biologics 16.4biologics 16.4.2015 prof.m.seitz, prof.p.m.villiger todays menu • lessons regarding...

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


Malignom – Risk under TNF-Blockade (Moulis G et al., PLoS One 2012; 7: e48991)

62


• 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

63


Malignomas – Risk upon TNF – Blockade from registry data (ARTIS)

64


• 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

biologics 16.4biologics 16.4.2015 prof.m.seitz, prof.p.m.villiger todays menu • lessons regarding...

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