1. NEW 2011/2012 CRA Recommendations for the Pharmacological Management of RA with Traditional and Biologic DMARDs: Part II Safety Presenter:

2. 2  CRA recommendations were supported by the Canadian Institutes of Health Research (CIHR) and matched funds from the CRA.  No pharmaceutical companies were involved in any phase of guideline development. Disclosures

3. 3 Commonly Used Abbreviations ABAT = Abatacept ADA = Adalimumab Anti-TNF = Anti-Tumor Necrosis Factor BCG = Bacille Calmette-Guérin CXR = Chest x-ray DMARD = Disease modifying anti-rheumatic drug ETN = Etanercept IFX = Infliximab IGRA = Interferon-gamma release assay LTBI = Latent tuberculosis infection MTX = Methotrexate RCT = Randomized controlled trial RTX = Rituximab TBST = Tuberculin skin test

4. 4 1.Briefly summarize how the NEW 2012 CRA safety recommendations for RA were developed. 2.Review 2012 CRA safety recommendations for RA. 1.Highlight available guideline resources and implementation tools. Learning Objectives

5. 5 Preamble The CRA developed recommendations for the pharmacological management of RA with traditional and biologic DMARDs in 2 parts. - Part I: Detailed methodology + 26 RA treatment strategy- driven recommendations with traditional and biologic DMARDs (reviewed separately). - Part II: Thirteen recommendations focusing on specific safety aspects of RA treatment with traditional and biologic DMARDs (reviewed here).

6. 6  What is covered? −Perioperative management (2) −Screening for latent tuberculosis before starting biologic therapy (4) −Optimal vaccination practices (3) −Treatment of RA patients with a history of malignancy (4) Scope

7. 7 Methods for Developing Recommendations

8. 8 Pooneh Akhavan, MD FRCPC Claire Bombardier, MD FRCPC Vivian Bykerk, MD FRCPC Glen Hazlewood, MD FRCPC James Pencharz, MD CCFP Janet Pope, MD FRCPC John Thomson, MD FRCPC Carter Thorne, MD FRCPC Majed Khraishi, MD FRCPC Sharon LeClercq, MD FRCPC Dianne Mosher, MD FRCPC Anne Dooley, Arthritis Patient Advocate Boulos Haraoui, MD FRCPC Jean Légaré, Arthritis Patient Advocate Orit Schieir, Project Coordinator Michel Zummer, MD FRCPC  Rheumatologist expert  Patient consumer  General practitioner  Coordinator External Clinical Experts: Johan Askling (Malignancy) Michael Gardam (TB, Vaccination) Multidisciplinary Working Group

9. 9 Modified- ADAPTE Framework 2. Identification of Guidelines Systematic review (2000-2010) + Grey literature 3. Quality Appraisal of Guidelines Guideline quality – Validated instrument (AGREE) 4. Synthesis of Guidelines Evidence tables of recommendations with supporting evidence 5. Adapt/develop recommendations Full working group voting and discussion 7. Dissemination Educational meetings/ local workshops + support tools 1. Define Key Questions A priori from results of a national needs assessment survey 1. Define Key Questions A priori from results of a national needs assessment survey 2. Identification of Guidelines Systematic review (2000-2010) + Grey literature 3. Quality Appraisal of Guidelines Guideline quality – Validated instrument (AGREE) 4. Synthesis of Guidelines Evidence tables of recommendations with supporting evidence 5. Adapt/develop recommendations Full working group voting and discussion 6. Extended Review & Endorsement External clinical experts (infectious disease, malignancy) + CRA executive 7. Dissemination Educational meetings/ local workshops + support tools Expanded searches: Public health guidelines, post- marketing surveillance + SLR for malignancy (2008-10) 6. Extended Review & Endorsement External clinical experts (infectious disease, malignancy) + CRA executive

10. 10 Level of EvidenceStrength of Recommendation I Meta-analyses/systematic reviews of RCTs, or individual RCTs A Strong Direct level I evidence II Meta-analyses, systematic reviews of case control/cohort studies or individual case control/ cohort studies OR RCT subgroup/post hoc analyses B Moderate Direct level II evidence or extrapolated level I evidence III Non-analytic studies, e.g. case reports, case series C Weak Direct level III evidence or extrapolated level II evidence IV Expert opinion D Consensus Expert opinion based on very limited evidence Strength of Evidence Bykerk et al. The Journal of Rheumatology 2011; 38:11; doi:10.3899/jrheum.110207

