Biologic therapy update in rheumatic disease

Biologic therapy update in rheumatic disease
경 희 의 료 원 류 마 티 스 내 과 이 연 아

RA : Synovitis & Joint Destruction
정상 류마티스 관절염 활막의 염증 활막 주된 세포 T 림프구 대식세포 Pannus 부수적인 세포 섬유모세포 형질세포 내피세포 수지상세포 연골 Rheumatoid arthritis (RA) is a chronic and progressive inflammatory disease, characterised by synovitis and joint destruction,1 and often results in significant disability and premature mortality.2 The pathogenesis of this chronic autoimmune disease is mediated by an interdependent network of cytokines, prostanoids, and proteolytic enzymes.3 Cytokines possess proinflammatory and immunosuppressive anti-inflammatory properties that regulate immune responses.1 An imbalance between proinflammatory and anti-inflammatory effects is thought to contribute to the chronic nature of RA. Hence, the current pathogenetic model for RA is one of a chronic, tissue-specific inflammatory process to which a variety of immune responses can contribute.1 This slide depicts the unique pathophysiological elements of RA that arise from interactions between the variety of leucocytes that invade the joint, and the native cellular components of joint tissue. 1. Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol. 1996;14: 2. Pincus T. The underestimated long term medical and economic consequences of rheumatoid arthritis. Drugs. 1995;50(suppl 1):1-14. 3. Tak PP, Bresnihan B. The pathogenesis and prevention of joint damage in rheumatoid arthritis. Advances from synovial biopsy and tissue analysis. Arthritis Rheum. 2000;43: 활액 주된 세포 중성구 관절 피막 연골이 얇아짐 Feldmann M, et al. Annu Rev Immunol. 1996;14:

자가면역 질환의 염증반응 기전 항원제시세포 B cells B 림프구 단백항원 T 림프구 다양한 염증반응 Cytokines

Cytokine pathway in RA N Engl J Med, Vol. 344, 2001

Cytokines in Inflammation
Pro-inflammatory Anti-inflammatory TNFa IL-1b sTNFR IL-10 IL-1Ra In RA the normal equilibrium between cytokines is disrupted leading to an excess of proinflammatory molecules in the synoviate of sufferers. 종양괴사 인자 (TNF-α) - 류마티스 관절염에서 가장 중요한 염증 매개 물질 - 관절 부종과 통증같은 염증반응과 연골 및 골파괴 일으킴

류마티스 관절염의 진행 진행성관절염 ( 65-70% ) : 대개는 만성 경과  관절 변형과 장애
이런한 류마티스 관절염은 그 진행정도를 방사선 검사에서도 확인할 수가 있는데 손가락 관절의 류마티스 관절염을 촬영한 것입니다. 골미란이 관철되며 연골소실에 따라 관절사이 간격이 좁아지고 더 진행하면 관절이 거의 파괴되고 붙는 모습을 볼 수 있습니다. 진행성관절염 ( 65-70% ) : 대개는 만성 경과  관절 변형과 장애

과거의 치료 전략 스테로이드 제제 비스테로이드성 소염 진통제 병합 피라미드 모델  “ Step-up” : 점차적으로 강한
단일 항류마티스제 HCQ SSZ MTX 피라미드 모델 : 점차적으로 강한 약물을 단계적 추가  “ Step-up”

과거 치료 전략의 문제점 신체기능 소실: 50% 환자가 첫 1-2년안에 중등도의 소실 직업 장애: 6개월째 13%
류마티스 관절염은 초기에 이미 비가역적 관절 손상이 존재 발병후 2년이내에 60%에서 골미란 발생 일단 관절파괴가 진행하기 시작하면 억제하기 어려움 “ 초기에 적극적인 치료를 도입해야 한다”는 개념이 대두

기회의 창 ( window of opportunity) 개념
성공적인 치료가 가능하다고 생각하는 시기 증상시작 2년이내 최근 3개월이내로 바뀌고 있음 6주 주 12주 소염진통제 /스테로이드제/ 항류마티스제 관해 가능성 5배 관절염 지속? 6주 조기 관절염

