Search

To compare the incidence rates of malignancy among patients with psoriatic arthritis (PsA) and patients with rheumatoid arthritis (RA) in the Consortium of Rheumatology Researchers of North America (CORRONA) registry.We analyzed 2,970 patients with PsA (7,133 patient-years of followup) and 19,260 patients with RA (53,864 patient-years of followup). Using a standardized adjudication process, we identified 40 confirmed malignancies in the patients with PsA and 307 confirmed malignancies in those with RA. Incidence rates were calculated per 100 patient-years. Incidence rate ratios were estimated, with adjustment for age, sex, disease duration, body mass index, disease activity, year of enrollment, and medication use.The overall malignancy incidence per 100 patient-years was similar between patients with PsA and patients with RA (0.56 [95% confidence interval (95% CI) 0.40-0.76] and 0.56 [95% CI 0.50-0.63], respectively). Nonmelanoma skin cancer was the most common type of cancer in the overall cohort, with an incidence rate of 0.21 (95% CI 0.12-0.35) in PsA, and 0.20 (95% CI 0.17-0.24) in RA, with a calculated incidence rate ratio of 1.05 (95% CI 0.61-1.80; P = 0.85). Lymphoma rates were similar in PsA and RA (0.04 [95% CI 0.01-0.12] and 0.04 [95% CI 0.02-0.06], respectively; incidence rate ratio 1.00 [95% CI 0.17-3.11]; P = 0.67). The adjusted incidence rate ratio of malignancy in PsA versus RA was 1.17 (95% CI 0.82-1.69; P = 0.37).The incidence rates across malignancy subtypes were similar in the PsA and RA cohorts from a US registry.

Immunization of nonautoimmune BALB/c mice with multimeric DWEYSVWLSN, a peptide mimotope of DNA, induces anti-DNA and other lupus-associated Abs. To further investigate the pathogenesis of the autoantibody response induced by peptide immunization, we generated hybridomas from peptide-immunized mice that bound peptide, dsDNA, cardiolipin, Sm/ribonucleoprotein (RNP), or some combination of these Ags. Analysis of 24 IgM Abs led to the identification of three groups of Abs: 1) Abs reactive with peptide alone, 2) anti-peptide Abs cross-reactive with one or more autoantigens, and 3) autoantibodies that do not bind to peptide. The gene families and particular VH-VL combinations used in those hybridomas binding DNA were similar to those used in the anti-DNA response in spontaneous murine lupus. Another similarity to the spontaneous anti-DNA response was the generation of arginines in the complementarity-determining region-3 of DNA-binding hybridomas. Interestingly, one Ab had the VH-VL combination present in the original R4A anti-DNA Ab used to select the DWEYSVWLSN peptide from a phage display library. Many of the heavy and light chains displayed evidence of somatic mutation, suggesting that they were made by Ag-activated B cells. Analysis of the Ab repertoire in peptide-induced autoimmunity may provide insights into the generation of anti-DNA Abs following exposure to foreign Ag. Furthermore, the recovery of an Ab with the heavy and light chain combination of the Ab originally used to isolate the immunizing peptide confirms the utility of phage display peptide libraries in generating true molecular mimics.

We have previously suggested that anti-DNA antibodies present in systemic lupus erythematosus patients can bind directly to tissues as a result of cross-reactivity with embryonal tissue-based antigens. Here we have analyzed the interaction between polyclonal and monoclonal mouse and human lupus autoantibodies and an embryonal cell line. We report that a murine embryonal stem cell line (ES) expresses a surface antigen which is recognized by mouse and human lupus autoantibodies. This surface antigen is down-regulated following maturation of the cells or incubation with corticosteroids. Adhesion molecules may serve as the target membrane antigen in ES cells since preincubation with these antibodies decreases the ability of ES cells to adhere to the plate.

Patients with systemic lupus erythematosus (SLE) can experience acute neurological events such as seizures, cerebrovascular accidents, and delirium, psychiatric conditions including depression, anxiety, and psychosis, as well as memory loss and general cognitive decline. Neuropsychiatric SLE (NPSLE) occurs in between 30 and 40% of SLE patients, can constitute the initial patient presentation, and may occur outside the greater context of an SLE flare. Current efforts to elucidate the mechanistic underpinnings of NPSLE are focused on several different and potentially complementary pathways, including thrombosis, brain autoreactive antibodies, and complement deposition. Furthermore, significant effort is dedicated to understanding the contribution of neuroinflammation induced by TNF, IL-1, IL-6, and IFN-γ. More recent studies have pointed to a possible role for the TNF family ligand TWEAK in the pathogenesis of neuropsychiatric disease in human lupus patients, and in a murine model of this disease. The blood brain barrier (BBB) consists of tight junctions between endothelial cells (ECs) and astrocytic projections which regulate paracellular and transcellular flow into the central nervous system (CNS), respectively. Given the privileged environment of the CNS, an important question is whether and how the integrity of the BBB is compromised in NPSLE, and its potential pathogenic role. Evidence of BBB violation in NPSLE includes changes in the albumin quotient (Q alb) between plasma and cerebrospinal fluid, activation of brain ECs, and magnetic resonance imaging. This review summarizes the evidence implicating BBB damage as an important component in NPSLE development, occurring via damage to barrier integrity by environmental triggers such as infection and stress; cerebrovascular ischemia as result of a generally prothrombotic state; and immune mediated EC activation, mediated by antibodies and/or inflammatory cytokines. Additionally, new evidence supporting the role of TWEAK/Fn14 signaling in compromising the integrity of the BBB in lupus will be presented.

We previously demonstrated an important role of the constant region in the pathogenicity of anti-DNA antibodies. To determine the mechanisms by which the constant region affects autoantibody binding, a panel of isotype-switch variants (IgG1, IgG2a, IgG2b) was generated from the murine PL9-11 IgG3 autoantibody. The affinity of the PL9-11 antibody panel for histone was measured by surface plasmon resonance (SPR). Tryptophan fluorescence was used to determine wavelength shifts of the antibody panel upon binding to DNA and histone. Finally, circular dichroism spectroscopy was used to measure changes in secondary structure. SPR analysis revealed significant differences in histone binding affinity between members of the PL9-11 panel. The wavelength shifts of tryptophan fluorescence emission were found to be dependent on the antibody isotype, while circular dichroism analysis determined that changes in antibody secondary structure content differed between isotypes upon antigen binding. Thus, the antigen binding affinity is dependent on the particular constant region expressed. Moreover, the effects of antibody binding to antigen were also constant region dependent. Alteration of secondary structures influenced by constant regions may explain differences in fine specificity of anti-DNA antibodies between antibodies with similar variable regions, as well as cross-reactivity of anti-DNA antibodies with non-DNA antigens.

