Transcript What is TNF? - Home - KSU Faculty Member websites

ATTRACT
 BY DR/ SULTAN ALMOGAIRIN
 CONSULTANT IN RHEUMATOLOGY SERVICE
HISTORY
 YOUNG LADY PRESENTED WITH TOW YEARS HISTORY
OF SYMMETRICAL NON EROSIVE ARTHERITIS
INVOLVING LARGE & SMALL JOINTS INCLUDING THE
HANDS WITH POSITIVE R.F & NEGATIVE ANA
 Pt WAS STARTED INITIALLY ON HQ & SULFASALAZINE
, BUT THERE WAS NO ADEQUATE RESPONSE AFTER
TWO YEARS OF MAXIMUM DOSE OF ABOVE
MEDICATIONS.
 LATER ON X.R OF JOINTS SHOWED ERROSIVE
CHANGES & Pt WAS STARTED ON MTX
HISTORY …cont
 Pt GOT SOME RESPONSE , BUT SHE CONT. TO
HAVE ACTIVITY OF ABOUT 7 – 10 JOINTS OF
HANDS IN THE FOLLOWING 14 MONTHS
 WE ADDED I.M GOLD , AGAIN THE Pt FELT
RELATIVELY BETTER WITH LESS FREQUENCY
FLARE UP & LESS ACTIVITY OF JOINTS BUT
THERE IS STILL NO ADEQUATE RESPONSE
 NEXT THERAPY ?!!!
Introduction to TNF Science &
TNF Inhibition
TNF "Family" Proteins
 Family of type II transmembrane proteins
 Single-binding domain
 Share 20%-30% amino acid homology
 Effects mediated through cell-cell contact
– Exceptions
– TNF
– Lymphotoxin-a
What Is Tumor Necrosis Factor?
 Purified in 1984 (cachectin, TNF) from mouse
macrophages
 Cytolytic for tumor cells (in vitro)
 Necrosis of transplanted tumors (mice)
 Mediates endotoxic shock
 Catabolic hormone
 Highly toxic when given directly
Tumor Necrosis Factor
 Member of TNF family of > 20 proteins
 17 kd trimeric transmembrane protein
 Produced by macrophages/T cells
 Produced in response to IL-1/endotoxin/TNF
 Released from cell surface by TACE (TNF-alpha–
cleaving enzyme)
Flier JS. N Engl J Med. 1996.
Effects of TNF
 Stimulates release of prostaglandins
and chemokines
 Induces tumor lysis (mouse fibrosarcoma)
 Mediates shock (endothelium)
 Stimulates T-cell proliferation
 Causes apoptosis
 Activates neutrophils
 Suppresses lipoprotein lipase
TNFa: Role in Host Defense
 Augments neutrophil microbicidal functions
 Promotes resistance against intracellular
pathogens and parasites
 ? Promotes resistance against viruses
Endotoxin
(LPS)
TNF
Activated
macrophage
TACE
TNF
IL-1
TNF Family Receptors
 Transmembrane proteins
 Cysteine-rich amino acid domains
 Mediate effects via cytoplasmic signals
 Present on many cells (p55 and p75)
 Most remain cell-associated
– Exceptions
– Naturally occurring soluble p55 and p75
Cell-Bound TNF Receptors
p75
p55
Extracellular region
(TNF binding site)
Transmembrane region
Cytoplasmic tail
(signaling)
TNF Receptors
Target
cell
TACE
TNF and TNF Receptors
Activated
macrophage
Target
cell
Signal
TNF
Events in Rheumatoid Arthritis
B cell
T cell
Macrophage
Synoviocyte
Cytokines
Increased cytokine
production (IL-1, IL-6)
Increased
inflammation
Increased adhesion
molecules
Increased production
of MMP
Cell migration
into joints
Tissue
remodeling
Events in Rheumatoid Arthritis
B cell
T cell
Macrophage
Synoviocyte
TNF
Increased cytokine
production (IL-1, IL-6)
Increased
inflammation
Endothelium
Increased adhesion
molecules
Cell migration
into joints
Increased production
of MMP
Tissue
remodeling
