Increased Development of Th1, Th17, and Th1.17 Cells Under T1 Polarizing Conditions in Juvenile Idiopathic Arthritis.

In juvenile idiopathic arthritis (JIA) inflammatory T cells and their produced cytokines are drug targets and play a role in disease pathogenesis. Despite their clinical importance, the sources and types of inflammatory T cells involved remain unclear. T cells respond to polarizing factors to initiate types of immunity to fight infections, which include immunity types 1 (T1), 2 (T2), and 3 (T17). Polarizing factors drive CD4+ T cells towards T helper (Th) cell subtypes and CD8+ T cells towards cytotoxic T cell (Tc) subtypes. T1 and T17 polarization are associated with autoimmunity and production of the cytokines IFNγ and IL-17 respectively. We show that JIA and child healthy control (HC) peripheral blood mononuclear cells are remarkably similar, with the same frequencies of CD4+ and CD8+ naïve and memory T cell subsets, T cell proliferation, and CD4+ and CD8+ T cell subsets upon T1, T2, and T17 polarization. Yet, under T1 polarizing conditions JIA cells produced increased IFNγ and inappropriately produced IL-17. Under T17 polarizing conditions JIA T cells produced increased IL-17. Gene expression of IFNγ, IL-17, Tbet, and RORγT by quantitative PCR and RNA sequencing revealed activation of immune responses and inappropriate activation of IL-17 signaling pathways in JIA polarized T1 cells. The polarized JIA T1 cells were comprised of Th and Tc cells, with Th cells producing IFNγ (Th1), IL-17 (Th17), and both IFNγ-IL-17 (Th1.17) and Tc cells producing IFNγ (Tc1). The JIA polarized CD4+ T1 cells expressed both Tbet and RORγT, with higher expression of the transcription factors associated with higher frequency of IL-17 producing cells. T1 polarized naïve CD4+ cells from JIA also produced more IFNγ and more IL-17 than HC. We show that in JIA T1 polarization inappropriately generates Th1, Th17, and Th1.17 cells. Our data provides a tool for studying the development of heterogeneous inflammatory T cells in JIA under T1 polarizing conditions and for identifying pathogenic immune cells that are important as drug targets and diagnostic markers.

Emergent high fatality lung disease in systemic juvenile arthritis.

OBJECTIVE: To investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA). METHODS: In a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data. RESULTS: LD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features. CONCLUSIONS: A rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed.

A case of severe acquired hypertriglyceridemia in a 7-year-old girl.

We report a case of severe type I hyperlipoproteinemia caused by autoimmunity against lipoprotein lipase (LPL) in the context of presymptomatic Sjögren's syndrome. A 7-year-old mixed race (Caucasian/African American) girl was admitted to the intensive care unit at Vanderbilt Children's Hospital with acute pancreatitis and shock. She was previously healthy aside from asthma and history of Hashimoto's thyroiditis. Admission triglycerides (TGs) were 2191 mg/dL but returned to normal during the hospital stay and in the absence of food intake. At discharge, she was placed on a low-fat, low-sugar diet. She did not respond to fibrates, prescription fish oil, metformin, or orlistat, and during the following 2 years, she was hospitalized several times with recurrent pancreatitis. Except for a heterozygous mutation in the promoter region of LPL, predicted to have no clinical significance, she had no further mutations in genes known to affect TG metabolism and to cause inherited type I hyperlipoproteinemia, such as APOA5, APOC2, GPIHBP1, or LMF1. When her TG levels normalized after incidental use of prednisone, an autoimmune mechanism was suspected. Immunoblot analyses showed the presence of autoantibodies to LPL in the patient's plasma. Autoantibodies to LPL decreased by 37% while patient was on prednisone, and by 68% as she subsequently transitioned to hydroxychloroquine monotherapy. While on hydroxychloroquine, she underwent a supervised high-fat meal challenge and showed normal ability to metabolize TG. For the past 3 years and 6 months, she has had TG consistently <250 mg/dL, and no symptoms of, or readmissions for, pancreatitis.

