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Презентация на тему Biologics in Rheumatology

Содержание

List of diseases treated with biologic drugsRheumatoid arthritisJuvenile arthritisPsoriatic arthritisAnkylosing spondylitisPsoriasisCrohn’s d-seUlcerative colitisSystemic Lupus ErythematosusAPLASAnterior uveitisOsteoporosisANCA-associated granulomatous vasculitisGiant cell arteritisTakayasu arteritisBehcet s-meAdult onset Still d-sePeriodic feversPyoderma gangrenosumHidradenitis suppurativaGoutB-cell LymphomaFamilial Mediterranean Fever
Biologics in RheumatologyDr Ira NovofastovskiHaEmek Medical Center, Afula List of diseases treated with biologic drugsRheumatoid arthritisJuvenile arthritisPsoriatic arthritisAnkylosing spondylitisPsoriasisCrohn’s d-seUlcerative Primer: Immunology and AutoimmunityStephanie C. Eisenbarth and Dirk Homann Primer: Immunology and AutoimmunityStephanie C. Eisenbarth and Dirk Homann Smolen&Steiner .Nature Rev Drug DiscIL-6 Cytokines disequilibrium in joints of patients with RAProinflammatoryAntiinflammatoryTNF-alphaIL-1Soluble TNFReceptorIL-1 receptorantagonistIL-10Feldman M et IL-6CTLA-4Ig / AbataceptAnti-CD20 / RituximabPro- inflammatory cytokines targeted hitherto:-TNF / INF, ETN, Key Actions Attributed to TNFa NucleusDNARNATNFTNF-R1TNF-R2Infliximab/Adalimumab (monoclonal AB)mechanism of action NucleusDNARNATNFTNF-R1TNF-R2Etanercept (soluble TNF receptors)Mechanism of action Anti TNF side effectsAnaphylaxisLocal site irritationRashChest painShortness of breathInfections- All+TB, histoplasmosis (Less with Relative contraindications to the use of TNF inhibitorsSLE, Lupus overlap s-me Multiple Potential Roles of B Cells in the Immunopathogenesis of RA Steps in the Maturation of B Cells RituximabRituximab is a genetically engineered anti-CD20 therapeutic monoclonal antibody that selectively depletes Rituximab: Mechanism of ActionRituximab initiates complement-mediated B-cell lysisRituximab initiates cell-mediated cytotoxicity Rituximab, side effectsMild to moderate infusion reactionsIncreased risk of infectionsHepatitis B reactivationProgressive Most Frequently Reported Adverse Events (up to Week 48)*% of patients reporting IL-6: Fundamental role in the inflammation that drives RAFirestein GS. Nature 2003;423:356–361; Articular effects of IL-6 in RA1,2SynoviocytesOsteoclast activationBone resorptionEndothelial cellsVEGFPannus formationJoint destructionMediation of Systemic effects of IL-6 in RAIL-6Acute-phaseresponse1Alterations in ironhomeostasis2LiverAcute-phase proteins (eg, CRP)Hepcidin Primer: Immunology and AutoimmunityStephanie C. Eisenbarth and Dirk Homann ABATACEPT / ORENCIACostimulation blockade in RAhttp://www.rheumatologysa.com/biologics.html XELJANZ (Tofacitinib): a new class of oral RA therapy that targets inflammation JAKs are intracellular enzymes that are activated by cytokines upon binding to Binding of cytokine receptors activates JAK signalling pathways Shuai 2003/p 900/col Tofacitinib targets JAK intracellular signalling pathwaysTofacitinib inhibits the autophosphorylation and activation of ANAKINRA – recombinant form of IL-1 receptor antagonist Anakinra indicationsAuto- inflammatory syndromes, periodic feversSystemic onset juvenile inflammatory arthritisAdult-onset Still’s diseaseFamilial Antigen-presenting cellT-cellB-cellMacrophageSynoviumTNF- blockersAnakinra blocks action of IL-1 Tocilizumab blocks action of IL-6Abatacept / BenlystaBLyS (B-Lymphocyte stimulator) = BAFF (B-cell Activating Factor)(anti-BLyS monoclonal antibody) BENLYSTA / BELIMUMABIndicationsAdult patients with active, autoantibody- positive SLE who are receiving Screening before starting biological treatmentScreening of TB (PPD / IGRA)Chest radiographyScreening of Tuberculosis screening Required screening of TB before starting of anti-TNF treatmentWhen the תודה על הקשבה
Слайды презентации

Слайд 2

Слайд 3 List of diseases treated with biologic drugs
Rheumatoid arthritis
Juvenile

