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Growth and weight gain in children with juvenile idiopathic arthritis: results from the ReACCh-Out cohort Guzman, Jaime; Kerr, Tristan; Ward, Leanne M; Ma, Jinhui; Oen, Kiem; Rosenberg, Alan M; Feldman, Brian M; Boire, Gilles; Houghton, Kristin; Dancey, Paul; Scuccimarri, Rosie; Bruns, Alessandra; Huber, Adam M; Watanabe Duffy, Karen; Shiff, Natalie J; Berard, Roberta A; Levy, Deborah M; Stringer, Elizabeth; Morishita, Kimberly; Johnson, Nicole; Cabral, David A; Larché, Maggie; Petty, Ross E; Laxer, Ronald M; Silverman, Earl; Miettunen, Paivi; Chetaille, Anne-Laure; Haddad, Elie; Spiegel, Lynn; Turvey, Stuart E; Schmeling, Heinrike; Lang, Bianca; Ellsworth, Janet; Ramsey, Suzanne E; Roth, Johannes; Campillo, Sarah; Benseler, Susanne; Chédeville, Gaëlle; Schneider, Rayfel; Tse, Shirley M L; Bolaria, Roxana; Gross, Katherine; Feldman, Debbie; Cameron, Bonnie; Jurencak, Roman; Dorval, Jean; LeBlanc, Claire; St. Cyr, Claire; Gibbon, Michele; Yeung, Rae S M; Duffy, Ciarán M; Tucker, Lori B Aug 22, 2017

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RESEARCH ARTICLE Open AccessGrowth and weight gain in children withjuvenile idiopathic arthritis: results from theReACCh-Out cohortJaime Guzman1,19* , Tristan Kerr19, Leanne M. Ward10, Jinhui Ma10, Kiem Oen6, Alan M. Rosenberg5,Brian M. Feldman9, Gilles Boire14, Kristin Houghton1, Paul Dancey17, Rosie Scuccimarri11, Alessandra Bruns14,Adam M. Huber16, Karen Watanabe Duffy10, Natalie J. Shiff18, Roberta A. Berard7, Deborah M. Levy9,Elizabeth Stringer16, Kimberly Morishita1, Nicole Johnson4, David A. Cabral1, Maggie Larché8, Ross E. Petty1,Ronald M. Laxer9, Earl Silverman9, Paivi Miettunen4, Anne-Laure Chetaille15, Elie Haddad12, Lynn Spiegel9,Stuart E. Turvey1, Heinrike Schmeling4, Bianca Lang16, Janet Ellsworth3, Suzanne E. Ramsey16, Johannes Roth10,Sarah Campillo11, Susanne Benseler4, Gaëlle Chédeville11, Rayfel Schneider9, Shirley M. L. Tse9, Roxana Bolaria2,Katherine Gross2, Debbie Feldman13, Bonnie Cameron9, Roman Jurencak10, Jean Dorval15, Claire LeBlanc11,Claire St. Cyr12, Michele Gibbon10, Rae S. M. Yeung9, Ciarán M. Duffy10 and Lori B. Tucker1AbstractBackground: With modern treatments, the effect of juvenile idiopathic arthritis (JIA) on growth may be less thanpreviously reported. Our objective was to describe height, weight and body mass index (BMI) development in acontemporary JIA inception cohort.Methods: Canadian children newly-diagnosed with JIA 2005–2010 had weight and height measurements every6 months for 2 years, then yearly up to 5 years. These measurements were used to calculate mean age- andsex-standardized Z-scores, and estimate prevalence and cumulative incidence of growth impairments, and the impactof disease activity and corticosteroids on growth.Results: One thousand one hundred forty seven children were followed for median 35.5 months. Mean Z-scores, and thepoint prevalence of short stature (height < 2.5th percentile, 2.5% to 3.4%) and obesity (BMI > 95th percentile, 15.8% to 16.4%) remained unchanged in the whole cohort. Thirty-three children (2.9%) developed new-onset short stature, while 27(2.4%) developed tall stature (>97.5th percentile). Children with systemic arthritis (n = 77) had an estimated 3-yearcumulative incidence of 9.3% (95%CI: 4.3–19.7) for new-onset short stature and 34.4% (23–49.4) for obesity. Most children(81.7%) received no systemic corticosteroids, but 1 mg/Kg/day prednisone-equivalent maintained for 6 monthscorresponded to a drop of 0.64 height Z-scores (0.56–0.82) and an increase of 0.74 BMI Z-scores (0.56–0.92). An increaseof 1 in the 10-cm physician global assessment of disease activity maintained for 6 months corresponded to a drop of 0.01height Z-scores (0–0.02).Conclusions: Most children in this modern JIA cohort grew and gained weight as children in the general population.About 1 in 10 children who had systemic arthritis, uncontrolled disease and/or prolonged corticosteroid use, hadincreased risk of growth impairment.Keywords: Juvenile arthritis, Growth, Obesity, Corticosteroids* Correspondence: jguzman@cw.bc.ca1From British Columbia Children’s Hospital and University of British Columbia,Vancouver, Canada19Division of Pediatric Rheumatology, BC Children’s Hospital, 4500 Oak St,Suite K4-122, Vancouver, BC V6H 3N1, CanadaFull list of author information is available at the end of the article© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Guzman et al. Pediatric Rheumatology  (2017) 15:68 DOI 10.1186/s12969-017-0196-7BackgroundJuvenile idiopathic arthritis (JIA) is the most commonrheumatic disease of childhood [1], and the seven JIAcategories have different characteristics and outcomes[2, 3]. Chronic inflammation in children with JIA maylead to growth delay and poor weight gain, while use ofcorticosteroids to control inflammation may lead togrowth delay and excessive weight gain. Our knowledgeabout growth in children with JIA is largely based onolder cross-sectional studies and retrospective cohortsfrom single centres [4, 5]. These studies included 20 to200 children each and reported frequent growth impair-ments (a deviation from healthy growth standards inheight, weight or body mass index, BMI) [5]. More re-cently, synthetic disease-modifying antirheumatic drugs(DMARDS) and biologic medications, which help controlinflammation and reduce the need for corticosteroids,have been reported to mitigate growth impairment [6–9].Yet, as recently as 2011, significant height growth delaywas reported in oligoarthritis, a usually mild JIA categoryrarely treated with systemic corticosteroids [10].In this study, we used data from a prospective multicen-tre inception cohort of over one thousand Canadianchildren to determine 1) height, weight and BMI trajector-ies over time in children with JIA managed with moderntreatments; 