ALBERT

Description: Introduction: The benefits of primary prophylaxis with a factor VIII (FVIII) product in pediatric patients with severe hemophilia A are well established. Fewer data are available on the benefits of secondary prophylaxis (started after ≥2 joint bleeds but before the onset of documented joint disease). The 3-year SPINART study compared the efficacy and safety of routine prophylaxis vs on-demand treatment in adolescents and adults with severe hemophilia A, all of whom were treated with Bayer's sucrose-formulated recombinant FVIII (rFVIII-FS). Primary 3-year data on magnetic resonance imaging (MRI) joint assessments in SPINART have been recently reported. Here we present additional analyses of the SPINART 3-year MRI data. Methods: SPINART was a 3-year, randomized, controlled, parallel-group, open-label study conducted at 31 centers in the United States, Bulgaria, Romania, and Argentina. Male patients aged 12–50 years were eligible for SPINART if they had severe hemophilia A (FVIII:C 12 consecutive months in the past 5 years, and 6–24 documented bleeding events or treatments in the previous 6 months. Eligible patients were randomly assigned 1:1 to on-demand treatment or prophylaxis. Patients assigned to prophylaxis received rFVIII-FS 25 IU/kg 3 times weekly; in patients with ≥12 bleeding episodes per year, dose increases of 5 IU/kg were permitted at years 1 and 2. All patients underwent MRI assessments at baseline and year 3 to evaluate the structure of 6 index joints (knees, ankles, elbows). Each MRI was read by 3 radiologists blinded to treatment assignment who independently completed the Extended MRI (eMRI) scale. The eMRI scale has 2 domains (soft tissue, osteochondral), and total eMRI scores range from 0 to 45 based on soft-tissue domain scores of 0 to 9 and osteochondral domain scores of 0 to 36; higher eMRI scores indicate greater joint structural damage. Change from baseline to year 3 in eMRI total score based on all 6 index joints was analyzed for the following baseline characteristics: region (US vs non-US), age (≤29 vs 〉29 years), and number of bleeding episodes in the previous 6 months (29

Description: Purpose Biomarkers of bone and cartilage turnover have frequently been evaluated for joint diseases such as rheumatoid arthritis (RA) and osteoarthritis (OA). Results have thus fare not been very conclusive. Some biomarkers such as urinary CTXII and serum COMP appear to correlate with severity of joint degeneration, whereas other are less distinctive. Hemophilic arthropathy (HA) is a very progressive joint degeneration as a result of frequent joint bleeds. From clinical practice it is concluded that the rate of degeneration exceeds that of OA and RA joints. This degeneration has characteristics of both inflammation mediated (as seen in RA) and degenerative (as seen in OA) joint disease. Furthermore, the joint damage is largely restricted to 3 major joints (ankle, knees, and elbows). Therefore, it might be that this rapidly progressive, localized joint degeneration can be used for the evaluation and validation of biomarkers of cartilage and bone turnover. In the present study we therefore investigated whether commercially available biomarkers of cartilage and bone in blood and/or urine are associated with severity of joint damage in patients with haemophilic arthropathy. Methods Blood and urine were collected from 36 patients suffering from haemophilia. Urine samples were assessed for the amount of CTX-I and CTX-II. Serum samples were assessed for the amount of CTX-I, CTX-II, COMP, C1,2C, C2C, and CS846. Radiographs of ankles, knees and elbows were scored according to Pettersson, a radiographic joint score specific for haemophilic arthropathy based on cartilage and bone changes. Results U-CTX-II (R=0.39; p=0.01), C1,2C (R=0.31; p=0.04) and CS846 (R=0.31; p=0.03) showed (marginal) correlations with the Pettersson score. Slightly better correlations were obtained when only narrowing of joint space width (JSW) as one of the items in the Pettersson score was used. The other biomarkers showed no correlation with the Pettersson score. Also the bone biomarkers did not correlate with specific bone changes. Interestingly, combined indexes of different markers, based on linear stepwise regression analysis, increased the correlation significantly up to R=0.65; p≤0.001) for the combination of U-CTX-II, COMP and CS846. Conclusions The present results show that even despite this rapidly progressive degeneration of 6 large joints, from the individual biomarkers determined only U-CTX-II, C1,2C and CS846 show correlation with the severity of arthropathy. Importantly, a relation improved when the markers were related to the process they are supposed to describe (cartilage degeneration markers with JSW narrowing). Most important, combination of markers, significantly improve the relation with the radiographically determined joint degeneration. In general however, it may be concluded that these markers alone seem not of sufficient value for evaluation of joint damage yet.

