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Arthritis care & research  2012;64(3):375-383.
To formulate consensus treatment plans (CTPs) for induction therapy of newly-diagnosed proliferative lupus nephritis (LN) in juvenile systemic lupus erythematosus (jSLE).
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.
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.
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.
PMCID: PMC3457803  PMID: 22162255
children; SLE; lupus nephritis; induction therapy; consensus
2.  Plasma levels of osteopontin identify patients at risk for organ damage in systemic lupus erythematosus 
Osteopontin (OPN) has been implicated as a mediator of Th17 regulation via type I interferon (IFN) receptor signaling and in macrophage activity at sites of tissue repair. This study assessed whether increased circulating plasma OPN (cOPN) precedes development of organ damage in pediatric systemic lupus erythematosus (pSLE) and compared it to circulating plasma neutrophil gelatinase-associated lipocalin (cNGAL), a predictor of increased SLE disease activity.
cOPN and cNGAL were measured in prospectively followed pSLE (n = 42) and adult SLE (aSLE; n = 23) patients and age-matched controls. Time-adjusted cumulative disease activity and disease damage were respectively assessed using adjusted-mean SLE disease activity index (SLEDAI) (AMS) and SLICC/ACR damage index (SDI).
Compared to controls, elevated cOPN and cNGAL were observed in pSLE and aSLE. cNGAL preceded worsening SLEDAI by 3-6 months (P = 0.04), but was not associated with increased 6-month AMS. High baseline cOPN, which was associated with high IFNalpha activity and expression of autoantibodies to nucleic acids, positively correlated with 6-month AMS (r = 0.51 and 0.52, P = 0.001 and 0.01 in pSLE and aSLE, respectively) and was associated with SDI increase at 12 months in pSLE (P = 0.001). Risk factors for change in SDI in pSLE were cOPN (OR 7.5, 95% CI [2.9-20], P = 0.03), but not cNGAL, cumulative prednisone, disease duration, immunosuppression use, gender or ancestry using univariate and multivariate logistic regression. The area under the curve (AUC) when generating the receiver-operating characteristic (ROC) of baseline cOPN sensitivity and specificity for the indication of SLE patients with an increase of SDI over a 12 month period is 0.543 (95% CI 0.347-0.738; positive predictive value 95% and negative predictive value 38%).
High circulating OPN levels preceded increased cumulative disease activity and organ damage in SLE patients, especially in pSLE, and its value as a predictor of poor outcome should be further validated in large longitudinal cohorts.
PMCID: PMC3672798  PMID: 23343383
7.  Association of IRF5 polymorphisms with activation of the interferon α pathway 
Annals of the rheumatic diseases  2009;69(3):611-617.
The genetic association of interferon regulatory factor 5 (IRF5) with systemic lupus erythematosus (SLE) susceptibility has been convincingly established. To gain understanding of the effect of IRF5 variation in individuals without SLE, a study was undertaken to examine whether such genetic variation predisposes to activation of the interferon α (IFNα) pathway.
Using a computer simulated approach, 14 single nucleotide polymorphisms (SNPs) and haplotypes of IRF5 were tested for association with mRNA expression levels of IRF5, IFNα and IFN-inducible genes and chemokines in lymphoblastoid cell lines (LCLs) from individuals of European (CEU), Han Chinese (CHB), Japanese (JPT) and Yoruba Nigerian (YRI) backgrounds. IFN-inducible gene expression was assessed in LCLs from children with SLE in the presence and absence of IFNα stimulation.
The major alleles of IRF5 rs13242262 and rs2280714 were associated with increased IRF5 mRNA expression levels in the CEU, CHB+JPT and YRI samples. The minor allele of IRF5 rs10488631 was associated with increased IRF5, IFNα and IFN-inducible chemokine expression in CEU (pc=0.0005, 0.01 and 0.04, respectively). A haplotype containing these risk alleles of rs13242262, rs10488631 and rs2280714 was associated with increased IRF5, IFNα and IFN-inducible chemokine expression in CEU LCLs. In vitro studies showed specific activation of IFN-inducible genes in LCLs by IFNα.
SNPs of IRF5 in healthy individuals of a number of ethnic groups were associated with increased mRNA expression of IRF5. In European-derived individuals, an IRF5 haplotype was associated with increased IRF5, IFNα and IFN-inducible chemokine expression. Identifying individuals genetically predisposed to increased IFN-inducible gene and chemokine expression may allow early detection of risk for SLE.
