Persistent inflammatory pathways in rheumatoid arthritis despite anti-rheumatic treatment

The past years have witnessed tremendous progress in the treatment of rheumatoid arthritis, a chronic debilitating autoimmune disease mainly characterized by joint inflammation with progressive tissue destruction and loss of function. This condition affects 0.5-1% of the population, is associated with important co-morbidities and represents a heavy economical burden. New strategies, employing early and aggressive therapies with classical drugs or new agents, have resulted in impressive improvements in controlling disease activity. In some cases they even lead to clinical remission. Despite potent and efficient biological agents that specifically modulate distinct pathological pathways a large proportion of patients remain unresponsive to these therapies; drug-free remission is also difficult to achieve since attempting discontinuation of treatment usually results in disease flare.

In rheumatoid arthritis joints there is a constant activation of complex networks of cytokines and factors mediating immune interactions and inflammation, in which prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) are important players and contributors to pathogenesis. Our research aimed to investigate the synovial expression of enzymes controlling prostaglandin E2 synthesis and degradation – cyclooxygenase (COX) 1 and 2, microsomal prostaglandin E2 synthase 1 (MPGES1) and 15-prostaglandin dihydrogenase (15-PGDH) as well as enzymes involved in leukotriene synthesis, such as 5-lipoxygenase (LO) and 15-LO. In addition, we evaluated how traditional and new therapies influence these pathways, by analyzing enzyme expression before and after systemic treatment with tumor necrosis factor (TNF) antagonists, rituximab or methotrexate, as well as before and after intra-articular treatment with glucocorticoids. We also evaluated the in vitro effects of TNF antagonists and glucocorticoids on synovial fluid cells and that of methotrexate on synovial fibroblasts.

We demonstrated that synovial tissue from RA patients displayed an important expression of enzymes involved in the metabolism of PGE2, as well as 5-LO and 15-LO. MPGES1 and COX-2, the inflammation-inducible enzymes co-localized mainly in fibroblasts and macrophage-like cells and accounted for the local PGE2 production. Intra-articular glucocorticoids significantly reduced all enzymes involved in the PGE2 cascade – COX-1 and COX-2, MPGES1 and 15-PGDH, but also 5-LO, responsible for leukotriene formation. However, they did not influence the expression of 15-LO, an enzyme involved in the formation of both pro-and anti-inflammatory lipid mediators. Regarding the effects of TNF blockers, rituximab or methotrexate, they did not alter the expression profile of enzymes involved in PGE2 metabolism despite showing clinical efficiency in improving disease activity. Although anti-TNF agents reduced the in vitro expression of MPGES1 and COX-2 in synovial fluid cells, the lack of effect ex vivo in biopsies emphasized once again the differences between synovial compartments and possibly the difficulty in mimicking the micro-environment at the site of inflammation in vitro.

In conclusion, this thesis demonstrates that potent anti-rheumatic drugs currently used in the clinic with good efficiency also leave inflammatory pathways un-affected, which may account for subclinical ongoing disease activity. Blocking the PGE2 pathway by using MPGES1 inhibitors as combination therapy may show benefit in dampening ongoing local inflammation.

List of scientific papers

I. Effects of anti-rheumatic treatments on the prostaglandin E2 biosynthetic pathway. Marina Korotkova, Marie Westman, Karina Roxana Gheorghe, Erik af Klint, Christina Trollmo, Lars Klareskog, Per-Johan Jakobsson. Arthritis & Rheumatism. 2005,52(11):3439-47.

II. Prostaglandin E2 synthesizing enzymes in rheumatoid arthritis B cells and the effects of B cell depleting therapy on enzyme expression. Karina Roxana Gheorghe, Rogier M. Thurlings, Marie Westman, Maartje J. Boumans, Vivianne Malmström, Christina Trollmo, Marina Korotkova, Per-Johan Jakobsson, Paul-Peter Tak. [Submitted]

III. Limited effects of methotrexate on enzymes of the PGE2 pathway in rheumatoid arthritis synovial tissue. Karina Roxana Gheorghe, Syed Sadique, Anca Irinel Catrina, Yvonne Wobst, Per-Johan Jakobsson, Marina Korotkova. [Manuscript]

IV. Expression of 5-lipoxygenase and 15-lipoxygenase in rheumatoid arthritis synovium and effects of intraarticular glucocorticoids. Karina Roxana Gheorghe, Marina Korotkova, Anca Irinel Catrina, Linda Backman, Erik af Klint, Hans-Erik Claesson, Olof Rådmark, Per-Johan Jakobsson. Arthritis Res Ther. 2009;11(3):R83.
https://doi.org/10.1186/ar2717

V. Structural basis for induced formation of the inflammatory mediator prostaglandin E2. Caroline Jegerschöld, Sven-Christian Pawelzik, Pasi Purhonen, Priyaranjan Bhakat, Karina Roxana Gheorghe, Nobuhiko Gyobu, Kaoru Mitsuoka, Ralf Morgenstern, Per-Johan Jakobsson, Hans Hebert. Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11110-5.
https://doi.org/10.1073/pnas.0802894105