Synoviocytes. Macrophage. B cell C H R O N I C. Neutrophil. Mast cell I N F L A M M A T I O N. Tissue cell. Endothelial cell. Th1/Th17 IL17 IL22

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4 DC IL12, IL23 chemokines, ECM, Co-stimulation IL17, IL22 IFNγ ± Macrophage peptidoglycan lipopolysaccharide heat shock proteins Th1/Th17 IL17 IL22 Cell contact, co-stimulation immune complexes acute phase reactants complement TNFα IL1 IL15 IL18 IL6 IL20 IL32 IL33 RANKL GM-CSF IL10 IL1Ra IL18BP sil1r stnfr IL27 IL35 TGFβ Synoviocytes B cell Neutrophil Mast cell Tissue cell Endothelial cell C H R O N I C I N F L A M M A T I O N

5 Cytokines in the pathogenesis of RA In RA, abnormal interactions between immune cells lead to a cytokine-mediated inflammatory response 1-5 Several cytokines are active in synovial tissues, including pro- and anti-inflammatory cytokines 1-5 The cytokine network can be disrupted, leading to chronic inflammation and tissue damage 1-5 Joint damage Cytokines Key cytokines in the pathogenesis of RA 1 IFNα and IFNß IL-6 IL-7 IL-10 IL-12 IL-15 IL-23 IL-1 IL-17 IL-18 TGF-ß TNF 1. Brennan FM, McInnes IB. J Clin Invest 2008;118: McInnes IB, Schett G. Nat Rev Immunol 2007;7: Murray PJ. J Immunol 2007;178: Smolen JS, Steiner G. Nat Rev Drug Discov 2003;2: Arend WP. Arthritis Care Res 2001;45:

6 Antigenpresenting cells ACTIVATION T-cells Mediators & modulators of inflammation Anti-inflammatory IL-1R antagonist Soluble IL-1R Soluble TNFR IL-10 IL-4 Pro-inflammatory TNF IL-1 IL-1R = interleukin-1 receptor TNFR = tumour necrosis factor receptor Rheumatoid arthritis

7 Rationale for targeting TNF

8 Involvement of TNF in rheumatoid arthritis Activated macrophage TNF

9 S S S S S S S S S S S S C H 3 C H 2 Fc portion of human immunoglobulin G1 Human p75 TNF receptor

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12 DC IL12, IL23 chemokines, ECM, Co-stimulation IL17, IL22 IFNγ ± Macrophage peptidoglycan lipopolysaccharide heat shock proteins Th1/Th17 IL17 IL22 Cell contact, co-stimulation immune complexes acute phase reactants complement TNFα IL1 IL15 IL18 IL6 IL20 IL32 IL33 RANKL GM-CSF IL10 IL1Ra IL18BP sil1r stnfr IL27 IL35 TGFβ Synoviocytes B cell Neutrophil Mast cell Tissue cell Endothelial cell C H R O N I C I N F L A M M A T I O N

13 Cytokines in the pathogenesis of RA In RA, abnormal interactions between immune cells lead to a cytokine-mediated inflammatory response 1-5 Several cytokines are active in synovial tissues, including pro- and anti-inflammatory cytokines 1-5 The cytokine network can be disrupted, leading to chronic inflammation and tissue damage 1-5 Joint damage Cytokines Key cytokines in the pathogenesis of RA 1 IFNα and IFNß IL-6 IL-7 IL-10 IL-12 IL-15 IL-23 IL-1 IL-17 IL-18 TGF-ß TNF 1. Brennan FM, McInnes IB. J Clin Invest 2008;118: McInnes IB, Schett G. Nat Rev Immunol 2007;7: Murray PJ. J Immunol 2007;178: Smolen JS, Steiner G. Nat Rev Drug Discov 2003;2: Arend WP. Arthritis Care Res 2001;45:

14 Antigenpresenting cells ACTIVATION T-cells Mediators & modulators of inflammation Anti-inflammatory IL-1R antagonist Soluble IL-1R Soluble TNFR IL-10 IL-4 Pro-inflammatory TNF IL-1 IL-1R = interleukin-1 receptor TNFR = tumour necrosis factor receptor Rheumatoid arthritis

15 Rationale for targeting TNF

16 Involvement of TNF in rheumatoid arthritis Activated macrophage TNF

17 S S S S S S S S S S S S C H 3 C H 2 Fc portion of human immunoglobulin G1 Human p75 TNF receptor

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20 Subsequent entry biologics in RA: What s next? Health Canada defines a SEB as "a biologic product that is similar to and would enter the market subsequent to an approved innovator biologic product 1 Both the CRA and the ORA have released position statements on SEBs. Issues tackled include: 1,2 Cost and accessibility to safe and effective drugs Traceability and clear nomenclature No automatic interchangeability or substitution with innovator molecules Ongoing assessment and post-marketing surveillance Health Canada approved two infliximab SEBs in January, Ontario Rheumatology Association. Position paper on subsequent entry biologics in Canada. November Available at: 2. Canadian Rheumatology Association. Position paper on the establishment of a Common Drug Review Procedure and Process for reviewing subsequent entry biologics (SEBs). October 4, Available at: 3. GaBI. Subsequent entry biologics approved in Canada. Available at: 22

21 The PCP s Role in Ongoing Management 23

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24 A woman on biologic therapy has a son who was exposed to chicken pox after attending a classmate s birthday party. What would you do?

