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Aerobic and anaerobic capacity in juvenile idiopathic arthritis: the cardiorespiratory response during.. Houghton, Kristin M. 2008-10-08

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AEROBIC AND ANAEROBIC CAPACITY IN JUVENILEIDIOPATHIC ARTHRITIS: THE CARDIORESPIRATORYRESPONSE DURING AEROBIC EXERCISEKristin M HoughtonBA, Cornell University, 1994MD, The University of British Columbia, 1998FRCPC Pediatrics, Dalhousie University, 2002FRCPC Rheumatology, The University of British Columbia, 2005A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THEREQUIREMENTS FOR THE DEGREE OFMASTER OF SCIENCEinTHE FACULTY OF GRADUATE STUDIES(Human Kinetics)THE UNIVERSITY OF BRITISH COLUMBIA(Vancouver)April 2008© Kristin M Houghton 2008AbstractJuvenile idiopathic arthritis (JIA) is a common chronic disease of childhood. Childrenwith JIA have lower peak oxygen consumption (V02 peak) than healthy children. In orderto examine the cardiorespiratory response during aerobic exercise and the anaerobic toaerobic ratio (metabolic index), maximal exercise tests were performed in JIA subjectsand age- and sex-matched controls (CON).Thirteen children aged 10 to 17 years with JIA and 9 CON participated. Peak power(watts, W) and total work (Joules, j) were determined with the Wingate anaerobic cyclingtest. VO2 peak was measured by a maximal staged exercise test on a cycle ergometer.Cardiac output (CO, liters/minute) was measured with Doppler echocardiography.Arterial — mixed venous oxygen index (A-V02) and systemic vascular resistance (SVR)were calculated. Patient questionnaires included habitual activity, visual analog scale forjoint pain and the childhood health assessment questionnaire. Physician completed dataincluded active joint count and articular severity index.Compared to CON and reference age-matched norms, JIA subjects had lower aerobicfitness. VO2 peak in JIA was 31.3 ml/min/kg (20.2-49.9), Z score -1.4 (-.06--2.4) and inCON was 47.9 ml/min/kg (32.7-54.1), Z score of -0.17 (-1.6-.87). [p = 0.013 V02 peak,p=0.011 Z score]. There were no significant differences in CO, A-V0 2 or SVR buttrends towards lower CO and higher SVR in JIA subjects were observed. Duringanaerobic exercise JIA subjects completed less total work (168.5 j/kg (107-252) JIA, 224j/kg (180-248) CON, p=.036) but had similar peak power (9.7 W/kg (5.6-13.7) JIA, 11.3iiW/kg (9.8-14.5) CON, p=.095). The metabolic index did not differ between JIA andCON. There was no significant correlation between disease activity, function and fitnessmeasures in JIA subjects.Children with JIA have moderate impairments in aerobic fitness. CO and A-V02 duringaerobic exercise did not significantly differ between JIA subjects and CON. Anaerobicfitness was mildly impaired with less total work completed by JIA subjects. Furtherresearch with larger numbers is required to determine factors contributing to limitedfitness in JIA.iiiTable of ContentsAbstract ^ .iiList of Tables viList of Abbreviations  ^viiAcknowledgements ^  viiiIntroduction ..1Methods ^  .4Subjects .4Experimental protocol ^ .5Anthropometric data .5Fitness measures ^ 5Cardiac output .7Arterial-mixed venous 02 difference andsystemic vascular resistance ^ 7Pain assessment ^ 7Disease activity assessment ^ .8Functional disability assessment  .8Physical activity assessment ^ 8Statistical analysis ^ 8Results ^ 10Discussion  15References ^  21Appendix 1^Control subjects — Pain QuestionnaireVisual Analog Scale ^ 25ivAppendix 2^JIA subjects — Pain QuestionnaireVisual Analog Scale ^ 26Appendix 3^Articular severity index ^  .27Appendix 4^Physical activity assessment questionnaire ^28Appendix 5^Review of exercise and fitness in children withjuvenile idiopathic arthritis ^ .34Appendix 6:^Review of measures of central and peripheralcontributions to maximal aerobic capacity ^ .37Appendix 7:^Tables: Individual specific data and correlationStudies ^ .39Ethics documents ^ .42vList of TablesTable 1.^Patient and control demographics ^ 10Table 2.^Patient disease characteristics ^ 12Table 3.^JIA subjects and control subjects fitness measures ^..13Table 4.^Correlations between aerobic and anaerobic fitnessmeasures in children with JIA ^ .14Appendix 7.Table 1 a.^Aerobic and anaerobic fitness parametersfor JIA subjects ^ 39Table lb:^Aerobic and anaerobic fitness parametersfor control subjects ^ 40Table 2:^Correlation between disease activity, function andfitness measures in subjects with JIA ^41viList of AbbreviationsASI^ articular severity indexA-V02 arterial — venous oxygen differenceBMI^ body mass indexBSA body surface areaCHAQ^childhood health assessment questionnaireCO cardiac outputDMARD^disease modifying anti-rheumatic disease therapyECG electrocardiogramJIA^ juvenile idiopathic arthritisHR heart ratej^ joulesLVOT left ventricular outflow tractMAP^ mean arterial blood pressureNIRS near infrared spectrophotometerNSAID^non-steroidal anti-inflammatory drug02 oxygenPA^ physical activityRER respiratory exchange ratioSVR^ systemic vascular resistanceVAS visual analog scaleVTI^ velocity-time integralVO2peak peak oxygen consumptionW^ wattsviiAcknowledgementsI wish to thank AJ Hollinger for performing the echocardiograms and calculating cardiacoutput, and Natalie Taha and Karen Slater for helping with the exercise testingprocedures.Special thanks to Jim Potts for sharing the Exercise Physiology Lab in the Children'sHeart Centre at BC Children's Hospital and his invaluable assistance in the development,testing and interpretation of the study results. I also thank Don McKenzie and Ross Pettyfor ongoing mentorship and inspiration.viiiIntroductionJuvenile idiopathic arthritis (JIA) is one of the more common chronic diseases ofchildhood, affecting one in 700 children. (1-5) The cause of JIA is unknown butconsiderable evidence suggests an autoimmune pathogenesis. JIA is defined as thepresence of arthritis (the presence of joint swelling or two or more of the following: jointpain, warmth, redness, and limited range of motion) for at least 6 weeks in a childyounger than age 16 after other types of childhood arthritis have been excluded. JIA isdivided into 7 categories based on clinical symptoms, family histories and laboratoryresults in the first 6 months of the disease. (6) JIA is a chronic illness and treatmentideally includes a multidisciplinary team to address issues of growth, development andphysical function, as well as pharmacologic therapies to limit joint pain, inflammationand damage. Historically, JIA has been viewed as a relatively benign disease but recentdata reveal that many children with JIA have active disease that persists into adulthoodand results in functional limitation. The recognition that disease damage occurs earlyhas led to earlier and more aggressive use of pharmacologic therapies. The majority ofchildren with JIA do not have clinical remission with non-steroidal anti-inflammatory(NSAID) drugs or local corticosteroid injections and require disease-modifying anti-rheumatic drugs (DMARDs), immuno-modulating agents that slow the radiologicprogression of disease.As a group, children with chronic disease or physical disability are less active than theirhealthy peers and studies show children with JIA have reduced vigorous physical activitylevels, sports participation and decreased fitness compared to healthy children. (7-9) Ameta-analysis of 5 studies, including 144 children with JIA, found aerobic fitness asmeasured by VO2peak was 22% lower than healthy children.