Disease control and health‐related quality of life in juvenile idiopathic arthritis

Objective

To examine variability in health‐related quality of life (HRQOL) in children with juvenile idiopathic arthritis (JIA) experiencing no or minimal clinical symptoms, and in a subgroup with polyarticular JIA treated with biologic agents for 12 months.

Methods

We defined 3 samples using a database of patients ages 2–18 years with JIA (n = 524; patient visits [PV] = 2,354): visits (PV = 2,155) with no or minimal clinical symptoms on at least 1 of 4 measures (active joint count, pain, physician global disease rating, Childhood Health Assessment Questionnaire); visits (PV = 941) with no or minimal symptoms on all 4 measures; and children (n = 31) with polyarticular JIA treated with biologic agents for 12 months. HRQOL was measured using the Pediatric Quality of Life Inventory (PedsQL) and the percentage of patients with suboptimal HRQOL was determined.

Results

In PV with a PedsQL score, suboptimal HRQOL by self‐report occurred in 362 (20.6%) PV with at least 1 indicator of minimal symptoms, and in 64 (7.9%) PV with all 4 measures indicating minimal symptoms (519 [25.7%] and 95 [10.7%], respectively, by parent report). For children with polyarticular JIA treated for 12 months with biologic agents, 7 (25.9%) patients by self‐report and 10 (35.7%) patients by parent report were in the suboptimal range of HRQOL.

Conclusion

A substantial percentage of patients with JIA who report no or mild clinical symptoms experience suboptimal HRQOL. This is also true for patients with polyarticular JIA treated with biologic agents for 12 months. Although disease activity and clinical symptoms are related to HRQOL, considerable unexplained variation in HRQOL exists. HRQOL needs to be assessed independently regardless of clinical status.

     

Normalization of Widespread Pressure Pain Hypersensitivity After Total Hip Replacement in Patients With Hip Osteoarthritis Is Associated With Clinical and Functional Improvements

Objective

To evaluate the relevance of ongoing nociceptive joint inputs to the maintenance of widespread pain hypersensitivity in patients with hip osteoarthritis (OA) and to determine whether a reversal in the widespread pressure hypersensitivity together with an improvement in pain and function occurs after total hip replacement in these patients.

Methods

Forty patients with hip OA participated. Twenty patients underwent total hip replacement, and the other 20 patients were assigned to a waiting list. Pressure–pain thresholds (PPTs) over the second metacarpal bone and the gluteus medius, vastus medialis, vastus lateralis, and tibialis anterior muscles were assessed bilaterally with a pressure algometer before and 3 months after total hip replacement surgery. Assessments of pain intensity (by visual analog scale [VAS]), physical function (by the Western Ontario and McMaster Universities Osteoarthritis Index), and health status (by the Short Form 12 health survey and the EuroQol 5‐domain index) were also performed.

Results

Patients who underwent total hip arthroplasty exhibited a reduction in widespread pressure pain hyperalgesia (increases in PPTs) over local and distant pain‐free areas, as compared with before surgery and as compared with the patients assigned to the waiting list. PPTs were related to hip pain intensity, and significant correlations were found between higher VAS scores and lower average PPTs over all points assessed (−0.409 < r < −0.306, P < 0.05). Patients who underwent total hip arthroplasty exhibited a greater decrease in pain intensity and greater increases in function and health status than did those who were on the waiting list. Changes in the intensity of hip pain were moderately associated with changes in pressure pain sensitivity in the hip arthroplasty group.

Conclusion

Normalization of widespread pressure pain hyperalgesia was found after successful hip joint replacement in patients with hip OA. Altered pain processing seems to be driven by ongoing peripheral joint pathology, which stresses the importance of reducing pain in OA.

     

Relationship of pain‐coping strategies and pain‐specific beliefs to pain experience in children with juvenile idiopathic arthritis

Objective

To examine whether pain‐specific beliefs and coping strategies of patients with juvenile idiopathic arthritis (JIA) independently predict their reported pain, while controlling for relevant demographic variables, disease activity, and parent‐rated disability. To compare use of pain‐coping strategies and pain‐related beliefs of a selected subgroup of patients with high pain and low disease activity (high pain group) with the remaining patients.

