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Examining Quality of Life and Treatment Options for Fibrodysplasia Ossificans Progressiva and Multiple Osteochondromas

Examining Quality of Life and Treatment Options for Fibrodysplasia Ossificans Progressiva and Multiple Osteochondromas

This publication was sponsored by Ipsen Pharma.
Fibrodysplasia ossificans progressiva (FOP) and multiple osteochondromas (MO) are 2 rare and debilitating bone disorders that can have a serious impact on the quality of life (QOL) of those individuals who are affected. FOP is an ultra-rare, progressive, disabling connective tissue disorder in which bone grows in abnormal places in the body. This process, known as heterotopic ossification (HO), severely and permanently reduces movement.1,2 MO, also known as hereditary multiple osteochondromas, multiple hereditary exostoses, and hereditary multiple exostoses, is a rare genetic musculoskeletal condition. In MO, numerous osteochondromas, also known as osteocartilaginous exostoses, or simply exostoses, form on bones. Although the tumors are usually benign, they compromise function and well-being by impinging on surrounding tissue, affecting form and function. MO is autosomal dominant and primarily inherited, but spontaneous cases can also occur.3,4 

According to the International Fibrodysplasia Ossificans Progressiva Association (IFOPA), FOP theoretically affects 1 in 2,000,000 people; however, based on their findings, they suggest the number might be closer to 1 in 1,500,000 people. IFOPA has identified 834 individuals living with FOP in the world.5 The prevalence of MO, like that of FOP, is low; however, investigators posit that the usual numbers cited are underestimated. One study posited that the prevalence of MO in Washington state was at least 1 in 50,000; however, not all cases were deemed to be captured.4 In addition, among certain isolated communities, such as the Chamorros of Guam, the prevalence may be even higher; investigators found 21 cases among the 32,000 Chamorros.6

FOP and MO can profoundly impact the QOL of those individuals who are affected, underscoring the importance of clinical awareness of the diseases.

FOP is caused by a mutation, usually spontaneous, to chromosome 2q23-24 in the area surrounded by markers D2S1399 and D2S1238.7 This mutation impacts the activin A type 1 receptor gene, altering Activin Receptor Type IA (ACVR1), a receptor in the bone morphogenetic protein signaling pathway.7 The disease can be the result of a new mutation or it can be familial, as evidenced in the results of 2 studies: one, of 28 patients with FOP by Smith and colleagues, found that none of the patients studied had a family history of myositis or atypical skeletal findings8; and another by Connor and colleagues who, conversely, studied a family with 3 generations of individuals with FOP.9

The disease manifests with characteristic signs at birth. The classic signs are malformed big toes and hallux valgus. In a study by Connor and Evans, and another study by Harrison et al, all patients had these abnormalities.10,11 Another common finding, malformed thumbs due to short first metacarpals, was found in 59% of patients (20 of 34) in the same study.10 Although the investigators were uncertain whether the deformities were present at birth, radiographs performed early in childhood of patients in the study revealed cervical vertebrae with abnormally small bodies, enlarged spinous processes, and large pedicles; as patients aged, bony ankylosis in the cervical spine was also common.10

Recognizing the classic skeletal abnormalities—hallux valgus and the malformed big toes and thumbs—as well as the tumor-like swellings are critical to the clinical diagnosis of FOP (Figure 1).12 The toes can be radiographed, if necessary, to confirm the diagnosis, but computed tomography, bone scan, magnetic resonance imaging, or biopsy should not be necessary.8

As patients with FOP age, they experience flare-ups consisting primarily of pain, swelling, and stiffness. Approximately 50% of patients in the Connor and Evans study reported pain associated with flare-ups, and 25% noted overlying erythema.10 The results of a survey study of patients with FOP by Pignolo et al indicated that swelling occurred in 93.1% of respondents during a flare-up, with the next most common flare-up symptom being pain (86.3%), and the third most common symptom being decreased movement (78.5%). Symptoms that most reliably predicted a flare-up were new swelling (39%) and pain (29%).13 Based on these findings, the study investigators advised that major criteria for a flare-up diagnosis should be 2 days of pain and swelling, with supporting features including warmth, stiffness, redness, and decreased movement.13

