biologics 16.4biologics 16.4.2015 prof.m.seitz, prof.p.m.villiger todays menu • lessons regarding...
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RIA Department of Rheumatology, Immunology and Allergology
Biologics 16.4.2015
Prof.M.Seitz, Prof.P.M.Villiger
Todays menu
• Lessons regarding pathogenesis
• Cytokines
• Cytokine inhibitors / antagonists
• Therapeutic antibodies beyond anti-cytokines
• Immunoreconstitution
Mono
Hypothalamus
Prostaglandine Fieber
Glukokortikoide
NSAID IL-1
TNF
IL-6
Bakterien
Nekrose
Endogenous pyrogens
Antibiotika
1
2
3
4
5 cytokine
cytokine receptor blood vessel
intracrine
juxtacrine
autocrine paracrine
endocrine Pyrogenese
IL-6: Multiples Myelom
IL-2: T-Lymphozyten
endothelium
chondrocytes
synoviocytes
monocytes
granulocytes IL-8
MCP-1
tissue resident cells blood
selectins
ICAM-1 IL-1, TNF
TNF-Inhibition: biological consequence?
Decrease of local inflammation
In case of autoimmune disorders:
benefit
In case of bacterial infection:
risk!!!
Delay of diagnosis, sepsis, death
cytokine
a2-macroglobulin
antibody
receptor
antagonist soluble
receptor
membrane
receptor
1 2
3
4
synthesis of
soluble receptor
Mechanisms of inhibition
T Zelle
Monozyt
immunologischer
Stimulus
TNF
IL-1 IL-
6 IL-8
Chemotaxis CRP Schmerz Fieber
B Zelle
TNF Hemmer
MabThera
Orencia
Actemra
Kineret
Anti-cytokine mechanisms
• Tumor necrosis factor (TNF)
Target
cell
Anti-cytokine mechanism: TNF
Macrophage
Target
cell
Infl
am
ma
tory
rea
ctio
n
activated macrophage
Target
cell
Infl
am
ma
tory
rea
ctio
n
Activated
macrophage
Activated
macrophage
Target cell
Infliximab
TNF-Blockade by Infliximab
Infliximab
Etanercept
TNF-a LTa
Specificity of Monoclonal Antibody vs. Fusion Protein
TNFa and Lymphotoxin Binding
Avidity
Measurement of the reversibility of binding
Infliximab
Etanercept
off-rate
on-rate
on-rate
off-rate
*
Antikörper
löslicher
Rezeptor
Hemm-Mechanismen
Infliximab (Remicade®)
Chimärer Antikörper gegen TNFa
Adalimumab (Humira®)
Humanisierter Antikörper gegen TNFa
Etanercept (Enbrel®)
Fusionsprotein (IgG1+TNF-Rezeptor)
Antikörper
Rezeptor-
blocker
löslicher
Rezeptor
Zytokin
1
2
3
Hemm-Mechanismen
Zytokinrezeptor
Clinical examples
• Rheumatoid Arthritis (RA)
– Joint Inflammation
• (Inflammation of tendons, bursae)
– Systemic inflammation
• ESR, CRP
• Anemia, Thrombocytosis
• Rheumafactor, CCP-Antibodies
Two levels of clinical reasoning • Disease activity
– How to measure • DAS
• ACR response criteria
• Disease damage – How to measure
• X-ray
• Magnetic resonance imaging
• Ultrasound
Disease activity score (DAS)
• Number of tender joints
• Number of swollen joints
• ESR
2
3
4
5
0 3 6 9 12 15 18 21 24 27 30
Months
>3.7=high disease activity
<2.4=low disease activity
Disease Activity Score
ACR Response Criteria • Improvement in tender joint count
• Improvement in swollen joint count
• Plus improvement in 3 of the following 5 criteria – Patient pain assessment
– Patient global assessment
– Physician global assessment
– Patient self-assessed disability
– Acute phase reactant (ESR or CRP)
ACR20 / 50 / 70 Response (24 Weeks)
65.7
53.7
26.9
Adalimumab
40 mg eow
14.5
47.8
65.8
8.1
31.9
42.5
4.8 10.1
19.2
0
10
20
30
40
50
60
70
ACR20 ACR50 ACR70
Placebo
% R
espo
nder
s
Adalimumab
(D2E7)
20 mg eow
Adalimumab
(D2E7)
80 mg eow
Examples of joint damage
Erosions
24.8.98
Joint space narrowing
20.1.97
3.6
4.3
0.0
1.2
-1.2
1.3
0.5
2.5
0.5
-1.7-2.0
-1.0
0.0
1.0
2.0
3.0
4.0
5.0Responders Non-Responders
Med
ian
Cha
nge
from
Bas
elin
e
N=40 N=25 N=31 N=38 N=10
N=33
N=32 N=38 N=28 N=34 *
* *
* *
*
*
MTX + Placebo
IFX 3mg q8+MTX
IFX 3mg q4+MTX
IFX 10mg q8+MTX IFX 10mg q4+MTX
Goals
• Treatment of disease activity • Prevention of joint destruction
„window of opportunity“
Other indications:
• Granuloma destruction
– Wegener‘s disease
– Crohn‘s disease
– Sarcoidosis
– Tuberculosis
21.6.2006
15.2.2006
21.6.2006
15.2.2006
Infliximab
Beyond anti-cytokine antibodies
B cells play an important role in the pathogenesis of RA
• Abundance of B cells in the synovium of affected joints – organised into lymphoid structures
• Three critical roles of B cells – Antigen presentation and T cell activation
– Auto-antibody production
– Cytokine production
autoantibody production
• Autoreactive B cells produce autoantibodies, including RF
• Formation of immune complexes leads to production of pro-inflammatory cytokines
cytokine production • TNF, IL-6,
• lymphotoxin, known to
promote inflammation
and joint damage in RA
• Lymphotoxin promotes
the formation of new
lymphoid structures in the
synovium
Steps in the maturation of B cells
Rituximab (MabThera®/Rituxan®)
Rituximab is a novel
