Comparison of renal response parameters for juvenile membranous plus proliferative lupus nephritis versus isolated proliferative lupus nephritis: a cross-sectional analysis of the CARRA Registry.

Lupus nephritis (LN) affects many patients with juvenile systemic lupus erythematosus (SLE) and is a significant cause of disease morbidity. Membranous plus proliferative LN (M + PLN) may represent a more difficult to treat subtype of juvenile LN, compared to isolated proliferative LN (PLN). In this retrospective observational study, we utilized data from the Childhood Arthritis and Rheumatism Research Alliance (CARRA) registry to compare response rates for pediatric M + PLN versus PLN. Response was assessed at the most recent CARRA registry visit gathered ≥6 months after diagnostic kidney biopsy. Estimated glomerular filtration rate (GFR) less than 90 ml/min/1.73 m(2), indicating renal insufficiency, was found in 16.1% of patients with M + PLN and 6.1% of patients with PLN (P = 0.071). We found no significant difference in achievement of response in either hematuria or proteinuria between PLN and M + PLN groups or between subgroups determined by presence of class III vs. class IV proliferative disease. Exposure rates to mycophenolate, cyclophosphamide, and rituximab were similar between groups. Future studies will be necessary to correlate pediatric LN renal histology data with treatment response as well as other disease outcome measures.

Annexin A5 anticoagulant activity in children with systemic lupus erythematosus and the association with antibodies to domain I of ß2-glycoprotein I.

Children with systemic lupus erythematosus (SLE) have a high prevalence of antiphospholipid (aPL) antibodies and are at increased risk for aPL-related thrombosis. We investigated the association between annexin A5 anticoagulant activity and antibodies to the domain I portion of ß2-glycoprotein I (anti-DI antibodies), and propose a potential mechanism for the pathogenesis of aPL-related thrombosis. Using samples from 183 children with SLE collected during the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial, we examined resistance to the anticoagulant effects of annexin A5, using the annexin A5 resistance (A5R) assay, and evaluated for anti-DI IgG antibodies. Children with SLE had higher frequency of anti-D1 antibodies (p = 0.014) and significantly reduced A5R compared to pediatric controls: mean A5R = 172 ± 30% versus 242 ± 32% (p < 0.0001). Children with SLE and positive anti-DI antibodies had significantly lower mean A5R levels compared to those with negative anti-DI antibodies: mean A5R = 155 ± 24% versus 177 ± 30% (p < 0.0001). In multivariate analysis, anti-DI antibodies (p = 0.013) and lupus anticoagulant (LA) (p = 0.036) were both independently associated with reduced A5R. Children with SLE have significantly reduced annexin A5 anticoagulant activity that is associated with the presence of LA and anti-DI antibodies.

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.

Laboratory markers of cardiovascular risk in pediatric SLE: the APPLE baseline cohort.

As part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) Trial, a prospective multicenter cohort of 221 children and adolescents with systemic lupus erythematosus (SLE) (mean age 15.7 years, 83% female) underwent baseline measurement of markers of cardiovascular risk, including fasting levels of high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), lipoprotein A (Lpa), homocysteine and high-sensitivity C-reactive protein (hs-CRP). A cross-sectional analysis of the baseline laboratory values and clinical characteristics of this cohort was performed. Univariable relationships between the cardiovascular markers of interest and clinical variables were assessed, followed by multivariable linear regression modeling. Mean levels of LDL, HDL, Lpa, TG, hs-CRP and homocysteine were in the normal or borderline ranges. In multivariable analysis, increased Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), prednisone dose, and hypertension (HTN) were independently associated with higher LDL levels. Higher hs-CRP and creatinine clearance were independently related to lower HDL levels. Higher body mass index (BMI), prednisone dose, and homocysteine levels were independently associated with higher TG levels. Only Hispanic or non-White status predicted higher Lpa levels. Proteinuria, higher TG and lower creatinine clearance were independently associated with higher homocysteine levels, while use of multivitamin with folate predicted lower homocysteine levels. Higher BMI, lower HDL, and longer SLE disease duration, but not SLEDAI, were independently associated with higher hs-CRP levels. The R(2) for these models ranged from 7% to 23%. SLE disease activity as measured by the SLEDAI was associated only with higher LDL levels and not with hs-CRP. Markers of renal injury (HTN, proteinuria, and creatinine clearance) were independently associated with levels of LDL, HDL, and homocysteine, highlighting the importance of renal status in the cardiovascular health of children and adolescents with SLE. Future longitudinal analysis of the APPLE cohort is needed to further examine these relationships.