Pilot study comparing the Childhood Arthritis & Rheumatology Research Alliance (CARRA) systemic Juvenile Idiopathic Arthritis Consensus Treatment Plans.

OBJECTIVES: To assess the feasibility of studying the comparative effectiveness of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) consensus treatment plans (CTPs) for systemic Juvenile Idiopathic Arthritis (JIA) using an observational registry. METHODS: Untreated systemic JIA patients enrolled in the CARRA Registry were begun on one of 4 CTPs chosen by the treating physician and patient/family (glucocorticoid [GC] alone; methotrexate [MTX] ± GC; IL1 inhibitor [IL1i] ± GC; IL6 inhibitor [IL6i] ± GC). The primary outcome of clinical inactive disease (CID) without current GC use was assessed at 9 months. TRIAL REGISTRATION: clinicaltrials.gov NCT01697254; first registered 9/28/12 (retrospectively enrolled). RESULTS: Thirty patients were enrolled at 13 sites; eight patients were started on a non-biologic CTP (2 GC, 6 MTX) and 22 patients on a biologic CTP (12 IL1i, 10 IL6i) at disease onset. Demographic and disease features were similar between CTP groups. CTP choice appeared to segregate by site preference. CID off GC was achieved by 37% (11 of 30) including 11/22 (50%) starting a biologic CTP compared to 0/8 starting a non-biologic CTP (p = 0.014). There were four serious adverse events: two infections, one appendicitis and one macrophage activation syndrome. CONCLUSIONS: The CARRA systemic JIA CTP pilot study demonstrated successful implementation of CTPs using the CARRA registry infrastructure. Having demonstrated feasibility, a larger study using CTP response to better determine the relative effectiveness of treatments for new-onset systemic JIA is now underway.

Chronic inflammatory arthritis of the ankle/hindfoot/midfoot complex in children with extreme obesity.

BACKGROUND: Childhood obesity is an increasing public health concern, but little is known about how obesity contributes to chronic arthritis. OBJECTIVE: The objective of this study was to identify and characterize children and adolescents who present with isolated arthritis of the ankle/hindfoot/midfoot complex and profound obesity. METHODS: We identified all patients with juvenile idiopathic arthritis who underwent fluoroscopic-guided injections of the feet and ankles between July 2009 and June 2012. We determined their disease category as well as clinical, demographic, and serological features. We also identified patients who had body mass indices (BMIs) that were outliers. RESULTS: Eighty-two patients received fluoroscopic-guided foot and ankle injections during the study period. Twenty-one percent of these patients were obese (BMI ≥95th percentile), and 33% were overweight or obese (BMI ≥85th percentile). We identified 5 of these patients who had isolated arthritis of the ankle/hindfoot/midfoot complex. All patients with isolated foot and ankle arthritis were significantly obese with BMI 98th to 99th percentile for age, and 3 had BMIs that were outliers from the broader population. These patients were also distinctive as being significantly older, more likely to be male, and less likely to have positive antinuclear antibody titers than other patients with ankle/hindfoot/midfoot complex arthritis. Finally, all 5 patients were negative for known laboratory markers associated with juvenile idiopathic arthritis. CONCLUSIONS: We have identified a subgroup of children with chronic inflammatory arthritis limited to their ankle/hindfoot/midfoot complex and significant obesity. This study suggests that there may be interplay between obesity, inflammation, and otherwise unexplained arthritis and highlights a previously unrecognized complication of childhood obesity.

Chronic granulomatous disease masquerading as Behçet disease: a case report and review of the literature.

We describe a patient who presented at 9 years of age with oral ulcers and cutaneous lesions, meeting diagnostic criteria for Behçet disease. At 11 years of age, she developed infectious complications and was proven to have chronic granulomatous disease, with characterization of the specific genetic mutation. We review available literature regarding overlap of these symptom complexes leading to delay in securing this important diagnosis. This is the second reported case of chronic granulomatous disease mimicking Behçet disease, and the first report to include identification of the specific genetic mutation of the nicotinamide adenine dinucleotide phosphate oxidase complex.