(10) Impairments tend to bemost pronounced in children with severe arthritis but suboptimal fitness is also seen inchildren with mild disease and often persists when disease is in remission. (7, 11)Suboptimal V02 peak may be due to central or peripheral limitations. Peripheral limitationsdue to muscle atrophy and weakness are hypothesized to largely account for diminishedaerobic fitness in children with JIA. Children with JIA have generalized muscleweakness and muscle atrophy, most pronounced in muscles surrounding inflamed jointsand often persisting even after clinical resolution of inflammation. (12-15) Muscleatrophy may lead to decreased oxygen extraction from the exercising muscle, resulting inhigh mixed venous oxygen content and a low V02 peak. Central and peripheral measuresof aerobic fitness in children with JIA have not been reported.There is little known about anaerobic fitness in children with JIA. Most childhood playand activities of daily living are anaerobic in nature. Impaired anaerobic fitness maymake activities difficult or impossible for children to perform. An association betweenanaerobic fitness and functional capacity has been described. (16)The purpose of this study is to examine the cardiorespiratory response during aerobicexercise and the anaerobic to aerobic ratio (metabolic index) in children with JIAcompared to healthy children.2HypothesisI . Children with JIA will have lower VO2 peak than their healthy age-matched peers.Based on recent meta-analysis the predicted impairment is 20%.(10)2. Children with JIA will have lower anaerobic fitness (peak power and total work) thantheir healthy age-matched peers.3. Children with JIA will have less efficient muscle oxygen utilization during maximalaerobic exercise, manifest by lower arterial — venous oxygen difference (A-V02)(corresponding to higher mixed venous oxygen difference) at a given CO and highersystemic vascular resistance (SVR).3MethodsSubjects: Patients between 8 and 18 years of age followed at British ColumbiaChildren's Hospital's Arthritis Clinic with a definite diagnosis of JIA and history of lowerextremity joint involvement were invited to participate. (6) Patients were excluded ifthey had active systemic disease manifest by fever, pericariditis or pleuritis; diseaseremission greater than one year; primary cardio-respiratory disease with the exception ofmild asthma; were unable to cycle due to pain or decreased range of motion of lowerextremity joints or were unable to tolerate the mouthpiece for VO2 peak testing due totemporomandibular joint disease. The control group (CON) were physically healthy age-and sex-matched peers, friends or relatives of patients with JIA. Study assessmentsoccurred between January and September 2007. All patients and caregivers providedassent and consent prior to participation. Ethical approval was obtained from theUniversity of British Columbia's Clinical Research Ethics Board and the Hospital'sResearch Review Committee.A power calculation based on mean values of VO2^fromfrom a recent meta-analysis inchildren with JIA and published reference norms of healthy children were used todetermine the number of subjects required. (10, 17) Assuming a normal distribution,unequal variance between the groups (larger reported standard deviation for JIA group)with a power of 0.8 and alpha level of 0.05 yields samples of 15 for the JIA group and 12for the CON. There are insufficient data for anaerobic fitness to calculate an appropriatesample size to show significant differences in peak power and total work. Clinically, I4would expect a 20% or greater impairment in total work to have potential impact on achild's ability to function and independently perform their activities of daily living.Experimental ProcedureStudy participants with JIA underwent a clinical assessment by a rheumatologist (KH) onthe same day as the exercise testing. Assessment included a complete physicalexamination including active joint count, calculation of the articular severity index (ASI),and data collection for age, sex, disease duration, history of previous cardiac orrespiratory disease, recent hemoglobin level and current medications. Subjectsunderwent all testing in the afternoon to negate morning stiffness as a potentialconfounding factor.Anthropometric data: height (Harpenden Stadiometer, London) and body mass (SECAElectronics, Hamburg, Germany) were measured to the nearest 0.1cm and 0.1kg,respectively. Body mass index (BMI, kg/m 2) was calculated. Obesity was defined as aBMI > than the 95th percentile according to reference data. (18)Fitness: A Wingate test was done first followed by a modified stress echocardiogramwith VO2 measurement. Both exercise tests were done on an upright cycle ergometer(Excalibur Sport, Lode BV, Groningen, The Netherlands). Anaerobic fitness: Subjectsinitially warmed up for a few minutes with easy pedaling interposed with 5 to 7 secondsprints. Subjects then performed the Wingate test; a 30 second maximal test on theupright cycle ergometer against a high constant resistance (0.070 Newton / kg). (19) Leg5peak power (Watts,W) in any 5 second period, peak power expressed per kg body mass(W/kg) and total work (Joules, j) completed were calculated by a computer softwarepackage (Wingate for Windows, Lode BV, Groningen, The Netherlands). Aerobicfitness: Subjects completed a maximal graded cycle ergometer exercise test to volitionalfatigue. After a 3 minute warm-up period, the initial workload of 0 watts was increasedby 20 to 40 watts (dependent on the age and fitness of the subject) every 3 minutes usinga staged protocol. Open circuit spirometry was used to determine respiratory gasexchange variables during exercise and averaged over 15-second intervals. Subjectsbreathed through a Han Rudolph valve (Hans Rudolph, Inc., Kansas City, MO.) Using aMOXUS Metabolic Cart (AEI Technologies, Inc, Pittsburgh, PA), expired gases wereanalyzed by oxygen and carbon dioxide analyzers (Model S-3A and CD-3A, respectively,AEI Technologies, Inc., Pittsburgh, PA). The system was calibrated before each test withstandard gases of known oxygen (20.93% and 15.00%) and carbon dioxide (0.03% and5.02%) concentrations. Volume was calibrated and verified using a 3-litre syringe (Hans-Rudolph, INC, Kansas City, MO). Measurements included total test duration, VO2 peak(defined as highest VO2 achieved in any 15 second period), maximal ventilation and peakrespiratory exchange ratio (RER). Pulsed-wave Doppler echocardiogram images(parasternal long axis view at the base of the sternum) were taken prior to exercise, 150seconds into each 3 minute stage of exercise, immediately post-exercise and 3 minutespost-exercise. Two lead electrocardiogram (ECG) recorded continuous heart rate (HR)measurements. Blood pressure was measured manually prior to exercise, 120 secondsinto each 3 minute stage of exercise, immediately post-exercise and 3 minutes post-exercise. Mean arterial blood pressure (MAP) was calculated [Pressure Diastolic +6(Pressure systolic - Pressure Diastolic)]. A maximal test was defined as achieving aRespiratory Exchange Ratio ( RER) > 1.0 or reaching a MHR greater than 195.