Efficacy and Safety of Ustekinumab in Patients With Active Systemic Lupus Erythematosus: Results of a Phase II Open-label Extension Study.

OBJECTIVE: To evaluate the long-term efficacy and safety of ustekinumab through 2 years in patients with active systemic lupus erythematosus (SLE). METHODS: This was a placebo-controlled (week 24), phase II study in 102 patients with seropositive active SLE. Patients were randomized to ustekinumab (approximately 6 mg/kg single intravenous infusion, then subcutaneous [SC] injections of 90 mg every 8 weeks) or placebo, added to background therapy. Placebo patients initiated ustekinumab (90 mg SC every 8 weeks) at week 24. Patients could enter an optional open-label study extension after week 40 (final ustekinumab administration at week 104). Efficacy assessments included Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), SLEDAI-2K Responder Index-4 (SRI-4), physician global assessment (PGA), and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Observed data are reported for the extension period. The final efficacy assessment was at week 112; safety was monitored through week 120. RESULTS: In this subset of patients who entered the study extension, 24 in the ustekinumab group and 14 in the placebo crossover group completed study treatment. At week 112, 79% and 92%, respectively, had an SRI-4 response; 92% in both groups had ≥ 4-point improvement from baseline in SLEDAI-2K score; 79% and 93%, respectively, had ≥ 30% improvement from baseline in PGA; 86% and 91%, respectively, had ≥ 50% improvement in active joint (pain and inflammation) count; and 79% and 100%, respectively, had ≥ 50% improvement in CLASI Activity Score. No deaths, malignancies, opportunistic infections, or tuberculosis cases occurred. Safety events were consistent with the known ustekinumab safety profile. CONCLUSION: Of the 46 patients who entered the voluntary extension of this phase II study, clinical benefit in global and organ-specific SLE activity measures was observed with ustekinumab through 2 years with no new or unexpected safety findings. [ClinicalTrials.gov: NCT02349061].

Cellular and Molecular Phenotypes of pConsensus Peptide (pCons) Induced CD8+ and CD4+ Regulatory T Cells in Lupus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with widespread inflammation, immune dysregulation, and is associated with the generation of destructive anti-DNA autoantibodies. We have shown previously the immune modulatory properties of pCons peptide in the induction of both CD4+ and CD8+ regulatory T cells which can in turn suppress development of the autoimmune disease in (NZB/NZW) F1 (BWF1) mice, an established model of lupus. In the present study, we add novel protein information and further demonstrate the molecular and cellular phenotypes of pCons-induced CD4+ and CD8+ Treg subsets. Flow cytometry analyses revealed that pCons induced CD8+ Treg cells with the following cell surface molecules: CD25highCD28high and low subsets (shown earlier), CD62Lhigh, CD122low, PD1low, CTLA4low, CCR7low and 41BBhigh. Quantitative real-time PCR (qRT-PCR) gene expression analyses revealed that pCons-induced CD8+ Treg cells downregulated the following several genes: Regulator of G protein signaling (RGS2), RGS16, RGS17, BAX, GPT2, PDE3b, GADD45ß and programmed cell death 1 (PD1). Further, we confirmed the down regulation of these genes by Western blot analyses at the protein level. To our translational significance, we showed herein that pCons significantly increased the percentage of CD8+FoxP3+ T cells and further increased the mean fluorescence intensity (MFI) of FoxP3 when healthy peripheral blood mononuclear cells (PBMCs) are treated with pCons (10 µg/ml, for 24-48 hours). In addition, we found that pCons reduced apoptosis in CD4+ and CD8+ T cells and B220+ B cells of BWF1 lupus mice. These data suggest that pCons stimulates cellular, immunological, and molecular changes in regulatory T cells which in turn protect against SLE autoimmunity.

Interferon Genes Are Influenced by 17ß-Estradiol in SLE.