Cognitive behavioral therapy for the treatment of juvenile fibromyalgia: a multisite, single-blind, randomized, controlled clinical trial.

OBJECTIVE: Juvenile fibromyalgia syndrome (FMS) is a chronic musculoskeletal pain disorder in children and adolescents for which there are no evidence-based treatments. The objective of this multisite, single-blind, randomized clinical trial was to test whether cognitive-behavioral therapy (CBT) was superior to fibromyalgia (FM) education in reducing functional disability, pain, and symptoms of depression in juvenile FMS. METHODS: Participants were 114 adolescents (ages 11-18 years) with juvenile FMS. After receiving stable medications for 8 weeks, patients were randomized to either CBT or FM education and received 8 weekly individual sessions with a therapist and 2 booster sessions. Assessments were conducted at baseline, immediately following the 8-week treatment phase, and at 6-month followup. RESULTS: The majority of patients (87.7%) completed the trial per protocol. Intent-to-treat analyses showed that patients in both groups had significant reductions in functional disability, pain, and symptoms of depression at the end of the study, and CBT was significantly superior to FM education in reducing the primary outcome of functional disability (mean baseline to end-of-treatment difference between groups 5.39 [95% confidence interval 1.57, 9.22]). Reduction in symptoms of depression was clinically significant for both groups, with mean scores in the range of normal/nondepressed by the end of the study. Reduction in pain was not clinically significant for either group (<30% decrease in pain). There were no study-related adverse events. CONCLUSION: In this controlled trial, CBT was found to be a safe and effective treatment for reducing functional disability and symptoms of depression in adolescents with juvenile FMS.

Effectiveness of dexamethasone iontophoresis for temporomandibular joint involvement in juvenile idiopathic arthritis.

OBJECTIVE: Temporomandibular joint (TMJ) involvement is common in juvenile idiopathic arthritis (JIA). Dexamethasone iontophoresis (DIP) uses low-grade electric currents for transdermal dexamethasone delivery into deeper anatomic structures. The purpose of this study was to assess the safety and effectiveness of DIP for the treatment of TMJ involvement in JIA, and to delineate variables that are associated with improvement after DIP. METHODS: Medical records of all JIA patients who underwent DIP for TMJ involvement at a larger tertiary pediatric rheumatology center from 1997-2011 were reviewed. DIP was performed using a standard protocol. The effectiveness of DIP was assessed by comparing the maximal interincisor opening (MIO(TMJ) ) and the maximal lateral excursion (MLE(TMJ) ) before and after treatment. RESULTS: Twenty-eight patients (ages 2-21 years) who received an average of 8 DIP treatment sessions per involved TMJ were included in the analysis. Statistically significant improvement in the median MIO(TMJ) (P < 0.0001) was observed in 68%. The median MLE(TMJ) (P = 0.03) improved in 69%, and resolution of TMJ pain occurred in 73% of the patients who had TMJ pain at baseline. Side effects of DIP were transient site erythema (86%), skin blister (4%), and metallic taste (4%). Improvement in TMJ range of motion from DIP is associated with lower MIO(TMJ) , lower MLE(TMJ) , and absence of TMJ crepitus at baseline. CONCLUSION: In this pilot study, DIP appeared to be an effective and safe initial treatment of TMJ involvement in JIA, especially among patients with decreased TMJ measurements. Prospective controlled studies are needed.

Combined pre-injection wrist and ankle MRI protocol and steroid joint injections in juvenile idiopathic arthritis.

Precise localization of affected compartments of the wrist and ankle in children with an established diagnosis of juvenile idiopathic arthritis (JIA) is clinically challenging. The purpose of this paper is to describe our experience utilizing a pre-injection MRI protocol of the wrist and ankle for localizing disease activity followed by fluoroscopically guided joint injections in children with JIA.

Actigraphy-based physical activity monitoring in adolescents with juvenile primary fibromyalgia syndrome.