(20)Cardiac output: Cardiac output (CO) was calculated using Doppler echocardiographyby a single echocardiographer (AH). A parasternal long-axis view was used to measurethe left ventricular outflow tract (LVOT) diameter at the aortic valve hinge-point duringsystole. The LVOT area was calculated from this diameter. From an apical 4-chamberview with the transducer tilted anteriorly towards the LVOT, a pulsed-wave Dopplersample volume was taken from the centre of the LVOT. The velocity-time integral (VTI)was calculated. The frequency of the transducer (7, 5S, or M3S MHz) varied dependingon the size of the child. Stroke volume (SV) was calculated as the product of the VTIand LVOT area. CO was calculated as the product of SV and HR. Both SV and COwere indexed to body surface area (BSA). Measurements were taken at rest, 150 secondsinto each stage of exercise, immediately post-exercise and 3 minutes post-exercise.Arterial-mixed venous 02 difference (A-V02) and systemic vascular resistance(SVR): A-V02 was calculated as the absolute oxygen uptake divided by the absolutecardiac output (A-V02 = VO2peak/C0). A-V02 is equal to arterial 02 content minus themixed venous 02 content. SVR was calculated from MAP and CO (SVR= MAP / CO).Joint Pain: Subjects with JIA completed a visual analogue scale (VAS) for joint pain onthe day of testing, over the previous week and immediately after testing using a 10 point7validated VAS scale from the Pediatric Pain Questionnaire. (21, 22) CON subjectscompleted the VAS after exercise testing. (Appendix 1).Disease activity assessment: Subjects with JIA were assessed on the day of testing priorto performing any exercise. Articular severity index (ASI) was calculated as the sum ofscores for joint swelling, pain on motion, tenderness, and limitation of motion. (23)(Appendix 2). Active joint count was determined as the number of joints with eitherswelling or painful, limited range of motion.Functional Disability: Subjects with JIA or their proxy (parent or guardian) completedthe childhood health assessment questionnaire (CHAQ), a valid and reliable measure offunction in children with JIA. (24) (Appendix 3).Physical activity: A questionnaire was completed by patients and controls to determinehabitual physical activity and general health. (Adapted from the Children's Exercise andNutrition Centre at McMaster University. Developed by Oded Bar-Or, MD, FACSM.)(Appendix 4).Statistical Analysis: Baseline characteristics were compared with the Student's T-tests.Descriptive statistics were calculated for fitness measures. Median values and ranges arepresented for non-normally distributed data. Z-scores are presented for individualsubjects. Differences in fitness measures between JIA subjects and CON subjects weredetermined using the Wilcoxin Mann-Whitney test for non-normally distributed data.8The association between continuous variables was assessed using Pearson and Spearmancorrelation coefficients. Linear regression models were used to explore the relationshipsbetween aerobic fitness, anaerobic fitness, disease activity and function in subjects withJIA. Correlation coefficients of 0.3 to 0.5 were set as low, 0.5 to 0.7 as moderate and 0.7to 1.0 as high correlation. The significance level for all tests was set at P<0.05. Statisticswere performed using SPSS 15.0 (SPSS Inc, Chicago, IL).9ResultsThirteen children and adolescents aged 10 to 17 years with JIA and 9 CON participatedin the study. Table 1 shows patient and CON demographics. There was no differencebetween the two groups. (for age; P=0.29 and for BMI; P=0.10). JIA subjects medianage was 13.9 (10.5-17.7) and the control subjects was 12.8 (11.3-16.5). Two of the JIAsubjects met the operational definition of obesity. (18)Table 1. Patient and Control Demo ra hiesPatient Age Sex BMIm2)____,/iPA CON Age Sex BMI(kg/m2)PA1 12.4 F 21.9 A 1 14.3 M 19.6 A2 14.9 M 19.0 NA 2 11.9 M 17.9 A3 12.8 F 21.6 A 3 11.9 M 18.4 A4 11.7 F 16.9 A 4 14.1 F 17.1 A5 16.8 F 32.7 NA 5 12.8 M 16.1 A6 16.9 F 34.6 A 6 14.5 F 19.2 A7 10.5 F 19.2 A 7 12.2 F 20.8 A8 14.7 M 19.2 A 8 11.3 F 17.0 A9 17.7 M 27.6 A 9 16.5 F 21.4 A10 12.8 M 16.5 A ,11 16.4 F 19.1 A12 13.5 M 18.1 A13 13.9 M 21.4 AMedian(Range)13.9(10.5-17.7)6M:7F 19.2(16.5-34.6)11active12.8(11.3-16.5)4M:5F 18.4(17.0-21.4)9activeF = Female, M = Male, BMI = Body Mass Index, PA = physical activity, NA = notactive, A= activeJIA subject disease characteristics are shown in Table 2. Median disease duration was 24(5-166) months. All JIA subjects were on at least one medication for their arthritis.Eleven (85%) were on a non-steroidal anti-inflammatory medication (NSAID), 9 (69%)on disease modifying anti-rheumatic disease therapy (DMARD), 2 (15%) on10corticosteroids and 1 (8%) on biologic anti-cytokine therapy. Disease activity wasvariable with median active joint count=1 (0-22) and ASI=6 (0-64). Function and painwas also variable with a median CHAQ score=0 (0-1.4); 5 patients had mild-to-moderatedisability. (25)Table 2. Patient Disease CharacteristicsPatient .IIAsubtypeDiseaseduration(months)ActivejointcountASIHgb(g(l-,) MedsCHAQ,VAS pain(0-100)1 Poly RF- 5 10 28 124MTX,Naproxen,Prednisone1.4, 642 ERA 21 2 7 129 MTX, SSZ,Naproxen 0.3, 173 Poly RF- 8 2 8 133 MTX,Naproxen 0, 134 EOJIA 98 1 7 129 MTX,Naproxen 0.4, 865 Ps A 166 0 3 117MTX,Naproxen,Prednisone0, 436 ERA 23 1 6 117 MTX 0,187 Poly RF- 24 0 0 142 None 0, 08 Poly RF + 32 22 64 108Infliximab,MTX,Naproxen0, 209 SJIA 44 7 11 120MTX,Naproxen,Prednisone0,010 E-OJIA 103 0 0 139 MTX 0,511 ERA 79 0 0 129 Naproxen,SSZ 0,1112 0 JIA 23 0 0 142 MTX,Ibuprofen 0.25,1013 ERA 22 0 3 139 Ibuprofen 0.5,70Median(Range)24(5-166)1(0-22)6(0-64)132(108-142).22 (0-1.4)17 (0-86)JIA = juvenile idiopathic arthritis, Poly RF- =polyarticular JIA rheumatoid factor negative, PolyRF+ --polyarticular JIA rheumatoid factor positive, ERA =Enthesitis related arthritis, 0 JIA=oligoarticular JIA, E OJIA =extended oligoarticular JIA, Ps A =psoriatic arthritis, SJIA=systemic JIA, ASI =articular severity index, Hgb = Hemoglobin, MTX = methotrexate, SSZ=sulfasalsazineFitness: Summary fitness measures are shown in Table 3. (Individual fitness measuresare shown in Appendix 7). All subjects were able to complete the exercise tests without11any adverse events. There