Background/Purpose: IL-17A is a central driver of spondyloarthritis (SpA) pathology. IL-17A production was originally proposed to be IL-23 dependent. Emerging preclinical and clinical evidence from SpA-related diseases such as Crohn’s disease suggest, however, that IL-17A and IL-23 have a partially overlapping but distinct biology. We aimed to assess to what extend IL-17A is dependent on IL-23 in SpA by selectively targeting the IL-23R in HLA-B27/Huβ2m transgenic rat model of SpA, which we showed previously to be IL-17A-dependent.

Methods: HLA-B27/Huβ2m tg rats were immunized with low dose heat-inactivated M. tuberculosis to induce experimental SpA. Rats were treated with anti-mouse/rat chimeric IL-23R antibody or vehicle in a prophylactic (treatment initiation before onset of symptoms) or therapeutic (treatment initiation after onset of clinical symptoms) experiment. Spondylitis and arthritis were clinically scored, hind limb swelling was measured. Ex vivo cytokine expression was measured in lymph nodes and spleen. Serum samples were analyzed for anti-IL23R exposure.

Results: During prophylactic treatment, 58% and 67% of the rats in the control group developed spondylitis and arthritis, respectively. The average arthritis score at the end of the study was 3.9±1.1 and the average hind paw swelling was 0.35±0.09 cm³. Prophylactic treatment completely protected against the development of spondylitis and arthritis (figure 1). In the therapeutic treatment strategy, however, anti-IL23R treatment failed to reduce incidence or decrease the severity of experimental SpA (figure 1). The differential effect of IL-23R targeting in the initiation phase versus established disease could not be explained by pharmacokinetic differences, serum analyses revealed similar exposure levels. Mechanistically, the expression of downstream effector cytokines such as IL-17A (p<0.05) and IL-22 (p<0.01) was reduced in the popliteal lymph nodes of rats treated prophylactically with anti-IL23R versus controls, with a similar trend in spleen. Accordingly, IL-17A production upon ex vivo re-stimulation was reduced in samples from prophylactically treated rats. In contrast, similar popliteal lymph node expression data in samples from the therapeutic experiment indicate no difference in IL-17A and IL-22 expression in the anti-IL23R treated rats compared to controls.

Conclusion: IL-17A expression and production is dependent on the IL-23 axis in the initiation phase of experimental SpA but not in established disease. Accordingly, targeting of this axis with an anti-IL23R antibody completely prevented the onset of arthritis and spondylitis in HLA-B27/Huβ2m transgenic rats, but failed to reduce axial and peripheral joint inflammation in established disease. The cellular origin of IL-23-independent IL-17A production and the relevance to human SpA remains to be investigated.