RA: A Deadly, Disabling Disease. Dr. Philip Baer Seacourses Asia CME December 2017

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2 RA: A Deadly, Disabling Disease Dr. Philip Baer Seacourses Asia CME December 2017

3 Copyright 2017 by Sea Courses Inc. All rights reserved. No part of this document may be reproduced, copied, stored, or transmitted in any form or by any means graphic, electronic, or mechanical, including photocopying, recording, or information storage and retrieval systems without prior written permission of Sea Courses Inc. except where permitted by law. Sea Courses is not responsible for any speaker or participant s statements, materials, acts or omissions.

4 i Faculty/Presenter Disclosure Faculty/Presenter: Dr. Philip Baer Relationships with commercial interests: Grants/research support: Speaker s bureau/honoraria: Consulting fees: Eli Lilly, Pfizer, Abbvie, Amgen, Janssen, Lifelabs Eli Lilly, Pfizer, Abbvie, Amgen, Paladin, Novartis, Sanofi Genzyme, Merck, Roche, Janssen, Takeda, Johnson & Johnson Other:

5 ii Disclosure of Commercial Support This program has received financial support in the form of an educational grant: N/A This program has received in-kind support in the form of logistical support: N/A Potential for conflict(s) of interest: N/A

6 iii Mitigating Potential Bias Potential sources of bias identified in the preceding 2 slides have been mitigated as follows: Information presented is evidence-based Recommendations made are evidence- or guidelines-based rather than personal recommendations of the presenter The Speaker completed the CPFC Mainpro Declaration of Conflict of Interest form evidencing compliance with Mainpro requirements, a requisite for this program to be given accredited status

7 Learning Objectives Recognize the importance of early referral in RA Understand the effects of co-morbidities in your RA patients Understand improved outcomes with biologic and targeted therapies and a treat-to-target approach

8 NEW 2011/2012 CRA Recommendations for the Pharmacological Management of RA with Traditional and Biologic DMARDs

9 RA: Diagnosis

10 RA: 2010 ACR/EULAR Classification Criteria Target population: Patients Who have 1 joint with definite clinical synovitis (swelling) Whose synovitis is not better explained by another disease Joint Involvement 1 large joint 2-10 large joints 1-3 small joints (with or without large joint involvement) 4-10 small joints >10 joints (at least 1 small joint) Serology ( 1 test result needed for classification) Negative RF and negative ACPA Low-positive RF or low-positive ACPA High-positive RF or high-positive ACPA Acute-phase reactants ( 1 test result needed for classification) Normal CRP and normal ESR Abnormal CRP or abnormal ESR Duration of symptoms <6 weeks 6 weeks 0 points 1 point 2 points 3 points 5 points 0 points 2 points 0 points 1 point 0 points 1 point Definite RA: Score 6/10

11 RA: Differential diagnosis

12 RA Topics What happens with lack of disease control? How do we measure the disease? Why early aggressive therapy? What therapy? What is new? What is coming? GP/FP role in RA Conclusion

13 RA: Preclinical Phase

14 RA: Clinical Phase

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16 Clinical Spectrum of RA: From Bad to Worse In the absence of optimal treatment

17 Rheumatoid Arthritis: Deformities Rheumaknowledgy.com

18 RA Is a Chronic Systemic Autoimmune Inflammatory Arthritis Associated With Extra-Articular Manifestations Joint inflammation 1-4 Fatigue 4 Myocardial infarction 5 Anemia (up to 60% of patients) 9 RA Cardiovascular disease (up to four-fold increased risk) 5 7 Stroke 8 Osteoporosis 11 Malignancy (up to two-fold increased risk of lymphoma) 10 1 Smolen J, et al. Nat Rev Drug Disc 2003;2: Grassi W, et al. Eur J Radiol 1998;27(Suppl 1):S18 S24. 3 Firestein G. Nature 2003;423: Smolen J, et al. Lancet 2007;370: Turesson C, et al. Ann Rheum Dis 2004;63: del Rincón I, et al. Arthritis Rheum 2001;44: Hochberg M, et al. Curr Med Res Opin 2008;24: Solomon DH. Ann Rheum Dis 2006;65: Peeters H, et al. Ann Rheum Dis 1996;55: Smitten A, et al. Arthritis Res Ther 2008;10:R Di Munno O and Delle Sedie A. J Endocrinol Invest 2008;31 (Suppl 7):43 47.