Recent evidence suggests the existence of a nexus between inflammatory pathways and the female sex hormone 17ß-estradiol, resulting in increased interferon-stimulated genes (ISGs), autoantibodies, and dysregulation of immune cells in SLE. However, the molecular mechanisms and the effect of estradiol on candidate target genes and their pathways remains poorly understood. Our previous work suggests that female SLE patients have increased estradiol levels compared to healthy controls. In the present study, we explored the effects of 17ß-estradiol treatment on expression of IFN (interferons)-stimulated genes and pro-inflammatory cytokines/chemokines. We found significantly increased (5-10-fold) expression of IFN-regulated genes in healthy females. Furthermore, we found significantly increased plasma levels of IL-6, IL-12, IL-17, IL-18, stem cell factor (SCF), and IL-21/IL-23 in SLE patients compared to healthy controls, and those levels positively correlated with the plasma levels of 17ß-estradiol. In addition, levels of IL-21 positively correlated with the SLE disease activity index (SLEDAI) score of SLE patients. In vitro treatment of PBMCs from either SLE patients or healthy controls with 17ß-estradiol at physiological concentration (~50 pg/ml) also significantly increased secretion of many pro-inflammatory cytokines and chemokines (IL-6, IL-12, IL-17, IL-8, IFN-γ; MIP1α, and MIP1ß) in both groups. Further our data revealed that 17ß-estradiol significantly increased the percentage of CD3+CD69+ and CD3+IFNγ+ T cells; whereas, simultaneous addition of 17ß-estradiol and an ERα inhibitor prevented this effect. Collectively, our findings indicate that 17ß-estradiol participates in the induction of pro-inflammatory cytokines and chemokines and further influences interferon genes and pathways.

Effects of Peptide-Induced Immune Tolerance on Murine Lupus.

The regulation of autoimmunity and the molecular mechanisms by which different immune cells, including T cells, polymorphonuclear leukocytes (PMN-granulocytes), and B cells suppress autoimmune diseases is complex. We have shown previously that BWF1 lupus mice are protected from autoimmunity after i.v. injection or oral administration of tolerogenic doses of pCons, an artificial synthetic peptide based on sequences containing MHC class I and MHC class II determinants in the VH region of a J558-encoded BWF1 anti-DNA Ab. Several T cell subsets can transfer this tolerance. In this study, we determined the potential roles of granulocytes, B cells and regulatory T cells altered by pCons treatment in the BWF1 (NZB/NZW) mouse model of lupus. Immunophenotyping studies indicated that pCons treatment of BWF1 mice significantly increased CD4+FoxP3+ T cells, reduced the percent of B cells expressing CD19+CD5+ but increased the percent of CD19+CD1d+ regulatory B cells and increased the ability of the whole B cell population to suppress IgG anti-DNA production in vitro. pCons treatment significantly decreased the expression of CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) in CD8+ T cells. In addition, peptide administration modified granulocytes so they became suppressive. We co-cultured sorted naïve B cells from mice making anti-DNA Ab (supported by addition of sorted naive CD4+ and CD8+ T cells from young auto-antibody-negative BWF1 mice) with sorted B cells or granulocytes from tolerized mice. Both tolerized granulocytes and tolerized B cells significantly suppressed the production of anti-DNA in vitro. In granulocytes from tolerized mice compared to saline-treated littermate controls, real-time PCR analysis indicated that expression of interferon-induced TNFAIP2 increased more than 2-fold while Ptdss2 and GATA1 mRNA were up-regulated more than 10-fold. In contrast, expression of these genes was significantly down-regulated in tolerized B cells. Further, another IFN-induced protein, Bcl2, was reduced in tolerized B cells as determined by Western blot analyses. In contrast, expression of FoxP3 was significantly increased in tolerized B cells. Together, these data suggest that B cells and granulocytes are altered toward suppressive functions by in vivo tolerization of BWF1 mice with pCons and it is possible these cell types participate in the clinical benefits seen in vivo.

Maintenance of Efficacy and Safety of Ustekinumab Through One Year in a Phase II Multicenter, Prospective, Randomized, Double-Blind, Placebo-Controlled Crossover Trial of Patients With Active Systemic Lupus Erythematosus.

