Background/Purpose: Today many treatment options for Rheumatoid Arthritis (RA) and degenerative inflammatory musculoskeletal diseases are available, however, not all patients respond properly or have to reduce or stop their medication due to adverse reactions. In such cases treatment with low dose-radiotherapy (LD-RT) with X-rays can be beneficial to attenuate inflammation, reduce pain and improve the quality of life, as suggested by studies by Ott et al. (2012-2014) and Seegenschmiedt et al. (1998). Preclinical in vitro models have revealed that doses of X-ray ranging from 0.1 Gray (Gy) to 1.0 Gy have an impact on immune cells and reduce the inflammatory phenotype of endothelial cells, neutrophils, and macrophages. A dose of 0.5 Gy has been shown to be the most efficient. Even though these mechanisms are well known and accepted, health care professionals and patients often refrain from low LD-RT. The main reasons for that are fear of radiation, lack of randomized trials and lack of in vivo examinations with inflammatory animal models. We therefore aimed to examine the impact of local LD-RT with 0.5 Gy on inflammation and bone homeostasis in human TNF-α transgenic (hTNF-αtg) mice.

Methods: Inflamed joints of hTNFα tg mice were locally irradiated (0.5 Gy, 250 kV, 15mA) and monitored over a time course of 30 days. Afterwards, paw sections were analyzed using histomorphological methods and the OsteoMeasure™ Software. In an ex vivo setting, we investigated the effects of LD-RT on bone marrow-derived osteoclasts (OC) of hTNFαtg mice as well as on murine and human fibroblast-like synoviocytes (FLS) using qPCR, ELISA and flow cytometry.

Results: A significant improvement of grip strength over 30 days in mice treated locally with 1x 0.5 Gy of X-rays was observed. Further histological analysis of irradiated paws showed a significant reduction of the inflammatory area as identified by decrease of leukocyte infiltration, reduction of bone loss, and OC numbers in comparison to mock treated control animals. Ex vivo differentiation of hTNFαtg mice derived OCs was also significantly reduced after exposure to X-rays in the dose range of 0.5 to 2.0 Gy. Further, OC function seems to be down-regulated after an irradiation with 2x 0.5 Gy as indicated by qPCR analysis. Irradiation of human RA FLS resulted in a dose-dependent reduction of cell growth and increased numbers of apoptotic cells.

Conclusion: On a mechanistic preclinical osteoimmunlogical basis our findings support that LD-RT can influence TNF dependent arthritis. The results from our OC experiments further imply that LD-RT does not only have a considerably decelerating effect on inflammation, but also on bone erosion. Future placebo controlled studies in humans need to address its effect in RA patients.

Acknowledgement: This project is supported by the German Federal Ministry of Education and Research (GREWIS, 02NUK017G).

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-osteoimmunological-mechanistic-basis-of-low-dose-radiotherapy-in-tnf-driven-arthritis/