Gloria C. Higgins

Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans.

Interindividual gene copy-number variation (CNV) of complement component C4 and its associated polymorphisms in gene size (long and short) and protein isotypes (C4A and C4B) probably lead to different susceptibilities to autoimmune disease. We investigated the C4 gene CNV in 1,241 European Americans, including patients with systemic lupus erythematosus (SLE), their first-degree relatives, and unrelated healthy subjects, by definitive genotyping and phenotyping techniques. The gene copy number (GCN) varied from 2 to 6 for total C4, from 0 to 5 for C4A, and from 0 to 4 for C4B. Four copies of total C4, two copies of C4A, and two copies of C4B were the most common GCN counts, but each constituted only between one-half and three-quarters of the study populations. Long C4 genes were strongly correlated with C4A (R=0.695; P<.0001). Short C4 genes were correlated with C4B (R=0.437; P<.0001). In comparison with healthy subjects, patients with SLE clearly had the GCN of total C4 and C4A shifting to the lower side. The risk of SLE disease susceptibility significantly increased among subjects with only two copies of total C4 (patients 9.3%; unrelated controls 1.5%; odds ratio [OR] = 6.514; P=.00002) but decreased in those with > or =5 copies of C4 (patients 5.79%; controls 12%; OR=0.466; P=.016). Both zero copies (OR=5.267; P=.001) and one copy (OR=1.613; P=.022) of C4A were risk factors for SLE, whereas > or =3 copies of C4A appeared to be protective (OR=0.574; P=.012). Family-based association tests suggested that a specific haplotype with a single short C4B in tight linkage disequilibrium with the -308A allele of TNFA was more likely to be transmitted to patients with SLE. This work demonstrates how gene CNV and its related polymorphisms are associated with the susceptibility to a human complex disease.

Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: Report of forty-six patients from an international multicenter series

OBJECTIVE To examine the safety and efficacy of the interleukin-1 (IL-1) receptor antagonist anakinra as first-line therapy for systemic juvenile idiopathic arthritis (JIA). METHODS Patients with systemic JIA receiving anakinra as part of initial disease-modifying antirheumatic drug (DMARD) therapy were identified from 11 centers in 4 countries. Medical records were abstracted using a standardized instrument, and resulting data were analyzed to characterize concomitant therapies, clinical course, adverse events, and predictors of outcome. RESULTS Among 46 patients meeting inclusion criteria, anakinra monotherapy was used in 10 patients (22%), while 67% received corticosteroids and 33% received additional DMARDs. Outcomes were evaluated at a median followup interval of 14.5 months. Fever and rash resolved within 1 month in >95% of patients, while C-reactive protein and ferritin normalized within this interval in >80% of patients. Active arthritis persisted at 1 month in 39% of patients, at 3 months in 27%, and at >6 months of followup in 11%. Approximately 60% of patients, including 8 of 10 receiving anakinra monotherapy, attained a complete response without escalation of therapy. Disease characteristics and treatment were similar in partial and complete responders, except that partial responders were markedly younger at onset (median age 5.2 years versus 10.2 years; P = 0.004). Associated adverse events included documented bacterial infection in 2 patients and hepatitis in 1 patient. Tachyphylaxis was not observed. CONCLUSION Anakinra as first-line therapy for systemic JIA was associated with rapid resolution of systemic symptoms and prevention of refractory arthritis in almost 90% of patients during the interval examined. These results justify further study of IL-1 inhibition as first-line, rather than rescue, therapy in systemic JIA.

Long-term safety and effectiveness of etanercept in children with selected categories of juvenile idiopathic arthritis†

OBJECTIVE This study was undertaken to evaluate the long-term safety and effectiveness of etanercept alone or in combination with methotrexate (MTX) in children with selected categories of juvenile idiopathic arthritis (JIA). METHODS Patients ages 2-18 years with rheumatoid factor (RF)-positive or RF-negative polyarthritis, systemic JIA, or extended oligoarthritis were eligible for the study. Patients received MTX alone (> or =10 mg/m(2)/week [ approximately 0.3 mg/kg/week], maximum dosage 1 mg/kg/week), etanercept alone (0.8 mg/kg/week, maximum dose 50 mg), or etanercept plus MTX for 3 years in an open-label, nonrandomized study. Safety was assessed by measuring rates of adverse events, and effectiveness was assessed using the physicians global assessment of disease activity and the pediatric total joint assessment. RESULTS A total of 197, 103, and 294 patients were enrolled in the MTX, etanercept, and etanercept plus MTX groups, respectively. Exposure-adjusted rates of adverse events were similar among the 3 treatment groups (18.3, 18.7, and 21.6 per 100 patient-years in the MTX, etanercept, and etanercept plus MTX groups, respectively). Respective rates per 100 patient-years of serious adverse events (4.6, 7.1, and 6.0) and medically important infections (1.3, 1.8, and 2.1) were also similar among the 3 treatment groups. Scores for physicians global assessment and total active joints improved from baseline, and improvement was maintained for the duration of the study. CONCLUSION These data confirm the findings of other long-term studies and suggest that etanercept or etanercept plus MTX has an acceptable safety and effectiveness profile in children with selected categories of JIA. Improvement was maintained for 3 years in those continuing to receive medication.

