title: Etanercept ameliorates inflammation and pain in a novel mono-arthritic multi-flare model of streptococcal cell wall induced arthritis.
abstract: 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.
authors.forename: Kalyan
authors.initials: K
authors.lastname: Chakravarthy
authors.forename: Robert
authors.initials: R
authors.lastname: Faltus
authors.forename: Gain
authors.initials: G
authors.lastname: Robinson
authors.forename: Raquel
authors.initials: R
authors.lastname: Sevilla
authors.forename: John
authors.initials: J
authors.lastname: Shin
authors.forename: Mark
authors.initials: M
authors.lastname: Zielstorff
authors.forename: Alan
authors.initials: A
authors.lastname: Byford
authors.forename: Erica
authors.initials: E
authors.lastname: Leccese
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Caniga
authors.forename: SuChun
authors.initials: S
authors.lastname: Hseih
authors.forename: Shuli
authors.initials: S
authors.lastname: Zhang
authors.forename: Chi-Sung
authors.initials: CS
authors.lastname: Chiu
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang-Hoover
authors.forename: Lily Y
authors.initials: LY
authors.lastname: Moy
authors.forename: Robbie L
authors.initials: RL
authors.lastname: McLeod
authors.forename: Dana
authors.initials: D
authors.lastname: Stoffregen
authors.forename: Weisheng
authors.initials: W
authors.lastname: Zhang
authors.forename: Anwar
authors.initials: A
authors.lastname: Murtaza
authors.affiliation: Discovery Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. milenko.cicmil@merck.com.
authors.forename: Milenko
authors.initials: M
authors.lastname: Cicmil
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D002473:Cell Wall; D000068800:Etanercept; D005260:Female; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D013291:Streptococcus
chemical_list: D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D000068800:Etanercept