Methotrexate In Juvenile Idiopathic Arthritis Research Articles

Relationship between SLCO1B1 polymorphisms and methotrexate intolerance in Mexican children with juvenile idiopathic arthritis.

The most frequent adverse events (AEs) of methotrexate (MTX) are gastrointestinal symptoms and hepatotoxicity, which can affect its adherence, leading to reduced effectiveness. The SLCO1B1 gene codes for a liver protein (OATP1B1) responsible for drug transportation. Genetic variations within the SLCO1B1 gene locus impact drug transport, leading to altered pharmacokinetic profiles, delayed MTX clearance, and increased risk of toxicity. This study aimed to determine the association between single nucleotide polymorphisms (SNPs) in the SLCO1B1 gene (rs4149056, rs2306283) with the development of AEs in patients with juvenile idiopathic arthritis (JIA) treated with MTX. We performed an observational retrospective study to analyze the relationship between SNPs in the SLCO1B1 gene and the development of AEs in pediatric patients treated with MTX for JIA. Thirty patients with JIA were included, 22 females (73.3%), with a median age of 11years (IQR 8.3-15). The most frequent JIA subtype was rheumatoid factor-positive polyarthritis (36.7%). Twenty patients (66.7%) reported AEs. The *1B haplotype was the most frequent in this group (53.3%) and conferred a higher risk of developing AEs (OR = 3.89, 95% CI = 1.23 -12.29, p = 0.03). Patients with the allele *1B may benefit from lower doses of MTX. SLCO1B1 genotyping is a promising technique to identify patients at higher risk of AEs during treatment with MTX, thus requiring dose optimization.

Which accessible clinical features and laboratory findings might predict methotrexate success in children with juvenile idiopathic arthritis in Bosnia and Herzegovina?

<p><strong>Aim</strong> To determine whether demographic data, clinical features, and laboratory variables at disease onset can predict the response to methotrexate in juvenile idiopathic arthritis (JIA) patients. <br /><strong>Methods</strong> A cohort of 143 newly diagnosed JIA patients initially treated with methotrexate was enrolled in this study. Demographic, clinical, and laboratory parameters were analysed using univariate and multivariate logistic regression to identify predictors of response to methotrexate. The variables included erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), platelets, IgA, IgG, the number of active joints and age at disease onset. Treatment response was assessed at six months, with patients classified as responders (those who achieved clinically inactive disease according to the American College of Rheumatology - ACR criteria) or non-responders. <br /><strong>Results</strong> Poor response to methotrexate was associated with the number of active joints (p=0.0001; OR=2.7), baseline levels of CRP (p=0.044; OR=1.138), IgA (p =0.004; OR=2.159), and platelet count (p=0.01; OR=1.05). IgG level (P=0.236) did not correlate with the treatment response. <br /><strong>Conclusion</strong> We identified widely available and clinically acceptable biomarkers that can be utilized as predictive indicators of response to methotrexate in JIA patients.</p>

Predictors of lack of response to methotrexate in juvenile idiopathic arthritis associated uveitis

Abstract Objectives To investigate clinical features associated with lack of response to MTX in juvenile idiopathic arthritis associated uveitis (JIA-U). Methods Clinical records of JIA-U patients were retrospectively reviewed. Differences among variables were assessed by Mann–Whitney and χ2 or Fisher’s exact tests as appropriate. Association between predictors and requirement of a biological disease-modifying antirheumatic drug (bDMARD) was evaluated by univariate Cox regression analysis and Kaplan–Meier curves. A multivariable logistic model was applied to estimate strength of association, adjusting for potential confounders. Results Data from 99 JIA-U patients treated with MTX were analysed (82.8% female), with a mean follow up of 9.2 years and a mean age at uveitis onset of 5.7 years. In 65 patients (65.7%) at least one bDMARD to control uveitis was required. Children requiring a bDMARD for uveitis had lower age at JIA and uveitis onset, more frequent polyarticular course, higher frequency of bilateral uveitis at onset and higher prevalence of systemic steroids’ use. Despite similar frequency of ocular damage at onset, MTX non-responders showed a higher percentage of ocular damage at last visit. Younger age at JIA onset, polyarticular course and a history of systemic steroids’ use resulted independent factors associated to lack of response to MTX at Cox regression analysis. Kaplan–Meier curves and the multivariate model confirm the independent role of both polyarticular course and systemic steroids’ use. Conclusions Younger age at JIA onset, polyarticular course and a history of systemic steroids’ use are predictors of a worse response to MTX in JIA-U.

