1050617生物製劑於風濕性疾病之應用

Inflammatory arthropathy

Rheumatoid arthritis (RA)

Ankylosing spondylitis (AS)

Psoriasis and Psoriatic arthropathy (PsA)

Juvenile chronic arthropathy (JCA)

Inflammatory bowel diseases

Crohn’s diseases (CD)

Ulcerative colitis (UC)

Systemic lupus erythematosus (SLE) Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis

(Wegener’s granulomatosis)

Others: Behcet’s disease, Autoinflammatory diseases..

Arthritis of hands

Tenosynovitis

Boutonniere deformity 關節

％

MCP, PIPs Wrists Knees Shoulders Ankles Feet Elbows

91 78 64 55 50 43 38

Volar subluxation, ulnar deviation, rheumatoid nodules

Swan neck deformity

Normal synovium

RA synovium

C1-2 subluxation

Serositis

Leukocytoclastic vasculitis

Leg ulcers (Felty syndrome)

Drop foot

Rheumatoid nodule

Before 1993:

1993~2001

Advent of novel therapeutics – Pathophysiology Introduction of early therapy – Treat to target “T2T” Development of new classification criteria – Early Dx Application of new effective treatment strategies –

EULAR, ACR, APLAR recommendations

Pathophysiology

Smolen et al. Lancet published on line May 3, 2016

MicroRNA 146a,155

Pathophysiology

Bare area

Pathophysiology

Pathophysiology

Target therapy

Target therapy

Etanercept Enbrel 恩博

Infliximab Remicade

Adalimumab Humira 復邁

Target

TNF

TNF

Half Life

3-5 days

Construct

Anakinra Kineret

Abatacept Orencia 恩瑞舒

Rituximab Mabthera 莫須瘤

Tocilizuma b Actemra 安挺樂

TNF

IL-1 receptor

T-Cell activation

B-Cell

IL-6

14 days

7-20 days

4-6 Hrs

13-16 Days

19 Days

10 days

Pegylated Fab fragment

Human mAb

Human mAb

CTLA-Fc IgG

Chimeric mAb

Human mAb

Once Daily

Monthly

Twice every 612 months

Monthly

Sub-Cut

I.V.

I.V.

I.V.

Certolizumab, Cimzia

Golimumab Simponi 欣普尼

TNF

TNF

8-10 days

10-20 days

Soluble p75 TNFa receptor

Chimeric mAb

Human mAb

Dosing

Once Biweeklyweekly

Once every 4-8 weeks

Once every 1-2 weeks

Monthly

Monthly

Route

Sub-Cut

I.V.

Sub-Cut

Sub-Cut

Sub-Cut

Early DX

2010 ACR/EULAR Classification Criteria for RA Morning stiffness ≥1 hr Arthritis of three or

more joint areas Arthritis of hand joints Symmetrical arthritis Rheumatoid nodules Serum rheumatoid

factor Radiographic changes

Criteria 1-4 must be present for at least 6 wks.

Well-established disease

Joint Involvement (synovitis) 1 Large joint⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅ 2-10 Large joints⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅ 1-3 small joints⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅ 4-10 small joints⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅ More than 10 joints (at least one small joints) ⋅⋅⋅⋅⋅⋅ Serology Negative RF and CCP⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅ Low titer positive CCP or RF⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅ High titer CCP or RF⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅ Duration less than 6 weeks⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅ 6 or more weeks⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅ Acute phase reactants Abnormal ESR or CRP⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅

0 1 2 3 5 0 2 3 0 1 1

(average 7 yrs’ disease duration) Early Dx!!

If you have another Dx, don’t apply criteria of RA. 21% higher sensitivity, 16% lower specificity

Early DX

28 y/o female had joint pain

for 4 weeks PE: arthritis over Bil. knees CRP: 1.2 mg/dL RF: 24 mg/dL (cut-off: 20

mg/dL) Anti-CCP antibody:21 No radiographic bony

change

Joint Involvement (synovitis) 1 Large joint⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅ 2-10 Large joints⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅ 1-3 small joints⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅ 4-10 small joints⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅ More than 10 joints (at least one small joints) ⋅⋅ Serology Negative RF and CCP⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅ Low titer positive CCP or RF⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅ High titer CCP or RF⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅ Duration less than 6 weeks⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅ 6 or more weeks⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅ Acute phase reactants Abnormal ESR or CRP⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅

0 1 2 3 5 0 2 3 0 1 1

Monitoring Tx response

Changes in disease activity: Number of tender joints (68) Number of swollen joints (68) ESR Physician global assessment Patient global assessment Morning stiffness Pain Disability