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 physician's 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 physician's 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 systemic lupus erythematosus.

Premature atherosclerosis is a recognized complication of systemic lupus erythematosus (SLE). Since life expectancy in SLE is improving, premature atherosclerosis is emerging as an ever more important clinical issue. Atherosclerosis begins in the pediatric age group, and interventions directed at prevention should begin in childhood as well. Possible etiologies include dyslipoproteinemia (DL) from the underlying chronic inflammatory disease or from corticosteroid therapy, hypercoagulation due to antiphospholipid antibodies or nephrotic syndrome, vasculitis, and hypertension. A relationship between DL and presence of anticardiolipin antibodies (aCL) has been reported. Dietary therapy is helpful, but many patients continue to have significant DL after both dietary modification and fish oil supplementation. Lipid lowering drugs may be indicated in this subgroup. Potential mechanisms of the DL are discussed. Other strategies to prevent atherosclerosis and its complications are reviewed.

Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group.

BACKGROUND: We evaluated the safety and efficacy of etanercept, a soluble tumor necrosis factor receptor (p75):Fc fusion protein, in children with polyarticular juvenile rheumatoid arthritis who did not tolerate or had an inadequate response to methotrexate. METHODS: Patients 4 to 17 years old received 0.4 mg of etanercept per kilogram of body weight subcutaneously twice weekly for up to three months in the initial, open-label part of a multicenter trial. Those who responded to treatment then entered a double-blind study and were randomly assigned to receive either placebo or etanercept for four months or until a flare of the disease occurred. A response was defined as an improvement of 30 percent or more in at least three of six indicators of disease activity, with no more than one indicator worsening by more than 30 percent. RESULTS: At the end of the open-label study, 51 of the 69 patients (74 percent) had had responses to etanercept treatment. In the double-blind study, 21 of the 26 patients who received placebo (81 percent) withdrew because of disease flare, as compared with 7 of the 25 patients who received etanercept (28 percent) (P=0.003). The median time to disease flare with placebo was 28 days, as compared with more than 116 days with etanercept (P<0.001). In the double-blind study, there were no significant differences between the two treatment groups in the frequency of adverse events. CONCLUSIONS: Treatment with etanercept leads to significant improvement in patients with active polyarticular juvenile rheumatoid arthritis. Etanercept is well tolerated by pediatric patients.

Family-level coping in juvenile rheumatoid arthritis: assessing the utility of a quantitative family interview.

OBJECTIVE: To explore the viability of a quantitative family interview to describe family-level coping strategies used to deal with juvenile rheumatoid arthritis (JRA)-related stressors for early and late adolescents. METHOD: A structured interview protocol with 30 adolescents with JRA and family members assessed ways JRA disrupts or changes family functioning. Emotional reactions, sequential phases of family response, and treatment adherence were discussed. Interviews were coded for family-level coping. To assess adjustment, family members completed the Youth Self Report and the Family Environment Scale. The pediatric rheumatologist provided medical information. RESULTS: The family interview produced both quantitative and qualitative data. Families reported multiple JRA-related stressors (mean 6.6). For many adolescents, treatment adherence was problematic. Families used all 3 types of coping strategies (appraisal-, problem-, and emotion-focused) to varying degrees. Problem-focused approaches were most commonly used and included seeking support (used by 73% of families), self-reliance (70%), and family coordination (70%) for dealing with specific problems, and seeking information about JRA (67%). Emotion-focused approaches, such as impulsive outbursts and diminished awareness of others' feelings, were associated with problematic adjustment. Few differences were found between the families of early and late adolescents. CONCLUSION: The quantitative family interview has the potential to be a useful tool in documenting JRA-related stressors, family-level coping processes, and how family-level coping is associated with treatment adherence and psychosocial adjustment.

Other rheumatic diseases in adolescence. Dermatomyositis, scleroderma, overlap syndromes, systemic vasculitis, and panniculitis.

In addition to juvenile rheumatoid arthritis (JRA) and systemic lupus erythematosus (SLE), dermatomyosytis, scleroderma, overlap syndromes, systemic vasculitis, and panniculitis also present in adolescence. The authors discuss the complex epidemiology, diagnosis, clinical features, diagnostic testing, treatment, and prognosis of these diseases.

Discontinuation of methotrexate treatment in juvenile rheumatoid arthritis.

