Optimal Disease Control Advised for Hemophilia B Patients

People with severe hemophilia B are likely to develop hemophilic arthropathy — a painful and degenerative joint disease caused by recurrent bleedings — despite the lower bleeding frequency relative to hemophilia A, a natural history study shows.

The data also highlights that prophylactic (preventive) treatment guidelines are not being adequately followed in children with severe hemophilia B. As such, treatment should be consistently applied to all patients with severe disease to improve their quality of life, researchers said.

The study, “Natural history study of factor IX deficiency with focus on treatment and complications (B‐Natural),” was published in the journal Haemophilia.

Hemophilia B, caused by a deficiency in the clotting factor IX (FIX), is less common and less studied than hemophilia A. Several studies have pointed out similarities between these two conditions, but differences also exist, including divergent proportions of clotting factor inhibitors — neutralizing antibodies that render replacement therapies ineffective.

Still, further research is needed to better understand these potential differences and the mechanisms behind them.

To increase understanding of clinical symptoms, treatment, and complications of hemophilia B, the Factor IX Treatment Network initiated the B‐Natural study (NCT02502409).

The observational trial recruited 224 patients (220 males and four females), with or without FIX inhibitors, from 107 families at 24 centers across the U.S., European Union, and Asia. Participants had a median age of 13.6 years (range, 1 to 73) with the majority (64.3%) being children and adolescents.

Patients were followed for six months, with collection of medical history and assessments of bleeding patterns, quality of life, and complications, including the development of joint disease and antibodies against FIX replacement therapy, and use of immune tolerance induction (ITI) and its outcomes, ITI is an approach used to remove FIX inhibitors and restore a normal response to replacement therapy.

Results showed that 42 (18.8%) participants had mild FIX deficiency, 114 (50.9%) had moderate deficiency, and 68 (30.4%) had severe disease.

This distribution was consistent with that reported previously for this patient population, the researchers said, but the proportion of patients with moderate disease was enriched, as there was a large number of U.S., Old Order Amish patients who carry a founder mutation that predicts moderate FIX deficiency.

“Interestingly, 21 families contained members with differing [disease] severities,” the team wrote, adding that the reason behind it is unclear, but may be due partly to differences in clotting factor tests.

In addition, 29 (12.9%) patients, all with severe disease, were positive for or had a history of FIX inhibitors, and 22 of them underwent one or more courses of ITI, which was deemed successful in 50% of the cases.

FIX inhibitor status and disease severity were the main factors influencing replacement therapy frequency in hemophilia B patients, similar to that reported for those with hemophilia A.

However, the number of treatment infusions was generally lower than those expected in people with severe hemophilia A without inhibitors. This may be related to less frequent prophylaxis use and the longer effect of FIX replacement therapy, as compared with that of hemophilia A, resulting in a need for fewer infusions and fewer bleedings, scientists said.

Among severe disease patients, 34.5% of those with FIX inhibitors and 48.7% of those without inhibitors were on prophylactic treatment before the development of inhibitors or in the first 50 days of treatment exposure. This highlighted that published guidelines for severe hemophilia B and prophylaxis have not been “uniformly applied,” the team wrote.

This may be due to the perception that preventive treatment “may not be required in HB [hemophilia B] due to the decreased number of bleeding episodes experienced, [and] that prophylaxis, when applied, is either provided after damage has occurred or is insufficient to adequately suppress all bleeding episodes,” the researchers added.

Importantly, patients with severe hemophilia B had worse joint damage (likely developing arthropathy) and poorer quality of life — those with inhibitors reported a higher level of anxiety/depression — compared with those who had milder disease.

This highlighted that a more regular prophylaxis in severe hemophilia B “is warranted and should be considered in all patients” to protect joints and prevent arthropathy, the team wrote.

“The B-Natural and other studies demonstrate that arthropathy will occur over time in severe HB even in the presence of fewer bleeding episodes per year compared to [hemophilia A],” the researchers added.

As such, differences in bleeding frequency may be less important than the resultant physical and psychosocial outcomes, suggesting that hemophilia B may need to be re-evaluated “in light of not just the frequency of bleeding but the sequelae of these events that accumulate over time,” the team said.

“B-Natural provides important data to support an increased understanding of the natural history of HB and its impact throughout life,” the researchers concluded, adding that “further analyses will contribute to an increased understanding of critical issues in HB.”