UNLABELLED: Juvenile primary fibromyalgia syndrome (JPFS) is a chronic pain condition associated with significant impairment in physical functioning, but no studies have used newer technologies such as actigraphy to document objective physical activity levels in JPFS. This is the first study to objectively describe physical activity in JPFS patients and examine the relationship of pain, perceived functional impairment, and depressive symptoms on physical activity. One hundred four clinically referred adolescents with JPFS (ages 11 to 18 years) wore a hip-mounted actigraph for 1 week. Data on pain intensity, functional disability, depressive symptoms, and psychiatric diagnoses were obtained using self- and parent-report measures and a standardized psychiatric interview. Results showed that younger patients were more active. Pain intensity was not significantly associated with physical activity levels overall, but the most highly active group of adolescents reported lower levels of pain and disability than the least active. Parent report of adolescents' physical functioning and depressive symptoms were significantly correlated with adolescents' physical activity levels. Actigraphy provides a unique source of information about physical functioning which is distinct from adolescents' self-report of physical functioning in JPFS. Preliminary findings suggest that further study of factors that predict perceived and actual physical functioning in JPFS is warranted. PERSPECTIVE: This study presents the results of physical activity monitoring in adolescents with JPFS using actigraphy. Results indicate that actigraphy provides a unique source of objective information that can advance our understanding of physical disability in JPFS and the factors associated with physical impairment.

Family factors, emotional functioning, and functional impairment in juvenile fibromyalgia syndrome.

OBJECTIVE: Family factors and emotional functioning can play an important role in the ability of adolescents with juvenile primary fibromyalgia syndrome (JPFS) to cope with their condition and function in their everyday lives. The primary objectives of this study were to determine 1) whether adolescents with JPFS and their caregivers differed from healthy age-matched comparison peers and their caregivers in terms of emotional distress and functional impairment; 2) whether there were any differences in the family environment of adolescents with JPFS compared with healthy comparison peers; and 3) which individual-, caregiver-, and family-level variables were associated with functional impairment in adolescents with JPFS. METHODS: Participants were 47 adolescents with JPFS recruited from a pediatric rheumatology clinic and 46 comparison peers without chronic illness matched for age, sex, and race. Participants and their caregivers (all mothers) completed a battery of standardized measures administered in their homes. RESULTS: Adolescents with JPFS had greater internalizing and externalizing symptoms than healthy comparison peers. Mothers of adolescents with JPFS reported twice as many pain conditions and significantly greater depressive symptoms than mothers of comparison peers. The JPFS group also had poorer overall family functioning and more conflicted family relationships. In adolescents with JPFS, maternal pain history was associated with significantly higher functional impairment. CONCLUSION: Increased distress and chronic pain are evident in families of adolescents with JPFS, and family relationships are also impacted. Implications for child functional impairment and the need for inclusion of caregivers in treatment are discussed.

Adherence to medications in systemic lupus erythematosus.

BACKGROUND: Lack of adherence is a ubiquitous problem which can be a hindrance in the treatment of chronic conditions like systemic lupus erythematosus (SLE). OBJECTIVES: A random sample of 63 SLE patients attending rheumatology clinics associated with University Medical Centers were surveyed to measure level of adherence to their SLE medications and to identify the risk factors that have been associated previously with nonadherence to these medications. METHODS: Information on traditional SLE outcomes was obtained by face-to-face interviews and medical record review. Various patient proposed strategies were identified to improve adherence to these medications. RESULTS: When considering adherence estimates of > or =80% as representing sufficient adherence for achieving a therapeutic response, adherence to medications was only modestly adherent, likely limiting the effectiveness of the prescribed medication regimens. Based on pharmacy refill information 61% of the patients were sufficiently adherent to prednisone, 49% to hydroxychloroquine, and 57% to other immunosuppressant medications. Significant risk factors of insufficient adherence included being single, low educational level, presence of other comorbidities, limited comprehension of physician explanations and instructions, and having to take the medication more than one daily. Based on subject reports, busy life styles were among the most important barriers to adherence whereas pillboxes were considered most helpful for helping with medication adherence. CONCLUSION: Although lack of sufficient adherence to medications appears to be a multifactorial problem, improved communication between the healthcare provider and the patient, and less complicated medication regimens, may be especially suitable interventions to improve adherence to medications.

