Faculty Bibliography

Atherosclerotic cardiovascular disease (ASCVD) contributes to morbidity and mortality in systemic lupus erythematosus (SLE). Immunologic derangements may disrupt cholesterol balance in vessel wall monocytes/macrophages and endothelium. We determined whether lupus plasma impacts expression of cholesterol 27-hydroxylase, an anti-atherogenic cholesterol-degrading enzyme that promotes cellular cholesterol efflux, in THP-1 human monocytes and primary human aortic endothelial cells (HAEC). THP-1 monocytes and HAEC were incubated in medium containing SLE patient plasma or apparently healthy control human plasma (CHP). SLE plasma decreased 27-hydroxylase message in THP-1 monocytes by 47 +/- 8% (p < 0.008) and in HAEC by 51 +/- 5.5% (n = 5, p < 0.001). THP-1 macrophages were incubated in 25% lupus plasma or CHP and cholesterol-loaded (50 microg ml(-1) acetylated low density lipoprotein). Lupus plasma more than doubled macrophage foam cell transformation (74 +/- 3% vs. 35 +/- 3% for CHP, n = 3, p < 0.001). Impaired cholesterol homeostasis in SLE provides further evidence of immune involvement in atherogenesis. Strategies to inhibit or reverse arterial cholesterol accumulation may benefit SLE patients

Purpose: Coagulation is one of the first pathways to be elicited by vascular injury, and its activation is followed by proinflammatory phenomena, in part due to loss of the anti-inflammatory activity of both the Protein C pathway and membrane Endothelial Protein C receptor (mEPCR). It has been recently demonstrated that mEPCR is highly expressed in the cortical peritubular capillaries of kidneys from patients (pts) with active lupus nephritis compared to normal human kidney. Profound upregulation of mEPCR was observed even in areas absent tubulointerstitial damage. This study addressed the hypothesis that changes in the microvasculature extend beyond the clinically targeted organ and that dysregulation is a fundamental characteristic of SLE. Methods: The study included SLE pts in whom renal disease was considered active as assessed by proteinuria and urinary sediment. Renal biopsies were performed in all pts. Thirty skin biopsies from non-lesional nonsunexposed skin (buttocks) were obtained in 26 pts (23 females, 3 males) and five healthy controls (4 females, 1 male). The paraffin skin sections were individually stained with specific antibodies against mEPCR and adiponectin (protective markers), ICAM-1 (proinflammatory) and CD31 (pan endothelial marker). Immunohistochemistry (IHC) was scored by counting peroxidase-brown labeled blood vessels (10-20 microns in diameter) without knowledge of the clinical information associated with the biopsy. The number of blood vessels with an intensity of at least 1+ were quantitatively scored with ranges 1-12. To account for the number of blood vessels per slide, the CD31 count had to be 12 to be included in the analysis. Results: The 28 renal biopsies comprised the following ISN/RPS classifications: 4 Class III, 7 Class IV, 8 Class V, I Class VI, 3 Class III/V, 3 Class IV/V. Nineteen percent of the pts had a GFR <60 (mean GFR, 82 ml/min). Abnormal laboratory values for complement and anti-dsDNA antibodies were reported in 72% and 75% of pts, respectively. Nephrotic range proteinuria was present in 37%. For IHC skin assessments of the controls, the mean score for mEPCR was 1 (highest 2), ICAM-1 was 4 (highest 7) and adiponectin was 1 (highest 2). In 17/25 (68%) of the SLE non-lesional non-sun exposed skin sections, mEPCR was expressed above the highest control. In 16/30 (53%) ICAM-1 staining exceeded 7. In contrast, only 6/25 (19%) expressed adiponectin above 2. For each specific stain there were no apparent differences between biopsy class, degree of proteinuria, presence of anti dsDNA or low complement levels. However, pts with mEPCR staining above 2 had higher GFR measurements than those with staining < 2 (88 ml/min +/- 31 versus 53 +/- 32, p= 0.0168). In contrast, GFR was unrelated to ICAM-1 and adiponectin expression. Conclusion: These data are consistent with the notion that there is widespread activation of the microvasculature. The capacity of endothelial cells to utilize anticoagulation pathways is not restricted to the kidney and expression of mEPCR in the microcirculation likely represents an attempt to limit microvascular inflammation in kidney and skin