5/7, with 20%, 50% and 70% improvement

Monitoring Tx response

TEMPO

ACR Response at 1 Year

100

% of patients responding

MTX (n=228)

*†

ENBREL (etanercept) (n=223)

85 80

*‡

75 76

ENBREL + MTX (n=231)

69

*‡

60 43

48

43

40 19

20 0

ACR 20

ACR 50

Analysis using last observation carried forward (LOCF) *p<0.01 vs MTX; †p<0.05 vs ENBREL; ‡p<0.01 vs ENBREL Klareskog L, et al. Lancet 2004;363:675–81

24

ACR 70

Monitoring Tx response

Patient global assessment; mm in

DAS28; cm in CDAI, SDAI

DAS28=disease activity score

using 28 joint counts.

SDAI=simplified disease activity index. CDAI=clinical disease activity index. TJC28=tender joint count (of 28). SJC28=swollen joint count (of 28). ESR=erythrocyte sedimentation rate (in mm).

GH=global health. CRP=C-reactive protein (in mg/dL).

DAS28-ESR=0・56 × √ (TJC28) +

0・28 × √(SJC28) + 0・70 × loge(ESR) +0・014 × GH.

DAS28-CRP=0・56 × √ (TJC28) +

0・28 × √(SJC28) + 0・36 × loge(CRP + 1) + 0・014 × GH + 0 ・96.

SDAI=TJC28 + SJC28 + PtGA + EGA

+ CRP.

CDAI=TJC28 + SJC28 + PtGA +

EGA.

Monitoring Tx response

T2T

Evaluation of disease activity at least every 3 months.

T2T

Low-dose glucocorticoids (10 mg/day of prednisone or equivalent) in patients with moderate or high RA

disease activity when starting DMARDs and in patients with DMARD failure or biologic failure or shortterm glucocorticoids for RA disease flares.

Glucocorticoids should be used at the lowest possible dose and for the shortest possible duration to provide the best benefit-risk ratio for the patient.

T2T

T2T

Treatment target should ideally be low disease activity or remission.

Tapering (reducing dose or dosing frequency) if remission, not discontinuing it and if done,

must be conducted slowly and carefully.

Biologics

TNF blockers:

Abatacept Orencia

http://img.medscape.com/fullsize/migrated/579/368/ajh579368.fig 1.g if

期i製u資i舒瘤b (應瘤bTh科r瘤)

Tofacitinib Xeljanz

MTX MTX MTX

TEMPO

Weinblatt, 1999

GO-BEFORE

GO-FORWARD GO-AFTER

FUNCTION

OPTION

RADIATE

DANCER

REFLEX

MTX MTX

PREMIER

MTX

ARMADA

AGREE

AIM

ATTAIN

IMAGE

73 new RCTs for a total of 90 RCTs; 79 RCTs with 32,874 participants provided usable data.

Codreanu et Al. Biologics: Targets and Therapy 2015:9 1â&#x20AC;&#x201C;6

Common concerns during biologic therapies

Serious infections Tuberculosis Hepatitis Lymphoma or cancer risk Antibodies to TNF antagonist Autoimmunity

Serious infections

Singh et al. Lancet 2015; 386: 258â&#x20AC;&#x201C;65

Serious infections

Singh et al. Cochrane Database of Systematic Reviews 2011, Issue 2. Art. No.: CD008794.

Serious infections

Strand et al. Arthritis Research & Therapy (2015) 17:362 In total, 66 randomized controlled trials and 22 long-term extension studies

HBV

Chen et al. Ann Rheum Dis 2011;70:1719â&#x20AC;&#x201C;1725.

TB

Biologics

LTE studies IR (95% CI)

2013 Cochrane Review Odds ratio (95% CI)

Certolizumab

474.29 (350.00-640.00)

4.43 (0.5-39.09)

Infliximab

347.70 (193.48-539.25)

2.82 (0.65-12.18)

Adalimumab

184.79 (87.00-318.89)

2.14 (0.33-13.78)

Golimumab

172.13 (57.59-341.83)

3.04 (0.12-75.13)

Tocilizumab

75.61 (36.10-129.54)

Not estimable

Etanercept

65.01 (18.22-136.84)

1.48 (0.06-36.93)

Abatacept

60.01 (18.22-125.97)

0.50 (0.03-8.11)

Rituximab

20 (0.10-60.00)

