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23rd July 2021
Elevated levels of low-density lipoprotein cholesterol (LDL-C) leads to the development of atherosclerosis and is a risk factor for cardiovascular disease. Some evidence suggests an association between childhood obesity and the subsequent risk of biochemical abnormalities in adults. Nevertheless, there is a lack of longitudinal data linking the presence of childhood cardiovascular risk factors with adult disease. Furthermore, little is known about the extent to which risk factors such as LDL-C levels vary during childhood and how this might contribute towards atherosclerosis and adverse cardiovascular outcomes in adult life. A better understanding the childhood trajectories of LDL-C cholesterol could lead to improved preventative strategies. In trying to shed more light on this topic, a team from the Division of General Medicine, Columbia University, Irving Medical Centre, New York, turned to data available in the International Childhood Cardiovascular Cohort (i3C) Consortium. While children virtually never experience adverse cardiovascular events, the i3C is the first longitudinal cohort study designed to locate adults with detailed and repeated childhood biological, and physical measurements and includes over 10,000 individuals from several countries. The Irving Medical Centre team used data from i3C individuals who had at least one LDL-C measurement between the ages of 3 and 17 years of age and extracted demographic and body mass index information from these participants. The team considered LDL-C levels greater than 160mg/dl (4.14mmol/l) as consistent with probable familial hypercholesterolaemia (FH) and used the more stringent criteria of an LDL-C of greater than 160mg/dl on at least two occasions and a level of LDL-C of 190mg/dl or greater as a threshold for FH. In order to examine LDL-C trajectories during childhood, the team fitted a linear model of LDL-C against age, adjusting for sex, ethnicity and body mass index.
A total of 15,045 children with a mean age of 9.9 years (48.7% male) were included in the analysis. Overall, 2.8% of children had an LDL-C greater than 160mg/dl and 0.6% had values exceeding 190mg/dL. Using the more stringent criteria, 1% of children had elevated LDL-C levels (> 160mg/dL) on two occasions and 0.3%, levels above 190mg/dl, consistent with FH. Using the linear model it could be seen that mean LDL-C cholesterol levels increased from age 3 to 10 years, decreased from age 10 to 15 but then increased again to reach adult levels. LDL-C levels were consistently and significantly higher in female children and those of Black ethnicity or with a higher body mass index.
In a discussion of their findings, the authors noted how LDL-C levels peaked between ages 9 and 11 and that these levels were comparable to those aged 18 years. This, the authors suggested, highlighted the importance of childhood lipid screening from as early as 9 years of age.
Zhang Y et al. Low-Density Lipoprotein Cholesterol Trajectories and Prevalence of High Low-Density Lipoprotein Cholesterol Consistent with Heterozygous Familial Hypercholesterolemia in US Children. JAMA Pediatr 2021
24th June 2021
The European Medicines Agency, has extended the licensed indication for teriflunomide to include its use in children from 10 years of age. The drug is used for the treatment of relapsing-remitting multiple sclerosis, a chronic, inflammatory, autoimmune disease that affects an estimated 2.8 million people worldwide. However, MS is not purely an adult disease and it is estimated that over 30,000 cases occur in those 18 years or less. This paediatric MS is normally defined as an MS with an onset before the age of 16 years (sometimes before the age of 18 years). There are also noticeable differences between paediatric MS adult disease. For instance, more than 98% of those with paediatric MS experience a relapsing-remitting pattern (compared to 84% in adults) and children have a three-fold greater (than adults) rate of disease relapse. Moreover, paediatric MS has a negative impact on a child’s psychological wellbeing, affecting their self-image, role functioning, mood, cognition as well as an adverse effect on schooling.
The mode of action of teriflunomide in MS is thought to be related to its effects on the proliferation of stimulated lymphocytes. The drug selectively and competitively blocks the enzyme, dihydro-orotate dehydrogenase, which plays a key role in the de novo synthesis of pyrimidines and which are required in proliferating lymphocytes. An oral formulation of the drug was approved by the EU in 2013 for the use in adults based on the results of four studies involving over 2700 adults with relapsing-remitting MS.
The extension of the license for paediatric use was granted by the European Medicines Agency (EMA) based on the results of the TERIKIDS study, which is a 96-week, randomised, double-blind, placebo-controlled, parallel-group Phase III study of teriflunomide in paediatric RMS patients. Participants receive either placebo or teriflunomide (based on body weight equivalent to 14mg in adults) and the eligibility criterion is that patients had greater than one or two relapses within the last 12 or 24 months. The study enrolled patients, aged 10–17 years, with a mean age of 14.6 years (67% female) with 109 in the teriflunomide and 57 in the placebo arms. The primary endpoint was the time to first confirmed relapse and one of the secondary outcomes was MRI lesion number.
A summary of the results were presented at the 2020 EAN Virtual Congress which revealed how teriflunomide reduced the risk of clinical relapse by 34% relative to placebo (75.3 vs 39.1 weeks), however, this reduction was not statistically significant (hazard ratio, HR = 0.66, 95% CI 0.66–1.10, p =0.29). The MRI analysis revealed that teriflunomide significantly reduced the number of T1 gadolinium (Gd)-enhancing lesions per MRI scan (relative reduction 75%; p<0.0001) as well as the number of new and enlarging T2 lesions per MRI scan (relative reduction 55%, p=0.0006). Furthermore, overall incidences of adverse events and serious adverse events were similar in the teriflunomide and placebo groups (88.1% vs 82.5%, and 11.0% vs 10.5%) respectively and there were no deaths. Overall, teriflunomide appeared to be well tolerated.