A registry of achondroplasia: a 6-year experience from the Czechia and Slovak Republic.

BACKGROUND: Achondroplasia (ACH) is one of the most prevalent genetic forms of short-limbed skeletal dysplasia, caused by gain-of-function mutations in the receptor tyrosine kinase FGFR3. In August 2021, the C-type natriuretic peptide (CNP) analog vosoritide was approved for the treatment of ACH. A total of six other inhibitors of FGFR3 signaling are currently undergoing clinical evaluation for ACH. This progress creates an opportunity for children with ACH, who may gain early access to the treatment by entering clinical trials before the closure of their epiphyseal growth plates and cessation of growth. Pathophysiology associated with the ACH, however, demands a long observational period before admission to the interventional trial. Public patient registries can facilitate the process by identification of patients suitable for treatment and collecting the data necessary for the trial entry. RESULTS: In 2015, we established the prospective ACH registry in the Czechia and the Slovak Republic ( http://www.achondroplasia-registry.cz ). Patient data is collected through pediatric practitioners and other relevant specialists. After informed consent is given, the data is entered to the online TrialDB system and stored in the Oracle 9i database. The initial cohort included 51 ACH children (average age 8.5 years, range 3 months to 14 years). The frequency of selected neurological, orthopedic, or ORL diagnoses is also recorded. In 2015-2021, a total of 89 measurements of heights, weights, and other parameters were collected. The individual average growth rate was calculated and showed values without exception in the lower decile for the appropriate age. Evidence of paternal age effect was found, with 58.7% of ACH fathers older than the general average paternal age and 43.5% of fathers older by two or more years. One ACH patient had orthopedic limb extension and one patient received growth hormone therapy. Low blood pressure or renal impairment were not found in any patient. CONCLUSION: The registry collected the clinical information of 51 pediatric ACH patients during its 6 years of existence, corresponding to ~ 60% of ACH patients living in the Czechia and Slovak Republic. The registry continues to collect ACH patient data with annual frequency to monitor the growth and other parameters in preparation for future therapy.

Effect of pirfenidone on lung function decline and survival: 5-yr experience from a real-life IPF cohort from the Czech EMPIRE registry.

INTRODUCTION: Pirfenidone, an antifibrotic drug, slows-down the disease progression in idiopathic pulmonary fibrosis (IPF) over 12 months, however limited data on the decline of lung function and overall survival (OS) in real-world cohorts on longer follow-up exists. PATIENTS/METHODS: Of the enrolled Czech IPF patients (n = 841) from an EMPIRE registry, 383 (45.5%) received pirfenidone, 218 (25.9%) no-antifibrotic treatment and 240 (28.5%) were excluded (missing data, nintedanib treatment). The 2- and 5-yrs OS and forced vital capacity (FVC) and diffusing lung capacity for carbon monoxide (DLCO) were investigated at treatment initiation and 6, 12, 18 and 24 months' follow-up. RESULTS: During a 2-yr follow-up, less than a quarter of the patients progressed on pirfenidone as assessed by the decline of ≥10% FVC (17.0%) and ≥ 15% DLCO (14.3%). On pirfenidone, the DLCO (≥10%) declines at 6, 12, 18 and 24 months' and DLCO (≥15%) declines at 6, 18 and 24 months' follow-up were associated with increased mortality. The DLCO decline showed higher predictive value for mortality than FVC decline. In patients with no-antifibrotics, FVC and DLCO declines were not predictive for mortality. Pirfenidone increased 5-yrs OS over no-antifibrotic treatment (55.9% vs 31.5% alive, P = 0.002). CONCLUSION: Our study observed the 2-yrs sustained effect of pirfenidone on the decline of lung function and survival in the real-world patient's IPF cohort. DLCO decline of ≥10% shows a potential as a mortality predictor in IPF patients on pirfenidone, and should be routinely evaluated during follow-up examinations.

EMPIRE Registry, Czech Part: Impact of demographics, pulmonary function and HRCT on survival and clinical course in idiopathic pulmonary fibrosis.

