FRI0150 Mtor blockade by rapamycin decreases arthritis and spondylitis development and severity in hla-b27 transgenic rats
Authors: S. Chen, M. van Tok, D. Pots, J. Taurog, M. van de Sande, D. Baeten, L. van Duivenvoorde
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> HLA-B27 misfolding is thought to play an important role in the pathogenesis of spondyloarthritis (SpA), possibly through triggering of ER stress and the unfolded protein response. One of the mechanisms that regulates the unfolded protein response is autophagy. Autophagy is a process that degrades proteins, cytoplasmic particles and organelles in lysosomes and is regulated by protein kinases, mechanistic target of rapamycin (mTOR) and AMP activated protein kinase. <h3>Objectives</h3> To study whether blockade of mTOR will affect spondyloarthritis development and/or severity in the <i>Mycobacterium tuberculosis</i> (<i>M. tub</i>) induced disease HLA-B27 tg rat model. <h3>Methods</h3> 6 weeks old, female or orchiectomized male HLA-B27/Huβ2m transgenic rats were immunised with 60–90 µg heat-inactivated <i>M. tub</i> in IFA. Rats were prophylactically or therapeutically treated three times a week intra-peritoneally with 1.5 mg/kg rapamycin or vehicle. Clinical measurements included weight, clinical scores for spondylitis and arthritis, and hind paw swelling measured by plethysmometry. After 5 weeks of treatment rats were sacrificed; axial and peripheral joints were isolated for histology and metacarpophalangeal joints, spleen and lymph nodes were isolated for RNA isolation. <h3>Results</h3> In the prophylactic experiment 72.7% (8/11) and 18.2% (2/11) rapamycin treated rats developed arthritis and spondylitis compared to respectively 100% (13/13; p=0.0225) and 92.3% (12/13; p&lt;0.0001) control animals. Also severity of arthritis and spondylitis was significantly decreased in rapamycin treated animals compared to control treated animals; mean arthritis severity of diseased rats was respectively 0.45 versus 7.15 on a scale from 0–12 (p&lt;0.0001) and mean spondylitis severity was respectively 0.18 versus 2.07 on a scale from 0–3 (p&lt;0.0001). Clinical findings were confirmed by histology with a significant decrease of inflammation (p&lt;0.0001), bone- and cartilage destruction (p=0.0021) and new bone formation (p=0.0010) in peripheral joints of rapamycin treated rats compared to vehicle treated rats and a similar trend was observed in spinal joints. Also in a therapeutic setting rapamycin treatment decreased arthritis severity (mean score of 6 compared to 8.8 in controls; p=0.0317) and spondylitis severity (mean score of 1.23 compared to 2.8 in controls; p=0.0159). Histology for the therapeutic experiment is currently being performed as well as RNA analyses for autophagy genes and pro-inflammatory cytokines, like IL-17A and TNF. <h3>Conclusions</h3> mTOR blockade significantly suppressed arthritis and spondylitis in the <i>M. tub</i> induced disease HLA-B27 transgenic rat model of SpA. <h3>Disclosure of Interest</h3> S. Chen: None declared, M. van Tok: None declared, D. Pots: None declared, J. Taurog: None declared, M. van de Sande: None declared, D. Baeten Employee of: UCB Pharma, L. van Duivenvoorde: None declared