Juvenile Arthritis

Study:

Functional, Physiologic and Immunologic Outcomes of
Quantitative Progressive Exercise Rehabilitation of the Lower Extremities in Juvenile Arthritis:

A Pilot Study
1997-2001

Principal Investigator :
Nadine M. Fisher, Ed.D.
Participating Investigators :
Kathleen M. O'Neil, M.D.
Jaya Venkatraman, Ph.D.

A Field-Initiated Research Proposal Submitted To:
National Institute on Disability and Rehabilitation Research
United States Department of Education
#H133G970156, $374,945, 1997-2001

Design of the Research and Demonstration Project

Specific Aims:

Children with juvenile arthritis (JA) have been shown to have reduced muscle and cardiovascular physiology and functional performance compared to normal children. The effects of a specifically prescribed exercise program, focusing on the musculature supporting the inflamed joint, have not been demonstrated. The goals of this application are threefold. First, the differences between normal children and those with JA, affecting the lower extremity joints, have been studied with respect to their functional, physiologic, biochemical and immunologic responses to exercise. The subjects were matched for age, gender and body surface area. These data will increase our understanding of the physiologic changes that contribute to disability in this chronic disease of childhood. Second, the efficacy and effects of a previously published muscle exercise program developed in our laboratory, Quantitative Progressive Exercise Rehabilitation (QPER), were studied in a group of children with JA. This program has been shown to be a more effective form of therapy for adults with rheumatoid arthritis and osteoarthritis than standard physical therapy or aerobic conditioning programs. The impact on disease activity, symptoms and a variety of functional outcome parameters have been assessed following completion of the program and 12 months later. Third, the biochemical and immunologic changes occurring as a result of exercise testing and the QPER program were studied. There are no data describing the effects of exercise on inflammatory cytokine activity in children with JA. These important parameters are known to be impacted by active inflammation and to play a role in the manifestations of chronic inflammatory disease. The effect of exercise on cytokine production, nutritional status and antioxidant defenses may be related to the mechanism by which exercise decreases disability.

ABSTRACTS:

NM Fisher, JT Venkatraman, KM O'Neil. The effects of resistance exercises on muscle and immune function in juvenile arthritis. Arthritis Rheum 44(9)Suppl:S276, 2001.
Resistance exercises decrease pain and increase the functional capabilities of adult arthritis patients. Programs for children with juvenile arthritis (JA) are not as common. This study examined the effects of an 8-week resistance training program (RT) on muscle function and immune function in JA. Muscle function (strength, endurance and contraction speed) was measured on 19 JA children (JAX) (mean age= 11.3±3 yrs) before, and after RT. JAX were compared to 23 normal children (C) (mean age=9.8±2.7 yrs) and 20 JA controls (JAC) (mean age=10.1±3 yrs) who did not participate in RT. Inflammatory mediators, i.e. IL-10, IL-6, IL-1ra, sTNF-RI, sTNF-RII, IL-1β, and TNF-α, were measured in plasma, PBMC supernatants and LPS-stimulated supernatants, to determine the effects of RT on inflammation. Data were analyzed using repeated measures ANOVA and univariate statistics (p<.05). After RT, JAX had dramatic increases in strength (22-31%), endurance (26%), contraction speed (24%), and electromyographic (EMG) activity (27%). Over the same 8-week period, JAC had relatively no change to a slight decrease in muscle function, while C showed a slight increase in these variables, averaging 5%. For JAX, plasma measures of IL-1ra (10%) increased, while IL-6 (66%), sTNF-RI (9%), sTNF-RII (9%), and IL-1β (78%) decreased. IL-10 and TNF-α were undetectable. For the 24-hr PBMC sups, IL-6 (117%), IL-1ra (33%), sTNF-Rll (33%), and IL-1β (50%) increased. In LPS-stimulated sups, IL-10 (9%); sTNF-RI (37%), sTNF-RII (7%), IL-β (8%), and TNF-α (7%) increased, while IL-6 (36%) and IL-1ra (18%) decreased. In general, there was not a significant change in inflammatory mediator production for JAC or C after the 8-week period. In summary, an 8-week resistance training program for children with JA can improve muscle function and immune function, with implications for decreasing joint pain and inflammation.

