Reviews and Opinions 1 RA. Key words rheumatoid arthritis biologics remission bone joint destruction. rheumatoid arthritis RA 10

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1 Reviews and Opinions Key words rheumatoid arthritis biologics remission bone joint destruction Spinal Surgery rheumatoid arthritisra 10 TNFtumor necrosis factoril6 interleukin6 RA DMARDsdisease modifying antirheumatic drugs RA RA 1 RA 1987 ACR RA Table RA Table1RA 1987 ACR MCP PIP X RA Table2 RA CRP ESR 6 3 RA 1994 RA Table 2 2 RA 2010 ACR EULAR RA 3,4 Table Address reprint requests toyuho Kadono, M.D., The University of Tokyo Hospital, Orthopaedic Surgery, 731 Hongo, Bunkyo ku, Tokyo , Japan VOL.27 NO

2 Table3RA 2010 ACREULAR A B ACPA ACPA 1 ACPA 1 C CRPESR CRPESR D DAS28 ESR0.56 TJC0.28 SJC 0.70 lnesr0.014 GH DAS28 CRP0.56 TJC0.28 SJC 0.70 lncrp GH0.096 Fig.1DAS28 Table4DAS28ESR A DAS28ESR 5.1 High Moderate 3.2 Low 2.6 Remission B DAS28 DAS Good Moderate No Moderate Moderate No 5.1 Moderate No No cyclic citrullinated peptideccpanticcp antibodyacpacrp Creactive protein ESRerythrocyte sedimentation rate 10 6 definite RA 2 RA RA DMARDs treat to targett2t Table5SDAI CDAI A 1 Boolean SJCTJCPtGApatient global assessmen010 scalecrpmgdl 1 2 SDAISJCTJCEGAPtGACRP mgdl 3.3 B 1 Boolean SJCTJCPtGA 1 2 CDAISJCTJCEGAPtGA DAS28disease activity score 2828 tender joint counttjcswelling joint countsjcesrcrpglobal health GHvisual analogue scalevas Fig.1 DAS28 RA Table 4 DAS VOL.27 NO

3 DAS good response T2T DAS282.6 DAS Fig.1 DAS28 SDAIsimplified disease activity indexcdaiclinical disease activity index2011 SDAICDAI 9,10 Table 5 Boolean SDAI CDAI index 3 MTX RA RA DMARDs methotrexatemtx MTX MTX MTX 2010 DMARDs 1 8 mg 2011 RA 8 mg 16 mg MTX MTX MTX MTX MTX 5 mg 1 MTX MTX MTX MTX MTX MTX B de novo MTX 4 RA RA MTX RA TNF IL6 T TNF TNF TNF IL6 CTLA4 cytotoxic Tlymphocyteassociated protein 4 Fc MTX DMARDs 3 4 VOL.27 NO

4 p0.001, IFXMTX vs placebomtx 14 Fig.2IFX 54 MTX 3 1 IFX 4 p0.0001, ETNMTX vs MTX p0.05, ETN vs MTX 17 Fig.3ETN 52 MTX total sharp scoretss 2.80 ETN MTX 0.54 DMARDs 1 infliximabifx TNF RA human antichimeric antibodyhaca 6 mg X CT 12 3 mgkg mgkg 6 mgkg mgkg 2 3 mgkg IFX RA MTX 1316 Fig etanerceptetn TNF TNF TNF Fc IFX mg mg MTX MTX VOL.27 NO

5 1721 Fig.3 3 IFX adalimumabada TNF IFXETN TNF mg 1 80 mg MTX ADA MTX TNF golimumabglm ADA TNF TNF 26,27 MTX mg mg mg GLM ETN ADA 5 tocilizumabtcz IL6 TCZ IL6 IL6 8 mgkg 4 28,29 Fig.4 6 abataceptabt CTLA4Fc CD80CD86 T CD28 RA T 1 IFX p0.01, TCZ vs MTX 29 Fig.4TCZ 52 MTX TSS 6.1 TCZ TSS kg 500 mg60100 kg 750 mg100 kg 1,000 mg ,28,31 IFX CT X D MTX B de novo VOL.27 NO

6 32 Fig.5B MTX HBs HBs HBc HBs HBs HBc HBVDNA HBs HBc HBVDNA 1 HBVDNA B HBV DNA HBs HBc HBs HBV HBs HBV HBV DNA HBVDNA HBV HBV HBV de novo B de novo B 2011 B 32 Fig.5 HBVDNA 6 MTX RA 3339 Table 6 RA 2010 AS TNF TNF TCZABT TCZ 6 ABT 10 TCZ IL6 CRP CRP VOL.27 NO

