Iron and inflammation: a joint problem: in blood-induced arthropathy

Musculoskeletal bleeding is the hallmark of hemophilia and cannot be fully prevented by prophylactic clotting factor replacement. Recurrent joint bleeding leads to disabling condition called hemophilic arthropathy. Although our understanding of the pathophysiology of hemophilic arthropathy has increased substantially over the past decades, this has not yet resulted in targeted therapies or patient tailored treatment. This thesis aimed at unravelling the pathophysiology further and determining the key factors in inducing blood-induced joint damage might lead to new targets for joint saving therapy.

A central role for iron in the pathophysiology of hemophilic arthropathy is demonstrated previously and in hereditary hemochromatosis joint destruction is caused by iron overload. In a literature review both disorders were compared on their clinical and histological characteristics. We showed that the irreversible joint damage in hemophilia results from the devastating combination of iron and inflammation. The harmful effects of iron to all components of the joint are aggravated in the presence of a pro-inflammatory signal.

Clinically, clear variability is observed in the severity of joint damage resulting from a similar number of bleeds. We hypothesized that genetic polymorphisms in iron control, HFE mutations and HMOX1 polymorphisms, increase iron exposition to the joint and therewith aggravates joint damage after a bleed. However, results from a large cohort study did not support this hypothesis.

To improve detection of early joint damage, we investigated the change in biochemical markers upon a joint bleed. We concluded that biochemical markers are sensitive to changes in joint tissue turnover induced by a single bleed, and as such might be useful in monitoring the impact of a joint bleed and in evaluation of treatment of such bleeds.

The last part of this thesis focused on potential new treatment modalities for blood-induced joint damage. We demonstrated that in vitro the degenerative process of blood-induced cartilage damage is hierarchically dominated by the pro-inflammatory effect of interleukin (IL)-1β, not TNFa. A recombinant human IL-1β monoclonal antibody or IL-1 receptor antagonist protected cartilage from blood-induced damage in a dose- and time-dependent manner. Blocking IL-1 seems a potential target for therapy.

Another approach to limit inflammation is the use of the anti-inflammatory cytokines IL-4 and IL-10. To overcome their limited bioavailability due to a low molecular weight, a fusion protein was constructed. We showed that this IL4-10 fusion protein is able to prevent blood-induced cartilage damage in vitro and in vivo.

For patients with advanced joint damage, we demonstrated in a proof of concept open prospective study that joint distraction seems a promising technique to alleviate pain, improve joint function, and induce structural tissue changes. This study is still ongoing, additional data and a longer follow-up are needed. For young patients with severe hemophilic ankle arthropathy not benefitting from conservative therapy joint distraction may be a promising treatment postponing more rigorous surgery like ankle arthrodesis.

In conclusion, this thesis further increased our understanding of the pathophysiology of blood-induced arthropathy and laid a foundation for new treatment strategies to prevent or treat hemophilic arthropathy.