치료 전략의 변화 과거 최근 “ 조기에 적극적 치료 !” 조기에 항류마티스 약물 투여 단독보다 병합요법 단계적 약물 추가
증상 발현후 기간 (개월) 질병 활성도 (%) 최근 “ 조기에 적극적 치료 !” 질병 활성도 (%) 증상 발현후 기간 (개월) 관절 손상 조기에 항류마티스 약물 투여 단독보다 병합요법 단계적 약물 추가

방사선학적 관절손상의 진행 발병 2년이내의 조기 류마티스 관절염 관해가 이루어진 경우에도 방사선학적 진행
환자를 장기 추적한 결과 DMARD 치료에도 방사선학적 변화 진행 관해가 이루어진 경우에도 방사선학적 진행 이 될 수 있음 관해 유지 ( 93명 ) 악화 ( 86명 ) -10 -5 5 10 15 20 25 30 방사선학적인 변화( vdH-S) Wolfe F and Sharp JT. Arthritis Rheum. 1998;41(9): Molenaar ETH, et al. Arthritis Rheum. 2004;50(1):36-42.

RA에서 치료 효과 평가 관절 손상이 왜 중요한가? 증상을 개선하는가? remission을 얼마만큼 유도하는가?
joint damage를 예방하거나 억제하는가?가장 중요한 장기목표 관절 손상이 왜 중요한가? 질병 활성도를 반영 장기 예후를 반영 손, 발의 관절 손상이 전체 관절의 손상을 반영

Assessment tool RA AS PsA Disease activity score (DAS) DAS 28, 44
ACR 20, 50, 70 BASDAI ASAS 20, 40 Radiological Larsen score Sharp score (TSS) VdH / Sharp BASRI PARS Sharp vdH-Sharp QoL (disability) MHAQ BASFI SF36 BASMI DAS28 = 0.56*TJC *SJC + 0.7*ln(ESR) *PGA *van der Heijde D. Ann Rheum Dis. 1990;49:916. †Prevoo M, et al. Arthritis Rheum. 1995;38:44.

Biologic agent - Targeted therapy
Biologics Protein-based, made by biological technology Specific effects- neutralise or block the target High efficacy Blocking cytokine activity TNF-α : infliximab, adalimumab, etanercept IL-1: anakinra IL-6: MRA Co-stimulation blockade CTLA-4 : abatacept B-cell depletion CD 20 : rituximab

Strategies of cytokine inhibition Receptor antagonist-Anakinra, MRA
Anticytokine Ab-Infliximab, Adalimumab Soluble cytokine receptor- Etanercept Receptor antagonist-Anakinra, MRA N EJ M, Vol. 344, 2001

종양괴사인자 (TNF) : 류마티스 질환에서 중요한 병인
염증성 사이토카인 케모카인 대식세포 염증 증가 부착인자 염증세포 침윤 내피세포 종양괴사인자 VEGF 혈관 신생 간세포 급성기 단백 CRP 증가 Add keratinocyte arrow TNF 활막세포 Metalloproteinase 합성 관절연골 손상 RANKL 발현 전구 파골세포 골미란

TNF-  : Mode of Action 표적세포 신호 활성화된 대식세포 sTNFR TNF

TNF-Targeted Biologic Agents
Human monoclonal TNF--antibody Chimeric monoclonal TNF--antibody p75-human- TNF-receptor- IgG1-Fc-fusion protein Specific Binding Site Human IgG1-Fc- Part 에타너셉트 ( 엔브렐 ® ) 아달리무맵 ( 휴미라 ® ) 인플릭시맵 ( 레미케이드 ® ) 염증 반응의 중추적 물질인 TNF-α 중화 높은 효율성

Infliximab / Adalimumab Mode of Action
Activated M f Target Cell Signal TNF TNFR

Infliximab ( Remicade ® )
적응증 : 투여법 : 보험적용 : 크론씨병 강직성 척추염 류마티스 관절염에서는 MTX 와 같이 투여해야함 3-5 mg/kg 0, 2, 6주 이후 8주간격으로 정맥주사 류마티스 관절염에서 아직 보험적용 안됨 Murine

