William Davis, MD, FACP January 2013

Biologic Targets Cytokines Anti-TNF Anti-IL1 Anti-IL6 Cell surface molecules T lymphocyte co-stimulator B lymphocyte stimulator B lymphocyte marker CD20

Anti-Cytokine Therapies Anti-TNF Anti-IL1 Anti-IL6

Cytokines in RA Harris: Kelley's Textbook of Rheumatology, 7th ed., Copyright © 2005

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: Proinflammatory Anti-inflammatory IL-1ra mAb to IL-6R mAb to TNF IL-1Ra sIL-1RII

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

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 TNFα TACE P55 P75 P55 P75 sTNF-R

MACROPHAGE TARGET EFFECTOR CELL SYSTEMIC CIRCULATION TNFα TACE P55 P75 P55 P75 sTNF-R X X X XX P75

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

Anti-TNF agents Infliximab Etanercept Adalimumab Golimumab Certolizumab pegol Rheumatoid arthritis Psoriatic arthritis Ankylosing spondylitis Crohn’s disease Ulcerative colitis Psoriasis Uveitis Hidradenitis suppurativa

Anti-TNF agents High peak vs “flatter” pharmacokinetics TNF-α specificity (mAb) vs TNF-α + LT- α (etanercept) Affinity mAb induce apoptosis in Crohn’s disease

Infliximab Chimeric mouse-human 70% human Etanercept Fusion protein 2(p75 TNF-R) : IgG Adalimumab Human ab produced repertoire cloning Golimumab human IgG1κ mAb trans-genic mice Certolizumab pegol Pegylated Fab fragment of human anti-TNF mAb

Infliximab T1/ days (3mg/kg) Etanercept 102 h Adalimumab 2 weeks Golimumab Certolizumab pegol 14 days

Infliximab 3-10 mg/kg, IV, Q4-8 weeks Etanercept 50 mg SC weekly Adalimumab 40 mg SC q1-2 weeks Golimumab 50 mg SC q 1 month Certolizumab pegol 200 mg SC q2wk 400 mg q4wk

Infliximab RA, PsA, psoriasis, AS, Crohn’s, UC Etanercept RA, PsA, psoriasis, AS, JIA Adalimumab RA, PsA, psoriasis, AS, JIA, Crohn’s Golimumab RA, PsA, AS Certolizumab pegol RA, Crohn’s

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

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 vs non-biologic comparator Relative risk:

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

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):

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

IL-1a IL-1b IL-1ra IL-1RI IL-1Rap IL-1RII IL-1 and IL-1R

Anakinra Recombinant IL-1ra 100 mg SC q24h T ½ 4-6 hours RA poorly effective Auto-inflammatory conditions Cryopyrin-Associated Periodic Syndromes (CAPS) NOMID, Muckle-Wells Adult onset Still’s Refractory acute gout?

Anti-IL-1 antagonists Rilonacept / IL-1 Trap Canakimumab Fusion protein IL-1RI and IL-1Rap + Fc IgG Efficiently binds IL-1 Studies in Cryopyrin- Associated Periodic Syndromes (CAPS), Gout Humanized anti-IL-1beta Binds only IL-1 beta Effective in CAPS, SJIA, Gout

Anti-IL-1 Adverse Events Infections Neutropenia

Anti-IL6, Tocilizumab Anti-IL-6R mAb Humanized mAb IL-6 IL-6R, sIL-6R gp130

Anti-IL6, Tocilizumab Sources Macrophage B lymphocyte T lymphocyte Fibroblast Endothelial cell Effects Monocyte activation PMN recruitment Thrombocytosis B cell differentiation Hepatocyte acute phase protein production (CRP) Osteoclast activation

MTX Naïve (n=570) Jones, G, et al. Ann Rheum Dis 2010; 69:88-96.

MTX Inadequate Responders(IR) (n=1812) Maini, RN, et al. Arthritis Rheum 2006; 54:

DMARD IR (n+1216) Genovese, MC, et al. Arthritis Rheum 2008; 58:

Anti-TNF IR (n=489) Emery P, et al. Ann Rheum Dis. 2008;67:

Anti-IL6, Tocilizumab Adverse Events Serious infections Intestinal (diverticular) perforations Lipid elevations: Total chol, LDL, HDL, triglycerides Elevated liver enzymes Neutropenia, thrombocytopenia

Cell surface molecules T lymphocyte co-stimulator Abatacept / Orencia B lymphocyte stimulator Belimumab / Benlysta B lymphocyte marker CD20 Rituximab / Rituxan

T Cell activation Signal 1 Signal 2

CTLA4 inhibits T Cell Activation

Abatacept (Orencia®) CTLA-Ig fusion protein Prevents B7 co- stimulation (signal 2) of lymphocytes

Abatacept in Inadequate Responders to Methotrexate (AIM)(n=652) Kremer J et al. Ann Intern Med 2006;144:

Abatacept in Anti-TNF IR (ATTAIN)(n=293) Genovese M, et al. N Engl J Med 2005, 353:

Abatacept: Adverse Effects Infusion reactions Infections COPD exacerbations or infections Screen for Tuberculosis Vaccinate before starting therapy

Biologic Targets Cytokines Anti-TNF Anti-IL1 Anti-IL6 Cell surface molecules T lymphocyte co-stimulator B lymphocyte stimulator B lymphocyte marker CD20

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

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

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

RTX in TNF IR (REFLEX)(n=520) Cohen SB, et al, Arthritis Rheum 2006; 54:

RTX in MTX IR (SERENE)(n=511) Emery P, et al. Ann Rheum Dis 2010;69:

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<0.001) Secondary end point – <10 mg/d prednisone RTX : 71% CTX: 62% P=0.10 Rituximab versus cyclophosphamide for ANCA- associated vasculitis

Rituximab Infusion reactions B cell depletion Infections PML, progressive multifocal leukoencephalopathy (CNS jc virus reactivation) Reactivation of hepatitis B virus Screen for HBV Vaccinate before treatment

Biologic therapies in RA Target TNF Target IL6 Inhibit T cell activation Deplete B cells Screen for tuberculosis, HBV Immunize Monitor: cytopenia, elevated liver enzymes, increase in lipids, infections, neoplasia