2) their risk of growth impairments; and 3) theimpact of disease activity and corticosteroid use on growth.MethodsSubjectsData from the Research in Arthritis in Canadian Childrenemphasizing Outcomes (ReACCh-Out) cohort were used.ReACCh-Out was designed to document disease out-comes in usual practice [3, 11]. It enrolled 1497 patientsnewly diagnosed with JIA between 2005 and 2010 at all 16Canadian pediatric rheumatology centres. JIA categorywas assigned using accepted criteria within 6 months ofenrolment [2, 3]. Study visits were scheduled at enrolmentand at 6, 12, 18, 24, 36, 48, and 60 months thereafter. Thestudy was approved by research ethics boards at each par-ticipating institution. Parents provided informed writtenconsent, and patients provided assent where appropriate.This report includes children recruited within 6 monthsof diagnosis who had at least two available height andweight records as of May 30th, 2012.Measures of growth and weight gainStanding height and weight were measured at each studyvisit as per usual clinic practices. We calculated age- andsex-standardized scores (Z-scores, 0 = mean of healthychildren, 1 = one standard deviation in healthy children)[12], for height, weight, and BMI for each child using stan-dards for healthy growth endorsed by the CanadianPediatric Endocrinology Group [13]. These are equivalentto the 2007 World Health Organization standards, exceptthat standards for both weight and BMI are provided upto age 18 years [14].Growth impairments were defined as follows:Short stature: a height below the 2.5th percentile forage and sex (corresponding to a Z-score < −2.0) [15].Tall stature: a height above the 97.5th percentile forage and sex.Obesity: a BMI above the 95th percentile for age andsex [12].Thinness: a BMI below the 5th percentile for age andsex.Growth delay: a decrease of 1.0 or more in height Z-score at a given visit, relative to the Z-score of that childat enrolment.Growth acceleration: an increase of 1.0 or more inheight Z-score at a given visit, relative to the Z-score ofthat child at enrolment.Excessive weight gain: an increase of 1.0 or more inBMI Z-score at a given visit, relative to the Z-score ofthat child at enrolment.Poor weight gain: a decrease of 1.0 or more in BMI Z-score at a given visit, relative to the Z-score of that childat enrolment.These definitions and cut-offs have been used in previ-ous studies, but they are not universally accepted. The Z-score at enrolment was calculated using the first availablemeasurements of height and weight (a median of0.5 months after diagnosis), representing our best estimateof the child’s baseline growth. A change of 1.0 Z-scoresfrom enrolment was chosen because it roughly corre-sponds to the crossing of a percentile channel on growthcharts [16], and it had been used in a previous study [10].Other measuresDisease activity and medication use were recorded at eachstudy visit, and at clinic visits in-between study visits. Dis-ease activity was reported by the pediatric rheumatologistusing a standard 10-cm horizontal visual analogue scalefrom 0 = inactive disease to 10 = very active disease [17].Early treatment responders (versus non-early responders)were defined as those who attained clinically inactive dis-ease within a year of diagnosis [3, 17].The name and current dose of oral and intravenous corti-costeroids recorded at each clinic visit were used to calcu-late mg/kg/day in prednisone equivalent using publishedconversion factors [18, 19], and the most recently recordedpatient’s weight. Children were categorized as non-users ofsystemic corticosteroids, transitory users (3 months or less)or prolonged users (>3 months of cumulative use duringthe study), irrespective of the doses or frequency of admin-istration; intraarticular corticosteroid administration wasnot considered in this categorization.Guzman et al. Pediatric Rheumatology  (2017) 15:68 Page 2 of 11The education level of the parent with the highest levelof education was used as a proxy for socio-economicstatus and self-reported ethnicity was recorded usingStatistics Canada standard categories.Statistical analysisAnalyses were conducted using STATA 12 software [Sta-taCorp LP, College Station, Texas]. Trajectories of themean Z-score over time were charted using locallyweighted scatter plot smoothing with a band width of 0.6to produce lines reflecting observed data without impos-ing a particular shape. Kaplan Meier survival methodswere used to estimate the cumulative incidence of new-onset growth impairments. These consider only the firstoccurrence of growth impairment, and do not reflect per-sistence or resolution of the impairment. Because thenumber of subjects in some JIA categories was small be-yond three years, we show plots only to three years afterdiagnosis. The log-rank test was used to compare survivalcurves. Mixed effects models assessed the impact of cu-mulative disease activity and corticosteroid use in the pre-vious six months on Z-scores, after adjusting for parentaleducation, ethnicity and JIA category. Models were imple-mented in STATA as growth curve models [20] with ran-dom intercept, random slope and a quadratic term fortime since diagnosis (see Additional file 1 for details).Sensitivity analyses to assess the robustness of our find-ings included use of alternative growth charts and mea-sures of disease activity [21], analyses in children of pre-pubertal age (defined as <7 years at diagnosis) and calcula-tion of cumulative incidence of reciprocal “growth impair-ments” (e.g. tall stature and growth acceleration) to assessto what extent our results were due to normal variabilityand the choice of cut-off, rather than true impairments.ResultsA total of 1147 children were included (Table 1). The rea-sons for ineligibility and subject disposition are shown inFig. 