Background/Purpose

The pathogenesis of rheumatoid arthritis (RA) is characterized by infiltration of inflammatory cells to the synovial tissues and their hyperplasia. Activated synovial fibroblasts become another source of inflammatory cytokines and a platform inducing further recruitment of inflammatory cells.

Cyclin-dependent kinases (CDK) are known to be key regulators of the cell cycle progression and targets in cancer treatment. We have revealed that a highly selective small-molecule CDK4/6 inhibitor (CDKI) ameliorated an animal model of RA, even with a dose one-fifth lower than the dose used in a cancer treatment model. Furthermore, CDKI combined with a cytokine blocker ameliorated early stage of arthritis additively without inhibiting antigen-specific immune responses.

In the clinical setting, we often treat RA patients with high disease activity. However, few agents were proven effective in treating established arthritis models. The drug effectiveness is usually estimated with early stage of arthritis in the pre-clinical study and is sometimes discrepant between animal models of arthritis and human RA. Therefore, it is difficult to predict which drug is promising in the patients with RA based on the results of arthritis models. However, the drug would be promising if it could ameliorate the established arthritis model. The present studies were carried out to discern if combination of CDKI and TNF blocker is effective in treating established arthritis.

Methods

DBA/1J mice immunized with bovine type II collagen emulsified in complete Freund’s adjuvant twice and evaluated for arthritis score and the joint deformity. Mice with collagen-induced arthritis (CIA) were divided into 4 groups equated the mean arthritis score of individual groups 30 days after the initial immunization and were treated with 20 mg/kg of CDKI, 3 mg/kg of (ETN), a combination of both, or a vehicle solution from 30 days until 42 days after the initial immunization.

Results

The arthritis became established with 9.1 of the mean arthritis score 30 days after the initial immunization. Mice with CIA were treated with a vehicle solution or CDKI or ETN – separately or together. The mean arthritis score changed from 9.1 to 10.4, 8.4, 8.1, and 6.4 respectively 42 days after the initial immunization. The percentage of deformed limbs was observed at 25%, 18%, 7%, and 4% respectively. Both monotherapies inhibited further development of arthritis and decreased the arthritis score, but their efficacies were not statistically significant. Combination therapy decreased the arthritis score significantly and inhibited the joint deformity.

Conclusion

The combination therapy of CDKI and TNF blocker is effective on established arthritis and could prevent joint deformity. Because TNF blockade disturbs the proliferative signaling and CDKI directly prohibits cell cycle progression, the combination of the two might act synergistically based on their mechanisms. We expect that the combination therapy of CDKI with cytokine blockers should help to increase the remission induction rate in RA patients even with high disease activity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-combination-therapy-of-cell-cycle-regulation-therapy-combined-and-tnf-blockade-ameliorated-the-established-arthritis/