Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10−8), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.

OBJECTIVES To determine if aggressive treatment initiated early in the course of rheumatoid factor positive or negative polyarticular juvenile idiopathic arthritis (poly-JIA) can induce clinical inactive disease (CID) within 6 months. METHODS Between May 2007 and October 2010 a multi-center, prospective, double blind, randomized, placebo controlled trial of two aggressive treatments was conducted in 85 children aged 2 to 16 years with polyarticular JIA of less than 12 months duration. Patients received either methotrexate 0.5 mg/kg/wk SQ (40 mg max), etanercept 0.8 mg/kg/wk (50 mg max), prednisolone 0.5 mg/kg/d (60 mg max) tapered to 0 by 17 weeks (Arm 1), or methotrexate (same dose as Arm 1), etanercept placebo, and prednisolone placebo (Arm 2). The primary outcome was CID at 6 months. An exploratory phase determined the rate of clinical remission on medication (6 months of continuous CID) at 12 months. RESULTS By 6 months, 17 of 42 (40%) of patients in Arm 1 and 10 of 43 (23%) in Arm 2 had achieved CID (X2 = 2.91; p = 0.088). After 12 months, 9 patients in Arm 1 and 3 in Arm 2 achieved clinical remission on medication (p = 0.0534). There were no significant inter-arm differences in adverse events. CONCLUSIONS Although this study did not meet its primary endpoint, early aggressive therapy in this cohort of children with recent onset polyarticular JIA resulted in substantial proportions of patients in both arms achieving CID by 6 months and clinical remission on medication within 12 months of treatment.

Physicians should consider treating pain more aggressively in children with arthritis, in order to preserve function in school and social domains, as well as physical function. Moreover, optimal pain management in children with arthritis should include therapeutic regimens addressing anxiety as well as standard pharmacologic interventions.

Objective The primary aim of this systematic review was to examine the evidence for a pain-sleep relationship in children with persistent pain by reviewing studies using single and mixed pediatric persistent pain samples. Method Electronic searches of Medline, PubMed, the Cochrane Database of Systematic Reviews, and PsycINFO were conducted to identify all relevant empirical studies. Studies were included in the review if the majority of participants were between 0-17 years and from one of the following pediatric pain populations: juvenile idiopathic arthritis, sickle cell disease, migraine/headache, functional abdominal pain, juvenile fibromyalgia syndrome, chronic musculoskeletal pain, or mixed populations including the aforementioned conditions. Results Research from single and mixed sample studies support the hypothesis that children and adolescents with persistent pain suffer from sleep impairment. Literature addressing factors that may influence or mediate the pain-sleep relationship and the functional outcomes of the pain-sleep relationship was reviewed, and a model of the interrelationships with pain and sleep developed. Conclusion Findings from this review highlight the need to assess and treat sleep problems in children presenting with persistent pain. Healthcare providers should consider conducting routine sleep screenings, including a comprehensive description of sleep patterns and behaviors obtained through clinical interview, sleep diaries, and/or the use of standardized measures of sleep. Future research focusing on investigating the mechanisms associating sleep and pediatric persistent pain and on functional outcomes of poor sleep in pediatric pain populations is needed.

Objective To formulate consensus treatment plans (CTPs) for induction therapy of newly-diagnosed proliferative lupus nephritis (LN) in juvenile systemic lupus erythematosus (jSLE). Methods A structured consensus formation process was employed by the members of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) after considering the existing medical evidence and current treatment approaches. Results After an initial Delphi survey (response rate 70%), a 2-day consensus conference, and two follow-up Delphi surveys (response rates 63–79%), consensus was achieved for a limited set of CTPs addressing the induction therapy of proliferative LN. These CTPs were developed for prototypic patients defined by eligibility characteristics, and included immunosuppressive therapy with either mycophenolic acid orally twice per day, or intravenous cyclophosphamide once per month at standardized doses for six months. Additionally, the CTPs describe three options for standardized use of glucocorticoids; including a primarily oral, a mixed oral/intravenous, and a primarily intravenous regimen. There was consensus on measures of effectiveness and safety of the CTPs. The CTPs were well accepted by the pediatric rheumatology providers treating children with LN, and up to 300 children per year in North America are expected to be candidates for the treatment with the CTPs. Conclusion CTPs for induction therapy of proliferative LN in jSLE based on the available scientific evidence and pediatric rheumatology group experience have been developed. Consistent use of the CTPs may improve the prognosis of proliferative LN, and support the conduct of comparative effectiveness studies aimed at optimizing therapeutic strategies for proliferative LN in jSLE.