OBJECTIVE: To evaluate the efficacy and safety of ustekinumab through 1 year in a phase II trial in patients with systemic lupus erythematosus (SLE). METHODS: Eligible patients were diagnosed as having clinically active SLE (based on Systemic Lupus International Collaborating Clinics criteria), despite standard background therapy. Active disease was defined by an SLE Disease Activity Index 2000 (SLEDAI-2K) score of ≥6 as well as having ≥1 British Isles Lupus Assessment Group (BILAG) A organ domain score and/or ≥2 BILAG B organ domain scores present at screening. Patients (n = 102) were randomized (3:2) to receive either ustekinumab (~6 mg/kg of single intravenous infusion at week 0, then 90-mg subcutaneous injections every 8 weeks beginning at week 8) or a matching placebo added to standard therapy. At week 24, the placebo group crossed over to receive a subcutaneous 90-mg dose of ustekinumab every 8 weeks, and the original ustekinumab group continued to receive therapy through week 40. Maintenance of efficacy was assessed using the SLEDAI-2K, the SLE Responder Index 4 (SRI-4), physician global assessment, and mucocutaneous and joint disease measures in a modified intent-to-treat population. RESULTS: SRI-4 response rates were significantly greater in the ustekinumab group (62%) versus the placebo group (33%) in the week 24 primary end point analysis (P = 0.006) and were maintained at week 48 (63.3%) in the ustekinumab group. In the ustekinumab group, response rates across other disease measures were also maintained through week 48. Among patients in the placebo group who crossed over to ustekinumab treatment (n = 33), increased response rates across efficacy measures were noted. Among all ustekinumab-treated patients, 81.7% had ≥1 adverse event (AE), and 15.1% had ≥1 serious AE through week 56. No deaths, malignancies, opportunistic infections, or tuberculosis cases were observed. CONCLUSION: Ustekinumab provided sustained clinical benefit in patients with SLE through 1 year, with a safety profile consistent with other indications.

Use of Consensus Methodology to Determine Candidate Items for Systemic Lupus Erythematosus Classification Criteria.

OBJECTIVE: Given the complexity and heterogeneity of systemic lupus erythematosus (SLE), high-performing classification criteria are critical to advancing research and clinical care. A collaborative effort by the European League Against Rheumatism and the American College of Rheumatology was undertaken to generate candidate criteria, and then to reduce them to a smaller set. The objective of the current study was to select a set of criteria that maximizes the likelihood of accurate classification of SLE, particularly early disease. METHODS: An independent panel of international SLE experts and the SLE classification criteria steering committee (conducting SLE research in Canada, Mexico, United States, Austria, Germany, Greece, France, Italy, and Spain) ranked 43 candidate criteria. A consensus meeting using nominal group technique (NGT) was conducted to reduce the list of criteria for consideration. RESULTS: The expert panel NGT exercise reduced the candidate criteria for SLE classification from 43 to 21. The panel distinguished potential "entry criteria," which would be required for classification, from potential "additive criteria." Potential entry criteria were antinuclear antibody (ANA) ≥ 1:80 (HEp-2 immunofluorescence), and low C3 and/or low C4. The use of low complement as an entry criterion was considered potentially useful in cases with negative ANA. Potential additive criteria included lupus nephritis by renal biopsy, autoantibodies, cytopenias, acute and chronic cutaneous lupus, alopecia, arthritis, serositis, oral mucosal lesions, central nervous system manifestations, and fever. CONCLUSION: The NGT exercise resulted in 21 candidate SLE classification criteria. The next phases of SLE classification criteria development will require refinement of criteria definitions, evaluation of the ability to cluster criteria into domains, and evaluation of weighting of criteria.

Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study.

