Participants were recruited as part of the SPARKS Childhood Arthritis Response to Medication Study (SPARKS-CHARMS), which examines genetic, immunobiological and psychological aspects of response to MTX or anti-TNF therapy given for arthritis [9, 10, 12, 13]. The study recruits children of any age with juvenile idiopathic arthritis (JIA), defined by ILAR criteria , who are under the care of the Rheumatology service at Great Ormond Street Hospital for Children (GOSH) or the Adolescent Rheumatology service at University College Hospital, London, UK. The practice in these two centres is that children start on a MTX dose equivalent to 15 mg per metre squared (as per evidence of efficacy ). In those who respond very well, the dose may not be increased as the child grows i.e. actual dose falls; in some children, the dose is increased with growth to maintain the 15 mg per metre square dose. The practice in these two centres is to offer folic acid from the start to all children taking MTX (1mg per day as syrup or in some cases 5mg per week). The practice for nausea is to offer and encourage use of anti-emetics, typically Ondansetron, to be used pre and post MTX as required. The practice with route is that for those who start on oral and develop regular nausea, many are offered the change to subcutaneous.
Children were recruited to the main study if they: a) were about to start taking MTX or anti-TNF, b) were currently taking MTX or, c) had taken MTX in the past.
For the psychological part of the study, we aimed to recruit the parent(s) of 230 children. Parents whose children were aged up to sixteen years, plus children aged five to sixteen years were asked to complete questionnaires about experiences of taking MTX and HRQoL. Recruitment was restricted to English-speakers because the questionnaire was available only in English (this was not a restriction in the main study). Parents were given the questionnaires to complete in the clinic but they could choose to take them home and return them by post. The aim was to recruit at least one parent but if both parents attended the clinic they were both invited to participate. Although fathers and the patients themselves participated in the study, mothers were the largest respondent group. We have previously shown that there can be high levels of discordance between mothers’ and fathers’ views about their child’s JIA , and others have reported discordance between parent and child reports , so to help ensure consistency we have limited this analysis to reports from one parent (mothers). This analysis is restricted to mothers of those children in the study who had taken MTX for at least six months, and were still taking it at the time the questionnaires were completed.
The study had full ethical approval from the Institute of Child Health/GOSH Local Research Ethics Committee, and all participants gave full, informed written consent (parental consent and age appropriate child/young person assent). The study conforms to the principles outlined in the Declaration of Helsinki.
A questionnaire on the experience of taking MTX was developed for the study as there was no appropriate questionnaire available on this topic. The questionnaire asked how frequently the child a) felt sick before taking MTX; b) felt sick after taking MTX; c) vomited after taking MTX. Response options were: never/hardly ever, less than once a month, about once a month, two or three times a month, every week. The questionnaire also asked about how frequently a dose of MTX was missed (1 item), and mothers’ views of MTX (4 items). The experience of needle-related problems was assessed with two questions from the treatment subscale of the Pediatric Quality of Life Inventory (PedsQL) Rheumatology scale . The questions asked how much of a problem anxiety about injections and about blood tests have been in the past month. Response options were: never, almost never, sometimes, often, almost always.
Adherence was estimated by the reported frequency a dose of MTX was missed for any reason. Response options were: never/hardly ever, less than once a month, about once a month, two or three times a month, every week. Missing a dose about once a month or more frequently was classified as non-adherence. This cut-off was used as it would represent an adherence rate of almost 80%, which is a conventional cut-off used in adherence research .
To capture their views on taking other medications, mothers were also asked how willing they would be for their child to try other arthritis medications prescribed in the future. This was assessed with a 100mm visual analogue scale (VAS) from ‘not willing’ (0) to ‘very willing’ (100).
Health-related quality of life (HRQoL) was assessed with the British version of the Child Health Questionnaire 50-item parent version (CHQ-PF50) , which has been validated for use in children with JIA . This measure provides two standardised norm-based summary scores – a physical summary score (PhS) and psychosocial summary score (PsS) – which each range from 0 – 100, have a mean of 50 and standard deviation of 10. Higher scores indicate a better quality of life.
Data on child’s age, gender, JIA category disease duration, MTX route, duration of use and dose, and MTX responder status, (assessed using the core set criteria and internationally agreed definition of improvement ) were also collected. Current disease severity was assessed by the number of limited and inflamed joints. Data on mother’s age and education were collected.
Statistical analyses were conducted in SPSS Statistics 21. To examine potential risk factors for MTX problems we examined the association between occurrence of each problem (sickness before taking, sickness after taking, vomiting after taking, anxiety about injections, anxiety about blood tests) with age, gender, current disease severity, duration of MTX use, route of MTX administration (oral or subcutaneous), current MTX dose and whether or not the child was taking folic acid, using binary logistic regression analyses. A problem was categorised as being present if it occurred frequently i.e. response options two or three times a month/every week (sickness-related questions) or often/almost always (needle-related problems).
The potential impact of MTX-related difficulties on adherence was analysed using Fishers Exact Tests to compare those classified as adherent or non-adherent on their likelihood of having experienced problems.
To examine which of the MTX experiences accounted for most variance in HRQoL measured with the CHQ-PF50, the independent variables were included in hierarchical multiple regressions using stepwise method. Two regressions were performed: one analysis examined the physical and the other the psychosocial summary scores of the CHQ-PF50. The independent variables were entered into the regression in blocks in the following order: 1. demographic variables; 2. disease variables; 3. route by which MTX taken, duration of MTX use, current dose; 4. MTX problems. This order was used because it enables examination to be made as to whether experience of MTX added to the explanation of quality of life once disease severity had been taken into account.
To examine whether experience of MTX-related problems affected mothers’ ratings of MTX and willingness to allow their child to take other medications, t-tests were conducted comparing those who rarely/never experienced each problem with those who had experienced it. To examine the relationship between current disease severity and mothers’ ratings of MTX, Spearman rho correlations were conducted.
To compare responders, partial responders and non-responders on experience of MTX-related difficulties and mothers’ views of MTX, we conducted χ2 tests and analyses of variance (ANOVA) respectively.