Evaluation of Bone Quality in Patients With Rheumatoid Arthritis Treated With Baricitinib: Single Centre, Mode of Action Study (BARE BONE)

Systemic and local bone loss is a pathognomonic feature of rheumatoid arthritis and can be seen in a very early phase of the disease. Understanding the pathogenesis of rheumatoid arthritis (RA) has advanced substantially in recent years. The mode of action of immunosuppressive medication on pro-inflammatory cytokines, different cell types or activation of cells is intensively studied and understood. In contrary, little is known on how these medications influence bone damage in peripheral joints in terms of bone density, bone microstructure, bone quality or erosions. This is due to different reasons. One factor is the lack of suitable, user-independent imaging tools for outcome measurements. For example, using conventional X-ray of the hand and fingers, no information can be obtained about the volumetric density, microarchitecture, bone quality or volumetric erosion size. Applying Dual-energy Xray absorptiometry (DXA) of peripheral joints, does also not provide information about the volumetric bone density and no accurate difference can be obtained regarding cortical or trabecular density parameters. Magnetic Resonance Imaging (MRI) as an outcome measure in RA enables good the detection and partly quantification of erosions, however no information about bone density can be quantified. HR-pQCT (high resolution peripheral quantitative computed tomography) imaging allows in detail (82 micrometer isotropic voxelsize) evaluation of density, microstructure parameters as well as quantification of erosions in peripheral joints. Furthermore, HR-pQCT data allows the biomechanical analysis of the bone and therefore statements on the bone quality can be made.

Modulating inhibitors targeting the Janus Kinase (JAK) - Signal Transducer and Activator of Transcription (STAT) pathway, effect pro-inflammatory cytokines and have been approved for therapy in RA patients. Analysis of the inhibition of the JAK-STAT pathway in rheumatoid arthritis synovium showed decreased phosphorylation of STAT1. Also pro-inflammatory activation of STAT1 and downstream targets were inhibited by JAK inhibition. More interesting, STAT1-/- mice have higher bone density due to Runx2 activation but are otherwise are indistinguishable from wildtype mice . Furthermore, inhibition of STAT1 accelerates bone repair after trauma, a similar process in our observation in rheumatoid arthritis joints. On the other hand, JAK1 deficient mice showed reduced body mass peri-natal which has been speculated to indicate bone growth delays. Focusing on bone loss, JAK inhibition (tofacitinib) suppressed osteoclast mediated bone destruction via reduction of T cell derived RANKL. In vitro we observed that osteoclast (OC) differentiation was not influenced by JAK inhibition in regard to OC numbers and transcription factor expression. Interestingly, in osteoblast cultures, JAK inhibition induced Runx2, Col1a and Osterix. In co-culture assays with osteoblasts and OC precursors JAK inhibition led to decreased OC differentiation.Thus JAK inhibition mediated OC function is not only influenced by T cell but also osteoblast derived RANKL and therefore interferes in the balance of bone turnover by activating osteoblasts.Using HR-pQCT measurements of fingers of RA patients treated with tofacitinib in a small sample size we detected an astonishing gain of volumetric bone mineral density (mg Hydroxylapatite/mm³). Furthermore, we noticed a decrease of the intra-articular cortical porosity and a positive change of erosion size. In these cases, volumetric bone density in metacarpal joints improved up to 20 %. In our experience, regarding other immunosuppressive medication for example anti-TNF Inhibition, no comparable effect was observed.

The longitudinal setup of this mode of action study is used to determine the effect of baricitinib on the change of the volumetric bone mineral density in RA patients with pathologic vBMD measured by HR-pQCT technique over 52 weeks.