We compared the prevalence and the clustering of the metabolic syndrome (MetS) components (obese body mass index [BMI; ≥30 kg/m(2) ], hypertriglyceridemia, low high-density lipids, hypertension, and diabetes mellitus) in patients with psoriatic arthritis (PsA) and rheumatoid arthritis (RA) in the Consortium of Rheumatology Researchers of North America (CORRONA) Registry.We included CORRONA participants with a rheumatologist-confirmed clinical diagnosis of PsA or RA with complete data. We used a modified definition of MetS that did not include insulin resistance, waist circumference, or blood pressure measurements. Logistic regression models were adjusted for age, sex, and race.In the overall CORRONA population, the rates of diabetes mellitus and obesity were significantly higher in PsA compared with RA. In 294 PsA and 1,162 RA participants who had lipids measured, the overall prevalence of MetS in PsA versus RA was 27% versus 19%. The odds ratio (OR) of MetS in PsA versus RA was 1.44 (95% confidence interval [95% CI] 1.05-1.96, P = 0.02). The prevalence of hypertriglyceridemia was higher in PsA compared with RA (38% versus 28%; OR 1.51 [95% CI 1.15-1.98], P = 0.003). The prevalence of type 2 diabetes mellitus was also higher in PsA compared with RA (15% versus 11%; OR 1.56 [95% CI 1.07-2.28], P = 0.02) in the adjusted model. Similarly, higher rates of hypertriglyceridemia and diabetes mellitus were observed in the subgroup of PsA and RA patients with obese BMI.Compared with RA, PsA is associated with higher rates of obesity, diabetes mellitus, and hypertriglyceridemia.

Anti-double-stranded (ds) DNA antibodies are not only an important diagnostic marker for SLE, but also play an important role in tissue injury. Microbial antigen may be a stimulus for the production of these antibodies. We isolated 99D.7E, an IgG2b monoclonal antibody from a nonautoimmune BALB/c mouse that is cross-reactive with both dsDNA and phosphorylcholine, the dominant hapten on the pneumococcal cell wall. While partially protective against a bacterial challenge, 99D.7E is also pathogenic to the kidney. To identify those molecular motifs that confer on anti-PC antibodies the potential for autoreactivity, we created a panel of 99D.7E mutants with single amino acid substitutions in the heavy chain, and examined the changes in antigen binding and renal deposition. Our results support the hypothesis that charge and affinity for dsDNA are not adequate predictors of the pathogenicity of anti-DNA antibodies. Differential renal damage from anti-dsDNA antibodies may be due to differences in fine specificity, rather than differential affinity for dsDNA. Importantly, high affinity IgG antibodies cross-reactive with bacterial and self antigen exist and can display pathogenic potential, suggesting that defects in peripheral regulation of B cells, activated by foreign antigen but cross-reactive with self antigen, might lead to autoimmune disorders.

The immune system's ability to distinguish self and nonself is essential for both host defense against foreign agents and protection of self-antigens from autoimmune destruction. Such discrimination is complicated by extensive structural homology shared between foreign and self antigens. One hypothesis to explain the development of an autoimmune response is that some B cells activated by foreign antigen acquire, through somatic mutation, specificity for both the eliciting foreign antigen and self antigen. If such clones arise frequently, there must be a mechanism for their elimination. We have analyzed the extent of autoreactivity arising in a nonautoimmune host during the response to a foreign antigen. To overcome the process of apoptosis in primary B cells that might routinely eliminate autoreactive clones, we generated B-cell hybridomas from spleen cells of immunized mice by using a fusion partner constitutively expressing bcl-2. Multiple lines were obtained that recognize simultaneously the hapten phosphorylcholine and the self antigen double-stranded DNA. This dual specificity was not present early but was detected by day 10 after immunization. Some of these cross-reactive antibodies deposit in kidneys in a pattern similar to what is seen in autoimmune disease. These results demonstrate that autoantibodies arise at a high frequency as part of a response to foreign antigen. It has previously been shown that autoreactivity is regulated by central deletion; these data demonstrate a need for negative selection in peripheral lymphoid organs also, to regulate autoantibodies acquiring their self-specificity by somatic mutation.

Exercise-induced hyponatremia is commonly believed to be associated only with extraordinary physical efforts, or particularly strenuous exercise. Hyponatremia complicating moderate exercise has not been described previously. The authors describe the characteristics of seven patients with life-threatening hyponatremia associated with mild to moderate exercise. All patients suffered from nausea, vomiting, agitation, and confusion, appearing during or after moderate physical activity. Grand mal convulsions occurred in five of the patients. In laboratory results, hyponatremia was as low as 115 mEq/L, with a relatively high sodium concentration in the urine. High serum creatine kinase activity levels were found in most of the patients. All patients were discharged in good condition, without neurologic sequela. The authors conclude that hyponatremia is a possible complication of moderate exercise, and not only of endurance sports, and that exercise-induced hyponatremia can produce severe neurologic manifestations. The mechanism of the hyponatremia is unclear, but may be due to a hemodynamically inappropriate stimulus for antidiuretic hormone secretion.

Stage A 55-year-old woman presented with polyarticular arthritis. She had had several attacks of symmetric arthritis during the previous few months, involving particularly the ankles, shoulders, and metacarpophalangeal and proximal interphalangeal joints. She also reported morning stiffness and fatigue, but no other systemic symptoms. No infection or febrile illness preceded the onset of her symptoms. Her medical history was otherwise unremarkable. Response The patient's age, the onset of symptoms, and the clinical picture support a presumptive diagnosis of rheumatoid arthritis. The absence of fever and the chronic, relapsing course are inconsistent with most infectious arthritides. A reactive arthritis is also . . .