List of diseases treated with biologic drugsRheumatoid arthritisJuvenile arthritisPsoriatic arthritisAnkylosing spondylitisPsoriasisCrohn’s

arthritis
Psoriatic arthritis
Ankylosing spondylitis
Psoriasis
Crohn’s d-se
Ulcerative colitis
Systemic Lupus Erythematosus
APLAS
Anterior uveitis
Osteoporosis

ANCA-associated granulomatous

vasculitis
Giant cell arteritis
Takayasu arteritis
Behcet s-me
Adult onset Still d-se
Periodic fevers
Pyoderma gangrenosum
Hidradenitis suppurativa
Gout
B-cell Lymphoma
Familial Mediterranean Fever





Слайд 4

Слайд 5 Primer: Immunology and Autoimmunity
Stephanie C. Eisenbarth and Dirk

Primer: Immunology and AutoimmunityStephanie C. Eisenbarth and Dirk Homann

Homann

Слайд 6 Primer: Immunology and Autoimmunity
Stephanie C. Eisenbarth and Dirk

Primer: Immunology and AutoimmunityStephanie C. Eisenbarth and Dirk Homann

Homann

Слайд 7 Smolen&Steiner .Nature Rev Drug Disc
IL-6

Smolen&Steiner .Nature Rev Drug DiscIL-6

Слайд 8 Cytokines disequilibrium in joints
of patients with RA
Proinflammatory
Antiinflammatory
TNF-alpha
IL-1
Soluble

Cytokines disequilibrium in joints of patients with RAProinflammatoryAntiinflammatoryTNF-alphaIL-1Soluble TNFReceptorIL-1 receptorantagonistIL-10Feldman M

TNF
Receptor
IL-1 receptor
antagonist
IL-10








Feldman M et al, Rheumatoid arthritis, cell 1996;

85:307-10

IL-6






B cell activation


Слайд 9

Слайд 10 IL-6
CTLA-4Ig / Abatacept
Anti-CD20 / Rituximab

Pro- inflammatory cytokines targeted

IL-6CTLA-4Ig / AbataceptAnti-CD20 / RituximabPro- inflammatory cytokines targeted hitherto:-TNF / INF,

hitherto:
-TNF / INF, ETN, ADA, GOL
- IL-1 / Anakinra


IL-6

/ Tocilizumab

Carrent Biological Targets in RA

Smolen&Steiner .Nature Rev Drug Disc

Small molecule
Tofacitinib

Слайд 11

Слайд 12 Key Actions Attributed to TNFa

Key Actions Attributed to TNFa

Слайд 13






Nucleus
DNA
RNA
TNF

TNF-R1
TNF-R2
Infliximab/Adalimumab
(monoclonal AB)
mechanism of action

NucleusDNARNATNFTNF-R1TNF-R2Infliximab/Adalimumab (monoclonal AB)mechanism of action

Слайд 14






Nucleus
DNA
RNA
TNF

TNF-R1
TNF-R2
Etanercept (soluble TNF
receptors)
Mechanism of action

NucleusDNARNATNFTNF-R1TNF-R2Etanercept (soluble TNF receptors)Mechanism of action

Слайд 15 Anti TNF side effects
Anaphylaxis
Local site irritation
Rash
Chest pain
Shortness of

Anti TNF side effectsAnaphylaxisLocal site irritationRashChest painShortness of breathInfections- All+TB, histoplasmosis (Less

breath

Infections- All+TB, histoplasmosis
(Less with etanercept)
Secondary malignancy? Lymphomas
Anti chimeric and

other Ab’s (no etanercept)
Demyelinating disease

Слайд 16 Relative contraindications to the use of TNF inhibitors
SLE,

Relative contraindications to the use of TNF inhibitorsSLE, Lupus overlap s-me

Lupus overlap s-me
Multiple sclerosis, optic neuritis, demyelinating disorders

Current, active, serious infections
Recurrent or chronic infections
Untreated latent or active mycobacterial infections
Hepatitis B infection
CHF
Pregnancy

Слайд 17 Potential Roles of B Cells in the Immunopathogenesis

Potential Roles of B Cells in the Immunopathogenesis of RA

of RA

Слайд 18 Steps in the Maturation of B Cells

Steps in the Maturation of B Cells

Слайд 19 Rituximab

Rituximab is a genetically engineered anti-CD20 therapeutic monoclonal

RituximabRituximab is a genetically engineered anti-CD20 therapeutic monoclonal antibody that selectively

antibody that selectively depletes CD20+ B cells
(Shaw et al,

2003; Silverman & Weisman, 2003)

CD20 is a 297 amino acid phosphoprotein (33–35 kD)
found on the surface of B cells
CD20 is highly expressed on B cells but not expressed on stem, dendritic or plasma cells
There are no known natural ligands for CD20

