or the fact that TNF is not a good therapeutic target for i.a treatment. The objective of this study was to explore the effects of i.a TNF blockade. METHODS: Thirty-one patients with rheumatoid or psoriatic arthritis were assigned to a single i.a. injection of 25mg etanercept or placebo in a double-blind randomised controlled clinical trial. The primary end point was target joint improvement, determined by a composite change index. RESULTS: Twenty-two patients received etanercept and 9 received placebo. Treatment was generally well tolerated. Treatment with etanercept resulted in a prompt and statistically significant improvement of the index (P<0.001) in comparison with placebo. As expected in light of the half-life of etanercept, the beneficial effect was transient and only statistically significant at week 1 and 2 after i.a. injection. CONCLUSION: The results support the development of novel approaches for long-term inhibition of TNF at the site of inflammation, such as gene therapy. TRIAL REGISTRATION: The Netherlands National Trial Register (NTR), www.trialregister.nl, NTR-1210.