LC–MS Metabolomics Links Blood Molecules to Lupus

While scientists have made good progress in using metabolomics, the study of the many small molecules in the body, to search for markers of lupus, an autoimmune disease in which the immune system attacks the body’s own tissues, few studies have looked at how these molecules relate to the specific ways lupus affects each patient, such as which organs are damaged and how the disease is progressing based on established measures. To help fill this gap, a team of researchers analyzed blood samples from 60 people with lupus, using liquid chromatography–mass spectrometry (LC–MS) to get a broad picture of the small molecules in each patient’s blood and see how these patterns matched up with their symptoms. The team published their findings in the journal Frontiers in Immunology.¹

What Is Lupus, and Why Is It So Hard to Develop New Treatments for It?

Lupus is an autoimmune disease in which the immune system mistakenly attacks the body’s own tissues, causing inflammation that can affect many different organs. It can cause serious illness and shorten lives, and most people with lupus end up with some lasting organ damage over time.² The disease mostly affects women, and it is more common and often more severe in people of non-European backgrounds, including people of African, Asian, and Indigenous descent.³

Because lupus varies so much from one person to another, it is hard for doctors to measure accurately how active the disease is or how well a treatment is working.² This has caused problems for many clinical trials, and as a result, very few new targeted treatments for lupus have been approved, which stands in contrast to other autoimmune conditions, such as rheumatoid arthritis, where there has been major progress.⁴ Finding reliable markers in the body that show how active a patient’s lupus is and how they’re responding to treatment could, in the opinion of the authors of the paper, make clinical trials more successful, which would ultimately lead to better treatments and better outcomes for patients.¹

How Did the Researchers Analyze the Data to Find Links Between Blood Molecules and Lupus Symptoms?

The researchers left out any molecules that were missing data or that they couldn’t identify with confidence. They then used two kinds of statistical analysis to look for links between the remaining molecules and patients’ symptoms. The first compared how much of each molecule was present in different groups of patients. The second was a machine-learning method that picks out the molecules most useful for predicting a particular feature of the disease while filtering out the rest. To make sure the results weren’t simply driven by other differences between patients, the analysis considered each person’s age, sex, and ethnicity, and whether their kidneys were working less well than normal. The team measured how active each patient’s lupus was using a standard scoring system that doctors use to rate symptoms and considered the disease to be affecting the kidneys if there was protein in the patient’s urine.¹

What Did the Study Find About the Links Between Blood Molecules and Different Features of Lupus?

The researchers looked at 364 molecules in blood samples from 58 people with lupus. Most patients were women (91%), their typical age was around 42, they were evenly split between Asian and European backgrounds, and half had active disease at the time.¹

Twenty molecules were linked to whether patients were taking steroid medications, although none of them could reliably predict steroid use on their own. Several molecules stood out in relation to lupus nephritis, which is kidney inflammation caused by lupus. A molecule that is likely a type of cholesterol-related compound was found at lower levels in patients whose kidney involvement had been confirmed by biopsy, as well as in those with active kidney disease. In contrast, two molecules, homocitrulline and a modified form of the amino acid lysine, were found at higher levels in patients with active kidney disease. Another related lysine compound was higher in patients with biopsy-confirmed kidney involvement. Glutamic acid, an amino acid, was higher in patients whose lupus was in remission without the need for steroids. These links held up when the researchers tested whether the molecules could predict each feature.¹

Looking at broader groups of related chemical processes in the body, the team found that different processes were tied to different aspects of the disease. The breakdown of certain amino acids was linked to active disease, while processes involved in energy production were linked to organ damage. Remission was associated with the processing of several amino acids, and remission without steroids was linked to processes such as the body’s handling of waste nitrogen and the breakdown of certain amino acids and the building blocks of DNA.¹

“Associations between glucocorticoid use and serum metabolites,” write the authors of the paper,¹ “highlight the importance of accounting for this in SLE metabolomics studies. Significant associations between serum metabolites and SLE phenotypes, particularly previously unreported associations between methylated and carbamylated lysine derivatives with LN, support the promise of serum metabolomics to identify prognostic SLE biomarkers.”

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References

1. Eades, L. E.; Barlow, C. K.; Jeppe, K. J. et al. Untargeted Serum Metabolomics in Systemic lupus Erythematosus Reveals Candidate Metabolomic Signatures Associated with Clinical Phenotypes and Glucocorticoid Use. Front Immunol. 2026, 17, 1925827. DOI: 10.3389/fimmu.2026.1925827
2. Morand, E. F.; Fernandez-Ruiz, R.; Blazer, A. et al. Advances in the Management of Systemic Lupus Erythematosus. BMJ 2023, 383, e073980. DOI: 10.1136/bmj-2022-073980
3. Eades, L. E.; Hoi, A. Y.; Liddle, R. et al. Systemic Lupus Erythematosus in Aboriginal and Torres Strait Islander Peoples in Australia: Addressing Disparities and Barriers to Optimising Patient Care. Lancet Rheumatol. 2024, 6 (10), e713-e726. DOI: 10.1016/S2665-9913(24)00095-X
4. Vincent, F. B.; Figgett, W. A.; Hibbs, M. L. B Cell-targeted Therapies in Systemic Lupus Erythematosus. In: Pathogenesis of Systemic Lupus Erythematosus: Insights From Translational Research, Hoi, A. Ed. Springer International Publishing, 2021. p. 37–52.