Etanercept ameliorates inflammation and pain in a novel mono-arthritic multi-flare model of streptococcal cell wall induced arthritis

BMC Musculoskeletal Disorders

Milenko Cicmil²  Anwar Murtaza²  Weisheng Zhang¹  Dana Stoffregen⁵  Robbie L McLeod²  Lily Y Moy²  Jie Zhang-Hoover²  Chi-Sung Chiu²  Shuli Zhang³  SuChun Hseih³  Michael J Caniga²  Erica Leccese²  Alan Byford²  Mark Zielstorff²  John Shin⁴  Raquel Sevilla¹  Gain Robinson¹  Robert Faltus²  Kalyan Chakravarthy² 

[1] Imaging, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA;Discovery Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA;Biologics Operations, Merck Research Laboratories, 901 S. California Avenue Palo Alto, CA 94304, USA;Immunology Discovery, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA;Safety Assessment and Laboratory Animal Resources, Merck Research Laboratories, 770 Sumneytowne Pike, West Point, PA 19486, USA

关键词: Immunogenicity;    Cytokines;    Etanercept;    Anti-TNF;    TNF;    SCW;    von-Frey;    Pain;    Inflammation;    Animal models;    Rheumatoid arthritis;   

Others  :  1091166
DOI  :  10.1186/1471-2474-15-409

 received in 2014-07-30, accepted in 2014-11-06,  发布年份 2014

【 摘 要 】

Background

The impact of anti-TNF, corticosteroid and analgesic therapy on inflammation and pain was evaluated in a novel mono-arthritic multi-flare rat Streptococcal Cell Wall (SCW) model using Etanercept, Dexamethasone and Buprenorphine.

Methods

Multiple flares of arthritis were induced with an intra-articular injection of SCW in the hind ankle on day 1, followed by intravenous challenges on days 21 and 42. Inflammation and pain were monitored in the hind paws. Cytokine profiling, cell phenotyping, bioluminescence imaging and histopathological evaluation were also performed.

Results

Local injection of SCW caused a rapid onset of inflammation and pain in the injected ankle which resolved within 4 days (Flare 1). Intravenous injection 20 days after sensitization resulted in an increase in ankle diameter and pain, which partially resolved in 8 days (Flare 2). The subsequent intra-venous injection in the same animals 14 days after resulted in a more chronic disease with inflammation and pain persisting over a period of 10 days (Flare 3). In Flare 2, therapeutic administration of Dexamethasone inhibited paw swelling (95%; P<0.001) and pain (55%; P<0.05). Therapeutic administration of Buprenorphine inhibited pain (80%; P<0.001) without affecting paw swelling (0%). Prophylactic administration of Etanercept in Flare 2 inhibited paw swelling (≥60%; P<0.001) and pain by ≥30%. Expression of IL-1β, IL-6, MCP-1 and CINC was reduced by >50% (P<0.001). Treatment with Etanercept in Flare 3 inhibited paw swelling by 60% (P<0.001) and pain by 25%. Prior treatment with Etanercept in Flare 2 followed by re-administration in Flare 3 led to a complete loss in the efficacy of Etanercept. Systemic exposure of Etanercept corroborated with lack of efficacy. Dexamethasone inhibited inflammation and pain in both Flares 2 and 3 (P<0.001).

Conclusions

We established a novel multi-flare SCW arthritis model enabling drug intervention in different stages of disease. We show for the first time the evaluation of inflammation and pain simultaneously in this model. Etanercept and Dexamethasone inhibited inflammation, pain and proinflammatory cytokines in this model. Taken together, this model facilitates the assessment of anti-rheumatic agents targeting inflammation and pain in the multiple flare paradigm and offers a powerful tool for drug discovery.

【 授权许可】

   
2014 Chakravarthy et al.; licensee BioMed Central Ltd.

【 图 表 】

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