On-demand treatment with the iron chelator deferasirox is ineffective in preventing blood-induced joint damage in haemophilic mice.

INTRODUCTION: Early intervention in the devastating process of haemophilic arthropathy (HA) is highly desirable, but no disease-modifying therapy is currently available. Considering the pivotal role of iron in the development of HA, iron chelation is considered a promising therapeutic approach. A previous study in haemophilic mice demonstrated that treatment with the iron chelator deferasirox (DFX) 8 weeks before joint bleed induction, attenuated cartilage damage upon blood exposure. However, in haemophilia patients this approach is not opportune given the unpredictable occurrence of hemarthroses. AIM: To evaluate the effectiveness of on-demand DFX treatment, initiated immediately after joint bleed induction. METHODS: A joint bleed was induced in 66 factor VIII-deficient mice by infra-patellar needle puncture. Mice were randomly assigned to treatment with either placebo (drinking water) or DFX (dissolved in drinking water) throughout the study. Five weeks after joint bleed induction, inflammation and cartilage damage were assessed histologically. Joints of ten bleed naive haemophilic mice served as controls. RESULTS: A joint bleed resulted in significant inflammation and cartilage damage in the blood-exposed joint compared with those of control animals, in both the placebo and DFX group (all p = <.05). No differences in tibiofemoral or patellar inflammation (p = .305 and p = .787, respectively) nor cartilage damage (p = .265 and p = .802, respectively) were found between the blood-exposed joints of both treatment groups. CONCLUSION: On-demand treatment with DFX does not prevent joint damage following blood exposure in haemophilic mice. DFX seems unable to reach the joint in time to exert its effect before the irreversible harmful process is initiated.

Proteoglycan synthesis rate as a novel method to measure blood-induced cartilage degeneration in non-haemophilic and haemophilic rats.

INTRODUCTION: Haemophilic animal models are used to study blood-induced cartilage damage, but quantitative and sensitive outcome measures are needed. AIM: To develop a novel quantitative method for detecting early cartilage degeneration in a haemophilic rat model of blood-induced joint damage. METHODS: The 35 Sulphate incorporation (35 SO4 2- assay) was applied to tibial and patellar cartilage of wild-type rats to quantify baseline proteoglycan synthesis and to evaluate the effect of 4-day blood exposure in vitro. Next, haemarthrosis was induced in 39 FVIII-deficient rats and characterized by changes in knee joint diameter and development of bone pathology (using micro-CT). Four- and 16-day posthaemarthrosis proteoglycan synthesis rate (PSR) was assessed using the 35 SO4 2- assay, with the contralateral knee as control. RESULTS: In vitro, a decrease in PSR in tibial and patellar cartilage was demonstrated following blood exposure. In vivo, joint diameter and development of bone pathology confirmed successful induction of haemarthrosis. In the blood-exposed knee, tibial and patellar PSR was inhibited 4 and 16 days after induced haemarthrosis. Interestingly, at day 16 the proteoglycan synthesis in the contralateral knee was also inhibited to an extent correlating with that of the blood-exposed knee. CONCLUSION: For the first time, early changes in cartilage matrix synthesis upon blood exposure were quantified with the 35 SO4 2- assay in a haemophilic rat model, establishing this assay as a novel method to study blood-induced cartilage damage.

Pathophysiology of hemophilic arthropathy and potential targets for therapy.

