Combination benefit of treatment with the cytokine inhibitors interleukin-1 receptor antagonist and PEGylated soluble tumor necrosis factor receptor type I in animal models of rheumatoid arthritis

Abstract

Objective To determine the potential for additive or synergistic effects of combination therapy with the recombinant anticytokine agents interleukin‐1 receptor antagonist (IL‐1Ra) and PEGylated soluble tumor necrosis factor receptor type I (PEG sTNFRI) in established type II collagen–induced arthritis (CIA) and developing adjuvant‐induced arthritis (AIA) in rats. Methods Rats with established CIA or developing AIA were treated with various doses of IL‐1Ra in a slow‐release hyaluronic acid vehicle or with PEG sTNFRI, either alone or in combination with the IL‐1Ra. The effects of treatment were monitored by sequential caliper measurements of the ankle joints or hind paw volumes, final paw weights, and histologic evaluation with particular emphasis on bone and cartilage lesions. Results Combination therapy with IL‐1Ra and PEG sTNFRI in rats with CIA resulted in an additive effect on clinical and histologic parameters when moderately to highly efficacious doses of each protein were administered. Greater‐than‐additive effects were seen when an inactive dose of IL‐1Ra was given in combination with moderately to minimally active doses of PEG sTNFRI. Plasma levels associated with the latter effect (for both proteins) were similar to those seen in rheumatoid arthritis (RA) patients in clinical trials with these agents. Combination therapy in the AIA model generally resulted in additive effects, but some parameters showed a greater‐than‐additive benefit. Conclusion The results provide preclinical support for the hypothesis that IL‐1Ra administered in combination with PEG sTNFRI might provide substantially more clinical benefit to RA patients than either agent alone at blood levels that are currently achievable in patients.

Single and combined inhibition of tumor necrosis factor, interleukin‐1, and RANKL pathways in tumor necrosis factor–induced arthritis: Effects on synovial inflammation, bone erosion, and cartilage destruction

“…This observation is consistent with the findings of our quantitative histologic assessment of inflammation, bone erosion, and cartilage damage in hTNFtg mice, which showed a predilection for IL-1Ra to inhibit the latter 2 pathophysiologic processes. Third, preliminary results of combined blockade of TNF and IL-1 suggest that such approaches may have additive effects, at least in experimental models (25,26).…”

Evaluation of therapeutic targets in animal models of arthritis: How does it relate to rheumatoid arthritis?

“…In rat AIA, treatment with PEGylated TNFR was effective in reducing paw swelling by 50% when given at the onset of clinical signs of arthritis (79). In rat CIA, treatment that was started after the appearance of clear clinical manifestations resulted in a mean reduction in ankle joint swelling of 46% (80).…”

Reduction of cPLA2α overexpression: An efficient anti‐inflammatory therapy for collagen‐induced arthritis

“…CIA was induced by immunizing susceptible animals (DBA/1 mice) with bovine type II collagen (CII) as described [39] using bovine type II collagen prepared at the Kennedy Institute of Rheumatology or purchased from MD Biosciences (Zürich, Switzerland). All mice were maintained in a specific pathogen-free environment and were fed standard mouse chow and water.…”