N.W. Jansen

Understanding haemophilic arthropathy: an exploration of current open issues

Haemophilic arthropathy is joint damage evolving from recurrent joint bleeds that occur in patients suffering from the clotting disorder haemophilia. Insight into the pathogenetic mechanism of this blood‐induced arthropathy yields possible treatment targets and modalities useful to reduce this invalidating co‐morbidity of haemophilia. Joint bleeding leads to initially independent adverse changes in both the synovial tissue and the articular cartilage. These subsequently influence each other: the synovial inflammatory changes enhancing cartilage damage and vice versa. Consequently, effective treatment strategies will have to affect both pathways.

Differential direct effects of cyclo-oxygenase-1/2 inhibition on proteoglycan turnover of human osteoarthritic cartilage: an in vitro study

Treatment of osteoarthritis (OA) with nonsteroidal anti-inflammatory drugs (NSAIDs) diminishes inflammation along with mediators of cartilage destruction. However, NSAIDs may exert adverse direct effects on cartilage, particularly if treatment is prolonged. We therefore compared the direct effects of indomethacin, naproxen, aceclofenac and celecoxib on matrix turnover in human OA cartilage tissue. Human clinically defined OA cartilage from five different donors was exposed for 7 days in culture to indomethacin, naproxen, aceclofenac and celecoxib – agents chosen based on their cyclo-oxygenase (COX)-2 selectivity. As a control, SC-560 (a selective COX-1 inhibitor) was used. Changes in cartilage proteoglycan turnover and prostaglandin E2 production were determined. OA cartilage exhibited characteristic proteoglycan turnover. Indomethacin further inhibited proteoglycan synthesis; no significant effect of indomethacin on proteoglycan release was found, and proteoglycan content tended to decrease. Naproxen treatment was not associated with changes in any parameter. In contrast, aceclofenac and, prominently, celecoxib had beneficial effects on OA cartilage. Both were associated with increased proteoglycan synthesis and normalized release. Importantly, both NSAIDs improved proteoglycan content. Inhibition of prostaglandin E2 production indirectly showed that all NSAIDs inhibited COX, with the more COX-2 specific agents having more pronounced effects. Selective COX-1 inhibition resulted in adverse effects on all parameters, and prostaglandin E2 production was only mildly inhibited. NSAIDs with low COX-2/COX-1 selectivity exhibit adverse direct effects on OA cartilage, whereas high COX-2/COX-1 selective NSAIDs did not show such effects and might even have cartilage reparative properties.

The combination of the biomarkers urinary C‐terminal telopeptide of type II collagen, serum cartilage oligomeric matrix protein, and serum chondroitin sulfate 846 reflects cartilage damage in hemophilic arthropathy

OBJECTIVE Hemophilic arthropathy, with characteristics of inflammatory (rheumatoid arthritis) and degenerative (osteoarthritis) joint damage, occurs at an early age, is associated with minor comorbidity, and is restricted to 3 pairs of large joints. The aim of this study was to determine whether commonly used serum and/or urinary biomarkers of cartilage and bone turnover for which assay kits are commercially available are associated with the severity of joint damage in patients with various degrees of hemophilic arthropathy and, thus, whether this disease could be useful in the identification and evaluation of such biomarkers. METHODS Blood and urine samples were collected from 36 patients with various degrees of hemophilic arthropathy. Commercially available assays for the most frequently investigated serum and urine biomarkers were performed: urinary C-terminal telopeptide of type I collagen (CTX-I), urinary CTX-II, serum CTX-I, serum CTX-II, serum cartilage oligomeric matrix protein (COMP), serum cartilage cleavage products C1,2C and C2C, and serum chondroitin sulfate 846 (CS-846). Radiographs of the ankles, knees, and elbows in all patients were evaluated for the degree of joint damage according to the Pettersson score, which is based on cartilage and periarticular bone changes and is specific for hemophilic arthropathy. RESULTS Urinary CTX-II, serum C1,2C, and serum CS-846 levels correlated with the overall Pettersson score and with the joint space narrowing component. Regression analysis showed that combined indexes of different markers increased the degree of correlation for the combination of urinary CTX-II, serum COMP, and serum CS-846. Bone-specific markers (urinary/serum CTX-I and serum C1,2C) did not correlate with specific bone-related items of the Pettersson score (osteoporosis and erosions). CONCLUSION These results support the idea that a combination of biomarkers relates significantly better to the severity of joint damage than do individual biomarkers. The combination of urinary CTX-II, serum COMP, and serum CS-846 correlated best with the degree of arthropathy. Because of its specific characteristics and restricted involvement, hemophilic arthropathy may prove useful in the screening of newly developed biomarkers of joint damage.