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20 Central Central Role Role of of TNF- TNF-alpha in RA in RA Kirwan JR. J Rheumatol. 1999;26:

21 Systemic effects of IL-6 in RA IL-6 Acute-phase proteins (e.g. CRP) Hepcidin production Acute-phase response 1 Alterations in iron homeostasis 2 Thrombocytosis 1 Alterations in lipid metabolism 3,4 Hypothalamicpituitaryadrenal axis 5 Osteoporosis 1 Mood/fatigue/pain 6 1 Choy E. Rheum Dis Clin North Am 2004;30: McGrath H & Rigby P. Rheumatology 2004;43: Al-Khalili L, et al. Mol Endocrinol 2006;20: van Hall G, et al. J Clin Endocrinol Metab 2003;88: Perlstein R, et al. Endocrinology 1993;132: Chrousos G. N Engl J Med 1995;332:

22 RA Topics What happens with lack of disease control? How do we measure the disease? Why early aggressive therapy? What therapy? What is new? What is coming? GP/FP role in RA Conclusion

23 Lord Kelvin Kelvingrove Park, Glasgow When you can measure what you are speaking about, and express it in numbers, you know something about it, when you cannot express it in numbers, your knowledge is of a meager and unsatisfactory kind; it may be the beginning of knowledge, but you have scarcely, in your thoughts advanced to the stage of science.

24 Assessment Tools for RA Commonly employed and validated tools include: Disease activity Radiology Functional status QoL ACR response criteria Sharp score HAQ SF-36 EULAR response criteria (Based on DAS score) Van der Heijde Modified score DAS/CDAI/SDAI Genant-modified Sharp score ACR, 2002; Felson et al, 1995; Kirwan & Reeback, 1986; Sharp, 2000; van Gestel et al, 1996; Genant H et al. Ann Rheum Dis 2005; 64(Suppl III): 56 HAQ = Health Assessment Questionnaire SF-36 = Short Form with 36 questions EULAR = European League Against Rheumatism DAS = Disease Activity Score QoL = Quality of life CDAI = Clinical Disease Activity Index SDAI = Simplified Disease Activity Index

25 Core Set for RA Clinical Trials* Tender joint count (TJC) Swollen joint count (SJC) Patient global assessment of disease activity Physician/Assessor global assessment of disease activity Pain Physical disability Acute phase reactant *Felson et al, Arthritis Rheum 1993;36:729-40; Boers et al, J Rheumatol 1994;21(suppl 41):86-9.

26 ACR Response Criteria ACR 20 ACR 50 ACR 70 Tender joint count 20%+ improvement 50%+ improvement 70%+ improvement Swollen joint count 20%+ improvement 50%+ improvement 70%+ improvement 3/5 other core set measures 20%+ improvement 50%+ improvement 70%+ improvement

27 Clinical Disease Activity Index (CDAI) Numerical sum of: SJC (28 joint count) TJC (28 joint count) Patient Global Assessment (VAS 0-10 cm) Physician Global Assessment (VAS 0-10 cm) Range: 0 76 Remission <2.8 Low <10 Moderate >10 and <22 High >22 28-joint count Validated against SDAI and DAS28 No acute-phase reactant = easier disease activity evaluation Aletaha D. Clin Exp Rheumatol 2005;23(sup 39):S100

28 Do not copy or distribute Amgen Canada 2016 All Rights Reserved

29 US and MRI images of MCP joint synovitis in RA Tan Y K et al. Rheumatology 2012;51:vii36-vii42 (A) Sagittal image of third MCP joint demonstrating power Doppler signal in the dorsal aspect of the joint. (B) Sagittal MRI of the same MCP joint demonstrating contrast-enhanced synovitis on dorsal and volar surfaces. (C)Axial MRI of the same hand with enhancing synovitis visible circumferentially in the third MCP joint. The Author Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please journals.permissions@oup.com

30 HAQ DI Scoring Scale Dressing 3 3=Very severe disability Activities Rising 2 2=Severe disability Gripping HAQ Subscales Eating 1 1.2=RA patients 1.0=Moderate disability Reaching Hygiene Walking =General Population 0=No disability

31 HAQ

32 RA: Labs and Imaging

33 RA Topics What happens with lack of disease control? How do we measure the disease? Why early aggressive therapy? What therapy? What is new? What is coming? GP/FP role in RA Conclusion