was a large range in aerobic fitness measures for JIA subjects.V02 peak was 31.3  ml/min/kg (20.2-49.9) corresponding to 67.7% (50.4-101.0) predictedand a Z score of -1.4 (-.06--2.4). Five (38%) JIA subjects had Z scores of -2 or lower.CON subjects V02 peak was 47.9 ml/min/kg (32.7-54.1) corresponding to 97.0% (77.4-126.6) predicted and a Z score of -.17 (-1.6-.87). The difference between JIA subjectsand CON subjects was significant (P = 0.013 for VO2 peak, P=0.012 for % predicted andP=0.011 for Z score).Anaerobic fitness measures were variable for JIA subjects. Peak power was 9.7 W/kg(5.6-13.7) and total work completed 168.5 j/kg (107-252) compared to CON subjectvalues of 11.3 W/kg (9.8-14.5) and 224 j/kg (180-248). There was no significantdifference between the two groups for peak power (P=.095) but there was for total workcompleted (P=.036). The metabolic index did not differ between the two groups. Twosubjects with JIA had a metabolic index less than 2.5, suggesting greater impairment ofthe anaerobic than aerobic system. (26)12Table 3. JIA subjects and control subjects fitness measuresJIA SubectsMedian (Range)CON SubectsMedian (Range)Wilcoxin-Mann-Whitney (P value)V02 peak (ml/min/kg) 31.3 47.9(20.2-49.9) (32.7-54.1) 0.013*V02 peak (% predicted) 67.7(50.4-101.0)97.0(77.4-126.6) 0.012*VO2 peak (score) (.06-1 -2.4) (1.6-1.28) 0.011*Max CO (L/min) 7.4 9.0(5.6-13.1) (6.7-11.5) 0.11A-V02 4.4(2.5-6.4)4.7(3.6-6.4)0.29Systemic VascularResistance (SVR)13.3(8.5-20.2)10.8(9.4-14.4) 0.12Peak power (watts/kg) 9.7(5.6-13.7)11.3(9.8-14.5) 0.095Total work (joules/kg) 168.5(107-252)224(180-248) 0 .036*Metabolic index(anerobic: aerobicpower)3.5(2.1-5.9)3.6(3.2-4.4) 0.57Cardiac output: Maximal cardiac output for JIA subjects was 7.4 L/min (5.6-13.1) andfor CON subjects 9.0 (6.7-11.5). There was a trend towards lower CO in JIA subjects butno significant difference between the two groups (P=0.11).Arterial-mixed venous 02 difference (A-V02) and systemic vascular resistance(SVR): A-VO2 did not differ between JIA subjects and CON subjects (P=0.29) but therewas a trend towards higher SVR in subjects with JIA. (P=0.12)13Physical activity: All CON subjects and 11 (85%) of JIA subjects were physicallyactive.Correlations: Correlations between aerobic and anaerobic fitness measures for JIAsubjects are shown in Table 4. VO2 peak showed moderate positive correlation with CO(.615, P=.025) and A-V02(.637, P=.019) consistent with the Fick principle. VO2 peakand CO showed low and high negative correlation, respectively, with SVR which isconsistent with basic physiology principles. Aerobic and anaerobic fitness showedmoderate postive correlation: V02 peak and peak power (0.664, P=.019) and V02 andtotal work (.619, P=.032). In JIA subjects, there was no significant correlation betweendisease activity, function and fitness measures. (Appendix 7)Table 4. Correlations between aerobic and anaerobic fitness measuresin children with JIAMax CO(L/min) AVO2SystemicVascularResistance(SVR)Peakpower(watts/kg)Totalwork(joules/kg)VO2 peak .615 .637 -.366 .664 .619(lid/min/kg) *1) =.025 *P=.019 P=.218 *P=.019 *P=.032Max CO -.204 -.800 .353 .325(L/min) P=.503 *P=.001 P=.260 P=.302Peakpower(watts/kg).786*P=.002*P less than 0.0514DiscussionChildren with JIA have moderate impairments (21.8% in meta-analysis) in aerobic fitnessas measured by VO2 peak (10, 27-29). Our patients' aerobic fitness is similar to previousreports with VO2peak 67.7% (50.4-101.0) predicted and a Z score of -1.4 (-.06--2.4).VO2peak is the gold standard for aerobic fitness and is equal to the product of cardiacoutput (maximal heart rate multiplied by maximal stroke volume), and arterial venousoxygen difference (A-V02 difference = arterial oxygen content — mixed venous oxygencontent) as defined by the Fick equation. Suboptimal V02^maymay be due to centrallimitations, characterized by suboptimal heart rate response, CO or arterial oxygencontent; or peripheral limitations, characterized by high mixed venous oxygen content(low A-V02).Maximal cardiac output in healthy children reaches three to four times the resting value.Most of the increase is due to HR with only 20-25% due to an increase in stroke volume.(30) V02 peak in children with JIA may be limited centrally by low stroke volume(deconditioning) or low maximal heart rate (cessation of exercise due to fatigue or painprior to reaching peak heart rate). (26) Children with JIA also have high sub-maximalenergy expenditures suggesting increased metabolic demands for routine physicalactivity.(28) Doppler echocardiography measures of cardiac output at a given VO2 didnot differ between our JIA subjects and controls. This finding supports our originalhypothesis that children with JIA have normal cardiac response to exercise andsuboptimal VO2 peak is due to peripheral limitations.15V02 peak may be limited peripherally by low arterial oxygen content or high mixed venousoxygen content. Low red cell mass leads to decreased arterial oxygen content, areduction in maximal A-V02 and limitation of VO2 peak. A moderate positive relationshipbetween VO2 peak and total body hemoglobin is well described. (31) Anemia is commonin children with poorly controlled polyarticular disease and systemic JIA. Only one ofour JIA subjects had anemia and this subject had a VO2 peak of 91.5% predicted, makingreduced arterial oxygen carrying capacity an unlikely contributor to suboptimal VO2 peakin our study population. Therefore, in our population high mixed venous oxygen contentlikely accounts for low A-V02 and low VO2 peak. High mixed venous oxygen content ispresent when there is suboptimal blood flow to exercising muscles or deficient oxygenextraction from exercising muscles. During aerobic exercise, arterial systolic bloodpressure increases in proportion to exercise intensity. Changes (increase or decrease) indiastolic pressure are smaller and reflect changes in peripheral vascular resistance. Meanarterial pressure (MAP), defined as the average arterial pressure during a single cardiaccycle, is considered the perfusion pressure seen by organs in the body. MAP and COboth increase during exercise. Lower SVR results in greater blood flow to exercisingmuscles.Children with JIA have generalized muscle weakness and muscle atrophy, mostpronounced in muscles surrounding inflamed joints and often persisting even afterclinical resolution of inflammation. (12-15, 32, 33) Children with JIA likely have acombination of peripheral limitations to their aerobic capacity including: increased SVRwhich may limit blood flow to exercising muscles; muscle atrophy may lead to decreased16oxygen extraction from the exercising muscle; and low muscle endurance may lead todecreased oxygen extraction at some stage during an exercise task. We found trendstowards higher SVR and lower muscle endurance (lower total work completed during theanaerobic Wingate Test) in our subjects with JIA. We did not specifically measuremuscle atrophy or muscle strength. We