Levetiracetam pharmacokinetics and its covariates: proposal for optimal dosing in the paediatric population.

OBJECTIVES: Levetiracetam is an anticonvulsive drug increasingly used in paediatric populations. Ontogenesis may alter its pharmacokinetics, demanding dose individualisation of levetiracetam in paediatric populations. We therefore aimed to explore levetiracetam pharmacokinetics and to propose its optimal dosing in the paediatric population. METHODS: Individual levetiracetam pharmacokinetic parameters were calculated based on therapeutic drug monitoring data, using a one-compartmental model, and regression models were used to explore possible covariates. RESULTS: 56 patients aged from 47 days to 18 years were included in the analysis. The median (IQR) volume of distribution and clearance of levetiracetam were 0.7 (0.58-0.85) L/kg and 0.123 (0.085-0.167) L/hour/kg, respectively. Levetiracetam pharmacokinetics were influenced by postnatal age, body size descriptors and renal functional status. CONCLUSIONS: Based on observed relationships, an individualised loading dose of 26.2 mg/kg body weight and maintenance dose of 20.7 mg/mL/min of estimated glomerular filtration rate were calculated as optimal. Since we observed increased levetiracetam clearance in association with valproate co-medication, caution should be used when combining these two drugs.

Can ultrasound help to overcome uncertainty in clinical joint assessment in juvenile idiopathic arthritis?

OBJECTIVES: Assessment of active synovitis is crucial for the management of juvenile idiopathic arthritis (JIA). We aimed to investigate the correlation of musculoskeletal ultrasound (MSUS) and clinical examination results and relate them to arthritis relapse rate. METHODS: JIA patients with questionable presence of active arthritis (Q-joints) and controls (JIA and healthy children) were recruited. MSUS of Q-joints, active joints and their inactive counterparts was performed at study entry. Standard disease activity parameters were prospectively recorded. RESULTS: Of 481 joints of 138 JIA patients, 99 joints (20.6%) of 58 patients had one or more Q-joints with 54/99 (54.5%) having MSUS features of active disease. Clinically inactive joints had lower proportion of MSUS synovitis (78/253, 30.8%) while MSUS activity was present in 114/129 (88.4%) of clinically active joints and in 2/105 (1.9%) joints of 36 healthy controls. Within the 15-month follow-up 23/99 (22%) Q-joints and 31/253 (12%) clinically inactive joints relapsed. Joints with subclinical synovitis relapsed more frequently than MSUS inactive ones (p<0.001). The relapse rate was higher in MSUS-active Q-joints (19/23, 82%) than in clinically inactive ones (16/31, 52%) with MSUS synovial hypertrophy as the main relapse predictor in multivariate analysis. Ankle and knee joints relapsed most frequently. CONCLUSIONS: Acknowledgement of joints with questionable synovitis may contribute to the assessment of disease activity in JIA. Presence of MSUS synovitis carries a clinically meaningful risk of disease recurrence in these joints. In clinical practice, our findings encourage timely MSUS assessment of the joints in question, especially in patients without any other features of active disease.

Outcomes of SARS-CoV-2 infection among children and young people with pre-existing rheumatic and musculoskeletal diseases.

OBJECTIVES: Some adults with rheumatic and musculoskeletal diseases (RMDs) are at increased risk of COVID-19-related death. Excluding post-COVID-19 multisystem inflammatory syndrome of children, children and young people (CYP) are overall less prone to severe COVID-19 and most experience a mild or asymptomatic course. However, it is unknown if CYP with RMDs are more likely to have more severe COVID-19. This analysis aims to describe outcomes among CYP with underlying RMDs with COVID-19. METHODS: Using the European Alliance of Associations for Rheumatology COVID-19 Registry, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry, and the CARRA-sponsored COVID-19 Global Paediatric Rheumatology Database, we obtained data on CYP with RMDs who reported SARS-CoV-2 infection (presumptive or confirmed). Patient characteristics and illness severity were described, and factors associated with COVID-19 hospitalisation were investigated. RESULTS: 607 CYP with RMDs <19 years old from 25 different countries with SARS-CoV-2 infection were included, the majority with juvenile idiopathic arthritis (JIA; n=378; 62%). Forty-three (7%) patients were hospitalised; three of these patients died. Compared with JIA, diagnosis of systemic lupus erythematosus, mixed connective tissue disease, vasculitis, or other RMD (OR 4.3; 95% CI 1.7 to 11) or autoinflammatory syndrome (OR 3.0; 95% CI 1.1 to 8.6) was associated with hospitalisation, as was obesity (OR 4.0; 95% CI 1.3 to 12). CONCLUSIONS: This is the most significant investigation to date of COVID-19 in CYP with RMDs. It is important to note that the majority of CYP were not hospitalised, although those with severe systemic RMDs and obesity were more likely to be hospitalised.