Background To assess the efficacy of novel anti-rheumatic agents on inflammation and pain we developed a novel mono-arthritic multi-flare rat Streptococcal Cell Wall (SCW) model which captures the remitting and chronic phases of arthritis similar to Rheumatoid Arthritis (RA). We have evaluated the impact of anti-TNF and steroid therapy using Etanercept and Dexamethasone to further understand the translatability of this model to human disease.
Objectives To assess the effects of Etanercept and Dexamethasone in multiple flares of a novel model of SCW induced arthritis in rats.
Methods SCW arthritis was induced in 6-8 week old female Lewis rats with an intra-articular injection in the hind ankle joint on day 1 followed by two intravenous challenges on days 21 and 42 of SCW extract PG-PS 100p. The contralateral paw was used as a negative control. Local inflammation and pain were monitored through the course of the study in the hind paws by measuring paw swelling and withdrawal threshold respectively. In addition, cytokine profiling, cell phenotyping, bioluminescence imaging and histopathological evaluation were also performed in the local joint. Then we assessed the efficacy of Etanercept and Dexamethasone in this model.
Results Local injection of SCW caused a rapid onset of inflammation and pain in the injected ankle joint which resolved in 4 days (Flare 1). Systemic intravenous injection 20 days after sensitization resulted in a profound increase in ankle diameter and pain, which resolved in 8 days (Flare 2). A subsequent systemic challenge in the same animals on day 42 resulted in a chronic disease phenotype with inflammation and pain that continued to persist over the period of 10 days (Flare 3). Prophylactic administration of Etanercept in Flare 2 significantly inhibited paw swelling by 60% (p<0.001) and partially inhibited pain by 30% respectively. Production of proinflammatory cytokines IL-1β, IL-6, MCP-1 and CINC was reduced by >70% (p<0.001). Histopathological analysis corroborated with our efficacy data. Furthermore, prophylactic treatment with Etanercept in Flare 3 inhibited paw swelling by 60% (p<0.001) and partially inhibited pain by 25%. 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 complete loss in efficacy, which could be due to potential immunogenicity. Serum exposure levels of Etanercept corroborated well with the lack of efficacy. Positive control Dexamethasone significantly inhibited inflammation and pain in both Flares 2 and 3 (p<0.001).
Conclusions This is the first report to demonstrate a novel multi-flare extended paradigm of the SCW model. This model exhibits certain aspects of the human disease such as reactivating remission and exacerbation flares enabling investigation of RA pathogenesis and drug intervention in different stages of disease progression. We also report that the model can be used to evaluate clinically relevant parameters of inflammation and pain simultaneously. Our data shows that Etanercept and Dexamethasone inhibit inflammation, pain and relevant cytokines in this model. Taken together our novel model can facilitate innovative assessment of anti-rheumatic agents in multiple flares and offers a powerful tool for drug discovery.
Disclosure of Interest None declared
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