OBJECTIVE: Children with juvenile rheumatoid arthritis (JRA) treated with methotrexate (MTX) were examined for their course after the discontinuation of the drug to define the relapse and remission rates and to identify predictors of relapse. METHODOLOGY: A retrospective chart review of all patients with JRA was conducted in two pediatric rheumatology centers. A total of 101 patients being treated with MTX were identified. Dose, response to the drug, and length of time until reaching a state of complete control were noted. The outcome of patients with a complete response in whom the drug was discontinued was examined with regards to length of time to relapse or continued remission. RESULTS: In 25 patients, MTX was discontinued after reaching complete control of the disease. There were no statistically significant predictors of response to MTX identified. Of 25 whose MTX was discontinued, relapse occurred in 13 (52%) after a mean of 11 months after discontinuation. There was no significant difference among patients who relapsed or those who remained in remission as to sex, subtype of JRA, number of months to complete control, or number of months in complete control until discontinuing MTX. Patients younger than 41/2 years at diagnosis were found to be more likely to relapse than patients diagnosed at a later age. In 10 of the patients who relapsed, complete control was induced within a mean of 7 months after restarting MTX. CONCLUSION: The optimal time for discontinuing MTX in children with JRA who have achieved complete control is unknown. Relapse occurred in approximately half of the patients in whom MTX was discontinued. Because response to reinstitution of the drug is good, it is reasonable to discontinue MTX after prolonged complete control. It remains to be seen whether the relapse rate can be improved by waiting for longer periods of time in complete control before its discontinuation.

Methotrexate treatment of Wegener granulomatosis in children.

Wegener granulomatosis traditionally has been treated with glucocorticoids and cyclophosphamide. Both the disease and its treatments are associated with significant morbidity and mortality rates. There has been an effort to find effective but less toxic alternative treatments. We describe three children with Wegener granulomatosis who responded well to treatment with glucocorticoids and methotrexate, similar to a regimen used in adults.

Hyperlipidemia and the rheumatic diseases.

Premature atherosclerosis is a recognized complication of systemic lupus erythematosus. Atherosclerosis begins in the pediatric age group, and interventions directed toward prevention should begin in childhood as well. A possible cause of premature atherosclerosis is dyslipoproteinemia from the underlying chronic inflammatory disease or from corticosteroid therapy. A relationship between dyslipoproteinemia and anticardiolipin antibodies has been demonstrated. Dietary therapy is helpful, but many patients continue to have significant dyslipoproteinemia after both dietary modification and fish oil supplementation. Lipid-lowering drugs may be indicated in this subgroup. Potential mechanisms of dyslipoproteinemia are discussed.

Immunoglobulin M immunoblot for diagnosis of Borrelia burgdorferi infection in patients with acute facial palsy.

We used immunoblotting to improve the specificity of the serologic diagnosis of Lyme borreliosis in cases of acute facial palsy. Twelve of 15 patients (80%) with suspected Lyme borreliosis, versus 0 of 10 controls, were positive by immunoglobulin M immunoblotting of acute-phase sera and 3 were negative, including 2 with borderline enzyme immunoassay results. Immunoglobulin M immunoblotting is a useful test to confirm Borrelia burgdorferi infection in patients with acute facial palsy and a positive enzyme immunoassay result.

Increased urinary NO3(-) + NO2- and neopterin excretion in children breast fed by mothers with silicone breast implants: evidence for macrophage activation.

OBJECTIVE: To determine whether children breast fed by mothers with silicone implants (BFSI) have increased urinary excretion of nitric oxide (NO) metabolites and neopterin, whether these are associated with esophageal dysmotility, and whether in vitro incubation of macrophages with silicone increases NO synthesis. METHODS: In a case-control study based on laboratory investigation, 38 BFSI children (17 male, 21 female, mean age 7.1 +/- 3.6 years, range 0.5-16.5) were compared with 30 controls (14 male, 16 female, mean age 8.4 +/- 3.5 years, range 2.5-17). Urinary NO was quantitated using the Griess reaction. Urinary neopterin was determined by radioimmunoassay. Murine macrophages were cultured with or without silicone and NO production assayed. RESULTS: Urinary NO and neopterin were significantly increased in BFSI children compared with controls. There was a significant inverse relationship between urinary neopterin excretion and the severity of esophageal dysfunction. In vitro nitrite production was nearly 60% higher in macrophages grown on silicone compared to other growth conditions. CONCLUSION: BFSI children have evidence of macrophage activation and this is associated with esophageal dysmotility. In vitro data support the proposal that silicone exposure causes macrophage activation.

Lack of autoantibody expression in children born to mothers with silicone breast implants.