Effectively measuring adherence to medications for systemic lupus erythematosus in a clinical setting.

OBJECTIVE: To assess the reliability and concurrent validity of the Medication Adherence Self-report Inventory (MASRI) when used in systemic lupus erythematosus (SLE), to investigate the predictive validity of the MASRI using pharmacy refill information as the criterion standard, and to propose a sensible approach to the screening for nonadherence in a clinical setting. METHODS: Adherence to 2 medications (hydroxychloroquine and prednisone) was measured in 55 patients using the MASRI, pill counts, and physician ratings (MD scale). Adherence based on pharmacy refill information served as a criterion standard with nonadherence defined as adherence rates <80%. To determine test-rest reliability of the MASRI, 20 patients completed the measure twice within a 2-week period. RESULTS: Using pharmacy information, 39% of the patients were nonadherent to prednisone and 51% to hydroxychloroquine. The MASRI had acceptable internal consistency (Cronbach's alpha 0.7) and good reliability. Irrespective of the drug assessed, MASRI ratings were moderately correlated with patient adherence (pharmacy), supporting the concurrent validity of the MASRI. The combination of adherence estimation by MD scale rating at <85% and by MASRI at <90% was 87% sensitive and 86% specific for identifying patients who were nonadherent to prednisone. These cutoff values also appeared suitable for identifying nonadherence to hydroxychloroquine. CONCLUSION: The MASRI is a reliable measure of adherence to medications in SLE. The measure has concurrent and predictive validity. When combined with the MD scale, the MASRI appears to be a useful screening tool for nonadherence in patients with SLE that could be suitable for clinical practice.

A kindred of children with interstitial lung disease.

BACKGROUND: Childhood interstitial lung disease (ILD) is a spectrum of diseases including many different rare lung conditions. We present a family with an unusual presentation of ILD in association with rheumatologic and immunologic abnormalities. METHODS: Eight children with a common father were evaluated for evidence of lung disease in association with rheumatologic findings. All underwent routine history and physical examination, hematologic evaluation, and chest radiography and/or CT scan of the chest. Seven children underwent a more extensive immunologic evaluation. Those who were able underwent pulmonary function testing, and four children underwent lung biopsy. RESULTS: Six of eight children with a common father were found to have radiographic findings consistent with ILD. These children also had evidence of autoimmune disease with joint symptoms, alopecia, rheumatoid factor production, and hypergammaglobulinemia. Open-lung biopsy in four children revealed a spectrum of pulmonary lymphoid proliferations ranging from reactive lymphoid hyperplasia to lymphoid interstitial pneumonia. CONCLUSION: The findings of ILD and autoimmunity in a kindred of children suggest a novel genetic disorder of autosomal dominant pattern and variable penetrance. Although the precise pathogenesis remains unclear, these cases provide valuable insight into childhood ILD.

Quantitative MR characterization of disease activity in the knee in children with juvenile idiopathic arthritis: a longitudinal pilot study.

BACKGROUND: The development of a quantifiable and noninvasive method of monitoring disease activity and response to therapy is vital for arthritis management. OBJECTIVE: The purpose of this study was to investigate the utility of quantitative dynamic contrast-enhanced MRI (DCE-MRI) based on pharmacokinetic (PK) modeling to evaluate disease activity in the knee and correlate the results with the clinical assessment in children with juvenile idiopathic arthritis (JIA). MATERIALS AND METHODS: A group of 17 children with JIA underwent longitudinal clinical and laboratory assessment and DCE-MRI of the knee at enrollment, 3 months, and 12 months. A PK model was employed using MRI signal enhancement data to give three parameters, K(trans') (min(-1)), k(ep) (min(-1)), and V(p) (') and to calculate synovial volume. RESULTS: The PK parameters, synovial volumes, and clinical and laboratory assessments in most children were significantly decreased (P < 0.05) at 12 months when compared to the enrollment values. There was excellent correlation between the PK and synovial volume and the clinical and laboratory assessments. Differences in MR and clinical parameter values in individual subjects illustrate persistent synovitis when in clinical remission. CONCLUSION: A decrease in PK parameter values obtained from DCE-MRI in children with JIA likely reflects diminution of disease activity. This technique may be used as an objective follow-up measure of therapeutic efficacy in patients with JIA. MR imaging can detect persistent synovitis in patients considered to be in clinical remission.