Background Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease characterized by production of pathogenic autoantibodies. These autoantibodies form immune complexes that can deposit in tissues causing organ damage. The clinical heterogeneity of SLE, and its manifestations that overlap other diseases, pose a diagnostic challenge (1–3). Early identification of disease and disease activity is key to curtailing permanent organ damage (3–5). More accurate diagnosic tools than those in current clinical use would have a significant impact on patient care. HealthTell has developed a high density peptide array platform to diagnose a disease based on differential Ab binding called ImmunoSignatures (IS). The IS technology uses arrays of hundreds of thousands of unique peptides designed to survey an individual9s Ab repertoire from a drop of blood, plasma, or serum (6). Differential binding profiles of the Ab on the array between patients with the disease of interest and control groups are selected as input to develop classification algorithms. The technology holds promise for detecting the presence of any disease that generates a specific B-cell response. Furthermore, for autoimmune diseases the technology has the potential to provide accurate differential diagnosis as well as detection of disease activity and progression. Objectives To establish the feasibility of the IS technology in identifying subjects with SLE. Methods Two well-annotated cohorts of serum samples were used representing i) 45 SLE cases and ii) 45 age, gender and race-matched normal donors. All SLE patients met ACR criteria, and as their primary clinical manifestation had joint (53%), renal (38%), skin (2%), or inactive disease (7%). Serum samples were diluted and applied on to the arrays. Ab-peptide binding was detected with fluorescently-labeled goat anti-human IgG. Peptide binding signal was quantified and features with significant differences in intensity between cases and controls were identified by Bonferroni adjusted t-test and log odds ratios. Support vector machine classification algorithms were trained using the most distinguishing peptides. Classifier model performance was evaluated by applying 100 iterations of a four-fold cross-validation routine that included feature selection, model training, and model testing. Results The cross-validated performance metrics of the 500-peptide IS classifier included an area under the Receiver Operator Curve of 0.99 (95% confidence interval (CI) 0.98–0.99) and an overall accuracy of 93% (95% CI 91%>96%) at equal sensitivity and specificity. Conclusions ImmunoSignature identification of SLE is feasible and highly accurate based on the preliminary cross-validated performance. These results need verification in larger cohorts and validation in blinded studies. Future studies will include control samples relevant to SLE differential diagnosis such as inflammatory and non-inflammatory rheumatic diseases, as well as active and inactive SLE. References Lateef A et. al. Arthritis Res Ther. 2012;14. Bertsias GK et.al. Nat Rev Rheumatol 2013;9:687–94. Tunnicliffe D et. al. Arthritis Care Res (Hoboken). 2015 Oct;67(10):1440–52. Ceccarelli F et.al. Autoimmun Rev. 2015 Jul;14(7):601–8. Sprangers B et.al. Nat Rev Nephrol. 2012 Dec;8(12):709–17. Legutki JB et.al. Nat Commun. 2014 Sep 3;5:4785. Disclosure of Interest B. Nayak Employee of: None, C. Putterman Consultant for: None, R. Gerwien Employee of: None, K. Sykes Employee of: None, T. Tarasow Employee of: None

Cutaneous lupus erythematosus (CLE) is a common disease manifestation in SLE patients. Ultraviolet-B irradiation (UVB) is well-known trigger of CLE; many lupus patients are photosensitive, and develop skin lesions following sun exposure. TWEAK, a TNF superfamily member, is a soluble cytokine that binds a sole signaling receptor, Fn14. TWEAK/Fn14 interactions are important in key biologic processes, including angiogenesis, cell death and inflammation, and are often upregulated during tissue injury. We found that MRL-lpr/lpr (MRL/lpr) lupus-prone mice deficient for the Fn14 receptor (Fn14KO) had markedly attenuated skin lesions following UVB irradiation, as compared to Fn14WT mice. Histologically, MRL/lpr Fn14WT mice had more keratinocyte apoptosis, degeneration of the basement membrane, and dermal inflammation. Further evaluation showed decreased infiltration of IBA-1+ macrophages, CD3+ T cells, and NGAL+ cells (neutrophils) in the skin of MRL/lpr Fn14KO mice. Depletion of macrophages in MRL/lpr mice using the CSF1R/fms kinase inhibitor GW2580 attenuated irradiation-induced tissue injury, confirming a pathogenic role for these Fn14-expressing cells in UVB-induced lesions. Several key chemokines (including MCP-1, MIP-1α, MIP-1β) were decreased following macrophage depletion and also differentially expressed between Fn14KO and WT mice, suggesting regulation through TWEAK/Fn14 signaling. Finally, both in vitro and in vivo, Fn14 was upregulated on dead and dying cells following irradiation, which can locally sensitize cells to the effects of TWEAK. Our data reveals important contributors to the pathogenesis of UVB-induced cutaneous lesions, and suggests a novel role for TWEAK/Fn14 signaling in skin disease.

In addition to an overt neuropsychiatric phenotype (depression and cognitive dysfunction), MRL/lpr mice display robust infiltration of lymphocytes through the brain choroid plexus (CP). However, the functional features of these cells, or their potential contribution to neuropsychiatric disease, have not been explored in detail. Localized tertiary lymphoid structures have been described in the kidney and peritoneum in spontaneous and inducible lupus models. Given the immunoprivileged nature of the brain and recent studies describing the critical role of the CP in immune surveillance, we evaluated 3D reconstructions of B-cell and T-cell infiltrates. We hypothesized that these CP infiltrates consist of tertiary lymphoid structures (ectopic germinal centers), induced in response to local and/or systemic inflammation. We found dramatically increased lymphotoxin-β and CXCL13, key molecules in lymphoid follicle organization, in the CP of MRL/lpr mice. Lymphotoxin-β and CXCL13 were upregulated by 8 weeks of age, well before any cellular infiltration was present. Organizational and phenotypic features of lymphoid follicles, including clusters of proliferating (PCNA+) T and B cells, organized according to local chemokine gradients, were present. Furthermore, we identified phenotypically distinct groups of B-cells (e.g. IgM+, GL7+, BCL6+) and T-cells (e.g. FoxP3+, BCL6+, GL7+), as well as follicular dendritic cells and extracellular reticular networks, consistent with lymphoid follicles. We therefore conclude that the CP of MRL/lpr mice contain germinal-center like structures. The contribution of these structures to the pathogenesis, including local production of neuropathic autoantibodies, remains to be determined.

Many cardiovascular manifestations have been described in systemic lupus erythematosus (SLE). Aortic involvement, however, is very rare. We describe a 30-year-old woman with SLE who presented with extensive aortic dissection, and review the few reported cases. We discuss possible pathogenic mechanisms for aortic involvement in lupus and the appropriate diagnostic work-up.

