Paradigm shift of the treatment in systemic autoimmune diseases
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1 Review Talk 4 in JSI212 Paradigm shift of the treatment in systemic autoimmune diseases Yoshiya Tanaka, MD, PhD Professor and Chairman, Department of Internal Medicine-I, School of Medicine and Deputy Director, The University Hospital, University of Occupational & Environmental Health, Japan
2 Paradigm shift of the treatment in systemic autoimmune diseases 1. Dream comes true with TNF inhibitors? 2. TNF is only a target? 3. Emerging only for RA? 4. Biologics are enough? 5. Biologics need for a lifetime?
3 DMARD cannot stop progress of joint destruction in RA patients with stage I: radiographic changes after 2-year treatment Ⅰ Ⅱ DMARD (n=41) Ⅰ Ⅱ 62.9 Combined DMARD (n=38) Ⅰ Ⅱ ( % ) *p<.5 Nakayamada S, et al Clin Rheumatol (23) 15, 27
4 Biologics purified from biological constructs in body (relative safety) pin-point therapy targeting certain molecule which is relevant to the disease (high efficacy)
5 Pathology of synovitis in rheumatoid arthritis osteoarthritis RA
6 Migration of lymphocytes into synovial tissue Rolling/tethering T-cell Activation of integrin High-affinity adhesion Vascular lumen chemokine Activated integrin Trans-endothelial migration TNF-α, IL-1, IL-6 Endothelial cells ICAM-1 TNF-α, IL-1, IL-6 Inhibition of a Activated disease lymphocyte process may lead to disease chemokine control macrophage Rheumatoid synovial tissue Tanaka Y, et al: Nature 361: 79, 1993
7 Biologics targeting RA launched in Japan infliximab etanercept adalimumab golimumab tocilizumab abatacept S Structure Chimeric IgG TNFR-IgG1 Human IgG Human IgG Humanized IgG CTLA4-IgG1 Target TNFα TNFα LTα TNFα TNFα Soluble and membrane-il-6r CD8/CD86 on APC Affinity 1.8x x x1 1.7x x1 7 Half life 8-1 days days ~14 days ~14 days days 1 days administration DIV SC SC SC DIV DIV Amount 3 mg/kg (~1) 5 mg 4 mg(~8mg) 5mg 1mg 8 mg/kg 5mg, 75mg, 1g Interval q8w (~q4w) 1/W q2w q4w q4w q4w Marketed 23/7 25/3 28/6 211/9 28/4 21/9
8 Revolution of treatment of RA by biotherapies Improvement of signs and symptoms was a goal (~1999) methotrexate (MTX) as an anchor drug + TNF-inhibitors 1) Clinical remission and its maintenance (SDAI 3.3) no signs, no symptoms, no laboratory abnormality 2) Structural remission ( mtss<.5) no progress of joint destruction 3) Functional remission (HAQ.5) no progress in functional disturbance
9 Efficacy of infliximab for refractory RA: DAS28 (RECONFIRM-2: UOEH, Saitama MC, Tokyo Women s U RC) > High activity 9% are at the high disease activity after 6-12 months 4% improved at the low disease activity and 3% became in the clinical remission moderate Low activity before At half a year At 1 year <2.3 DAS28-CRP (N=41, LOCF) Clinical remission Tanaka Y, et al. Mod Rheumatol (28) 18, 146
10 Efficacy of infliximab for refractory RA: ΔmTSS (RECONFIRM-2J: UOEH, Saitama MC, Tokyo Women s U RC) Ave.=21.33 Ave.=-.3 week week 54 week week 54 mtss of enrolled 67 patients were at week Yearly progression of TSS (LOCF) Takeuchi T, et al. Mod Rheumatol (28) 18: 447
11 Role of TNF/IL-6 in joint destruction in RA MCP-1 Monocyte (precursor of osteoclast) migration RANK RANKL osteoclasts Maturation and activation LFA-1 ICAM-1 Activated osteoclasts NF-κB Synovial cells and T cells TNF, IL-6 TCZ, TNF-inhibitors Tanaka Y and Okada Y. Curr Drugs Targets (25) 4, 325
12 Average of HAQ score 1 years outcome of ETN for RA (US): HAQ Long established RA (disease duration > 3Y, average=12.4 Y, #714) Early RA (disease duration < 3Y, average=.9y, #558) Treatment with etanercept (years) Weinblatt M et al, Arthritis Care Res (211) 63, 373
13 Paradigm shift of the treatment in systemic autoimmune diseases 1. Dream comes true with TNF inhibitors? 2. TNF is only a target? 3. Emerging only for RA? 4. Biologics are enough? 5. Biologics need for a lifetime?