BACKGROUND: Ustekinumab is a monoclonal antibody targeting interleukin (IL)-12 and IL-23 and is approved for the treatment of plaque psoriasis, psoriatic arthritis, and Crohn's disease. IL-12 and IL-23 have been implicated in systemic lupus erythematosus. We aimed to assess the efficacy and safety of ustekinumab for the treatment of systemic lupus erythematosus in patients with moderate-to-severe disease activity despite conventional treatment. METHODS: This was a multicentre, double-blind, phase 2, randomised, controlled trial of adult patients with active, seropositive systemic lupus erythematosus, done at 44 private practices and academic centres in Argentina, Australia, Germany, Hungary, Mexico, Poland, Spain, Taiwan, and the USA. Eligible adults were aged 18-75 years, weighed at least 35 kg, and had a diagnosis of systemic lupus erythematosus at least 3 months before the first administration of study drug. Eligible patients were randomly assigned (3:2) to the ustekinumab or placebo group using an interactive web response system with stratification by skin biopsy, lupus nephritis presence, baseline systemic lupus erythematosus medications and systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K) score combined factor, site, region, and race. Patients and investigators were masked to treatment allocation. Patients received an intravenous infusion of ustekinumab (260 mg for patients weighing 35-55 kg, 390 mg for patients weighing >55 kg and ≤85 kg, and 520 mg for patients weighing >85 kg) followed by subcutaneous injections of ustekinumab 90 mg every 8 weeks or intravenous infusion of placebo at week 0 followed by subcutaneous injections of placebo every 8 weeks, both in addition to standard-of-care therapy. The primary endpoint was the proportion of patients achieving a SLEDAI-2K responder index-4 (SRI-4) response at week 24. Efficacy analyses were done in a modified intention-to-treat population of patients who received at least one dose (partial or complete, intravenous or subcutaneous) of their randomly assigned study treatment. Safety analyses were done in all patients who received at least one dose of study treatment, regardless of group assignment. This study is registered at ClinicalTrials.gov, number NCT02349061. FINDINGS: Between Oct 6, 2015, and Nov 30, 2016, 166 patients were screened, of whom 102 were randomly assigned to receive ustekinumab (n=60) or placebo (n=42). At week 24, 37 (62%) of 60 patients in the ustekinumab group and 14 (33%) of 42 patients in the placebo group achieved an SRI-4 response (percentage difference 28% [95% CI 10-47], p=0·006). Between week 0 and week 24, 47 (78%) of 60 patients in the ustekinumab group and 28 (67%) of 42 patients in the placebo group had at least one adverse event. Infections were the most common type of adverse event (27 [45%] in the ustekinumab group vs 21 [50%] in the placebo group). No deaths or treatment-emergent opportunistic infections, herpes zoster, tuberculosis, or malignancies occurred between weeks 0-24. INTERPRETATION: The addition of ustekinumab to standard-of-care treatment resulted in better efficacy in clinical and laboratory parameters than placebo in the treatment of active systemic lupus erythematosus and had a safety profile consistent with ustekinumab therapy in other diseases. The results of this study support further development of ustekinumab as a novel treatment in systemic lupus erythematosus. FUNDING: Janssen Research & Development, LLC.

Th17 cells in inflammation and autoimmunity.

T helper 17 (Th17), a distinct subset of CD4(+) T cells with IL-17 as their major cytokine, orchestrate the pathogenesis of inflammatory and autoimmune diseases. Dysregulated Th17 cells contribute to inflammatory and autoimmune diseases. Candidate biologics are in development for targeting IL-17, IL-17 receptors or IL-17 pathways. Several drugs that impact the IL-17 pathway are already in clinical trials for the treatment of autoimmune diseases. In this review we provide evidence for the role of Th17 cells in immune-mediated diseases. An understanding of the role of Th17 in these conditions will provide important insights and unravel novel targets for therapeutic intervention.

Laquinimod delays and suppresses nephritis in lupus-prone mice and affects both myeloid and lymphoid immune cells.