Role of TNF in Arthritis
 Produced by synoviocytes/macrophages
 Increased levels in serum and synovial fluid
 Activates the endothelium (E-selectin/PGI2)
 Stimulates fibroblast proliferation
 Induces MMP production (synoviocytes)
 Stimulates production of IL-1 and IL-6 (+TNF)
 Activates osteoclasts via IL-1 stimulation
SS
S
S
S
S
Etanercept
SS
CH3
S
S
S
S
SS
CH2
Fc region of
human IgG1
Extracellular domain of
human p75 TNF receptor
TNF Inhibition: Etanercept
Etanercept
Activated
macrophage
Target
cell
Signal
TNF
Etanercept
Summary: TNF in RA
 Binds and activates both p55 and p75 receptors
 Is an important inflammatory cytokine
 Can initiate events seen in joint inflammation
 Levels are increased in serum and synovial fluid
 Is an appropriate anti-inflammatory target
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Treatment of Early RA: Clinical
Response and Radiographic
Progression (The ERA Trial)
ERA Trial: Study Objectives
 Demonstrate in patients with early, active RA
that etanercept:
– Reduces the rate of joint damage
– Is clinically effective in patients not previously
treated with methotrexate
– Is safe and well tolerated
Finck B. Arthritis Rheum. 1999.
Study Endpoints Prospectively Defined
 Primary
– Change in Sharp score over 12 mo
– Clinical improvement measured by area under
the curve (AUC) of ACR-N over 6 mo
 Secondary
– ACR20, ACR50, ACR70 at 6 mo
Finck B. Arthritis Rheum. 1999.
Eligibility Criteria
 Disease duration  3 yr
 No prior treatment with methotrexate
 Active disease:  10 swollen joints
 12 tender joints
 Rheumatoid factor–positive or erosions on
baseline x-rays
 Stable prednisone ( 10 mg/d) and NSAID
Finck B. Arthritis Rheum. 1999.
Study Design
 Randomized, multicenter, double-blind study
 632 patients
 Three treatment groups
– Etanercept 25 mg + placebo tablets
– Etanercept 10 mg + placebo tablets
– Methotrexate (7.5-20 mg) + placebo injections
 Analysis by intent-to-treat (patients followed
and analyzed if study drug discontinued)
Methotrexate Dose Escalation
 Rapid dose escalation of oral study drug required
by protocol to optimize methotrexate treatment
 Escalated from initial dose of 7.5 mg/wk
– To 15 mg/wk at wk 4
– To 20 mg/wk at wk 8
– If any active joints present
 Decrease of 5 mg allowed once
 Final mean methotrexate dose 18.3 mg/wk
 All patients on folic acid 1 mg qd
Finck B. Arthritis Rheum. 1999.
Mean Dose of Oral Tablets
8
No. of tablets/wk
7
Etanercept 25 mg
6
Etanercept 10 mg
Methotrexate
5
4
3
2
0
Finck B. Arthritis Rheum. 1999.
2
4
6
Month
8
10
12
Demographics
Etanercept
Methotrexate
(n = 217)
10 mg
(n = 208)
25 mg
(n = 207)
49
21-80
50
19-86
51
21-82
75
75
74
11.9
10.9
11.9
89
88
87
Age
Mean
Range
Female (%)
RA duration (mean mo)
Rheumatoid factor–positive (%)
Finck B. Arthritis Rheum. 1999.
Mean Baseline Arthritis Activity
Tender-joint count
Swollen-joint count
Physician global
Patient global
Pain (VAS)
HAQ disability
Disease activity score (DAS)
AM stiffness (hr)
CRP (mg/dL)
Finck B. Arthritis Rheum. 1999.