Haemophilic arthropathy: the importance of the earliest haemarthroses and consequences for treatment

Summary.  In a case of massive bleeding, the possibility of puncturing the joint can be considered to reduce the total load of intra‐articular blood, and thus the total load of iron which, in time, can be found in the synovium with devastating long‐term effects. Subsequent initiation of prophylaxis, still very early in life, might be more beneficial for the preservation of joints. Thus, it might be argued that the initiation of primary prophylaxis should be based on joint haemorrhage history rather than age and, according to some authors, preferably after the bleed in a single joint. The high cost of recombinant factor VIII may make widespread acceptance of prophylaxis impractical. Thus, beneficial results should be balanced with cost considerations. In this balance of treatment cost and efficacy, it must be taken into account that improperly treated haemophilia patients make great demands on healthcare systems (in terms of costs) because of their need for additional treatments such as expensive joint replacement surgery. However, where resources are limited, it can be argued that prophylaxis may be stopped in adulthood, in a certain proportion of all adult patients, with acceptable consequences for orthopaedic outcome in the long term. By doing so, limited amounts of clotting factor can be used for young patients with optimal cost effectiveness.

IL-4 alone and in combination with IL-10 protects against blood-induced cartilage damage

OBJECTIVE It has been reported that interleukin (IL)-10 limits blood-induced cartilage damage. Our aim was to study the effect of IL-4 alone and in combination with IL-10 on blood-induced cartilage damage. DESIGN Healthy human full thickness cartilage explants were cultured for 4 days in the presence of 50% v/v blood. IL-4, IL-10, or a combination of both cytokines was added during blood exposure. Cartilage matrix turnover was determined after a recovery period; additionally cytokine production, chondrocyte apoptosis, and expression of the IL-4 and IL-10 receptors were analyzed directly after exposure. RESULTS Blood-induced damage to the cartilage matrix was limited by IL-4 in a dose-dependent way (P<0.05). Also IL-10 limited this damage, although to a lesser extent (P<0.03). The effect of IL-4 plus IL-10 was more pronounced and protective than IL-10 alone (P<0.05). Production of IL-1β and tumor necrosis factor (TNF)-α was limited by both IL-4 and IL-10 (P<0.05), but more strongly by IL-4. Blood-induced apoptosis of chondrocytes was limited by IL-4 and the combination, and not by IL-10 alone. No direct beneficial effect of IL-4 or IL-10 on cartilage was found, however, the chondrocyte receptor expression of both cytokine receptors was upregulated by exposure to blood. CONCLUSIONS This study demonstrates that IL-4 alone and in combination with IL-10 prevents blood-induced cartilage damage. Expectedly, anti-inflammatory effects on monocytes in the blood fraction and protective effects on chondrocytes are both involved. IL-4 in combination with IL-10 might be used to prevent blood-induced joint damage as a result of trauma or surgery.

Interleukin-10 protects against blood-induced joint damage.

Despite prophylactic treatment, haemophilia patients suffer from spontaneous joint bleeds, which lead to severe joint damage. Also after joint trauma, an intra‐articular haemorrhage can add to joint damage over time. This study evaluated interleukin 10 (IL‐10) in the search for possible interventions to prevent or limit the damaging effects of joint bleeds. Human articular cartilage tissue explants were cultured in the presence or absence of 50% v/v blood (or its cellular components) for 4 d (the expected blood load in vivo after a joint haemorrhage), followed by a recovery period of 12 d. Pharmacological dosages of IL‐10 reached during treatment (1 or 10 ng/ml) were added. Additionally, cartilage and synovial tissue obtained from joints with end‐stage haemophilic arthropathy (HA) were cultured in the presence of IL‐10 (10 ng/ml). IL‐10 protected cartilage from the damaging effects of blood exposure, measured by its effects on proteoglycan turnover. In addition, IL‐10 beneficially influenced cartilage from patients with HA and reduced the production of the inflammatory cytokines IL‐1β and tumour necrosis factor‐α by haemophilic synovial tissue. Taken together, although effects were obtained in vitro, IL‐10 protects against blood‐induced joint damage and might be further evaluated as candidate in treatment of tissue damaging effects of joint haemorrhages.

Very rapid clearance after a joint bleed in the canine knee cannot prevent adverse effects on cartilage and synovial tissue

OBJECTIVE Joint bleeding leads to joint destruction. In vitro exposure of human and canine cartilage to blood results in long-lasting severe adverse changes in cartilage. An in vivo joint haemorrhage in the canine knee joint demonstrates similar adverse effects although significantly less outspoken. As a possible explanation for this discrepancy, we studied the clearance rate of blood from the canine knee joints. METHODS Blood was injected into the knee joint of Beagle dogs either 48 h, 24h or 15 min before termination. The amount of red blood cells (RBC) and white blood cells (WBCs) present in the joint cavity was determined. Chondrocyte activity and cartilage matrix integrity as well as cartilage destructive activity of synovial tissue were determined biochemically. Additionally, synovial tissue was analyzed by use of histochemistry. RESULTS The amount of blood was decreased to <5% within 48 h. Within this time period the cartilage was negatively affected and the synovial tissue showed cartilage destructive activity. Evaluation of the synovial tissue 15 min post-injection revealed countless numbers of intact RBC that were almost completely disappeared after 48 h without significant recruitment of macrophages. CONCLUSIONS Blood is cleared very rapidly from the canine knee joint, but already has adverse effects on both cartilage and synovial tissue within that short time span. This rapid clearance can play a role in the discrepancy between long-term in vitro and in vivo effects of blood-induced joint damage since more than 10% v/v blood present for at least 48 h is needed to induce long-term adverse effects in vitro.