OBJECTIVE: Lupus nephritis depends on autoantibody deposition and activation of multiple immune cell types that promote kidney inflammation, including lymphocytes and monocyte/macrophages. Laquinimod, currently in clinical trials for multiple sclerosis and lupus nephritis, reduces infiltration of inflammatory cells into the spinal cord in experimental autoimmune encephalomyelitis. Activated monocyte/macrophages infiltrate the kidneys during nephritis in systemic lupus erythematosus (SLE). We undertook this study to determine whether using laquinimod to reduce monocyte/macrophage-driven tissue damage as well as to alter lymphocytes in SLE nephritis could have greater therapeutic benefit than current treatments that primarily affect lymphocytes, such as mycophenolate mofetil (MMF). METHODS: To test laquinimod efficacy, we used the (NZB × NZW)F1 mouse model of SLE, in which disease manifests as nephritis. Preventive and therapeutic studies were performed to determine whether laquinimod could prevent or delay nephritis, as measured by proteinuria, serum creatinine, survival, and renal pathology. Spleen and kidney leukocyte populations and suppression assays were analyzed by flow cytometry. RESULTS: Laquinimod prevented or delayed lupus manifestations at levels equal to or better than MMF. Laquinimod treatment was associated with reduced numbers of monocyte/macrophages, dendritic cells, and lymphocytes, as well as with induction of myeloid-derived suppressor cells in spleens and kidneys. Laquinimod suppressed macrophage-secreted tumor necrosis factor α and induced production of interleukin-10 (IL-10). In addition, laquinimod suppressed interferon-γ and IL-17 production by lymphocytes and down-regulated expression of activation/costimulatory markers on antigen-presenting cells. CONCLUSION: The effects of laquinimod on myeloid and lymphoid cells may contribute to improvements in (NZB × NZW)F1 mouse survival, proteinuria, and glomerulonephritis. Future development of laquinimod as a therapeutic agent for lupus nephritis is promising.

A panel of biomarkers is associated with increased risk of the presence and progression of atherosclerosis in women with systemic lupus erythematosus.

OBJECTIVE: An increased frequency of atherosclerosis (ATH) in systemic lupus erythematosus (SLE) is well-documented but not fully explained by the presence of traditional cardiac risk factors. Several nontraditional biomarkers, including proinflammatory high-density lipoprotein (piHDL) and leptin, have been individually associated with subclinical ATH in SLE. The aim of this study was to examine whether these and other biomarkers can be combined into a risk profile, the Predictors of Risk for Elevated Flares, Damage Progression, and Increased Cardiovascular Disease in Patients with SLE (PREDICTS), that could be used to better predict future progression of ATH. METHODS: In total, 210 patients with SLE and 100 age-matched healthy control subjects (all women) participated in this prospective cohort study. The longitudinal presence of carotid plaque and intima-media thickness (IMT) were measured at baseline and followup (mean ± SD 29.6 ± 9.7 months). RESULTS: At followup, carotid plaque was present in 29% of SLE patients. Factors significantly associated with plaque, determined using Salford Predictive Modeling and multivariate analysis, included age ≥48 years (odds ratio [OR] 4.1, P = 0.002), high piHDL function (OR 9.1, P < 0.001), leptin levels ≥34 ng/dl (OR 7.3, P = 0.001), plasma soluble TWEAK levels ≥373 pg/ml (OR 28.8, P = 0.004), and history of diabetes (OR 61.8, P < 0.001). Homocysteine levels ≥12 µmoles/liter were also a predictor. However, no single variable demonstrated an ideal combination of good negative predictive values (NPVs), positive predictive values (PPVs), sensitivity, and specificity. A high-risk PREDICTS profile was defined as ≥3 positive biomarkers or ≥1 positive biomarker plus a history of diabetes; for high-risk SLE patients, the PPV was 64%, NPV was 94%, sensitivity was 89%, and specificity was 79%. In multivariate analysis, SLE patients with the high-risk profile had 28-fold increased odds for the longitudinal presence of plaque (P < 0.001) and increased progression of IMT (P < 0.001). CONCLUSION: A high-risk PREDICTS score confers 28-fold increased odds of the presence of any current, progressive, or acquired carotid plaque, both in patients with SLE and in control subjects, and is significantly associated with higher rates of IMT progression.

