title: Cell cycle regulation therapy combined with cytokine blockade enhances antiarthritic effects without increasing immune suppression.
abstract: OBJECTIVE
  Biological disease-modifying antirheumatic drugs (DMARDs) that inhibit aberrant immune reactions in rheumatoid arthritis (RA) cannot induce complete remission in all patients. Combination therapies using two biological DMARDs have failed to exert additive effects and increased serious infections. We have found that cell cycle inhibition of synovial fibroblasts with cyclin-dependent kinase (CDK) inhibitors ameliorated the disease in animal models of RA without attenuating acquired immunity. The objective of this study was to determine whether a clinically well-tolerated selective CDK 4/6 inhibitor (CDKI), palbociclib, is effective and whether combination with cytokine blockers acts additively without enhancing immune suppression.
  
  
  METHODS
  The effects of CDKI on haematopoiesis and physical and behavioural findings in mice were evaluated. Mice with collagen-induced arthritis (CIA) were treated with CDKI, etanercept or anti-interleukin (IL)-6 receptor antibody (MR16-1) alone or with a combination of CDKI with etanercept or MR16-1. Their clinical, histological and radiographic scores, serum anti-(type II collagen (CII)) antibody levels and proliferative responses of lymph node cells to CII were determined.
  
  
  RESULTS
  Although CDKI induced marginal myelosuppression, it was well tolerated and ameliorated CIA dose-dependently. The combinations of low-dose CDKI and either tumour necrosis factor-α or IL-6 blocker enhanced the antiarthritic effects additively. The addition of CDKI to either cytokine blocker did not affect the levels of anti-CII antibodies and proliferative responses of lymphocytes to CII.
  
  
  CONCLUSIONS
  A clinically well-tolerated CDK4/6 inhibitor exerted antiarthritic effects in this mouse model. By combining therapeutic agents targeting immune reaction and synovial proliferation, we have demonstrated for the first time that two molecular targeting treatments act additively and may not increase immune suppression.
authors.affiliation: Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan Japan Science and Technology Agency-CREST Program, Tokyo, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Hosoya
authors.affiliation: Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan Global Center of Excellence (GCOE) Program, International Research Center for Molecular Science in Tooth and Bone Disease, Tokyo, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Iwai
authors.affiliation: Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
authors.forename: Kimito
authors.initials: K
authors.lastname: Kawahata
authors.affiliation: Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan Global Center of Excellence (GCOE) Program, International Research Center for Molecular Science in Tooth and Bone Disease, Tokyo, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Miyasaka
authors.affiliation: Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan Japan Science and Technology Agency-CREST Program, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kohsaka
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use / Q000633:toxicity; D000917:Antibody Formation / Q000187:drug effects; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001688:Biological Products / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004359:Drug Therapy, Combination; D000068800:Etanercept / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008811:Mice, Inbred DBA; D058990:Molecular Targeted Therapy / Q000379:methods; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D001688:Biological Products; D010879:Piperazines; D011725:Pyridines; D019947:Receptors, Interleukin-6; C500026:palbociclib; D000068800:Etanercept
keywords: DMARDs (biologic); Rheumatoid Arthritis; Synovitis; Treatment