34 Standardized mortality ratio RA: Early Optimal Care Decreases Mortality Patients who present earlier to rheumatologists may have decreased risk of mortality 4 Risk of all-cause mortality Early presenters* Late presenters * 5 years disease at presentation; n=252 >5 years disease at presentation; n=196 Symmons DPM, et al. J Rheumatol 1998;25:

35 RA and DMARD Therapy: See a Rheumatologist Early Patients with new onset RA within the first year of their diagnosis should be seen by a rheumatologist and should not delay treatment with DMARDs Source: Widdifield, J et al. (2011). Arthritis Care & Research, 63(1), Quality care in seniors with new-onset rheumatoid arthritis: a Canadian perspective There is evidence to suggest that DMARDs may delay disease progression, need for joint replacement and use of biologics

36 Ontario RA Database: More RA Patients, Same Number of Rheumatologists

37 RA Topics What happens with lack of disease control? How do we measure the disease? Why early aggressive therapy? What therapy? What is new? What is coming? GP/FP role in RA Conclusion

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39 ACR-EULAR 2011 Definition of Remission For clinical trials Boolean SJC, TJC, PtGA, CRP all 1 Index-based SDAI 3.3 For clinical practice Boolean SJC, TJC, PtGA all 1 Index-based CDAI 2.8 SDAI=SJC+TJC+PhGA+PtGA+ CRP (mg/dl) CDAI=SJC+TJC+PhGA+PtGA

40 DAS RA Therapy: Better results with an intensive strategy TICORA Study: Significant improvements in outcomes were observed with an intensive care treatment strategy compared to routine care Time (Months) Routine Group Intensive Group

41 RA: What is a DMARD? Drug shown to change the course of RA for at least 1 year by demonstrating one of: Improvement in physical function Decrease in inflammatory synovitis AND Slowing of structural joint damage

42 RA: Traditional DMARDs Methotrexate-the anchor drug (MTX) Sulfasalazine (SSZ) Hydroxychloroquine (HCQ) Leflunomide (LEF) Intramuscular gold Azathioprine Cyclosporin A Minocycline (Penicillamine)

43 RA: Common Combination Therapies MTX + HCQ MTX + HCQ + SSZ MTX + LEF MTX + Gold MTX + AZA MTX + Cyclosporin A

44 RA Topics What happens with lack of disease control? How do we measure the disease? Why early aggressive therapy? What therapy? What is new? What is coming? GP/FP role in RA Conclusion

45 Evolution of RA Treatment MTX, Oral gold Anakinra Adalimumab Tocilizumab Gold HCQ, Steroids SSZ D-Pen, AZA Leflunomide Infliximab Etanercept Rituximab Abatacept Golimumab Certolizumab Tofacitinib ASA s 1950s 1960s 1970s 1980s 1998/ Gold (monotherapy) Era MTX Era Biologic Era Treat Signs and Symptoms in Established Disease Combination and Biologic Rx Disease Modification

46 Biotechnology: The Future in Rheumatology

47 Newest: IV golimumab; SC tocilizumab and abatacept; biosimilar infliximab and etanercept

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50 ACR Responses: Current Biologics in TNF-naïve Patients 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% ACR 20 ACR 50 ACR 70 Nonresponders Responders

51 % Responders Early RA Patients Do Better: 6 Month Results Adalimumab 40 mg eow + MTX Placebo + MTX ACR ACR50 ACR70 ACR20 ACR50 ACR70 RA 2 years RA >2 years E Keystone et al. Ann Rheum Dis 2003; 62 (suppl 1): 170.

52 % Patients RA: Combination Therapy Does Better Weeks 104 Weeks 43* 49* MTX ADA ADA + MTX * p<0.001 for ADA + MTX vs. MTX and ADA alone Premier Study:Breedveld FC, et al. Arthritis Rheum Jan;54(1):26-37.

53 RA: Side Effects of TNF Antagonists Infection - common/opportunistic (TB) Bone marrow suppression (rare) Psoriasis-like rashes Malignancy (non-melanoma skin cancers) Exacerbation of CHF Exacerbation of MS

54 Biologic Safety Screening Tool

55 RA Topics What happens with lack of disease control? How do we measure the disease? Why early aggressive therapy? What therapy? What is new? What is coming? GP/FP role in RA Conclusion