1. The median age at diagnosis was 9.5 years (25th,75th centile: 4, 13) and 64% were female. The median timefrom diagnosis to enrolment was 0.5 months (0, 1.9).Height and weight measurements were available on 5909visits for a median follow-up of 35.5 months (25th, 75thcentile: 23, 49). Additional file 1: Table S1 shows subjectswith data at each visit.Height, weight and BMI trajectoriesFigure 2 shows trajectories of height, weight, and BMImean Z-scores for the whole cohort and for each JIA cat-egory. Mean height Z-scores remained unchanged for thewhole cohort (Fig. 2d). Children with enthesitis-relatedarthritis had an estimated mean height Z-score at diagnosisof +0.2 and remained unchanged over 3 years. In contrast,children with systemic arthritis also had an estimated meanheight Z-score at diagnosis of +0.2 but it decreased and didnot return to baseline within 3 years. Using quadratic fitequations the corresponding 95% CI become non-overlapping by one year (Additional file 1: Fig. S1).Mean weight and BMI Z-scores in the whole cohortand in the most frequent JIA categories (oligoarthritis,RF-negative polyarthritis, enthesitis-related, undifferenti-ated) remained stable over time (Fig. 2). These parame-ters increased during the first year after diagnosis inchildren with systemic JIA and RF-positive polyarthritis,but their estimates at diagnosis were different: a meanBMI Z-score of +0.6 for systemic and −0.1 for RF-positive polyarthritis. Mean values of weight and BMI Z-scores of children with psoriatic arthritis were high atenrolment and decreased over time.Growth impairmentsThe point prevalence of short stature in the whole cohortremained stable during the study (2.5 to 3.4%, Fig. 3).Thirty-three children (2.9%) had new-onset short stature(<2.5th percentile), while 27 (2.4%) had new-onset tallstature (>97.5th percentile) during the study. Ninety-threechildren (8.1%) had growth delay, while 64 (5.6%) hadgrowth acceleration. The estimated cumulative incidenceof growth delay within 3 years of diagnosis for the wholecohort was 8.5% (95%CI: 6.8–10.6, Table 2). It varied from5.7% to 9.9% across JIA categories, except for systemicarthritis (22.5%, 14.2–34.7).The point prevalence of obesity in the whole cohortremained stable during the study (15.8 to 16.8%, Fig. 3).Ninety-seven children (8.5%) developed new onset obesity,while 43 (3.7%) developed new onset thinness. The esti-mated cumulative incidence of obesity within three yearsof diagnosis was 10.8% (95%CI: 8.8–13.2, Table 2); it variedfrom 5.9% to 14.1% across JIA categories, except for sys-temic arthritis (34.4%, 23.0–49.4). The estimated cumula-tive incidence of excessive weight gain within 3 years ofdiagnosis varied from 5% to 15% across JIA categories, ex-cept for systemic arthritis (28.1%, 19.0–40.3).Impact of corticosteroids and disease activityIn adjusted mixed effects models, a dose of 1 mg/kg/dayprednisone equivalents maintained for 6 months corre-sponded to a decrease of 0.64 in height Z-scores (95%CI:0.56–0.82) and an increase of 0.74 in BMI Z-scores (0.56–0.92) (Table 3). Additional file 1: Fig. S2 shows trajectoriesof mean corticosteroid dose for each JIA category. Mostchildren received no systemic corticosteroids during thestudy (n = 943, 81.7%), while 88 (7.6%) were transitoryusers and 123 (10.6%) were prolonged users (>3 months).The estimated cumulative incidence of short statureamong prolonged corticosteroid users was 6.6% within3 years, compared to 2.6% for non-users (p = 0.07, log-rank test for survival curves). The estimated cumulativeGuzman et al. Pediatric Rheumatology  (2017) 15:68 Page 3 of 11Table 1 Characteristics of patients by JIA categoryaCharacteristic All(N = 1147)SystemicArthritis(n = 77)Oligoarthritis(n = 443)RF-negativepolyarthritis(n = 232)RF-positivepolyarthritis(n = 44)Psoriaticarthritis(n = 70)Enthesitis-relatedArthritis (n = 164)Undifferentiated(n = 117)% Female 64.0 47.4 70.2 77.6 95.5 67.1 25.0 68.4Age atdiagnosis (yrs)9.5(4.0, 13.1)6.6(3.1, 12.2)6.4(3.0, 11.5)9.1(3.4, 12.7)12.8(9.4, 15.2)11.6(5.3, 13.6)13.1 (10.8,14.5) 9.5 (3.7, 13.1)Disease duration(months)5.8(3.1, 10.9)2.9(1.9, 5.4)5.3(3.0, 8.9)6.1(3.4, 12.4)5.5(3.6, 10.6)6.5(3.0, 13.6)8.9 (4.2,17.3) 5.9 (3.5, 9.0)Follow-up(months)35.5(23,49)40.7(24,52)35.0(23,49)36.7(24,52)33.1(23, 49)34.5(18, 49)30.9 (19, 40) 35.7 (23, 48)Height Z-scoreat enrolment0.02(−0.70, 0.82)0.09(−0.69, 0.91)0.06(−0.65, 0.83)−0.13(−0.77, 0.58)0.02(−0.59, 0.69)0.12(−0.68, 0.99)0.16 (−0.52, 0.98) −0.19(−0.92, 0.62)Weight Z-scoreat enrolment0.31(−0.37, 1.06)0.58(0.04, 1.25)0.25(−0.35, 0.90)0.17(−0.53, 0.94)0.16(−0.83, 0.94)0.66(−0.26, 1.4)0.61 (−0.52, 1.4) 0.29(−0.53, 0.96)BMI percentileat enrolment66(34, 89)80.4(62, 90)62.6(35, 87)64.6(34, 87)55.8(18, 88)75.3(46, 96)65.8 (28, 93) 67.0 (38, 88)Disease activity(mm)28 (12, 50) 37 (13, 62) 19 (8, 34) 46 (27, 66) 52 (26, 71) 23 (11, 51) 30 (12, 46) 26 (12, 48)ESR, mm/hb 18 (7, 36) 58 (25, 89) 17 (7, 31) 18 (8, 36) 36 (16, 53) 15 (8, 36) 10 (4, 24) 16 (5, 35)TreatmentscDMARDs (%) 55.7 71.1 33.9 84.9 97.7 50.0 58.7 53.8Biologics (%) 11.7 34.2 3.6 15.9 40.9 7.1 12.2 10.3Corticosteroidjoint injections (%)44.3 17.1 55.5 43.5 43.2 41.4 31.4 41.9Systemic corticosteroids(%)18.2 85.5 9.3 28.0 63.6 17.1 23.8 23.1Corticosteroids >3months (%)10.6 65.0 0.9 10.8 29.5 2.9 9.3 11.1EthnicitydBritish (%) 50.2 41.9 44.7 54.1 44.2 60.6 54.6 53.5French (%) 31.2 22.1 35.8 26.1 18.6 34.8 22.7 42.1IndigenousCanadian (%)8.1 5.8 8.9 7.7 16.3 6.1 5.5 8.8Other (%) 25.4 26.7 21.8 31.5 34.9 16.7 30.7 16.7Parental educationeLess than highschool (%)2.01 1.6 1.9 2.9 0 1.6 2.6 1.0High school/somepostsecondary (%)50.24 53.1 45.8 51.7 61.9 54.1 51.6 56.4University/postgraduatedegree (%)47.75 45.3 51.6 46.4 38.1 44.3 45.8 42.6Inactive diseasewithin 1 year ofdiagnosis (%)49.5 44.7 65.48 36.6 22.7 42.9 37.8 39.3aNumbers are median and (25th, 75th centiles) unless otherwise specifiedbESR