PURPOSE: It was hypothesised that the coding variant (R77H), rs1143679, within ITGAM could predict specific clinical manifestations associated with systemic lupus erythematosus (SLE). METHOD: To assess genetic association, 2366 patients with SLE and 2931 unaffected controls with European ancestry were analysed. The patients with SLE were coded by the presence or absence of individual American College of Rheumatology criteria. Logistic regression and Pearson chi(2) tests were used to assess statistical significance. RESULTS: For overall case-control analysis, a highly significant association was detected (p=2.22x10-21, OR 1.73). Using case-only analysis, a significant association was detected with renal criteria (p=0.0003), discoid rash (p=0.02) and immunological criteria (p=0.04). When patients with SLE were compared with healthy controls, the association became stronger for renal (p=4.69x10-22, OR 2.15), discoid (p=1.77x10-14, OR 2.03) and immunological (p=3.49x10-22, OR 1.86) criteria. Risk allele frequency increased from 10.6% (controls) to 17.0% (SLE), 20.4% (renal), 18.1% (immunological) and 19.5% (discoid). CONCLUSION: These results show a strong association between the risk allele (A) at rs1143679 and renal disease, discoid rash and immunological manifestations of SLE

OBJECTIVE: To evaluate the sensitivity and specificity of magnetic resonance imaging (MRI) in detecting erosions, bone edema, and synovitis in the metacarpophalangeal and wrist joints for rheumatoid arthritis (RA). METHODS: MRI scans of bilateral hands and wrists of 40 healthy subjects and 40 RA patients were performed using 0.2 T extremity-MRI and read blindly using a modified RA MRI (RAMRIS) system (no contrast injection, imaging in 1 plane only). To determine interreader reliability, images of 10 randomly selected subjects were read independently by a musculoskeletal radiologist. RESULTS: A total of 3360 bones were evaluated. Patients with RA had significantly more erosions as well as higher scores for bone edema and synovitis than healthy subjects. Age had a significant effect on the number of erosions in both groups. However, when disease duration was factored in, age became insignificant in RA patients. Erosion number correlated with positive rheumatoid factor and higher C-reactive protein values. The intraclass correlation coefficient between the 2 readers was 0.76 for individual joints and 0.88 for total scores. When having a single erosion was used as a positive test for RA, the sensitivity of this test was 90%, but the specificity was only 35%. Presence of bone edema provided 65% sensitivity and 82.5% specificity. Eliminating the lunate from scoring for bone edema increased the specificity to 87.5% while decreasing the sensitivity to 62.5%. CONCLUSION: While MRI is a highly sensitive tool for identifying and tracking the progression of erosions, erosions detected by MRI with measures commonly used in a rheumatologist's office (no contrast, imaging in 1 plane) provide low specificity for RA. Bone marrow edema is the most specific MRI lesion for RA in this setting

INTRODUCTION: The TAM (tyro 3, axl, mer) kinases are key regulators of innate immunity and are important in the phagocytosis of apoptotic cells. Gas6 and protein S are ligands for these TAM kinases and bind to phosphatidyl serine residues exposed during apoptosis. In animal models, absence of TAM kinases is associated with lupus-like disease. To test whether human systemic lupus erythematosus (SLE) patients might have deficient levels of TAM ligands, we measured Gas 6 and protein S levels in SLE. METHODS: 107 SLE patients were recruited. Of these, 45 SLE patients were matched age, gender and ethnicity with normal controls (NC). Gas6 and free protein S were measured with sandwich enzyme linked immunosorbent assays (ELISAs). RESULTS: Overall, the plasma concentrations of Gas6 and free protein S were not different between 45 SLE patients and 45 NC. In SLE patients, the levels of free protein S were positively correlated with age (r = 0.2405, P = 0.0126), however those of Gas6 were not. There was no correlation between the concentrations of Gas6 and free protein S in individuals. Levels of free protein S were significantly lower in SLE patients with a history of serositis, neurologic disorder, hematologic disorder and immunologic disorder. Gas6 levels were elevated in patients with a history of neurologic disorder. The SLE patients with anti-Sm or anti-cardiolipin IgG showed lower free protein S levels. Circulating free protein S was positively correlated with complement component 3 (C3) (r = 0.3858, P < 0.0001) and complement component 4 (C4) (r = 0.4275, P < 0.0001). In the patients with active BILAG hematologic involvement, the levels of free protein S were lower and those of Gas6 were higher. CONCLUSIONS: In SLE, free protein S was decreased in patients with certain types of clinical history and disease activity. Levels of free protein S were strongly correlated with C3 and C4 levels. Gas6 levels in SLE patients differed little from levels in NC, but they were elevated in the small numbers of patients with a history of neurological disease. The correlation of decreased protein S levels with lupus disease activity is consistent with a role for the TAM receptors in scavenging apoptotic cells and controlling inflammation. Protein S appears more important functionally in SLE patients than Gas6 in this regard