O'Neil KM, NM Fisher, JT Venkatraman. Immunologic Effects of Acute Exercise on Inflammatory Mediators in Children with Juvenile Idiopathic Arthritis. Arthritis Rheum 44(9)Suppl:S339, 2001.
Exercise is used to treat inflammatory arthritis, but data regarding its effect on inflammation is sparse. The immunologic consequences of acute exercise in children with stable juvenile idiopathic arthritis (JA, n= 19) and healthy control children (C, n=23) were studied using a graded bicycle stress test (GXT) to determine if acute exercise promotes or inhibits inflammatory mediator release. TNF-alpha, sTNF-RI, sTNF-RII, IL-1-beta, IL-1RA, IL-6 and IL-10 were measured in plasma and cell culture supernatants of peripheral blood mononuclear cells (PBMC) from JA and C subjects immediately prior to and following GXT. Children with JA differed from controls in their responses to acute exercise in LPS-induced TNF production (p=0.047), with a rise in TNF releasability after exercise (from 1267± 245 to 1402±256 pg/ml), compared to a decrease in controls (791±71 to 656±83 pg/mI). Plasma TNF concentrations were generally undetectable. Unstimulated PBMC TNF production did not differ in response to GXT between subjects and controls. IL-6, IL-10 and IL-1-beta responses to GXT also did not differ between groups. IL-1RA in plasma was similar in JA and C, but LPS-induced production from PBMC decreased more dramatically after GXT in C (from 4838±1171 to 4639±1086 pg/mI) than JA subjects (from 1933±574 to 1404±325 pg/mI; p=0.029). Unstimulated PBMC IL-1RA production after GXT was more suppressed by GXT in JA than controls (p =0.054). Both TNF-RI and RII were affected similarly by GXT in JA and C subjects, although LPS-induced sTNF-RI was increased slightly in JA (from 28.5±4.3 to 34.5±6.3 pg/mI) and decreased more substantially in C (from 85.7±25.4 to 18.4±1.6 pg/ml; p=0.078). LPS-stimulated PBMC from JA subjects produced significantly more IL-10 than those of controls before exercise (1927± 536 vs. 527±56 pg/ml; p=0.042), more IL-1 after exercise (2535±245 vs. 1716±53pg/ml; p=0.040) and more IL-1RA after exercise (4639±1085 vs. 1404±325 pg/mI). Thus, children with JA responded to acute exercise with a substantial increase in LPS-induced TNF releasability of PBMC versus a minimal decline in controls, and though not significant, a trend toward less IL-1RA produced by unstimulated PBMC after exercise in JA than in controls. This suggests the possibility that acute aerobic exercise could increase inflammatory activity in children with JA. In other studies, we have shown resistance training may have antiinflammatory effects.
Disclosure: Supported by NIDRR #H133670156.

Lin H, JT Venkatraman, N Fisher, K O'Neil, P Gong, W Chu. Effects of quantitative rehabilitation exercise (QPER) on biochemical indices in juvenile arthritis (JA) . FASEB J 13:A931,#687.8, 1999.
Children with JA typically experience chronic pain, joint inflammation, stiffness and deformity. Appropriately prescribed exercise rehabilitation programs may reduce inflammation. The present study evaluated the effects of 8 wks of QPER on physiologic, biochemical and immunologic function in JA children. Eighteen children (age: 6-14 yrs; Control (C)-8; JA-C: 4, JA-Ex: 6) participated in the study. Blood was collected at baseline (pre-1); after a graded exercise test (CV) (pre-2); after 8 wks (post-1) and after 8 wks+CV test (post-2). ANOVA revealed significantly lower levels of plasma lactate in JA-C Vs C (p<0.03). Plasma lactate levels significantly increased after the CV test in the C group (17+1.3mg to 32.6+3.3mg/100ml) while not in the JA group. After 8wks of QPER, lactate levels increased significantly after post-2 test (15mg to 22mg/100ml) in the JA-Ex group. Plasma hemoglobin levels were significantly lower in the JA children. Plasma glucose level (60-80mg/100ml) was similar in all the groups and was not altered by the CV test. Plasma cholesterol and triglycerides (TG) levels were significantly lower in children with JA compared to C. Preliminary data suggest that the QPER program had no adverse effects and increased the anaerobic glycolytic capacity in JA children. (Funded by National Institutes of Disability & Rehabilitation Research).

