IL-6 receptor antagonist as adjunctive therapy with clotting factor replacement to protect against bleeding-induced arthropathy in hemophilia

Abstract

The most common morbidity that results from hemophilia is bleeding-induced hemophilic arthropathy (HA), which once established may not be interrupted completely even by prophylactic clotting factor replacement. Specific therapies to oppose inflammatory cytokines, including Interleukin 6 (IL-6) receptor antagonists, have become important in the management of inflammatory arthritides. We investigated combining therapy using MR16-1, a rat IgG antibody directed against mouse IL-6 receptor (anti-IL-6R), with factor VIII (FVIII) replacement to protect against bleeding-induced arthropathy in hemophilia A mice. Three recurrent hemarthroses were induced in the knee joint capsule of FVIII knockout mice. Treatment at the time of each hemorrhage included either: no treatment; FVIII replacement given at the time of hemorrhage; FVIII replacement at hemorrhage plus anti-IL-6R as 4-weekly injections; FVIII replacement with non-specific control antibody (rat IgG); and anti-IL-6R alone without FVIII replacement. Six weeks following the first hemarthosis, joints were harvested and histopathology was scored for synovitis, for cartilage integrity and for macrophage infiltration. Animals that received anti-IL-6R as an adjunct to FVIII replacement demonstrated the best survival and the least acute joint swelling and pathology on histologic examination of the synovium and cartilage (P<0.05 for each parameter). All histopathologic parameters in the mice receiving FVIII+anti-IL-6R were limited and were comparable to findings in injured hemostatically normal mice. The major benefits of adjunctive anti-IL-6R were decreasing synovial hyperplasia, hemosiderin deposition and macrophage infiltration. Short-course specific inhibition of inflammatory cytokines as an adjunct to replacement hemostasis may be an approach to minimize hemophilic joint degeneration.