PMCID: PMC3135414  PMID: 19854706
8.  Understanding Premature Atherosclerosis in Pediatric SLE: Risk Factors of Increased Carotid Intima Medial Thickness (CIMT) in the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) Cohort 
Arthritis and rheumatism  2009;60(5):1496-1507.
To evaluate risk factors of sub-clinical atherosclerosis in a pediatric SLE population.
A prospective multicenter cohort of 221 patients underwent baseline measurements of carotid intima medial thickening (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 thickness of the bilateral common carotids and mean maximal IMT of 12 segments. Univariable analysis identified potential associations with CIMT that were examined in multivariable linear regression modeling.
Based on mean-mean common or mean-max CIMT as the dependent variable, univariable analysis showed significant associations with increased CIMT: increasing age, longer SLE duration, minority status, higher BMI, male sex, increased creatinine clearance, higher Lp(a), proteinuria, azathioprine use, and prednisone dose. Azathioprine use (P=0.005 for mean-mean common; P=0.102 for mean-max model) and male sex (P< 0.001) were both associated with increases in mean-max CIMT. Moderate dose prednisone (0.15–0.4 mg/kg/day) was associated with decreases in mean-max CIMT (P=0.024) while high or low dose prednisone was associated with mean-mean common CIMT (P=0.021) or 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 Lp(a) (P=0.005) were associated with increased mean-max CIMT.
Traditional as well as non-traditional risk factors are associated with increased CIMT in pediatric SLE patients in this cohort. Azathioprine treatment was associated with increased CIMT. The relationship of CIMT with prednisone dose may not be linear.
PMCID: PMC2770725  PMID: 19404953
9.  High density genotyping of STAT4 gene reveals multiple haplotypic associations with Systemic Lupus Erythematosus in different racial groups 
Arthritis and rheumatism  2009;60(4):1085-1095.
Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disorder with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in SLE pathogenesis. STAT1 and STAT4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for SLE susceptibility.
Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 genes on chromosome 2 were genotyped using Illumina platform as a part of extensive association study in a large collection of 9923 lupus cases and controls from different racial groups. DNA from patients and controls was obtained from peripheral blood. Principal component analyses and population based case-control association analyses were performed and the p values, FDR q values and Odds ratios with 95% confidence intervals (95% CIs) were calculated.
We observed strong genetic associations with SLE and multiple SNPs located within the STAT4 gene in different ethnicities (Fisher combined p= 7.02×10−25). In addition to strong confirmation of the association in the 3rd intronic region of this gene reported previously, we identified additional haplotypic association across STAT4 gene and in particular a common risk haplotype that is found in multiple racial groups. In contrast, only a relatively weak suggestive association was observed with STAT1, probably due to the proximity to STAT4.
Our findings indicate that the STAT4 gene is likely to be a crucial component in SLE pathogenesis among multiple racial groups. The functional effects of this association, when revealed, might improve our understanding of the disease and provide new therapeutic targets.
PMCID: PMC2776081  PMID: 19333953
The Journal of rheumatology  2008;35(12):2430-2438.
Melanoma-associated antigen gene B2 (MAGE-B2) encodes an embryonic antigen normally silenced after birth except in testis and placenta. We identified the MAGE-B2 gene and autoantibodies in pediatric patients with systemic lupus erythematosus (SLE) glomerulonephritis. Our purpose herein was to determine the prevalence of MAGE-B2 autoantibodies in association with active SLE, as well as to infer a pathogenetic role of MAGE-B2 protein through its distribution in cells and tissues.
A cross-sectional study analyzed the frequency of MAGE-B2 autoantibodies in 40 pediatric SLE patients, 23 adult controls, and 16 pediatric juvenile rheumatoid arthritis (JRA) patients using Western blots containing recombinant MAGE-B2. SLE disease activity index 2000 (SLEDAI-2K) and British Isles Lupus Assessment Group (BILAG) index measured SLE disease activity. Tissue distribution of MAGE-B2 protein was also assessed by immunohistochemistry, immunofluorescence, and Western blots.