Hemophilia is a congenital clotting factor deficiency characterized by spontaneous and trauma-related bleeding. Spontaneous bleeding shows a predilection for joints, and repeated hemarthroses lead to a disabling condition called hemophilic arthropathy. Treatment of this condition consists of preventing joint bleeding on the one hand and orthopedic surgery as a last resort on the other. Up till now, there is no disease modifying therapy available to fill the gap between these extremes. This review provides an overview of the pathogenesis of hemophilic arthropathy in order to identify potential targets for therapy. Joint bleeding induces synovial inflammation, cartilage degeneration and bone damage. These processes interact with each other and result in a vicious circle. Hemarthrosis promotes synovial hypertrophy and neoangiogenesis, increasing the susceptibility to mechanical damage and subsequent bleeding. The inflamed synovium affects the cartilage, while cartilage is also directly affected by blood via the release of cytokines and metalloproteinases, and via hydroxyl radical formation inducing chondrocyte apoptosis. Apart from the inflammatory pathways, iron plays a pivotal role in this process, as does the fibrinolytic system. Considering its pathogenesis, potential targets for disease modifying therapy in hemophilic arthropathy are iron, inflammation, vascular remodeling, hyperfibrinolysis, bone remodeling and cartilage regeneration. So far, iron chelators, anti-inflammatory therapy, anti-fibrinolytics and bone remodeling agents have demonstrated beneficial effects, predominantly in a preclinical setting. There is still a long way to go before these interventions will translate into clinical practice. The most important challenges are: establishing a universal outcome measure to predict efficacy in humans, and determination of the optimal route and timing to administer disease modifying therapy.

Pharmacokinetics of oral vs. intravenous dexamethasone in patients hospitalized with community-acquired pneumonia.

AIM: The use of corticosteroids as adjunctive therapy might be effective in patients with community-acquired pneumonia (CAP). Oral administration of dexamethasone is a practical and safer alternative to the intravenous route. Since patients hospitalized with pneumonia might have delayed gastric emptying, this study explored systemic exposure in terms of area under the concentration-time curve (AUC) of oral dexamethasone in patients hospitalized with CAP. METHODS: In this randomized, open label study, 30 patients admitted with CAP were randomized to receive either 4 mg intravenous or 6 mg oral dexamethasone for 4 consecutive days. Serial blood samples were obtained before and after drug administration. RESULTS: Median AUC to infinity was 626 µg l(-1) h (IQR 401-1161) for the intravenous group and 774 µg l(-1) h (IQR 618-1146) for the oral group. The AUC ratio of 6 mg oral and 4 mg intravenous dexamethasone was 1.22 (95% confidence interval (CI) 0.81, 1.82), which represents a bioavailability of 81% (95% CI 54, 121) after correction for differences in dexamethasone dose. CONCLUSIONS: Bioavailability of oral dexamethasone in patients hospitalized with pneumonia is sufficient. This makes oral dexamethasone an appropriate alternative for intravenous administration in these patients.

Non-fatal cardiovascular disease, malignancies, and other co-morbidity in adult haemophilia patients.

INTRODUCTION: With increasing life expectancy, more haemophilia patients will be confronted with age-related problems. To ensure optimal care, it is important to know the occurrence of both fatal and non-fatal cardiovascular disease, malignancies and other types of co-morbidity in these patients. Our aim was to retrospectively assess the occurrence of co-morbidity and causes of death in a substantial birth-cohort of haemophilia patients. METHODS: Data on all types of co-morbidity were collected from medical records of 408 haemophilia patients (204 severe, 204 non-severe) born before 1971, and compared with the Dutch age-matched general male population. RESULTS: Ten patients had 11 myocardial infarctions, none of which were fatal. The cumulative incidence of non-fatal myocardial infarction was significantly lower in patients with severe haemophilia than in the general population (0.5% versus 4.8%), but was not decreased in patients with non-severe haemophilia (4.4%). Intracranial bleeding occurred significantly more often in haemophilia patients. The occurrence of non-virus related malignancies, and other non-virus related co-morbidities was similar in haemophilia patients and the general population. HIV infection was present in 12% of patients, and hepatitis C infection in 56%. Seventy-eight patients (19%) were deceased. Main causes of death were malignancies, AIDS, hepatitis C, and intracranial bleeding. CONCLUSIONS: Our results showed a decreased occurrence of myocardial infarction in patients with severe haemophilia, suggesting a protective effect of very low clotting factor levels on thrombotic cardiac events. No differences were found between haemophilia patients and the general population in the occurrence of any other type of non-virus related co-morbidity.