OBJECTIVE: We determined systematically the prevalence of autoantibodies in children born to mothers with silicone breast implants and the relationships with clinical symptoms and methods of exposure. METHODS: Autoantibody expression was determined in 80 children born to mothers with silicone implants and in 42 controls. A clinical assessment score was assigned to each patient. Antinuclear antibodies as well as antibodies to mitochondrial, smooth muscle, striational, myocardial, parietal cell, reticulin tissues, or subcellular compartments were measured by indirect fluorescent assay. Antibodies to nRNP (U1-RNP/snRNP); Sm; SS-A; SS-B; Scl-70; thyroid microsome; immunoglobulin (Ig)G, IgM, and IgA antibodies to cardiolipin; and antibodies to native and denatured human types I and II collagen were measured by enzyme-linked immunosorbent assay. Serum complement components C3 and C4 and IgM rheumatoid factor were measured by nephelometry. RESULTS: Autoantibody prevalence was not significantly different between children born to mothers with silicone implants and controls. The presence of autoantibodies was not related to the children's clinical symptoms or to the method of exposure. CONCLUSIONS: Determination of autoantibody production is of limited clinical utility in the evaluation of children born to mothers with silicone breast implants.

Effects of dietary modification and fish oil supplementation on dyslipoproteinemia in pediatric systemic lupus erythematosus.

OBJECTIVE: To determine if a program of dietary modification and fish oil supplementation is effective in treating the dyslipoproteinemia in pediatric systemic lupus erythematosus (SLE). METHODS: Prospective clinical trial where each patient serves as his/her own control. Twenty-four consecutive adolescents fulfilling SLE classification criteria were screened with fasting lipid profiles. Patients were identified as having dyslipoproteinemia of active disease or of corticosteroid therapy. Patients were treated for 6 weeks with dietary modification and if dyslipoproteinemia did not normalize with another 6 weeks of dietary modification and fish oil supplementation. RESULTS: Seventeen patients (71%) had dyslipoproteinemia; 10 of active disease, 4 of steroid therapy; 3 with a combined pattern. Eleven patients underwent dietary modification. There was a significant decrease in serum triglyceride concentrations (p < 0.05). Total cholesterol, low density lipoprotein cholesterol, and high density lipoprotein cholesterol did not change significantly. A further significant decline in serum triglycerides was achieved with fish oil supplementation (p < 0.05). Five of the 11 patients who underwent treatment continued to have dyslipoproteinemia. CONCLUSION: Dyslipoproteinemia is common in pediatric SLE. Dietary modification and fish oil supplementation appear to be effective in improving serum lipid profiles, and blinded studies are warranted. a significant number of patients may require pharmacologic therapy for persistent dyslipoproteinemia to prevent complications of premature atherosclerosis.

Muscle, reticuloendothelial, and late skin manifestations of Lyme disease.

In addition to classic organ system involvement, Lyme disease may be characterized by myositis, liver and spleen involvement, and atypical cutaneous manifestations. Myositis is characteristically localized near an involved joint or localized neuropathy. Nuclear imaging with gallium-67 may be useful for detection. Myositis responds to treatment with intravenous or oral antibiotics. Patients with erythema migrans have been observed to have liver function test abnormalities in the absence of symptomatic hepatitis. Splenomegaly has been noted infrequently in patients with Lyme disease. Chronic cutaneous manifestations of Lyme disease--including erythema migrans, acrodermatitis chronica atrophicans, and lymphadenosis benigna cutis--have been observed more frequently in Europe than in the United States. It appears that they are caused primarily by the Borrelia afzelii genomic group of Borrelia burgdorferi, which has been found exclusively in Europe.

Interpretation of immunoblot in pediatric Lyme arthritis.

OBJECTIVE: To determine the pattern of bands present on an immunoblot (Western blot) in children with Lyme arthritis. METHODS: Sera from 20 children with Lyme arthritis from an endemic area were assayed, and the results compared with those obtained in 162 control sera from the same area. The study was retrospective, serum bank based. RESULTS: Eighty-seven percent of control sera revealed no bands on immunoblot, and all had < or = 4 bands. All Lyme arthritis sera revealed > or = 5 bands (mean 8.4, range 5-13 bands). Bands of molecular weight 25, 28, 39, 47, 50, and 93 kDa were seen in patients and not in controls. There was no correlation between duration of arthritis or activity of arthritis at presentation and number of bands present. CONCLUSION: Criteria were derived for a positive immunoblot based on the number and molecular weights of bands seen in our laboratory. These are the presence of 5 or more bands, of which at least one is an apparently specific band (25, 28, 39, 47, 50, or 93 kDa). Results of immunoblot are useful to confirm clinically suspected Lyme arthritis.