Слайд 20 Rituximab: Mechanism of Action
Rituximab initiates complement-mediated B-cell lysis
Rituximab

Rituximab: Mechanism of ActionRituximab initiates complement-mediated B-cell lysisRituximab initiates cell-mediated cytotoxicity

initiates cell-mediated cytotoxicity via macrophages and natural killer cells
Rituximab

induces B-cells apoptosis


(Clynes et al, 2000; Reff et al, 1994)


B cell


Macrophage

B-cell lysis


B cell


Apoptosis


Complement
cascade

Слайд 21 Rituximab, side effects
Mild to moderate infusion reactions
Increased risk

Rituximab, side effectsMild to moderate infusion reactionsIncreased risk of infectionsHepatitis B

of infections
Hepatitis B reactivation
Progressive multifocal leukoencephalopathy (PML)- very low

in patients with RA


It is possible to treat:
Patients with solid tumors in past
Patients with latent TB


Слайд 22 Most Frequently Reported Adverse Events (up to Week

Most Frequently Reported Adverse Events (up to Week 48)*% of patients

48)


*% of patients reporting an event
**Hypo/hypertension defined as >30

mmHg change in diastolic or systolic blood pressure

Lymphocyte depletion, In some reduced Ig, non TB infections
Infusion related reactions

Слайд 23 IL-6: Fundamental role in the inflammation that drives

IL-6: Fundamental role in the inflammation that drives RAFirestein GS. Nature

RA
Firestein GS. Nature 2003;423:356–361; Smolen JS and Steiner G.

Nat Rev Drug Disc 2003;2:473–488

Endothelial cells


Osteoclast activation

Bone resorption

B cells

Hyper γ-globulinaemia

Auto-antibodies (RF)

Maturation of megakaryocytes

Thrombocytosis

T cell activation

Hepatocytes

Monocytes/ macrophages

Mesenchymal cells,
fibroblasts/synoviocytes

IL-6

Acute-phase proteins hepcidin, CRP

Слайд 24 Articular effects of IL-6 in RA1,2
Synoviocytes
Osteoclast activation
Bone resorption
Endothelial

Articular effects of IL-6 in RA1,2SynoviocytesOsteoclast activationBone resorptionEndothelial cellsVEGFPannus formationJoint destructionMediation

cells


VEGF
Pannus formation
Joint destruction
Mediation of chronic
inflammation
IL-6
Macrophage
T cell
B cell
Neutrophil
Antibody
production






1. Adapted from

Choy E. Rheum Dis Clin North Am. 2004;30:405−415;
2. Gabay C. Arthritis Res Ther. 2006;8(suppl 2):S3.

Слайд 25 Systemic effects of IL-6 in RA
IL-6
Acute-phase
response1
Alterations in iron
homeostasis2
Liver
Acute-phase

Systemic effects of IL-6 in RAIL-6Acute-phaseresponse1Alterations in ironhomeostasis2LiverAcute-phase proteins (eg, CRP)Hepcidin

proteins (eg, CRP)
Hepcidin production
Osteoporosis1
Alterations in
lipid metabolism3
Thrombocytosis1
1. Choy E. Rheum

Dis Clin North Am. 2004;30:405−415;
2. McGrath H et al. Rheumatology. 2004; 43:1323−1325;
3. Al-Khalili L et al. Mol Endocrinol. 2006; 20:3364−3375.

Слайд 26

Слайд 27 Primer: Immunology and Autoimmunity
Stephanie C. Eisenbarth and Dirk

Primer: Immunology and AutoimmunityStephanie C. Eisenbarth and Dirk Homann

Homann

Слайд 28 ABATACEPT / ORENCIA
Costimulation blockade in RA
http://www.rheumatologysa.com/biologics.html

ABATACEPT / ORENCIACostimulation blockade in RAhttp://www.rheumatologysa.com/biologics.html

Слайд 29 XELJANZ (Tofacitinib): a new class of oral RA

XELJANZ (Tofacitinib): a new class of oral RA therapy that targets

therapy that targets inflammation from inside the cell
First Oral

Agent To Compete with Biologics
A novel nonbiologic medicine for rheumatoid arthritis (RA)
It is the first Janus kinase (JAK) inhibitor for this disease

Слайд 30 JAKs are intracellular enzymes that are activated by

JAKs are intracellular enzymes that are activated by cytokines upon binding

cytokines upon binding to cell surface receptors1,2
Activated JAKs generate

immune and inflammatory responses1

Janus kinases (JAKs)

Ghoreschi 2011/p 4234/para 1/ln 1-10

O’Sullivan 2007/p 2497/col 1/ para 1/ ln 9-18

JAKs play a central role in immune and inflammatory responses

Ghoreschi K et al. J Immunol 2011;186:4234–4243.
O’Sullivan LA et al. Mol Immunol 2007;44:2497–2506.