Acute myeloid leukemia developed through myeloproliferative features during immunosuppressive therapy for juvenile idiopathic arthritis.

A 17-year-old male with thrombocytosis and exacerbation of arthralgia during intensified immunosuppressive therapy with tocilizumab, prednisolone, and methotrexate for juvenile idiopathic arthritis (JIA) was referred to our department. Bone marrow examination revealed myelodysplastic syndrome/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U). Peripheral myeloblasts disappeared temporarily after discontinuation of tocilizumab but progressed to acute myeloid leukemia six months after the development of MDS/MPN-U. The patient sustained complete remission after unrelated bone marrow stem cell transplantation, followed by chemotherapy. The arthralgia also improved after chemotherapy. The possibility of developing malignancies during immunosuppressive therapy in patients with JIA should be considered. J. Med. Invest. 71 : 335-339, August, 2024.

Single nucleotide polymorphisms associated with methotrexate-induced nausea in juvenile idiopathic arthritis

BackgroundContext: Methotrexate (MTX) is a cornerstone in the treatment of juvenile idiopathic arthritis (JIA). MTX treatment is commonly associated with nausea. Large inter-individual variation exists in the level of MTX-induced nausea, possibly due to genetic factors.Purpose: To investigate whether MTX-induced nausea was associated with single nucleotide polymorphisms (SNPs) in genes encoding MTX-transporter proteins, a MTX metabolizing enzyme and a nausea receptor.FindingsMethods: Children aged ≥9 years treated with MTX for JIA were eligible. MTX-induced nausea was registered by the children’s completion of a nausea diary (min. 7 days) and the parents’ completion of the MTX intolerance severity score (MISS). The selected SNPs were: SLCO1B1 (rs4149056; rs4149081), SLCO1B3 (rs2117032), SLC19A1 (rs1051266), ABCC2 (rs2273697; rs3740066; rs717620), ABCB1 (rs2032582; rs1045642), MTHFR (rs1801131, rs1801133), HTR3A (rs1062613; rs1985242; rs1176713) and HTR3B (rs1176744).Result: Enrolled were 121 JIA patients (82 girls: 39 boys) with a median age of 13.3 years (IQR: 11.3–15.1). The median MTX dose was 9.7 mg/m2/week (IQR: 9.0–10.9). The median MTX treatment duration prior to enrolment was 340 days (IQR: 142–766). The SNP analysis was available for 119 patients. MTX intolerance was associated with the genotype distribution of rs1801133 (MTHFR) (p = 0.02). There was no additive effect of the minor alleles for any of the selected SNPs, nor any significant haplotype associations.ConclusionSummary: MTX-induced nausea may be influenced by genetic polymorphisms in a MTX metabolizing enzyme (rs1801133; MTHFR).Implications: Further analyses involving inclusion of larger cohorts are needed to understand the impact of SNPs on MTX-induced nausea in JIA.