11. 11 Recommendations

12. 12 Recommendations reviewed here are intended to be read in conjunction with Part I of CRA Recommendations for RA. These recommendations address specific safety questions that were identified a priori. They are not intended to cover all safety aspects concerning treatment with traditional and biologic DMARDs. Disclaimer

13. 13 RecommendationLevel of Evidence Strength 1. Methotrexate can be safely continued in the perioperative period for RA patients undergoing elective orthopedic surgery. IA 2. Biologics should be held prior to surgical procedures. The timing for withholding therapy should be based on the individual patient, the nature of the surgery, and the pharmacokinetic properties of the agent. Biologic DMARDs may be restarted postoperatively if there is no evidence of infection and wound healing is satisfactory. II, IVC Perioperative Care Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165

14. 14 Mean half-lives of biologic agents licensed for use in Canada Mean half-life (days) 2 half-lives (days) 5 half-lives (days) Etanercept (ETN)4.38.621.5 Adalimumab (ADA)142870 Infliximab (IFX)8-1016-2040-50 Golimumab (GOL)122460 Certolizumab (CTZ)142870 Rituximab (RTX)2142105 Abatacept (ABAT)132665 Tocilizumab (TCZ)132665 Health Canada Drug Product Database (accessed 04-2011): http://www.hc-sc.gc.ca/dhp-mps/prodpharma/databasdon/index-eng.phphttp://www.hc-sc.gc.ca/dhp-mps/prodpharma/databasdon/index-eng.php Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165

15. 15 RecommendationLevel of Evidence Strength 3. Screening for latent tuberculosis infection (LTBI) is recommended prior to starting Anti-TNF therapy (II), abatacept (ABAT) and tocilizumab (TCZ) (IV). Screening should consist of a history including an assessment of LTBI epidemiologic risk factors, physical exam, tuberculin skin test (TBST) and a chest x-ray in high-risk groups (II). Physicians should exercise clinical judgment as to the need to repeat screening in patients who tested negative in prior screening and have new epidemiologic risk factors (IV). II, IVB Latent Tuberculosis Infection (LTBI) Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165

16. 16 Close contact with individuals known or suspected to have TB (e.g., family members or people sharing living spaces) History of active TB or x-ray suggestive of past TB that was not adequately treated Living in (and/or traveling to) communities with high rates of latent/ active TB Low income populations (e.g. urban homeless) Residents of long-term care and correctional facilities Occupational exposure to high risk groups (e.g. healthcare workers) Risk Factors for Latent Tuberculosis Infection (LTBI) Latent Tuberculosis Infection (LTBI) Public Health Agency of Canada (PHAC) 2008 Tuberculosis Fact Sheet: http://www.phac-aspc.gc.ca/tbpc-latb/fa-fi/tb_can-eng.phphttp://www.phac-aspc.gc.ca/tbpc-latb/fa-fi/tb_can-eng.php Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165

17. 17 RecommendationLevel of Evidence Strength 4. Interferon-gamma release assays (IGRAs) may be an option to identify false positive tuberculin skin tests (TBSTs) in patients who have received the Bacille Calmette-Guérin (BCG) vaccine and have no epidemiologic risk factors. IVD Latent Tuberculosis Infection (LTBI) Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165

18. 18 RecommendationLevel of Evidence Strength 5. Any RA patient with latent tuberculosis infection (LTBI) should be considered for prophylactic therapy. IIB Latent Tuberculosis Infection (LTBI) Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165

19. 19 RecommendationLevel of Evidence Strength 6. Biologic agents may be started 1-2 months after the initiation of latent tuberculosis infection (LTBI) prophylaxis. II, IVB Latent Tuberculosis Infection (LTBI) Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165

20. 20 Summary of CRA Recommendations for Vaccination in Patients with RA (Recommendations 7-9) Inactivated/ Killed VaccinesLive attenuated vaccines Influenza (annual) Pneumococcal (booster after 3-5 years) Hepatitis B Herpes Zoster Other Methotrexate* ✓✓✓†✓† ✓ †† Caution Leflunomide ✓✓✓†✓† ✓ †† Caution Sulfasalazine ✓✓✓†✓† ✓ †† Caution All biologics ✓✓✓†✓† Avoid ✓ Recommended; ideally administer prior to initiating therapy. † Recommended in high-risk groups including residents, travelers or close contact with individuals from hepatitis B endemic areas, illicit drug users, persons engaging in risky sexual behaviors/history of STI, men who have sex with men, chronic liver disease, occupational exposures, frequent blood transfusions. †† Recommended in RA patients > 60 years old. * Methotrexate ≤ 25 mg per week. Vaccination Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165