56 RA: Newest Agents JAK-STAT Inhibitors Oral tofacitinib (Xeljanz) approved in 2014 Oral baricitinib (Olumiant) approved in EU and Japan 2017 IL-6 inhibitors Sarilumab approved in 2017; Sirukumab rejected in 2017 Biosimilars (Subsequent Entry Biologics) Inflectra (infliximab) approved in Canada 2014 Brenzys (etanercept) approved in Canada 2016 Erelzi (etanercept) approved in Canada 2017 Biosimilar adalimumab coming

57 Tofacitinib: A Janus kinase inhibitor Tofacitinib modulates cytokines important to the pathogenesis of RA 1-4 tofacitinib Cytokines in the pathogenesis of RA Cytokines JAKs IL-2 JAK1/JAK3 IL-4 JAK1/JAK3 Cytokine IL-7 JAK1/JAK3 IL-15 JAK1/JAK3 IL-21 JAK1/JAK3 IL-6 JAK1/JAK2/Tyk2 IFNα and IFNβ JAK1/Tyk2 IFNg JAK1/JAK2 JAK JAK IL-10 JAK1/Tyk2 Cytoplasm IL-12 IL-23 JAK2/Tyk2 JAK2/Tyk2 IL-1, IL-17, IL-18, TGFβ, TNF JAK-independent * The relevance of specific JAK combinations to therapeutic effectiveness is not known. 1. Shuai K, Liu B. Nat Rev Immunol 2003;3(11): Jiang JK, et al. J Med Chem 2008;51(24): Meyer DM, et al. J Inflamm (Lond) 2010;7:4. 4. Flanagan ME et al. J Med Chem 2010;53:

58 JAK Inhibitor Pipeline

59 RA Topics What happens with lack of disease control? How do we measure the disease? Why early aggressive therapy? What therapy? What is new? What is coming? GP/FP role in RA Conclusion

60 RA Case 66 year old woman RA for 12 years Swollen joints 2, tender joints 4 ESR 30 Happy with RA control Husband calls to cancel her follow-up appointment: She died of a heart attack last week.

61 RA Case Revisited 66 year old woman Smoker Total cholesterol 6.6 mmol/l BMI 29 BP 140/90 Sedentary

62 RA and Cardiovascular Disease Inflammation Inflammation

63 Inflammatory Mediators and Atherosclerosis Lymphocytes, Neutrophils IL-4,6 IL-4,6 CRP VCAM-1 ICAM-1 [NFkB] Ross R. Nature 1993 Libby P. Circulation 2001;104:365

64 CVD Events per 1,000 Years RA: Biologic DMARDs Reduce First CV Events Age-sex adjusted risk ratio = 0.57 (95% CI: ; P < 0.05) Anti-TNF Treatment No Anti-TNF Treatment Jacobsson LTH, et al. Arthritis Rheum. 2003;48(Suppl):S241 [Abstract 540].

65 CV Risk: Think of RA Like Diabetes Variable Goal LDL-C < 2.6 mmol/l BP <130 SBP & <80 DBP Smoking Stop Blood glucose A1C < 7.0 Obesity Weight loss Consider low dose ASA

66 RA: Practical management tips RA patients on biologic and non-biologic DMARDs Monitoring lab tests Surgery Infections Immunizations Pregnancy Malignancy

67 RA: Monitoring Lab Tests Bhupinder, who is on Methotrexate, asks what labwork is required as part of routine monitoring of her condition What if she were on other traditional DMARD therapy? What if she were on biologic DMARD therapy?

68 RA: Drug Initiation Monitoring

69 RA: Monitoring Lab Tests

70 Real Life Vignette 1 I get back a low hemoglobin of 72 on routine monitoring of a 43 y.o. female RA patient on MTX who was stable 6 weeks ago at the last visit, when her Hgb was 116 WBC and platelets are wnl ESR and CRP are wnl I quickly contact patient and FP No one told me patient had new heavy menstrual bleeding and was already seeing a gynecologist

71 Real Life Vignette 2 I give a patient a form for q6week monitoring of her MTX therapy (CBC, liver enzymes, renal function, ESR, CRP) At 2AM one night, I am awoken by the lab telling me that the patient has a critical lab value Random glucose of 32 Moral: Please don t take a rheumatologist s lab requisition and add your own unrelated tests to it

72 RA: Surgery Ashley, who has been on Methotrexate and an anti-tnfα agent for 12 months, calls because she is booked for an elective total knee replacement in 3 months She wants to know if she should stop any of her drugs

73 RA: Surgery

74 RA: Surgery

75 RA: Active infection Mark, who has been on an anti-tnfα agent for just over 2 months, calls because he has a sore throat He wants to know if he should stop therapy

