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Collaborative lupus research uncovers two new findings

Two separate findings by an expert in systemic lupus erythematosus (SLE or lupus) have identified blood biomarkers that predict which lupus patients will develop heart disease in the future, and found new urine biomarkers for diagnosing lupus nephritis (LN) in children with lupus.

The findings were made by Dr Chandra Mohan, professor of biomedical engineering in the UH Cullen College of Engineering, University of Houston.

Lupus and cardiovascular disease

Lupus is associated with an increased incidence of acute and chronic cardiovascular disease as compared to the general population.

Mohan’s team, in collaboration with Dr Maureen McMahon at University of California Los Angeles, used a comprehensive metabolomic screen of baseline sera from lupus patients to identify metabolites that predict future carotid plaque progression, after eight to nine years of follow-up. Nine patients had SLE without plaque progression, eight had SLE and went on to develop atherosclerotic plaques, and eight patients were controls who did not have SLE.

“The arachidonic acid pathway metabolites, leukotriene B4 (LTB4) and 5-hydroxyeicosatetraenoic acid (5-HETE), and the oxidised lipids 9/13-hydroxyoctodecadienoic acid (HODE) were found to be significantly altered (p < 0.05 and fold-change >2) in SLE patients compared to SLE patients without plaque progression,” reported Mohan in Frontiers in Cardiovascular Medicine. “SLE patients also exhibited significantly altered levels of branched chain amino acid (BCAA) metabolites and plasmalogens compared to the non-SLE controls.”

Combined with the rich literature on these metabolites, the findings suggest that the identified metabolites may not only be prognostic of cardiovascular disease development in SLE patients, but they may also be active drivers of atheroma formation. Early identification of these high risk SLE patients may help institute preventive measures early in the disease course.

The first author, Sahar Baig, is an undergraduate student at the University of Houston.

Children and lupus nephritis

Lupus nephritis, or inflammation of the kidneys, is one of the most severe complications for SLE patients. Kidney disease is a leading cause of death among SLE patients – roughly a quarter of all lupus patients succumb to end-stage renal disease.

Mohan’s team, determined to discover non-invasive biomarkers of LN to replace painful serial kidney biopsies in children, reported his recent findings in Frontiers in Immunology.

With collaborator Dr Scott Wenderfer at Texas Children’s Hospital, Mohan’s team evaluated the performance of 10 urine protein markers of diverse nature including cytokines, chemokines and adhesion molecules in distinguishing disease activity in childhood SLE among 84 paediatric patients.

“Urine concentrations of ALCAM, KIM-1, PF4 and VCAM-1 were significantly higher in active LN patients compared to active non-renal SLE, inactive SLE and healthy controls, with strong diagnostic potential,” said Mohan.

“Urinary ALCAM, PF4, and VCAM-1 are potential biomarkers for predicting kidney disease activity in cSLE and hold potential as surrogate markers of nephritis flares and prognosis in these patients,” he said.

The lead author on this paper was Dr Samar Soliman at Minia University in Egypt. Other clinical contributors were Dr Larry Greenbaum, Emory University, and Dr Sherene Mason, University of Connecticut School of Medicine.

Study 1 details

Baseline Elevations of Leukotriene Metabolites and Altered Plasmalogens Are Prognostic Biomarkers of Plaque Progression in Systemic Lupus Erythematosus.

Sahar Baig, Kamala Vanarsa, Huihua Ding, Anto Sam Crosslee Louis Sam Titus, Maureen McMahon, Chandra Mohan.

Published in Frontiers in Cardiovascular Medicine on 2022

Systemic lupus erythematosus (SLE) is associated with an increased incidence of acute and chronic cardiovascular disease as compared to the general population. This study uses a comprehensive metabolomic screen of baseline sera from lupus patients to identify metabolites that predict future carotid plaque progression, following 8–9 years of follow-up. Nine patients had SLE without plaque progression, 8 had SLE and went on to develop atherosclerotic plaques (SLEPP), and 8 patients were controls who did not have SLE. The arachidonic acid pathway metabolites, leukotriene B4 (LTB4) and 5-hydroxyeicosatetraenoic acid (5-HETE), and the oxidized lipids 9/13-hydroxyoctodecadienoic acid (HODE) were found to be significantly altered (p < 0.05 and fold-change >2) in SLEPP patients compared to SLE patients without plaque progression. SLEPP patients also exhibited significantly altered levels of branched chain amino acid (BCAA) metabolites and plasmalogens compared to the non-SLE controls. Taken together with the rich literature on these metabolites, these findings suggest that the identified metabolites may not only be prognostic of cardiovascular disease development in SLE patients, but they may also be active drivers of atheroma formation. Early identification of these high risk SLE patients may help institute preventive measures early in the disease course.