Methods

Children with JIA (n = 56) completed the Pain Coping Questionnaire, a revised version of the Survey of Pain Attitudes, and a 3‐week pain diary. The parents completed the Childhood Health Assessment Questionnaire (CHAQ). Second order principal component analyses were conducted in order to reduce the number of independent variables. Regression analyses of the dependent measure were performed. The use of coping strategies and health beliefs were compared using t‐tests for independent samples. Pearson's correlation coefficients were calculated to examine the direct associations between each individual coping and belief scale, and the pain measure.

Results

Only the CHAQ and the cognitive belief composite factor score made statistically significant contribution to the prediction of pain after controlling for other variables. Significant differences were found between the scores of high pain patients and the rest of the group for the health belief subscale of disability (mean ± SD 2.0 ± 0.6 and 1.2 ± 0.7, respectively), and for the health belief subscale of harm (mean ± SD 2.7 ± 0.6 and 1.8 ± 0.7, respectively). Significant correlations were obtained between the pain measure and the pain‐coping subscale of catastrophizing, the pain belief subscales of disability, harm, solicitude (inverse), control, and medical cure.

Conclusion

These results support a model of pain experience in patients with JIA where psychological factors are strongly influential. It may be efficient to focus behavioral interventions on a subgroup of children where the pain experience seems to be in discordance with the disease activity.

     

Health‐related quality of life in adolescents with juvenile idiopathic arthritis

Objective

To describe the health‐related quality of life (HRQOL) of adolescents with juvenile idiopathic arthritis (JIA), and to examine the usefulness of the Juvenile Arthritis Quality of Life Questionnaire (JAQQ) in a UK context. It was hypothesized that HRQOL would decrease with worsening disease and disability.

Methods

Patients with JIA ages 11, 14, and 17 years were recruited from 10 major rheumatology centers. HRQOL was measured using the JAQQ. Other data were core outcome variables including the Childhood Health Assessment Questionnaire, demographic characteristics, arthritis‐related knowledge, and satisfaction with health care.

Results

Questionnaires were completed by 308 adolescents. One‐fifth had persistent oligoarthritis. Median disease duration was 5.7 years (range <1–16 years). The JAQQ was shown to have good psychometric properties when used in the UK, but was not without limitations. HRQOL of adolescents with JIA was less than optimal, particularly in the domains of gross motor and systemic functioning. Items most frequently rated as adolescents' biggest psychological problems were “felt frustrated” and “felt depressed,” rated by 30.2% and 23.4%, respectively. These were particularly problematic for the 17‐year‐olds, with 39% reporting frustration as one of their biggest problems and 63.6% reporting depression. Variation in the adolescent JAQQ scores was explained by functional disability, pain, and disease activity.

Conclusion

JIA can have a significant adverse effect on the HRQOL of adolescents. The JAQQ is a useful tool to assess the HRQOL of UK adolescents with JIA, but there is need for improved measures that incorporate developmentally appropriate issues.

     

Cytokine gene polymorphisms and susceptibility to juvenile idiopathic arthritis

Objective

To investigate the involvement of candidate cytokine genes in the pathogenesis of juvenile idiopathic arthritis (JIA).

Methods

Single nucleotide polymorphisms and intragenic microsatellite markers within 8 candidate cytokine genes (interleukin‐1α [IL‐1α], IL‐2, IL‐4, IL‐6, IL‐10, interferon‐α1 [IFNA1], interferon‐γ [IFNG], and interferon regulatory factor 1 [IRF‐1]) were investigated in 417 Caucasian patients with clinically characterized JIA and a panel of 276 unrelated, healthy Caucasian controls, all from the United Kingdom.

Results

A novel 3′–untranslated region (3′UTR) polymorphism in IRF‐1 was found to be associated with susceptibility to JIA (corrected P = 0.002). No significant association with IL‐1α, IL‐2, IL‐4, IL‐6, IL‐10, IFNA1, or IFNG was observed.

Conclusion

An association between JIA and a previously unreported 3′UTR polymorphism of IRF‐1 was observed. This association was not found to be specific to any particular JIA subgroup. This suggests that IRF‐1 may contribute to a common pathogenesis shared by all JIA patients, regardless of clinical phenotype. This is most likely to be a genetic contribution to the chronic inflammatory process that underlies JIA pathology.