Objective.Antiphospholipid antibodies (aPL) play an active role in the pathogenesis of the antiphospholipid syndrome (APS). Primary prevention in APS may be aimed at decreasing existing elevated aPL levels, or preventing high aPL titers and/or lupus anticoagulant (LAC) from developing in the first place. Hydroxychloroquine (HCQ) has been shown in retrospective studies to decrease aPL titers in laboratory studies, and to decrease thrombosis risk in patients with systemic lupus erythematosus (SLE). We investigated an association between HCQ use and persistent aPL and/or LAC in SLE.Methods.We identified all patients over 21 years old with SLE from an urban tertiary care center who had aPL and LAC measured on at least 2 occasions at least 12 weeks apart. We defined the presence of persistent LAC+ and/or at least 1 aPL ≥ 40 U [immunoglobulin A (IgA), IgG, or IgM] as the main outcome variable.Results.Among 90 patients included in the study, 17 (19%) had persistent LAC+ and/or at least 1 aPL ≥ 40 U. HCQ use was associated with significantly lower odds of having persistent LAC+ and/or aPL ≥ 40 U (OR 0.21, 95% CI 0.05, 0.79, p = 0.02), adjusted for age, ethnicity, and sex.Conclusion.This is the first study to show that HCQ use is associated with lower odds of having persistently positive LAC and/or aPL. Data from this study provide a basis for the design of future prospective studies investigating the role of HCQ in primary and secondary prevention of APS.

There is significant unmet need in the treatment of lupus nephritis (LN) patients. In this review, we highlight the role of the TWEAK/Fn14 pathway in mediating key pathologic processes underlying LN involving both glomerular and tubular injury, and thus the potential for renal protection via blockade of this pathway. The specific pathological mechanisms of TWEAK – namely promoting inflammation, renal cell proliferation and apoptosis, vascular activation and fibrosis – are described, with supporting data from animal models and in vitro systems. Furthermore, we detail the translational relevance of these mechanisms to clinical readouts in human LN. We present the opportunity for an anti-TWEAK therapeutic as a renal protective agent to improve efficacy relative to current standard of care treatments hopefully without increased safety risk, and highlight a phase II trial with BIIB023, an anti-TWEAK neutralizing antibody, designed to assess efficacy in LN patients. Taken together, targeting the TWEAK/Fn14 axis represents a potential new therapeutic paradigm for achieving renal protection in LN patients.

Affinity for DNA and cross-reactivity with renal antigens are associated with enhanced renal pathogenicity of lupus autoantibodies. In addition, certain IgG subclasses are enriched in nephritic kidneys, suggesting that isotype may determine the outcome of antibody binding to renal antigens. To investigate if the isotype of DNA antibodies affects renal pathogenicity by influencing antigen binding, we derived IgM, IgG1, IgG2b and IgG2a forms of the PL9–11 antibody (IgG3 anti-DNA) by in vitro class switching or PCR cloning. The affinity and specificity of PL9–11 antibodies for nuclear and renal antigens were analyzed using ELISA, Western blotting, surface plasmon resonance (SPR), binding to mesangial cells, and glomerular proteome arrays. Renal deposition and pathogenicity were assayed in mice injected with PL9–11 hybridomas. We found that PL9–11 and its isotype-switched variants had differential binding to DNA and chromatin (IgG3 > IgG2a > IgG1 > IgG2b > IgM) by direct and competition ELISA, and SPR. In contrast, in binding to laminin and collagen IV the IgG2a isotype actually had the highest affinity. Differences in affinity of PL9–11 antibodies for renal antigens were mirrored in analysis of specificity for glomeruli, and were associated with significant differences in renal pathogenicity in vivo and survival. Our novel findings indicate that the constant region plays an important role in the nephritogenicity of antibodies to DNA by affecting immunoglobulin affinity and specificity. Increased binding to multiple glomerular and/or nuclear antigens may contribute to the renal pathogenicity of anti-DNA antibodies of the IgG2a and IgG3 isotype. Finally, class switch recombination may be another mechanism by which B cell autoreactivity is generated.

The mechanism by which anti-DNA antibodies mediate lupus nephritis has yet to be conclusively determined. Previously, we found that treatment of mesangial cells with anti-DNA antibodies induced high expression of neutrophil gelatinase-associated lipocalin (NGAL), an iron-binding protein up-regulated in response to kidney injury. We undertook this study to determine whether NGAL is instrumental in the pathogenesis of nephritis, is induced as part of repair, or is irrelevant to damage/repair pathways.To investigate the role of NGAL in antibody-mediated nephritis, we induced nephrotoxic nephritis by passive antibody transfer to 129/SyJ and C57BL/6 mice. To determine if NGAL up-regulation is instrumental, we compared the severity of renal damage in NGAL wild-type mice and NGAL-knockout mice following induction of nephrotoxic nephritis.We found that kidney NGAL expression, as well as urine NGAL levels, were significantly increased in mice with nephrotoxic nephritis as compared to control-injected mice. Tight correlations were observed between NGAL expression, renal histopathology, and urine NGAL excretion. NGAL-knockout mice had attenuated proteinuria and improved renal histopathology compared to wild-type mice. Similarly, following nephritis induction, NGAL injection significantly exacerbated nephritis and decreased survival. NGAL induced apoptosis via caspase 3 activation and up-regulated inflammatory gene expression in kidney cells in vitro and when injected in vivo.We conclude that kidney binding of pathogenic antibodies stimulates local expression of NGAL, which plays a crucial role in the pathogenesis of nephritis via promotion of inflammation and apoptosis. NGAL blockade may be a novel therapeutic approach for the treatment of nephritis mediated by pathogenic antibodies, including anti-glomerular basement membrane disease and lupus nephritis.

Systemic Lupus Erythematosus (SLE) is a multi-systemic autoimmune disorder that can have severe and potentially life-threatening manifestations. One such manifestation is lupus nephritis. While survival rates have improved significantly, SLE, and in particular lupus nephritis, continues to be associated with significant morbidity and mortality. The incidence of SLE varies greatly among different populations. As a whole, rates are highest in non-Caucasians. Estimated incidence rates of SLE are similar in the US and in Europe where Caucasians have rates of 3.5-4 per 100,000 and those of African descent have significantly higher rates of 9.2-11.4 per 100,000.1,2 While the disease is present to a certain degree in all populations, SLE affects primarily women in their child-bearing years with a ratio of 9:1 compared to men.3,4 When men do present with SLE there is evidence that they have worse disease outcomes including increased mortality.5,6 Regardless of race or gender, mortality in SLE has improved significantly since the 1950’s, where the 5-year survival rate was approximately 50%.7 Currently, 10-year survival rates range between 85% and 95%.7 Despite improved overall survival, lupus nephritis (seen in upwards of 60% of all SLE patients) continues to significantly affect morbidity and mortality.8 While 5-year survival for those without nephritis is approximately 92%, those with this complication have a much lower rate of 82%.8 Both in the US and in Europe, non-Caucasians have increased rates of nephritis, where not only is the condition more prevalent in these groups, it also tends to be more severe.5,9 In the US, risk factors for progression to end-stage renal disease include: being African American, Hispanic, male, less than 24 years old and having high activity and chronicity on renal biopsy.10 Risk factors notwithstanding, it has been shown that patients that receive early treatment have better outcomes.11,12 However, even with early and aggressive treatment, one study has found no change in the incidence of end-stage renal disease from lupus nephritis.13 Therefore, it appears that while medications are usually effective in controlling renal inflammation, a substantial amount of patients fail treatment. In addition, conventional therapies are not target-specific and can lead to significant toxicity. Therefore, given that B cells play such an integral role in the pathogenesis of SLE and lupus nephritis, these cells are potential targets for more specific therapies.

