Irene Blanco

Urinary TWEAK as a biomarker of lupus nephritis: a multicenter cohort study

IntroductionTNF-like weak inducer of apoptosis (TWEAK) has been implicated as a mediator of chronic inflammatory processes via prolonged activation of the NF-κB pathway in several tissues, including the kidney. Evidence for the importance of TWEAK in the pathogenesis of lupus nephritis (LN) has been recently introduced. Thus, TWEAK levels may serve as an indication of LN presence and activity.MethodsMulticenter cohorts of systemic lupus erythematosus (SLE) patients and controls were recruited for cross-sectional and longitudinal analysis of urinary TWEAK (uTWEAK) and/or serum TWEAK (sTWEAK) levels as potential biomarkers of LN. The performance of TWEAK as a biomarker for nephritis was compared with routinely used laboratory tests in lupus patients, including anti-double stranded DNA antibodies and levels of C3 and C4.ResultsuTWEAK levels were significantly higher in LN patients than in non-LN SLE patients and other disease control groups (P = 0.039). Furthermore, uTWEAK was better at distinguishing between LN and non-LN SLE patients than anti-DNA antibodies and complement levels, while high uTWEAK levels predicted LN in SLE patients with an odds ratio of 7.36 (95% confidence interval = 2.25 to 24.07; P = 0.001). uTWEAK levels peaked during LN flares, and were significantly higher during the flare than at 4 and 6 months prior to or following the flare event. A linear mixed-effects model showed a significant association between uTWEAK levels in SLE patients and their disease activity over time (P = 0.008). sTWEAK levels, however, were not found to correlate with the presence of LN or the degree of nephritis activity.ConclusionsHigh uTWEAK levels are indicative of LN, as opposed to non-LN SLE and other healthy and disease control populations, and reflect renal disease activity in longitudinal follow-up. Thus, our study further supports a role for TWEAK in the pathogenesis of LN, and provides strong evidence for uTWEAK as a candidate clinical biomarker for LN.

Metabolic Disturbances Associated with Systemic Lupus Erythematosus

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.

Urinary Biomarkers in Lupus Nephritis

Renal involvement in patients with systemic lupus erythematosus in the form of severe lupus nephritis is associated with a significant burden of morbidity and mortality. Conventional laboratory biomarkers in current use have not been very successful in anticipating disease flares, predicting renal histology, or decreasing unwanted outcomes. Since early treatment is associated with improved clinical results, it is thus essential to identify new biomarkers with substantial predictive power to reduce the serious sequelae of this difficult to control lupus manifestation. Indeed, considerable efforts and progress have been made over the last few years in the search for novel biomarkers. Since urinary biomarkers are more easily obtainable with much less risk to the patient than repeat renal biopsies, and these may more accurately discern between renal disease and other organ manifestations than their serum counterparts, there has been tremendous interest in studying new candidate urine biomarkers. Below, we review several promising urinary biomarkers under investigation, including total proteinuria and microalbuminuria, urinary proteomic signatures, and the individual inflammatory mediators interleukin-6, vascular cell adhesion molecule-1, CXCL16, IP-10, and tumor necrosis factor-like weak inducer of apoptosis.

Lymphoma risk in systemic lupus: effects of disease activity versus treatment

Objective To examine disease activity versus treatment as lymphoma risk factors in systemic lupus erythematosus (SLE). Methods We performed case–cohort analyses within a multisite SLE cohort. Cancers were ascertained by regional registry linkages. Adjusted HRs for lymphoma were generated in regression models, for time-dependent exposures to immunomodulators (cyclophosphamide, azathioprine, methotrexate, mycophenolate, antimalarial drugs, glucocorticoids) demographics, calendar year, Sjogrens syndrome, SLE duration and disease activity. We used adjusted mean SLE Disease Activity Index scores (SLEDAI-2K) over time, and drugs were treated both categorically (ever/never) and as estimated cumulative doses. Results We studied 75 patients with lymphoma (72 non-Hodgkin, three Hodgkin) and 4961 cancer-free controls. Most lymphomas were of B-cell origin. As is seen in the general population, lymphoma risk in SLE was higher in male than female patients and increased with age. Lymphomas occurred a mean of 12.4 years (median 10.9) after SLE diagnosis. Unadjusted and adjusted analyses failed to show a clear association of disease activity with lymphoma risk. There was a suggestion of greater exposure to cyclophosphamide and to higher cumulative steroids in lymphoma cases than the cancer-free controls. Conclusions In this large SLE sample, there was a suggestion of higher lymphoma risk with exposure to cyclophosphamide and high cumulative steroids. Disease activity itself was not clearly associated with lymphoma risk. Further work will focus on genetic profiles that might interact with medication exposure to influence lymphoma risk in SLE.