Methotrexate
(n = 217)
30
24
6.0
6.1
5.6
1.4
5.2
3.7
3.7
Etanercept
10 mg
25 mg
(n = 208) (n = 207)
31
31
24
24
6.3
6.2
6.1
6.1
5.6
5.9
1.4
1.5
5.2
5.2
3.7
3.8
4.4
3.3
Demographics
Methotrexate
(n = 217)
Any prior DMARDs (%)
Mean no. prior DMARDs
DMARDs at washout (%)
Any
Hydroxychloroquine
Concomitant therapy (%)
NSAIDs
Corticosteroids
Mean daily dose (mg)
Finck B. Arthritis Rheum. 1999.
Etanercept
10 mg
25 mg
(n = 208) (n = 207)
46
0.6
39
0.5
40
0.5
24
16
25
20
23
15
80
41
7
76
42
7
86
39
9
Study Drug Completion Status at 1 Year (%)
Etanercept
Methotrexate
(n = 217)
10 mg
(n = 208)
25 mg
(n = 207)
Completed 1 yr of study drug
Oral dose reduced for AE
79
151
80
3
85
2
Discontinued study drug
Adverse events
Loss of efficacy
Other
21
112
4
6
20
6
7
8
15
5
5
5
1. P < 0.001.
2. P = 0.03. Methotrexate vs etanercept 25 mg.
Finck B. Arthritis Rheum. 1999.
Modified Sharp Scoring Method1




Standardized method used in clinical trials
46 joints scored for erosion (grades 0-5)
42 joints scored for narrowing (grades 0-4)
Total Sharp score = erosion score plus joint space
narrowing score
 Modifications
– Included feet (van der Heijde2)
– Added percentage joint eroded or narrowed to grading
method (Rau3)
1. Sharp. Arthritis Rheum. 1971.
2. van der Heijde. Br J Rheumatol. 1992.
3. Rau. J Rheumatol. 1995.
Radiographic Methods
 Change in Sharp scores over 1 yr
 X-rays of hands/wrists and forefeet at baseline,
6 mo, and 1 yr
 Each case read by 2 of 6 qualified physicians
trained in the modified Sharp reading method
(inter-reader r=0.85)
 Sequence of films blinded to readers
Finck B. Arthritis Rheum. 1999.
Baseline Radiographic Features
Methotrexate
(n = 217)
Total Sharp score
Mean
Calculated rate of annual
progression
Erosion score
Mean
Calculated rate of annual
progression
Joint space narrowing score
Mean
Calculated rate of annual
progression
Finck B. Arthritis Rheum. 1999.
Etanercept
10 mg
25 mg
(n = 208)
(n = 207)
12.9
9.5
11.2
8.3
12.4
8.7
7.5
5.4
6.1
4.6
6.4
4.3
5.4
4.1
5.0
3.8
6.0
4.4
Predicted and Actual Annual Change
in Total Sharp Score
10
Etanercept 25 mg
Etanercept 10 mg
Methotrexate
8.7
9.5
8.3
Mean change
8
6
4
2
0
1.4
0.8
Predicted Actual
Predicted
Actual
1.3
Predicted Actual
Mean Change in Erosion and Joint
Space Narrowing Scores Over 1 Year
Mean change
2
Etanercept 25 mg
Etanercept 10 mg
Methotrexate
1
0.8
0.4
0.4*
0
* P < 0.05 vs methotrexate.
Finck B. Arthritis Rheum. 1999.
0.9
Joint erosion
0.5
Joint space
narrowing
0.4
Patients With No New Erosions at 1 Year
All patients
Patients with
baseline erosions
Patients with no
baseline erosions
Finck B. Arthritis Rheum. 1999.