attempted to non-invasively measure of tissueoxygenation using near infrared spectrophotometer (NIRS) technology but were unable toobtain reliable data in our subjects (data not published). (34, 35) There are no data on A-V02 in children with JIA or other chronic musculoskeletal conditions.Anaerobic exercise is high intensity exercise that can't be sustained for more than 30 to60 seconds. Anaerobic fitness depends predominantly on non-oxidative energy turnoverand is related to local characteristics of working muscle groups. There is recognition thatchildren's play activities are anaerobic in nature with short, intense bursts of high energyactivity. Anaerobic fitness improves during childhood and adolescence concomitant withincreased muscle mass, increased glycolytic capability and improved neuromuscularcoordination. Until very recently, there was limited data on anaerobic fitness in JIA. (29,36, 37) Two recent Dutch studies describe significant anaerobic impairment in childrenand adolescents with JIA. (38, 39) They performed Wingate exercise tests on 62 childrenwith JIA and found impairment of mean power (66.7% predicted) and peak power(65.5% predicted) compared to healthy children. (38) A similar study of 22 adolescentswith JIA found lower mean power for adolescent girls (74%) and boys (88%) and lowerpeak power for girls (67%). (39)17Anaerobic fitness may be lower in children with JIA due to muscle atrophy. In adultswith rheumatoid arthritis, neuromuscular complications are not uncommon. Bothneuropathy and a selective reduction in type II muscle fibres have been described. (40-42) A single study of muscle biopsies in children with JIA demonstrated the presence ofinflammatory changes in the muscle but no evidence of type II muscle fibre hypotrophyor neuropathy. (43)In our study, we found children with JIA had mild impairments in anaerobic fitness withless total work completed and a trend towards lower peak power. There are severalpossible reasons that our subjects with JIA did not have significant impairments. Ourclinic's philosophy is to encourage activity and most of our patients participate in regularphysical activity. There was also a study selection bias; the patients who volunteered toparticipate were generally quite fit and interested in sport. Impaired total work duringmaximal anaerobic exercise suggests poor muscle endurance. Poor muscle endurancemay translate to muscular fatigue in daily activities. Given the anaerobic nature ofchildren's activities they may be limited by low muscular endurance rather thansuboptimal oxygen consumption. Children with significant anaerobic impairment may beunable to perform all their activities of daily living. In support of this hypothesis, arecent study described a positive relationship between functional ability and anaerobicfitness in children with JIA (44).The anaerobic: aerobic ratio or metabolic index is usually greater than 2.5 in healthychildren. A lower ratio implies that anaerobic power is compromised more than aerobic18power. Children with advanced neuromuscular disease have a low metabolic index. (26)The metabolic index in our patients did not differ from our control population orreferenced normative data.Most studies show aerobic fitness is not significantly related to disease severity oractivity but may be related to disease duration. (10, 27-29, 44) Increased physicalactivity levels and self efficacy for exercise correlate with improved aerobic capacity buta causal effect has not been established.(44) There is suggestion that anaerobic fitness ispositively related to function. (16) We did not find any significant correlation betweenfitness measures, disease activity and function in this study.This study has several limitations. Small subject numbers, a heterogeneous JIApopulation, and enrollment bias of fitter patients and controls limits generalization of ourresults. Age and gender differences for VO2 peak are captured by normative data andcalculation of Z scores. There are no gender differences in cardiac output and A-V02 inchildren so measures amongst JIA subjects and controls were grouped. (45, 46) We didnot subdivide participants based on pubertal status due to small numbers. This may limitgeneralization of our findings as prepubertal children have lower maximal CO and higherA-V02 at a given V02 peak. (47) Future studies with larger numbers, subgroups ofpubertal status and disease subtype may allow greater power to determine differences inaerobic and anaerobic fitness for children and teenagers with JIA.19In summary, we found moderate impairments in aerobic fitness in a cohort of childrenwith JIA. Cardiac output and A-V02 during aerobic exercise did not significantly differfrom healthy controls. According to Fick principle VO2 peak is dependent on CO and A-V02. Redistribution of CO and / or a combination of peripheral limitations such asincreased systemic vascular resistance, decreased oxygen extraction from exercisingmuscles due to muscle atrophy or poor muscle endurance may account for the lower VO2peak seen in our cohort of children with JIA. Anaerobic fitness was mildly impaired withless total work completed in children with JIA. This may translate to fatigue in dailyactivities. Further research with larger numbers is required to determine factorscontributing to limited aerobic and anaerobic fitness in children with JIA and to guideexercise therapies. Exercise capacity is increasingly recognized as an important predictorof mortality. (48, 49) Fitness as measured by VO2 peak may emerge as an importantoutcome measure for children with JIA.20References1. Gare BA. Epidemiology. Baillieres Clin Rheumatol 1998;12(2):191-208.2. Manners PJ, Bower C. Worldwide prevalence of juvenile arthritis why does itvary so much? 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Acta Physiol Scand 2000;168(4):615-22.24Appendix 1Control Subjects —Pain QuestionnaireVisual Analog ScaleAfter the exercise test my pain is:WorstNo^ PossiblePain Pain0^1^2^3^4^5^6^7^8^9^1025Appendix 2JIA Subjects — Pain QuestionnaireVisual Analog ScaleOver the past week my pain has been:WorstNo^ PossiblePain Pain0^1^2^3^4^5^6^7^8^9^10Today my pain is:WorstNo^ PossiblePain Pain0^1^2^3^4^5^6^7^8^9^10After the exercise test my pain is:WorstNo^ PossiblePain Pain0^1^2^3^4^5^6^7^8^9^1026Appendix 3Articular Severity Index (ASI)Four clinical indexes of inflammation are assessed: swelling, pain on passive motion(POM), tenderness to palpation, and passive limitation to motion (LOM). A joint withactive arthritis is defined as a joint with swelling or, if no swelling is present, a joint withpassive LOM accompanied by either hear, pain or tenderness. Severity of jointinvolvement is graded on a 4 point scale (0-3) for swelling, POM and tenderness topalpation. Swelling is graded as follows: 0=no swelling, 1=mild swelling (definiteswelling, but with no loss of bony contour), 2=moderate swelling (loss of distinctivenessof bony contour), and 3—marked