---

LTE: long-term extension; IR: incidence rate per 100,000patientyears

TB

Liao et al. PLoS ONE 11(4): e0153217

14.3%

3.4%

4.0%

0.003%

TB

TB

TB

Cancer

ADA

Human anti-chimeric antibody HACA

Neutralizing

Human anti-human antibody HAHA

Non-neutralizing

ADA

Bartelds et al. JAMA. 2011;305(14):1460-1468 Percentage of Anti-adalimumab Development Over Time

Median Adalimumab Concentrations Over Time

Sustained Disease Activity and Remission in Patients With and Without Anti-adalimumab Antibodies

ANA

Autoantibody profiles and frequencies of CIC formation before and after adalimumab treatment Adalimumab (n=44)

Seroconversion

Wk o

Wk 48

ANA

10 (22.7)

23 (52.2)*

23 (52.2)

Anti-SSA/Ro

12 (27.2)

12 (27.2)

0

Anti-SSB/La, Sm, RNP

0

0

0

Anti-dsDNA

0

2 (4.5)

2 (4.5)

Anti-histone

2 (4.5)

5 (11.3)*

4 (9.0)

Anti-ssDNA

1 (2.2)

11 (25.0)*

10 (22.7)

Antinucleosome

3 (6.8)

6 (13.6)*

4 (9.0)

aCL-IgG

0

0

0

aCL-IgM

3 (6.8)

13 (29.5)*

10 (22.7)

0

4 (9.0)*

4 (9.0)

CIC

Mean titers of anti-SSA/Ro antibodies

Autoantibodies

Elevation anti-ssa/ro titers during adalimumab therapy (n = 13) â&#x2C6;&#x161; Anti-histone, anti-ssDNA antibodies X Anti-cardiolipin antibody IgM

0

24

36

48

No lupus-like syndrome had been documented among TNF blocker users in Taiwan.

2015年修訂版風濕病醫學會免疫風濕病患接受腫

瘤壞死因子抑制劑類生物製劑結核感染篩檢與防 治共識建議

2012年風濕病醫學會免疫風濕病患接受生物製劑

治療B型肝炎篩檢與防治共識建議

Arthritis Care & Resear 2016; 68, 1:1â&#x20AC;&#x201C;25

Arthritis Care & Resear 2016; 68, 1:1â&#x20AC;&#x201C;25

Cantini, et al. Seminars inArthritisandRheumatism45(2016)519â&#x20AC;&#x201C;532

75/197 met steroid-free, and sustained DAS28-ESR remission for more than 6 months The remission rate (83%) and the rates of low disease activity (91%) in the adalimumab continuation group were significantly higher than those (48% and 62%, respectively) in the adalimumab discontinuation group 1 year later.

Predictive factors related to sustaining remission: DAS28-ESR at the discontinuation <1.98 (deep remission) and disease duration (<2 years).

IL-12

IL-23

J Am Acad Dermatol 2015;73:400-9

Secukinumab (79.0%) was superior to ustekinumab (57.6%) as assessed by PASI 90

response at week 16 (P<.0001).

The 100% improvement from baseline PASI score at week 16 was also significantly greater with secukinumab (44.3%) than ustekinumab (28.4%) (P<.0001).

The safety profile of secukinumab was comparable with ustekinumab.

Biologic agents

RA

Plaque psoriasis

PsA

CD

UC

AS

JIA

+ + +

+ +

+

+ + +

+ +

Organ transplant

NHL

MS

Tumor necrosis factor blockers Infliximab Adalimumab Etanercept Certulizimab Golimumab

+ + + + +

+ + +

+ +

+

Lymphocyte inhibitors

+

Doclizumab Rituximab Abatacept

+ +

+ + +

Basiliximab Specific receptor antagonists Anakinra Efalizumab Alefacept Natalizumab

+ + + +

+

Sugiyama et al. Clinical Therapeutics, 2016

In France, the direct annual costs of RA were

estimated to be €4,000 in 2000 (before the introduction of biological agents) and about €12,000 in a 2005 study in which 20% of patients were receiving these agents.

In Taiwan, NT 3000/month → NT 36000/month

Systemic lupus erythematosus (SLE) â&#x20AC;&#x201C; Belimumab (mAb of B

lymphocyte activating factor) Anti-neutrophil cytoplasmic antibody (ANCA) associated

vasculitis (Wegenerâ&#x20AC;&#x2122;s granulomatosis) -- Rituximab