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.

Identification of new SLE-associated genes with a two-step Bayesian study design.

In our earlier study, we utilized a Bayesian design to probe the association of approximately 1000 genes (approximately 10,000 single-nucleotide polymorphisms (SNPs)) with systemic lupus erythematosus (SLE) on a moderate number of trios of parents and children with SLE. Two genes associated with SLE, with a multitest-corrected false discovery rate (FDR) of <0.05, were identified, and a number of noteworthy genes with FDR of <0.8 were also found, pointing out a future direction for the study. In this report, using a large population of controls and adult- or childhood-onset SLE cases, we have extended the earlier investigation to explore the SLE association of 10 of these noteworthy genes (109 SNPs). We have found that seven of these genes exhibit a significant (FDR<0.05) association with SLE, both confirming some genes that have earlier been found to be associated with SLE (PTPN22 and IRF5) and presenting novel findings of genes (KLRG1, interleukin-16, protein tyrosine phosphatase receptor type T, toll-like receptor (TLR)8 and CASP10), which have not been reported earlier. The results signify that the two-step candidate pathway design is an efficient way to study the genetic foundations of complex diseases. Furthermore, the novel genes identified in this study point to new directions in both the diagnosis and the eventual treatment of this debilitating disease.

Epstein-Barr virus burden in adolescents with systemic lupus erythematosus.

OBJECTIVE: We sought to determine whether patients with systemic lupus erythematosus (SLE) and a presumed primary or reactivated Epstein-Barr virus (EBV) serologic response had evidence of an active EBV infection. BACKGROUND: Patients with SLE often have what appears to be a primary or reactivated EBV serologic response. If these patients then present with fever, fatigue, adenopathy or leukopenia, it is not clear whether these symptoms are caused by worsening SLE or EBV infection. Establishing the correct diagnosis is crucial for management. METHODS: We examined the EBV burden in 13 adolescents with SLE and a presumed primary or reactivated EBV serologic response. All were taking prednisone; 2 each were also on azathioprine or intravenous pulse cyclophosphamide. EBV serologies were performed for all, and EBV burdens were assessed via immortalization assays and EBV DNA amplification of blood and saliva at least once. RESULTS: Seven patients had serologic patterns indicative of a primary EBV infection, while six had serologies indicative of a reactivated (secondary) EBV infection. Two of the latter were the only ones in whom a small amount of biologically active EBV was detected. CONCLUSION: In our series active EBV infection was not seen in most patients, despite serologic data that could be interpreted as a primary or reactivated infection. Thus the serologic profiles were more likely a consequence of immune dysregulation secondary to SLE or its therapy rather than rampant infection with EBV.

Effects of methotrexate on radiologic progression in juvenile rheumatoid arthritis.

OBJECTIVE: To assess the effects of methotrexate (MTX) therapy on radiologic progression in juvenile rheumatoid arthritis (JRA). METHODS: We evaluated serial wrist radiographs for carpal length in 23 JRA patients with bilateral wrist involvement, before and during MTX treatment. These carpal length measurements were compared with established norms for carpal length in a healthy pediatric population. RESULTS: Both clinical responders to MTX (17 of 23 patients) and nonresponders (6 of 23) had decreasing carpal length prior to initiation of the treatment. Eleven of the 17 clinical responders had improved carpal length after a mean of 2.5 years of MTX treatment. All 6 clinical nonresponders had progressive loss of carpal length. CONCLUSION: MTX treatment resulted in radiologic improvement, as measured by carpal length, in the majority of children with JRA who had a clinical response to MTX.

Intermittent intravenous cyclophosphamide therapy for lupus nephritis.

We carried out a preliminary study to determine whether intermittent intravenous cyclophosphamide therapy could be safely and effectively used in the treatment of childhood lupus nephritis. Sixteen children (4 to 18 years of age) with lupus nephritis were treated with cyclophosphamide monthly for 6 months and then every 3 months. Eight children were treated because of corticosteroid-unresponsive active lupus nephritis, with a fall in their creatinine clearance to less than 100 ml/min/1.75 m2, and eight children were treated because of corticosteroid-dependent nephrotic syndrome or active lupus nephritis with unacceptable corticosteroid-induced side effects. Cyclophosphamide treatment was associated with significant improvement at 1 year in mean levels of hemoglobin (11.3 +/- 0.5 to 13.1 +/- 0.3 gm/dl), C3 (52 +/- 5.9 to 108 +/- 13.7 mg/dl), and C4 (7.6 +/- 0.9 to 15.9 +/- 2.2 mg/dl) (all p less than 0.005), despite a significant reduction in mean prednisone dosage (31 +/- 5 to 14 +/- 2 mg/day; p less than 0.005). There was a decrease in 24-hour urine protein excretion from 3121 +/- 913 to 1016 +/- 364 mg/24 hours (p less than 0.05). For children whose initial creatinine clearance was less than 100 ml/min/1.75 m2, creatinine clearance also improved significantly (57.5 +/- 11 to 121 +/- 24.5 ml/min/1.75 m2; p less than 0.05). The long-term safety of intravenous cyclophosphamide therapy and its long-term efficacy in comparison with prednisone alone remain to be established. In the interim, intravenous cyclophosphamide therapy should be reserved for children with severe, unacceptable corticosteroid side effects or with corticosteroid-resistant and potentially life-threatening disease.

Potential of human polymorphonuclear leukocytes to synthesize and secrete sulfated proteoglycans.

To analyze the function of proteoglycans (PG) in different types of leukocytes, both the relative amounts and specific types of proteoglycans produced by cultured human peripheral blood polymorphonuclear leukocytes (PMN) were were determined and compared to mononuclear leukocytes (PBMC). Media from 3-day cultured PMN contained significantly less (less than 10%) 35SO2-4-labeled PG than media from PBMC cultures. Incorporation of 35SO2-4 into cell-associated material was comparable for both types of white blood cells. In contrast to PBMC, PMN could not increase their synthesis or secretion of PG after exposure to concanavalin A or phorbol-12-myristate-13-acetate. Various inducers of leukocyte chemotaxis also failed to enhance PG production by PMNs. Release of prelabeled PG from PMNs could be induced by exposure to either opsonized or unopsonized zymosan (yeast) as well as the bacteria S. aureus, suggesting that particle ingestion may be accompanied by PG exocytosis. Both chondroitinase ABC and AC digested greater than 90% of PMN 35S-labeled material in media and 75% in cell lysates; HNO3 treatment removed less than 5% of N-linked 35SO4 from radiolabeled media and 25% from cells. Treatment with 0.5 N NaOH released shortened glycosaminoglycan chains from 35S-labeled PMN cell lysates. beta-D-xylosides did not stimulate an increase in polysaccharide chain production by cultured PMNs. These data suggest that PMNs can produce chondroitin 4-sulfate PG whose synthesis is not affected by treatments that alter PMN functions; in contrast to PBMCs, PMNs will actively release these molecules when exposed to micro-organisms that stimulate phagocytosis.