The relationship of the immune response mediator genes’ polymorphic variants with the methotrexate efficacy in juvenile idiopathic arthritis

Background/aim The aim of the study was to analyze the relationship of the immune response mediator genes’ polymorphic loci (TNFA rs1800629, LTA rs909253, IL1B rs16944, IL2-IL21 rs6822844, IL2RA rs2104286, IL6 rs1800795, IL10 rs1800872, MIF rs755622, CTLA4 rs3087243, NFKB1 rs28362491, PTPN22 rs2476601, PADI4 rs2240336) variants with the methotrexate efficacy in juvenile idiopathic arthritis (JIA).Materials and methods The study included 274 JIA patients from the Republic of Bashkortostan, Russia. Achieving the American College of Rheumatology Pediatric 30 (ACR Pedi 30) response was regarded as the presence of the response to methotrexate (otherwise, as the absence), while achieving clinical remission on medication (Wallace et al., 2011) - as the sufficient response (otherwise, as the insufficient). Genotyping was conducted by the real-time polymerase chain reaction.Results Associations with an altered risk of the nonresponse to methotrexate in JIA were observed for the alleles/genotypes of the loci IL10 rs1800872 (in girls) and NFKB1 rs28362491 (in girls); with an altered risk of the insufficient response to methotrexate in JIA – for the alleles/genotypes of the loci IL1B rs16944 (in boys), CTLA4 rs3087243 (in boys), NFKB1 rs28362491 (in girls) and the haplotype TNFA rs1800629*A - LTA rs909253*G (in girls).Conclusion As a result of the study, the relationship of the alleles/genotypes of the IL1B rs16944, IL10 rs1800872, CTLA4 rs3087243, NFKB1 rs28362491 polymorphic loci and the TNFA rs1800629*A - LTA rs909253*G haplotype with the methotrexate efficacy in JIA was established (taking into account the differences by sex).

Methotrexate in juvenile idiopathic arthritis. Adverse effects and associated factors

IntroductionMethotrexate (MTX) is the drug of choice for juvenile idiopathic arthritis. Its clinical efficacy is limited due to the development of adverse effects (AEs). Patients and methodsA retrospective observational study was conducted on the AEs associated with MTX therapy in children diagnosed with juvenile idiopathic arthritis followed-up in a tertiary hospital between 2008 and 2016. ResultsThe study included a total of 107 patients, of whom 71 (66.3%) were girls (66.3%). The median age at diagnosis was 6.4 years (IQR 3.1–12.4), with a median follow-up of 45.7 months (IQR 28.8–92.4). There were 48 patients (44.9%) with oligo arthritis, and 26 children (24.3%) with rheumatoid-factor negative polyarthritis. Of these, 52/107 (48.6%) developed AEs, with the most frequent being gastrointestinal symptoms (35.6%) and behavioural problems (35.6%). An age older than 6 years at the beginning of therapy increased the risk of developing AEs, both in the univariate (OR = 3.5; 95% CI: 1.5–7.3) and multivariate (12% increase per year) analyses. The doses used, administration route, or clinical form according to International League of Associations for Rheumatology (ILAR) clasiification, were not associated with the development of AEs. Twenty children required a dosage or route of administration modification, which resolved the AE in 11 (55%) cases. MTX was interrupted due to the development of AEs in 37/107patients (34.6%), mainly due to increased plasma transaminases (n = 14, 37.8%), gastrointestinal symptoms (n = 9, 24.3%) and behavioural problems (n = 6, 16.3%). ConclusionsMTX is the therapy of choice for patients with juvenile idiopathic arthritis, but50% of the children develop some form of AE. Although the AEs are not severe, they lead to interruption of therapy in 35% of the children.

Association of SLCO1B1 *14 Allele with Poor Response to Methotrexate in Juvenile Idiopathic Arthritis Patients.