7 Table6 95 den Broeder Hirano Giles Kawakami TNF 3639 RA RA RA 1Arnett FC, Edworthy SM, Bloch DA, et althe American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum , Aletaha D, Neogi T, Silman AJ, et al2010 Rheumatoid arthritis classification criteriaan American College of RheumatologyEuropean League Against Rheumatism collaborative initiative. Arthritis Rheum , Aletaha D, Neogi T, Silman AJ, et al2010 Rheumatoid arthritis classification criteriaan American College of RheumatologyEuropean League Against Rheumatism collaborative initiative. Ann Rheum Dis , American College of Rheumatology Subcommittee on Rheumatoid Arthritis GuidelinesGuidelines for the management of rheumatoid arthritis. Arthritis Rheum , Saag KG, Teng GG, Patkar NM, et alamerican College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic diseasemodifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum , Singh JA, Furst DE, Bharat A, et al2012 update of the 2008 American College of Rheumatology recommendations for the use of diseasemodifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res , Smolen JS, Aletaha D, Bijlsma JW, et altreating rheumatoid arthritis to targetrecommendations of an international task force. Ann Rheum Dis , Felson DT, Smolen JS, Wells G, et alamerican College of RheumatologyEuropean League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis , Matsui T, Kuga Y, Nishino J, et alcomparison of composite disease activity indices for rheumatoid arthritis. Mod Rheumatol , MTX MTX RA TNF Maini R, St Clair EW, Breedveld F, et alinfliximabchimeric antitumour necrosis factor alpha monoclonal antibody versus placebo in rheumatoid arthritis patients receiving concomitant methotrexatea randomised phase trial. Lancet , Lipsky PE, van der Heijde DM, St Clair EW, et al Infliximab and methotrexate in the treatment of rheumatoid arthritis. AntiTumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med , Smolen JS, Han C, Bala M, et alevidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvementa detailed subanalysis of data from the antitumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study. Arthritis Rheum , 2005 VOL.27 NO

8 16Smolen JS, Han C, van der Heijde DM, et alradiographic changes in rheumatoid arthritis patients attaining different disease activity states with methotrexate monotherapy and infliximab plus methotrexatethe impacts of remission and tumour necrosis factor blockade. Ann Rheum Dis , Klareskog L, van der Heijde D, de Jager JP, et altherapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritisdoubleblind randomised controlled trial. Lancet , van der Heijde D, Klareskog L, RodriguezValverde V, et alcomparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis twoyear clinical and radiographic results from the TEMPO study, a doubleblind, randomized trial. Arthritis Rheum , van der Heijde D, Klareskog L, Landewé R, et aldisease remission and sustained halting of radiographic progression with combination etanercept and methotrexate in patients with rheumatoid arthritis. Arthritis Rheum , Emery P, Breedveld FC, Hall S, et alcomparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis COMETa randomised, doubleblind, parallel treatment trial. Lancet , Kekow J, Moots RJ, Emery P, et alpatientreported outcomes improve with etanercept plus methotrexate in active early rheumatoid arthritis and the improvement is strongly associated with remissionthe COMET trial. Ann Rheum Dis , Weinblatt ME, Keystone EC, Furst DE, et al Adalimumab, a fully human antitumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexatethe ARMADA trial. Arthritis Rheum , Weinblatt ME, Keystone EC, Furst DE, et allong term efficacy and safety of adalimumab plus methotrexate in patients with rheumatoid arthritis ARMADA 4 year extended study. Ann Rheum Dis , Breedveld FC, Weisman MH, Kavanaugh AF, et althe PREMIER studya multicenter, randomized, double blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum542637, van der Heijde D, Breedveld FC, Kavanaugh A, et al Disease activity, physical function, and radiographic progression after longterm therapy with adalimumab plus methotrexate5year results of PREMIER. J Rheumatol , Keystone EC, Genovese MC, Klareskog L, et al Golimumab, a human antibody to tumour necrosis factor alpha given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapythe GOFORWARD Study. Ann Rheum Dis , Emery P, Fleischmann R, van der Heijde D, et althe effects of golimumab on radiographic progression in rheumatoid arthritisresults of randomized controlled studies of golimumab before methotrexate therapy and golimumab after methotrexate therapy. Arthritis Rheum , RA Nishimoto N, Hashimoto J, Miyasaka N, et alstudy of active controlled monotherapy used for rheumatoid arthritis, an IL6 inhibitor SAMURAIevidence of clinical and radiographic benefit from an x ray reader blinded randomised controlled trial of tocilizumab. Ann Rheum Dis , Schiff M, Keiserman M, Codding C, et alefficacy and safety of abatacept or infliximab vs placebo in ATTEST a phase, multicentre, randomised, doubleblind, placebocontrolled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis , RA B Bibbo C, Goldberg JWInfectious and healing complications after elective orthopaedic foot and ankle surgery during tumor necrosis factoralpha inhibition therapy. Foot Ankle Int , Wendling D, Balblanc JC, Brousse A, et alsurgery in patients receiving antitumour necrosis factor alpha treatment in rheumatoid arthritisan observational study on 50 surgical procedures. Ann Rheum Dis , Talwalkar SC, Grennan DM, Gray J, et altumour necrosis factor alpha antagonists and early postoperative complications in patients with inflammatory joint disease undergoing elective orthopaedic surgery. Ann Rheum Dis , Giles JT, Bartlett SJ, Gelber AC, et altumor necrosis factor inhibitor therapy and risk of serious postoperative orthopedic infection in rheumatoid arthritis. Arthritis VOL.27 NO

9 Rheum , den Broeder AA, Creemers MC, Fransen J, et alrisk factors for surgical site infections and other complications in elective surgery in patients with rheumatoid arthritis with special attention for antitumor necrosis factora large retrospective study. J Rheumatol , Hirano Y, Kojima T, Kanayama Y, et alinfluences of antitumour necrosis factor agents on postoperative recovery in patients with rheumatoid arthritis. Clin Rheumatol , Kawakami K, Ikari K, Kawamura K, et alcomplications and features after joint surgery in rheumatoid arthritis patients treated with tumour necrosis factor alpha blockersperioperative interruption of tumour necrosis factoralpha blockers decreases complications? RheumatologyOxford , 2010 VOL.27 NO