Role of methotrexate in juvenile idiopathic arthritis: where we have been and where we are going

Becker, Mara L.

doi:10.2217/ijr.12.81

Cited by 3 publications

(6 citation statements)

References 62 publications

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“…Pharmaceutical companies have, for a long time, shunned paediatric research by ignoring the importance of therapeutic trials of medication in children [1][2][3][4]. This was because pharmaceutical companies considered the paediatric population as a small and unlucrative market to sponsor, where their cost of rigorous clinical trials could not be reclaimed [5,6].…”

Section: Paradox Of the Paediatric Orphanmentioning

confidence: 99%

“…In order to evade paediatric endorsement, pharmaceutical companies placed a clause on medication labels, not recommending their medications for paediatric usage [7,9]. In fact, in 1991 in the USA, 81% of medications contained this disclaimer [10], and as a consequence, most medications prescribed for children were officially not licensed (unlicensed); or used outside of the terms of the license (off-labelled) [2][3][4]. This meant prescribers were left to draw on the results of adult studies to conclude the child's therapeutic response and dosage requirements [1,4], whilst making assumptions as to the physical and physiological differences between adults and children [7,10], and the pharmacokinetic variances seen from childhood to young adulthood (neonates, infants, children, and adolescents) that can alter drug absorption, distribution, metabolism and excretion [4,11].…”

Section: Paradox Of the Paediatric Orphanmentioning

confidence: 99%

“…Due to a lack of paediatric specific research, the treatment of JIA was conservatively based on adult rheumatic disease [21]. Adult mainstay treatment followed the principles of the therapeutic pyramid [22], in other words, an escalation of steps [23], to target excessive inflammation and pain [3,21]. Generally, this was achieved through mild analgesia, NSAIDs such as salicylic acid (Aspirin), and if needed, corticosteroids [3,21,24].…”

Section: Treatment Guided By Expert Opinion and Close Monitoringmentioning

confidence: 99%

“…Adult mainstay treatment followed the principles of the therapeutic pyramid [22], in other words, an escalation of steps [23], to target excessive inflammation and pain [3,21]. Generally, this was achieved through mild analgesia, NSAIDs such as salicylic acid (Aspirin), and if needed, corticosteroids [3,21,24]. Children were then closely monitored for side effects, such as gastrointestinal irritation and hepatotoxicity [24], osteopenia and growth retardation [25].…”

Section: Treatment Guided By Expert Opinion and Close Monitoringmentioning

confidence: 99%

“…This turned the principles guiding the therapeutic triangle upside down [30], as the focus of care turned to early aggressive treatment to control disease and prevent tissue damage [23,29]. The disease-modifying antirheumatic drugs (DMARD), methotrexate (MTX), became the forefront of treatment, for children that failed to respond sufficiently to the NSAIDs [3,31]. MTX is a folic acid analogue that inhibits the folate pathway, interfering with tissue cell reproduction [32], transforming the outlook for many children with JIA [29].…”

Section: Early Aggressive Treatment and The Promotion Of Self-managementmentioning

confidence: 99%

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Paediatric Rheumatology Fails to Meet Current Benchmarks, a Call for Health Equity for Children Living with Juvenile Idiopathic Arthritis, Using Digital Health Technologies

Butler,

Sculley,

Santos

et al. 2024

Curr Rheumatol Rep

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Purpose of Review This critical review begins by presenting the history of Juvenile Idiopathic Arthritis (JIA) management. To move the conversation forward in addressing the current shortcomings that exist in the clinical management of children living with JIA, we argue that to date, the advancement of successful treatments for JIA has been historically slow. Factors implicated in this situation include a lack of rigorous research, JIA being considered a rare disease, and JIA’s idiopathic and complex pathophysiology. Recent Findings Despite the well-intended legislative changes to increase paediatric research, and the major advancements seen in molecular medicine over the last 30 years, globally, paediatric rheumatology services are still failing to meet the current benchmarks of best practice. Provoking questions on how the longstanding health care disparities of poor access and delayed treatment for children living with JIA can be improved, to improve healthcare outcomes. Summary Globally, paediatric rheumatology services are failing to meet the current benchmarks of best practice. Raising awareness of the barriers hindering JIA management is the first step in reducing the current health inequalities experienced by children living with JIA. Action must be taken now, to train and well-equip the paediatric rheumatology interdisciplinary workforce. We propose, a resource-efficient way to improve the quality of care provided could be achieved by embedding digital health into clinical practice, to create an integrative care model between the children, general practice and the paediatric rheumatology team. To improve fragmented service delivery and the coordination of interdisciplinary care, across the healthcare system.