Cell-bound complement activation products in systemic lupus erythematosus: comparison with anti-double-stranded DNA and standard complement measurements

Objective To compare the performance characteristics of cell-bound complement (C4d) activation products (CBCAPS) on erythrocyte (EC4d) and B cells (BC4d) with antibodies to double-stranded DNA (anti-dsDNA) and complement C3 and C4 in systemic lupus erythematosus (SLE). Methods The study enrolled 794 subjects consisting of 304 SLE and a control group consisting of 285 patients with other rheumatic diseases and 205 normal individuals. Anti-dsDNA and other autoantibodies were measured using solid-phase immunoassays while EC4d and BC4d were determined using flow cytometry. Complement proteins were determined using immunoturbidimetry. Disease activity in SLE was determined using a non-serological Systemic Lupus Erythematosus Disease Activity Index SELENA Modification. A two-tiered methodology combining CBCAPS with autoantibodies to cellular and citrullinated antigens was also developed. Statistical analyses used area under receiver operating characteristic curves and calculations of area under the curve (AUC), sensitivity and specificity. Results AUC for EC4d (0.82±0.02) and BC4d (0.84±0.02) was higher than those yielded by C3 (0.73±0.02) and C4 (0.72±0.02) (p<0.01). AUC for CBCAPS was also higher than the AUC yielded by anti-dsDNA (0.79±0.02), but significance was only achieved for BC4d (p<0.01). The combination of EC4d and BC4d in multivariate testing methodology with anti-dsDNA and autoantibodies to cellular and citrullinated antigens yielded 80% sensitivity for SLE and specificity ranging from 70% (Sjogrens syndrome) to 92% (rheumatoid arthritis) (98% vs. normal). A higher proportion of patients with SLE with higher levels of disease activity tested positive for elevated CBCAPS, reduced complement and anti-dsDNA (p<0.03). Conclusions CBCAPS have higher sensitivity than standard complement and anti-dsDNA measurements, and may help with the differential diagnosis of SLE in combination with other autoantibodies.

Psychosocial dimensions of sLe: implications for the health care team

Background: The purpose of this exploratory study was threefold, ie, to clarify the unique psychosocial challenges facing those living with systemic lupus erythematosus (SLE), to distinguish which sociodemographic variables impact the lives of SLE patients, and generate knowledge regarding the way patients perceive SLE medication regimens. Methods: This was a cross-sectional exploratory study in 378 patients diagnosed with SLE and receiving services from the SLE Lupus Foundation in New York City. In addition to sociodemographic variables, the instrument used consisted of two scales, ie, the Systemic Lupus Erythematosus Needs Questionnaire (SLENQ) and the Multidimensional Health Locus of Control Scale, as well as questions regarding subjective perceptions of side effects from SLE medication. Results: The highest general cause of self-reported depressive and anxious feelings was changes in appearance due to SLE, and limitations in physical abilities due to SLE (primarily from muscle and joint pain). The higher the sense of control over SLE, the less likely respondents were to report feeling depressed and anxious. African-American and Hispanic SLE patients reported a higher level of unmet psychological needs due to SLE than did their other ethnic counterparts. Weight gain and hair loss were the most likely medication side effects and also the most likely causes of SLE-related depression and anxiety. Conclusion: Those living with SLE are at risk for feelings of depression and anxiety. African-American and Hispanic women are at higher risk for these emotional states. Comprehensive assessment across the disciplines should screen this group of patients for depression and anxiety, and be prepared to refer them to patient education and social work counseling as indicated.

Racial differences in gait velocity in an urban elderly cohort.

To investigate whether there are racial differences in gait velocity in elderly adults.

Increased Education is Associated with Decreased Compliance in an Urban Multi-Ethnic Lupus Cohort

Objectives To investigate the factors associated with medication compliance in a multi-ethnic population of patients with systemic lupus erythematosus in an urban community. Methods We surveyed patients in our cohort using the standardized measures of the Compliance-Questionnaire-Rheumatology (CQR), the Beliefs about Medications Questionnaire (BMQ), as well as patient self-reported compliance. Demographic and clinical characteristics of compliant and non-compliant patients underwent bivariate analysis. A multivariate analysis was then performed on variables of interest. Results Of the 94 patients who agreed to participate in the survey, 89 fully completed each questionnaire. Overall, 48% of patients were compliant by CQR. In multivariate analyses, higher education level was associated with non-compliance. Spanish-speaking patients and those with an income of greater than

Women Coping With Chronic Disease: The Psychosocial Impact of Lupus

15,000 per year were more likely to be compliant. Conclusions In this urban lupus population, several factors may influence medication compliance. Factors associated with non-compliance are not what have been found in other populations. Further studies looking into specific reasons for certain areas of non-compliance as well as addressing these issues will be important in both treatment and outcomes in lupus patients in implementing appropriate interventions.

SLE: Serving the Underserved in an Academic Medical Center

ABSTRACT The purpose of this cross-sectional study (n = 92) was the further identification of the unique psychosocial challenges facing those living with lupus. Specifically, the study aim was to clarify which particular lupus symptomatology may result in which emotional states. The authors review relevant literature, discuss findings, and provide evidence-based recommendations for social workers providing services to patients with lupus. Key findings include the following: Frequent flare-ups resulted in the highest need for assistance with feelings of depression, anxiety, and socioeconomic challenges. Hair loss had the most significant impact on depression, anxiety, and socioeconomic coping. Being hospitalized in the past year for lupus also significantly impacted depression, anxiety, and socioeconomic coping. And, finally, the participants reported that having friends to rely on reduced their reported depression and anxiety. Fatigue from lupus was seen as the highest correlate of anxiety.