Study 2 details

Urine ALCAM, PF4 and VCAM-1 Surpass Conventional Metrics in Identifying Nephritis Disease Activity in Childhood-Onset Systemic Lupus Erythematosus

Samar Soliman, Anam Haque, Kamala Vanarsa, Ting Zhang, Faten Ismail, Kyung Hyun Lee, Claudia Pedroza, Larry A. Greenbaum, Sherene Mason, M. John Hicks, Scott Wenderfer, Chandra Mohan.

Published in Frontiers in Immunology on 26 May 2022

Objective
Serial kidney biopsy for repeat evaluation and monitoring of lupus nephritis (LN) in childhood-onset Systemic Lupus Erythematosus (cSLE) remains challenging, thus non-invasive biomarkers are needed. Here, we evaluate the performance of 10 urine protein markers of diverse nature including cytokines, chemokines, and adhesion molecules in distinguishing disease activity in cSLE.

Methods
Eighty-four paediatric patients meeting ≥4 ACR criteria for SLE were prospectively enrolled for urine assay of 10 protein markers normalised to urine creatinine, namely ALCAM, cystatin-C, hemopexin, KIM-1, MCP-1, NGAL, PF-4, Timp-1, TWEAK, and VCAM-1 by ELISA. Samples from active renal (LN) and active non-renal SLE patients were obtained prior to onset/escalation of immunosuppression. SLE disease activity was evaluated using SLEDAI-2000. 59 patients had clinically-active SLE (SLEDAI score ≥4 or having a flare), of whom 29 patients (34.5%) were classified as active renal, and 30 patients (35.7%) were active non-renal. Twenty-five healthy subjects were recruited as controls.

Results
Urine concentrations of ALCAM, KIM-1, PF4 and VCAM-1 were significantly increased in active LN patients versus active non-renal SLE, inactive SLE and healthy controls. Five urine proteins differed significantly between 2 (hemopexin, NGAL, MCP1) or 3 (Cystatin-C, TWEAK) groups only, with the highest levels detected in active LN patients. Urine ALCAM, VCAM-1, PF4 and hemopexin correlated best with total SLEDAI as well as renal-SLEDAI scores (p < 0.05). Urine ALCAM, VCAM-1 and hemopexin outperformed conventional laboratory measures (anti-dsDNA, complement C3 and C4) in identifying concurrent SLE disease activity among patients (AUCs 0.75, 0.81, 0.81 respectively), while urine ALCAM, VCAM-1 and PF4 were the best discriminators of renal disease activity in cSLE (AUCs 0.83, 0.88, 0.78 respectively), surpassing conventional biomarkers, including proteinuria. Unsupervised Bayesian network analysis based on conditional probabilities re-affirmed urine ALCAM as being most predictive of active LN in cSLE patients.

Conclusion
Urinary ALCAM, PF4, and VCAM-1 are potential biomarkers for predicting kidney disease activity in cSLE and hold potential as surrogate markers of nephritis flares in these patients.

 

Frontiers in Cardiovascular Medicine article – Baseline Elevations of Leukotriene Metabolites and Altered Plasmalogens Are Prognostic Biomarkers of Plaque Progression in Systemic Lupus Erythematosus (Open access)

 

Frontiers in Immunology article – Urine ALCAM, PF4 and VCAM-1 Surpass Conventional Metrics in Identifying Nephritis Disease Activity in Childhood-Onset Systemic Lupus Erythematosus (Open access)

 

See more from MedicalBrief archives:

 

UK releases first guideline on care and treatment of adults with lupus

 

Hydroxychloroquine linked to less heart risk in rheumatoid arthritis and lupus

 

The high costs to a medical watchdog of challenging bad science

 

 

 

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