     

Comparing the efficacy of cyclooxygenase 2–specific inhibitors in treating osteoarthritis: Appropriate trial design considerations and results of a randomized,placebo‐controlled trial

Objective

To compare the efficacy of the cyclooxygenase 2 (COX‐2)–specific inhibitors celecoxib and rofecoxib in treating the signs and symptoms of osteoarthritis (OA).

Methods

In this randomized, placebo‐controlled, double‐blind, multicenter study, 475 patients with OA of the knee received either celecoxib 200 mg/day (n = 189), rofecoxib 25 mg/day (n = 190), or placebo (n = 96) for 6 weeks. Arthritis assessments were performed at baseline, week 3, and week 6 (or at the time of early termination).

Results

In primary measures of efficacy (OA pain score on a 100‐mm visual analog scale [VAS] and total domain score on the Western Ontario and McMaster Universities Osteoarthritis Index), celecoxib 200 mg/day and rofecoxib 25 mg/day demonstrated similar efficacy. At week 6, celecoxib was associated with a 34‐mm mean improvement on the VAS for OA pain, compared with 31.6 mm for rofecoxib and 21.2 mm for placebo. The difference between celecoxib and rofecoxib was −2.5 mm, with an upper limit of the 95% confidence interval of 2.7 mm and within the prespecified definition of noninferiority. Secondary measures of efficacy showed similar results. All differences in primary and secondary measures of efficacy between the 2 active treatments and placebo were statistically significant (P < 0.02), whereas all of the comparisons of efficacy between celecoxib and rofecoxib met the predefined criteria for noninferiority. All treatments were well tolerated throughout the study, with similar proportions of patients withdrawing due to adverse events.

Conclusion

Celecoxib 200 mg/day and rofecoxib 25 mg/day are equally efficacious in treating the signs and symptoms of OA.

     

Risk factors for development of uveitis differ between girls and boys with juvenile idiopathic arthritis

Objective

Uveitis is the most common extraarticular manifestation of juvenile idiopathic arthritis (JIA) and is associated with considerable morbidity. The aim of this study was to examine the risk factors associated with uveitis in JIA.

Methods

We conducted a chart review of 1,047 patients with JIA from a single tertiary care pediatric rheumatology center for factors associated with the development of uveitis. Special emphasis was put on the following known risk factors: oligoarthritis, antinuclear antibody (ANA) status, sex, and age at the time of onset of JIA.

Results

The risk of uveitis developing was age dependent in girls but not in boys. Among girls, the risk was maximal (47%) in those who were ANA positive and were ages 1–2 years at the time of the onset of JIA; this risk decreased to <10% in those in whom the age at onset was >7 years. Only girls had an age‐dependent and ANA‐associated increased risk of uveitis. The time interval from the diagnosis of JIA to the diagnosis of uveitis was statistically significantly longer in patients in whom the onset of JIA occurred at a younger age (P = 0.04). This effect was even more pronounced in ANA‐positive patients (P = 0.004). The JIA subtype did not influence a patient's risk of the development of uveitis.

Conclusion

An age‐associated risk of uveitis was observed only in girls who were younger than 7 years of age at the time of the onset of JIA. The duration of time between the diagnosis of JIA and the onset of uveitis was longer in patients in whom JIA was diagnosed at a younger age, especially in those who were ANA positive. We suggest that our findings have implications for uveitis screening in patients with JIA.

     

Pregabalin for the treatment of fibromyalgia syndrome: Results of a randomized,double‐blind,placebo‐controlled trial

Objective

Fibromyalgia syndrome (FMS) is characterized by widespread musculoskeletal pain and lowered pain threshold. Other prominent symptoms include disordered sleep and fatigue. FMS affects an estimated 2% of the population, predominantly women. This trial was designed to evaluate the efficacy and safety of pregabalin, a novel α₂‐δ ligand, for treatment of symptoms associated with FMS.

Methods

This multicenter, double‐blind, 8‐week, randomized clinical trial compared the effects of placebo with those of 150, 300, and 450 mg/day pregabalin on pain, sleep, fatigue, and health‐related quality of life in 529 patients with FMS. The primary outcome variable was the comparison of end point mean pain scores, derived from daily diary ratings of pain intensity, between each of the pregabalin treatment groups and the placebo group.