Venkatraman JT, N Fisher, K O'Neil, H Lin, W Chu. Effects of quantitative rehabilitation exercise (QPER) on the function of neutrophils (PMN) in children with juvenile arthritis (JA). FASEB J 13:A846,#644.4, 1999.
Neutrophils have been implicated in tissue destructive events in inflammatory disease. Their function depends on their ability to adhere to microvascular endothelium and extracellular matrix components and to respond with a respiratory burst. The present study evaluated the effects of 8 wks of QPER on PMN function in JA children. A total of 18 children (ages of 6-14 yrs; Control (C): 8; JA-C: 4, JA-EX: 6) participated in this study. Blood was collected at baseline (pre-1), after a graded exercise (CV) test (pre-2), 8wks later (post-1) and 8 wks later after the CV test (post-2). PMN were separated from blood using HistopaqueR gradients. The adherence and respiratory burst of PMN was tested in the presence of formyl-methionyl-leucyl-phenylalanine (fMLP; a chemotactic peptide) and phorbol 12-myristate 13-acetate (PMA). ANOVA revealed that the adherence of PMN was significantly lower (40% lower0 in JA children. Adherence increased to normal levels after 8wks of QPER. There were significant differences in the respiratory burst of PMN between the C and JA groups. Significant differences in respiratory burst were also observed between Pre-1 & Pre-2 and Pre-2 & Post-2. Preliminary data suggest that abnormalities occur in neutrophil adherence and respiratory burst in JA children. A specific muscle exercise training program may have potential for normalizing PMN function and reducing inflammation in JA children. (Funded by NIDRR).

Fisher NM, JT Venkatraman, KM O'Neil. Effects of resistance exercise on children with juvenile arthritis. Arthritis Rheum 42(9)Suppl:S396, 1999.
Juvenile arthritis (JA) is a common chronic condition in children, leading to long term disability. This project measured the effects of exercise rehabilitation on muscular, cardiovascular and functional performance, and pain in children with JA. Six subjects (JA-EX mean age=10+2.7yrs) diagnosed with JA participated in an 8-week resistance exercise program. Pre and post-tests of maximal isometric strength and endurance of the quadriceps and hamstrings, speed of muscle contraction, submaximal and maximal oxygen consumption (VO2), heart rate (HR), blood pressure (BP), as well as pain, disability and functional performance were conducted. The individualized resistance exercise program was designed based on the pre-test results. Two control groups, normal controls (C, n=13, age=9.2+2.4 yrs) and JA controls (JA-C, n=5, age=8.8+1.8 yrs) participated in the pre and post-tests, but not the exercise program. Results were statistically analyzed using repeated measures ANOVA (p<.05). After resistance exercise, the JA-EX group had significant increases in quadriceps strength (48%), hamstring strength (99%), quadriceps endurance (32%), hamstring endurance (59%), and contraction speed (46%-69%). VO2max, maximal HR and systolic BP increased 15%, 5%, and 10%, respectively. Overall functional performance (10%) and functional status (32%) increased and pain (42-51%), disability (26%) and the number of medications used (25%) decreased significantly. The JA subjects were more compromised than C on most variables. Whereas C increased hamstring strength (17%) and endurance (25%). JA-C decreased (42-45%) from pre to post. Also, JA-C had increased pain (74%), disability (10%) and medication use (54%). This project provides evidence that a specific resistance exercise rehabilitation program has a positive physiological and functional impact, as well as the ability to reduce pain, disability and medication use, on children with JA. (Supported by the National Institute on Disability and Rehabilitation Research, #H133G70156)