ATTRACT: 2-Year Radiographic Effect of Infliximab
Randomized, double-blind study patients with active RA and incomplete response to MTX N=428 MTX + Placebo (n=88) MTX + INF 3 mg/kg q4 weeks (n=86) MTX + INF 3 mg/kg q8 weeks (n=86) MTX + INF 10 mg/kg q4 weeks (n=81) MTX + INF 10 mg/kg q8 weeks (n=87) Disease duration : mean Years Lipsky PE, et al. N Engl J Med. 2000;343: Maini RN, et al. Arthritis Rheum. 2004;50(4):

ATTRACT : 인플릭시맵의 방사선학적 진행억제
MTX에 비한 억제효과 Lipsky PE, et al. N Engl J Med. 2000;343: Maini RN, et al. Arthritis Rheum. 2004;50(4): *P < vs MTX at each time point

Adalimumab ( Humira ® ) Human 적응증 : 투여법 : 보험적용 : 류마티스 관절염 40mg 2주 간격
Constant (Fc) Variable Human 적응증 : 투여법 : 보험적용 : 류마티스 관절염 40mg 2주 간격 피하주사 류마티스 관절염에서 아직 보험적용 안됨 아직 국내 시판 안됨

PREMIER: 2-Year Radiographic Effect of Adalimumab
Randomized, double-blind study MTX-naïve patients with active early RA N=799 MTX (escalated to 20 mg/week) Adalimumab (40 mg eow) Adalimumab + MTX 75% female, Mean age: 52 years, 83% RF+ Mean RA duration : 0.7 years Mean DAS28 = 6.3, Mean HAQ = 1.5, Mean TSS = 19.5 Breedveld FC, et al. 2004; presented at American College of Rheumatology, poster LB520.

PREMIER: 아달리무맵의 방사선학적 진행 억제
/kg q8 주(87명) 억제효과 * * † † *P < vs MTX †P < vs MTX or ADAL Breedveld FC, et al. 2004; Poster presented at American College of Rheumatology, #B520.

Etanercept ( Enbrel ® ) : TNF soluble receptor
사람 TNF-a수용체 면역글로불린 부위 적응증 : 투여법 : 보험적용: 장점 : 류마티스 관절염 강직성 척추염 25mg 1주에 2회 또는 50mg 1주에 1회 피하주사 항류마티스제를 사용해도 조절되지 않는 류마티스 관 절염, 강직성 척추염에서 보 험적용됨 집에서 자가로 맞을 수 있다. This cartoon is a schematic representation of recombinant human TNF receptor (p75) Fc fusion protein (TNFR:Fc). It consists of two molecules of the extracellular domain of p75 TNFR linked to the Fc region of human IgG1. Because of its bivalent nature, TNFR:Fc is an effective competitive inhibitor of TNF binding to cell surface receptors. July 15, 1997 Slide No. 13

에타너셉트 ( 엔브렐 ® ) 집에서 자가로 맞을 수 있다

Etanercept Mode of Action
sTNFR:Fc Activated M Target Target M f f Cell Cell TNFR TNFR Signal Signal sTNFR sTNFR TNF TNF sTNFR:Fc (엔브렐) sTNFR:Fc

TEMPO: 2-Year Radiographic Effect of Etanercept
Double-blind, randomized, placebo-controlled trial active RA, mean disease duration : Yrs inadequate response to one DMARD other than MTX Three treatment groups (n=682) Etanercept 25 mg sc twice weekly + oral placebo once weekly (qw) (n=223) Oral MTX (maximum 20 mg/week) + placebo sc biw (n=228) Etanercept 25 mg sc biw plus MTX qw (n=231) Blinded extension up to 3 yrs Klareskog L, et al. Lancet. 2004;363:

TEMPO Trial: 에타너셉트의 증상개선 효과
ACR20 ACR50 ACR70 † †‡ †‡ †‡ * †‡ *P < 0.05, ETN versus MTX †P < 0.05, combination versus MTX ‡P <0.05, combination versus ETN Klareskog L, et al. Lancet. 2004;363:

Patients in Remission (DAS44 <1.6)
TEMPO Trial: 에타너셉트의 관해 유도율 Patients in Remission (DAS44 <1.6) *† *† Klareskog L, et al. Lancet. 2004;363: *P < 0.05, combination vs MTX †P < 0.05, combination vs ETN

TEMPO Trial: 에타너셉트의 방사선학적 진행 억제
(Disease Duration >3 yrs) 방사학적인 변화 억제효과 *† *† 관절 손상 복구 가능성 시사 *P < 0.05 vs MTX †P < 0.05 vs ETN van der Heijde D, et al. 2004; Poster presented at American College of Rheumatology, #526.