was obtained in 88% of the cohort at enrolmentcTreatments received at any time during the studydSelf-reported ethnicity was available in 96% of the cohort. Other ethnicity includes Asian, African, Latin American and other European ethnicities. The sum ofethnicities may add to more than 100% because each child could report up to 6 ethnic backgroundseThe level of education of the parent who had a higher level of education. Parental education for at least one parent was obtained in 93% of the cohortat enrolmentGuzman et al. Pediatric Rheumatology  (2017) 15:68 Page 4 of 11incidence of obesity among prolonged corticosteroid userswas 25% within 3 years, compared to 8.5% for non-users(p < 0.0001, log-rank test for survival curves, Additionalfile 1: Fig. S3).In adjusted models, a 1 cm increase in the 10 cmphysician global assessment of disease activity main-tained for 6 months was associated with a decrease of0.01 in height Z-scores (95%CI: 0.00–0.02) (Table 3).The association between disease activity and changes inBMI Z-scores was not significant. Mean disease activitydecreased in all JIA categories after diagnosis (Additionalfile 1: Fig. S2) and 567 children (49.5%) attained inactivedisease within the first year. Early treatment respondersand non-early treatment responders had similar prob-ability of growth impairments (Additional file 1: Fig. S4).Sensitivity analysesUsing the Centers for Disease Control growth chartshad minimal impact on our estimates of growth impair-ments, except for a lower cumulative incidence of obes-ity within 3 years of diagnosis of 7.5% (95%CI: 5.9–9.6)(Additional file 1: Table S2). Calculations for reciprocal“growth impairments” (growth acceleration, tall stature,poor weight gain and thinness) are shown in Additionalfile 1: Table S3 and suggest a substantial portion of theincidence of growth impairments reported in Table 2 isdue to normal variability and our choice of cut-offs ra-ther than to the disease; for example, the 3-year cumula-tive incidence of tall stature for the whole cohort was2.3%, compared to 3.0% for short stature. Childrenyounger than 7 years at diagnosis had higher cumulativeincidence of growth impairments, relative to the wholecohort, and a different distribution of JIA categories(Additional file 1: Table S4). Use of the active joint countor the Juvenile Arthritis Disease Activity Score [21], asalternative measures of disease activity, did not substan-tially change our findings (Additional file 1: Table S5).DiscussionWe used data from a large prospective inception cohortof Canadian children with JIA to estimate impact of thedisease and its treatment on height, weight and BMI de-velopment. For children in the most frequent JIA cat-egories (oligoarthritis, RF-negative polyarthritis,enthesitis-related arthritis and undifferentiated arthritis,83.5% of the cohort) the impact was negligible. On theother hand, children with systemic arthritis showed a de-crease in height Z-scores and increase in BMI Z-scores,with no apparent return to baseline within 3 years. Toput things in perspective, the decrease in mean heightZ-scores in children with systemic JIA corresponds toapproximately 2 cm for a 9 year old child. Children withRF-positive polyarthritis or psoriatic arthritis had rela-tively minor, but measurable, risk of growth impair-ments. For the whole cohort, point prevalence for shortstature and obesity remained unchanged over the 3 yearsafter diagnosis, suggesting the observed growth impair-ments affected too few children and/or were too short-lived to affect the overall prevalence.Most children received no systemic corticosteroids, inthose who did, larger doses of corticosteroids were clearlyassociated with lower height and higher BMI Z-scores. Asimilar impact of corticosteroids on BMI has been shownin children with a variety of rheumatic diseases [22]. Inour cohort, most children with systemic JIA receivedhigh-dose corticosteroids, which likely mediated their ob-served growth impairments. Increased disease activity wasassociated with lower height Z-scores but the impact wasminor, relative to that of corticosteroids.Our original protocol considered a change of 1.0 Z-scores relative to baseline indicative of growth impairmentbecause this roughly corresponds to crossing a percentilechannel in growth charts [16], and it had been used in aprevious study [10]. However, we later realized this defin-ition may lead to apparent growth impairments even inhealthy children. Growth in healthy children is complexand may have periods of relative stasis or rapid growth[23]. This may result in apparent delay or acceleration ofFig. 1 Subject eligibility and dispositionGuzman et al. Pediatric Rheumatology  (2017) 15:68 Page 5 of 11growth when comparing a child to normative growthcurves [12]. For example, children with enthesitis-relatedarthritis in our cohort had a virtually flat trajectory ofmean height Z-score (i.e. they grew at the same pace thanhealthy children), but over 3 years they still had a 7.2%cumulative incidence of growth delay and a 7.7% cumula-tive incidence of growth acceleration. We believe cumula-tive incidences of this level using the 1.0 Z-score cut-offlikely reflect normal periods of relative stasis or rapidgrowth, rather than true growth impairments. This coulda bc dFig. 2 Smoothed trajectories of mean Z-scores. Shown are trajectories of (a) height, (b) weight, and (c) BMI for each JIA category in the 3 yearsafter diagnosis. Panel (d) shows Z-score trajectories for the whole cohort. Trajectories of the mean Z-score were charted using locally weightedscatter plot smoothing with a band width of 0.6. The black dashed horizontal line represents healthy growth standardsa bFig. 3 Point prevalence of short stature and obesity in the whole cohort. Shown are the point prevalences of a) short stature and b) obesity inthe whole cohort at