Venkatraman JT, NM Fisher, HJ Lin, KM O'Neil. Effects of resistance exercise on plasma levels and production of cytokines and lipid mediators in juvenile arthritis . Arthritis Rheum 42(9)Suppl:S396, 1999.
An abnormal production of proinflammatory cytokines and lipid mediators may lead to inflammation and the progression of many autoimmune diseases. The present study evaluated the effects of 8 weeks of resistance exercise training on plasma levels and the production of cytokines and lipid mediators produced by PBMN cells in JA children. Eighteen children (ages 6-14 yrs; Control (C, n=8); JA-Control (JA-C, n=4); JA-EX, n=6) participated in the study. Blood was collected at baseline (pre-1), after a graded cycle exercise test (GXT) (pre-2), 8 wks later (post-1) and 8 wks later after GXT (post-2). PBMN cells were prepared using HistopaqueR gradients. Cells were cultured with LPS and PHA; cytokines and lipid mediators were determined by ELISA. Results were analyzed statistically using ANOVA (p<.05). PGE2, LTB4, IL-2, IFN-( and plasma TXB2 and IL-4 were significantly different between the C and JA groups. Significant differences were also observed between JA-C and JA-EX for IFN-(, IL-4 and IL-8. From pre-1 to post-1, there were significant differences between groups in PGE2, IL-4, plasma IFN-( and IL-4 levels. From pre-2 to post-2, there were changes between groups in IL-2, IFN-(, plasma IFN-( and IL-4, JA-EX was different from JA-C for IL-12 and plasma PGE2, IL-2, IFN-(, after resistance exercise. There were significant effects on the production of IL-2, IFN-( and plasma IFN-( from pre to post-GXT. Significant effects between pre-1 vs. post-1 and pre-2 vs post-2 were observed for the production of IL-2, IFN-( and plasma levels of IFN-(, IL-12 and PGE2 (pre-2 vs post-2 only) Data from the present study suggest that the levels of cytokines and lipid mediators are different between the JA and C subjects. The 8-week resistance exercise program significantly modulated these levels in JA. A specific muscle exercise rehabilitation program in JA children may have potential in correcting the imbalances in proinflammatory cytokines and lipid mediators and thereby, reduce inflammation in JA. (Supported by the National Institute on Disability and Rehabilitation Research. #H133G70156)

Velazquez V, NM Fisher, JT Venkatraman, KM O'Neil. Effect of lower extremity resistance exercise rehabilitation on interleukin-1-beta, interleukin-1RA, and interleukin-6 in juvenile arthritis . Arthritis Rheum 42(9)Suppl:S185, 1999.
Inflammation in juvenile arthritis (JA) is promoted by the cytokines, interleukin-1( (IL-1), and interleukin-6 (IL-6), and is opposed by the IL-1 receptor antagonist (IL-1RA). Exercise may affect inflammatory activity in JA by influencing production of cytokines or their antagonists. We examined the effects of an 8 week individualized resistance exercise program on plasma concentrations and cultured mononuclear cell production (24 hr sups + 100 ng/ml LPS) of IL-1, IL-6, and IL-1RA in 9 children with JA and 9 healthy controls (C). Six JA subjects exercised; 3 served as disease controls. Blood was sampled prior to and following cycle graded exercise testing (GXT), both pre- and post-exercise training. Cytokines were measured with ELISA kits (R&D). IL-1 was undetectable in 6/9 plasmas in each group. In unstimulated sups, IL-1 was detectable in 0/9 C and 4/9 JA subjects. In LPS-stimulated C sups, IL-1 increased with GXT from 2534+658 to 2807+533 pg/ml (mean+sem); JA did not differ from C before or after exercise training, and showed no consistent response to GXT. IL-6 was detected in plasma from 1/10 C and 4/9 JA subjects. In unstimulated PBMC sups from C, 189+73 pg/ml IL-6 was present at baseline, and did not change with GXT. JA sups contained 657+586 pg/ml IL-6 and did not change with GXT, but dropped significantly to 233+195 pg/ml after exercise training. Plasma IL-1RA was detected in 3/10 C subjects (all after GXT), and 5/9 JA subjects (3 pre- and 5-post GXT). Unstimulated sups from C contained 361+48 pg/ml IL-1RA at baseline; sups from JA contained 453+89 pg/ml, and neither changed with GXT. Following exercise training, IL-1RA in unstimulated JA sups fell to normal at 344+57 pg/ml. Il-1RA in LPS-stimulated C sups was 566+77 pg/ml at baseline, and 659+95 after GXT. In JA sups, IL-1RA was 651+71 pg/ml at baseline, and was 707+103 after GXT. Following exercise training, stimulated IL-1RA production decreased to 474+39 pg/ml and not change with GXT.
Resistance exercise training affects production of inflammatory mediators in JA.