Results

Pregabalin at 450 mg/day significantly reduced the average severity of pain in the primary analysis compared with placebo (−0.93 on a 0–10 scale) (P ≤ 0.001), and significantly more patients in this group had ≥50% improvement in pain at the end point (29%, versus 13% in the placebo group; P = 0.003). Pregabalin at 300 and 450 mg/day was associated with significant improvements in sleep quality, fatigue, and global measures of change. Pregabalin at 450 mg/day improved several domains of health‐related quality of life. Dizziness and somnolence were the most frequent adverse events. Rates of discontinuation due to adverse events were similar across all 4 treatment groups.

Conclusion

Pregabalin at 450 mg/day was efficacious for the treatment of FMS, reducing symptoms of pain, disturbed sleep, and fatigue compared with placebo. Pregabalin was well tolerated and improved global measures and health‐related quality of life.

     

Efficacy and safety of four doses of lumiracoxib versus diclofenac in patients with knee or hip primary osteoarthritis: A phase II,four‐week,multicenter, randomized,double‐blind,placebo‐controlled trial

Objective

To compare the efficacy and tolerability of the novel cyclooxygenase 2‐selective inhibitor lumiracoxib with placebo and diclofenac in osteoarthritis (OA).

Methods

Adults (n = 583) with knee or hip OA were randomized to receive for 4 weeks lumiracoxib 50, 100, or 200 mg twice daily or 400 mg once daily; placebo; or diclofenac 75 mg twice daily. Efficacy assessments included overall joint pain intensity and Western Ontario and McMaster Universities Osteoarthritis Index subscales; tolerability was evaluated by adverse event and physician reporting.

Results

All lumiracoxib doses were superior to placebo in relieving pain, improving stiffness, and improving physical function after 4 weeks. At study endpoint, pain relief was comparable among all lumiracoxib dosages and similar to diclofenac. Lumiracoxib tolerability was superior to diclofenac and comparable to placebo.

Conclusion

Lumiracoxib provides predictable and sustained relief from pain, stiffness, and impaired physical function in OA. Lumiracoxib shows clinically comparable efficacy and superior tolerability to diclofenac.

     

Positive association of SLC26A2 gene polymorphisms with susceptibility to systemic‐onset juvenile idiopathic arthritis

Objective

To investigate SLC26A2, the gene that causes diastrophic dysplasia, in juvenile idiopathic arthritis (JIA).

Methods

Nine polymorphisms across the SLC26A2 gene locus were investigated using MassArray genotyping in 826 UK Caucasian JIA cases and 617 ethnically matched healthy controls.

Results

Significant associations between multiple single‐nucleotide polymorphisms (SNPs) across SLC26A2 and systemic‐onset JIA were found. In each case, homozygosity for the minor allele conferred the increased risk of disease susceptibility: rs1541915 (odds ratio [OR] 2.3, 95% confidence interval [95% CI] 1.4–3.7, P = 0.0003), rs245056 (OR 2.8, 95% CI 1.7–4.6, P = 0.00002), rs245055 (OR 2.5, 95% CI 1.2–5.0, P = 0.004), rs245051 (OR 2.3, 95% CI 1.4–3.7, P = 0.0005), rs245076 (OR 2.7, 95% CI 1.3–5.4, P = 0.0015), and rs8073 (OR 2.3, 95% CI 0.9–5.6, P = 0.04).

Conclusion

These findings show the value of using monogenic disease loci as candidates for investigation in JIA. We identified a subgroup‐specific association between SNPs within the SLC26A2 gene and systemic‐onset JIA. Our findings also highlight systemic‐onset JIA as being a distinctly different disease from that in the other JIA subgroups.

     

Attentional functioning in fibromyalgia,rheumatoid arthritis,and musculoskeletal pain patients

Objectives

To investigate whether chronic pain patients have deficits in attentional functioning compared with pain‐free controls, and whether fibromyalgia patients have larger deficits in attentional functioning compared with rheumatoid arthritis and musculoskeletal pain patients.

Methods

Sixty patients (20 in each of 3 patient groups) and 20 pain‐free controls completed measures assessing pain intensity, mood, pain‐related disability, somatic awareness, and catastrophic thinking about pain. Attentional functioning was assessed using an age‐standardized, ecologically valid test battery. Analyses were made of between‐group differences.