ObjectiveVariants in the SLCO1B1 gene, encoding a hepatic methotrexate (MTX) transporter, affect clearance of high‐dose MTX. We tested whether in the *14 and *15 alleles of SLCO1B1 influenced the response to low‐dose MTX in juvenile idiopathic arthritis (JIA) patients.MethodsThe study included 310 JIA patients genotyped for three single nucleotide polymorphisms (SNPs) in SLCO1B1 (rs4149056, rs2306283, and rs11045819). A patient's SLCO1B1 diplotype was determined by combining the SNPs into the *1a, *1b, *4, *5, *14, and *15 alleles. Number of active joints at follow‐up (visit closest to 6 months of treatment and prior to starting a tumor necrosis factor inhibitor) was used as the dependent variable in a negative binomial regression model that included active joint count at baseline as a covariate.ResultsThe SLCO1B1*14 allele was associated with less response to MTX (P = 0.024) and the *15 allele was not associated with response to MTX (P = 0.392).Conclusion SLCO1B1 alleles may be associated with poor response to MTX in JIA patients. The *14 allele has been associated with fast clearance (low exposure) after high‐dose MTX in patients with leukemia. Thus, the SLCO1B1 gene may be informative for precision dosing of MTX in JIA patients. Patients carrying the *14 allele may require a higher dose than noncarriers to achieve a similar response to MTX.

3019 Metabolomic Markers of Methotrexate Response in Juvenile Idiopathic Arthritis

OBJECTIVES/SPECIFIC AIMS: In this study, a semi-targeted metabolomics approach is used to identify metabolic markers of methotrexate (MTX) response in juvenile idiopathic arthritis (JIA) and in vitro. METHODS/STUDY POPULATION: A comparative metabolomic analysis was used to identify metabolomic markers and metabolic pathways associated with MTX activity in vitro and in vivo. Cell-based studies assessed metabolomic profiles in K562 erythroblastoid cells with or without MTX treatment. In vivo analysis utilized plasma samples from JIA patients treated with MTX (n=30) and included samples collected prior to the initiation of MTX and after 3-months of MTX treatment. Plasma samples were from an IRB-approved single center prospective cohort study of biomarkers of MTX response in patients with JIA and were stratified based on American College of Rheumatology pediatric (ACR Pedi) response criteria. Semi-targeted global metabolomic profiles including over 800 metabolites across three analytical platforms at the NIH West Coast Metabolomics Center at UC-Davis and were analyzed by univariate and multivariate analysis using MetaboAnalyst 3.0. RESULTS/ANTICIPATED RESULTS: In K562 cells, MTX treatment was associated with statistically significant changes in 550 of the 850 intracellular metabolites detected (false discovery rate less than 0.05). Major metabolic pathways inhibited by MTX included branched-chain amino acid metabolism, purine and pyrimidine biosynthesis, and lipid metabolism including the inhibition of arachidonic acid metabolism. In patients with JIA, far fewer plasma metabolites were significantly altered following the initiation of MTX and included only 15 of the 833 plasma metabolites detected. Interestingly, MTX treatment was associated with the inhibition of arachidonic acid synthesis, inhibition of purine metabolism, and a dramatic reduction in plasma levels of various exogenous metabolites. In particular, MTX treatment was associated reductions in known metabolic markers of intestinal microbiota metabolism, including: biotin and dehydrocholic acid. Further, stratification of patients based on ACR Pedi response demonstrated that clinical response was associated with a greater reduction in plasma dehydrocholic acid levels following the initiation of MTX. DISCUSSION/SIGNIFICANCE OF IMPACT: This work demonstrates that MTX therapy is associated with a number of biochemical changes in vitro and in vivo, including: inhibition of purine metabolism, inhibition of arachidonic acid metabolism, and an apparent inhibition of gut microbiota metabolism. Most notably, inhibition of gut microbiota metabolism appears to demonstrate a relationship with the observed clinical efficacy of MTX in JIA.

Serum calprotectin as a predictive biomarker in the treatment of psoriasis vulgaris with methotrexate

