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1 2012 1 2 ?3 ?! ?! ?! , ?! ?! ?! 4 ( ) ( ) D (HLA-DR) (HLA-B27) 5 6 7 8 (surface receptor) (cytokines ) 9 10 Enbrel etanerceptRemicade infliximabHUMIRA adalimumabMabthera rituximabOrencia abataceptSimponi golimumabActemra tocilizumab B- T- IL-6R 2002 2003 12 2004 6 2006/07 2009 10 2010 2010 61 43 64 (1-2 ) (4 ) (1-2 ) (3-4 ) ( ) (1-2 ) (1 ) , 8 2 4.

2 TNF B (interleukin-6)CTLA-4 TNF TNF B RANKL (interleukin-1) B 12 13 Anti-TNF for Rheumatoid arthritisRoute & dosageStudyEtanercept50mg weeklyTEMPOERAA dalimumab40mg every 2 weeklyARAMADAPREMIERG olimumab50mg every 4 weeklyGO -FORWARDGO -BEFOREGO -AFTERI nfliximab3mg/kg/infusionATTRACTASPIREC ertolizumab400mg every 4 weeklyRAPID-1 RAPID-2 FAST4 WARD 14 TNF ACR20, DAS, global ESR, CRP / R Maini, et alLancet 1999;354:1932-39 Non -antiTNF Bio -DMARDD osageStudyRituximab 1000mg x2 infusionDANCER (dose ranging)REFLEX (ant-TNF failure)Tocilizumab 8mg/kg/mth SATORI (monotherapy in MTX failure)STREAM (monotherapy in DMARD failure)AMBITION (monotherapy vs MTX)CHARISMA (MTX failure)OPTION (MTX failure)TOWARD (combined traditional DMARD)RADIATE (anti-TNF failure)Abatacept 10mg/kg/mth(with 2ndwkinfusion)ATTAIN (anti-TNF failure)AIM (MTX failure)AGREE (MTX na ve or limited exposure, early RA)ARRIVE (Anti-TNF failure)ATTEST (vs infliximab) 16 CTLA4-Ig T T RA CTLA4Ig (costimulationblocker) CTLA4Ig APC CD80 (B7-1)

3 & CD86 (B7-2) CD28 APC CD80/86 T C Barr. J Infusion Nursing. 2007;30:96-104 Kremer JM et al. NEJM 2003;349:1907-15 Tocilizumab (mIL -6R/sIL-6R) gp130gp130 Classical membrane signallingTrans-signallingIL-6IL-6 Mihara M, et al. Int Immunopharmacol2005; 5:1731 2010: (1) ( ) DAS-28 > 3 (2) (moderate to good EULAR response) (3) 19 2012 RA Treatment (Prognostic Factors):- (functional limitations)- : - (RF) anti-CCP- X - <6 - >6 - - - 20JA Singh, et al.

4 Arthritis Care Research 2012(64);625-639 Target low disease activity or remission 2012 RA : : Anti-TNF MTX : or MTX+HCQ : : : : 21JA Singh, et al. Arthritis Care Research 2012(64);625-639 Target low disease activity or remission 2012 RA : MTX 1. 2. Anti-TNF3. Abatacept or Rituximab : 22JA Singh, et al. Arthritis Care Research 2012(64);625-639 Target low disease activity or remission 23 TNF Adalimumab Etanercept Golimumab Infliximab 26 EtanerceptInfliximabSourceGorman JD et 2002;346:1349-56 Brand J et 2002;359:1187-93 Drug usedRecombinant human TNF receptor (p75): Fc fusion protein25mg twice weekly Neutralising chimeric monoclonal antibody against TNF 5mg/kg iv infusionAt 0,2,6 weeksStudy duration 4 month (DBPC/RCT)12 weeks (DBPC/RCT)No.

5 Of subjects 20 vs 2035 vs 35 DMARDS table dose of (at least 4 wks before randomization)Withdrawn 4 wk beforeOutcome measures1. 20% improvement in at least 3 out of 5 measures of disease activity2. Physician global, measure of spinal mobility, score of enthesitis, peripheral joint tenderness, CRP, ESR1. 50% improvement in BASDAI2. Improvement in VAS for: BADRI, BASMI, SF-36, CRP, ESRR esult80% (actively treated) vs 30% (placebo) 53% (actively treated) vs 9% (placebo) anti-TNF ASAS (2009 ) anti-TNF / (BASDAI 4/10; ) NSAID( ) DMARD salazopyrin van der Heijde D, et al.

6 Update of the ASAS Recommendations On the Use of TNF-Blockers in Ankylosing Spondylitis [abstract]. Arthritis Rheum 2009;60 Suppl 10 :1790 DOI: 29 TNF Adalimumab Etanercept Golimumab Infliximab 30 EULAR 2012 recommendations for management of psoriatic arthritis with pharmacology therapies 31L Gossec, et al. Ann Rheum Dis 2012;71:4-12 TNF DMARD dactylitis NSAID NSAID 32 JIA treatment groupACR recommendations4 MTX TNF5 MTX TNF TNF Abatacept (sacroiliac) TNF ( ) Anakinra ( ) (steroid sparing agent) 33 Arthritis Care Rheumatism 2011.

7 63:465-482 (SLE) 34 1%-3% complement ( ) T B (BLyS/BAFF) (SLE) Rituximab Belimumab 37 38 39 Rituximab in ANCA Jones RB et al. Arthritis Rheum 2009;60:2156 A retrospective, open label study conducted in UK RTX regimens NOT standardised Use of RTX suggestive to be an effective agent for induction B cell depletion was associated with a higher rate of complete remission (75%) Rituximab vs CTX for induction of remission in ANCA-associated vasculitis: A randomised controlled trial (RAVE study) JH Stone, PA Merkel, P Seo et al.

8 (ACR 09 abstract presentation) (Takayasu s) TNF 41A Mekinian et al. Rheumatology 2012;51:882-882 B (Rituximab) (Takayasu s)42BF Hoyer, et al. Rheumatology Ann Rheuma Dis 2012; 71:75-79 (Giant Cell Arteritis) 43C Beyer, et al. Ann Rheum Dis 2011;70:1874-75 / 44 / IL-1 , IL-6, IL-18, IL 10, TNF MMPs, arginase, PGs, TLRCD68, PPAR- , TGF- , n-PGD synthetaseQuiescent phaseInflammasomeactivation phaseProinflammatorymediatorsAmplificati on phaseTissue damagemediatorsIntercriticalgoutResoluti on phaseAnti-inflammatorymediatorsAdapted from Burn CM, Wortmann RL Lancet 2011;377:165-77 CytokineAction in goutSourceIL-1 Endothelial adhesionEndogenous pyogenMonocytes, macrophageDendritic cellTNF Cellular activationEndothelial adhesionPhagocytosisMonocytes, macrophage,lining cellIL-6?

9 Monocyte, macrophageG-CSFN eutrophil survival and proliferationEndothelium, macrophageCXCL1 (KC, Groa) Neutrophil chemotaxisMacrophage, neutrophilCXCL8 Neutrophil chemotaxisMacrophage, endotheliumCCL2 Monocyte and dendritic cell chemotaxisMast cell degranulationCCL3 Neutrophil chemotaxisMonocyte, macrophage MacrophageAnakinraCanakinumabIL-1 RilonaceptSignalIL1-R1IL1-RacP 48 49 50 51 52 Hotline.

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