every study visits for the 3 years after enrolment, and after excluding children who received corticosteroids. The vertical linesrepresent 95%CIGuzman et al. Pediatric Rheumatology  (2017) 15:68 Page 6 of 11only be confirmed by following healthy children at thesame time intervals and applying the 1.0 Z score cut-off;we are not aware of any such study.Defining growth impairments as a change of 1.0 Zscores from baseline uses the child as his/her own con-trol and allows identification of substantial changes ingrowth that may not be apparent when using the ex-treme limits (e.g. below 2.5th percentile or above 95thpercentile). Nevertheless, some such changes may be de-sirable. For example, a child who is obese at baselinemay drop more than 1.0 BMI Z-scores in follow-up andbecome closer to his/her ideal BMI (by our definitionthis is “poor weight gain”).Although the World Health Organization has proposedstandard terminology to describe growth impairments[15], it has not been universally adopted. The recom-mended term for a stature <−2.0 Z-scores is ‘stunting’, butwe chose to use the term short stature instead, as we feltthe implication that 2.5% of healthy children have stuntedgrowth had overtly negative connotations. At the end, wechose to use neutral descriptive terms and most import-antly, we defined them explicitly.The high prevalence and cumulative incidence of obesityobserved in our cohort may be a reflection of the currentepidemic of obesity among North American children. Anobesity point prevalence of 10.5 to 16.3% has been reportedamong Canadian children aged 5 to 11 years old [24], andnew onset obesity has been reported in 11.9% of children inthe United States between the ages of 5 and 14 years old[25]. However, children with systemic arthritis in our co-hort had a three times higher incidence of obesity thanthese reported population values.There were some interesting differences across JIA cat-egories in growth parameters at enrolment (Table 1).These may reflect disease impact between symptom on-set and enrolment, but they should be interpreted withcaution as chance alone may explain these differences.One could postulate for example that the mean weightZ-score of 0.31 at enrolment for the whole cohort repre-sents the current obesity epidemic among Canadian chil-dren, and that the mean z-score of 0.16 for RF-positivepolyarthritis reflects weight loss during the nearly sixmonths from symptom onset, while the mean Z-score of0.58 for systemic JIA reflects corticosteroid-associatedweight gain during the 2.9 months since symptom onset.Again, one ought to be careful not to over-interpretthese differences given the large variability in growth pa-rameters across children and small sample sizes in someJIA categories in this cohort. Of note, children withpsoriatic arthritis had the highest mean weight Z-scoreTable 2 Estimates of the cumulative incidence (%) of growth delay, short stature, excessive weight gain and obesity within 1 and3 years after diagnosis in seven JIA categoriesJIA Category Growth delay Short stature Excessive weight gain Obesity1-yearcumulativeincidence(95% CI)3-yearcumulativeincidence(95% CI)1-yearcumulativeincidence(95% CI)3-yearcumulativeincidence(95% CI)1-yearcumulativeincidence(95% CI)3-yearcumulativeincidence(95% CI)1-yearcumulativeIncidence(95% CI)3-yearcumulativeIncidence(95% CI)All (N = 1147) 3.2 (2.4, 4.5) 8.5 (6.8, 10.6) 1.2 (0.7, 2.1) 3.0 (2.1, 4.4) 4.8 (3.7, 6.2) 10.7 (8.8, 12.9) 5.2 (4.0, 6.9) 10.8 (8.8, 13.2)Systemicarthritis(n = 77)6.8 (2.9, 15.7) 22.5 (14.2, 34.7) 1.4 (0.2, 9.8) 9.3 (4.3, 19.7) 17.2 (10.4, 27.8) 28.1 (19.0, 40.3) 22.7 (13.9, 35.9) 34.4 (23.0, 49.4)Oligoarthritis(n = 443)3.8 (2.3, 6.1) 7.8 (5.3, 11.3) 1.2 (0.5, 2.9) 2.3 (1.2, 4.4) 3.8 (2.3, 6.1) 10.5 (7.6, 14.4) 3.3 (1.9, 5.7) 8.2 (5.5, 12.1)RF-negativepolyarthritis(n = 232)4.0 (2.1, 7.6) 7.4 (4.5, 12.0) 0.9 (0.2, 3.6) 0.9 (0.2, 3.6) 3.6 (1.8, 7.0) 8.9 (5.6, 14.1) 3.5 (1.7, 7.2) 8.5 (5.2, 13.8)RF-positivepolyarthritis(n = 44)— 9.9 (3.1, 28.7) — 4.3 (0.6, 27.1) 9.1 (3.5, 22.6) 15.0 (7.2, 31.9) — 5.9 (0.8, 35.0)Psoriaticarthritis(n = 70)2.9 (0.7, 10.9) 9.5 (4.0, 21.8) 2.9 (0.7, 11.1) 9.5 (3.9, 22.0) 3.0 (0.7, 11.4) 5.0 (1.6, 14.9) 4.1 (1.0, 15.5) 11.7 (5.0, 26.0)Enthesitis-relatedarthritis(n = 164)1.2 (0.3, 4.7) 7.2 (3.6, 14.4) 0.6 (0.1, 4.5) 1.6 (0.4, 6.3) 3.7 (1.7, 8.1) 8.3 (4.5, 14.9) 5.4 (2.6, 10.9) 9.7 (5.4, 17.2)Undifferentiated(n = 117)1.9 (0.5, 7.2) 5.7 (2.4, 13.5) 1.9 (0.5, 7.4) 3.6 (1.1, 11.4) 3.6 (1.4, 9.3) 7.6 (3.9, 14.7) 8.4 (4.3, 16.0) 14.1 (8.4, 23.1)Growth delay: a decrease of 1.0 or more in height Z-score relative to the z-score of that child at enrolment. Short stature: a height below the 2.5th percentile forage and sex. Excessive weight gain: an increase of 1.0 or more in BMI Z-score relative to the z-score of that child at enrolment. Obesity: a BMI above the 95thpercentile for age and sex— = Cumulative incidence could not be calculated as no child had experienced the growth impairment at this timeGuzman et al. Pediatric Rheumatology  (2017) 15:68 Page 7 of 11of 0.66 at enrolment and they rarely, if ever, usedcorticosteroids.Two published retrospective cohorts are of particular rele-vance to our study. In a study of 67 Canadian children withJIA, Liem and Rosenberg reported that relative to childrenwith oligoarthritis, a lower height Z-score was apparent inthe second year after diagnosis for children with systemicarthritis [26]. A similar change was apparent from the firstyear in our study. Children with RF-positive polyarthritistended to have negative Z-scores, while children with RF-negative polyarthritis tended to have positive Z-scores [26].In our study, children with RF-negative polyarthritis hadpractically normal growth while those with RF-positive poly-arthritis had measurable, but mild growth impairments.In the second study, Padeh et al. reported