Methotrexate
Etanercept
25 mg
57%
(123/217)
75%
(154/206)
P < 0.001
52%
72%
P < 0.001
(98/188)
(130/181)
86%
96%
(25/29)
(24/25)
P = 0.159
Methotrexate-Dose: Patients With No
New Erosions Over 1 Year
Methotrexate Methotrexate
< 20 mg/wk
20 mg/wk
Patients with no
new erosions
48%
(20/42)
59%
(103/175)
Etanercept
25 mg
75%
(155/206)
Definition of ACR20 Response
 20% or greater improvement in
– Tender-joint count
– Swollen-joint count
– Three of the following five
 Pain assessment
 Physician global assessment
 Patient global assessment
 Patient self-assessment of disability
 ESR or CRP
Arthritis Rheum. 1995.
ACR20
80
*
% Patients
60
*
*
40
*
Etanercept 25 mg
20
0
Methotrexate
0
2
Max MTX dose
*P < 0.05, methotrexate vs etanercept 25 mg.
Finck B. Arthritis Rheum. 1999.
4
6
Months
8
10
12
ACR Responses
80
*
% Patients
60
ACR20
*
*
40
ACR50
*
*
*
20
*
* *
*
0
Max MTX dose
*
ACR70
Etanercept 25 mg
Methotrexate
*
*
0
*
2
* P < 0.05.
Finck B. Arthritis Rheum. 1999.
4
6
Months
8
10
12
Calculation of Numeric ACR (ACR-N)
Compared to ACR20
ACR20
At least 20% improvement in:
 Swollen-joint count
 Tender-joint count
 Three of five remaining
criteria:
–
–
–
–
–
MD global assessment
Patient global assessment
VAS for pain
HAQ
CRP or ESR
ACR-N
Least percent improvement in:
 Swollen-joint count
 Tender-joint count
 Third highest of five
remaining criteria:
–
–
–
–
–
MD global assessment
Patient global assessment
VAS for pain
HAQ
CRP
Calculation of Numeric ACR (ACR-N)
Patient #1
Patient #2
Swollen-joint count
Tender-joint count
28%
21%
48%
55%
MD global assessment
Pt global assessment
VAS for pain
HAQ
CRP or ESR
40%
35%
26%
22%
47%
52%
51%
49%
22%
47%
ACR20
ACR50
ACR70
ACR-N
Yes
Yes
21%
48%
Criteria
No
No
No
No
Numeric ACR (ACR-N) Over Time
50
Mean ACR-N
40
30
Etanercept 25 mg
Methotrexate
20
10
0
0
2
4
6
Months
Finck B. Arthritis Rheum. 1999.
8
10
12
AUC of Numeric ACR
Etanercept 25 mg
Methotrexate
50
Mean ACR-N
40
30
20
10
0
0
P = 0.002 over 6 mo.
P = 0.009 over 12 mo.
* Primary endpoint.
Finck B. Arthritis Rheum. 1999.
2
4
6*
Months
8
10
12
AUC of Numeric ACR
AUC of Mean ACR-N
40
Etanercept 25 mg
Methotrexate
34.9†
30
20
28.7
15.3*
11.5
10
0
*P = 0.002.
†P = 0.009.
Finck B. Arthritis Rheum. 1999.
0-6 mo
0-12 mo
AUC of Improvement in
Swollen-Joint Count
Etanercept 25 mg
Methotrexate
Mean % improvement
60
40
20
0
0
P = 0.004.
Finck B. Arthritis Rheum. 1999.
1
2
3
Months
4
5
6
AUC of Improvement in HAQ
Etanercept 25 mg
Methotrexate
Mean % improvement
60
40
20
0
0
P = 0.002.
Finck B. Arthritis Rheum. 1999.
1
2
3
Months
4
5
6
AUC of Improvement in CRP
Etanercept 25 mg
Methotrexate
Mean % improvement
80
60
40
20
0
0
P < 0.001.
Finck B. Arthritis Rheum. 1999.
1
2
3
Months
4
5
6
AUC of Improvement in ACR Criteria
AUC of mean % improvement
30
Etanercept 25 mg
Methotrexate
*
*
*
20
*
*
*
10
0
Pain
*P < 0.05.
Finck B. Arthritis Rheum. 1999.
