Long-term joint outcomes in adolescents with moderate or severe haemophilia A

Introduction: Favourable joint outcomes are expected with modern haemophilia A (HA) management. Evaluation of long-term treatment outcomes is hampered by the delay between bleeding episodes during childhood and resulting joint outcomes in adulthood. Aim: To measure the long-term joint health of adolescents with moderate and severe HA, according to severity and inhibitor status. Methods: Pilot cross-sectional study of five European PedNet centres in moderate and severe HA patients aged 10–19 years. Structured assessment of joint status by physical examination (HJHS) and ultrasound (HEAD-US). Results: In total, 141 HA patients were evaluable, 100 without inhibitors (81 severe, 19 moderate HA), and 41 severe HA with current/past inhibitors. On physical examination, 12/81 (15%) of severe HA without inhibitors, 3/19 (16%) of moderate HA, and 13/41 (32%) of severe HA patients with inhibitors exhibited joint abnormalities. Inhibitor persistence, longer inhibitor duration, and a high peak inhibitor level were associated with impaired joint health. Ultrasound showed joint damage (bone or cartilage) in 13/49 (27%) of severe HA without inhibitors, 1/12 (8%) of moderate HA, and 10/28 (36%) of severe HA patients with inhibitors. A discordant ankle evaluation by ultrasound versus physical examination was present in 53/169 joints (31%). Conclusions: Most adolescents with severe or moderate HA show favourable joint health. Future research with combined ultrasound and/or MRI is needed to better understand joint outcomes in the remaining patients. Patents with inhibitors showed a two-fold increased proportion with joint deterioration. Ultrasound paired with physical examination increases sensitivity for detection of joint damage

Risk Factors for the Progression from Low to High Titres in 260 Children with Severe Haemophilia A and Newly Developed Inhibitors

In children with severe haemophilia A, inhibitors to factor VIII (FVIII) usually develop during the first 50 treatment exposure days and are classified as low or high titre depending on the peak inhibitor titre being greater or less than 5 Bethesda units/mL (BU/mL). Classification of the inhibitor may change with time, as some low-titre inhibitors progress to high titre following re-exposure to FVIII concentrate. The aimof this studywas to investigate potential risk factors for such a progression in children with severe haemophilia A and newly diagnosed inhibitors. This study was a follow-up study of the PedNet Registry and included 260 children with severe haemophilia A and inhibitors born between 1990 and 2009 and recruited consecutively from 31 haemophilia centres. Clinical and laboratory data were collected fromthe date of each child’s first positive inhibitor test for at least 3 years. At the timeof first positive inhibitor test, 49% (n = 127) had low-titre inhibitors,with 50% of them progressing to high titre and only 25% maintaining low titres. The FVIII gene (F8) mutation type was known in 247 patients (95%), and included 202 (82%) null mutations. The progression to high-titre inhibitors was associated with null F8 mutations (odds ratio [OR]: 2.6; 95% confidence interval [CI]: 1.0–6.5), family history of inhibitors (OR: 7.2; 95% CI: 1.8–28.4) and the use of high-dose immune tolerance induction, defined as 100 IU FVIII concentrate/kg/d (OR: 3.9; 95% CI: 1.5–10.0). These results suggest that high-dose immune tolerance induction should be avoided as the initial strategy in patients who develop low-titre FVIII inhibitors