on 95 chil-dren with oligoarticular JIA in a single centre in Israel.After a mean follow-up of 6 years they reported “severegrowth retardation” (a decrease in height Z-score of 1.0or more relative to baseline) in 11.6% of children [10].This estimate is compatible with our 3-year cumulativeincidence of growth delay of 7.8% using the same cut-off, but as stated above, we suspect this level of apparentgrowth impairment reflects normal periods of relativestasis and not true impairment.Table 3 Impact of corticosteroid use, disease activity and covariates on height Z-scores and BMI Z-scoresImpact on height Z-scores Impact on BMI Z-scoresVariable Unadjusteda(95% CI)p value Adjusted(95% CI)p value Unadjusted(95% CI)p value Adjusted(95% CI)p valueCumulative corticosteroidsb −0.69 (−0.82, −0.56) <0.01 −0.64 (−0.77, −0.50) <0.01 0.79 (0.63, 0.96) <0.01 0.74 (0.56, 0.92) <0.01Cumulative diseaseactivityc−0.02 (−0.03, −0.01) <0.01 −0.01 (−0.02, 0.00) 0.04 0.00 (−0.01, 0.01) 0.49 −0.01 (−0.02, 0.00) 0.17Parental educationdLess than high school Reference Reference Reference ReferenceHigh school/secondary 0.29 (−0.18, 0.77) 0.23 0.31 (−0.18, 0.80) 0.21 0.005 (−0.50, 0.51) 0.98 0.09 (−0.43, 0.61) 0.73Some post-secondary 0.34 (−0.12, 0.80) 0.15 0.39 (−.08, 0.87) 0.11 −0.01 (−0.50, 0.48) 0.96 0.09 (−0.41, 0.60) 0.72University degree 0.32 (−0.14, 0.78) 0.18 0.36 (−0.11, 0.84) 0.14 −0.17 (−0.66, 0.31) 0.49 −0.08 (−0.58, 0.43) 0.77Postgraduate degree 0.40 (−0.08, 0.89) 0.10 0.43 (−0.07, 0.93) 0.09 −0.25 (−0.76, 0.26) 0.33 −0.11 (−0.64, 0.42) 0.68Primary EthnicityeBritish Reference Reference Reference ReferenceFrench −0.09 (−0.26, 0.09) 0.32 −0.11 (−0.29, 0.07) 0.24 −0.36 (−0.55, −0.17) <0.01 −0.33 (−0.52, −0.13) <0.01Indigenous Canadian 0.15 (−0.15, 0.45) 0.34 0.15 (−0.16, 0.46) 0.33 −0.05 (−0.37, 0.27) 0.76 −0.03 (−0.36, 0.30) 0.84Other European 0.03 (−0.14, 0.19) 0.74 0.03 (−0.14, 0.20) 0.75 −0.31 (−0.49, −0.13) <0.01 −0.23 (−0.41, −0.05) 0.01South Asian 0.33 (0.0, 0.66) 0.05 0.34 (0.0, 0.67) 0.05 −0.13 (−0.48, 0.22) 0.47 −0.13 (−0.49, 0.23) 0.48Other −0.07 (−0.27, 0.13) 0.47 −0.03 (−0.24, 0.18) 0.75 −0.23 (−0.44, −0.02) 0.03 −0.13 (−0.35, 0.09) 0.25JIA categoriesOligoarthritis Reference Reference Reference ReferenceRF-neg polyarthritis −0.17 (−0.34, −0.01) 0.04 −0.14 (−0.32, 0.03) 0.10 −0.01 (−0.18, 0.17) 0.96 0.00 (−0.18, 0.19) 0.99Enthesitis-related 0.17 (−0.01, 0.36) 0.07 0.21 (0.01, 0.40) 0.04 0.08 (−0.12, 0.27) 0.45 −0.04 (−0.25, 0.18) 0.74Systemic −0.36 (−0.61, −0.10) 0.01 −0.23 (−0.51, 0.05) 0.10 0.68 (0.41, 0.95) <0.01 0.44 (0.15, 0.74) <0.01Psoriatic 0.04 (−0.23, 0.30) 0.79 0.16 (−0.12, 0.44) 0.26 0.41 (0.13, 0.69) <0.01 0.31 (0.01, 0.61) 0.05RF-pos polyarthritis −0.13 (−0.46, 0.19) 0.43 −0.03 (−0.36, 0.31) 0.88 −0.13 (−0.47, 0.21) 0.46 −0.25 (−0.60, 0.10) 0.17Undifferentiated −0.18 (−0.39, 0.04) 0.11 −0.11 (−0.33, 0.12) 0.37 0.03 (−0.20, 0.25) 0.82 0.02 (−0.22, 0.26) 0.86aUnadjusted Beta coefficients and (95% CI) were obtained from mixed effect models including only one independent variable at a time. Adjusted beta coefficientsare from a mixed effects model where cumulative corticosteroids in previous 6 months, cumulative disease activity in previous 6 months, parental education,ethnicity and JIA category were entered together. Cumulative prednisone and disease activity were time-variant variables. All mixed effects models were run bysubject and included random intercept, random slope and a quadratic term for time since diagnosis in weeks. They can be represented by: dependent vari-able = b1*constant + b2*time + b3*time square + b4* first independent variable + b5* second independent variablebCumulative corticosteroids were calculated as area under the curve of daily prednisone equivalents per kilogram of body weight recorded at each clinic visit,using the trapezoid method; a one unit change corresponds to an increase of 1 mg/Kg of prednisone equivalents per day sustained for 6 months. For the firststudy visit, corticosteroids were assumed to start at diagnosiscCumulative disease activity was calculated as area under the curve of the physician global assessment of disease activity recorded at each clinic visit, using thetrapezoid method; a one unit change corresponds to an increase of 1 cm in the physician global assessment sustained for 6 months. For the first study visit thephysician global assessment was assumed to be zero the day before disease onsetdThe level of education of the parent who had a higher level of educationeThe ethnic group listed first; up to six ethnic groups could be listed for each child as defined by Statistics CanadaGuzman et al. Pediatric Rheumatology  (2017) 15:68 Page 8 of 11Recent studies suggest DMARDs and biologic agentsmitigate growth impairments in children with JIA [6, 7].It is not clear whether this is due to better control of thedisease, reduced doses of corticosteroids, or both. Onenon-controlled trial of anakinra monotherapy in sys-temic arthritis avoided use of corticosteroids in 13 of 20children [27]. The 2013 update of the American Collegeof Rheumatology juvenile arthritis treatment recommen-dations includes initial monotherapy with biologics as anoption in children with systemic arthritis [28]. It will beimportant to ascertain if early monotherapy with bio-logics prevents the growth impairments observed in pa-tients with systemic JIA in our cohort.Study strengths and limitationsTo our knowledge, this is the largest prospective study ofgrowth in children with JIA published to date. It reflectsmore recent treatment practices than previous studies andwe analysed growth in multiple ways to ensure our find-ings were robust. Nonetheless, our data should be inter-preted in light of five limitations. First, although Z-scoresare age- and sex-standardized this may not fully adjust forthe effect of age and pubertal status on the child’s