Synovial 5-Lipoxygenase-Derived Oxylipins Define a Lympho-Myeloid-Enriched Synovium.

OBJECTIVE: Oxylipins are bioactive lipids derived from polyunsaturated fatty acids (PUFAs) that modulate inflammation and may remain overexpressed in refractory synovitis. In plasma, they could also be biomarkers of synovial pathology. The aim of this study is to determine if synovial oxylipins in inflamed joints correlate with plasma oxylipins and with synovial histologic patterns. METHODS: Patients with established rheumatoid or psoriatic arthritis with active disease despite treatment were recruited, and paired synovial tissue (ST) and plasma were collected. Oxylipins were determined by liquid chromatography with tandem mass spectrometry and were classified into groups according to their PUFA precursor and enzyme. The expression of CD20, CD68, CD3, and CD138 was obtained to describe synovial histology. Cell-specific expression of oxylipin-related genes was identified by examining available synovial single-cell RNA sequencing data. RESULTS: We included a total of 32 ST and 26 paired-plasma samples. A total of 71 oxylipins were identified in ST, but only 24 were identified in plasma. Only levels of 9,10-dihydroxyoctadecenoic acid and tetranor-Prostaglandin FM had a significant positive correlation between plasma and ST. Several oxylipins and oxylipin-related genes were differentially expressed among synovial phenotypes. Specifically, several 5-lipoxygenase (LOX)-derived oxylipins were statistically elevated in the lympho-myeloid phenotype and associated with B cell expression in rheumatoid arthritis samples. CONCLUSION: The lack of correlation between ST and plasma oxylipins suggests that ST lipid profiling better characterizes active pathways in treated joints. Synovial 5-LOX-derived oxylipins were highly expressed in lympho-myeloid-enriched synovium. Combination therapy with 5-LOX inhibitors to improve refractory inflammation may be needed in patients with this histologic group.

Synovial tissue metabolomic profiling reveal biomarkers of synovial inflammation in patients with osteoarthritis.

Objective: Inflammatory responses are associated with changes in tissue metabolism. Prior studies find altered metabolomic profiles in both the synovial fluid (SF) and serum of osteoarthritis subjects. Our study determined the metabolomic profile of synovial tissue (ST) and SF of individuals with osteoarthritis (OA) and its association with synovial inflammation. Design: 37 OA ST samples were collected during joint replacement, 21 also had SF. ST samples were fixed in formalin for histological analysis, cultured (explants) for cytokine analysis by enzyme-linked immunosorbent assay, or snap-frozen for metabolomic analysis. ST samples were categorized by Krenn synovitis score and picrosirius red. CD68 and vimentin expression was assessed by immunohistochemistry and semi-quantified using Image J. Proton-nuclear magnetic resonance (1H NMR) was used to acquire a spectrum from ST and SF samples. Chenomx NMR suite 8.5 was used for metabolite identification and quantification. Metaboanalyst 5.0, SPSS v26, and R (v4.1.2) were used for statistical analysis. Results: 42 and 29 metabolites were detected in the ST and SF respectively by 1H NMR. Only 3 metabolites, lactate, dimethylamine, and creatine positively correlated between SF and ST. ST concentrations of several metabolites (lactate, alanine, fumarate, glutamine, glycine, leucine, lysine, methionine, trimethylamine N-oxide, tryptophan and valine) were associated with synovitis score, mostly to the lining score. IL-6, acetoacetate, and tyrosine in SF predicted high Krenn synovitis scores in ST. Conclusion: Metabolomic profiling of ST identified metabolic changes associated with inflammation. Further studies are needed to determine whether metabolomic profiling of synovial tissue can identify new therapeutic targets in osteoarthritis.

Lipidomic Profiling in Synovial Tissue.

The analysis of synovial tissue offers the potential for the comprehensive characterization of cell types involved in arthritis pathogenesis. The studies performed to date in synovial tissue have made it possible to define synovial pathotypes, which relate to disease severity and response to treatment. Lipidomics is the branch of metabolomics that allows the quantification and identification of lipids in different biological samples. Studies in animal models of arthritis and in serum/plasma from patients with arthritis suggest the involvement of different types of lipids (glycerophospholipids, glycerolipids, sphingolipids, oxylipins, fatty acids) in the pathogenesis of arthritis. We reviewed studies that quantified lipids in different types of tissues and their relationship with inflammation. We propose that combining lipidomics with currently used "omics" techniques can improve the information obtained from the analysis of synovial tissue, for a better understanding of pathogenesis and the development of new therapeutic strategies.

