Genetic determinants for methotrexate response in juvenile idiopathic arthritis

Abstract

Juvenile idiopathic arthritis (JIAs) is the most common chronic rheumatic disease of childhood and is an important cause of disability. The folic acid analog methotrexate is the first choice disease-modifying anti-rheumatic drug in this disease, however, 35–45% of patients fail to respond. Molecular elements, such as variants in genes of pharmacological relevance, influencing response to methotrexate in JIA, would be important to individualize treatment strategies. Several studies have evaluated the effects of candidate genetic variants in the complex pathway of genes involved in methotrexate pharmacodynamics and pharmacokinetics, however, results are still contrasting and no definitive genetic marker of methotrexate response useful for the clinician to tailor therapy of children with JIA has been identified. Recently, genome-wide approaches have been applied, identifying new potential biological processes involved in methotrexate response in JIA such as TGF-beta signaling and calcium channels. If these genomic results are properly validated and integrated with innovative analyses comprising deep sequencing, epigenetics, and pharmacokinetics, they will greatly contribute to personalize therapy with methotrexate in children with JIA.

Methotrexate efficacy, but not its intolerance, is associated with the dose and route of administration

“…Treatment response at 6 and/or 12 months is expressed by the percentage of patients achieving ACRpedi70 and/or CID. Proportion of MTX responders at 6 months is similar across most of the studies ranging from 38 to 56 % of patients [ 33 , 44 – 53 ], similar to our results. Only a few studies provide information on the rate of inactive disease [ 43 ].…”

“… 51/NA 66/NA 152 0.8 yrs (med) 0.42 mg/kg (s.c.) 53/NA Bulatovič 2012 [ 13 ] 104 ≥1 yrs 9.8 mg/m 2 (NA) 38.5/NA 50/NA Wallace 2012 [ 43 ] 43 5.2 mo (mean) 0.5 mg/kg (s.c.) NA/23.3 NA/16.3 Moncrieffe2013 [ 51 ] 87 1.3 yrs (med) 10–15 mg/m 2 (70 % p.o.) 56.3/NA Pastore 2015 [ 53 ] 69 1.0 yrs (med) 15 mg/m 2 (62 % p.o.) 52.2/NA Fraňova 2016 55 3.5 mo (med) 14.2 mg/m 2 (18 % p.o.)…”

“…Among these high serum concentration of MRP8/14 protein at baseline [ 51 ] and long-chain MTX polyglutamates at 3 months of the treatment [ 52 ] predicted a favourable response to MTX. From genetic factors single-nucleotide polymorphisms of genes involved in MTX metabolic pathways and some novel candidate genes have been suggested, though their relevance is yet to be confirmed [ 53 – 55 ].…”

Disease modifying anti-rheumatic drugs in juvenile idiopathic arthritis: striving for individualized therapy

“…Pharmacogenomic approaches towards the determination of the role of genetic variation on MTX response in JIA has recently been reviewed elsewhere [86]. The majority of these efforts have used targeted pharmacogenetic strategies to evaluate the relationship between polymorphisms of candidate genes and clinical response to MTX.…”

Pharmacogenetics – Instrument for Prognosis of the Efficacy and Safety of Methotrexate

“…Однако проведенные исследования не выявили закономерности между концентрацией глутаминированных метаболитов в эритроцитах и активностью заболевания или частотой развития нежелательных реакций [10,11]. На уровень концентрации метотрексата может оказывать влияние уровень экспрессии мембранного белка Р-гликопротеина из семейства ABC-транспортеров, который принимает участие в элиминации фолатов и антифолатов из клетки [12]. Кроме того, установлено, что на фоне низких доз метотрексата повышается высвобождение аденозина.…”