suscep-tibility to growth impairment, and we did not collect dataon pubertal status in this cohort. Second, because proce-dures to measure height and weight were not standardizedand the stadiometers and balances were not cross-calibrated, some differences in Z-scores may be due tomeasurement variability. Third, cumulative corticosteroidsand cumulative disease activity in the previous 6 monthswere based on few measurements, since we did not usecorticosteroid diaries and disease activity was onlyassessed at clinic visits. Fourth, we did not report on local-ized growth impairments such as leg length discrepancyor jaw asymmetry, which may occur in juvenile arthritis.Finally, our estimates refer to 3 years after diagnosis, andthe risk of growth impairments may change with longerfollow-up. It is important to emphasize that the reportedgrowth impairments may be transitory and that finalheight and weight may be normal due to catch up growthand delayed puberty. Most children in this cohort had notcompleted their growth at the last assessment, and we hadno parental height data to allow calculation of geneticgrowth potential.Implications for practiceFamilies of children with JIA should know that withmodern treatments, their child’s disease will not sub-stantially affect growth and weight gain, unless the childhas systemic JIA, requires prolonged corticosteroid use(>3 months) and/or has uncontrolled disease. Families ofchildren with systemic arthritis should know that sys-temic corticosteroids may control the disease, but at thecost of potential growth impairment; a 1 in 10 risk ofshort stature and a 1 in 3 risk of obesity within 3 yearsof diagnosis. Practitioners should be wary of prolongedcorticosteroid use and our results quantify their effecton growth.ConclusionsMost children with JIA in this cohort grew and gainedweight at a pace similar to modern North American popu-lations. Children in the most frequent JIA categories grewwell, but about 1 in 10 children who had systemicarthritis, uncontrolled disease activity, and/or requiredprolonged use of systemic corticosteroids were at risk ofgrowth impairment. These children may benefit from earl-ier aggressive therapy to help prevent growth impairment,or early consultation with a pediatric endocrinologist tomitigate growth impairment by other means.Additional fileAdditional file 1: Growth and Weight Gain in Juvenile Arthritis.(DOCX 2958 kb)AbbreviationsBMI: Body Mass Index; DMARDs: Disease modifying Antirheumatic drugs;JIA: Juvenile idiopathic arthritis; ReACCh-Out: The Research in Arthritis inCanadian Children Emphasizing Outcomes Cohort; RF: Rheumatoid factorAcknowledgmentsA heartfelt thank you to all the Canadian families who enrolled their childrenin the Research in Arthritis in Canadian Children emphasizing Outcomescohort and made this study possible.FundingThis study was funded by a New Emerging Team research grant fromthe Canadian Institutes of Health Research. Additional funding supportfor Ms. Michele Gibbon was provided by the Fast Foundation, Toronto,Canada. Mr. Tristan Kerr received a studentship from the CanadianRheumatology Association for his work with this project. Dr. Ward wassupported by the Departments of Pediatrics and Surgery, Children’sHospital of Eastern Ontario and a University of Ottawa Research Chairaward. Dr. Guzman was funded by a Clinical Investigator Award fromthe Child and Family Research Institute, Vancouver, Canada.Availability of data and materialsAccess to unpublished data may be granted to other investigatorsprovided that 1) they collaborate in a team that includes at least oneReACCh-Out investigator, and 2) their research protocol is approved bythe Canadian Alliance of Pediatric Rheumatology Investigators ScientificProtocol Evaluating Committee. For more details, contact Dr. Guzman(corresponding author).Authors’ contributionsJG: drafted the initial proposal for this study, conducted statisticalanalyses, provided substantial input on the interpretation of findings,drafted the initial manuscript and coordinated revisions to themanuscript. TK: drafted the initial proposal for this study, conductedstatistical analyses, and drafted the initial manuscript. LMW: contributedsubstantially to the final study proposal, the interpretation of findingsand drafting of the manuscript. JM: contributed substantially to the finalstudy proposal, design of statistical analyses, interpretation of findingsand the drafting of the manuscript. KO: designed the original ReACCh-Out study that provided the data, obtained the original research grant,contributed substantially to the final proposal and interpretation offindings, and to the drafting of the manuscript. AMR: contributedGuzman et al. Pediatric Rheumatology  (2017) 15:68 Page 9 of 11substantially to the final study proposal, the interpretation of findingsand drafting of the manuscript. BMF: contributed substantially to thefinal study proposal, the interpretation of findings and drafting of themanuscript. GB: contributed substantially to the final study proposal, theinterpretation of findings and drafting of the manuscript. KH, PD, RS, AB,AMH, KWD, NJS, RAB, DML, ES, KM, NJ, DAC, ML, REP, RML, ES, PM, ALC,EH, LS, SET, HS, BL, JE, SER, JR, SC, SB, GC, RS, SMLT, RB, KG, DF, BC, RJ,JD, CL and CSC participated in subject enrolment and follow-up, andin two rounds of revisions for the manuscript. MG: was the maincoordinator for the ReACCh-Out cohort, oversaw data collection anddata entering and participated in two rounds of revisions for the manuscript.RSMY: designed the original ReACCh-Out study that provided the data,obtained the original research grant and participated in two rounds of revisionsfor the manuscript. CMD: was the nominated principal investigator for theReACCh-Out study, designed the original ReACCh-Out study thatprovided the data, obtained the original research grant and participatedin two rounds of revisions for the manuscript. LBT: drafted the initialproposal for this study, designed the original ReACCh-Out study thatprovided the data, obtained the original research grant, providedsubstantial input on interpretation of findings and drafting of themanuscript, and supervised Mr. Kerr’s involvement in this project. Allauthors read and approved the final manuscript.Ethics approval and consent to participateThe study was approved by research ethics boards at each participatinginstitution. Parents provided informed written consent, and patientsprovided assent where appropriate.Consent for publicationNot applicable.Competing interestsThe authors declare that they have no competing interests.Author details1From British Columbia Children’s Hospital and University of British Columbia,Vancouver, Canada. 