Results

Sixty percent of patients had at least one score in the clinical range of neuropsychological impairment, independent of demography and mood. Fibromyalgia patients were more anxious and somatically aware than rheumatoid arthritis or musculoskeletal pain patients, but did not show larger attentional deficits than other patient groups.

Conclusion

All 3 groups of chronic pain patients, regardless of diagnosis, had impaired cognitive functioning on an ecologically sensitive neuropsychological test of everyday attention.

     

Development and preliminary validation of a Children's Arthritis Self‐Efficacy Scale

Objective

To develop a valid and reliable measure of arthritis self‐efficacy for use with school‐age children with juvenile idiopathic arthritis (JIA).

Methods

Construction of the 11‐item Children's Arthritis Self‐Efficacy Scale (CASE) was based on an existing body of knowledge and the results of focus groups with children, their parents, and health professionals. Data for validation of the CASE were collected by self‐administered questionnaires completed by 89 children and 151 caregivers.

Results

Analyses revealed a 3‐factor structure relating to self‐efficacy for managing symptoms, emotional consequences, and activities, explaining 76.5% of the total variance. The CASE demonstrated high internal consistency, concurrent validity, and construct validity.

Conclusion

Preliminary findings suggest that the CASE is worthy of further psychometric testing and may have the potential to help delineate variations in adjustment among children with JIA.

     

Synovial fluid proteins differentiate between the subtypes of juvenile idiopathic arthritis

Objective

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of inflammatory diseases, and no clinically useful prognostic markers to predict disease outcome in children with JIA are currently available. Synovial fluid likely reflects the proteins present in the inflamed synovium. The purpose of this study was to delineate the synovial fluid proteome and determine whether protein expression differs in the different subtypes of JIA.

Methods

Synovial fluid samples obtained from children with oligoarticular JIA, polyarticular JIA, or systemic JIA were compared. Two‐dimensional gel electrophoresis for protein separation and matrix‐assisted laser desorption ionization−time‐of‐flight mass spectrometry and quadripole time‐of‐flight mass spectrometry for protein identification were used for this study. Synovial fluid cells were analyzed by polymerase chain reaction (PCR) for the presence of haptoglobin messenger RNA (mRNA).

Results

The synovial fluid proteome of the samples was delineated. The majority of proteins showed overexpression in JIA synovial fluid as compared with noninflammatory control samples. There were 24 statistically significantly differentially expressed spots (>2‐fold change; P < 0.05) between the subtypes of JIA. PCR analysis revealed haptoglobin mRNA, suggesting that haptoglobin is locally produced in an inflamed joint in JIA.

Conclusion

Despite the similar histologic appearance of inflamed joints in patients with different subtypes of JIA, there are differences in protein expression according to the subtype of JIA. Haptoglobin is differentially expressed between the subtypes of JIA and is locally produced in an inflamed joint in JIA. Haptoglobin and other differentially expressed proteins may be potential biomarkers in JIA.

     

Brief Report: Incidence of Selected Opportunistic Infections Among Children With Juvenile Idiopathic Arthritis

Objective

To compare incidence rates of selected opportunistic infections among children with and children without juvenile idiopathic arthritis (JIA).

Methods

Using US national Medicaid administrative claims data from 2000 through 2005, we identified a cohort of children with JIA based on physician diagnosis codes and dispensed medications. We also identified a non‐JIA comparator cohort of children diagnosed as having attention deficit hyperactivity disorder (ADHD). We defined 15 types of opportunistic infection using physician diagnosis or hospital discharge codes; criteria for 7 of these types also included evidence of treatment with specific antimicrobial agents. We calculated infection incidence rates. The rates in the ADHD comparator cohort were standardized to the age, sex, and race distribution of the JIA cohort. We calculated incidence rate ratios (IRRs) with 95% confidence intervals (95% CIs) to compare infection rates.