swelling (bulging synovial proliferation wit cysticcharacteristics of effusion). Pain on motion (POM) or tenderness to palpation are gradedas follows: 0= no POM or tenderness, 1=mild POM or tenderness (patient complains ofpain or tenderness), 2=moderate POM or tenderness (patient withdraws or changes facialexpression upon joint motion or palpation), and 3—severe POM or tenderness (patientresponds markedly to joint motion or palpation). Passive LOM is graded by thefollowing scale: 0—full range of motion (ROM), 1=1-25% LOM, 2=26-50% LOM,3=51-75% LOM, and 4=76-100% LOM fibrous or bony ankylosis). The articular diseaseseverity index is a calculated by summing all the scores. (23)27Appendix 4Physical activity assessment questionnaire(Adapted from the Children's Exercise and Nutrition Centre at McMaster University.Developed by Oded Bar-Or, MD, FACSM.)The purpose of this questionnaire is to help us evaluate your child's activity habits.Please be as accurate as possible in your answers. Feel free to add any details that seemrelevant.1. How would you compare the physical activity of your child with that of her.hisfriends?Child is as active as her / his friends ^Child is more active than her / his friends ^Child is less active than her / his friends ^It is difficult to make such a comparison ^Details2. How would you compare the physical activity of your child with that of yourother children?This child is as active as my other children ^This child is more active than my other children ^This child is less active than my other children ^It is difficult to make such a comparison ^Details283.^Does this child take part in physical education classes at school?Child participates in all activities with no exception ^Child participates in some activities only ^Child does not participate ^Child does not attend school ^Details (especially activities the child does not take part in) ^4. If this child is limited in activity at school, for what reason? (Check as many asare applicable)Advice of physician ^Advice of teacher ^Decision of parents ^Child does not want to participate ^Other reasons (please specify)5. Is the child a member of a sports team at school or in the community?No ^Yes, within school (intramural) ^Yes, representing the school ^Yes, other ^Yes, in the past but no more ^6.^If this child is a member of a team, in which activity or activities?29Hours per week Time of year Comments1237.^If this child trains regularly, what is the nature of his or her training?8.^How many hours on a typical day is the child engaged in the following? Pleasecomplete for a school day and weekend day.School dayActivityLess than1 hour1-2 hours 2-3 hours 3-4 hours More than4 hoursTVVideo gamesComputerPhoneWeekend dayActivityLess than1 hour1-2 hours 2-3 hours 3-4 hours More than4 hoursTVVideo gamesComputerPhone30Type of activity Time of year Hours per week12349.^Does this child participate in any recreational physical activity or activities?(Examples include skiing, cycling, swimming) Please specify.10.^Does any member of the family participate in recreational physical activity orsport? Please specify.YesNo Family member Type of activity Time of year123411.^Does this child complain of any difficulty during or after physical exertion?No complaint ^Shortness of breath ^Coughing ^Wheezing ^31Pain^Where? ^Fainting ^Fatigue ^Other (please specify) ^Details12. In your opinion, is your child as she / he should be?Yes ^Child is too active ^Not sufficiently active ^13. If this child is not as active as she / he should be, what, in your opinion, is thereason? Select all answers that apply.Lack of interest ^Disease ^Lack of opportunity / suitable conditions ^Other ^I don't know^Details3214.^Please check of any of the following statements you agree with (you can checkmore than one statement):Physical activity is important because it is fun. ^Physical activity is necessary for keeping fit. ^Physical activity is good for health reasons. ^Physical activity may be dangerous to one's health. ^Physical activity can prevent a person from becoming overweight. ^33Appendix 5Review of exercise and fitness in children with juvenile idiopathic arthritisJuvenile idiopathic arthritis (JIA) (previously called juvenile rheumatoid arthritis) is acommon childhood chronic disease with a prevalence of 1 in 700. (1-5) There are 7subtypes of JIA, likely representing different pathogenic mechanisms.(6) Arthritis isdefined by 1) the presence of joint swelling or 2) two or more of the following: joint pain,warmth, redness, and limited range of motion for at least 6 weeks. Constitutional signsand symptoms include anorexia, weight loss, growth failure and fatigue. JIA can alsohave extra-articular manifestations with ocular, cardiac, pulmonary and hematopoeticinvolvement. JIA persists into adulthood in up to 55% of patients, which may have amajor impact on physical and psychosocial function.Physical activity affects children's musculoskeletal health and overall aerobic fitness.Increased physical activity is associated with improved health, decreased morbidity anddelayed mortality from chronic illness. Children with arthritis experience joint pain,swelling and reduced range of motion which can contribute to decreased mobility,activity, fitness and function. Children with JIA have reduced vigorous physical activitylevels, sports participation and decreased fitness compared to healthy children. (7-9)Muscle atrophy, weakness, and anemia likely contribute to lower fitness butdeconditioning due to reduced physical activity is likely the greatest cause. Lowerparticipation rates may be due to severity of disease symptoms, treatment-related sideeffects or concerns from parents, teachers and physicians that exercise may aggravatetheir disease.34Conventionally, children with arthritis were advised to limit strain on arthritic joints forfear it may aggravate joint pain and swelling, increasing risk of injury. Muscle atrophysurrounding active joints and periarticular osteopenia may increase the risk of fracture.The effect of tissue loading during exercise on joint surfaces and growth plates inchildren with arthritis is unknown and requires further study.Young children with JIA may have gross motor delays compared to healthy peers, whichaffects sport readiness. In addition, children with long-standing JIA may havedifficulties with endurance sports. Greater sub-maximal energy expenditures have beenreported suggesting increased metabolic demands for routine physical activity. A meta-analysis of 5 studies, including 144 children with JIA, found aerobic fitness was 22%lower than healthy children. (10) Impairments tend to be most pronounced in childrenwith severe arthritis but suboptimal fitness is also seen in children with mild disease andoften persists when disease is in remission. (7, 11) Interestingly, most research suggestsaerobic fitness is not significantly related to disease severity or activity but may berelated to disease duration. (10, 16, 