2Department of Pediatrics University of British Columbia,Vancouver, Canada. 3Stollery Children’s Hospital and University of Alberta,Edmonton, Canada. 4Alberta Children’s Hospital and University of Calgary,Calgary, Canada. 5Royal University Hospital and University of Saskatchewan,Saskatoon, Canada. 6Department of Pediatrics and Child Health, University ofManitoba, Winnipeg, Canada. 7London Health Sciences Centre and WesternUniversity, London, Canada. 8McMaster University, Hamilton, Canada.9Hospital for Sick Children and University of Toronto, Toronto, Canada.10Children’s Hospital of Eastern Ontario and University of Ottawa, Ottawa,Canada. 11McGill University Health Centre and McGill University, Montreal,Canada. 12Centre Hospitalier Universitaire Ste. Justine and Université deMontréal, Montréal, Canada. 13Université de Montréal, Montréal, Canada.14Centre Hospitalier Universitaire de Sherbrooke and Université deSherbrooke, Sherbrooke, Canada. 15Centre Hospitalier Universitaire de Lavaland Université Laval, Quebec, Canada. 16IWK Health Centre and DalhousieUniversity, Halifax, Canada. 17Janeway Children’s Health and RehabilitationCentre and Memorial University, Saint John ’s, Canada. 18Shands Children’sHospital and University of Florida, Gainesville, USA. 19Division of PediatricRheumatology, BC Children’s Hospital, 4500 Oak St, Suite K4-122, Vancouver,BC V6H 3N1, Canada.Received: 13 May 2017 Accepted: 14 August 2017References1. Harrold LR, Salman C, Shoor S, Curtis JR, Asgari MM, Gelfand GM, et al.Incidence and prevalence of juvenile idiopathic arthritis among children ina managed care population, 1996-2009. J Rheumatol. 2013;40(7):1218–25.2. Petty RE, Southwood TR, Manners P, et al. International league ofassociations for rheumatology classification of juvenile idiopathic arthritis:second revision, Edmonton, 2001. J Rheumatol2004;31(2):390–2.3. Guzman J, Oen K, Tucker LB, Huber AM, Shiff N, Boire G, Scuccimarri R,Berard R, Tse SM, Morishita K, Stringer E, Johnson N, Levy DM, Duffy KW,Cabral DA, Rosenberg AM, Larché M, Dancey P, Petty RE, Laxer RM,Silverman E, Miettunen P, Chetaille AL, Haddad E, Houghton K, Spiegel L,Turvey SE, Schmeling H, Lang B, Ellsworth J, Ramsey S, Bruns A, Campillo S,Benseler S, Chédeville G, Schneider R, Yeung R, Duffy CM, for the ReACCh-Out investigators. The outcomes of juvenile idiopathic arthritis in childrenmanaged with contemporary treatments: results from the ReACCh-Outcohort. Ann Rheum Dis. 2015;74(10):1854–60.4. Simon D. Inflammation and growth. J Pediatr Gastroenterol Nutr. 2010;51(Suppl3):S133–4.5. Bechtold S, Simon D. Growth abnormalities in children and adolescentswith juvenile idiopathic arthritis. Rheumatol Int. 2014;34(11):1483–8.6. Chédeville G, Quartier P, Miranda M, Brauner R, Prieur AM. Improvements ingrowth parameters in children with juvenile idiopathic arthritis associatedwith the effect of methotrexate on disease activity. Joint Bone Spine. 2005;72(5):392–6.7. Giannini EH, Ilowite NT, Lovell DJ, Wallace CA, Rabinovich CE, Reiff A,Higgins G, Gottlieb B, Chon Y, Zhang N, Baumgartner SW. Effects of long-term etanercept treatment on growth in children with selected categoriesof juvenile idiopathic arthritis. Arthritis Rheum. 2010;62(11):3259–64.8. Tynjälä P, Lahdenne P, Vähäsalo P, Kautiainen H, Honkanen V. Impact ofanti-TNF treatment on growth in severe juvenile idiopathic arthritis. AnnRheum Dis. 2006;65(8):1044–9.9. Uettwiller F, Perlbarg J, Pinto G, Bader-Meunier B, Mouy R, Compeyrot-Lacassagne S, Melki I, Wouters C, Prieur AM, Landais P, Polak M, Quartier P.Effect of biologic treatments on growth in children with juvenile idiopathicarthritis. 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Incidence of childhood obesity inthe United States. N Engl J Med. 2014;370(5):403–11.26. Liem JJ, Rosenberg AM. Growth patterns in juvenile rheumatoid arthritis.Clin Exp Rheumatol. 2003;21(5):663–8.27. Vastert SJ, de Jager W, Noordman BJ, Holzinger D, Kuis W, Prakken BJ,Wulffraat NM. Effectiveness of first-line treatment with recombinantinterleukin-1 receptor antagonist in steroid-naive patients with new-onsetsystemic juvenile idiopathic arthritis: results of a prospective cohort study.Arthritis Rheumatol. 2014;66(4):1034–43.28. Ringold S, Weiss PF, Beukelman T, DeWitt EM, Ilowite NT, Kimura Y, Laxer RM,Lovell DJ, Nigrovic PA, Robinson AB, Vehe RK. American College ofRheumatology. 2013 update of the 2011 American College of Rheumatologyrecommendations for the treatment of juvenile idiopathic arthritis:recommendations for the medical therapy of children with systemic juvenileidiopathic arthritis and tuberculosis screening among children receivingbiologic medications. Arthritis Rheum. 2013;65(10):2499–512.•  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript atwww.biomedcentral.com/submitSubmit your next manuscript to BioMed Central and we will help you at every step:Guzman et al. Pediatric Rheumatology  (2017) 15:68 Page 11 of 11

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