Social functioning and peer relationships of adolescents with juvenile fibromyalgia syndrome.

OBJECTIVE: To assess peer relationships of adolescents with juvenile primary fibromyalgia syndrome (JPFS) compared with matched classroom comparison peers (MCCPs) without a chronic illness. JPFS is characterized by chronic musculoskeletal pain, sleep disturbance, fatigue, and difficulty with daily functioning. Adolescents with JPFS often report problems with school and participating in peer activities, placing them at risk for social isolation from their peers and psychosocial adjustment problems. METHODS: Participants were 55 adolescents with JPFS (ages 12-18 years) from a pediatric outpatient rheumatology clinic and 55 MCCPs. Data on peer reputation and peer acceptance were collected from teachers, peers, and self report in a classroom setting with no focus on JPFS. RESULTS: Adolescents with JPFS were perceived (by peer and self reports) as being more isolated and withdrawn and less popular. Adolescents with JPFS were less well liked, were selected less often as a best friend, and had fewer reciprocated friendships. CONCLUSION: Our findings suggest that adolescents with JPFS are experiencing problems with peer relationships. Given the central role that peer relationships play in psychological development of children, and because peer rejection and isolation have been associated with subsequent adjustment problems, these findings are concerning. Longitudinal studies of adolescents with JPFS are needed to ascertain whether these patients are at long-term risk and will provide a foundation for the need for early interventions. Results are discussed within the context of earlier findings for other adolescents with chronic illness and rheumatic conditions, such as juvenile idiopathic arthritis, who demonstrated no social problems.

Differences in disease outcomes between medicaid and privately insured children: possible health disparities in juvenile rheumatoid arthritis.

OBJECTIVE: To determine the relationship between health insurance status and disease outcome in children with juvenile rheumatoid arthritis (JRA). METHODS: JRA patients followed at a tertiary pediatric rheumatology center were assessed for the number of active joints and number of joints with limited range of motion. Disease activity, patient well-being, and pain were measured. Disability was assessed by the Childhood Health Assessment Questionnaire, health-related quality of life by the Pediatric Quality of Life Inventory (PedsQL) Generic Core Scale, and the PedsQL Rheumatology Module. Health care resource utilization was estimated based on the number of billing events for health services coded in administrative databases; these databases also provided information on patient health insurance status. Children insured by Medicaid or similar state programs for low-income families were considered to have Medicaid status. Disease outcomes of children with Medicaid status was compared with that of children with private health insurance. RESULTS: Forty (14%) of the 295 children with JRA had Medicaid status. Patients with Medicaid status were more often of nonwhite race (P < or = 0.04) and more frequently had a polyarticular or systemic disease course (P = 0.04) compared with other patients (n = 255). After correction for differences in disease duration, race, JRA onset, and JRA course between groups, children with Medicaid status continued to have significantly higher disability (P < 0.0003), and lower mean PedsQL Generic Core Scale scores (P < 0.05), while health resource utilization appeared similar between groups. CONCLUSION: Despite apparently similar health resource utilization and joint involvement, Medicaid status is associated with significantly lower health-related quality of life and higher disability in JRA.

Gastrointestinal symptoms and their association with health-related quality of life of children with juvenile rheumatoid arthritis: validation of a gastrointestinal symptom questionnaire.

