Prophylaxis is not the end of the story for haemophilia

Widespread availability of factor prophylaxis – at least in developed nations – has changed the lives of people with haemophilia. But as clinicians we should continue to strive for better treatments.

The flagship presentation the last month’s EAHAD conference – the Arosenius Lecture – was given by Marilyn Manco-Johnson who, as part of the team at the University of Colorado’s Hemophilia and Thrombosis Center, has carried out extensive research on prophylaxis.

The Arosenius Foundation, named after the Swedish artist Ivar Arosenius (1878 – 1909), who had haemophilia B, was founded in 1996 by the Swedish Haemophilia Society, to support research and education in haemophilia and allied disorders.

Professor Manco-Johnson began by describing the ‘toolbox’ of outcomes we need to determine the impact of prophylaxis for people with haemophilia. Among these, mortality is important but rare and difficult to measure. By contrast, there are several clinical (imaging, joint disease), laboratory and patient-reported outcomes (PROs) such as quality of life, treatment burden and restriction on education and employment.

Joint disease is the most widely used endpoint because it affects 90% of patients with haemophilia without treatment. Formal joint assessment involves MRI, the gold standard for evaluating joint structural change, and the Haemophilia Joint Health Score, the gold standard for joint function. Both correlate well with PROs.

What do these tools tell us about the effectiveness of prophylaxis? Analysis of studies published before prophylaxis was available showed that the annualised bleeding rate and joint function score level out at the relatively young age of 30 – 40 but structural damage continues to progress. MRI showed this was due to osteochondral changes, not soft tissue damage.

In more recent studies in those who received prophylaxis, the rate of joint disease progression was similar for all groups except those who started prophylaxis before age three, in whom it was greatly reduced. By age six, prophylaxis reduced the risk of joint disease by 84% compared with on-demand therapy. However, this difference did not emerge before age six even though joint bleeds had been reduced immediately. By age 18, one-third of the boys who treated with early prophylaxis had at least one joint with structural damage (vs. 77% of delayed starters). But MRI showed that, beneficial as early prophylaxis was, it had not prevented a steady deterioration in joint structure due to osteochondral damage.

The impact of prophylaxis on joint range of movement was investigated in the US Hemophilia Treatment Center Network and the Centers for Disease Control and Prevention surveillance registry. The prevalence of target joints was greatly reduced as more patients were treated with prophylaxis and there were virtually none in the youngest age group. Despite this, joint range of movement did not change in any age group between 1998 and 2010, showing that prophylaxis had no effect on range of movement regardless of its other beneficial effects.

This evidence shows that prophylaxis decreases joint bleeding, improves physical joint outcomes and reduces target joints. Only starting prophylaxis before age three will slow progression of joint damage and no study has shown that conventional prophylaxis prevents arthropathy.

There is no relationship between structural damage (shown by MRI) and total joint bleed rate or global physical joint exam score but there is a statistically significant correlation when individual joints are measured over time – in other words, the per-joint bleed rate and per-joint physical exam are accurate measures of joint damage. It’s the changes in individuals that we need to measure, not the population-level ones.

In summary, Professor Manco-Johnson pointed out that haemophilia management has achieved huge improvements since the advent of early prophylaxis. Children can now expect to have the same opportunities as their peers. But this, she emphasised, is not enough because progressive arthropathy occurs despite our very best efforts with prophylaxis. We need even better therapies. Extended half-life factors, non-factor therapies and gene therapy all offer the prospect of improved outcomes but we also need better-designed studies, ways to detect early evidence of joint damage and reliable and sensitive outcome measures which are relevant to patients as well as clinicians.