The first clinical study that followed for three years a group of patients with progressive ossifying fibrodysplasia, a disease that affects the skeletal system and causes the uncontrolled growth of bone tissue outside the site, was published in Genetics in Medicine. This is the first global clinical evaluation of the disease over such a long period of time, and aims to better understand how symptoms evolve, how it progresses in all age groups, and what the consequences are on the life and disability of children. patients. The results showed that the disease does not stop throughout life and is highly disabling, but the greatest incidence of new ossifications occurs in childhood and early adulthood.
What is progressive ossifying fibrodysplasia
Progressive ossifying fibrodysplasia is an ultra-rare genetic disease that affects just over one person in every million individuals. It appears in childhood, in fact the average age at diagnosis is 5 years, and it is a progressive disease that can lead to disability and also greatly reduce the life expectancy of those who suffer from it. In general it manifests itself with bone growths outside the skeletal system, both in the joints and in the soft tissues (heterotopic ossifications), painful, irreversible and which can flare up over time. Episodes of exacerbation, in which at least two symptoms return – pain, swelling, redness, warmth, joint stiffness and reduced range of motion – contribute to the formation of new ossifications. Most patients require a wheelchair by age 20 and are not autonomous in everyday activities.
Three years of disease progression
114 people between the ages of four and 56 took part in the study, divided into eight international centers. The mean age was 15 years, they were predominantly male and 33 of them were able to complete the full 36-month observation period. All participants had bunion malformations and about half had thumb malformations at the start of the study, and two thirds (66.7%) reported at least one flare-up episode during monitoring. “Natural history studies are fundamental for the understanding of ultra-rare diseases with high unmet needs, such as progressive ossifying fibrodysplasia, and allow us to deepen our knowledge of disease development, diagnosis, monitoring techniques, potential biomarkers and measurement parameters of results ”, explains Robert Pignolo, Professor of Geriatric Medicine at the Mayo Clinic, in the United States. “It is the first study of its kind that follows the progression of progressive ossifying fibrodysplasia for three years. These results confirm the significant impact of the disease on the people affected by it. Furthermore, it will facilitate the evaluation of the significant objectives to be used in the development of new therapies, which are strongly needed by patients ”.
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During the period, progression of heterotropic ossifications was assessed by total body computed tomography at enrollment, and thereafter at 12, 24, and 36 months. In patients who reported at least two symptoms related to exacerbations (among those listed above), the study also included a clinical evaluation using computed tomography or radiography on the same day and approximately 12 weeks later, to assess whether the extent of ossification was changed in the affected area.
The disease progresses more among the younger ones
The results showed that, after 36 months, the patients studied reported 2.6 new ossifications on average: more (about 3.9) if they were aged between 2 and 8 years, and a little less ( 1.5) between 25 and 65 years. Regardless of age, however, 70% of patients continued to accumulate new ossifications throughout the duration of the study. These data confirm the progressive nature of the disease, which proceeds by accumulating ossifications starting from the upper body area (shoulders and torso), and then extending to the lower areas (in the hips and legs).
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Exacerbations also appear to be more likely in childhood, between the ages of 2 and 8. Overall, however, 229 cases were recorded in 82 people, most commonly in the upper back (17.9%), hip (14.8%) and shoulder (10.9%). Among those who developed flare-ups, the most common symptoms were pain and swelling of soft tissue, and imaging tests revealed the presence of ossification at the onset of symptoms, and in most cases also during the next 12 weeks.
Consequences in everyday life
In addition to the progression of the disease, the study also focused on evaluating changes in the function of the joints affected by ossification, the increased need for assistance and the need for assistive and adaptive devices. All of these conditions were shown to worsen with the increase in ossification, and nine out of ten people needed new assistive devices during the study. Total body computed tomography data performed over the three years confirmed that the volume of new ossifications per year is a clinically significant parameter that can be used in interventional clinical trials. “With progressive ossifying fibrodysplasia being an ultra-rare disease, we still need to understand much of its nature and progression,” said Howard Mayer, head of research and development at the Ipsen biopharmaceutical company, who collaborated on the study. “This first study, carried out over a 3-year period, helped us to progress in understanding the important characteristics of the disease, including the likelihood of new ossifications occurring in relation to age and their progression over time, as well as better understanding the relationship between the use of assistive and adaptive devices and the joint mobility of patients. We are grateful to the significant number of people affected by progressive ossifying fibrodysplasia who participated in this important study ”.