PEG sTNF-RI and/or IL-1 RA
Recombinant Osteoprotegerin (OPG)
PEG-hirudin

OP0016 Osteoclast Numbers in Joints of Rats with Adjuvant Arthritis are Decreased by Treatment with IL-1RA and/or PEG STNF-R1
U Feige, YL Hu, S Morony, G Campagnuolo, D Duryea, B Bolon

In this study, inflammation, erosions, and osteoclast numbers were assessed in male Lewis rats with adjuvant arthritis (AdA) after treatment with IL-1ra and/or PEG sTNF-R1. The methods were similar to those used in abstract OP0061 above in that treatment was initiated on Day 9 following AdA induction, rats were necropsied on Day 16, and n=6/group. Treatment consisted of IL-1ra (0.2, 1.0, or 5.0 mg/kg/hr s.c. infusion) or PEG sTNF-R1 (0.25, 1.0, or 4.0 mg/kg/day s.c. bolus) alone and in all possible combinations.

Treatment with high doses of IL-1ra and PEG sTNF-R1, both alone and in combination, resulted in a reduction in inflammation, erosions, and osteoclast numbers, and thereby protecting the structural integrity of the arthritic joints.

Editorial Comment: IL-1ra and other TNF inhibitors (etanercept and infliximab) have been shown in human RA studies to be disease modifying, decreasing x-ray progression of erosions and joint space narrowing. Although duplication in an animal model is reassuring, from a RA treatment perspective, this study adds little to our current knowledge.

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OP0061 Recombinant Osteoprotegerin (OPG) Regulates Bone Erosions and Osteoclast Numbers in a Schedule-Dependent Manner in Joints of Male Lewis Rats with Adjuvant Arthritis
U Feige, G Campagnuolo, B Bolon

In a follow up study (highlights from EULAR 2000), Feige et al assessed whether an abbreviated schedule of treatment with recombinant human Osteoprotegerin (OPG) could reduce bone destruction in a rat model of adjuvant arthritis (AdA).

Methods: AdA was induced in 24 male Lewis rats that then developed clinical arthritis by Day 9. Rats were divided into four treatment groups (n=6/group) and received daily s.c. bolus of rhOPG by one of the following dosing schedules: 1) no rhOPG; 2) days 9-15; 3) days 9-11 (early intervention); 4) days 13-15 (delayed intervention). All rats were necropsied on day 16 and bone mineral density (BMD), bone erosion, inflammation, and osteoclast numbers were assessed.

Results: AdA control rats (Group 1) had a decrease in BMD, and an increase in inflammation scores (4.0 ± 0), erosions (4.5 ± 0.5), and osteoclast production (4.0 ± 0). OPG control rats had no change in BMD, increased inflammation (3.7 ± 0.5) and a reduction in erosions (1.2 ± 0.4) and osteoclast production (0.8 ± 0.8) in comparison to Group 1. Rats that received early intervention treatment with rhOPG had similar BMD and inflammation scores when compared to rats in Group 2, as well as the no significant differences in erosion scores and osteoclast production, 1.2 ± 0.4 and 1.7 ± 0.5, respectively. When comparing the outcomes in group 4 to those in Groups 2 and 3, rats receiving delayed intervention had similar effectiveness on BMD, inflammation and osteoclast production (2.0 ± 0.3), but was less effective in preventing erosions (2.5 ± 1.4).

These data indicate that, in order to maintain bone integrity, early intervention with rhOPG is needed to achieve the greatest clinical benefit.

Editorial Comment: OPG is member of the TNF receptor superfamily that inhibits osteoclast differentiation, preventing osteoporosis and bony erosions in animal models of inflammatory arthritis. It holds promise as a future agent to prevent structural joint damage in RA. This study in adjuvant induced arthritis in rats demonstrates greater effect when this agent is used early. This is analogous to studies in humans that demonstrate greater efficacy of DMARD agents when used early in the course of RA. Although difficult to draw parallels between animal models and human disease, this would support the approach of early DMARD therapy in RA.

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THU0081 Amelioration of Collagen Induced Arthritis by Thrombin Inhibition
N Busso, I Marty, V Peclat, G Kirdaite, R Salvi

Because fibrin has been observed in arthritic joints, the aim of this study was to assess the effect of a thrombin inhibitor, PEG-hirudin in the pathogenesis of collagen induced arthritis (CIA) in a murine model. Treatment with PEG-hirudin (1 or 0.1 mg/kg per day, s.c.) was given either as a preventative treatment (beginning day 20) or as a curative treatment (beginning at onset of clinical symptoms).

Preventative treatment with PEG-hirudin significantly reduced the incidence and severity of CIA and histologically showed a significant diminution of synovial hyperplasia in a dose-dependent manner when compared to un-treated mice. Additionally, IL-1band IL-12p35 mRNAs were significantly down-regulated in the treated mice. Immunohistochemistry revealed a significant reduction in intra-articular fibrin in the treated mice when compared to the control mice. This reduction was positively correlated with clinical and histological findings. Curative treatment with PEG-hirudin also had a demonstrable effect.

These data suggest that thrombin inhibition may have a therapeutic benefit in treating arthritis.

Editorial Comment: Coagulation pathways are activated in the rheumatoid joint with marked deposition of fibrin and thrombin. Thrombin plays a role in the activation of the kinin pathway and inhibition of fibrinolysis. This study demonstrates the beneficial effect of thrombin inhibition in an animal model of inflammatory arthritis and raises optimism for treatment of human disease.

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