INTRODUCTION: Prognostic factors of idiopathic pulmonary fibrosis (IPF) currently recognized include changes in vital capacity and radiologic findings. However, most of the prognostic studies in IPF are based on clinical studies with preselected IPF populations. Therefore, we decided to analyze the factors influencing IPF prognosis based on the real-practice data from our IPF registry. METHODS: Data of 514 subjects consecutively entered since 2012 into Czech EMPIRE IPF registry were analyzed. RESULTS: Median age of our patient cohort was 67 years (50-82). Median overall survival (OS) of the cohort was 63.1 months. The clinical course of IPF according to FVC (forced vital capacity) changes was stabilized in 32.8% of patients (29.7% according to DLCO [diffuse lung capacity] changes), slowly progressive in 39.5% (45%), rapidly progressive in 23.5% (20.7%); and 1.7% patients had at least one acute exacerbation during follow-up. Deterioration in FVC of ≥10% at month 12 and in DLCO of ≥15% at months 12, 18, and 24 influenced the OS significantly. The fast progressors defined by the DLCO decline rate had higher risk of death compared to those defined by the FVC change over time. In multivariate analysis, age ≥70 years, interstitial HRCT scores ≥3, and change in DLCO of ≥15% at month 12 were confirmed as factors negatively influencing OS. CONCLUSIONS: DLCO changes over time were shown as a better predictor of mortality compared with FVC changes in our study. In our opinion it is necessary to implement the DLCO analysis into clinical trials and routine practice.

European Cross-Sectional Survey of Current Care Practices for Duchenne Muscular Dystrophy Reveals Regional and Age-Dependent Differences.

BACKGROUND: Publication of comprehensive clinical care guidelines for Duchenne muscular dystrophy (DMD) in 2010 was a milestone for DMD patient management. Our CARE-NMD survey investigates the neuromuscular, medical, and psychosocial care of DMD patients in Europe, and compares it to the guidelines. METHODS: A cross-sectional survey of 1677 patients contacted via the TREAT-NMD patient registries was conducted using self-report questionnaires in seven European countries. RESULTS: Survey respondents were 861 children and 201 adults. Data describe a European DMD population with mean age of 13.0 years (range 0.8-46.2) of whom 53% had lost ambulation (at 10.3 years of age, median). Corticosteroid medication raised the median age for ambulatory loss from 10.1 years in patients never medicated to 11.4 years in patients who received steroids (p < 0.0001). The majority of patients reported receiving care in line with guidelines, although we identified significant differences between countries and important shortcomings in prevention and treatment. Summarised, 35% of patients aged≥ nine years received no corticosteroid medication, 24% of all patients received no regular physiotherapy, echocardiograms were not performed regularly in 22% of patients, pulmonary function was not regularly assessed in 71% of non-ambulatory patients. Patients with regular follow-up by neuromuscular specialists were more likely to receive care according to guidelines, were better satisfied, and experienced shorter unplanned hospitalization periods.

Mapping the differences in care for 5,000 spinal muscular atrophy patients, a survey of 24 national registries in North America, Australasia and Europe.

Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder characterised by the degeneration of motor neurons and progressive muscle weakness. It is caused by homozygous deletions in the survival motor neuron gene on chromosome 5. SMA shows a wide range of clinical severity, with SMA type I patients often dying before 2 years of age, whereas type III patients experience less severe clinical manifestations and can have a normal life span. Here, we describe the design, setup and utilisation of the TREAT-NMD national SMA patient registries characterised by a small, but fully standardised set of registry items and by genetic confirmation in all patients. We analyse a selection of clinical items from the SMA registries in order to provide a snapshot of the clinical data stratified by SMA subtype, and compare these results with published recommendations on standards of care. Our study included 5,068 SMA patients in 25 countries. A total of 615 patients were ventilated, either invasively (178) or non-invasively (437), 439 received tube feeding and 455 had had scoliosis surgery. Some of these interventions were not available to patients in all countries, but differences were also noted among high-income countries with comparable wealth and health care systems. This study provides the basis for further research, such as quality of life in ventilated SMA patients, and will inform clinical trial planning.