에타너셉트의 장기 치료 효과 ACR20 ACR50 ACR70
Weinblatt ME, et al. Arthritis Rheum. 2004;50(9):S184. Weinblatt ME, et al. Poster presented at 2004 ACR Annual Scientific Session, #356.

Pharmacokinetics of TNF inhibitors
Etanercept Infliximab Adalimumab Half-life (days) 5 9±1 16±2 Bind lymphotoxin a o X Bolus effect Fix complement Lyse cells T cell anergy in vivo ? Reversible binding

Clinical Efficacy……..All the same?
Disease Etanercept Infliximab Inflammatory Arthritis o Heart Failure Neutral worsens Crohn’s X Clinical practice - switching may work  Efficacy etanercept after failure infliximab mechanism ?   lymphotoxin on biopsy (Buch et al ARD 2004;63(10):1344-6)

류마티스 관절염에서 최선의 치료전략 조기 진단과 조기 치료 초기에 항류마티스제 투여: 단독보다는 병합이 더 효과적
관해 유도를 위해 최선을 다할것 항류마티스제가 실패할 경우 TNF 차단제의 사용고려 스테로이드제재는 가능한 소량, 짧은기간 동반된 질환에도 관심: 심혈관질환, 골다공증

TNF Inhibitors in SpA (PsA and AS)
Agent Type Administration FDA Status Enbrel® etanercept Soluble TNF receptor protein SC injection Self-administered Approved for PsA/Pso Approved for AS Remicade® infliximab Chimeric TNF antagonist (mAb) Infusion Administered at infusion center Under investigation for PsA/Pso (phase 3) Humira® adalimumab Human TNF antagonist (mAb) PsA/Pso (phase 3) and AS (phase 3)

MRI Activity Score: ASspiMRI-a
1 Vertebral Unit Grade 1 Grade 2 Grade 3 Bone Edema Grade 4 Grade 5 Grade 6 Erosion Braun J et al. Arthritis Rheum. 2003;48:

Example of Patient Pre- and Post-Treatment Gadolinium-enhanced T1
Baseline Week 24

P = NS between groups for each measure
IMPACT: Infliximab in Psoriatic Arthritis (PsA) Change in TSS at 50 Weeks Antoni CE, et al. Arthritis Rheum. 2004;50(9):450. P = NS between groups for each measure

Etanercept in PsA: Change in TSS Over Time
Open-label Phase Double-blind Phase † * *P = , Stratified rank test †P = , Stratified rank test Mease PJ, et al. Ann Rheum Dis. 2004;63:99.

Improvement in MRI Activity Score at 24 Weeks
ASSERT: Infliximab in AS Improvement in MRI Activity Score at 24 Weeks Median Improvement (IQR)1 0.00 (-3.00, 0.57) 2.72 (-9.00, 0.00) Braun, et al. ACR 2004 late breaking abstract

ASSERT Week 24: Additional Efficacy Measures
* * * van der Heijde D, et al. Arthritis Rheum. 2005;52(2): *P < 0.05 vs placebo

Etanercept in AS: Effect on Spinal Inflammation
* * * * *P < 0.01 vs baseline After 24 weeks, PBO patients could switch to etanercept. Evaluated using T2-fat saturated MRI Baraliakos, et al. 2004; Poster presented at American College of Rheumatology, #L1.

ASAS Response to Etanercept After 48 Weeks (Open-Label)
Davis JC, et al. Arthritis Rheum. 2004; 50(9): S611.