27-29)The potential benefits of exercise therapies in children with JIA are not yet realized.Extreme inactivity results in a loss of proteoglycans, cartilage and decreased bonemineral density which have a negative impact on diseased joints. Inactive children arealso at risk for obesity which can worsen joint load and their health overall. Physical35activity is an important aspect of healthy lifestyles which should be encouraged in allchildren. The psychosocial benefits of group participation cannot be understated.Research suggests that children with JIA can participate in aquatic or land-based weight-bearing exercise programs without disease exacerbation. However, most publishedstudies are small, not randomized, have great variation in study design and use differentexercise modalities (e.g. aquatic, stationary bike, land-based aerobic, circuit aerobic, andland-based resistance). The exercise intensity, frequency and duration also vary.Factoring in these limitations, studies suggest an exercise program (minimum 6 weeks)may lead to improved aerobic fitness; better muscle strength and function; decreaseddisease activity; improved self-efficacy, energy level and quality of life; and reduced painand medication use with no clear effect on functional status. (9, 11, 50-60) Importantly,sports participation does not appear to exacerbate disease. (61)36Appendix 6Review of measures of central and peripheral contribution tomaximal aerobic capacityV02 peak is the gold standard for aerobic fitness and is equal to the product of cardiacoutput (maximal heart rate multiplied by maximal stroke volume), and arterial venousoxygen (A-V 02) difference as defined by the Fick equation. Limitations to aerobiccapacity may be identified as central, characterized by suboptimal cardiac output, orperipheral, characterized by high mixed venous oxygen content.V02^maymay be limited centrally by low stroke volume (deconditioning) or low maximalheart rate (cessation of exercise due to fatigue or pain prior to reaching peak heart rate).VO2 peak may be limited peripherally by significant anemia, low arterial oxygen content,high mixed venous oxygen content due to suboptimal muscle oxygen utilization, lowmuscle strength or low muscle endurance.Estimation of cardiac output (CO) during exercise is feasible using invasive (direct Fick,thermo dilution or dye dilution) or noninvasive techniques. For ethical reasons,noninvasive measurements are preferred. CO can be measured indirectly by the carbondioxide re-breathing technique (using measures of VCO2 , venous carbon dioxide contentand arterial carbon dioxide content after inhalation of CO2 enriched gas) but estimates arelimited to steady state conditions. The acetylene re-breathing method determines the rateof disappearance of an inert gas (acetylene) from an inhaled gas mixture but thistechnique requires mass spectrometry and expensive measurement equipment. Dopplerechocardiography can assess cardiac dimensions and stroke volume during exercise and37is operator dependant. The most indirect and simple measure of cardiovascular responseto exercise is maximal heart rate since it is largely unaffected by body composition ortraining level. In children, increased stroke volume only contributes 20-25% to maximalCO, with greater contribution reported in trained child athletes.(62)Direct mixed venous oxygen content measurements require invasive procedures anddirect sampling of blood. Near infrared spectrophotometer (NIRS) is widely used as anon-invasive means to measure tissue oxygenation in the tissue under the probe byanalysis of differential absorption properties of hemoglobin and myoglobin in the near-infrared range; at 760nm deoxygenated hemoglobin / myoglobin has a higher absorbencyand at 850 nm oxygenated hemoglobin / myoglobin has a higher absorbency.(63) NIRScan assess dynamic changes in tissue oxyhemoglobin, deoxyhemoglobin and total bloodhemoglobin value and has been found to be reliable and valid in the adult population inboth health and disease states.(34, 35) There is some evidence to suggest peripheralmuscle oxygenation kinetics reflect systemic oxygen intake as measured by V02^inthe healthy adult population. Peripheral muscle oxygenation kinetics correlated withVO2peak with positive correlation between deoxygenated hemoglobin and VO 2peak andnegative correlation between oxygenated hemoglobin and VO2 peak.(64) However, thisrelationship may not hold true in disease states.(65) Mixed venous oxygen content canbe also be calculated using the Fick equation, as the absolute oxygen uptake divided bythe absolute cardiac output.38Appendix 7Supplemental TablesTable la. Aerobic and anaerobic fitness parameters for JIA subjectsVO2peak,,,,,,(irrili"vmin)VO2 peak(ml/kWrnin)„,_% predictedVO2peak(Z-score)Max CO/gin)AVO2(V02max /CO)AVO2/COSystemicVascularResistance(SVR)Peakpower(wa)(watts/kg)Total work(joules/kg)Fatigueindex(watts/sec)Metabolicindex(anerobic:aerobicpower)1 26.9 66.4 -2.1 7.5 3.6 0.48 15.6 5.6 107 4.1 3.12 34.2 64.2 -1.7 7.0 4.9 0.70 17.2 9.9 142 11.1 4.23 24.7 62.6 -2.4 6.7 3.7 0.55 11.6 7.6 178 6.3 2.24 32.6 78 -0.72 7.4 4.4 0.59 12.3 8.6 190 4.9 3.65 20.2 50.4 -3.3 6.8 3.0 0.44 14.1 NA NA NA NA6 22.8 56.9 -2.8 9.2 2.5 0.27 10.7 7.8 108 17.6 5.97 28.3 67.7 -1.1 7.3 3.9 0.14 13.3 5.8 116 3.2 3.38 48.8 91.5 -0.41 9.8 5.0 0.51 10.4 11.3 224 12.6 3.69 28.6 56.1 -2.4 5.6 5.1 0.91 20.2 13.6 222 32 5.210 48.1 97.4 -0.15 7.5 6.4 0.85 14.8 10.8 215 7.6 2.911 31.3 78.0 -1.44 5.9 5.3 0.17 19.0 9.5 159 12.4 4.512 49.9 101.0 0.06 13.1 3.8 0.29 8.5 13.7 252 16.1 3.413 46.6 86.3 -0.31 9 5.2 0.58 10.6 11.6 142 11 2.1Mean(SD)34.1(10.6) 73.6 (16.5)-1.20(1.1) 7.9 (2.0)4.4(1.1).50(.24) 13.7 (3.25) 9.6 (2.7)171.2(49.8)11.6(7.9) 3.7 (1.1)Median(Range)31.3(20.2-49.9)67.7 (50.4-011^' 0)-1.4(.06--2.4)7.4 (5.6-13.1)4.4(2.5-6.4).51(.14-.91)13.3 (8.5-20.2)9.7 (5.6-13.7)168.5 (107-252)11.1(3.2-32)3.5 (2.1-5.9)NA = not availableTable lb Aerobic and anaerobic fitness parameters for control subjectsVO2peak(mUkg/min)V02 peak(mllkg/tnin),% predictedVO2peak(Z-score)Max CO(L/tnin)AVO2(V02max /CO)AVO2/COSystemicVascularResistance(SVR)Peakpower(Watts/kg)Total work(joules/kg)Fatigueindex(watts/sec)Metabolicindex(anerobic:aerobicpower)1 97.451.9 -0.12 11.5 4.5 0.39 10.2 12.0 248 15.0 3.22 54.1 109.4 0.53 9.2 5.9 0.64 9.6 10.2 224 5.7 3.53 51.7 104.6 0.26 8.1 6.4 0.79 9.8 11.6 205 11.0 3.44 39.1 91.1 -0.21 10 3.9 0.39 9.4 11.2 231 9.4 3.65 47.9 97 -0.17 7.5 6.4 0.85 12.4 11.3 234 7.4 3.26 33.2 77.4 -1.6 9.2 3.6 0.11 11.4 10.3 180 11.6 4.47 32.7 80.7 -1.2 6.7 4.9 0.15 14.3 9.8 190 12.6 4.38 52.9 126.6 0.87 NA NA NA NA 12.5 187 12.8 3.89 38.5 96.8 -0.26 8.8 4.4 0.11 14.3 14.5 237 23.0 4.4Mean(SD)44.7(8.75) 97.9 (14.9)-.21(0.73) 8.9 (1.5)5.0(1.1)0.43(0.30) 11.4 (2.0) 11.5 (1.4)215.1(25.0)12.1(5.0) 3.75 (.50)Median(Range)47.9(32.7-54.1)97.0 (77.4-126.6)-.17(1.6-1.28)9. 11.5)9.0 (6.7-, 4.7(3.6-6.4)39(.11-. 