Premature atherosclerosis in pediatric systemic lupus erythematosus: Risk factors for increased carotid intima‐media thickness in the atherosclerosis prevention in pediatric lupus erythematosus cohort

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. RESULTS Based on the mean-mean common or the mean-max CIMT as the dependent variable, univariable analysis showed significant associations of the following variables with increased CIMT: increasing age, longer SLE duration, minority status, higher body mass index (BMI), male sex, increased creatinine clearance, higher lipoprotein(a) level, proteinuria, azathioprine treatment, and prednisone dose. In multivariable modeling, both azathioprine use (P=0.005 for the mean-mean model and P=0.102 for the mean-max model) and male sex (P<0.001) were associated with increases in the mean-max CIMT. A moderate dosage of prednisone (0.15-0.4 mg/kg/day) was associated with decreases in the mean-max CIMT (P=0.024), while high-dose and low-dose prednisone were associated with increases in the mean-mean common CIMT (P=0.021) and the mean-max CIMT (P=0.064), respectively. BMI (P<0.001) and creatinine clearance (P=0.031) remained associated with increased mean-mean common CIMT, while increasing age (P<0.001) and increasing lipoprotein(a) level (P=0.005) were associated with increased mean-max CIMT. CONCLUSION Traditional as well as nontraditional risk factors were associated with increased CIMT in this cohort of patients in the APPLE trial. Azathioprine treatment was associated with increased CIMT. The relationship between CIMT and prednisone dose may not be linear.

The Localized Scleroderma Skin Severity Index and Physician Global Assessment of Disease Activity: A Work in Progress Toward Development of Localized Scleroderma Outcome Measures

Objective. To develop and evaluate a Localized Scleroderma (LS) Skin Severity Index (LoSSI) and global assessments’ clinimetric property and effect on quality of life (QOL). Methods. A 3-phase study was conducted. The first phase involved 15 patients with LS and 14 examiners who assessed LoSSI [surface area (SA), erythema (ER), skin thickness (ST), and new lesion/extension (N/E)] twice for inter/intrarater reliability. Patient global assessment of disease severity (PtGA-S) and Children’s Dermatology Life Quality Index (CDLQI) were collected for intrarater reliability evaluation. The second phase was aimed to develop clinical determinants for physician global assessment of disease activity (PhysGA-A) and to assess its content validity. The third phase involved 2 examiners assessing LoSSI and PhysGA-A on 27 patients. Effect of training on improving reliability/validity and sensitivity to change of the LoSSI and PhysGA-A was determined. Results. Interrater reliability was excellent for ER [intraclass correlation coefficient (ICC) 0.71], ST (ICC 0.70), LoSSI (ICC 0.80), and PhysGA-A (ICC 0.90) but poor for SA (ICC 0.35); thus, LoSSI was modified to mLoSSI. Examiners’ experience did not affect the scores, but training/practice improved reliability. Intrarater reliability was excellent for ER, ST, and LoSSI (Spearman’s rho = 0.71–0.89) and moderate for SA. PtGA-S and CDLQI showed good intrarater agreement (ICC 0.63 and 0.80). mLoSSI correlated moderately with PhysGA-A and PtGA-S. Both mLoSSI and PhysGA-A were sensitive to change following therapy. Conclusion. mLoSSI and PhysGA-A are reliable and valid tools for assessing LS disease severity and show high sensitivity to detect change over time. These tools are feasible for use in routine clinical practice. They should be considered for inclusion in a core set of LS outcome measures for clinical trials.

Use of Atorvastatin in Systemic Lupus Erythematosus in Children and Adolescents

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.

