ALS/MND 2023: European study spotting factors that affect progression
Analyses of data covering nearly 21,600 patients taking part in PRECISION-ALS
Consistent with known risk factors for ALS progression, C9ORF72 genetic mutations, bulbar-onset disease, and faster functional declines were linked to a shorter survival time, as was older age at disease onset.
However, differences were seen among the project’s centers in the time it took for interventions like feeding tube placement (gastrostomy) or noninvasive ventilation to be needed, and the reasons require further study, according to the scientists.
Harry McDonough, a clinical researcher at the University of Sheffield in England, and Alejandro Caravaca Puchades, a clinician at the Hospital of Bellvitge in Spain, discussed findings in the oral presentation “Mapping the natural history of ALS in Europe,” given at the 34th International Symposium on ALS/MND held last week in Basel, Switzerland, and virtually. It was supported by Biogen, which also supports the PRECISION-ALS study.
Likely ALS progression via factors like speed of diagnosis, disease type at onset
PRECISION-ALS, launched last year, is a European collaboration with the broad goal of better understanding the natural history of ALS and the factors that influence differences in disease symptoms and progression among patients.
“We know that ALS is a condition with lots of variation between individuals,” McDonough said in the presentation. “By studying the natural history we hope to be able to understand the factors that impact this variation, and hopefully, in turn, that helps us clinically to improve outcomes for our patients … [and] hopefully directing them towards trials that are most likely to benefit them.”
Nine clinical sites across eight countries are involved in the project, which brings together clinical researchers, data scientists, and industry partners.
The recent analysis concerned PRECISION-ALS’ extant data study, meaning it was an analysis of previously collected and existing clinical data. All nine sites contributed information from patients in their individual databases, which were combined for a population-based assessment of ALS progression from symptom onset, to diagnosis, clinical interventions, and death.
Data covered 21,571 ALS patients, mostly male (57.2%). Across the entire group, the median age at symptom onset was 63.9, with a delay of about one year between symptom onset and an ALS diagnosis.
Disease onset tended to be earlier in men, patients with spinal-onset ALS — where symptoms of limb weakness are the first to emerge — and those with mutations in the ALS-associated genes FUS or SOD1.
Individuals with bulbar-onset ALS — where symptoms initially affect muscles in the head and neck needed for speech, swallowing, and breathing — and those with mutations in the C9ORF72 gene experienced a shorter diagnostic delay.
An earlier symptom onset tended to link with a slower functional decline — indicated by a less than 0.3 point monthly decline in a patient’s ALS Functional Rating Scale-Revised (ALSFRS-R) scores — compared with patients with intermediate or quickly progressing disease. In turn, a faster functional decline, defined as a monthly change in ALSFRS-R scores of more than 1.06, was associated with a shorter diagnostic delay.
Earlier need for gastrostomy seen with bulbar onset, C9ORF7 mutations
Overall median survival among these patients was 2.59 years. Bulbar-onset ALS, fast disease progression, older age at onset (ages 70 and older), and FUS and C9ORF7 mutations all were seen as independent predictors of poorer survival in a final analysis. Better lung function and a slower arrival at a definitive ALS diagnosis linked with longer survival times.
The time to reach certain clinical interventions — namely, gastrostomy and noninvasive ventilation — also were influenced by these factors, with bulbar-onset ALS and C9ORF7 mutations linked to an earlier need for a gastrostomy.
In adjusted statistical analyses, the start of noninvasive ventilation was significantly associated with respiratory-onset ALS and male sex, whereas better lung function and a longer diagnostic delay again were seen to protect against a need for such ventilation.
Notably, significant differences among clinical sites were seen in the time from ALS diagnosis to a gastrostomy or noninvasive ventilation, as well as in patients’ average lung function when ventilation started.
Analyses taking these factors into account indicated that centers with less ready use of noninvasive ventilation had poorer survival outcomes, but these differences were not statistically significant.
“It’s important to note that given the significant amount of missing data that we have, it is difficult to draw conclusions on this alone,” McDonough said.
Currently, it’s not clear whether differences among clinical sites are “due to differences in clinical practice, differences in the cohorts between these clinical centers, or data collection or a combination of these factors,” the scientists noted.
PRECISION-ALS is working on a prospective study, where data will be collected across its nine sites using a specific data platform, to help improve uniformity.