Results

The JIA cohort included 8,503 children with 13,990 person‐years of followup. The ADHD comparator cohort included 360,362 children with 477,050 person‐years of followup. When all opportunistic infections were considered together as a single outcome, there were 42 infections in the JIA cohort (incidence rate 300 per 100,000 person‐years; IRR 2.4 [95% CI 1.7–3.3] versus ADHD). The most common opportunistic infections among children with JIA were 3 cases of Coccidioides (incidence rate 21 per 100,000 person‐years; IRR 101 [95% CI 8.1–5,319] versus ADHD), 5 cases of Salmonella (incidence rate 35 per 100,000 person‐years; IRR 3.8 [95% CI 1.2–9.5]), and 32 cases of herpes zoster (incidence rate 225 per 100,000 person‐years; IRR 2.1 [95% CI 1.4–3.0]).

Conclusion

Opportunistic infections are rare among children with JIA. Nevertheless, children with JIA had a higher rate of opportunistic infections, including an increased rate of Coccidioides, Salmonella, and herpes zoster compared to children with ADHD.

     

Aggrecanase cleavage in juvenile idiopathic arthritis patients is minimally detected in the aggrecan interglobular domain but robust at the aggrecan C‐terminus

Objective

To investigate aggrecan degradation in juvenile idiopathic arthritis (JIA).

Methods

The pattern and abundance of aggrecan fragments in synovial fluid (SF) aspirates from JIA patients were analyzed and compared with aggrecan fragments in SF from patients with other arthritides, children with knee injury, and a knee‐healthy reference group. Concentrations of sulfated glycosaminoglycan (sGAG) in SF were measured by Alcian blue precipitation assay. Aggrecan fragments were purified by dissociative CsCl density‐gradient centrifugation, deglycosylated, and analyzed by Western blot using antibodies specific for either aggrecanase‐derived ARGS, SELE, and KEEE neoepitopes or the aggrecan G3 domain.

Results

The concentration of sGAG in SF from patients with JIA was significantly lower compared with that in SF from patients with osteoarthritis (OA) (P < 0.001), patients with juvenile knee injury (P = 0.006), and knee‐healthy controls (P = 0.022). Western blot analysis revealed KEEE, SELE, and G3 fragments generated by aggrecanase cleavage in the chondroitin sulfate–rich region of aggrecan in patients with JIA. The pattern of aggrecan fragments in JIA patients was not identical to that in pooled OA SF, although there were notable similarities. Surprisingly, aggrecanase‐derived ARGS fragments were barely detectable in JIA SF, in marked contrast to levels in OA SF.

Conclusion

Aggrecanases appear to cleave minimally in the interglobular domain of aggrecan in JIA patients despite robust levels of cleavage in the chondroitin sulfate–rich region. These results suggest that in JIA, unlike other arthritides, aggrecanase cleavage in the aggrecan interglobular domain might not be a major pathogenic event.

     

Genetic loci contributing to hemophagocytic lymphohistiocytosis do not confer susceptibility to systemic‐onset juvenile idiopathic arthritis

Objective

To investigate whether single‐nucleotide polymorphisms (SNPs) within the genes PRF1, GZMB, UNC13D, and Rab27a, which are involved in natural killer cell dysfunction and known to contribute to the risk of hemophagocytic lymphohistiocytosis (HLH), confer an increased risk of susceptibility to systemic‐onset juvenile idiopathic arthritis (JIA).

Methods

Four SNPs across the PRF1 gene locus, 5 for GZMB, 7 for UNC13D, and 11 for Rab27a were investigated using MassArray genotyping in 133 UK Caucasian patients with systemic‐onset JIA and 384 ethnically matched unrelated control subjects. Additional control genotypes were accessed from the data generated by the Wellcome Trust Case Control Consortium.

Results

No significant association was found between any SNP within the 4 selected loci and systemic‐onset JIA, by either single‐point or haplotype analysis.

Conclusion

The results of this study demonstrate that genes involved in HLH do not confer a significant risk of association with systemic‐onset JIA.

     

Identification of a novel susceptibility locus for juvenile idiopathic arthritis by genome‐wide association analysis

Objective

Juvenile idiopathic arthritis (JIA) is a chronic rheumatic disease of childhood. Two well‐established genetic factors known to contribute to JIA susceptibility, HLA and PTPN22, account for less than half of the genetic susceptibility to disease; therefore, additional genetic factors have yet to be identified. The purpose of this study was to perform a systematic search of the genome to identify novel susceptibility loci for JIA.