Objective Statins reduce atherosclerosis and cardiovascular morbidity in the general population, but their efficacy and safety in children and adolescents with systemic lupus erythematosus (SLE) are unknown. This study was undertaken to determine the 3-year efficacy and safety of atorvastatin in preventing subclinical atherosclerosis progression in pediatric-onset SLE. Methods A total of 221 participants with pediatric SLE (ages 10–21 years) from 21 North American sites were enrolled in the Atherosclerosis Prevention in Pediatric Lupus Erythematosus study, a randomized double-blind, placebo-controlled clinical trial, between August 2003 and November 2006 with 36-month followup. Participants were randomized to receive atorvastatin (n = 113) or placebo (n = 108) at 10 or 20 mg/day depending on weight, in addition to usual care. The primary end point was progression of mean-mean common carotid intima-media thickening (CIMT) measured by ultrasound. Secondary end points included other segment/wall-specific CIMT measures, lipid profile, high-sensitivity C-reactive protein (hsCRP) level, and SLE disease activity and damage outcomes. Results Progression of mean-mean common CIMT did not differ significantly between treatment groups (0.0010 mm/year for atorvastatin versus 0.0024 mm/year for placebo; P = 0.24). The atorvastatin group achieved lower hsCRP (P = 0.04), total cholesterol (P < 0.001), and low-density lipoprotein (P < 0.001) levels compared with placebo. In the placebo group, CIMT progressed significantly across all CIMT outcomes (0.0023–0.0144 mm/year; P < 0.05). Serious adverse events and critical safety measures did not differ between groups. Conclusion Our results indicate that routine statin use over 3 years has no significant effect on subclinical atherosclerosis progression in young SLE patients; however, further analyses may suggest subgroups that would benefit from targeted statin therapy. Atorvastatin was well tolerated without safety concerns.

Objective. To evaluate risk factors for subclinical atherosclerosis in a population of patients with pediatric systemic lupus erythematosus (SLE).Methods. In a prospective multicenter study, a cohort of 221 patients underwent baseline measurements of carotid intima-media thickness (CIMT) as part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial. SLE disease measures, medications, and traditional risk factors for atherosclerosis were assessed. A standardized protocol was used to assess the thickness of the bilateral common carotid arteries and the mean maximal IMT of 12 segments. Univariable analysis identified potential associations with CIMT, which were examined in multivariable linear regression modeling.ClinicalTrials.gov identifier: NCT00065806.

BackgroundPain in children with rheumatic conditions such as arthritis is common. However, there is currently no standardized method for the assessment of this pain in children presenting to pediatric rheumatologists. A more consistent and comprehensive approach is needed to effectively assess, treat and monitor pain outcomes in the pediatric rheumatology population. The objectives of this study were to: (a) develop consensus regarding a standardized pain assessment tool for use in pediatric rheumatology practice and (b) test the feasibility of three mediums (paper, laptop, and handheld-based applications) for administration.MethodsIn Phase 1, a 2-stage Delphi technique (pediatric rheumatologists and allied professionals) and consensus meeting (pediatric pain and rheumatology experts) were used to develop the self- and proxy-report pain measures. In Phase 2, 24 children aged 4-7 years (and their parents), and 77 youth, aged 8-18 years, with pain, were recruited during routine rheumatology clinic appointments and completed the pain measure using each medium (order randomly assigned). The participant's rheumatologist received a summary report prior to clinical assessment. Satisfaction surveys were completed by all participants. Descriptive statistics were used to describe the participant characteristics using means and standard deviations (for continuous variables) and frequencies and proportions (for categorical variables)ResultsCompleting the measure using the handheld device took significantly longer for youth (M = 5.90 minutes) and parents (M = 7.00 minutes) compared to paper (M = 3.08 and 2.28 minutes respectively p = 0.001) and computer (M = 3.40 and 4.00 minutes respectively; p < 0.001). There was no difference in the number of missed responses between mediums for children or parents. For youth, the number of missed responses varied across mediums (p = 0.047) with the greatest number of missed responses occurring with the handheld device. Most children preferred the computer (65%, p = 0.008) and youth reported no preference between mediums (p = 0.307). Most physicians (60%) would recommend the computer summary over the paper questionnaire to a colleague.ConclusionsIt is clinically feasible to implement a newly developed consensus-driven pain measure in pediatric rheumatology clinics using electronic or paper administration. Computer-based administration was most efficient for most users, but the medium employed in practice may depend on child age and economic and administrative factors.