Young adult outcomes of childhood prophylaxis for severe hemophilia A: results of the Joint Outcome Continuation Study.

The Joint Outcome Study (JOS), a randomized controlled trial, demonstrated that children with severe hemophilia A (HA) initiating prophylactic factor VIII (FVIII) prior to age 2.5 years had reduced joint damage at age 6 years compared with those treated with episodic FVIII for bleeding. The Joint Outcome Continuation Study (JOS-C) evaluated early vs delayed prophylaxis effects on long-term joint health, following JOS participants to age 18 years in an observational, partially retrospective study. Index joint magnetic resonance imaging (MRI) scores of osteochondral (OC) damage (primary outcome), joint physical examination scores, and annualized rates of joint/other bleeding episodes (secondary outcomes) were collected. Thirty-seven of 65 JOS participants enrolled in JOS-C, including 15 randomized to prophylaxis at mean age 1.3 years ("early prophylaxis"); 18 initially randomized to episodic treatment, starting "delayed prophylaxis" at mean age 7.5 years; and 4 with high-titer inhibitors. At JOS-C exit, MRI OC damage was found in 77% of those on delayed and 35% of those on early prophylaxis for an odds ratio of OC damage, in the delayed vs early prophylaxis group, of 6.3 (95% confidence interval, 1.3, 29.9; P = .02). Annualized bleeding rates were higher with delayed prophylaxis (mean plus or minus standard deviation, 10.6 ± 6.6 vs 3.5 ± 2.1; P < .001), including when only comparing time periods on prophylaxis (6.2 ± 5.3 vs 3.3 ± 1.9; P < .05). In severe HA, early initiation of prophylaxis provided continued protection against joint damage throughout childhood compared with delayed initiation, but early prophylaxis was not sufficient to fully prevent damage. This trial was registered at www.clinicaltrials.gov as #NCT01000844.

Clinical effects and safety of rituximab for treatment of refractory pediatric autoimmune diseases.

OBJECTIVE: To evaluate the safety, tolerability, and clinical effects of rituximab, an anti-CD20 monoclonal antibody, in the treatment of severe pediatric autoimmune diseases. STUDY DESIGN: We reviewed the records of 10 patients treated with rituximab for severe, refractory autoimmune diseases at a single tertiary care children's hospital. Adverse events as well as treatment effects were recorded. RESULTS: All patients received 4 weekly doses of rituximab at 375 mg/m2 per dose. One patient died as the result of complications of her underlying systemic lupus erythematosus 7 weeks after rituximab therapy. Three patients had serious infections, all of which resolved with standard therapy. Rituximab led to transient or sustained improvement in clinical and laboratory parameters in nine subjects. At a median follow-up of 9 months, the median prednisone dose was reduced in the responders by 0.75 mg/kg per day (mean decrease of 63%), and four patients were able to discontinue corticosteroids entirely. With longer follow-up (median, 22 months), we found that 5 of 9 patients remained clinically stable after rituximab therapy, whereas 4 patients had recurrent or new features of their underlying autoimmune disorders requiring additional corticosteroids or other immunosuppressive medications. CONCLUSIONS: Rituximab had an acceptable toxicity profile in this group of patients with severe, refractory autoimmune diseases, although there were three serious infections and one patient death. Rituximab appears to be beneficial for patients with refractory autoimmune diseases and may reduce corticosteroid exposure. Although rituximab therapy provided a durable clinical benefit for some patients in this population, other patients had reemergence of their underlying autoimmune disease.