Background Psoriasis is a chronic inflammatory disease that poses a challenge in its pathogenesis and treatment. Calprotectin is upregulated in psoriatic epidermis and is supposed to have a role in the inflammatory process of psoriasis. Calprotectin was suggested as a biomarker to detect responders to methotrexate in juvenile idiopathic arthritis. Objective To evaluate the relation of calprotectin serum level and psoriasis severity and to assess if it can predict response to methotrexate and disease relapse after stoppage of the treatment. Patients and methods Thirty patients with psoriasis vulgaris and 30 controls were included. Serum calprotectin was measured in controls and in patients before and after methotrexate therapy for 3 months. The patients were followed up for 6 months to detect disease stability or relapse and its relation to calprotectin level at the end of therapy. Results Higher calprotectin level in psoriatic patients was detected before methotrexate treatment than after treatment. Significant positive correlation was found between serum calprotectin and psoriasis area and severity index score. Calprotectin was higher in patients before starting methotrexate in those defined as responders than nonresponders (P=0.015) and can predict response to treatment with a cutoff value of 60 ng/ml (sensitivity 82.35% and specificity 69.23%). The level of calprotectin was higher in patients during their clinical remission who relapsed after stoppage of methotrexate than the nonrelapsed cases (P=0.021) and can predict the relapse with a cutoff value of 56.5 ng/ml (sensitivity 66.67% and specificity 100%). Conclusion Calprotectin can be a marker of psoriasis severity. Higher level of baseline serum calprotectin can predict psoriatic patients who will improve on methotrexate therapy. In addition, higher calprotectin levels were associated with relapse risk after stoppage of methotrexate.

Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients.

Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10-7 for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.

Update on subcutaneous methotrexate for inflammatory arthritis and psoriasis.

Methotrexate (MTX) is one of the mainstays of treatment for several immune-mediated inflammatory joint and skin diseases, especially rheumatoid arthritis (RA) and moderate-to-severe psoriasis. Oral MTX has been used for the treatment of such diseases for decades for many reasons. There is, however, a relevant interpatient variability of clinical and safety outcomes that can also be related to differences in patients’ individual pharmacogenomic profile. Orally administered MTX has been found to have a saturable intestinal absorption and nonlinear pharmacokinetics, with significant consequences on drug bioavailability and clinical efficacy. The current evidence shows that parenterally administered MTX results in rapid and complete absorption, higher serum levels, and less variable exposure than oral dosing. The use of parenteral MTX, particularly when administered as a subcutaneous (SC) injection, has recently raised great interest in order to overcome the limitations of oral MTX. The effectiveness and safety of SC MTX have mostly been assessed in rheumatological settings, especially in patients with RA. There are only a limited number of data on SC MTX in juvenile idiopathic arthritis and even fewer in psoriatic disease. Various clinical experiences have suggested that SC MTX is more effective than oral MTX and may provide significant benefit even in patients in whom oral MTX proved to be inadequate. The increased efficacy of SC MTX resulting from higher drug exposure compared with oral MTX has been associated with a similar safety profile and in various reports even with a lower frequency of gastrointestinal complaints. The aim of this article was to review the available literature data on SC MTX treatment of inflammatory arthritis, with special emphasis on RA and psoriasis, examining differences with oral MTX treatment. A brief mention of pharmacokinetics, pharmacodynamic features and pharmacoeconomic considerations is also given.

The experience of taking methotrexate for juvenile idiopathic arthritis: results of a cross-sectional survey with children and young people

BackgroundChildren and young people (CYP) with juvenile idiopathic arthritis (JIA) are known to have impaired health-related quality of life (HRQoL), which is improved significantly for many by treatment with methotrexate (MTX). However, a significant proportion of CYP experience difficulties in taking MTX, which may reduce its potential benefits for HRQoL. The aim of this research was to examine how CYP with JIA perceive MTX treatment and how this relates to HRQoL.MethodsCYP aged 8–16 years taking MTX for JIA completed an adapted Parent Adherence Report Questionnaire, which contains 100 mm visual analogue scales, to assess difficulty taking MTX, adherence, frequency of negative reactions and helpfulness of MTX. They also completed the Pediatric Quality of Life Inventory (PedsQL) Generic and Rheumatology scales. We collected data on age, gender, JIA course, disease duration, MTX duration of use, route and dose. Number of inflamed and limited joints were indicators of disease severity.ResultsOne hundred sixteen CYP participated. Most considered MTX helpful (median 87; interquartile range (IQR) 50.75–98) and reported adherence was high (median 98; IQR 90–100). There was greater variability on scores for difficulty (median 22; IQR 2–69) and frequency of negative reactions (median 14.5; IQR 1.25–80). Mean (S.D.) scores on the PedsQL Physical and Psychosocial subscales were 71.63 (24.02) and 71.78 (19.59) respectively, indicating poorer HRQoL than that reported by healthy children. After controlling for demographic and disease variables, poorer physical HRQoL was significantly accounted for by greater difficulty in taking MTX. Poorer psychosocial HRQoL was significantly accounted for by subcutaneous MTX administration, a lower rating of MTX helpfulness and a greater reported difficulty in taking MTX.ConclusionsTaking MTX for JIA was viewed as helpful by most CYP but HRQoL was poorer in those who reported greater difficulty in taking MTX.

