Targeting synovitis by immunomodulation as a novel therapeutic approach for hemophilic arthropathy

In severe hemophilia, recurrent hemarthroses lead to hemophilic arthropathy (HArt), characterized by chronic synovitis and cartilage destruction, reminiscent of rheumatoid arthritis. Unlike inflammatory synovitis, HArt lacks disease-modifying, joint-directed, targeted therapies.

To assess whether methotrexate (MTX), a reference treatment for inflammatory synovitis, can reduce joint damage when combined with extended half-life factor IX (EHL-FIX) prophylaxis in a murine model of hemophilia B.

Hemophilia B mice underwent 3 biweekly knee joint punctures to induce recurrent hemarthroses. In part 1, mice received either EHL-FIX prophylaxis alone (100 IU/kg intravenously every 3 days) or EHL-FIX combined with MTX (20 mg/kg subcutaneously once weekly) for 6 weeks as prophylaxis in an attempt to prevent HArt. In part 2, MTX was delayed until after 3 joint punctures. Joint outcomes were assessed using histology and magnetic resonance imaging scans.

Knee diameter measurements and magnetic resonance imaging scans confirmed successful induction of joint bleeding and synovitis in all injured mice in both parts. Prophylactic MTX combined with EHL-FIX reduced the severity of the synovitis, significantly reduced the vascular density in the synovial pannus, and decreased the degree of cartilage damage compared with EHL-FIX alone. Following targeted treatment of chronic synovitis, combined FIX + MTX therapy resulted in significantly reduced synovial hyperplasia, vascularity, and macrophage infiltration. No differences in cartilage erosion and proteoglycan loss were observed.

MTX combined with FIX prophylaxis limits cartilage damage and pathologic synovial angiogenesis in experimental HArt, supporting its evaluation as a potential disease-modifying adjunct therapy.