Persistently elevated antiphospholipid antibodies and positive lupus anticoagulant (LAC) are associated with an increased risk of thrombosis. The objective of this study was to explore whether antiphospholipid antibody and/or LAC positivity were associated with the traditional risk factors for thrombosis or with medication use in patients without autoimmune diseases hospitalised with arterial or venous thrombosis.Cross-sectional study.Montefiore Medical Center, a large urban tertiary care centre.270 patients (93 with deep vein thrombosis (DVT) or pulmonary embolism (PE), and 177 with non-haemorrhagic stroke (cerebrovascular accident (CVA)) admitted between January 2006 and December 2010 with a discharge diagnosis of either DVT, PE or CVA, who had LAC and antiphospholipid antibodies measured within 6 months from their index admission. Patients with lupus or antiphospholipid syndrome were excluded.The main dependent variable was antiphospholipid antibodies of 40 units or greater (antiphospholipid antibody positivity) and/or LAC positivity. Independent variables were traditional thrombosis risk factors, statin use, aspirin use and warfarin use.31 (11%) patients were LAC positive and/or antiphospholipid antibody positive. None of the traditional risk factors at the time of DVT/PE/CVA was associated with antiphospholipid antibody positivity. Current statin use was associated with an OR of 3.2 (95% CI 1.3 to 7.9, p=0.01) of antiphospholipid antibody positivity, adjusted for age, ethnicity and gender. Aspirin or warfarin use was not associated with antiphospholipid antibody levels.If statin therapy reflects the history of previous hyperlipidaemia, high levels of antiphospholipid antibodies may be a marker for earlier endothelial damage caused by hyperlipidaemia.

Systemic lupus erythematosus (SLE) is the prototypical autoimmune disease, associated with autoantibody production and evidence for immune complex deposition among the many aspects of its pathophysiology. SLE occurs most commonly in women during their reproductive years. The disease is approximately nine times more common among women than men. Virtually any organ can be affected by SLE. However, constitutional symptoms, mucocutaneous features, mus-culoskeletal involvement, and renal and central nervous system disease are the most common manifestations. Many aspects of SLE appear to be triggered by classic inflammatory mechanisms, accompanied by elevated acute phase reactants, and responsive to immunosuppres-sive therapies. Other aspects, such as those associated with antiphospholipid antibodies (aPL), are associated with hypercoagulability. Although inflammation contributes to these aspects as well, the approach to the treatment of aPL-mediated disease manifestations is usually centered on anticoagulation. Autoantibodies can occur in the absence of clinical features of SLE, but strong evidence implicates certain autoantibodies in the mediation of tissue damage in the kidney and other organs. Genetics plays a significant role in SLE, but the disease is clearly polygenic, with multiple genetic risk factors contributing incrementally to the overall genetic risk. Environmental risk factors are also critical. Established environmental risk factors for the disease include hormones, ultraviolet light, the exposure to certain medications, and possibly dietary exposures and infectious agents.

Stage A 23-year-old woman of Moroccan Jewish origin was admitted to the hospital with abdominal pain. She had had recurrent attacks of abdominal pain, sometimes with fever, for the previous three months. There were no other gastrointestinal or urinary tract symptoms. Her medical history was unremarkable, and her parents were not related. Response Acute abdominal pain may occur in a number of medical conditions. Common causes include gastroenteritis, urinary tract infection, salpingitis, intestinal obstruction, intestinal ischemia, and irritable bowel syndrome. However, a history of recurrent attacks of abdominal pain with fever in a patient of Mediterranean origin immediately suggests a . . .

The metabolic disturbances that underlie systemic lupus erythematosus are currently unknown. A metabolomic study was executed, comparing the sera of 20 SLE patients against that of healthy controls, using LC/MS and GC/MS platforms. Validation of key differences was performed using an independent cohort of 38 SLE patients and orthogonal assays. SLE sera showed evidence of profoundly dampened glycolysis, Krebs cycle, fatty acid β oxidation and amino acid metabolism, alluding to reduced energy biogenesis from all sources. Whereas long-chain fatty acids, including the n3 and n6 essential fatty acids, were significantly reduced, medium chain fatty acids and serum free fatty acids were elevated. The SLE metabolome exhibited profound lipid peroxidation, reflective of oxidative damage. Deficiencies were noted in the cellular anti-oxidant, glutathione, and all methyl group donors, including cysteine, methionine, and choline, as well as phosphocholines. The best discriminators of SLE included elevated lipid peroxidation products, MDA, gamma-glutamyl peptides, GGT, leukotriene B4 and 5-HETE. Importantly, similar elevations were not observed in another chronic inflammatory autoimmune disease, rheumatoid arthritis. To sum, comprehensive profiling of the SLE metabolome reveals evidence of heightened oxidative stress, inflammation, reduced energy generation, altered lipid profiles and a pro-thrombotic state. Resetting the SLE metabolome, either by targeting selected molecules or by supplementing the diet with essential fatty acids, vitamins and methyl group donors offers novel opportunities for disease modulation in this disabling systemic autoimmune ailment.

In order to describe the clinical and serologic features of a cutaneous vasculitis due to cocaine contaminated with the adulterant levamisole, we report four new cases of this syndrome along with 12 previously reported cases identified through a PubMed Literature search (1964 to March 2011). Of the 16 patients described, the average age was 43, with a female predominance (81% of patients). Over half of patients had involvement of the earlobes, and the rash frequently affected the extremities in a "retiform" pattern. Leukopenia or neutropenia was reported in 56% of patients. Ninety-three percent were anti-neutrophil cytoplasmic antibody positive, and 63% tested positive for anti-phospholipid antibodies. The predominant pattern seen on histopathological examination of the skin was small vessel vasculitis and/or a thrombotic vasculopathy. Treatment in these patients varied widely, with several patients showing improvement or resolution of the rash without specific therapy following cessation of illicit drug use. This new cutaneous vasculitis syndrome can be recognized by its characteristic rash and skin pathology, together with leukopenia and autoantibody production. Certain clinical features can be attributed to the adulterant levamisole, though cocaine as well may play a role in its pathogenesis.