76 Intercurrent infections & anti-tnfα agents Mild infection (e.g., common cold) Continue treatment with increased vigilance Moderate or severe infection Stop treatment Treat promptly with antibiotics Discuss immediately with rheumatologist Tuberculosis suspected Stop treatment Discuss immediately with rheumatologist Product monographs for Enbrel, Humira, Remicade and Simponi

77 Latent Tuberculosis Infection (LTBI) Recommendation 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). Level of Evidence II, IV Strength B Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi: /jrheum

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

79 RA: Immunizations Jean, 54, was prescribed an anti-tnfα agent by her rheumatologist in July It is now October, and she wants to know if she should get her annual flu shot

80 Vaccination Summary of CRA Recommendations for Vaccination in Patients with RA (Recommendations 7-9) Methotrexate* Leflunomide Sulfasalazine All biologics Influenza (annual) Inactivated/ Killed Vaccines Pneumococcal (booster after 3-5 years) Hepatitis B Live attenuated vaccines Herpes Zoster Other Caution Caution Caution Avoid 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. Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi: /jrheum

81 RA: Pregnancy Sandra is on combination DMARD therapy She is 28, has one infant son and would like to have more children

82 Pregnancy and RA RA improves in pregnancy, although not in those with highly active disease. Ensure good disease control before conception 75-85% of RA patients improve significantly during pregnancy Post-partum flare is avoidable with medications 90% of RA patients will flare post-partum within first 6 months Providing tighter RA control during pregnancy improves maternal and baby health outcomes Treating pregnant RA patients is not necessary Rheumatoid arthritis does not affect pregnancy outcome

83 Temprano K et al. Rheumatoid Arthritis and Pregnancy: Treatment and Medication. Available at Accessed Sep 10, 2009; U.S. Prescribing Information for Cimzia, Enbrel, Humira, Orencia, Remicade, Rituxan, Simponi. Pregnancy: FDA drug categories Biologics Certolizumab Etanercept Adalimumab Abatacept Infliximab Rituximab Golimumab Tocilizumab Non-biologics Hydroxychloroquine Leflunomide Methotrexate Sulfasalazine B B B C B C B C C X X B A controlled studies in humans show no risk B no evidence of risk in animals, no controlled studies in humans OR evidence of risk in animals, not confirmed in humans C evidence of risk in animals, no controlled studies in humans OR no studies available in animals or humans; potential benefits may justify the potential risk D positive evidence of human fetal risk, but potential benefits may outweigh the risks X - contraindicated in pregnancy

84 Class Agent FDA Comments NSAIDs Celecoxib C Diclofenac C Ketorolac C Piroxicam C All Others B 3 rd Trimester D Minimal first and second trimester risk Significant maternal and fetal effects in third trimester Corticosteroids Prednisone C Cortisone All others D C Minimal risk

85 Also Motherisk and OTIS

86 RA: Malignancy Sandra has had RA for 3 years and is not controlled with triple DMARD therapy. A biologic therapy is indicated but she had breast cancer 6 years ago. She is now in remission after surgery, chemotherapy and radiation. Which treatments would be reasonable?

87 Rheumatoid Arthritis and Neoplasia No overall increase in malignancy in RA Decreased : adenocarcinoma of colon, breast cancer Increased : lymphoma, lung cancer, and nonmelanoma skin cancers Possibly increased: leukemia, melanoma Increased rates of lymphoma in: Long-standing, active RA Prior immunosuppressive Rx Patients receiving TNF inhibitors, AZA, alkylating agents Lymphoma Leukemia Melanoma NMSC Lung RA Colon Breast Cush JJ, Dao KH. Drug Safety Quarterly 2012; 3(2): 1-4

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

89 RA Topics What happens with lack of disease control? How do we measure the disease? Why early aggressive therapy? What therapy? What is new? What is coming? GP/FP role in RA Conclusion

90 COMPONENTS TO BEST CARE -RA Optimal Outcome OPTIMAL PATIENT CARE EAF Joints Comorbidities P H A R M MDs NURSES Rheumatology Health Team PT OT S O C I A L New Drugs Treat to Target 21 ST CENTURY KNOWLEDGE

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92 Resources

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97 Barriers to Change: RA Common disease but relatively rare in each primary care practice Recognizing early RA is difficult Prevention of joint damage is much improved, but cardiovascular and other comorbidities are underrecognized Shortage of rheumatologists

98 Questions?