Tamar Rubinstein

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.

Urinary neutrophil gelatinase-associated lipocalin as a novel biomarker for disease activity in lupus nephritis

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 visits 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.

The novel role of neutrophil gelatinase-B associated lipocalin (NGAL)/Lipocalin-2 as a biomarker for lupus nephritis

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.

Biomarkers for kidney involvement in pediatric lupus

Lupus nephritis (LN), the renal involvement in systemic lupus erythematosus, is currently diagnosed by histopathology obtained by percutaneous renal biopsy and is associated with increased morbidity and mortality in both adults and children. LN is more prevalent and severe in children, requiring aggressive and prolonged immunosuppression. The consequences of the diagnosis and its treatment have devastating long-term effects on the growth, well-being and quality of life of affected children. The paucity of reliable clinical indicators of the presence and severity of renal involvement have contributed to a halt in the reduction of progression to end-stage renal disease in recent years. Here, we discuss the recent development of biomarkers in the management of LN and their role as therapeutic targets.

Identifying Targets for Improving Mental Healthcare of Adolescents with Systemic Lupus Erythematosus: Perspectives from Pediatric Rheumatology Clinicians in the United States and Canada

Objective. To identify targets for improving mental healthcare of adolescents with systemic lupus erythematosus (SLE) by assessing current practices and perceived barriers for mental health intervention by pediatric rheumatology clinicians. Methods. Members of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) completed a Web-based survey assessing current mental health practices, beliefs, and barriers. We examined associations between provider characteristics and the frequency of barriers to mental health screening and treatment using multivariable linear regression. Results. Of the 375 eligible CARRA members, 130 responded (35%) and 119 completed the survey. Fifty-two percent described identification of depression/anxiety in adolescents with SLE at their practice as inadequate, and 45% described treatment as inadequate. Seventy-seven percent stated that routine screening for depression/anxiety in pediatric rheumatology should be conducted, but only 2% routinely used a standardized instrument. Limited staff resources and time were the most frequent barriers to screening. Respondents with formal postgraduate mental health training, experience treating young adults, and practicing at sites with very accessible mental health staff, in urban locations, and in Canada reported fewer barriers to screening. Long waitlists and limited availability of mental health providers were the most frequent barriers to treatment. Male clinicians and those practicing in the Midwest and Canada reported fewer barriers to treatment. Conclusion. Pediatric rheumatology clinicians perceive a need for improved mental healthcare of adolescents with SLE. Potential strategies to overcome barriers include enhanced mental health training for pediatric rheumatologists, standardized rheumatology-based mental health practices, and better integration of medical and mental health services.

Delays to Care in Pediatric Lupus Patients: Data From the Childhood Arthritis and Rheumatology Research Alliance Legacy Registry

Prompt treatment for lupus is important to prevent morbidity. A potential barrier to early treatment of pediatric lupus is delayed presentation to a pediatric rheumatologist. To better understand factors contributing to delayed presentation among pediatric lupus patients, we examined differences in demographic and clinical characteristics of lupus patients within the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry with regard to time between symptom onset and presentation to a pediatric rheumatologist.

Disordered eating in adulthood is associated with reported weight loss attempts in childhood.

OBJECTIVE To determine whether history of attempted weight loss in childhood (age ≤ 12 years) is associated with binge eating disorder (BED) and unhealthy weight loss behaviors in adults. METHOD Cross-sectional analysis from baseline visit data of 588 participants of a clinical trial. Data were collected from survey answers on health status, nutritional status, weight loss history, and weight loss behaviors. RESULTS History of childhood weight loss attempts was associated with high odds of BED in adults (odds ratio [OR] 3.4; 95% confidence interval [CI] 2.8-6.3) and high odds of unhealthy weight loss behaviors (OR 2.3; 95% CI 1.2, 2.6). A linear trend was observed in which young age at first attempted weight loss was associated with increased odds of both BED and unhealthy weight loss behaviors. DISCUSSION Weight loss attempts in childhood may be a risk factor for the development of unhealthy eating behaviors and BED in adults.

Addressing Mental Health in Pediatric Rheumatology

Purpose of reviewTo review the current evidence for the management of mental disorders for youth with rheumatologic diseases, and elucidate gaps in knowledge requiring further investigation to improve management of mental health conditions for these patients.Recent findingsDepression and anxiety are common in youth with pediatric rheumatologic diseases and are associated with poor adherence, quality of life, and long-term outcomes. They have a complex etiology and require consideration of overall disease management as well as contributing psychosocial factors. Increasing evidence indicates that current screening strategies fail to fully support this patient population and that many patients with mental health problems go untreated.SummaryEffective strategies to approach mental health in pediatric rheumatology patients are likely those that incorporate both behavioral and pharmacological therapies, and include families and social support. Preliminary evidence shows that adopting screening practices in pediatric rheumatology clinics will improve detection of mental disorders and is acceptable to patients and families. Broad mental health screening strategies should be considered for youth with rheumatologic diseases. Further research is necessary to better understand which treatments are most effective for depression, anxiety, and other forms of mental disorders observed in pediatric rheumatology.

Gaps in Mental Health Care for Youth with Rheumatologic Conditions: A Mixed Methods Study of Perspectives from Behavioral Health Providers

To identify behavioral health provider perspectives on gaps in mental health care for youth with rheumatologic conditions.

Mental health care for youth with rheumatologic diseases – bridging the gap

Youth with rheumatologic diseases have a high prevalence of comorbid mental health disorders. Individuals with comorbid mental health disorders are at increased risk for adverse outcomes related to mental health as well as their underlying rheumatologic disease. Early identification and treatment of mental health disorders has been shown to improve outcomes, but current systems of care fall short in providing adequate mental health services to those in need. Pediatric rheumatologists are uniquely positioned to provide mental health screening and intervention for youth with rheumatologic diseases due to the frequency of patient encounters and ongoing therapeutic relationship with patients and families. However, additional training is likely required for pediatric rheumatologists to provide effective mental health care, and focusing efforts on providing trainees with mental health education is key to building competency. Potential opportunities for improved mental health education include development of clinical guidelines regarding mental health screening and management within pediatric rheumatology settings and incorporation of mental health didactics, workshops, and interdisciplinary clinic experiences into pediatric rheumatology fellowship curricula. Additional steps include mental health education for patients and families and focus on system change, targeting integration of medical and mental health care. Research is needed to better define the scope of the problem, determine effective strategies for equipping pediatric rheumatologists with skills in mental health intervention, and develop and implement sustainable systems for delivery of optimal mental health care to youth with rheumatologic diseases.