Methotrexate polyglutamates as a potential marker of adherence to long-term therapy in children with juvenile idiopathic arthritis and juvenile dermatomyositis: an observational, cross-sectional study.
BACKGROUND
Methotrexate (MTX) is a cornerstone of treatment in a wide variety of inflammatory conditions, including juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis (JDM). However, owing to its narrow therapeutic index and the considerable interpatient variability in clinical response, monitoring of adherence to MTX is important. The present study demonstrates the feasibility of using methotrexate polyglutamates (MTXPGs) as a biomarker to measure adherence to MTX treatment in children with JIA and JDM.


METHODS
Data were collected prospectively from a cohort of 48 children (median age 11.5 years) who received oral or subcutaneous (SC) MTX therapy for JIA or JDM. Dried blood spot samples were obtained from children by finger pick at the clinic or via self- or parent-led sampling at home, and they were analysed to determine the variability in MTXPG concentrations and assess adherence to MTX therapy.


RESULTS
Wide fluctuations in MTXPG total concentrations (>2.0-fold variations) were found in 17 patients receiving stable weekly doses of MTX, which is indicative of nonadherence or partial adherence to MTX therapy. Age (P = 0.026) and route of administration (P = 0.005) were the most important predictors of nonadherence to MTX treatment. In addition, the study showed that MTX dose and route of administration were significantly associated with variations in the distribution of MTXPG subtypes. Higher doses and SC administration of MTX produced higher levels of total MTXPGs and selective accumulation of longer-chain MTXPGs (P < 0.001 and P < 0.0001, respectively).


CONCLUSIONS
Nonadherence to MTX therapy is a significant problem in children with JIA and JDM. The present study suggests that patients with inadequate adherence and/or intolerance to oral MTX may benefit from SC administration of the drug. The clinical utility of MTXPG levels to monitor and optimise adherence to MTX in children has been demonstrated.


BACKGROUND
ISRCTN Registry identifier: ISRCTN93945409 . Registered 2 December 2011.
Clinical and Practice Research Group, School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, BT9 7BL, Belfast, UK. a.hawwa@aston.ac.uk.|Aston Pharmacy School, Aston University, Birmingham, UK. a.hawwa@aston.ac.uk.
Ahmed F
AF
Hawwa
Clinical and Practice Research Group, School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, BT9 7BL, Belfast, UK. aalbawab02@qub.ac.uk.|Faculty of Pharmacy, Al Zaytoonah University, Amman, Jordan. aalbawab02@qub.ac.uk.
AbdelQader
A
AlBawab
Centre for Infection and Immunity, School of Medicine and Biomedical Sciences, Queen's University Belfast, Belfast, UK. m.rooney@qub.ac.uk.
Madeleine
M
Rooney
Institute of Child Health, University College London, London, UK. l.wedderburn@ucl.ac.uk.|Arthritis Research UK Centre for Adolescent Rheumatology, University College London, University College London Hospital, London, UK. l.wedderburn@ucl.ac.uk.|Department of Rheumatology, Great Ormond Street Hospital NHS Foundation Trust, London, UK. l.wedderburn@ucl.ac.uk.
Lucy R
LR
Wedderburn
Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, The Alder Hey Children's NHS Foundation Trust, Liverpool, UK. m.w.beresford@liverpool.ac.uk.
Michael W
MW
Beresford
Clinical and Practice Research Group, School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, BT9 7BL, Belfast, UK. j.mcelnay@qub.ac.uk.
James C
JC
McElnay
D000293:Adolescent; D018501:Antirheumatic Agents / Q000378:metabolism / Q000627:therapeutic use*; D001171:Arthritis, Juvenile / Q000188:drug therapy*; D015415:Biomarkers / Q000097:blood; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D003430:Cross-Sectional Studies; D003882:Dermatomyositis / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D055118:Medication Adherence; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000097:blood; D011446:Prospective Studies; D053719:Tandem Mass Spectrometry
D018501:Antirheumatic Agents; D015415:Biomarkers; D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; D008727:Methotrexate