William Davis, MD, FACP January 2013. Biologic Targets Cytokines Anti-TNF Anti-IL1 Anti-IL6 Cell...
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Biologic Therapy in Rheumatoid Arthritis William Davis, MD, FACP January 2013
William Davis, MD, FACP January 2013. Biologic Targets Cytokines Anti-TNF Anti-IL1 Anti-IL6 Cell surface molecules T lymphocyte co-stimulator B lymphocyte
Cytokines in RA Harris: Kelley's Textbook of Rheumatology, 7th
ed., Copyright 2005
Slide 5
TGF- MMPs TIMPs IL-1 TNF- GM-CSF IFN- IL-2 IL-6 IL-8 IL-15
IL-16 IL-17 IL-18 Autoimmune diseases sTNFR IL-4 IL-10 IL-11 IL-13
IL-18 BP Cytokine Balance Adapted from Arend WP. Arthritis Rheum.
2001;45:101-106. Proinflammatory Anti-inflammatory IL-1ra mAb to
IL-6R mAb to TNF IL-1Ra sIL-1RII
Slide 6
TNF- Induction of other cytokines (IL-1, IL-6) and chemokines
(IL-8) Increasing endothelial adhesion molecule expression and
function Induction of acute phase reactant synthesis Induction of
matrix metalloproteinase production
Slide 7
TNF- Produced by activated macrophages Expressed as 26-kD
transmembrane protein Cleaved by TNF- Converting Enzyme (TACE) to
17-kD soluble protein TNR-RI (55kD, CD120a) TNF-RII (75kD, CD120b)
Signaling cascades Transcription factors, NFkB Protein kinases,
JKK, p38 MAP kinase Proteases, caspase
MACROPHAGE TARGET EFFECTOR CELL SYSTEMIC CIRCULATION TNF TACE
P55 P75 P55 P75 sTNF-R X X X XX P75
Slide 10
TREATMENT OF RHEUMATOID ARTHRITIS WITH CHIMERIC MONOCLONAL
ANTIBODIES TO TUMOR NECROSIS FACTOR MICHAEL J. ELLIOTT, RAVINDER N.
MAINI, MARC FELDMANN, ALICE LONG-FOX, PETER CHARLES, PETER
KATSIKIS, FIONULA M. BRENNAN, JEAN WALKER, HANNY BIJL, JOHN
GHRAYEB, and JAMES N. WOODY ARTHRITIS & RHEUMATISM Volume 36
Number 12, December 1993, pp. 1681-1690
Anti-TNF agents High peak vs flatter pharmacokinetics TNF-
specificity (mAb) vs TNF- + LT- (etanercept) Affinity mAb induce
apoptosis in Crohns disease
Slide 14
Infliximab Chimeric mouse-human 70% human Etanercept Fusion
protein 2(p75 TNF-R) : IgG Adalimumab Human ab produced repertoire
cloning Golimumab human IgG1 mAb trans-genic mice Certolizumab
pegol Pegylated Fab fragment of human anti-TNF mAb
Slide 15
Infliximab T1/2 8-9.5 days (3mg/kg) Etanercept 102 h Adalimumab
2 weeks Golimumab Certolizumab pegol 14 days
TNF inhibitors: Adverse Effects Antigenicity Auto-antibodies,
Lupus like syndromes Infusion reactions Reactivation of
granulomatous infections Tuberculosis, coccidioidomycosis
Demyelinization Lymphoma, other cancers Heart failure Pregnancy
risk category B
Slide 19
TNF inhibitors and Infections RA patients start with increased
risk for infection Prednisone increases risk of infection 1.5-2X 8
Observational cohort studies: Absolute rate / 100 patient years
2.9-8.2 vs 1.4-7.8 non-biologic comparator Relative risk:
1.05-4.6
Slide 20
TNF Inhibitors and Cancer Lymphoma, non-melanoma skin cancer
increased in RA Early warning on anti-TNF agents after patients on
etanercept, infliximab and adalimumab developed lymphoma 2011
Cochrane review included 22,657 patients and found no increase
between TNF treated patients vs DMARD Singh J.A., Wells G.A.,
Christensen R., et al: Adverse effects of biologics: a network
meta-analysis and Cochrane overview. Cochrane Database Syst Rev.
(2): 2011
Slide 21
TNF Inhibitors and Skin Cancer 2011 meta-analysis: Results from
four studies showed increased risk of non- melanoma skin cancer RR
1.45 (95% CI 1.15 to 1.76) Increased risk of melanoma RR 1.79 (95%
CI 0.92 to 2.67) Mariette X - Ann Rheum Dis - 01-NOV-2011; 70(11):
1895-904
Slide 22
Anti-TNF agents 1 st line biologic addition to methotrexate
therapy for RA Prevent erosions and deformity Screen for TB Monitor
and treat infections agressively Neoplasia may occur
Slide 23
IL-1a IL-1b IL-1ra IL-1RI IL-1Rap IL-1RII IL-1 and IL-1R
Cell surface molecules T lymphocyte co-stimulator Abatacept /
Orencia B lymphocyte stimulator Belimumab / Benlysta B lymphocyte
marker CD20 Rituximab / Rituxan
Slide 36
T Cell activation Signal 1 Signal 2
Slide 37
CTLA4 inhibits T Cell Activation
Slide 38
Abatacept (Orencia) CTLA-Ig fusion protein Prevents B7 co-
stimulation (signal 2) of lymphocytes
Slide 39
Abatacept in Inadequate Responders to Methotrexate (AIM)(n=652)
Kremer J et al. Ann Intern Med 2006;144:365-876
Slide 40
Abatacept in Anti-TNF IR (ATTAIN)(n=293) Genovese M, et al. N
Engl J Med 2005, 353:1114-1123
Slide 41
Abatacept: Adverse Effects Infusion reactions Infections COPD
exacerbations or infections Screen for Tuberculosis Vaccinate
before starting therapy
Slide 42
Biologic Targets Cytokines Anti-TNF Anti-IL1 Anti-IL6 Cell
surface molecules T lymphocyte co-stimulator B lymphocyte
stimulator B lymphocyte marker CD20
Slide 43
Belimumab Human monoclonal antibody Inhibits B lymphocyte
stimulator protein (BLyS) Inhibits the survival of B cells
including autoreactive B cells Reduces the differentiation of B
cells into immunoglobulin-producing plasma cells Indicated as an
adjunct to standard therapy for the treatment of active,
autoantibody-positive, systemic lupus erythematosus
Slide 44
Rituximab: anti-CD20 A chimeric anti-CD20 monoclonal antibody
Effective adjunct in treatment of non-Hodgkin lymphoma Rituximab
depletes B cells that have CD20 on their surface pre-B cells
through mature B cells not stem cells or plasma cells
Slide 45
B Lymphocytes Auto-antibody production rheumatoid factor and
anti-CCP antibodies Antigen presenting cells (APC) T cell
activation T cell activation of macrophages Cytokine production
TNF- ; IL-1 IL6; IL10
Slide 46
RTX in TNF IR (REFLEX)(n=520) Cohen SB, et al, Arthritis Rheum
2006; 54:2793-2806
Slide 47
RTX in MTX IR (SERENE)(n=511) Emery P, et al. Ann Rheum Dis
2010;69:1629-1635
Slide 48
Primary end point: remission at 6 months RTX group: 64% (63/99)
CTX group 53% (52/98) 11% difference not significant (95.1%
confidence interval [CI], 3.2 to 24.3 percentage points; P=0.09)
Non-inferiority (P