The role of miRNA in inflammation and autoimmunity.

miRNAs are small non-coding RNA molecules that modulate the expression of multiple protein-encoding genes at the post-transcriptional level. They have recently been recognized as powerful regulators of numerous genes and pathways in the pathogenesis of inflammatory and autoimmune diseases. The targets of most miRNAs remain unknown and their roles in biological processes such as cell differentiation, proliferation, and death (apoptosis) are not clearly understood. In this review we will discuss how certain candidate miRNAs affect inflammatory and immune mediated diseases by regulating their cellular and molecular targets. We focused the influence of gender and sex hormones on miRNA. We believe that understanding the role of miRNAs could shed light on the cause and progression of many inflammatory and autoimmune diseases and eventually lay the groundwork for therapeutic options.

Blockade of programmed death-1 in young (New Zealand Black x New Zealand White)F1 mice promotes the suppressive capacity of CD4+ regulatory T cells protecting from lupus-like disease.

Programmed death-1 (PD-1) usually acts as a negative signal for T cell activation, and its expression on CD8(+)Foxp3(+) T cells is required for their suppressive capacity. In this study, we show that PD-1 signaling is required for the maintenance of functional regulatory CD4(+)CD25(+)Foxp3(+) regulatory T cells (CD4(+) T(reg)) that can control autoimmunity in (New Zealand Black × New Zealand White)F1 lupus mice. PD-1 signaling induced resistance to apoptosis and prolonged the survival of CD4(+) T(reg). In vivo, the blockade of PD-1 with a neutralizing Ab reduced PD-1 expression on CD4(+) T(reg) (PD1(lo)CD4(+) T(reg)). PD1(lo)CD4(+) T(reg) had an increased ability to promote B cell apoptosis and to suppress CD4(+) Th as compared with CD4(+) T(reg) with elevated PD-1 expression (PD1(hi)CD4(+) T(reg)). When PD-1 expression on CD4(+) T(reg) was blocked in vitro, PD1(lo)CD4(+) T(reg) suppressed B cell production of IgG and anti-dsDNA Ab. Finally, in vitro studies showed that the suppressive capacity of CD4(+) T(reg) depended on PD-1 expression and that a fine-tuning of the expression of this molecule directly affected cell survival and immune suppression. These results indicate that PD-1 expression has multiple effects on different immune cells that directly contribute to a modulation of autoimmune responses.

Plasma levels of osteopontin identify patients at risk for organ damage in systemic lupus erythematosus.

INTRODUCTION: 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. METHODS: 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). RESULTS: 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%). CONCLUSION: 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.

Accelerated atherosclerosis in patients with SLE--mechanisms and management.

Rapid-onset cardiovascular disease (CVD) is a major concern for many patients with systemic lupus erythematosus (SLE). Cardiovascular events occur more frequently and with earlier onset in patients with SLE compared with healthy individuals. Traditional risk factors, such as altered lipid levels, aging and smoking, do not fully explain this increased risk of CVD, strongly suggesting that autoimmunity contributes to accelerated atherosclerosis. Altered immune system function is recognized as the primary contributor to both the initiation and progression of atherosclerosis. Multiple manifestations of autoimmunity, including changes in cytokine levels and innate immune responses, autoantibodies, adipokines, dysfunctional lipids, and oxidative stress, could heighten atherosclerotic risk. In addition, multiple SLE therapeutics seem to affect the development and progression of atherosclerosis both positively and negatively. SLE-specific cardiovascular risk factors are beginning to be discovered by several groups, and development of a comprehensive, clinically feasible biomarker panel could be invaluable for identification and treatment of patients at risk of developing accelerated atherosclerosis. Here, we discuss the epidemiology of CVD in SLE and the implications of immune system dysfunction on the development and progression, monitoring and treatment of atherosclerosis in individuals with this disease.

Tolerance induced by anti-DNA Ig peptide in (NZB×NZW)F1 lupus mice impinges on the resistance of effector T cells to suppression by regulatory T cells.

We have previously shown that immune tolerance induced by the anti-DNA Ig peptide pCons in (NZB×NZW)F(1) (NZB/W) lupus mice prolonged survival of treated animals and delayed the appearance of autoantibodies and glomerulonephritis. Part of the protection conferred by pCons could be ascribed to the induction of regulatory T cells (T(Reg)) that suppressed the production of anti-DNA antibodies in a p38 MAPK-dependent fashion. Here we show that another effect of pCons in the induction of immune tolerance in NZB/W lupus mice is the facilitation of effector T cell suppression by T(Reg). These new findings indicate that pCons exerts protective effects in NZB/W lupus mice by differentially modulating the activity of different T cell subsets, implying new considerations in the design of T(Reg)-based approaches to modulate T cell autoreactivity in SLE.