OBJECTIVE: B cells are likely to contribute to the pathogenesis of systemic lupus erythematosus (SLE), and rituximab induces depletion of B cells. The Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trial tested the efficacy and safety of rituximab versus placebo in patients with moderately-to-severely active extrarenal SLE. METHODS: Patients entered with >or=1 British Isles Lupus Assessment Group (BILAG) A score or >or=2 BILAG B scores despite background immunosuppressant therapy, which was continued during the trial. Prednisone was added and subsequently tapered. Patients were randomized at a ratio of 2:1 to receive rituximab (1,000 mg) or placebo on days 1, 15, 168, and 182. RESULTS: In the intent-to-treat analysis of 257 patients, background treatment was evenly distributed among azathioprine, mycophenolate mofetil, and methotrexate. Fifty-three percent of the patients had >or=1 BILAG A score at entry, and 57% of the patients were categorized as being steroid dependent. No differences were observed between placebo and rituximab in the primary and secondary efficacy end points, including the BILAG-defined response, in terms of both area under the curve and landmark analyses. A beneficial effect of rituximab on the primary end point was observed in the African American and Hispanic subgroups. Safety and tolerability were similar in patients receiving placebo and those receiving rituximab. CONCLUSION: The EXPLORER trial enrolled patients with moderately-to-severely active SLE and used aggressive background treatment and sensitive cutoffs for nonresponse. No differences were noted between placebo and rituximab in the primary and secondary end points. Further evaluation of patient subsets, biomarkers, and exploratory outcome models may improve the design of future SLE clinical trials

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by increased type I interferons (IFNs) and multiorgan inflammation frequently targeting the skin. IFN-kappa is a type I IFN expressed in skin. A pooled genome-wide scan implicated the IFNK locus in SLE susceptibility. We studied IFNK single nucleotide polymorphisms (SNPs) in 3982 SLE cases and 4275 controls, composed of European (EA), African-American (AA), and Asian ancestry. rs12553951C was associated with SLE in EA males (odds ratio = 1.93, P = 2.5 x 10(-4)), but not females. Suggestive associations with skin phenotypes in EA and AA females were found, and these were also sex-specific. IFNK SNPs were associated with increased serum type I IFN in EA and AA SLE patients. Our data suggest a sex-dependent association between IFNK SNPs and SLE and skin phenotypes. The serum IFN association suggests that IFNK variants could influence type I IFN producing plasmacytoid dendritic cells in affected skin

OBJECTIVE:The aim of this review is to provide an up-to-date overview of treatment approaches for systemic lupus erythematosus (SLE), highlighting the multiplicity and heterogeneity of clinical symptoms that underlie therapeutic decisions. Discussion will focus on the spectrum of currently available therapies, their mechanisms and associated side-effects. Finally, recent developments with biologic treatments including rituximab, epratuzumab, tumor necrosis factor (TNF) inhibitors, and belimumab, will be discussed. RESEARCH DESIGN AND METHODS/METHODS:A MEDLINE literature search for 'systemic lupus erythematosus' and 'damage' and 'treatment' was undertaken for 1996-2008. Secondary citations were obtained from selected manuscripts. Individual case studies were excluded. FINDINGS/RESULTS:SLE is an autoimmune disease involving multiple organ systems, a clinical pattern of flares and remissions, and the presence of anti-nuclear autoantibodies. Whereas early symptoms most frequently involve the skin and joints, disease morbidity and mortality are usually associated with cardiovascular events and damage to major organs, particularly the kidneys. Many of the current therapeutic options are considered to be inadequate because of toxicities, accrual of organ damage, and insufficient control of the underlying disease pathology. Improved understanding of SLE pathogenesis and immunology has led to the identification of new treatment targets. Current interest is mainly focused on the targeted immunosuppressive actions provided by biologic therapy. Although the potential long-term beneficial or harmful effects of the new molecular treatments are unclear, their precise molecular targeting may reveal key relationships within the immune system and advance the cause of individualized molecular medicine. CONCLUSIONS:Biologic compounds that target specific immunologic mechanisms offer a new paradigm in the treatment of SLE, one that may, at best, reverse the course of the disease and, at the very least, might provide some new alternatives to reduce symptoms and limit tissue damage without undue contribution to overall morbidity and mortality.