Metabolite Reductions Reveal Insights into Chronic Pruritus of Unknown Origin Pathogenesis

Shawn Kwatra, MD

Credit: University of Maryland, School of Medicine

A new study identified reductions in several circulating plasma metabolites in patients with chronic pruritus of unknown origin (CPUO), along with the downregulation of pathways associated with catecholamine and tryptophan biosynthesis.¹

“Our study found a distinct deficit in certain metabolite biomarkers, including several important amino acids and other metabolites involved in immune system regulation in patients with CPUO compared to a healthy control group,” said lead investigator Shawn Kwatra, MD, the Joseph W. Burnett Endowed Professor and Chair of Dermatology at UMSOM and Chief of Service Dermatology at the University of Maryland Medical Center (UMMC), in the press release.² “This is an exciting finding because it provides novel insights into the cause of this condition and identifies potential future therapeutic targets to consider.”

CPUO is characterized by a chronic itch lasting ≥ 6 weeks without an identifiable primary cause.¹ This condition is most prevalent among older adults, and all the current therapies used to manage symptoms are off-label.

Treatment options often have poor efficacy and leave patients with a significantly impaired quality of life; it has been documented that CPUO impairs quality of life similar to patients suffering from congestive heart failure or stroke. However, a phase 2 open-label, single-center, nonrandomized trial published back in June showed 200 mg of orally administered abrocitinib was effective and well-tolerated in patients with CPUO.³

Identifying circulating blood biomarkers can illuminate the disease pathogenesis.¹ Thus, investigators conducted a cross-sectional study to investigate changes in circling blood metabolites in patients with CPUO and to identify potential therapeutic targets. This marked the first study to use plasma metabolomics for CPUO.

Kwatra and colleagues collected plasma from 11 patients with CPUO and 11 controls for mass-spectrometry-based metabolite data. Patients were matched 1:1 based on age, sex, and race. Patients with CPUO and controls had a mean age of 68.55 ± 15.68 and 59.81 ± 11.99 years, respectively.

The samples of patients with CUPO and controls detected 39 metabolites. Using a t-test analysis, the team observed 15 metabolites differed significantly in the blood of patients with CPUO compared to controls (q-value [FDR-adjusted p-value] < .001).

These metabolites included 9 amino acids (isoleucine, L-tyrosine, threonine, DL-tryptophan, L-valine, methionine, glycine, lysine, and L-phenylalanine), 4 amino acid derivatives (creatinine, DL-carnitine, acetyl-L-carnitine, and indole-3-acrylic acid), and 2 aromatic and fatty acid derivatives (2-hydroxycinnamic acid and oleamide).

“Many of these biomarkers that we found in depleted amounts in the blood of CPUO patients, like tryptophan and glycine, could contribute to the underlying pathogenesis of this condition, but we certainly need larger studies to investigate this further,” Kwatra said.²

Metabolites were also correlated with itch severity.¹ For instance, lower glycine levels were associated with more severe itching, indicating that glycine may play a role in regulating cell growth and itch severity in psoriasis.

The metabolic set enrichment analysis identified significant downregulation of several pathways in CPUO, including phenylalanine, tyrosine, and tryptophan biosynthesis (P = 1.52 × 10–8); phenylalanine metabolism (P = 1.52 × 10–8); and glycine, serine, and threonine metabolism (P = 2.82 × 10–11).

“Our study identifies a distinct functional circulating plasma metabolic deficit in CPUO patients, including amino acids, amino acid derivatives, and aromatic and fatty acid derivatives,” investigators concluded. “These findings must be considered in the context of itch pathogenesis, particularly the role of neuronal and immune modulators in pruritus.”

References

1. ^{Manjunath J, Parthasarathy V, Joel MZ, et al. Plasma metabolomic profiling reveals a novel circulating biomarker signature in chronic pruritus of unknown origin. Sci Rep. 2024;14(1):17472. Published 2024 Jul 29. doi:10.1038/s41598-024-67170-y}
2. ^{Patients with Unexplainable Chronic Itch Have Unique Blood Biomarkers that Could Eventually Lead to New Targeted Treatments. News Wire. August 14, 2024. https://www.newswise.com/articles/view/815598/. Accessed August 27, 2024.}
3. ^{Smith, T. Abrocitinib Effective for Patients with Prurigo Nodularis, Chronic Pruritus of Unknown Origin. HCPLive. June 6, 2024. https://www.hcplive.com/view/abrocitinib-effective-for-patients-with-prurigo-nodularis-chronic-pruritus-of-unknown-origin. Accessed August 27, 2024.}