Lifetime impact of achondroplasia study in Europe (LIAISE): findings from a multinational observational study

Abstract

Background: Achondroplasia, caused by a pathogenic variant in the fibroblast growth factor receptor 3 gene, is the most common skeletal dysplasia. The Lifetime Impact of Achondroplasia Study in Europe (LIAISE; NCT03449368) aimed to quantify the burden of achondroplasia among individuals across a broad range of ages, including adults.

Methods: Demographic, clinical and healthcare resource use data were collected from medical records of achondroplasia patients enrolled in 13 sites across six European countries in this retrospective, observational study. Descriptive statistics or event rates per 100 person-years were calculated and compared across age groups as well as by history of limb lengthening. Patient-reported outcomes (quality of life [QoL], pain, functional independence, work productivity and activity impairments) were evaluated using questionnaires at the time of enrolment. An exploratory analysis investigated correlations between height (z-score or centimetres) and patient-reported outcomes.

Results: Overall, 186 study patients were included, with a mean age of 21.7 ± 17.3 years (range 5.0-84.4). At least one complication or surgery was reported for 94.6% and 72.0% of patients, respectively, at a rate of 66.6 and 21.5 events per 100 person-years. Diverse medical and surgical complications were reported for all ages in a bimodal distribution, occurring more frequently in the youngest and oldest age groups. A total of 40 patients had previously undergone limb lengthening (capped at 20% per the study protocol). The most frequent surgery types varied by age, in line with complication profiles. Healthcare resource use was high across all age groups, especially among the youngest and oldest individuals, and did not differ substantially according to history of limb lengthening. Compared to general population values, patients reported impaired QoL particularly for physical functioning domains. In addition, patients reported difficulty carrying out daily activities independently and pain starting in childhood. Patient height correlated with multiple patient-reported outcomes.

Conclusions: The findings of this study suggest that, across an individual's lifetime, achondroplasia is associated with multisystem complications, reduced QoL and functionality, and increased pain. These results highlight the large amount of healthcare resources that individuals with achondroplasia require throughout their lifespans and provide novel insights into current achondroplasia management practices across Europe. Trial registration ClinicalTrials.gov, NCT03449368, Submitted 14 December 2017 - prospectively registered, https://clinicaltrials.gov/ct2/show/record/NCT03449368.

Keywords: Achondroplasia; Disease burden; Fibroblast growth factor receptor 3 (FGFR3); Natural history; Skeletal dysplasia.

Fig. 1

Burden of medical and surgical complications by age at time of event. Each patient may have several complications reported across the lifespan and may therefore be included in multiple age subgroups. Event rates per 100 person-years were calculated as the number of events divided by the total number of patient historical years, multiplied by 100. ENT Ear, nose and throat

Fig. 2

Surgical burden by age at time of event. Each patient may have had several surgeries reported across their lifespan and may therefore be included in multiple age subgroups. Event rates per 100 person-years were calculated as the number of events divided by the total number of patient historical years multiplied by 100. ‘Other’ surgeries were those not pre-defined in the CRF used to record data, and mainly consisted of other orthopaedic procedures (e.g., medical device removal, osteotomy, epiphysiodesis)

Fig. 3

Healthcare resource use by age subgroup. Event rates per 100 person-years were calculated as the number of events divided by the total number of patient historical years multiplied by 100. **Results are displayed for healthcare professional types with an event rate of > 10 per 100 person-years in at least one age category. ‘Other’ healthcare professional visits include those to cardiologists, dentists, dermatologists, dieticians, emergency doctors, endocrinologists, geneticists, gynaecologists, neurologists, neurosurgeons, occupational therapists, ophthalmologists, orthopaedic physicians or respiratory physicians. ENT Ear, nose and throat

Fig. 4

QoLISSY results (patients aged 8–17 years; parents of patients aged 5–17 years; subset of study population). QoLISSY scores for each domain range from 0 to 100 (where higher scores indicate better QoL). Empty bars correspond to missing (not available/reported) data, rather than scores of 0. Error bars are SD. Published QoLISSY scores for age-matched average stature (individuals with a height no more than 2 SDs below average height) children and parents of average stature children are also provided [24]. LL limb lengthening, QoLISSY Quality of Life in Short Stature Youth, SD Standard deviation

Fig. 5

PedsQL results (patients aged 5–17 years; parents of patients aged 5–17 years; subset of study population). PedsQL scores for each domain/summary scale range from 0 (poor health-related QoL) to 100 (perfect health-related QoL). Published PedsQL scores for average stature populations are also provided. Error bars are SD. Published PedsQL scores for reference populations are also provided [25]. LL limb lengthening, PedsQL Pediatric Quality of Life Inventory, SD Standard deviation

Fig. 6

EQ-5D-5L results (patients aged ≥ 18 years; subset of study population). The EQ-5D-5L measure is comprised of two sections: the first assesses five domains impacting quality of life (mobility, self-care, usual activity, pain/discomfort and anxiety/depression). Combining the levels for each domain creates the overall index value. The second section measures self-rated (global) health status utilising a vertically oriented visual analogue scale (VAS) where 100 represents the “best imaginable health state” and 0 represents the “worst imaginable health state.” Error bars are SD. Population norms are provided for the EQ-5D-5L index values for Germany (0.902), Spain (0.915) and Italy (0.899) [26]. SD Standard deviation, VAS Visual analogue scale

Fig. 7

NHP results (patients aged ≥ 18 years; subset of study population). *NHP scores for each domain range from 0 to 100 (with 0 indicating no distress [good subjective health] and 100 indicating severe distress [poor subjective health]). Error bars are SD. LL Limb lengthening, NHP Nottingham Health Profile, SD Standard deviation