Metabolomics profiling predicts outcome of tocilizumab in rheumatoid arthritis: an exploratory study.

INTRODUCTION: To study metabolic signatures can be used to identify predictive biomarkers for a patient's therapeutic response. OBJECTIVES: We hypothesized that the characterization of a patients' metabolic profile, utilizing one-dimensional nuclear magnetic resonance (1H-NMR), may predict a response to tocilizumab in patients with rheumatoid arthritis (RA). METHODS: 40 active RA patients meeting the 2010 ACR/EULAR classification criteria initiating treatment with tocilizumab were recruited. Clinical outcomes were determined at baseline, and after six and twelve months of treatment. EULAR response criteria at 6 and 12 months to categorize patients as responders and non-responders. Blood was collected at baseline and after six months of tocilizumab therapy. 1H-NMR was used to acquire a spectra of plasma samples. Chenomx NMR suite 8.5 was used for metabolite identification and quantification. SPSS v.27 and MetaboAnalyst 4.0 were used for statistical and pathway analysis. RESULTS: Isobutyrate, 3-hydroxybutyrate, lysine, phenylalanine, sn-glycero-3-phosphocholine, tryptophan and tyrosine were significantly elevated in responders at the baseline. OPLS-DA at baseline partially discriminated between RA responders and non-responders. A multivariate diagnostic model showed that concentrations of 3-hydroxybutyrate and phenylalanine improved the ability to specifically predict responders classifying 77.1% of the patients correctly. At 6 months, levels of methylamine, sn-glycero-3-phosphocholine and tryptophan tended to still be low in non-responders. CONCLUSION: The relationship between plasma metabolic profiles and the clinical response to tocilizumab suggests that 1H-NMR may be a promising tool for RA therapy optimization. More studies are needed to determine if metabolic profiling can predict the response to biological therapies in RA patients.

Association of myostatin, a cytokine released by muscle, with inflammation in rheumatoid arthritis: A cross-sectional study.

ABSTRACT: Myostatin is a cytokine produced and released by myocytes that might have an outstanding role not only in muscle wasting during cachexia but also in inflammation. Herein we explore the association between myostatin levels and inflammatory parameters in rheumatoid arthritis (RA).One hundred twenty-seven women without rheumatic diseases and 84 women with a diagnosis of RA were assessed in a cross-sectional study. Outcomes reflecting the activity of the arthritis including Disease Activity Score (DAS28-ESR) and impairment in functioning by the Health Assessment Questionnaire-Disability Index were assessed in RA. We obtained Skeletal muscle mass index (SMI), fat-free mass index (FFMI), and fat mass index using dual-energy x-ray absorptiometry. Serum myostatin was determined by enzyme-linked immunosorbent assay. Myostatin levels were correlated with disease activity and parameters of muscle mass.The SMI was lower and concentration of myostatin was higher in RA patients than in controls (P = .008 and P < .001, respectively). Myostatin significantly positively correlated with C-reactive protein (rho = 0.48, P < .001), erythrocyte sedimentation rate (rho  = 0.28, P = .009), and DAS28-ESR (rho = 0.22, P  = .04), and negatively correlated with SMI (rho = -0.29, P = .008), (FFMI) (rho = -0.24, P = .027). In the multivariate logistic regression analysis, levels of myostatin remained associated with disease activity in RA (P = .027).In our study, myostatin was associated with disease activity in RA patients, suggesting a mechanistic link between myostatin, muscle wasting and inflammation in RA.

Circulating Pro- and Anti-Inflammatory Metabolites and Its Potential Role in Rheumatoid Arthritis Pathogenesis.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that affects synovial joints, leading to inflammation, joint destruction, loss of function, and disability. Although recent pharmaceutical advances have improved the treatment of RA, patients often inquire about dietary interventions to improve RA symptoms, as they perceive pain and/or swelling after the consumption or avoidance of certain foods. There is evidence that some foods have pro- or anti-inflammatory effects mediated by diet-related metabolites. In addition, recent literature has shown a link between diet-related metabolites and microbiome changes, since the gut microbiome is involved in the metabolism of some dietary ingredients. But diet and the gut microbiome are not the only factors linked to circulating pro- and anti-inflammatory metabolites. Other factors including smoking, associated comorbidities, and therapeutic drugs might also modify the circulating metabolomic profile and play a role in RA pathogenesis. This article summarizes what is known about circulating pro- and anti-inflammatory metabolites in RA. It also emphasizes factors that might be involved in their circulating concentrations and diet-related metabolites with a beneficial effect in RA.