OBJECTIVES: The objectives of this study were to perform an initial validation of the Gastrointestinal Symptom Scale for Kids (GISSK) in children with juvenile rheumatoid arthritis (JRA); and too evaluate the relationship between gastrointestinal (GI) symptoms and health-related quality of life (HRQOL) in JRA. METHODS: A convenience sample of 77 children (median age, 10 years; range, 2-18 years) with JRA requiring second-line agents and one of their parents were interviewed. GI symptoms during the preceding 1 week were measured using the GISSK, which consists of 2 components, a visual analog scale of GI symptom severity (GISSK-VAS) and an 8-item questionnaire (GISSK-Q; score 0-8; 0= no GI symptoms). Information on medications, joint involvement with arthritis, and a physician rating of disease activity were obtained. Patient-centered outcomes included the Childhood Health Assessment Questionnaire (CHAQ) to assess disability and discomfort. HRQOL was measured by the Pediatric Quality of Life Generic Core Scale (PedsQL-GC) and the Rheumatology Module (PedsQL-RM), as well as a visual analog scale (VAS-health). To determine test-retest reliability, the GISSK was completed by 40 parents twice within a 1- to 2-week period. To determine the quality of parent proxy-reporting, parent ratings were compared with those of their children aged 8 years or older. RESULTS: GI symptoms were present in the majority of the patients with JRA (58%). Compared with other patients with JRA, those with a GISSK-Q score of > or =2 had significantly lower HRQOL (PedsQL-GC: P < 0.04; PedsQL-RM: P < 0.05; VAS-health: P < 0.02) and more disability (CHAQ: P < 0.002), despite similar disease activity and joint findings. Similar relationships were observed for the GISSK-VAS with traditional outcomes and HRQOL. The test-retest reliability of the GISSK was good (ICCGISSK-Q = 0.60; ICCGISSK-VAS = 0.67). The quality of parent proxy-reporting was fair to good (ICCGISSK-Q = 0.47; ICCGISSK-VAS = 0.66). CONCLUSION: GI symptoms are frequent among children with JRA requiring advanced therapies and, if moderate or severe, are associated with significantly lower HRQOL. The GISSK is a reliable and valid measure of GI symptoms and their severity in JRA. This self-administered measure can be used to screen for GI symptoms in clinical practice and may be useful to assess the effects of medication changes on the perceived GI side effects in children with JRA.

Association between lack of angiogenic response in muscle tissue and high expression of angiostatic ELR-negative CXC chemokines in patients with juvenile dermatomyositis: possible link to vasculopathy.

OBJECTIVE: To investigate the relationship between the vasculopathy of juvenile dermatomyositis (juvenile DM) and the balance between the angiostatic ELR- and angiogenic ELR+ CXC chemokines in the muscle of patients with the disease. METHODS: The expression of 3 ELR- CXC chemokines (interferon-inducible protein 10 [IP-10], monokine induced by interferon-gamma, and interferon-inducible T cell alpha-chemoattractant) and 2 ELR+ CXC chemokines was quantitated in muscle biopsy samples from 7 patients with juvenile DM and 7 healthy children, by real-time polymerase chain reaction. The findings were correlated with various histopathologic features, with particular emphasis on the degree of vasculopathy. Synovial biopsy specimens from patients with juvenile rheumatoid arthritis (JRA) were used for additional comparison. RESULTS: The angiostatic ELR- chemokines were expressed at high levels, while the angiogenic ELR+ chemokines were barely detectable, in most juvenile DM samples. This contrasted sharply with the findings in both normal muscle biopsy specimens and JRA synovial tissue specimens. The expression of the ELR- chemokines in juvenile DM samples correlated with the intensity of mononuclear cell infiltration. Furthermore, the juvenile DM samples with the highest degree of capillary loss had the highest levels of ELR- CXC chemokines. The presence of IP-10 in juvenile DM muscle specimens was confirmed by immunohistochemistry analysis. In addition, immunohistochemical staining of muscle tissue revealed that CXCR3, a receptor utilized by ELR- CXC chemokines, was expressed in vascular endothelial cells. CONCLUSION: Increased expression of the interferon-induced angiostatic ELR- CXC chemokines is a feature of juvenile DM that parallels the degree of vasculopathy in patients with the disease. Collectively, these findings are consistent with a model in which a subset of inflammatory cells secrete angiostatic ligands, which then contribute to a local atrophying effect on the muscle's vasculature via a receptor-mediated process.