Development of consensus treatment plans for juvenile localized scleroderma: A roadmap toward comparative effectiveness studies in juvenile localized scleroderma

Juvenile localized scleroderma (LS) is a chronic inflammatory skin disorder associated with substantial morbidity and disability. Although a wide range of therapeutic strategies has been reported in the literature, a lack of agreement on treatment specifics and accepted methods for clinical assessment has made it difficult to compare approaches and identify optimal therapy. Our objective was to develop standardized treatment plans, clinical assessments, and response criteria for active, moderate to high severity juvenile LS.

Ocular involvement in children with localised scleroderma: A multi-centre study

Background: Most of the available documentation in the literature on ocular involvement in localised scleroderma (LS) are descriptions of single cases in adult patients. This article reports the frequency and specific features of ocular involvement in a large cohort of children with juvenile LS (JLS). Methods: Data from a large, multi-centre, multinational study of children with LS were used to collect and analyse specific information on ocular involvement. Results: 24 out of 750 patients (3.2%) revealed a significant ocular involvement. 16 were female and 8 male. 16 patients (66.7%) had scleroderma “en coup de sabre” (ECDS) of the face, 5 (20.8%) had the linear subtype, 2 (8.3%) had generalised morphea (GM) and one (4.2%) had plaque morphea (PM). Of the 24 patients with eye involvement, 10 patients (41.7%) reported adnexa (eyelids and eyelashes) abnormalities, 7 (29.2%) anterior segment inflammation (5 anterior uveitis, 2 episcleritis) and 3 central nervous system-related abnormalities. 4 patients presented single findings such as paralytic strabismus (1), pseudopapilloedema (1) and refractive errors (2). Other extracutaneous manifestations were detected in a significantly higher number of patients with ocular involvement and were mostly neurological. Conclusion: Ocular abnormalities are not unusual in patients with JLS, especially in the ECDS subtype. They are frequently associated with other internal organ involvement, particularly the central nervous system (CNS). Careful ophthalmic monitoring is recommended for every patient with JLS, but is mandatory in those with skin lesions on the face and/or concomitant CNS involvement.

Genetic Sophistication of Human Complement Components C4A and C4B and RP-C4-CYP21-TNX (RCCX) Modules in the Major Histocompatibility Complex

Human populations are endowed with a sophisticated genetic diversity of complement C4 and its flanking genes RP, CYP21, and TNX in the RCCX modules of the major histocompatibility complex class III region. We applied definitive techniques to elucidate (a) the complement C4 polymorphisms in gene sizes, gene numbers, and protein isotypes and (b) their gene orders. Several intriguing features are unraveled, including (1) a trimodular RCCX haplotype with three long C4 genes expressing C4A protein only, (2) two trimodular haplotypes with two long (L) and one short (S) C4 genes organized in LSL configurations, (3) a quadrimodular haplotype with four C4 genes organized in a SLSL configuration, and (4) another quadrimodular structure, with four long C4 genes (LLLL), that has the human leukocyte antigen haplotype that is identical to ancestral haplotype 7.2 in the Japanese population. Long-range PCR and PshAI-RFLP analyses conclusively revealed that the short genes from the LSL and SLSL haplotypes are C4A. In four informative families, an astonishingly complex pattern of genetic diversity for RCCX haplotypes with one, two, three and four C4 genes is demonstrated; each C4 gene may be long or short, encoding a C4A or C4B protein. Such diversity may be related to different intrinsic strengths among humans to defend against infections and susceptibilities to autoimmune diseases.

Treatment of pediatric localized scleroderma: results of a survey of North American pediatric rheumatologists.

Objective. We surveyed pediatric rheumatologists (PR) in North America to learn how they treat pediatric localized scleroderma (LS), a disease associated with significant morbidity for the growing child. Methods. A Web-based survey was sent to the 195 PR members of the pediatric rheumatology research alliance CARRA (Childhood Arthritis and Rheumatology Research Alliance). Members were asked which medications they use to treat LS and which factors modify their treatment strategies. Clinical vignettes were provided to learn the specific treatment regimens used. Results. A total of 158 PR from over 70 clinical centers in the United States and Canada participated in the survey, representing 81% of the CARRA membership. These PR saw over 650 patients with LS in the prior year. Nearly all respondents treated LS with methotrexate (MTX) and corticosteroids; most of them intensify treatment for lesions located on the face or near a joint, and about half intensify treatment for recent disease onset (< 6 months). Most PR reserve topical medications for limited treatment situations. Clinical vignettes showed that PR use a broad range of treatment doses and durations for MTX and corticosteroids. Conclusion. Most PR in North America treat localized scleroderma with a combination of MTX and corticosteroids. However, there is no consensus on specific treatment regimens. There is a need for controlled treatment trials to better determine optimal therapy for this potentially disabling disease.