Prostaglandins and other lipids as therapeutic targets and prognostic biomarkers in rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease characterised by systemic inflammation, joint destruction, and chronic pain. Current insights into RA pathogenesis have led to the development of various novel disease-modifying antirheumatic drugs (DMARDs) that suppress inflammation but do not cure the disease. Prostaglandins, along with other lipid mediators, play roles in multiple inflammatory diseases. However, their specific contributions to RA pathogenesis remain largely unknown, and their potential as biomarkers for predicting treatment outcomes has not been thoroughly explored. Therefore, the primary aim of this thesis is to elucidate the mechanisms by which prostaglandin signalling pathways are implicated in RA and to investigate the potential of prostaglandins and lipids as prognostic biomarkers.

In Paper I, we examined the metabolism of 15-deoxy-∆12,14-prostaglandin J2 (15dPGJ2), a metabolite of prostaglandin D2 (PGD2), via microsomal glutathione S- transferase 3 (MGST3). We identified novel cyclopentenones and incorporated them into a comprehensive oxylipin panel for biomarker discovery. In Paper II, we analysed the RNA and protein expression of prostaglandin E2 receptor 2 (EP2) and EP4 receptors in monocytes from RA patients. We observed increased mRNA levels of EP2 and EP4 in monocytes from RA patients; however, their protein expression was suppressed, particularly in CD16+ monocytes. We next focused on biomarker discovery using urine and plasma samples from the NORD-STAR trial. In Paper III, we found that urinary prostanoids increased following anti-TNF and anti-IL6R treatments in RA; however, urinary prostanoids were not predictive of treatment outcomes. In Paper IV, we observed that high baseline levels of very-low-density lipoprotein (VLDL) triglycerides (TG) predicted non-responsiveness to abatacept. RA patients with total TG levels above 150 mg/dl had a remission rate of 10% at week 12, whereas those with total TG levels below 100 mg/dl had remission rates exceeding 50%.

In summary, the findings of this thesis advance our understanding of the roles of prostaglandins and lipids in RA development and progression. These results also encourage further research into the impact of MGST3 depletion and triglyceride metabolism in the pathogenesis of RA.

List of scientific papers

I. Biosynthesis of prostaglandin 15dPGJ2-glutathione and 15dPGJ2- cysteine conjugates in macrophages and mast cells via MGST3. Julia Steinmetz-Späh, Jianyang Liu, Rajkumar Singh, Maria Ekoff, Sanjaykumar Boddul, Xiao Tang, Filip Bergqvist, Helena Idborg, Pascal Heitel, Elin Rönnberg, Daniel Merk, Fredrik Wermeling, Jesper Z Haeggström, Gunnar Nilsson, Dieter Steinhilber, Karin Larsson, Marina Korotkova, Per-Johan Jakobsson. J Lipid Res. 2022; 63(12):100310. https://doi.org/10.1016/j.jlr.2022.100310

II. Reduced expression of prostaglandin E receptors on circulating monocytes as a potential self-protective mechanism in RA. Jianyang Liu, Patricia Riedlova, Helena Idborg, Katerina Chatzidionysiou, Kieran Woolcock, Marina Korotkova, Carl Goodyear, Per-Johan Jakobsson. [Manuscript]

III. Urinary prostanoids are elevated by anti-TNF and anti-IL6 receptor disease-modifying antirheumatic drugs but are not predictive of response to treatment in early rheumatoid arthritis. Jianyang Liu, Helena Idborg, Marina Korotkova, Kristina Lend, Ronald van Vollenhoven, Jon Lampa, Anna Rudin, Dan Nordström, Bjorn Gudbjornsson, Gerdur Gröndal, Till Uhlig, Kim Hørslev-Petersen, Merete Lund Hetland, Mikkel Østergaard, Michael Nurmohamed, Per-Johan Jakobsson. Arthritis Res Ther. 2024; 26(1):61. https://doi.org/10.1186/s13075-024-03295-9

IV. High plasma very-low-density lipoprotein-triglyceride predicts non-responsiveness to abatacept in early untreated rheumatoid arthritis. Jianyang Liu, Mohan Ghorasaini, Kristina Lend, Aswin Verhoeven, Marina Korotkova, Jon Lampa, Michael Nurmohamed, Anna Rudin, Dan Nordström, Tuulikki Sokka-Isler, Bjorn Gudbjornsson, Gerdur Gröndal, Marte Schrumpf Heiberg, Till Uhlig, Kim Hørslev-Petersen, Merete Lund Hetland, Mikkel Østergaard, Ronald van Vollenhoven, Helena Idborg, Martin Giera, Per-Johan Jakobsson. [Manuscript]