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Section: Paradox Of the Paediatric Orphanmentioning

confidence: 99%

Section: Paradox Of the Paediatric Orphanmentioning

confidence: 99%

Section: Treatment Guided By Expert Opinion and Close Monitoringmentioning

confidence: 99%

Section: Treatment Guided By Expert Opinion and Close Monitoringmentioning

confidence: 99%

Section: Early Aggressive Treatment and The Promotion Of Self-managementmentioning

confidence: 99%

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Paediatric Rheumatology Fails to Meet Current Benchmarks, a Call for Health Equity for Children Living with Juvenile Idiopathic Arthritis, Using Digital Health Technologies

Butler,

Sculley,

Santos

et al. 2024

Curr Rheumatol Rep

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PP13. Intravenous methotrexate: a single-centre experience

Mosley¹,

Warrier²,

Kelsall³

et al. 2015

Rheumatology

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Erythrocyte Folyl Polyglutamate Synthetase Activity Profiling as a Potential Tool for the Prediction of Methotrexate Efficacy and Toxicity in Rheumatoid Arthritis

Kumar,

Arain,

Bhadbhade

et al. 2023

Future Pharmacology

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Methotrexate (MTX) is the cornerstone of therapy in the treatment of rheumatoid arthritis (RA). However, its efficacy and toxicity are variable and remain unpredictable. Interindividual variation in the metabolism of MTX by the enzyme folyl polyglutamate synthetase (FPGS) has been associated with response variability in RA. In this work, we propose the development of a FPGS phenotyping assay that can be evaluated as a tool for the prediction of efficacy and toxicity in patients with RA prior to initiating MTX therapy. FPGS activity was measured in erythrocyte lysate by monitoring methotrexate polyglutamate (MTX + Glun) formation using ultra-performance liquid chromatography tandem–mass spectrometry (UPLC/MS/MS). Erythrocyte FPGS activity was measured in newly diagnosed RA (n = 35) and osteoarthritis (n = 7) patients. The enzymatic assay was optimized for measuring FPGS activity in 25 µL of packed erythrocytes over two hours. The coefficient of variation for intra- and inter-day analysis was found to be 5% and 12%, respectively. The method was used to measure FPGS enzyme kinetics, resulting in a mean (SD) Km of 30.3 (4.8) µM and a Vmax of 612 (193) pmol MTX + Glu2/h/mL of packed erythrocytes. Mean (SD) erythrocyte FPGS activity in patients with RA was found to be 445.93 (344.50) pmol MTX + Glu2/h/mL and with a 26-fold difference in the range (range: 83–2179 pmol MTX + Glu2/h/mL) whereas for patients with OA, it was found to be 409.80 (157.66) pmol MTX + Glu2/h/mL with a 3.5-fold difference in the range (range: 200.95–683.93 pmol MTX + Glu2/h/mL). Monitoring erythrocyte FPGS activity may be a feasible strategy of phenotyping for methotrexate efficacy and toxicity in patients with RA.

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Role of methotrexate in juvenile idiopathic arthritis: where we have been and where we are going

Cited by 3 publications

References 62 publications

Paediatric Rheumatology Fails to Meet Current Benchmarks, a Call for Health Equity for Children Living with Juvenile Idiopathic Arthritis, Using Digital Health Technologies

Paediatric Rheumatology Fails to Meet Current Benchmarks, a Call for Health Equity for Children Living with Juvenile Idiopathic Arthritis, Using Digital Health Technologies

PP13. Intravenous methotrexate: a single-centre experience

Erythrocyte Folyl Polyglutamate Synthetase Activity Profiling as a Potential Tool for the Prediction of Methotrexate Efficacy and Toxicity in Rheumatoid Arthritis

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