14 IL-6 Mechanisms of actions of tocilizumab tocilizumab IL-6 Soluble IL-6 receptor (sil-6r) Membrane-bound IL-6 receptor (IL-6R) gp13 Outer space Cell membrane Inner space Jak-Stat signal pathway transcription DNA
15 Mechanism of action of CTLA4-Ig abatacept activated B cell antigen-presenting cell T cell autoantibody IL-6 MHC TCR antigen (main) signal TNF-α IL-2 CD8/86 CD28 co-stimulatory signal IFN-γ RANKL CTLA4-Ig abatacept activated macrophage IL-6 TNF-α IL-1
16 Biologics for autoimmune diseases Murine IgG CDR Soluble receptor p75 Human IgG PEG chimeric humanized human IgG PEG-IgG Ig-fusion protein TNF-α (infliximab) CD2 (rituximab) IL-6R (tocilizumab) CD2 (ocrelizumab) CD22 (epuratuzumab) TNF-α (adalimumab) (golimumab) BLyS (belimumab) CD2 (ofatumumab) IFNα (cifalimumab) IL-12/IL-23 (p4) (ustekinumab) RANKL (denosumab) TNF-α (certolizumab) TNFR2-Ig (etanercept) CTLA4-Ig (abatacept) TACI-Ig (atacicept)
17 Paradigm shift of the treatment in systemic autoimmune diseases 1. Dream comes true with TNF inhibitors? 2. TNF is only a target? 3. Emerging only for RA? 4. Biologics are enough? 5. Biologics need for a lifetime?
18 Systemic manifestations of SLE Ocular (1%) Sicca (15%) Neuro-psychiatric (NPSLE) (6%) Systemic: fatigue, malaise fever, annorexia, weight loss (95%) Cutaneous (8%) Musculoskeletal (95%) Thrombosis (1%) Cardiopulmonary (6%) Renal (8%): lupus nephritis Gastrointestinal (4%) Hematologic (85%) Vasculitis (5%) Hahn BH. In Harrison s Principles of Internal Medicine, 18 th edition (211) 2724
19 Algorism of initial therapy of SLE Diagnosis, estimation of disease activity and organ involvement Not life- or organ-threatening Life- or organ-threatening QOL: acceptable QOL: not accepatable High dose GC + (MMF or IVCY) Conservative management Conservative treatment With low-dose GC response No response Maintenance By Low GC + MMF or AZ Developing agents (anti-cd2, anti-cd22, CTLA4-Ig, anti-baff, etc Hahn BH. In Harrison s Principles of Internal Medicine, 18 th edition (211) 2724
20 Biphasic reduction of B cells by rituximab in SLE CD4 absent µh-chain + stem cell pro-b cell µh-chain + pre-b cell CD2 + IgD + CD27 - naive B cell CD2 + IgD - CD27 + CD4 + CD8 + memory B cell CD2 high memory T cell CD4L + IgG + CD38 + VH plasma cell rituximab [LONG-TERM EFFECT] Inhibition of differentiation of B cells Re-constitution of B cells Resetting immunity and remission-induction Humoral immunity (immune-complex-mediated) rituximab [RAPID EFFECT] Preferential reduction of CD2 high CD4 + CD8 + B cells Regulation of B-T cell activation Reduction of disease activity Cellular immunity (B and T cell-mediated) Ig
21 Paradigm shift of the treatment in systemic autoimmune diseases 1. Dream comes true with TNF inhibitors? 2. TNF is only a target? 3. Emerging only for RA? 4. Biologics are enough? 5. Biologics need for a lifetime?