Flare-ups can occur with or without cause. Patients with FOP surveyed in the Pignolo et al study reported that up to 61% of flare-ups had no precipitating factor. When a flare-up was associated with a trigger, about 88% were reported to occur because of limb overuse, a viral infection, or an injury. In about 25% of flare-ups, the reported cause was intramuscular (IM) immunization, which resulted in bone formation in 84.3% (97 of 115) of patients.13 Additional triggers of abnormal bone formation reported by Connor et al (1982) included trauma, surgery, biopsies, dental work, incautious blood draws, and IM injections.10

FOP is disease is progressive and disabling,8,13 and the nature of the disease leads to low reproductive fitness.14 As the swelling associated with a flare-up regresses, it leaves stiffness and new bone that permanently decrease range of motion.10 According to Connor and Evans, areas most prone to ossification were found to be the paraspinal muscle connective tissue, the muscles of mastication, and the limb girdle muscles. Other commonly involved foci were the plantar fasciae, joint capsules, and ligaments.10

To further assess the nature of ossification in patients with FOP, Cohen et al administered a questionnaire to 60 patients who were members of the IFOPA (Figure 2).15 Of the 44 who responded, the age when HO first became apparent ranged from birth to 25 years (mean age [SD], 5 ± 4.9 years). More than half of patients (59%) reported that HO first occurred in the neck while 45% reported its first occurrence in the spine or shoulder. The sum of these numbers exceeds 100% because in some cases, HO simultaneously occurred in more than 1 area; 61% of patients reported concurrent initial HO at different sites. By the time patients reached age 15 years, almost all (>95%) had severe loss of upper-limb range of motion, usually followed within 10 years by severe loss of mobility in the lower extremities.15

Connor and Evans reported similar results. By age 10 years, all patients in the study had stiffness in the shoulders and spine; by age 20 years, most patients had problems with 1 or both hips; and by age 30 years, most could not leave their chair or bed. Furthermore, all patients in the study had decreased range of motion in their shoulders or spine, and 71% had an affected jaw. Bone formation in the musculature and joint capsules deprived every patient of normal movement and left them with physical handicap.10

Thirty months of self-reported patient registry data for 99 patients with FOP from the IFOPA and analyzed by Peng et al indicated that 56% to 67% of patients reported moderate to severe pain (≥4 on a scale of 0 to 10) during a flare-up, and a large proportion—30% to 55%—also reported similar pain when they were not experiencing a flare-up. Forty-five percent to 74% of patients reporting moderate to severe pain also reported depression, anxiety, and irritability, while 36% to 48% of those reporting no to mild pain still reported emotional problems. Neuropathic pain was reported by 13% of respondents. QOL inversely correlated with pain severity.16

Despite usually worsening FOP, surgery is sometimes required. In a systematic review of the literature, Eekhoff et al found a 100% chance of HO after jaw surgery,17 and the results of a 2005 study based on a questionnaire sent to 269 patient-members of the IFOPA by Kitterman et al found that 35% of patients who had been biopsied and 60% of patients who had undergone surgery suffered permanent complications.12

The leading cause of mortality in patients with FOP (54%), as reported by Kaplan et al, was found to be cardiorespiratory failure resulting from thoracic insufficiency syndrome. The next most common cause was pneumonia (15%), and the third most common cause was complications from a fall (11%). The median age of death were 42, 40, and 41 years old for those who died of cardiorespiratory failure, pneumonia, and fall complications, respectively.18

Current treatments for FOP focus on managing the symptoms of flares and include steroids and nonsteroidal anti-inflammatory drugs. Among patients with FOP surveyed by Pignolo et al, more than half (55%) of respondents reported that prednisone sometimes improved symptoms correlating with flare-ups, while 30.5% reported it always did. Approximately 82% reported that prednisone decreased flare-up swelling, and about 67% reported that prednisone helped control pain; however, 43% reported rebound after finishing steroid treatment. Preservation of joint function and inhibition of HO was found to be infrequent with prednisone use. Less than half reported the use of ibuprofen (33%) and 23% reported using montelukast, a leukotriene receptor antagonist.13

There is a role for antibiotics and for modification of the patient’s environment in the management of patients with FOP. Current treatment considerations from the International Clinical Council (ICC) on FOP and consultants, indicate that patients with an ankylosed jaw who are vomiting, for instance, should be given empiric antibiotics to cover for aspiration pneumonia. According to ICC, patients with FOP should also start antibiotics according to CDC recommendations when they are suspected of having, or have been exposed to, pertussis. This is due to the modified immunization schedules recommended by ICC for patient with FOP.

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