Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: The pathogenesis of rheumatoid arthritis (RA) is characterized by infiltration of immune cells to the synovial tissues and their hyperplasia. Aim of the current therapeutic strategies of RA is blockade of proinflammatory cytokines or inhibition of immune cell activity. Anti-tumor necrosis factor and interleukin (IL)-6 biological agents have been proven more effective than conventional oral anti-rheumatic drugs. However, they cannot induce complete remission in all patients and render treated patients susceptible to infections. Combination treatments with other molecular targeting drugs failed to enhance anti-rheumatic effects but increased adverse effects. To explore non-immunosuppressive treatment, we have focused on proliferation of synovial fibroblasts as a target pathological process. We have revealed that cell cycle regulation of synovial fibroblasts by cyclin-dependent kinase (CDK) inhibition ameliorated animal models of RA without inhibiting immune responses. A small molecule CDK4/6 inhibitor (smCDKI) has been tolerated clinically as an anti-cancer drug with the toxic effect being transient myelosuppression. The present studies were carried out to discern if smCDKI under toxic doses enhances the anti-arthritic effect of cytokine blockade and reduces their adverse effects in treating collagen induced arthritis (CIA).
Methods: DBA/1J mice were immunized with bovine type II collagen (CII) emulsified in complete Freund’s adjuvant. Arthritis score and peripheral blood counts of the CIA mice treated with different doses of smCDKI were assessed. The arthritis score, radiographic score and histological score of the mice treated with smCDKI alone, with anti-IL-6 receptor antibody (IL-6R-Ab) or etanercept (ETN) alone, or with combination of smCDKI and cytokine blockade were assessed. Serum anti-CII antibodies were quantified with enzyme-linked immunosorbent assay. CII specific proliferation of T cells derived from draining lymph nodes was assessed with thymidine incorporation assay.
Results: The smCDKI monotherapy suppressed arthritis, radiographic and histological scores of CIA dose-dependently. The therapeutic effects were observed without myelosupression. Both of IL-6R-Ab and ETN monotherapies were also effective. Their efficacy was further enhanced in the all scores when combined with smCDKI administration. Of note, the combination of smCDKI and ETN suppressed arthritis almost completely. Serum anti-CII antibody levels and CII-specific T cell proliferation were comparable among all the treated and control groups.
Conclusion: This is the first report demonstrating that combination of molecular targeting therapies exerted synergistic effects without increase in immune suppression. The smCDKI treatment combined with the anti-cytokine treatment might be more effective than anti-inflammatory monotherapy without increasing infection risks in treating RA. We hope that development of smCDKI as an anti-rheumatic drug will help to increase the remission induction rate in RA treatment without inducing infections.
Disclosure:
T. Hosoya,
None;
H. Iwai,
None;
Y. Yamaguchi,
None;
N. Miyasaka,
Pfizer Japan, Chugai Pharmaceutical,
2;
H. Kohsaka,
Takeda Pharmaceutical,
2,
Chugai Pharmaceutical,
5.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cell-cycle-regulation-therapy-combined-with-cytokine-blockade-enhances-anti-arthritic-effects-without-increase-of-immune-suppression/