TNF 차단제의 문제점 Demyelinating conditions CHF
Few reported cases among TNF-targeted agents : MS relapse, Paresthesia, Optic neuritis Some resolve spontaneously or upon discontinuation of Tx CHF Elevated TNF-a levels in patients with CHF associated with LV dysfunction Deleterious effects on LV remodeling Trials of TNF-targeted agents showed no benefit in CHF infliximab worsening

TNF 차단제의 문제점 - tuberculosis
Etanercept Infliximab Adalimumab Patients treated Patient-years exposure TB Reports United States Ex USA Extrapulmonary Time to onset 150000 230000 38 20 18 50% 11 months 200000 172 55 117 45% 75% by 6 weeks 2500 4900 13 3 10 40% 3–8 months Data through 4th quarter of 2002. American College of Rheumatology website. Available at: Accessed 3/12/04.

TNF 차단제의 문제점 - Infections Observed in Clinical Trials
Etanercept Infliximab Adalimumab Infections (%)* Serious infections (%)* Serious infections per pt/yr 38 1 0.04 39 6 0.03 51.9 1.3 *Incidence of infections and serious infections equal to placebo. US Etanercept Prescribing Information. Wyeth Pharmaceuticals; Collegeville, Pennsylvania:October 2003. US Infliximab Prescribing Information. Centocor, Inc.; Malvern, Pennsylvania:September 2003. US Adalimumab Prescribing Information. Abbott Laboratories; North Chicago, Illinois:January 2003. Fleischman R and Yocum D. Arthritis Res Ther. 2004;6(Suppl 2):S12-8.

Atypical Infections Infliximab Etanercept Tuberculosis 36 295
Candidiasis 73 59 Pneumocystis carinii 4 44 Atypical mycobacteria 11 37 Histoplasmosis 2 Listeriosis 27 Aspergillosis 7 26 Cytomegalovirus 8 20 Through June, 2002. Ruderman EM, et al. Arthritis Rheum. 2003;48(9 Suppl):S241.

Incidence of Infections in Subjects With/Without RA
Doran MF, et al. Arthritis Rheum. 2002;46(9):

Chambers CD, et al. Arthritis Rheum. 2004;50(9 Suppl):S479.
Pregnancy outcomes Outcome Infliximab (n=4) Etanercept (n=29) RA Control (n=77) Non-RA Control (n=50) P- value Spontaneous abortion, n (%) 1 (25) 3 (11) 5 (7) 2 (4) 0.36 Pre-term delivery, n (%) 2 (67) 7 (28) 16 (24) <0.01 Rate of malformations similar in TNF groups (3%) to both controls (4%) Mean birth weight lower in TNF-treated group and RA Control vs Non-RA control Major structural defects appeared to be consistent with population rates Risk for pre-term delivery and low birth weight likely due to disease condition and/or use of systemic steroids Chambers CD, et al. Arthritis Rheum. 2004;50(9 Suppl):S479.

Malignancy and Lymphoma Clinical Trial Data
Etanercept Infliximab Adalimumab Patients Pt-yr follow-up Expected CA* Observed CA Observed Lymphoma† Lymphoma SIR† 1272 3806 47.5 49 9 3.5 1298 2458 16 18 4 6.4 2468 4870 38 10 5.4 *NCI (SEER), 2001, adjusted for age, sex distribution; †All RA patients. FDA Briefing Document. Available at: Accessed 3/11/04. Schiff MH, et al. Arthritis Rheum. 2003;48 (Suppl): S700.

TNF 차단제의 문제점 결핵 위험이 높다 - 우리나라의 경우 잠복 결핵의 활성화 종양 발생 가능성 감염 질환의 발생 비용문제
: 림프종 외에 다른 암의 발생이 증가한다는 보고는 아직 없음 감염 질환의 발생 : 류마티스 관절염이라는 질환 자체가 감염위험이 높으므로 판단하기 어려움 비용문제 효과가 모든 환자에서 있는 것은 아니며, 중단시 다시 악화

Biologics Can Provide Benefit When DMARDs Fail
Many clinical trials of TNF-targeted biologic agents have assessed treatment in patients refractory to conventional DMARDs Treatment Refractory therapy Outcome measure % response INF (10 mg q8 wks)+ MTX (ATTRACT) MTX ACR70 25 ETN + MTX (TEMPO) DMARDs (not MTX) ACR70 DAS remission 44 41 ADAL + DMARD (ReACT) ≥1 DMARD 18 Lipsky PE, et al. N Eng J Med. 2000;343: Klareskog L, et al. Arthritis Rheum. 2004: 50(9): S238. Burmester G, et al. Poster presented at EULAR 2004; #61.

