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

Abstract

Background The major morbidity of 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. Objectives 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. Methods Three recurrent hemarthroses were induced in the knee joint capsule of factor VIII 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 four weekly injections; FVIII replacement with non-specific control antibody (rat IgG); 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. Results 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 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. Conclusions Short-course specific inhibition of inflammatory cytokines as an adjunct to replacement hemostasis may be an approach to minimize hemophilic joint degeneration.

Joint bleeding in factor VIII deficient mice causes an acute loss of trabecular bone and calcification of joint soft tissues which is prevented with aggressive factor replacement

“…Uncontrolled bleeding in this experimental model of hemarthrosis is not only associated with acute intra-articular inflammation [28–30] and loss of bone density in the adjacent tibia, but is additionally associated in our study with rapid calcification of the joint soft tissues. Acute mineralization of the joint following joint bleeding and associated inflammation could have long term consequences.…”

IL-1β, in contrast to TNFα, is pivotal in blood-induced cartilage damage and is a potential target for therapy

“…A protective effect of blocking IL-6 on cartilage damage and synovitis upon joint bleeding in a hemophilia mouse model has been shown when administered in combination with clotting factor replacement. 46 The main limitations of this study are related to the use of an in vitro model. Besides the lack of involvement of synovial tissue as mentioned previously, also the replenishment of blood cells in an ongoing bleed is not included in this system.…”

Inflammation is key to hemophilic arthropathy

“…4 It was demonstrated that these damaging effects, which were probably mediated by IL-1b and tumor necrosis factor (TNF) a, were enhanced by IL-6 but protected by IL-10, IL-4, and anti-IL-6. 5,6 These experimental data were backed by clinical observations in patients with severe hemophilia that even among those who bled frequently into their joints, not all sustained cartilage injury whereas others had damaged cartilage with very few bleeds. This suggested that additional mediators were involved in the response to hemarthrosis.…”