22 Emerging treatments for autoimmune diseases rituximab ocrelizumab ofatumumab Antigenpresenting cell CD8/CD86 atacicept CD2 TACI B cell APRIL BCMA belimumab BAFF-R Syk-i Fostamatinib BAFF (BLyS) CD4L CD28/CTLA-4 abatacept CD4 T cell Jak-i Tofacitinib CD8/CD86 CD22 epratuzumab anti-il-6 sirukumab sarilumab anti-il-17 secukinumab LY anti-gmcsf-r mavrilimumab anti-p4 (IL-12/23) ustekinumab anti-il-2 NNC19-12 anti-ifnα sifalimumab rontalizumab anti-ifnr MEDI-546 anti-rankl denosumab
23 Jak3: role in cytokine signaling and SCID γc IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 P P X SCID Stat P Jak1 Jak3 P Jak3-SCID P P CP-69,55 a Jak inhibitor Stat P P Stat transcription Yamaoka K, O Shea JJ, et al. Blood. 25;16:3227
24 Syk (spleen tyrosine kinase) antigen, Ig B cell receptor Fc receptor integrin fostamatinib (R788 transmembrane adaptor PY SH2 phosphorylation by Src-family kinase ITAM PY SH2 Syk or ZAP Downstream signaling Iwata S, et al. J Allergy Clin Invest (in press)
25 Significance of Syk in B cell activation Costimulatory molecule B cell receptor Syk-inhibitor Syk TLR CpG-DNAfor TLR9 (ssdna, dsdna) TRAF6 NFκB Ig IL-6 Iwata S, et al. J Allergy Clin Invest (in press)
26 Paradigm shift of the treatment in systemic autoimmune diseases 1. Dream comes true with TNF inhibitors? 2. TNF is only a target? 3. Emerging only for RA? 4. Biologics are enough? 5. Biologics need for a lifetime?
27 Paradigm shift of treatment of RA w/ biologics Relief from joint pain MTX + TNF-inhibitors 1. Induction of clinical remission (SDAI < 3.3) Sustained remission 2. Structural remission ( mtss <.5) 3. Functional remission (HAQ <.5) Biologic-free remission?
28 A case who discontinued infliximab 35F (stage Ⅱ) MTX Infliximab 3mg/kg MS TJ# SJ# MTX discontinued IFX discontinued 6 CRP (mg/dl) DAS28 DAS28<2.6 DAS28 3 6/ / / /1 3 6
29 RRR study: study flow diagram and results Enrolled in RRR IFX was discontinued (n=114) withdrawn (n=12) RRR-achieved DAS28 at year 1 <3.2: n=56 (55%) remission (DAS28<2.6): n=44 (43%) LDA (2.6 DAS28<3.2): n=12 (12%) Estimated at year 1 (n=12) RRR-failed Failed from LDA for 1 year: n=46 (45%) DAS28 at year 1 3.2: n=17 (17%) flared up within 1 year: n=29 (28%) LDA: low disease activity Tanaka Y, et al. Ann Rheum Dis (21) 69:1286
30 Baseline factors affecting bio-free remission in RA treated with IFX: logistic multivariate analysis (in our department) estimated SE χ2 P-value gender Disease duration #SJC CRP DAS RF Changes of positivity of RF by TNF-inhibitors By biologic-free 77% 52% By drug-free 4% % MMP HAQ MTX dose RF: (-), 1(+) PSL dose Is next target immunological remission?
31 1 Contribution of TNF-α to SKG Mice Incidence of arthritis (%) Arthritis severity scores TNF-α +/+ (n=24) TNF-α +/- (n=28) TNF-α -/- (n=27) Weeks Weeks Hata H, et al: J Clin Invest (24) 114: 582
32 Revolution of treatment of autoimmune diseases Improvement of signs and symptoms Anti-rheumatic drug methotrexate + Biologics TNF-inhibitors TCZ, ABT, RTX 1) Clinical remission 2) Structural remission 3) Functional remission RA Anti-lupus drug HGQ, MMF, AZ, CY, Syk-I + Biologics anti-cd2, CD22, BAFF? ABT, atacicept? 1) Clinical remission 2) improvement of organ damage 3) improvement of life span SLE
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Although this presentation includes information regarding pharmaceuticals (including products under development), the information is not intended as
Although this presentation includes information regarding pharmaceuticals (including products under development), the information is not intended as any advertisement and/or medical advice. Forward-Looking
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