Consensus on Biologics
TNF-targeted therapy recommended for treatment of active RA, PsA, AS, and juvenile idiopathic arthritis after failing another DMARD Etanercept: RA, JIA, PsA, AS Indicated for severe, active, progressive RA patients not previously treated with MTX (EU) Infliximab: RA, PsA, AS Adalimumab: RA Furst DE, et al. Ann Rheum Dis. 2004;63(S2):ii1-12.

Consensus on Biologics (continued)
Additional possible indications for TNF-targeted biologic Tx Wegener’s granulomatosis Giant cell arteritis Takayasu’s arteritis Adult-onset Still’s disease Hepatitis C Behçet’s disease Uveitis Polymysositis Dermatomyositis SLE Systemic sclerosis Asthma IPF Sjögren’s syndrome Furst DE, et al. Ann Rheum Dis. 2004;63(S2): ii1-ii12.

현재 TNF 차단제 사용에 대한 견해 MTX와 TNF 차단제의 병합이 현재로서는 가장 효과적으로
관절 손상을 중지시킬 수 있는 치료 기존의 항류마티스제로 활성이 조절되지 않는 류마티스 질환에서 권장됨 * 엔브렐 : MTX 치료경력이 없어도 심한 진행성 류마티스 관절염 에서는 일차 치료로 투여하기도 함 (유럽) 금기 사항등을 주의한다면 TNF 차단제는 대부분의 환자들에게 안전하게 사용할 수 있음.

Anakinra (Kineret ®) recombinant human form of the naturally
occurring IL-1 receptor antagonist Anakinra IL-1 No signalling IL-1Ra Kineret® (anakinra) is the first and only selective antagonist of IL-1.1 Anakinra is a recombinant form of the naturally occurring IL-1 receptor antagonist.1 Kineret® treatment counteracts the damaging cellular events mediated by IL-1 in rheumatoid arthritis, reducing pain and inflammation.1-3 1. Bresnihan B, Alvaro-Gracia JM, Cobby M, et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum. 1998;41: 2. Cohen S, Hurd E, Cush J, et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate. Arthritis Rheum. 2002;46: 3. Cohen SB, Moreland LW, Cush JJ, et al. Anakinra (recombinant interleukin-1 receptor antagonist): a large placebo-controlled efficacy trial of anakinra in patients with erosive rheumatoid arthritis disease [Late-breaking abstract]. American College of Rheumatology 65th Annual Meeting; November 11-15, 2001; San Francisco, Ca, USA.

