Low-Dose Radiotherapy Leads to a Systemic Anti-Inflammatory Shift in the Pre-Clinical K/BxN Serum Transfer Model and Reduces Osteoarthritic Pain in Patients

Abstract

Osteoarthritis (OA) is the leading degenerative joint disease in the western world and leads, if left untreated, to a progressive deterioration of joint functionality, ultimately reducing quality of life. Recent data has shown, that especially OA of the ankle and foot are among the most frequently affected regions. Current research in OA points towards a complex involvement of various cell and tissue types, often accompanied by inflammation. Low-dose radiotherapy (LDRT) is widely used for the treatment of degenerative and inflammatory diseases. While the reported analgesic effects are well known, the underlying molecular mechanisms are only poorly understood. We therefore correlated a clinical approach, looking at pain reduction in 196 patients treated with LDRT with a pre-clinical approach, utilizing the K/BxN serum transfer mouse model using flow cytometry and multiplex ELISA for analysis. While an improvement of symptoms in the majority of patients was found, patients suffering from symptoms within the tarsi transversa show a significantly lower level of improvement. Further, a significant impact of therapy success was detected depending on whether only one or both feet were affected. Further, patients of younger age showed a significantly better outcome than older ones while needing fewer treatment series. When looking on a cellular level within the mouse model, a systemic alteration of immune cells namely a shift from CD8+ to CD4+ T cells and reduced numbers of DCs was observed. A general reduction of inflammatory cytokines was detected, with significant alterations in IL-4 and IL-17 levels, all of which could potentially be responsible for the highly effective clinical improvement in patients. Taken together our data indicate that LDRT can be regarded as a highly effective treatment option for patients suffering from OA of the foot and ankle, in terms of analgesic effects, especially in younger patients. Furthermore, the observed effects are mediated by an interplay of cellular and soluble immune factors, as observed in the K/BxN serum transfer model. With this interdisciplinary approach we aim to encourage the usage of LDRT as an additive treatment strategy not only as a last resort, but also earlier in the course of disease.

Effects of serial radon spa therapy on pain and peripheral immune status in patients suffering from musculoskeletal disorders– results from a prospective, randomized, placebo-controlled trial

“…A second major endpoint of the RAD-ON02 trial was the evaluation of the longitudinal immune status after radon spa, as immunomodulatory effects are under discussion as a mode of action of radon spa. For therapy with X-rays, the modulation of the immune system and the amelioration of inflammation has already been confirmed in preclinical models and in clinical investigations (8,9,11,41,42). In agreement, longitudinal systemic immune modulations in patients suffering from MSDs have also been detected in the observatory RAD-ON01 trial (21,26).…”

ArthroRad trial: randomized multicenter single-blinded trial on the effect of low-dose radiotherapy for painful osteoarthritis—final results after 12-month follow-up

“…All these effects are maximal after single doses of 0.3–0.7 Gy [ 7 – 9 ]. More recent research shows a shift in blood cell counts, while the total number of leukocytes remains unchanged and a general reduction in inflammatory cytokines [ 10 , 11 ]. Furthermore, low-dose radiotherapy inactivates mitochondrial function [ 12 ].…”