Genetic determinants for methotrexate response in juvenile idiopathic arthritis.

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.

Predictors of response to methotrexate in juvenile idiopathic arthritis.

BackgroundThe response to methotrexate so far is unpredictable in patients with juvenile idiopathic arthritis. Thus such predictors have to be determined in a large patient cohort.MethodsDemographic, clinical, articular and laboratory variables of patients newly treated with methotrexate were analysed by bivariate and logistic regression analysis to identify predictors of response to methotrexate. Minimal response was defined by the American College of Rheumatology pediatric (PedACR) 30 and strong response by the PedACR 70 criteria.ResultsThe patient population consisted of 731 patients. At month 3, 77.4% and at month 12 83.1% of patients were responders according to the PedACR 30 criteria, while 43.1% and 65.9% of patients had a PedACR 70 response at month 3 and at month 12. Thus minimal response was frequently already reached at month 3 while strong response to MTX treatment took usually longer to achieve.In multivariate analysis the number of tender joints (p = 0.002), active joints (p < 0.001), concomitant use of NSAID (p = 0.027) and the parents evaluation of overall well-being (p < 0.001) were significant baseline parameters for minimal response at month 3, while at month 12 the determinants for reaching PedACR 70 were a disease duration < 1 year (p =0.001), a lower number of tender (p <0.001) but a higher number of active joints (p <0.001), a higher score of the parent’s evaluation of child’s pain (p =0.029), and the presence of morning stiffness (p =0.014).ConclusionsBaseline parameters for minimal response after 3 months of treatment and strong response after 12 months of treatment could be identified. Beside parameters defining activity and severity of disease, the disease duration and the concomitant use of NSAID were influencing factors. Overall the model of prediction could support physicians in making treatment decisions.

Genome-wide data reveal novel genes for methotrexate response in a large cohort of juvenile idiopathic arthritis cases

Clinical response to methotrexate (MTX) treatment for children with juvenile idiopathic arthritis (JIA) displays considerable heterogeneity. Currently, there are no reliable predictors to identify non-responders: earlier identification could lead to targeted treatment. We genotyped 759 JIA cases from the UK, Netherlands and Czech Republic. Clinical variables were measured at baseline and 6 months after start of treatment. In Phase I analysis samples were analysed for association with MTX response using ordinal regression of ACR-pedi categories and linear regression of change in clinical variables, and identified 31 genetic regions (P<0.001). Phase II analysis increased SNP density in the most strongly associated regions, identifying 14 regions (P<1×10−5): three contain genes of particular biological interest (ZMIZ1, TGIF1 and CFTR). These data suggest a role for novel pathways in MTX response and further investigations within associated regions will help reach our goal of predicting response to MTX in JIA.

