Background The IL-17 axis has been identified as a crucial pathophysiological pathway in spondyloarthritis (SpA). This concept was recently validated by phase II and III clinical trials with secukinumab (anti-IL17A), brodalumab (anti-IL17RA), and ustekinumab (anti-IL23/IL12p40) in ankylosing spondylitis and psoriatic arthritis. Targeting the IL-17 axis significantly suppressed inflammation and halted bone and cartilage destruction in these trials. The potential impact of IL-17A inhibition on new bone formation, the major form of structural damage in SpA, remains unknown. Assessment of this feature in SpA requires large patient numbers treated for an extended period and appropriate control groups. Therefore, we aimed to assess the impact of anti-IL17A on new bone formation in a validated animal model of SpA.
Methods 6 weeks old, orchiectomized, HLA-B27/huβ2m tg rats were immunized with 45 μg heat-inactivated M. tuberculosis in IFA. One week after immunization, rats (n=6/group) were treated weekly with an anti-mouse/rat IL-17A antibody or an IgG2a isotype control at 15mg/kg i.p. Clinical measurements included weight, clinical scores for spondylitis and arthritis, and hind limb swelling measured by plethysmometry. After 6 weeks, rats were sacrificed for skeletal analysis by micor-CT imaging and histology.
Results Control animals failed to gain weight over time, whereas anti-IL-17A-treated rats showed a significant increase in weight compared to baseline (102% versus 134%; p<0.05). In the control group, spondylitis and arthritis were observed in 100% of the rats at day 31 and day 19, respectively, after immunization. In contrast, only 83% and 33% of the anti-IL-17A treated rats developed spondylitis and arthritis at these time points. Accordingly, there was a significant delay in the mean appearance of spondylitis (day 28 vs day 14; p<0.05) and arthritis (day 27 vs day 14; p<0.05) in treated versus control animals. Arthritis severity was lower in the anti-IL-17A-treated group compared to the controls, both by clinical scoring (p<0.05) and by plethysmometry (p<0.05). Quantitative analysis of structural damage by micro-CT of foot and ankle joints (figure 1) showed a significantly higher total bone volume in anti-IL-17A treated rats compared to controls (17% more, p<0.05), suggesting decreased bone loss. Moreover, the total volume of low density bone, reflecting newly formed bone, was significantly lower in the anti-IL-17A treated rats than in controls (p<0.05). Histological images of the peripheral joints confirmed differences in new bone formation. Control treated rats showed severe lesions of both endochondral and periosteal new bone formation.
Conclusions IL-17A blockade significantly suppressed spondylitis and arthritis in the M. tub-induced disease B27 tg rat model of SpA. Moreover, micro-CT data indicated that IL-17A blockade also impacts structural damage, including pathological new bone formation.
Disclosure of Interest None declared