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