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Preprint WatchMildNovember 5th, 2026

IL-23 licenses the transition from preclinical autoimmunity to inflammatory arthritis through IL-17A-dependent mechanisms

Jarlborg, M.; Circiumaru, A.; Lamacchia, C.; Vaillant, L.; Rakotoarijaonina, E.; Venken, K.; Elewaut, D.; Rodriguez, E.; Caruso, A.; Huard, A.; Santuari, L.; Chammartin, N.; Courvoisier, D. S.; Andreatta, M.; Carmona, S. J.; Finckh, A.; Gabay, C.

IL-23 licenses the transition from preclinical systemic autoimmunity to inflammatory arthritis through IL-17A-dependent cellular and myeloid pathways.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

This preprint reports that sustained IL-23 overexpression converts a mild collagen-induced arthritis phenotype in C57BL/6 mice into a highly penetrant arthritis, that neutralizing IL-17A prevents disease, and that IL23R, IL23A and CCR2 expression is increased in rheumatoid arthritis synovium relative to controls, with IL23R higher in early than established disease. The authors position IL-23 as a regulator of the transition from systemic autoimmunity to clinical arthritis. The Claidex graph holds one IL23A program that stopped early, brazikumab in Crohn's disease, and it stopped on a portfolio decision rather than for lack of effect (brazikumab-il23a-crohns-disease-intrepid-phase2b3-strategic-discontinuation). The flag is mild for two reasons. The one claim on file sits in a different indication, and its archetype is strategic reprioritization, so the Claidex record carries no efficacy evidence against IL-23 blockade that this preprint would contradict. The preprint's own framing is about disease initiation in at-risk individuals, which is a different clinical question from treating established arthritis.

Abstract excerpt

Objectives: The mechanisms driving transition from systemic autoimmunity to clinical rheumatoid arthritis (RA) remain poorly understood. We investigated the role of interleukin-23 (IL-23) in disease transition using a murine model of experimental arthritis, complemented by human transcriptomic analyses in individuals at risk of RA and RA synovial tissue. Methods: Collagen-induced arthritis (CIA) was induced in less susceptible C57BL/6 mice and combined with sustained systemic IL-23 overexpression. Disease severity, histopathology, immune responses, and tissue gene expression were evaluated. The contribution of IL-17A was assessed using a neutralizing anti-IL-17A antibody. Expression of IL-23 pathway-related genes was assessed in whole-blood transcriptomic data from a large cohort of first-degree relatives of patients with RA (n=1080) and in an independent synovial RNA-sequencing dataset (n=218). Results: In mice, sustained IL-23 overexpression converted a mild CIA phenotype into a highly penetrant arthritis characterized by increased expression of innate inflammatory mediators, and enhanced antigen-specific production of IL-17A and IFN-{gamma}, despite unchanged collagen-specific antibody responses. Neutralization of IL-17A prevented arthritis development. In human whole blood longitudinal analyses, lower RORC and KLRB1 expression was associated with a higher risk of RA onset. KLRB1 expression was persistently lower in progressors, whereas RORC expression showed a steeper decline before diagnosis, although this difference did not remain significant after correction for multiple testing. In RA synovium, IL23R, IL23A, and CCR2 expression was increased compared with controls, while IL23R expression was higher in early than established RA. Conclusions: IL-23 acts as a critical regulator of the transition from systemic autoimmunity to inflammatory arthritis by promoting IL-17A-dependent cellular and myeloid inflammatory pathways. The change in IL-23 pathway signatures in at-risk individuals and early RA supports the translational relevance of this pathway during disease initiation.

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.