Session Title: Rheumatoid Arthritis: Animal Models
Session Type: Abstract Submissions (ACR)
Spleen tyrosine kinase (SYK) is expressed in hematopoietic cells and is a major downstream regulator of signaling through Fcγ and immunoglobulin receptors as well as non-immunoglobulin receptors associated with adaptor proteins DAP12 and FcRg in osteoclasts. Inhibition of SYK has been shown to reduce the severity of collagen-induced arthritis (CIA). This provided the rationale for the development of the SYK inhibitor, fostamatinib (R788), as a potential treatment for rheumatoid arthritis (RA). In the present rat CIA study, we characterize the activity of fostamatinib alone or with co-administered methotrexate (MTX), on paw inflammation, bone erosion, serum biomarkers of bone destruction, and synovial proinflammatory cytokine expression.
Syngeneic LOU rats were immunized on day 0 with native type II collagen. At the onset of arthritis (day 10), a total of 59 rats were treated with either a vehicle control, fostamatinib at one of two dose levels (15 or 30 mg/kg q.d. by p.o. gavage), MTX alone (0.4 mg/kg s.c., q.w. for 3 weeks), or fostamatinib (15 or 30 mg/kg) in combination with s.c. MTX q.w.. Hind limbs were scored daily for clinical arthritis severity using a standardized method based on the degree of joint inflammation. Serum and synovial tissue were harvested at sacrifice, and biomarker expression was assessed by ELISA. Blinded high resolution digital radiographs and micro3D-CT of hind limbs were obtained at the end of the study (day 28).
Results: Arthritis severity was significantly reduced within 7 days after initiation of fostamatinib therapy and continued to improve throughout the study. By day 28, the mean clinical score in the vehicle group was 7.4 compared with 4.1 and 2.4 in the fostamatinib groups (15 and 30 mg/kg, p< 0.0003 and 0.0001, respectively). Co-administration of MTX with fostamatinib further reduced the clinical scores to 3.6 and 2.1 (15 and 30 mg/kg, respectively, p< 0.0001 vs vehicle, p< 0.0001 vs MTX alone, p> 0.05 vs fostamatinib alone). Radiographs (day 28) demonstrated a significant reduction in joint damage: 5.1 (vehicle) vs. 0.6, 0.0, 0.5, and 0.08 (15 mg/kg and 30 mg/kg fostamatinib alone, 15 mg/kg and 30 mg/kg fostamatinib with MTX, respectively, p< 0.0001 for all groups vs vehicle). Treatment with MTX alone significantly reduced joint damage, although the response was not as robust as that seen with fostamatinib (mean radiographic score = 2.8, p< 0.02 vs vehicle). These findings were confirmed with micro3D-CT analysis. Serum RANKL and COMP were reduced in fostamatinib-treated rats, and combination treatment did not further reduce the level of bone biomarkers. Synovial IL-18, IL-6, and IL-1b were reduced (30 mg/kg fostamatinib with or without MTX vs vehicle). Fostamatinib and MTX treatment were well tolerated and had no overt adverse effects.
Fostamatinib significantly reduced the severity of established rat CIA, had modest additional improvement with co-administered MTX, and was superior to MTX alone. These results indicate that fostamatinib may have potential therapeutic benefits for both the inflammatory synovitis and bone erosions of CIA. Fostamatinib is currently in Phase III trials for RA.
B. Y. Chang,
E. B. Grossbard,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-syk-inhibitor-fostamatinib-administered-alone-or-in-combination-with-methotrexate-in-rat-collagen-induced-arthritis-reduces-bone-erosions-biomarkers-of-cartilagebone-destruction-and-syn/