A Translational Study of TNF-Alpha Antagonists as an Adjunctive Therapy for Preventing Hemophilic Arthropathy

Repeated intra-articular hemorrhages lead to hemophilic arthropathy in severe hemophilia. Inflammation and pro-inflammatory cytokines (e.g., tumor necrosis factor alpha (TNF&alpha
)) might be involved in this pathogenesis. We hypothesized that anti-TNF&alpha
may provide adjuvant protection for hemophilic arthropathy management. We measured TNF&alpha
in synovial lavage from hemophilia mice subjected to hemarthrosis induction and synovial fluid from patients with hemophilic arthropathy (n = 5). In hemophilia mice, recurrent hemarthroses were induced, anti-TNF&alpha
was initiated either from day (D)7 after one hemarthrosis episode or D21 after three hemarthroses episodes (n &ge
7/treatment group). In patients with hemophilic arthropathy (16 patients with 17 affected joints), a single dose of anti-TNF&alpha
was administered intra-articularly. Efficacy, characterized by synovial membrane thickness and vascularity, was determined. Elevated TNF&alpha
in synovial lavage was found in the hemophilia mice and patients with hemophilic arthropathy. Hemophilia mice subjected to three hemarthroses developed severe synovitis (Synovitis score of 6.0 &plusmn
1.6). Factor IX (FIX) replacement alone partially improved the pathological changes (Synovitis score of 4.2 &plusmn
0.8). However, anti-TNF&alpha
treatment initiated at D7, not D21, significantly provided protection (Synovitis score of 1.8 &plusmn
0.9 vs. 3.9 &plusmn
0.3). In patients with hemophilic arthropathy, intra-articular anti-TNF&alpha
significantly decreased synovial thickness and vascularity during the observed period from D7 to D30. Collectively, this preliminary study seems to indicate that TNF&alpha
may be associated with the pathogenicity of hemophilic arthropathy and anti-TNF&alpha
could provide adjuvant protection against hemophilic arthropathy. Further studies are required to confirm the preliminary results shown in this study.