Anakinra (kineret) : improve in patient function with RA
Placebo (n = 251) Kineret® 100 mg/day (n = 250) 0.22 change from baseline considered clinically meaningful 0.0 –0.1 –0.2 –0.3 –0.4 Mean 24-Week Change From Baseline in HAQ Disease Index ± SE IMPROVEMENT * Kineret® improves patient functionality, as measured by the Health Assessment Questionnaire (HAQ).1–3 This slide shows the mean change over time in the HAQ disease index for patients receiving Kineret® 100 mg/day or placebo. Patients were also receiving stable doses of methotrexate (MTX). At baseline, mean HAQ disease index (on a scale from 0–3) was 1.36 for Kineret® recipients and 1.32 for placebo recipients.3 Patients receiving Kineret® 100 mg/day experienced a 61% greater improvement in HAQ disease index compared with patients receiving placebo (P <0.05). Kineret® produced a mean change in HAQ disease index score at 24 weeks, relative to baseline, that was greater than –0.22,4 indicating that this improvement was clinically meaningful.1,2 Brief description of the Confirmatory Efficacy Study design1,2 Patients (n = 501) aged 18 years were randomised to receive daily subcutaneous injections of Kineret® 100 mg or placebo. Patients met the American College of Rheumatology criteria for rheumatoid arthritis, with clinical features typical of active disease. This included six or more swollen joints, nine or more tender or painful joints, and at least one of the following criteria: C-reactive protein levels of at least 1.5 mg/dL erythrocyte sedimentation rate of at least 28 mm/h. Patients also had radiographic evidence of at least one bone erosion in the hands, wrists, or feet. Patients had received MTX for a continuous 6 month period, with a stable weekly dosage of 15 to 25 mg for at least 3 months prior to study enrolment. The HAQ was used to evaluate functional status at baseline and at 4-weekly intervals throughout the treatment period. The HAQ is a validated, self-administered questionnaire composed of twenty items relating to function and four items relating to aids and devices. These comprise eight scales: dressing and grooming, arising, hygiene, reach, eating, walking, grip, and activities. Items are scored from 0 (able to function without difficulty) to 3 (unable to function). The HAQ disease index is a weighted sum of the scale scores, with a higher score indicating poorer function. Decreases in the HAQ disease index exceeding –0.22 are considered to be clinically important.4 1. Cohen SB, Moreland LW, Cush JJ, et al. Anakinra (recombinant interleukin-1 receptor antagonist): a large placebo-controlled efficacy trial of anakinra in patients with erosive rheumatoid arthritis disease [Late-breaking abstract]. American College of Rheumatology 65th Annual Meeting; November 11-15, 2001; San Francisco, Ca, USA. 2. Amgen Inc. Kineret (anakinra) FDA Briefing Information, August 16, Available at: 3. Data on file. Amgen Inc; Thousand Oaks, Ca, USA. 4. Wells GA, Tugwell P, Kraag GR, Baker PRA, Groh J, Redelmeier DA. Minimum important difference between patients with rheumatoid arthritis: the patient’s perspective. J Rheum. 1993;20:557–560. 4 8 12 16 20 24 Study Week *P <0.05 vs placebo; HAQ = Health Assessment Questionnaire

Rate of reponse of Anakinra
Nancy J. Olsen NEJM 2004;350:

Abatacept (Orencia) IgG1 CTLA4-Ig
External Cell membrane Internal Cytotoxic T lymphocyte-associated antigen 4 CTLA4-Ig : an Immunoglobulin fusion protein

Effects of fusion protein CTLA4Ig : for RA patients refractory to MTX
Joel M. Kremer, NEJM 2003;349:

Abatacept for RA refractory to TNF-α Inhibition
Mark C. Genovese, NEJM 2005;353:

Co-Stimulation Blockade with CTLA4Ig in Human Psoriasis
Abrams JR, et al. J Clin Invest. 1999;103(9):

Rituximab (Mabthera®)

B cells depeletion in RA Tx
Potential roles of B cells AutoAb production Ag presentation Co-stimulation Cytokine production Chemokine production CD20: B-cell surface antigen Rituximab: anti-CD20 monoclonal Ab Relapsed or refractory low grade or follicular CD20+ B cell NHL Causes selective transient depletion of CD 20 + B cell subpopulation

Rituximab for RA : Study protocol
Active seropositive RA despite MTX use at least 10mg/week , > 16 week 1. Control: oral MTX 10mg or more / week plus placebo 2. Rituximab + placebo for MTX and cyclophsphamide 3. Rituximab + cyclophsphamide in IV 750mg on 3 ,17 + placebo for MTX 4. Rituximab + MTX + placebo for cyclophsphamide MPD 100mg IV, PDL 60mg, 30mg

Inflammation in RA joints
Abatacept Rituximab Inflammation in RA joints Nancy J. Olsen NEJM 2004;350:

Conclusion Biologic agents
: important advance in the treatment of rheumatic diseases TNF-targeted biologics : some of the challenges in the treatment of rheumatic diseases TNF-targeted biologics: established, long-term efficacy across several indications : RA, AS, PsA, Other conditions (eg, Crohn’s) Use expanding to additional diseases/indications

Biologic therapy update in rheumatic disease

Similar presentations

Presentation on theme: "Biologic therapy update in rheumatic disease"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Biologic therapy update in rheumatic disease

Similar presentations

Presentation on theme: "Biologic therapy update in rheumatic disease"— Presentation transcript:

Similar presentations

About project

Feedback