85)10.8 (9.4-14.4)11.3 (9.8-14.5)224 (180-248)11.6(5.7-23.0) 3.6 (3.2-4.4)NA = not availableTable 2: Correlation between disease activity, function and fitness measures insubjects with JIA.Diseaseduration ASI CHAQ VO2PeakPowerTotalWorkDisease^Pearson Correlationduration 1 -.252 -.320 -.141 .199 .368Sig. (2-tailed) .406 .287 .645 .536 .239N 13 13 13 13 12 12ASI^Pearson Correlation -.252 1 .184 .232 .015 .164Sig. (2-tailed) .406 .547 .445 .962 .611N 13 13 13 13 12 12CHAQ^Pearson Correlation -.320 .184 1 -.008 -.332 -.382Sig. (2-tailed) .287 .547 .980 .292 .220N 13 13 13 13 12 12VO2^Pearson Correlation -.141 .232 -.008 1 .664(*) .619(*)Sig. (2-tailed) .645 .445 .980 .019 .032N 13 13 13 13 12 12Peak^Pearson CorrelationPower .199 .015 -.332 .664(*) 1 .786(**)Sig. (2-tailed) .536 .962 .292 .019 .002N 12 12 12 12 12 12Total^Pearson CorrelationWork .368 .164 -.382 .619(*) .786(**) 1Sig. (2-tailed) .239 .611 .220 .032 .002N 12 12 12 12 12 12** Correlation is significant at the 0.01 level (2-tailed).* Correlation is significant at the 0.05 level (2-tailed).41The University of British ColumbiaOffice of Research Services,Clinical Research Ethics Board - Room 210.828 West 10 1h Avenue, Vancouver. BC V5Z I L8Certificate of Full Board ApprovalClinical Research Ethics Board Official NotificationPRINCIPAL INVESTIGATORHoughton, K.DEPARTMENTPaediatricsNUMBERCO5-0571INSTITUTION(S) WHERE RESEARCH WILL BE CARRIED OUTChildren's & Women's Health CentreCO-INVEST1GATORS:McKenzie, Donald, Human Kinetics; Potts, James, PaediatricsSPONSORING AGENCIESUnfunded ResearchTITLE: .. -.Aerobic Capacity iu Juvenile Idiopathic Arthritis: Central Vends Peripheral LimitationsAPPROVAL DATE17 February 2006TERM (YEARS)1DOCUMENTS INCLUDED IN THIS APPROVAL'Protocol version 1 dated 25 October 2005; Subject ConsentForm version 2 dated 15 February 2006; Control ConsentForm version 2 dated 15 February 2006; Assent Form version2 dated 15 February 2006; Control Assent Form version 2dated 15 February 2006; QuestionnairesCERTIFICATION:In respect of clinical trials:1.The membership of this Research Ethics Board complies with the membership requirements for Research EthicsBoards defined in Division 5 of the Food and Drug Regulations.2. The Research Ethics Board carries out its functions in a manner consistent with Good Clinical Practices.3. This Research Ethics Board has reviewed and approved the clinical Mal protocol and informed consent form for the trialwhich is to be conducted by the qualified investigator named above at the specified clinical trial site. This approval and theviews of this Research Ethics Board have been documented in writing.The documentation included for the above-named project has been reviewed by the UBC CREB, and theresearch study, as presented in the documentation, was found to be acceptable on ethical grounds forresearch involving human subjects and was approved by the UBC CREB.The CREB approval for this study expires one year from the approval date.SWApproval of the Clinical Research Ethics Board by one ofDr. Gail Bellward, ChairDr. James McCormack, Associate Chair42McKenzie, Donald; Potts, JimC&W DEPARTMENTS, PATIENT BASED PROGRAMS AND ADMINISTRATIVE JURISDICTIONS IMPACTED BY THIS STUDY:Pediatrics;SPONSORING AGENCIES:UnfundedCO•INVESTIGATORS:allp CHILDREN'S & WOMEN'S HEALTHCENTRE OF BRITISH COLUMBIAResearch Review CommitteeSeptember 5, 2006Room 202, 950 West 28" AvenueVancouver, BC V5Z 4H4Phone: 604-875-3103/3194Fax 604-875-2496Certificate of Approval-- AMENDMENT --ObicTERMS OF APPROVALFebruary 24 2006 -February 16 2007CERTIFICATION:AMENDMENT:Exercise Protocol version 2 dd August 212006;Consent-controls version 3 dd August 212006; )Consent-subjects (JIA) version 3 dd August 212006;Assent-controls version 3 dd August 212006;Assent-subjects version 3 dd August 21 2006 AMENDMENT APPROVED:September 5, 2006The protocol for the above-named project has been reviewed by the Research Review Committeeand has been found to be appropriate with respect to ethics, methodology, patient impact andavailability of C&W resourcesApproval ISf the C&W Research Review CommitteeDr. M. Levine, ChairDr. M. Bond, Associate ChairThis Certificate of Approval is valid for the above term provided there is no change in theresearch protocol43Page 2 of 2The amendment(s) for the above-named project has been reviewed by the Chair of the University of British ColumbiaClinical Research Ethics Board and the accompanying documentation was found to be acceptable on ethical grounds forresearch involving human subjects.Approval of the Clinical Research Ethics Board by one of411111111r 111111111111- ainikDr. Ca:Dr. Gail Beliward, o Dr. James McCormack,^ Strahltor Dr. John Russell, Associate Chair or ASSOCifChair^r Associate ChairChair ^9/5/200644Approval of the Clinical Research Ethics Board by one ofPage 1 of 2The University of British ColumbiaOffice of Research ServicesClinical Research Ethics Board - Room 210, 828 West 10th Avenue, Vancouver, BC V5Z1L8ETHICS CERTIFICATE OF EXPEDITED APPROVAL:AMENDMENTPRINCIPAL INVESTIGATOR:Kristin HoughtonDEPARTMENT: UBC CREB NUMBER:H05-70571INSTITUTIONS) WHERE RESEARCH WILL BE CARRIED OUT:Institution^ I^ SiteChildren's and Women's Health Centre of BC (incl. Sunny ^Children's and Women's Health Centre of BC (inel. SunnyHill)^Hill)Other iocations where the research will be conducted:N/ACO-INVESTIGATOR(S):Donald C. McKenzieWilliam SheetJames E. PottsSPONSORING AGENCIES:Unfunded Research - "Aerobic Capacity in Juvenile Idiopathic Arthritis: Central Versus Peripheral Limitations"PROJECT TITLE:Aerobic Capacity in Juvenile Idiopathic Arthritis: Central Versus Peripheral LimitationsREMINDER: The current UBC CREB approval for this study expires: February 17, 2007AMENDMENT(S): AMENDMENT APPROVAL DATE:Document Name I Version I Date September 17, 2006Investigator Brochures:recruitment letter 1 September 1,2005CERTIFICATION:In respect of clinical trials:1.The membership of this Research Ethics Board complies with the membership requirements fbr Research Ethics Boardsdefined in Division 5 of the Food and Drug Regulations.2. The Research Ethics Board carries out its functions in a manner consistent with Good Clinical Practices.3. This Research Ethics Board has reviewed and approved the clinical trial protocol and informed consentfirrm for the trialwhich is to be conducted by the qualified investigator named above at the specified clinical trial site. This approval and theviews of this Research Ethics Board have been documented in writing.The amendments) for the above-named project has been reviewed by the Chair of the University of British ColumbiaClinical Research Ethics Board and the accompanying documentation was found to be acceptable on ethical grounds forresearch involving human subjects.Dr. Cahttns.//ri se. ubc.ea/ri se/Doc/O/OVFPNPOOR271C1F310490B6P E89/fromString.html ^9/20/200645Page 2 of 2Dr. Gail Bellward,^Dr. James McCormack,^ StrahleChair or Associate Chair^orDr. John Russell, Associate Chair or AssochChair^9/20/200646


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