Prevention of Posttraumatic Arthritis Through Interleukin-1 and Tumor Necrosis Factor-alpha Inhibition

Despite surgical and mechanical stabilization of an acutely injured joint through ligament reconstruction, meniscus repair, or labral repair, the risk of posttraumatic arthritis remains high. Joint injury triggers three phases of pathogenic events: the early (acute) phase involves joint swelling, hemarthrosis, expression of inflammatory cytokines (especially interleukin-1 [IL-1] and tumor necrosis factor-alpha [TNF-alpha]), and biomarkers of cartilage catabolism; an intermediate phase is characterized by reduction of joint inflammation, ongoing joint catabolism, but no evidence yet for typical features of radiographic osteoarthritis (OA); and a late phase characterized by radiographic OA. We hypothesize that the early phase of acute knee injury represents a window of opportunity for providing biologic treatment to promote healing and to slow or prevent a subsequent cascade of destructive joint processes leading to OA. We propose a phase II, randomized, placebo-controlled, double-blinded, clinical trial to treat acute knee injuries with intraarticular injection of an IL-1 inhibitor. Patient-centered outcomes will include pain reduction and improvement of knee function. MR imaging and measurement of biochemical markers will be monitored during the subsequent 2 years to determine if the structural response to injury can be reversed. If this model is validated, modulation of the molecular pathways responsible for articular cartilage breakdown will augment current reconstructive procedures in the treatment of acute joint injuries and prevent the development of injury-related arthritis.