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Rheumatoid arthritis at 'epidemic' level
New 'target' identified for cortisone therapy with minimal side effects

Ulm University

With over half a million sufferers in Germany alone, rheumatoid arthritis is the most prevalent form of chronic joint inflammation. Patients often receive cortisone-based medications over the course of many years to help alleviate the pain. Such a long-term treatment, however, can have severe side effects - from osteoporosis to diabetes. A research team led by Ulm University's Professor Jan Tuckermann and Dr. Ulrike Baschant (TU Dresden) has now uncovered hitherto unknown molecular mechanisms of cortisone treatment. Their results were published in 'Annals of the Rheumatic Diseases' and could contribute to a more targeted, low-side-effect treatment of this rheumatoid illness.

Physical activities such as climbing stairs become torturous. In addition to the painful inflammation of the joints, sometimes to the point of destruction, the condition can also affect internal organs. During acute episodes, many rheumatoid arthritis patients rely on cortisone-based drugs to cope with daily life. However, ongoing anti-inflammatory therapy with cortisone can be complicated by resistances and severe side effects such as osteoporosis. Scientists have now traced in detail how cortisone acts on a molecular level and identified important cell types for the anti-inflammatory effect. The development goal for new, more targeted medications: patients should benefit from the pain-relieving effect of the substance without risking consequences for their health.

The group was able to demonstrate both in cell cultures and mouse models with partly inhibited cortisone receptors that so-called synovial fibroblasts play a crucial yet indirect role in analgesic cortisone treatment. These are connective tissue cells in the joint space which proliferate in arthritis and induce inflammation. In cortisone therapy, these fibroblasts primarily activate phagocyting cells (macrophages) which eradicate centres of inflammation. In contrast, the effect of the substance on immune cells via the glucocorticoid receptor is not sufficient to reduce inflammation. 'Thus far, the effect of cortisone-based drugs on synovial fibroblasts was researched in cell cultures only, which made it hard to understand the interplay with other cells. For the first time, we were able to show in the mouse model that this interaction between fibroblasts and phagocyting cells is crucial for the success of the anti-inflammatory cortisone therapy,' says Professor Jan Tuckermann, Director of the Institute of Comparative Molecular Endocrinology in Ulm. The researchers were furthermore able to disprove an established doctrine: evidently, the suppression of 'classical cytokines' - these are the chemical messengers that regulate the immune response - does not play a key role in arthritis treatment.

These laboratory results suggest concrete improvements in rheumatism therapy: 'Future medications should deliver anti-inflammatory agents precisely to connective tissue cells in the joint space, the synovial fibroblasts, or to mediators which we identified in RNA analyses,' says Mascha Koenen from Ulm University, who is first author of the study. Aiming directly at these pharmacological targets could optimise the treatment of rheumatoid diseases and reduce side effects. Chronic joint inflammation not only affects seniors: rheumatoid arthritis can occur at any age - and in young patients it is particularly important to avoid harmful long-term consequences of analgesic and anti-inflammatory therapies.

The research team comprising scientists from the Universities of Ulm, Dresden, Erlangen-Nürnberg and Lyon I as well as the Leibniz Institute on Aging - Franz Lipmann Institute (Jena) received funding from the German Research Foundation DFG (Priority Programme Immunobone). Other supporters were Ulm's Collaborative Research Center 1149, the Boehringer Ingelheim Foundation, The Trilateral Consortium for Osteoporosis as well as a number of funding programmes of Ulm University. 

Text and Media Contact: Annnika Bingmann

Koenen, Mascha; Culemann, Stephan; Vettorazzi, Sabine; Caratti, Giorgio; Frappart, Lucien; Baum, Wolfgang; Krönke, Gerhard; Baschant, Ulrike*; Tuckermann, Jan; Ulm University. The glucocorticoid receptor in stromal cells is essential for glucocorticoid-mediated suppression of inflammation in arthritis. Annals of the Rheumatic Diseases. Published Online First: 11 July 2018. doi: 10.1136/annrheumdis-2017-212762
Prof. Dr. Jan Tuckermann is Director of the Institute of Comparative Molecular Endocrinology at Ulm University
Prof. Dr. Jan Tuckermann is Director of the Institute of Comparative Molecular Endocrinology at Ulm University
First author Mascha K (photo: private)
First author Mascha K (photo: private)
Histological examination of arthritic wild-type mice (top row) and mice with a mutation in the glucocorticoid receptor (GR) in non-immune cells. Wild-type and mutant arthritic mice (left) show strong infiltration of inflammatory cells in the joint (stars). With steriod therapy (right), the inflammatory cells disappear in wild-type mice but not in the mutant mice (right).