Degenerated and healthy cartilage are equally vulnerable to blood-induced damage

Background: Joint bleeds have a direct adverse effect on joint cartilage, leading to joint deterioration and, ultimately, to disability. Objective: To examine the hypothesis that because degenerated cartilage has a limited repair capacity, it is more susceptible than healthy cartilage to blood-induced cartilage damage. Methods: Healthy, degenerated (preclinical osteoarthritic) and osteoarthritic (clinically defined) human cartilage was exposed to 10% vol/vol whole blood for 2 days, followed by a recovery period of 12 days in the absence of blood. The effect of exposure to blood on cartilage was determined by measuring proteoglycan synthesis rate, release and content, as well as protease (matrix metalloproteinase (MMP)) activity. Results: In general, exposure to blood led to a decrease in proteoglycan synthesis rate, an increase in the release of proteoglycans and in MMP activity, and therefore, ultimately, in a decrease of the proteoglycan content of the tissue. Impaired cartilage was as least as susceptible as healthy cartilage to this blood-induced damage. Conclusion: These results demonstrate that degenerated cartilage is not more susceptible than healthy cartilage to blood-induced damage. Even though these are just in vitro findings, it remains of great importance, also, in joints already affected, to prevent joints bleeds, and when they do occur, to treat them adequately.

Blood-Induced Joint Damage The Devastating Effects of Acute Joint Bleeds versus Micro-Bleeds

Objective: Four days of blood exposure leads to irreversible cartilage damage in vitro. In contrast, intermittent intra-articular blood injections twice a week during 4 weeks (mimicking micro-bleeds) in a canine model resulted in transient damage only. In this study, it was evaluated whether acute joint bleeds are more harmful than micro-bleeds in a canine model of knee arthropathy. Design: Seven dogs received 4 sequential daily intra-articular blood injections twice in 2 weeks (mimicking 2 acute 4-day joint bleeds). Seven other dogs received the same blood load but in a total of 8 injections intermittently over the 4-week period with at least 1 day in between (mimicking micro-bleeds over the same timespan). Contralateral knees served as controls. Ten weeks after the last injection cartilage matrix turnover and synovial inflammation were evaluated. Results: Only after the acute joint bleeds the release of newly formed and total (resident) cartilage matrix glycosaminoglycans were increased (P = 0.04 and P = 0.01, respectively). Furthermore, in animals with the acute joint bleeds cartilage glycosaminoglycan content was decreased (P = 0.01) and not in animals with micro-bleeds. Mild synovial inflammation was observed in both groups (both P < 0.0001) but was not different between groups. Conclusions: In contrast to micro-bleeds, 2 acute joint bleeds lead to prolonged cartilage damage independent of the level of synovial inflammation. This model suggests that micro-bleeds are less devastating than acute joint bleeds with respect to joint damage, which might be of relevance to treatment of joint bleeds in clinical practice.

Digital scoring of haemophilic arthropathy using radiographs is feasible

Summary.  Radiographs are important tools to evaluate structural changes in many joint diseases. In the case of haemophilic arthropathy (HA), the Pettersson score is widely used. The rising of digital radiography enables evaluation of these changes in a more quantitative and detailed manner, potentially improving diagnosis and follow‐up. The aim of this study was to evaluate whether digital image analysis in the case of HA is feasible, using a presently available method for radiographic changes in knee osteoarthritis (OA), knee image digital analysis (KIDA). Sixty‐two knee radiographs were scored according to Pettersson and with KIDA, each by two independent observers. Inter‐observer variation and correlations between the two scoring methods were determined. The inter‐observer variation was smaller for KIDA than for Pettersson and for KIDA not significantly different from evaluation of OA joints. Good correlations were found for the two methods where comparison of parameters was appropriate. Importantly, for each of the parameters within one point in the ordinal Pettersson score, a large window still existed in the continuous KIDA grading. Digital analysis of radiographs to quantify joint damage in HA is feasible. The use of continuous variables, as used in a digital method such as KIDA has the advantage that it enables objective and much more sensitive detection of small changes than by use of an ordinal analogue method such as the Pettersson score. Based on the present results, it would be worthwhile to adapt the KIDA method for the specific characteristics of HA and to extend the method to elbow and ankle radiographs.