Velazquez V, NM Fisher, JT Venkatraman, KM O'Neil. The effect of a lower extremity resistance exercise rehabilitation program on TNF-alpha and TNF receptors in juvenile arthritis. Arthritis Rheum 42(9)Suppl:S230, 1999.
Tumor necrosis factor-( and its soluble receptors play an important role in arthritis. TNF-( promotes, and its soluble receptors can inhibit inflammation. Exercise can improve function in arthritis, but its effect on inflammation is not defined. We studied the effects of an 8 wk. resistance exercise program in juvenile arthritis (JA) on TNF and sTNF-RI and RII in plasma and PBMC supernatants. Nineteen children, ages 6-14 yr., 10 healthy controls (C) and 9 with JA affecting lower extremities were enrolled. Six JA subjects exercised; 3 served as disease controls. Blood was drawn before and after graded cycle exercise testing (GXT) both pre- and post-exercise training. Mononuclear cells were cultured for 24 hr + 100 ng/ml LPS. TNF-alpha, sTNF-RI and sTNF-RII were measured using ELISA. Data were analyzed with one-way ANOVA. TNF was undetectable (<4.4 pg/ml) in all plasmas. In unstimulated PBMC sups, TNF was detected in 2/10 C and 5/9 JA subjects, and showed no consistent response to GXT or exercise training in any group. LPS-stimulated sups from control subjects contained 669+98 pg/ml TNF pre-GXT (mean+sem), compared to 1191+121 pg/ml in JA sups; following exercise training, JA pre-GXT TNF was normal at 664+246 pg/ml. The GXT increased LPS-induced TNF in all groups: to 801+102 pg/ml in C, 1362+237 pg/ml in JA, and 694+289 pg/ml in JA after the exercise program. sTNF-RI was detected in few sups: 2/25 C and 2/24 JA unstimulated; and 3/25 C and 1/12 JA LPS-stimulated. Plasma TNF-RI in C and JA subjects before the exercise program was similar (C=748+64 pg/ml and JA=864+45 pg/ml). After training, sTNF-RI in JA was higher at 1018+69 pg/ml pre-GXT and 988+62 pg/ml post-GXT. sTNF-RII was found in all plasmas and stimulated sups, but did not differ among groups, after GXT, or exercise training. JA subjects demonstrated a decrease in LPS-induced TNF-alpha production to normal, and an increase in plasma sTNF-RI following exercise training. Thus, the balance between TNF and sTNF-RI is shifted by the resistance exercise rehabilitation program toward anti-inflammatory conditions. (Supported by NIDRR #H133G70156)

Venkatraman JT, NM Fisher, K Meksawan, A Krishnan, A Downie. Effects of resistance exercise training (RET) on chemokine levels in juvenile arthritis (JA ) . FASEB J 14(4):A526,#367.1, 2000.

A specific RET program has a positive physiological and functional impact in children with JA. This may be due to the modulation of chemokines and cytokines, which are implicated in mediating chemotaxis and inflammation. This study evaluates the effect of a RET on the levels of chemokines in JA children. Eighteen children (ages 6-16 yrs; Control (C, n=8); JA-Control (JA-C, n=4); JA-Exercise (JA-Ex, n=6) participated in the study. Blood was collected at baseline (pre-1), after a graded cycle exercise test (GXT) (pre-2), 8 wks later (post-1), and 8 wks later after a GXT (post-2). PBMN cells were cultured with LPS and PHA and chemokines were determined by ELISA. The production of RANTES by PBMN cells was significantly different in the C and JA groups. Significant differences were also observed between JA-C and JA-Ex for MIP-1alpha, MIP-1beta and RANTES production by PBMN cells. Significant decreases (48%) in MIP-1alpha and in MIP-1beta (34%) levels in post-1 compared to pre-1 were observed. MIP-1alpha was significantly decreased (36%) in post-2 compared to pre-2. The levels of MIP-1alpha and MIP-1beta were lower in JA-Ex while RANTES was significantly higher in JA-Ex. This study suggests that chemokine levels are different in C and JA groups. The RET program can modulate the levels of specific chemokines in JA subjects and may have potential in normalizing chemotaxis, resulting in the reduction of inflammation in JA. (Funded by NIDRR #H133G70156)