Methods

A genome‐wide association study using Affymetrix GeneChip 100K arrays was performed in a discovery cohort (279 cases and 184 controls). Single‐nucleotide polymorphisms (SNPs) showing the most significant differences between cases and controls were then genotyped in a validation sample of cases (n = 321) and controls, combined with control data from the 1958 UK birth cohort (n = 2,024). In one region in which association was confirmed, fine‐mapping was performed (654 cases and 1,847 controls).

Results

Of the 112 SNPs that were significantly associated with JIA in the discovery cohort, 6 SNPs were associated with JIA in the independent validation cohort. The most strongly associated SNP mapped to the HLA region, while the second strongest association was with a SNP within the VTCN1 gene. Fine‐mapping of that gene was performed, and 10 SNPs were found to be associated with JIA.

Conclusion

This study is the first to successfully apply a SNP‐based genome‐wide association approach to the investigation of JIA. The replicated association with markers in the VTCN1 gene defined an additional susceptibility locus for JIA and implicates a novel pathway in the pathogenesis of this chronic disease of childhood.

     

Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets

Objective

To determine whether peripheral blood mononuclear cells (PBMCs) from children with recent‐onset polyarticular juvenile idiopathic arthritis (JIA) exhibit biologically or clinically informative gene expression signatures.

Methods

Peripheral blood samples were obtained from 59 healthy children and 61 children with polyarticular JIA prior to treatment with second‐line medications, such as methotrexate or biologic agents. RNA was extracted from isolated mononuclear cells, fluorescence labeled, and hybridized to commercial gene expression microarrays (Affymetrix HG‐U133 Plus 2.0). Data were analyzed using analysis of variance at a 5% false discovery rate threshold after robust multichip analysis preprocessing and distance‐weighted discrimination normalization.

Results

Initial analysis revealed 873 probe sets for genes that were differentially expressed between polyarticular JIA patients and healthy controls. Hierarchical clustering of these probe sets distinguished 3 subgroups within the polyarticular JIA group. Prototypical patients within each subgroup were identified and used to define subgroup‐specific gene expression signatures. One of these signatures was associated with monocyte markers, another with transforming growth factor β–inducible genes, and a third with immediate early genes. Correlation of gene expression signatures with clinical and biologic features of JIA subgroups suggested relevance to aspects of disease activity and supported the division of polyarticular JIA into distinct subsets.

Conclusion

Gene expression signatures in PBMCs from patients with recent‐onset polyarticular JIA reflect discrete disease processes and offer a molecular classification of disease.

     

B lymphocyte stimulator expression in pediatric systemic lupus erythematosus and juvenile idiopathic arthritis patients

Objective

To assess the expression of B lymphocyte stimulator (BLyS) in patients with pediatric systemic lupus erythematosus (SLE) or juvenile idiopathic arthritis (JIA).

Methods

Blood samples collected from patients with pediatric SLE (n = 56) and patients with JIA (n = 54) at the beginning and end of a 6‐month interval were analyzed for plasma BLyS protein levels by enzyme‐linked immunosorbent assay and for blood leukocyte full‐length BLyS and ΔBLyS messenger RNA (mRNA) levels by quantitative real‐time polymerase chain reaction (normalized to 18S expression). Healthy siblings (n = 34) of these patients served as controls.

Results

In pediatric SLE, plasma BLyS protein and blood leukocyte BLyS mRNA levels were each significantly elevated, and plasma BLyS protein levels, but not blood leukocyte BLyS mRNA levels, were correlated with disease activity. In contrast, plasma BLyS protein levels were normal in JIA despite blood leukocyte BLyS mRNA levels being elevated to degrees similar to those in pediatric SLE. Among JIA patients, neither BLyS parameter was correlated with disease activity. In both pediatric SLE and JIA, the BLyS expression profiles remained stable at 6 months.

Conclusion

Our findings indicate that, as previously noted in adult SLE, plasma BLyS protein and blood leukocyte BLyS mRNA levels are elevated in pediatric SLE. The correlation of plasma BLyS protein levels with disease activity points to BLyS as a candidate therapeutic target in pediatric SLE. Contrary to previous observations in adults with rheumatoid arthritis, plasma BLyS protein levels are normal in JIA despite elevated blood leukocyte BLyS mRNA levels. The absence of correlation between either of the BLyS parameters and disease activity in JIA calls for circumspection prior to assigning BLyS as a candidate therapeutic target in this disorder.