Background/Purpose: The IL-17 axis has been identified as a central pathway in SpA pathogenesis. Targeting this axis in AS and PsA significantly suppresses inflammation and stops bone and cartilage destruction. Retinoic acid receptor related orphan receptor gamma t (RORγt) is a transcription factor required for differentiation of IL-17-producing T cells and innate immune cells. We studied the therapeutic effect of a small molecule RORγt antagonist on a validated animal model of SpA (Front Immunol 2017;8:920).

Methods: Thirty male Lewis rats transgenic for HLA-B*2705, human β2microglobulin, and deficiency of the gene Dazl (21-3×283-2×17-9, Arthritis Rheum 2012;64:2518), 61-90 d old, were injected i.d. with 90 µg heat-inactivated M. tuberculosis in IFA. Starting on d 25, rats were divided into three matched groups and treated with (1) RORγt inhibitor, 100 mg/kg daily p.o., (2) vehicle only daily p.o. (disease control), or (3) mAb anti-rat IL-17, 15 mg/kg i.p. twice weekly (treatment control). Clinical measurements included weight, visual scores for arthritis and spondylitis, and hind paw volume by plethysmometry. After 5 wks of treatment, rats were sacrificed for cytokine analysis, skeletal µCT imaging and histology.

Results: All rats developed ankle swelling and tail spondylitis by d 25. Both RORγt inhibitor and anti-IL-17 significantly suppressed arthritis severity and bone damage in the arthritic ankle, compared with vehicle alone (Figs. 1, 2). Additionally, both RORγt and IL-17 inhibition were able to reduce damage in the axial skeleton (caudal spine) and in the paws, as measured by μCT (Fig. 3) and histology.

Fig. 1. Hind paw volumes (△ vehicle only; ○ drug; ☐ anti-IL-17)

Fig. 2. Arthritis scores (4 paws)

Fig. 3. µCT of R tarsus after 5 wk of treatment

Conclusion: The RORγt antagonist significantly suppressed clinical signs of arthritis in both the peripheral and axial skeleton in Mtb-induced SpA in B27/hβ2m TG rats. This finding was verified by both μCT and histologic evaluation of ankle and spine at study termination. These data provide evidence that inhibition of RORγt has potential clinical benefit for treatment of spondyloarthritis.