Regulatory T cells in systemic lupus erythematosus (SLE); role of peptide tolerance.

Regulatory T cells play an important role in the maintenance and regulation of immune tolerance and in the prevention of autoimmunity. Recent studies have demonstrated a deficiency in number and function of regulatory T cells in lupus and other autoimmune diseases. This may contribute to immune dysregulations and a defect in self-tolerance mechanisms. How to balance and "reset" the immune response from harmful pro-inflammatory to beneficial anti-inflammatory is the current strategy of the research. In this regard, several studies have been performed with various peptides, drugs, steroids and epigenetic agents to induce or modify regulatory cells and some measure of success has been achieved in the animal model of SLE and with lupus patient cells. Challenges ahead include the heterogeneous nature, phenotype and function of regulatory cells and the difficulties in manipulation of regulatory function in healthy versus diseased states. In this review, we will provide some recent findings indicating challenges and potential benefits of targeting of regulatory T cells in lupus.

Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility.

Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the CFH-CFHRs region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic CFH SNP (rs6677604, in intron 11, P(meta) = 6.6×10(-8), OR = 1.18) and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, P(meta) = 2.9×10(-7), OR = 1.17) rather than to previously identified disease-associated CFH exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ~146 kb block extending from intron 9 of CFH to downstream of CFHR1. Within this block, the deletion of CFHR3 and CFHR1 (CFHR3-1Δ), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of CFHR3-1Δ (P(meta) = 3.2×10(-7), OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (P(meta) = 3.5×10(-4), OR = 1.14). These results suggested that the CFHR3-1Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of CFH, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE.

High plasma leptin levels confer increased risk of atherosclerosis in women with systemic lupus erythematosus, and are associated with inflammatory oxidised lipids.

BACKGROUND: Patients with systemic lupus erythematosus (SLE) are at increased risk of atherosclerosis, even after accounting for traditional risk factors. High levels of leptin and low levels of adiponectin are associated with both atherosclerosis and immunomodulatory functions in the general population. OBJECTIVE: To examine the association between these adipokines and subclinical atherosclerosis in SLE, and also with other known inflammatory biomarkers of atherosclerosis. METHODS: Carotid ultrasonography was performed in 250 women with SLE and 122 controls. Plasma leptin and adiponectin levels were measured. Lipoprotein a (Lp(a)), oxidised phospholipids on apoB100 (OxPL/apoB100), paraoxonase, apoA-1 and inflammatory high-density lipoprotein (HDL) function were also assessed. RESULTS: Leptin levels were significantly higher in patients with SLE than in controls (23.7±28.0 vs 13.3±12.9 ng/ml, p<0.001). Leptin was also higher in the 43 patients with SLE with plaque than without plaque (36.4±32.3 vs 20.9±26.4 ng/ml, p=0.002). After multivariate analysis, the only significant factors associated with plaque in SLE were leptin levels in the highest quartile (≥29.5 ng/ml) (OR=2.8, p=0.03), proinflammatory HDL (piHDL) (OR=12.8, p<0.001), age (OR=1.1, p<0.001), tobacco use (OR=7.7, p=0.03) and hypertension (OR=3.0, p=0.01). Adiponectin levels were not significantly associated with plaque in our cohort. A significant correlation between leptin and piHDL function (p<0.001), Lp(a) (p=0.01) and OxPL/apoB100 (p=0.02) was also present. CONCLUSIONS: High leptin levels greatly increase the risk of subclinical atherosclerosis in SLE, and are also associated with an increase in inflammatory biomarkers of atherosclerosis such as piHDL, Lp(a) and OxPL/apoB100. High leptin levels may help to identify patients with SLE at risk of atherosclerosis.