Description: Introduction Arthropathy, the most costly chronic complication of severe hemophilia A (HemA) can be prevented by routine replacement of factor VIII (FVIII) when initiated prior to joint bleeding (primary prophylaxis) [NEJM;357:535]. However, the efficacy of prophylaxis initiated after the onset of recurrent hemarthroses or with established arthropathy (secondary or tertiary prophylaxis) is unknown. This individual patient meta-analysis was performed to derive the natural history of arthropathy in HemA patients treated only in response to acute bleeding (on demand therapy) as a baseline for future work to estimate the amelioration of arthropathy attributable to secondary or tertiary prophylaxis. Methods Data from individual participants in 3 studies who received on demand therapy were aggregated into a single database. Eligibility for this analysis included FVIII ≤ 2%, negative history for inhibitor, bleeding history for 12 months prior to study data acquisition and assessment of both ankles, knees and elbows; joints were assessed using physical examination (PE) and T2* gradient echo MRI scored as previously described using the World Federation of Hemophilia Gilbert score and the 45 point extended MRI scales [Haemophilia;6:649; ISTH OP Mon 7/1/13, 9 am]. MRI data were divided into soft tissue and osteochondral changes. Bleeding and Gilbert data for all 6 joints and MRI data for knees and ankles were analyzed using standard descriptive statistics and regression methods to quantify the rate of change in scores of joint damage with age. Results The 3 studies included the Joint Outcome Study [NEJM;357:535] and the JOS Continuation Study (JOSc), the Spinart Study baseline results [JTH;11:1119] and a Cross-Sectional MRI study [Haemophilia;189 Suppl3:117]. The 3 studies provide data on 275 individuals aged 1 to 50 years. Clinical, Gilbert and MRI data were extracted and analyzed from multiple joints in each of 157 individuals who were receiving on-demand treatment only. The median age was 21 (range 1 – 50), and across all studies the median number of bleeding episodes in the prior 12 months was 18 (range 0 to 82). The rate of change in outcomes as a function of age is shown in Table 1 and Figure 1. The number of bleeding episodes was approximately constant at 20 bleeding episodes per year regardless of age (Figure 1a; p = 0.72 for relationship with age). Gilbert scores showed a steeper rise in young patients but did not increase after the late teens (Figure 1b; change of 0.34 Gilbert points/year of life, p=0.07). MRI scores, in contrast to bleeding rates and Gilbert scores, showed continued age-related deterioration (Figure 1c; change of 2 MRI points/year of life, p 〈 0.0001). Age-related total and osteochondral deterioration on MRI increased steadily with age (on average 2 MRI-points/year of age, p 〈 0.0001 for each), whereas soft tissue scores increased rapidly to approximately 9 by age 20, and then plateaued at a score of approximately 10 for ages 20-50 (0.08 MRI points/year, p =0.28). Conclusions Individual patient meta-analysis of bleeding frequency, joint PE and MRI joint structure was useful to determine the natural history of hemophilic arthropathy in patients treated with on-demand therapy, and showed a continuous increase in joint bone and cartilage abnormalities across the age span despite an early leveling in bleeding rate and joint physical function. These data will be critical to determine the quantitative effects of prophylaxis on mitigation of joint deterioration when initiated at various ages following the onset of joint bleeding. Disclosures: Manco-Johnson: Bayer HealthCare: Research Funding. Lundin:Bayer HealthCare: Research Funding. Hong:Bayer HealthCare: Employment. Oldenburg:Octapharma AG: Consultancy, Investigator Other. Manco-Johnson:Biogen Idec: Membership on an entity’s Board of Directors or advisory committees; Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees; CSL Behring: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bayer HealthCare: Membership on an entity’s Board of Directors or advisory committees, Research Funding; NovoNordisk: Membership on an entity’s Board of Directors or advisory committees; Eisai: Research Funding.