To date, CNS disease and neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE) have been understudied compared to end-organ failure and peripheral pathology. In this review, we focus on a specific mouse model of lupus and the ways in which this model reflects some of the most common manifestations and potential mechanisms of human NP-SLE. The mouse MRL lymphoproliferation strain (a.k.a. MRL/lpr) spontaneously develops the hallmark serological markers and peripheral pathologies typifying lupus in addition to displaying the cognitive and affective dysfunction characteristic of NP-SLE, which may be among the earliest symptoms of lupus. We suggest that although NP-SLE may share common mechanisms with peripheral organ pathology in lupus, especially in the latter stages of the disease, the immunologically privileged nature of the CNS indicates that early manifestations of particularly mood disorders maybe derived from some unique mechanisms. These include altered cytokine profiles that can activate astrocytes, microglia, and alter neuronal function before dysregulation of the blood-brain barrier and development of clinical autoantibody titres.

Idiopathic systemic capillary leak syndrome (Clarkson's disease) is characterized by recurring attacks of increased capillary permeability, resulting in severe hypovolemic shock due to plasma extravasation. Additional laboratory features include association with a monoclonal gammopathy, extreme hemoconcentration, and hypoalbuminemia. Rare manifestations of this syndrome are renal damage and rhabdomyolysis due to increased compartment pressure and ischemic myonecrosis. We present the findings in two patients with capillary leak syndrome complicated by severe rhabdomyolysis, in one case leading to acute renal failure. We review therapeutic aspects of this rare syndrome and emphasize the importance of early diagnosis and of prompt and aggressive fluid replacement.

Reactive arthritis is associated with several gastrointestinal pathogens, particularly Shigella, Salmonella, Campylobacter , and Yersinia . Another, less well recognized bowel infection leading to reactive arthritis is pseudomembranous colitis, caused by Clostridium difficile . An illustrative case is presented, and the clinical features and characteristics of all reported patients with this association are reviewed. The pathogenesis of the reactive arthritis seems to be related to an immunological response in joints and other tissues against bacterial antigens, which gain access to the systemic circulation through increased intestinal permeability. Therapy with nonspecific antiinflammatory drugs, antiolostridial agents, or a combination of the above is effective. Despite the possibility of persistent articular involvement after gastrointestinal symptoms have subsided, the long-term prognosis seems to be excellent.

Relapsing polychondritis is characterized by recurrent inflammation of the cartilaginous tissues of the ears, nose, peripheral joints, and the tracheobronchial tree. The eye is also a frequent target organ in relapsing polychondritis, and proptosis is a well-recognized manifestation of eye involvement. Similar to other rheumatologic diseases, an association of relapsing polychondritis with malignancy has been reported. We describe a patient with relapsing polychondritis who presented with exophthalmos. When treatment directed toward control of her underlying disease was only partially effective, further investigation revealed that she had an orbital mucosa-associated lymphoid tissue (MALT)-type B cell lymphoma. We hypothesize that the lymphoma resulted from malignant transformation of the relapsing polychondritis-induced inflammatory pseudotumor and emphasize that neoplastic disease should be considered in the differential diagnosis in patients with relapsing polychondritis presenting with exophthalmos.

Objectives While anatomical and physiological changes in the spleen are reported in systemic lupus erythematosus (SLE), a complex autoimmune disease that can affect most organ systems, calcifications have not been described as a characteristic feature. We report 4 lupus patients with extensive splenic calcifications with no apparent cause except for their primary disease. The relevant literature on calcifications of the spleen in SLE is also reviewed. Methods Four lupus patients with extensive splenic calcifications are described, identified by radiologists at 2 large urban academic centers. In addition, the relevant literature was reviewed (PubMed search 1947 through May 2010) using the following terms: "lupus," "spleen," and "calcified," "calcification," "calcifications," or "microcalcifications." English-language case reports and series were selected. Results Four lupus patients were found to have a unique pattern of splenic calcifications. The age range was 36 to 73 years. Two of the patients were women, and 1 of these had SLE and limited systemic sclerosis. On reviewing the literature, 6 additional cases of lupus and splenic calcifications were found, 1 of which had pathologic assessment of the spleen on autopsy. The incidence of infection was apparently not increased in affected patients. Conclusions A unique pattern of calcifications of the spleen may be found in lupus patients, which can suggest the diagnosis of the underlying connective tissue disease. Whether splenic calcification can predispose to hyposplenism remains to be determined. While the exact significance of diffuse splenic calcification is still unknown, this unique radiologic finding may be a result of the disease process itself.

Emotional disturbances are among the most common neuropsychiatric manifestations of SLE, a systemic autoimmune disease with a strong female predominance. In this study, we evaluated young MRL/lpr mice, directly comparing males and females. MRL/lpr females exhibited significant depression as early as 5 weeks (at which time elevated levels of autoantibodies were already present), as compared to MRL/lpr males, where depression was noted only at 18 weeks. Depression was significantly correlated with autoantibodies against nuclear antigens, NMDA receptor, and ribosomal P. Our results are consistent with a primary role of autoantibodies in the pathogenesis of early neuropsychiatric deficits in this lupus model, which translate into gender-based differences in clinical phenotype.

Objectives. Clinical and laboratory markers in current use have limited specificity and sensitivity for predicting the development of renal disease in lupus patients. In this longitudinal study, we investigated whether urinary neutrophil gelatinase-associated lipocalin (uNGAL) predicts active nephritis and renal flares in lupus patients with and without a history of biopsy-proven lupus nephritis. Methods. Renal disease activity and flare status was determined by SLEDAI and BILAG scores. Random effects models were used to determine whether uNGAL was a significant predictor for renal disease activity in SLE patients, and for renal flares in patients with established nephritis. To assess the predictive performance of uNGAL, receiver operating characteristic (ROC) curves were constructed using the previous visit’s uNGAL level. These curves were then compared with curves constructed with currently used biomarkers. Cut-offs determined by ROC curves were tested in an independent validation cohort. Results. uNGAL was found to be a significant predictor of renal disease activity in all SLE patients, and a significant predictor for flare in patients with a history of biopsy-proven nephritis, in multivariate models adjusting for age, race, sex and anti-double-stranded (ds)DNA antibody titres. As a predictor of renal flare in patients with biopsy-proven nephritis, uNGAL outperformed anti-dsDNA antibody titres. These results were confirmed in an independent validation cohort. Conclusions. uNGAL predicts renal flare in patients with a history of biopsy-proven nephritis with high sensitivity and specificity. Furthermore, uNGAL is a more sensitive and specific forecaster of renal flare in patients with a history of lupus nephritis than anti-dsDNA antibody titres.