Mothers’ reports of the difficulties that their children experience in taking methotrexate for Juvenile Idiopathic Arthritis and how these impact on quality of life

BackgroundChildren who take methotrexate for juvenile idiopathic arthritis may experience side effects, including nausea and vomiting, leading to anticipatory nausea in some children, and fear of injections or blood tests. The aim of this study was to examine the prevalence and extent of these difficulties and their impact on quality of life.MethodsParticipants were mothers of children with JIA who were currently taking methotrexate (MTX). Mothers completed a questionnaire about MTX that was developed for the study, two questions from the treatment subscale of the Pediatric Quality of Life Inventory (PedsQL) Rheumatology scale to assess needle-related problems and the Child Health Questionnaire 50-item parent version (CHQ-PF50) to assess health-related quality of life (HRQoL).Results171 mothers participated in the study. More than half of children were reported to have experienced one or more of: nausea or vomiting after taking MTX, anticipatory nausea, fear of blood tests or fear of injections. There was no significant difference in reported rates of sickness or needle-related problems between MTX responders (ACR70 or above), partial responders (ACR30 or ACR50) and non-responders. In multivariate analyses, variables that were significant independent predictors of one or more MTX-related difficulties included younger age, taking MTX subcutaneously and having a larger number of currently active joints. Feeling sick after taking MTX was a significant independent predictor of poorer scores on the physical summary scale of the CHQ-PF50. Anxiety about injections and feeling sick after taking MTX were significant independent predictors of poorer scores on the psychosocial summary scale.ConclusionsDifficulties in taking MTX are experienced by a significant proportion of children with JIA and these may have an adverse impact on HRQoL. Approaches to help minimize these difficulties are required.

Dr. de Rotte, et al reply

To the Editor: We thank Dr. Ranganathan for her interesting comments1 on our work2. In our recently published prediction model for methotrexate (MTX) non-response in juvenile idiopathic arthritis (JIA)3, ABCB1 rs1045642 was described, indicating the relative importance of this polymorphism to predict nonresponse to MTX in JIA. Also, we were able to reproduce this finding in a prospective cohort of 387 adult patients with rheumatoid arthritis (RA) receiving MTX: the ABCB1 rs1045642 polymorphism showed an association with improved clinical response (lower Disease Activity Score-28; ß = −0.16, p = 0.001). We agree that finding genetic predictors for MTX-induced toxicity and gastrointestinal (GI) adverse events is equally as important as response, because toxicity limits the considerations of a dose increase or continuation of MTX, and … Address correspondence to R. de Jonge, Department of Clinical Chemistry, Erasmus MC, 's-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands. E-mail: r.dejonge{at}erasmusmc.nl

Translational medicine from bedside to bench and back again: methotrexate revisited

Translational medicine efforts, geared towards the development of new drugs, have brought numerous biologicals from the bedside of rheumatoid and juvenile idiopathic arthritis patients to bench. Biologicals took the attention of the pharmaceutical industry, as well as rheumatologists, away from the first drug that advanced the treatment of rheumatic diseases – methotrexate (MTX). As a consequence, crucial unmet needs surrounding MTX still remain poorly elucidated, even though this anchor drug is taken by many more patients than biologicals and its efficacy has not consistently been surpassed by biologicals in MTX-naive patients. These unmet needs include an incomplete understanding of anti-inflammatory actions of MTX and the inability to predict MTX response. Addressing these needs will result not only in optimization of MTX use, but also of biological use, leading to personalized tailor-made therapy. This review will discuss the place of MTX in juvenile idiopathic arthritis, illustrated by examples from ...

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

Methotrexate is a cornerstone of therapy worldwide for juvenile idiopathic arthritis, yet there remains vast variability in drug dosing and administration, as well as unpredictable outcomes on the drug. Recent efforts through worldwide organization and collaboration have resulted in large registries from which we can now collect clinical data, attempts to standardize therapeutic management with methotrexate and ongoing goals to further individualize drug therapy. Recent studies in juvenile idiopathic arthritis have begun to predict outcomes on the drug by investigating clinical, genetic and cellular biomarkers in children. Pediatric rheumatology as a field has grown from extrapolating data from adult studies to overcoming the barriers to conduct needed investigations in children; however, there remains much to learn and discover about this commonly used drug in juvenile idiopathic arthritis. This nonsystematic review will briefly discuss the history of methotrexate use in juvenile arthritis, the current c...