Background Treatment of patients with hemophilia has advanced over the past decades, but it is unknown whether this has resulted in a normal life expectancy in the Netherlands. Objective This observational cohort study aimed to assess all‐cause and cause‐specific mortality in patients with hemophilia in the Netherlands between 2001‐2018 and to compare mortality and life‐expectancy with previous survival assessments from 1973 onwards. Patients/methods All 1066 patients with hemophilia who participated in a nationwide survey in 2001 were followed until July 2018. Results Information on 1031 individuals (97%) was available, of whom 142 (14%) deceased during follow‐up. Compared with the general Dutch male population, mortality of patients with hemophilia was still increased (standardized mortality ratio: 1.4, 95% confidence interval: 1.2‐1.7). Intracranial bleeding and malignancies were the most common causes of death. Estimated median life expectancy of patients with hemophilia was 77 years, six years lower than the median life expectancy of the general Dutch male population (83 years). Over the past 45 years, death rates of patients with hemophilia have consistently decreased, approaching the survival experience of the general population. Over the past decades, mortality due to human immunodeficiency virus and hepatitis C virus infections has decreased, death due to intracranial hemorrhages has increased and death due to ischemic heart disease has remained consistently low over time. Conclusions Survival in patients with hemophilia in the Netherlands has improved over time but is still lower than that of the general population.

Joint bleeding after (sports) trauma, after major joint surgery, or as seen in hemophilia in general leads to arthropathy. Joint degeneration is considered to result from the direct effects of blood components on cartilage and indirectly from synovial inflammation. Blood-provided proinflammatory cytokines trigger chondrocytes and induce the production of cartilage-degrading proteases. In the presence of erythrocyte-derived iron, cytokines stimulate radical formation in the vicinity of chondrocytes inducing apoptosis. To unravel the role of interleukin (IL) 1β and tumor necrosis factor (TNF) α in the pathogenesis of this blood-induced cartilage damage, the effect of antagonizing these cytokines was examined in human in vitro cultures. Addition of recombinant human IL-1β monoclonal antibody or IL-1 receptor antagonist resulted in a dose- and time-dependent protection of cartilage from blood-induced damage. In higher concentrations, almost complete normalization of cartilage matrix proteoglycan turnover was achieved. This was accompanied by a reduction in IL-1β and IL-6 production in whole blood cultures, whereas TNFα production remained unaffected. Interestingly, addition of a TNFα monoclonal antibody, although demonstrated to inhibit the direct (transient) effects of TNFα on cartilage, exhibited no effect on blood-induced (prolonged) cartilage damage. It is demonstrated that IL-1β is crucial in the development of blood-induced joint damage, whereas TNFα is not. This hierarchical position of IL-1β in blood-induced joint damage warrants studies on targeting IL-1β to potentially prevent joint degeneration after a joint bleed. Publisher9s Note: There is an Inside Blood Commentary on this article in this issue. Key Points Blood-induced joint damage is fully prevented by blocking IL-1β with a monoclonal antibody or receptor antagonist, not by TNFα blockade. IL-1β blockade prevents release of IL-6 but not TNFα from monocyte/macrophages, whereas TNFα blockade does not affect IL-1β or IL-6 release.

Joint bleeds cause major morbidity in haemophilia patients. The synovial tissue is responsible for removal of blood remnants from the joint cavity. But blood components, especially iron, lead to a series of changes in the synovial tissue: inflammation, proliferation and neovascularization. These changes make the synovium vulnerable to subsequent bleeding and as such a vicious cycle of bleeding‐synovitis‐bleeding may develop leading to chronic synovitis. The initial step in the treatment is adequate clotting factor supplementation and immediate physiotherapeutic involvement. If these measures fail, synovectomy may be indicated. Non‐surgical options are chemical and radioactive synovectomy. This is a relatively non‐invasive procedure to do synovectomy, leading to a reduction in pain and joint bleeds. Radioactive synovectomy seems more effective than chemical synovectomy in larger joints. Surgical options are open and arthroscopic synovectomy. Open synovectomy has been found to decrease the incidence of breakthrough bleeds but at the cost of loss of joint motion. Use of arthroscopic synovectomy has been advocated to reduce bleeding episodes with less morbidity to extra‐articular tissue and preservation of joint motion. Use of a continuous passive motion (CPM) machine and early mobilization can decrease the postoperative stiffness and promote early recovery. This review addresses the current understanding of synovitis and its treatment options with specific emphasis on chemical and radioactive synovectomy and surgical options.