HAQ
Disability
MD
Global
Pt
Global
Swollen
Joints
Tender
Joints
CRP
Safety
 Noninfectious adverse events
 Infections
 Malignancies
 Laboratory abnormalities
 Antibodies to etanercept
Finck B. Arthritis Rheum. 1999.
Patients (%) With Noninfectious
Adverse Events
> 10% of Patients
Injection-site reaction
LFT elevation
Headache
Nausea
Rash
Rhinitis
Diarrhea
Asthenia
Dizziness
Dyspepsia
Back pain
Abdominal pain
Alopecia
Mouth ulcer
Yellow = P < 0.05.
Finck B. Arthritis Rheum. 1999.
Etanercept
Methotrexate
(n = 217)
10 mg
(n = 208)
25 mg
(n = 207)
7
46
27
29
23
14
12
12
11
10
6
10
12
14
30
27
25
14
16
17
13
9
5
10
6
11
7
6
37
28
22
17
12
15
15
13
12
12
11
10
6
5
Infectious Adverse Events
Etanercept
Methotrexate
(n = 217)
(193 pt-yr)
10 mg
(n = 208)
(185 pt-yr)
25 mg
(n = 207)
(189 pt-yr)
72*
1.91*
61
1.54
67
1.54
No. infections per pt-yr
39
0.61
27
0.45
35
0.54
% of pts w/infections
60
1.30*
51
1.08
51
0.99
Infections by Type
Any type:
% of
pts w/infections
URI:
* P <0.05.
No. infections per pt-yr
Finck. Arthritis Rheum. 1999.
Non-URI:
Malignancies
Etanercept
Methotrexate
10 mg
Expected*
1.8
1.9
2.0
Observed
2
2
3
• Bladder
• Colon
* NCI SEER database.
Finck B. Arthritis Rheum. 1999.
• Breast
• Lung
25 mg
• Carcinoid
(lung)
• Hodgkin’s
• Prostate
Laboratory Abnormalities
 Routine laboratory testing and autoimmune
testing performed at regular intervals
 No treatment emergent abnormalities detected
with etanercept treatment
Finck B. Arthritis Rheum. 1999.
Antibodies to Etanercept
Etanercept
Assay
Methotrexate
(n = 207)
N (%)
10 mg
(n = 198)
N (%)
25 mg
(n = 202)
N (%)
ELISA
0
5 (2.5)
6 (3.0)
Neutralizing
0
0/5
0/6
Finck B. Arthritis Rheum. 1999.
Summary of Safety
 Rate of adverse events less in etanercept group
compared to methotrexate group (P = 0.01)
 Fewer infections of any type seen in patients receiving
etanercept compared to methotrexate (P < 0.01)
 AE-related withdrawals, including pneumonitis, more
common in patients receiving methotrexate (P = 0.02)
 No treatment-associated laboratory abnormalities
Finck B. Arthritis Rheum. 1999.
Summary of Efficacy
 Etanercept
– Has a clinical response in the first month that is
sustained
– Is effective as a single agent in reducing
symptoms of early, active rheumatoid arthritis
– Stopped erosion in 75% of patients and more
effective than methotrexate
(P < 0.001)
Finck B. Arthritis Rheum. 1999.
Summary of Efficacy (cont.)
 Etanercept and methotrexate are both effective
DMARDs
 Etanercept is more efficient than methotrexate
in slowing the rate of new erosions
 Etanercept stopped the development of new
erosions in 75% of patients
Finck B. Arthritis Rheum. 1999.
Conclusions
In patients with early, active rheumatoid arthritis,
etanercept:
– Reduces the rate of joint damage
– Is clinically effective in patients not previously
treated with methotrexate
– Is safe and well tolerated
Finck B. Arthritis Rheum. 1999.
‫قال النبى صلى هللا عليه وسلم ‪:‬‬
‫من ترك صالة العصر حتى خرج‬
‫وقتها من غير عذر حبط‬
‫عمله‬