Background/Purpose: We developed a novel mono-arthritic multi-flare Rat Streptococcal Cell Wall (SCW) model which captures certain aspects of disease with flares and remission of inflammation similar to Rheumatoid Arthritis (RA). To delineate the role of TNF, T cells, and IL-1 in pathogenesis of SCW-induced arthritis, we investigated the activity of clinical agents, Etanercept, Abatacept and Anakinra. Comparative evaluation of these targeted therapies was also performed in the rat Collagen Induced Arthritis (CIA) model.

Methods: SCW arthritis was induced in female Lewis rats with an intra-articular injection in the hind ankle joint on day 1 (flare 1) followed by two intravenous challenges on days 21 (flare 2) and 42 (flare 3) of SCW extract PG-PS 100p. CIA was induced using methods previously described in literature. Inflammation and pain were monitored by measuring paw swelling (mechanical calipers) and withdrawal threshold (von-Frey assay) respectively. Additional biomarkers assessed by cytokine profiling, cell phenotyping, bioluminescence/µCT imaging and histopathology were also performed in the local joint.

Results: In the SCW model late prophylactic administration of Etanercept, Abatacept and Anakinra significantly inhibited paw swelling by ≥60% (p<0.001), ≥60% (p<0.001), 88% (p<0.001) and pain by 37% (p<0.05), ≥28% (p<0.05) and 64% respectively in flare 2. Etanercept in flare 3 inhibited paw swelling by 60% (p<0.001) and partially inhibited pain by 27%. Interestingly, prior treatment with Etanercept in flare 2 followed by a wash out period of 14 days and re-administration in flare 3 led to a loss in efficacy, potentially due to immunogenicity. Abatacept administration in flare 3 had no effect on either paw swelling or pain in rats that were treated in flare 3 alone or in rats that were treated previously in flare 2. In the CIA model, both late prophylactic and therapeutic treatment with Etanercept inhibited paw swelling by 50% (p<0.001). A loss of efficacy with Etanercept was also observed in the CIA model when administered prophylactically possibly due to immunogenicity. Prophylactic, late prophylactic and therapeutic administration of Abatacept in the CIA model significantly inhibited paw swelling by 100% (p<0.001), 42% (p<0.001) and 34% (p<0.001) respectively. The additional biomarkers corroborated with efficacy in both models.

Conclusion: We developed a novel multi-flare SCW model that can be used to evaluate clinically relevant parameters of inflammation and pain simultaneously. Using clinical agents Etanercept, Abatacept and Anakinra targeting TNF, T cells and IL-1 respectively we have delineated distinct pathogenic mechanisms of inflammation and pain at different stages of disease in the SCW model. We also show similar profiles of efficacy in late prophylactic and therapeutic regimens in the CIA model. The flaring mechanism in the SCW model allows for drug washout periods in between compound administration. This might provide useful pre-clinical insights on potential immunogenicity mechanisms that may be relevant in a clinical setting. Our novel model can facilitate innovative assessment of anti-rheumatic agents in multiple flares and offers a powerful tool for drug discovery.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/etanercept-abatacept-and-anakinra-treatment-ameliorates-inflammation-and-pain-in-a-novel-mono-arthritic-multi-flare-model-of-streptococcal-cell-wall-induced-arthritis-further-characterization-in-a-r/