Ghoreschi 2011/p 4234/para2/ln 1-2

JAK, Janus kinase; P, phosphate; STAT, signal transducer and activator of transcription.

Слайд 31 Binding of cytokine receptors activates JAK signalling pathways

Binding of cytokine receptors activates JAK signalling pathways Shuai 2003/p 900/col




Shuai 2003/p 900/col 1/para 1 & p 901/Fig 1
JAKs

activate STATs, which then act as transcription factors

1. Shuai K, et al. Nat Rev Immunol 2003;3:900–911.

JAK, Janus kinase; P, phosphate; STAT, signal transducer and activator of transcription.

Rapid membrane to nucleus signalling:
Cytokines bind trans-membrane receptors that are associated with JAKs
Binding activates JAKs
JAKs phosphorylate receptors
STATs bind to receptors
JAKs phosphorylate STATs
STAT translocate to the nucleus
STATs bind DNA and activate transcription to produce proteins that mediate immune responses/inflammation

Слайд 32 Tofacitinib targets JAK intracellular signalling pathways



Tofacitinib inhibits the

Tofacitinib targets JAK intracellular signalling pathwaysTofacitinib inhibits the autophosphorylation and activation

autophosphorylation and activation of JAK.2 JAKs cannot phosphorylate the

receptors, which therefore cannot dock STATs


Cytokine binding to its cell surface receptor leads to receptor polymerisation1

3

Shuai 2003/p 900/col 1/para 1/ln 8-18 & p 901/Fig 1

Jiang 2008/ p 15/ Fig 5 & p 5/para 3

2

Tofacitinib blocks the JAK signalling pathway at the point of JAK phosphorylation

1. Shuai K, et al. Nat Rev Immunol. 2003;3:900–911,
2. Jiang JK, et al. J Med Chem. 2008;51:8012–8018.

JAK, Janus kinase;
STAT, signal transducer and activator of transcription.

Tofacitinib

Слайд 33 ANAKINRA – recombinant form of IL-1 receptor antagonist

ANAKINRA – recombinant form of IL-1 receptor antagonist

Слайд 34 Anakinra indications
Auto- inflammatory syndromes, periodic fevers
Systemic onset juvenile

Anakinra indicationsAuto- inflammatory syndromes, periodic feversSystemic onset juvenile inflammatory arthritisAdult-onset Still’s

inflammatory arthritis
Adult-onset Still’s disease
Familial Mediterranean Fever/ Amyloidosis
(limited use for

the treatment of RA)

Слайд 35 Antigen-presenting cell
T-cell
B-cell
Macrophage






Synovium

TNF- blockers
Anakinra blocks action of IL-1
Tocilizumab

Antigen-presenting cellT-cellB-cellMacrophageSynoviumTNF- blockersAnakinra blocks action of IL-1 Tocilizumab blocks action of

blocks action of IL-6
Abatacept prevents full T-cell activation
Rituximab targets

B-cells

Слайд 36 / Benlysta
BLyS (B-Lymphocyte stimulator) = BAFF (B-cell Activating

/ BenlystaBLyS (B-Lymphocyte stimulator) = BAFF (B-cell Activating Factor)(anti-BLyS monoclonal antibody)

Factor)
(anti-BLyS monoclonal antibody)

Слайд 37 BENLYSTA / BELIMUMAB
Indications
Adult patients with active, autoantibody- positive

BENLYSTA / BELIMUMABIndicationsAdult patients with active, autoantibody- positive SLE who are

SLE who are receiving standard drug therapy
Contraindications
Active glomerulonephritis
CNS

manifestations
Concomitant use with other biologics or cyclophosphamide
Prior anaphylactic reactions to Belimumab
Pregnancy




Слайд 38 Screening before starting biological treatment
Screening of TB (PPD

Screening before starting biological treatmentScreening of TB (PPD / IGRA)Chest radiographyScreening

/ IGRA)
Chest radiography
Screening of viral hepatitis (HBV HCV)
Blood analysis

(WBC PLT count, Liver enzymes)

Слайд 39 Tuberculosis screening
Required screening of TB before starting

Tuberculosis screening Required screening of TB before starting of anti-TNF treatmentWhen

of anti-TNF treatment
When the TST (PPD) between 5-10 have

to rely on the blood test IGRA to diagnose latent TB
If the test TST ≥10 or IGRA is positive should be treated as diagnosis of latent tuberculosis



Слайд 40

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