25 Bombardier C, et al. J Rheumatol 2012;39: ; Canadian Immunization Guide (2014). Public Health Agency of Canada, Ottawa. 27

26 Bombardier C, et al. J Rheumatol 2012;39: ; Canadian Immunization Guide (2014). Public Health Agency of Canada, Ottawa; Keystone EC. J Rheumatol 2011;38:

27 British Society for Rheumatology. Vaccinations in the Immunocompromised Person: Guidelines for the Patient taking Immunosuppressants, Steroids and the New Biologic Therapies. January 28, 2002; Canadian Immunization Guide (2014). Public Health Agency of Canada, Ottawa; Keystone EC. J Rheumatol 2011;38:

28 Live vaccines Oral live polio vaccine (OPV) a Suggested alternative Inactivated polio vaccine (IPV) Measles, mumps, rubella (MMR) b Yellow fever Live typhoid vaccine Inactivated vaccine (but only 70% protective) Chickenpox/shingles (Varicella) Bacillus Calmette-Guérin (BCG) a Must not be given to patient OR household contacts b Must not be given to patients; household contacts OK If the patient is travelling to an endemic region, please consult your travel/id expert for further management information British Society for Rheumatology. Vaccinations in the Immunocompromised Person: Guidelines for the Patient taking Immunosuppressants, Steroids and the New Biologic Therapies. January 28, 2002; Canadian Immunization Guide (2014). Public Health Agency of Canada, Ottawa; van Assen S et al. Ann Rheum Dis 2011;70:

29 British Society for Rheumatology. Vaccinations in the Immunocompromised Person: Guidelines for the Patient taking Immunosuppressants, Steroids and the New Biologic Therapies. January 28, 2002; Canadian Immunization Guide (2014). Public Health Agency of Canada, Ottawa; van Assen S et al. Ann Rheum Dis 2011;70:

30 Key recommendations During immunosuppressive therapy 1,2 1. Canadian Immunization Guide (2014). Public Health Agency of Canada, Ottawa; 2. Bombardier C, et al. J Rheumatol 2012;39: ; 3. Lindsey S, et al. ACR Abstracts #1836; ACR 2014, Boston, MA; available at: 32

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33 A man on biologic therapy presents with an upper respiratory tract infection. How would you manage his condition?

34 Patients should be screened for TB, hepatitis B virus, and hepatitis C virus prior to initiation of anti-tnf therapy 1. Steering committee, personal communication, September 2014; 2. Enbrel (Etanercept) product monograph. 3. Humira (adalimumab) product monograph. 4. Remicade (infliximab) product monograph. 5. Simponi (Golimumab) product monograph. 36

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36 A man on biologic therapy is planning to have elective surgery for a bunion. How should his medications be managed?

37 Drug Treatment-free interval prior to surgery based on risk of intra-operative contamination 1 Low-risk surgery Very high-risk surgery Adalimumab (Humira ) ~ 4 weeks ~ 10 weeks Certolizumab (Cimzia ) ~ 4 weeks ~ 10 weeks Etanercept (Enbrel ) ~ 2 weeks ~ 4 weeks Infliximab (Remicade ) ~ 3 weeks ~ 8 weeks Golimumab (Simponi ) ~ 4 weeks ~ 10 weeks 1. Pham T, et al. Joint Bone Spine 2011;78(S1):S109-15; 2. Bombardier C, et al. J Rheumatol 2012;39:

38 Non-biologic DMARD No need to stop Prednisone Stress doses may be ordered perioperatively Also consider Biologic DMARD The type of surgery The risk for infection based on the surgical procedure The patient s general health and risk for infections The half-life of the biologic agent Should be stopped prior to surgery*; restart if no evidence of infection and wound healing is satisfactory *A recent meta-analysis showed that the increased rate of infection in surgical patients treated with anti- TNFs was not improved by stopping anti-tnf before surgery Bombardier C, et al. J Rheumatol 2012;39: ; 2. Saag KG, et al. Arthritis Rheum 2008;59:762-84; 3. Hall J, Schmidt G. Wood L. Principles of Critical Care (2005, 3rd ed). New York: McGraw-Hill Professional; 4. Mabille C, et al. ACR abstract #466; 2014 ACR, Boson, MA; available at: 40

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40 A woman on biologic therapy would like to start a family. What would you tell her about RA and pregnancy?

41 With proper planning, women with RA can have a successful pregnancy 1 1. Ateka-Barrutia O, Nelson-Piercy C. In J Clin Rheumatol 2012;7:541-58; 2. Barnabe C et al. Int J Rheumatol 2011;345727; 3. Nørgaard M et al. J Int Med 2010;268:329-37; 4. Brouwer J et al. Ann Rheum Dis 2014 May 15 [Epub ahead of print]. 43

42 Drug Biologics FDA Drug Category Pregnancy Safety Breastfeeding Anti-TNF agents 1 * B Safe (1 st and 2 nd trimesters) Safe Certolizumab 1 B Probably safe Probably safe Abatacept 1 C Unknown Unknown (probably safe) Rituximab 1 C Avoid (consider in severe disease) Unknown (probably safe) Tocilizumab 1 C Unknown Unknown (probably safe) Non-biologics Sulfasalazine 1 B Safe Safe Hydroxychloroquine 1 C Safe Safe Tofacitinib 2 C Not listed Not listed Leflunomide 1 X Avoid Avoid Methotrexate 1 X Avoid Avoid *Adalimumab, etanercept, infliximab, golimumab; Supplement with folate 5 mg once daily preconception and throughout pregnancy; Had not received regulatory approval at time of article publication 1. Ateka-Barrutia O, Nelson-Piercy C. In J Clin Rheumatol 2012;7:541-58; 2. U.S. Prescribing Information for Xeljanz. 44

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