21. 21 Classification of Common Vaccines Live attenuated vaccines Bacillus Calmette Guérin (BCG) Influenza - nasal Measles/mumps/rubella (MMR) Polio - oral Smallpox Typhoid (oral) Varicella/ Herpes Zoster Yellow fever Inactivated/killed vaccines Diphtheria Hemophilus influenza type B (protein conjugate) Hepatitis A Hepatitis B Human Papilloma Virus (HPV) Inactivated poliomyelitis (IPV) Influenza - intramuscular Meningococcal Pertussis Pneumococcal (23-valent polysaccharide) Pneumococcal (seven-valent protein conjugate) Rabies Tetanus* Typhoid - intramuscular * Tetanus + diphtheria toxoids adsorbed + component pertussis (Tdap); tetanus + diphtheria (Td); component pertussis + diphtheria + tetanus toxoids adsorbed (DTaP) Vaccination Public Health Agency of Canada (PHAC) Canadian Immunization Guide: http://www.phac-aspc.gc.ca/publicat/cig-gci/ p01-eng.phphttp://www.phac-aspc.gc.ca/publicat/cig-gci/ p01-eng.php Rahier et al. Rheumatology 2010. Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165

22. 22 Given the limited research evidence for malignancy, recommendations are generally grouped as follows: Medications that are / should be: 1) An option (either evidence that there is no increased risk or no theoretical increased risk) 1) Used with caution due to unknown risks 1) Used with caution; at least some evidence of  risks Malignancy

23. 23 Summary of CRA Recommendations for Malignancy in RA (Recommendations 10-13) An optionUse with caution (Risk unknown/ no evidence) Use with caution; (Some evidence of increased risk) Active Malignancy (Receiving Chemotherapy/Radiation) *** History of Malignancy Lymphoma Sulfasalazine Hydroxychloroquine Rituximab Abatacept Tocilizumab Methotrexate Anti-TNF Non-melanoma skin cancer Methotrexate Leflunomide Sulfasalazine Hydroxychloroquine Abatacept Rituximab Tocilizumab Anti- TNF Solid tumor Methotrexate Leflunomide Sulfasalazine Hydroxychloroquine Abatacept Rituximab Tocilizumab Anti- TNF (melanoma) * Treatment decisions should be made on a case-by-case basis in conjunction with a cancer specialist & the patient. Malignancy Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165

24. 24 Accessing CRA Recommendations?

25. 25 Journal of Rheumatology Publications http://jrheum.org/search?fulltext=schieir&journalcode=jrheum%7Cjrheumsupp&submit=yes&x=0&y=0 Drug monitoring Health Canada Drug Product Database http://www.hc-sc.gc.ca/dhp-mps/prodpharma/databasdon/index-eng.php  Health Canada MedEffect Homepage http://www.healthcanada.gc.ca/medeffectwww.healthcanada.gc.ca/medeffect  US FDA MedWatch Safety Alerts for Human Medical Products http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/default.htm TB Public Health Agency of Canada 2007 Canadian Tuberculosis Standards: http://www.phac-aspc.gc.ca/tbpc-latb/pubs/tbstand07-eng.php  Online TST/ IGRA Interpreter Tool (Version 3.0) http://www.tstin3d.com/en/calc.html Vaccination 2006 Public Health Agency of Canada Canadian Immunization Guide http://www.phac-aspc.gc.ca/publicat/cig-gci/p01-eng.php Other Useful Links

26. 26 For any queries/ comments about CRA recommendations for RA, please contact raguidelines@rheum.ca Acknowledgements Dr. Johan Askling (Malignancy) Dr. Michael Gardam (TB, Vaccination) Expert Consultants Dr. Pooneh Akhavan Dr. Vivian Bykerk Dr. Claire Bombardier Mrs. Anne Dooley Dr. Paul Haraoui Dr. Glen Hazlewood Dr. Majed Khraish Dr. Sharon LeClercq Mr. Jean Légaré Dr. Diane Mosher Dr. James Pencharz Dr. Janet Pope Ms. Orit Schieir Dr. John Thomson Dr. Carter Thorne Dr. Michel Zummer RA Guidelines Working Group