genetically engineered
anti-CD20 therapeutic
monoclonal antibody
that selectively depletes
CD20+ B cells
CD20: An ideal B cell target • 297-amino acid
phosphoprotein
• highly expressed on B cells but not on stem, dendritic or plasma cells
• No known natural ligands for CD20
CD20 protein structure
complement-dependent cytotoxicity • rituximab bound
to CD20 interacts with C1q
• triggers activation of the complement system
• leads to B cell lysis via formation of pores in the membrane
Clinical examples
RA
• Am J Pathol 1997 • Three distinct patterns of histology
– Diffuse lymphoid infiltrate – Tertiary lymphoid structures – Granuloma formation
• So far no correlation with response to
biologicals described
Pachymeninigitis in a patient with RA
Wegener‘s disease
• Limited (localized) – Granuloma formation – cANCA negative
• Generalized
– Granuloma and vasculitis (necrotic, small vessel)
– cANCA positive
Anti-TNF antibodies
B cell depletion
ANCA Titerverlauf
55
4347
39
58
7365
5451
4042
2729272734
43
5750
56
73
4648
343229
49
2430
19172524
34
01020304050607080
1 4 7 10 13 16 19 22 25 28 31 341-04 2-06 6-07
Siccasyndrome – Sjögren Syndrome
• Sicca-syndrome: dryness of mouth, eye, vagina broad differential diagnosis
– Associated with autoimmune diseases
– Caused by drugs (antidepressive drugs, …)
• Sjögren Syndrome: Defined systemic autoimmune disease of the family of CTD
Co-stimulation
Signal 2 (Co-stimulation)
Signal 3 (Cytokines)
Signal 1 (TcR)
T Cell APC
How are T cells recruited ?
T
cell
Antigen-presenting cell
(APC)
MHC
II
CD28
B7
TCR
First Signal:
TCR binds
to MHC complex
on APC
Second Signal:
CD28 binds to B7
on APC
T cell
proliferation
T
cell
Antigen-presenting cell
(APC)
MHC
II
B7
CTLA4:
Cytotoxic
Tcell
Leukocyte
Antigen 4
TCR
T cell receives no second
signal from B7!
First Signal:
TCR binds
to MHC complex on
APC
CTLA4 binds to B7 on APC!
T cell apoptosis/ anergy!
CTLA4
Ig
Blockade of the CD28 pathway
Clinical examples
• Rheumatoid Arthritis
After review of the existing literature and thorough discussion:
• Screening for Tbc and latent Tbc infection should be performed in all patients prior to any anti- TNF-a therapy
• The screening should be based on history, chest X-ray and an IGRA test.
– History: a detailed history of exposure to or prior treatment for Tbc, considering the risk associated with birthplace or country of origin
– Chest X-ray: a single PA chest X-ray for detecting past or present Tbc
– IGRA test
Malignoma – Risk under TNF-Blockade (Moulis G et al., PLoS One 2012; 7: e48991)
60
Universitätsklinik für Rheumatologie, Klinische Immunologie und Allergologie
Malignom – Risk under TNF-Blockade (Moulis G et al., PLoS One 2012; 7: e48991)
61
Universitätsklinik für Rheumatologie, Klinische Immunologie und Allergologie
Malignom – Risk under TNF-Blockade (Moulis G et al., PLoS One 2012; 7: e48991)
62
Universitätsklinik für Rheumatologie, Klinische Immunologie und Allergologie
• Non-significant tendency for more NMSC (non-melanoma skin cancer)
- OR von 1.37 [0.71-2.66] for ‘per protocol model’ - OR von 1.90 [0.98-3.67] for ‘intention to treat model’
No enhanced risk for malignomas – upon anti-TNFs from the German Registry (RABBIT)
• TNFi vs. csDMARDs with a HR 0.7 • TNFI vs. gen.Population with a HR 0.8 Strangfeld A et al., Arthritis Res Ther 2010; 12: R5
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Universitätsklinik für Rheumatologie, Klinische Immunologie und Allergologie
Malignomas – Risk upon TNF – Blockade from registry data (ARTIS)
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Universitätsklinik für Rheumatologie, Klinische Immunologie und Allergologie
• HR of 1.5 for melanoma in RA patients under anti-TNFs in the national swedish ARTIS registry
Raaschou P et al. , BMJ 2013; 346: f1939
Lymphomrisiko in Sjögren Syndrom
• Ann Rheum Dis. 2006 Jun;65(6):704-6 • Lymphoma and other malignancies in primary Sjogren's
syndrome: a cohort study on cancer incidence and lymphoma predictors. risk of lymphoproliferative disease or other malignancy (standardised incidence ratios (SIRs)), in patients with primary Sjogren's syndrome
• Malmo Primary SS Register, Swedish Cancer Register, Cause-of-Death Register
• 507 patients, median follow up 8 years (range 1 month to 19 years)
• SIRs (95% CI) for non-Hodgkin's lymphomas was 15.57 (7.77 to 27.85)
• predictors of lymphoproliferative disease were
– purpura/skin vasculitis (hazard ratio (HR) = 4.64)
– low complement factor C3: 6.18; low C4: 9.49
– CD4+ T lymphocytopenia: 8.14
– CD4+/CD8+ T cell ratio ≤ 0.8: 10.92
RIA Department of Rheumatology, Immunology and Allergology
The End