Niemann-Pick disease is a metabolic disorder resulting in accumulation of sphingomyelin in visceral organs. The adult form (type B) is characterized by the sparing of brain involvement, allowing those affected to have a relatively benign course. Although the abnormal lipid accumulation in the liver is commonly recognized, hepatocellular compromise is extremely rare. We describe a patient with adult Niemann-Pick disease who over the course of over 35 years developed hepatic failure and portal hypertension, and we review the literature regarding hepatic involvement in this rare disease.

Histopathological analysis of some systemic autoimmune diseases and syndromes led us to the conclusion that the common feature of the organs involved might be their embryonal origin. We suggest that organs derived from the same germ layer express common germ-layer-specific antigens. Such antigens could serve as target antigens for the autoimmune response.

Acquired right ventricular outflow tract obstruction due to extrinsic compression of the pulmonary artery is a rare manifestation of non-Hodgkin's lymphoma (NHL). We report a case of a 17 year old boy who was referred for evaluation of a large anterior mediastinal mass, causing dyspnea and cough and resulting in a harsh systolic murmur. Echocardiography demonstrated compression of the pulmonary artery by the mass, with a severe pressure gradient. Biopsy revealed intermediate grade, diffuse large cell NHL. Systemic chemotherapy rapidly led to a significant decrease in the size of the mass, and virtual disappearance of the pressure gradient. In this report, the use of echocardiography for diagnosis and follow up of extracardiac tumors is reviewed. It is suggested that this technique may also be useful for the routine staging of mediastinal lymphomas because of the potential consequences of clinically undetectable hemodynamic compromise.

Objective Traditional means of testing rheumatology fellows do not adequately assess some skills that are required to practice medicine well, such as humanistic qualities, communication skills, or professionalism. Institution of the New York City Rheumatology Objective Structured Clinical Examination (ROSCE) and our sequential 5 years of experience have provided us with a unique opportunity to assess its usefulness and objectivity as a rheumatology assessment tool. Methods Prior to taking the examination, all of the fellows were rated by their program directors. Fellows from the participating institutions then underwent a multistation patient-interactive examination observed and rated by patient actors and faculty raters. Assessments were recorded by all of the participants using separate but overlapping sets of instruments testing the Accreditation Council of Graduate Medical Education (ACGME) core competencies of patient care, interpersonal and communication skills, professionalism, and overall medical knowledge. Results Although the program directors tended to rate their fellows more highly than the ROSCE raters, typically there was agreement between the program directors and the ROSCE faculty in distinguishing between the highest- and lowest- performing fellows. The ROSCE faculty and patient actor assessments of individual trainees were notable for a high degree of concordance, both quantitatively and qualitatively. Conclusion The ROSCE provides a unique opportunity to obtain a patient-centered assessment of fellows' ACGME-mandated competencies that traditional knowledge-based examinations, such as the rheumatology in-service examination, cannot measure. The ability of the ROSCE to provide a well-rounded and objective assessment suggests that it should be considered an important component of the rheumatology training director's toolbox.

Type I IFNs are potent regulators of innate and adaptive immunity and are implicated in the pathogenesis of systemic lupus erythematosus. Here we report that clinical and pathological lupus nephritis and serum anti-nuclear Ab levels are greatly attenuated in New Zealand Mixed (NZM) 2328 mice deficient in type I IFN receptors (IFNAR). To determine whether the inflammatory environment in NZM 2328 mice leads to IFNAR-regulated changes in dendritic cells (DC), the number, activation, and function of DC subsets were compared in 2- and 5-mo-old (clinically healthy) female NZM and NZM-IFNAR−/− mice. Numbers of activated CD40high plasmacytoid DC (pDC) were significantly increased in renal lymph nodes of 2-mo-old NZM but not NZM-IFNAR−/− mice, suggesting an early IFNAR-dependent expansion and activation of pDC at disease sites. Relative to NZM spleens, NZM-IFNAR−/− spleens in 5-mo-old mice were significantly decreased in size and contained reduced numbers of conventional DC subsets, but not pDC. Splenic and renal lymph node NZM-IFNAR−/− DC analyzed directly ex vivo expressed significantly less CD40, CD86, and PDL1 than did NZM DC. Upon activation with synthetic TLR9 ligands in vitro, splenic NZM-IFNAR−/− DC produced less IL-12p40/70 and TNF-α than did NZM DC. The limited IFNAR−/− DC response to endogenous activating stimuli correlated with reduced numbers of splenic activated memory CD4+ T cells and CD19+ B cells in older mice. Thus, IFNAR signaling significantly increases DC numbers, acquisition of Ag presentation competence, and proinflammatory function before onset of clinically apparent lupus disease.

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) of0.05, were identified, and a number of noteworthy genes with FDR of0.8 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 (FDR0.05) 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.

Objective Systemic lupus erythematosus (SLE) is the prototypical 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 terms of the pathogenesis of SLE. STAT-1 and STAT-4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for involvement in SLE susceptibility. Methods Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 on chromosome 2 were genotyped using the Illumina platform, as part of an extensive association study in a large collection of 9,923 lupus patients and control subjects from different racial groups. DNA samples were obtained from the peripheral blood of patients with SLE and control subjects. Principal components analyses and population-based case–control association analyses were performed, and the P values, false discovery rate q values, and odds ratios with 95% confidence intervals were calculated. Results We observed strong genetic associations with SLE and multiple SNPs located within STAT4 in different ethnic groups (Fisher's combined P = 7.02 × 10−25). In addition to strongly confirming the previously reported association in the third intronic region of this gene, we identified additional haplotypic association across STAT4 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 its proximity to STAT4. Conclusion Our findings indicate that STAT4 is likely to be a crucial component in SLE pathogenesis in multiple racial groups. Knowledge of the functional effects of this association, when they are revealed, might improve our understanding of the disease and provide new therapeutic targets.

The cytokine TWEAK demonstrates potent kidney proinflammatory and proliferative effects. Recently, we have shown that interactions of TWEAK with its receptor Fn14 are instrumental in the pathogenesis of nephritis in the chronic graft-versus-host (cGVH) induced model of lupus. Fn14 is expressed by macrophages and resident kidney cells; we hypothesized that TWEAK binding to both cell types contributes to the pathogenesis of lupus nephritis. To address this question, we generated bone marrow chimaeras and compared the progression of nephritis during cGVH induced lupus in mice expressing Fn14 only on bone marrow-derived cells, versus mice displaying Fn14 only on non-bone marrow-derived cells. While Fn14 deficiency did not significantly affect autoantibody titers, Fn14 deficiency on bone marrow-derived cells did not inhibit nephritis initiation in mice with Fn14 sufficient non-hematopoeitic cells. Conversely, expression of Fn14 only on bone marrow-derived cells resulted in a delayed, milder disease course. To further explore the role of macrophages, we depleted macrophages during cGVH induction. Surprisingly, we found that macrophage depleted mice displayed significantly increased titers of anti-DNA antibodies and worse kidney disease. We conclude that the presence of Fn14 on resident kidney cells alone may be sufficient to initiate nephritis in this murine model of lupus.

