Background/Purpose: Patients with neuropsychiatric systemic lupus erythematosus (NPSLE) experience impaired quality of life, whereas the underlying cause(s) remain unclear. The heterogeneity within NPSLE subtypes poses challenges for diagnosis, treatment, and research into disease pathogenesis1. While altered tryptophan metabolism has been reported in SLE2, this study focuses on measuring tryptophan metabolites in specific NPSLE patients to identify clinically relevant subgroups.

Methods: Serum levels of tryptophan (TRP), kynurenine (KYN), and serotonin were measured by ELISA in two independent cohorts. The Peking Union Medical College Hospital (PUMCH) cohort included patients with NPSLE (n=46), lupus nephritis (LN, n=15), SLE without major organ involvement (WMOI, n=30), and healthy controls (HC, n=45). The University of Washington (UW) cohort consisted of patients with NPSLE (n=9), non-NPSLE (n=10), and HC (n=20). IDO activity was assessed indirectly via the KYN/TRP ratio. Unsupervised hierarchical clustering was performed using R4.4.0 and the cluster quality was assessed using the Hopkins’s statistic. Statistical analysis utilized Mann-Whitney U tests and Spearman’s correlation.

Results: TRP metabolite patterns were similar between two cohorts. TRP and serotonin levels were significantly decreased in NPSLE compared to WMOI and HC (Figs. 1, 2A-B), while KYN/TRP ratios were significantly elevated in NPSLE compared to non-NPSLE and HC (Figs. 1, 2C-D). Lower serotonin levels were correlated with higher SLE disease severity and activity (Figs. 2E-F). Clustering of 13 neuropsychiatric symptoms and 4 tryptophan metabolism biomarkers yielded three distinct patient subgroups (Hopkins=0.757). Cluster 1 (n=26) was characterized by the highest prevalence of seizure, cerebrovascular disease, and headaches, alongside the lowest KYN levels and KYN/TRP ratio. Cluster 2 (n=7) exhibited markedly elevated KYN and KYN/TRP ratio and high rates of cognitive impairment, psychosis, and delirium, accompanied by decreased TRP and serotonin levels. Cluster 3 (n=4) featured myelopathy, demyelination, and cranial neuropathy symptoms with the highest KYN levels and increased KYN/TRP ratios, combined with reduced serotonin levels.

Conclusion: Our study is the first to classify NPSLE into three main subgroups based on differential expression of tryptophan metabolites, which simultaneously influence the mental health, nervous, and immune systems3. Variations in biomarker profiles among subgroups can inform clinical diagnosis and treatment strategies. Further studies are needed to determine whether subtypes within each subgroup share similar pathogenic mechanisms. References:1. The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum. 1999;42:599-608.2. Lood C, Tyden H, Gullstrand B, et al. Type I interferon-mediated skewing of the serotonin synthesis is associated with severe disease in systemic lupus erythematosus. PLoS One. 2015;10:e0125109.3. Cervenka I, Agudelo LZ, Ruas JL. Kynurenines: Tryptophan’s metabolites in exercise, inflammation, and mental health. Science. 2017;357.

Figure 1. Serum levels of tryptophan metabolites and correlations between serotonin and clinical scores in patients from PUMCH cohort.

Serum levels of (A) Tryptophan; (B) Serotonin; (C) Kynurenine; (D) the Kynurenine/Tryptophan ratio were analyzed in patients with Neuropsychiatric Systemic Lupus Erythematosus (NPSLE, n=46), lupus nephritis (LN, n=15), SLE without major organ involvement (WMOI, n=30), and healthy controls (HC, n=45). Correlations between serotonin and (E) Physician Global Assessment (PGA) total scores; (F) Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). For statistical analyses, *p < 0.05, **p < 0.01, ***p < 0.001, **** p < 0.0001.

Figure 2. Serum levels of tryptophan metabolites in patients from UW cohort.

Serum levels of (A) Tryptophan; (B) Serotonin; (C) Kynurenine; (D) the Kynurenine/Tryptophan ratio were analyzed in patients with Neuropsychiatric Systemic Lupus Erythematosus (NPSLE, n=9), non-NPSLE (n=10), and healthy controls (HC, n=20).

Figure 3. Different tryptophan metabolism biomarkers and clinical symptoms of the patients in three clusters

TRP: tryptophan; KYN: kynurenine; CNS: central nervous system; PNS: peripheral nervous system.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/altered-tryptophan-metabolism-in-neuropsychiatric-lupus-a-cluster-analysis-to-identify-distinct-subgroups/