Seventeen (43%) of 40 pediatric SLE patients had MAGE-B2 autoantibodies as compared to 0 of 16 JRA patients and 2 of 23 adult controls. SLE disease activity was significantly higher in MAGE-B2 autoantibody-positive vs. autoantibody-negative patients (SLEDAI-2K: mean 10.9 vs. 5.2, p=0.013; BILAG: mean 15.3 vs. 6.3, p=0.023). Active nephritis was more prevalent (60% vs. 24%) in MAGE-B2 autoantibody-positive SLE patients. MAGE-B2 protein was visualized in SLE kidney proximal convoluted tubules and in tumor epithelial cells, but not in lymphoblastoid cells.
MAGE-B2 autoantibody appears to be a clinically relevant biomarker for pediatric SLE disease activity and nephritis.
PMCID: PMC2765927  PMID: 19004030
Systemic lupus erythematosus; MAGE-B2; autoantibody; disease biomarker; glomerulonephritis; pediatric
11.  Plasmin Immunization Preferentially Induces IgG-Anticardiolipin Antibodies That Are Potentially Prothrombotic in MRL/MpJ Mice 
Arthritis and rheumatism  2009;60(10):3108-3117.
To test the hypothesis, utilizing 2 experimental mouse models, that plasmin is an important autoantigen that drives the production of certain IgG–anticardiolipin (aCL) antibodies in patients with the antiphospholipid syndrome.
BALB/cJ and MRL/MpJ mice were immunized with Freund’s complete adjuvant in the presence or absence of human plasmin. The mouse sera were analyzed for production of IgG-antiplasmin, IgG-aCL, and IgG–anti–β2-glycoprotein I (anti-β2GPI) antibodies. IgG monoclonal antibodies (mAb) were generated from the plasmin-immunized MRL/MpJ mice with high titers of aCL, and these 10 mAb were studied for their binding properties and functional activity in vitro.
Plasmin-immunized BALB/cJ mice produced high titers of IgG-antiplasmin only, while plasmin-immunized MRL/MpJ mice produced high titers of IgG-antiplasmin, IgG-aCL, and IgG–anti-β2GPI. Both strains of mice immunized with the adjuvant alone did not develop IgG-antiplasmin or IgG-aCL. All 10 of the IgG mAb bound to human plasmin and cardiolipin, while 4 of 10 bound to β2GPI, 3 of 10 bound to thrombin, and 4 of 10 bound to the activated coagulation factor X (FXa). Functionally, 4 of the 10 IgG mAb inhibited plasmin activity, 1 of 10 hindered inactivation of thrombin by antithrombin III (AT), and 2 of 10 inhibited inactivation of FXa by AT.
Plasmin immunization leads to production of the IgG mAb antiplasmin, aCL, and anti-β2GPI in MRL/MpJ mice, but leads to production of only IgG-antiplasmin in BALB/cJ mice. IgG mAb generated from the plasmin-immunized MRL/MpJ mice bind to various antigens and exhibit procoagulant activity in vitro. These results suggest that plasmin may drive the potentially prothrombotic activities of aCL in genetically susceptible individuals.
PMCID: PMC2775083  PMID: 19790056
12.  Type III Mixed Cryoglobulinemia and Antiphospholipid Syndrome in a Patient With Partial DiGeorge Syndrome 
We studied a 14 year-old boy with partial DiGeorge syndrome (DGS), status post complete repair of Tetralogy of Fallot, who developed antiphospholipid syndrome (APS) and type III mixed cryoglobulinemia. He presented with recurrent fever and dyspnea upon exertion secondary to right pulmonary embolus on chest computed tomography (CT). Coagulation studies revealed homozygous methylene tetrahydrofolate reductase 677TT mutations, elevated cardiolipin IgM antibodies, and elevated β2-glycoprotein I IgM antibodies. Infectious work-up revealed only positive anti-streptolysin O (ASO) and anti-DNAse B titers. Autoimmune studies showed strongly positive anti-platelet IgM, elevated rheumatoid factor (RF), and positive cryocrit. Renal biopsy for evaluation of proteinuria and hematuria showed diffuse proliferative glomerulonephritis (DPGN) with membranoproliferative features consistent with cryoglobulinemia. Immunofixation showed polyclonal bands. Our patient was treated successfully with antibiotics, prednisone, and mycophenolate mofetil (MMF). This is the first report of a patient with partial DGS presenting with APS and type III mixed cryoglobulinemia possibly due to Streptococcal infection.
PMCID: PMC2270767  PMID: 17162366

Results 1-12 (12)