TNF-α has both proinflammatory and immunoregulatory functions. Whereas a protective role for TNF administration in systemic lupus erythematosus (SLE)-prone (New Zealand Black × New Zealand White)F1 mice has been established, it remains uncertain whether this effect segregates at the individual TNFR. We generated SLE-prone New Zealand Mixed 2328 mice genetically deficient in TNFR1, in TNFR2, or in both receptors. Doubly-deficient mice developed accelerated pathological and clinical nephritis with elevated levels of circulating IgG anti-dsDNA autoantibodies and increased numbers of CD4+ T lymphocytes, especially activated memory (CD44highCD62Llow) CD4+ T cells. We show that these cells expressed a Th17 gene profile, were positive for IL-17 intracellular staining by FACS, and produced exogenous IL-17 in culture. In contrast, immunological, pathological, and clinical profiles of mice deficient in either TNFR alone did not differ from those in each other or from those in wild-type controls. Thus, total ablation of TNF-α-mediated signaling was highly deleterious to the host in the New Zealand Mixed 2328 SLE model. These observations may have profound ramifications for the use of TNF and TNFR antagonists in human SLE and related autoimmune disorders, as well as demonstrate, for the first time, the association of the Th17 pathway with an animal model of SLE.

A 27-year-old woman experienced hemorrhagic shock after delivery. One week later she was seen in an obtunded state of consciousness. The results of laboratory evaluation were consistent with the syndrome of inappropriate antidiuretic hormone secretion caused by hypopituitarism. Hydrocortisone rapidly corrected sodium levels. Syndrome of inappropriate secretion of antidiuretic hormone caused by Sheehan's syndrome should be considered in the differential diagnosis of postpartum hyponatremia.

Many lupus patients develop neuropsychiatric manifestations, including cognitive dysfunction, depression, and anxiety. However, it is not clear if neuropsychiatric lupus is a primary disease manifestation, or is secondary to non-CNS disease. We found that MRL/lpr lupus-prone mice exhibited significant depression-like behavior already at 8 weeks of age, despite normal visual working memory, locomotor coordination and social preference. Moreover, depression was significantly correlated with titers of autoantibodies against DNA, NMDA receptors and cardiolipin. Our results indicate that lupus mice develop depression and CNS dysfunction very early in the course of disease, in the absence of substantial pathology involving other target organs.

Lupus nephritis, a potentially devastating outcome of systemic lupus erythematosus (SLE), poses a real challenge in the management of SLE patients because of the difficulty in diagnosing its onset and identifying relapses before serious renal damage has ensued. Neutrophil gelatinase-B associated lipocalin (NGAL)/Lipocalin-2 has been implicated in the pathogenesis of several disease states in different organ systems, and especially in kidney diseases. Lipocalin-2 may play a protective role in the context of renal insults through the induction or prevention of apoptosis by an iron-transport dependent mechanism. Clinically, urinary Lipocalin-2 significantly correlates with measures of lupus nephritis disease activity, and may be an important and convenient marker for relapses.

Adult respiratory distress syndrome (ARDS) is a major cause of morbidity and mortality in critically ill patients. This form of acute respiratory failure represents a stereotypic response of the lung to many injurious mediators. Adult respiratory distress syndrome is characterized by pulmonary infiltrates, severe hypoxemia, and reduced lung compliance, and expresses clinically as an increased-permeability pulmonary edema. Despite modern treatment modalities, the high mortality rate (>50%) from ARDS has not appreciably decreased over the last 20 years. A major issue of controversy in the therapy of ARDS is the use of corticosteroids (CS) for the prophylaxis and treatment of this syndrome. In this report, current concepts of the pathophysiology of ARDS are discussed, while focusing on potential areas of benefit of CS. Experience with steroids is then reviewed, considering human studies of CS in established ARDS and pulmonary fibrosis, and the prevention of ARDS in high risk patients. After considering available data, it is concluded that the use of CS cannot be recommended for the prevention or therapy of ARDS.

Central venous catheterization is one of the most common invasive vascular procedures performed in hospitals today. Though catheter related sepsis occurs only in a small percentage of catheterized patients, this complication has a tremendous impact due to the ubiquitous use of central venous catheters and consequent morbidity and even mortality. Recent studies have considerably advanced our knowledge regarding the pathogenesis, diagnosis, and prevention of catheter sepsis. In this paper, current concepts regarding catheter-related sepsis are reviewed, regarding the incidence, pathophysiology, diagnosis, prevention, and therapy of this complication. Particular emphasis is placed upon recent research and clinical advances in this field, which have clarified important question and suggested promising approaches to the prevention and treatment of catheter bacteremia. The excessive morbidity and mortality due to catheter-related sepsis can be markedly decreased, by attention to simple infection control methods, and by future implementation of new experimental techniques.

In an effort to identify potential biomarkers in lupus nephritis, urine from mice with spontaneous lupus nephritis was screened for the presence of VCAM-1, P-selectin, TNFR-1, and CXCL16, four molecules that had previously been shown to be elevated in experimental immune nephritis, particularly at the peak of disease. Interestingly, all four molecules were elevated ∼2- to 4-fold in the urine of several strains of mice with spontaneous lupus nephritis, including the MRL/lpr, NZM2410, and B6.Sle1.lpr strains, correlating well with proteinuria. VCAM-1, P-selectin, TNFR-1, and CXCL16 were enriched in the urine compared with the serum particularly in active disease, and were shown to be expressed within the diseased kidneys. Finally, all four molecules were also elevated in the urine of patients with lupus nephritis, correlating well with urine protein levels and systemic lupus erythematosus disease activity index scores. In particular, urinary VCAM-1 and CXCL16 showed superior specificity and sensitivity in distinguishing subjects with active renal disease from the other systemic lupus erythematosus patients. These studies uncover VCAM-1, P-selectin, TNFR-1, and CXCL16 as a quartet of molecules that may have potential diagnostic significance in lupus nephritis. Longitudinal studies are warranted to establish the clinical use of these potential biomarkers.