Rheumatoid Arthritis Management: Turning Treatment Failures Into Successes Supported by an educational grant from Lilly USA, LLC.

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Program Director and Core Faculty Program Chair Gregg J. Silverman, MD Professor, Department of Medicine NYU School of Medicine New York, New York Sergio Schwartzman, MD Franchellie M. Cadwell Associate Professor of Medicine Weill Medical College of Cornell University   Hospital for Special Surgery   New York Presbyterian Hospital  New York, New York

Speaker and Disclosure Information Gregg J. Silverman, MD, has disclosed that he has received consulting fees from Bristol-Myers Squibb and Pfizer and has received fees for non-CME/CE activities from Bristol-Myers Squibb and Genentech. Sergio Schwartzman, MD, has disclosed that he has received consulting fees from AbbVie, Crescendo, Discus Analytics, Epirus, Genentech, Hospira, Janssen, National Psoriasis Foundation, Novartis, Pfizer, and Regeneron and has served on speaker bureaus for AbbVie, Crescendo, Genentech, Hospira, Janssen, Novartis, and Pfizer.

Implementing a Treat-to-Target Strategy in Early Rheumatoid Arthritis

Case Woman 60 yrs of age with 2 mos of rheumatoid arthritis symptoms and persistent disease activity She has 2 hrs of morning stiffness and has difficulty working as a secretary Labs: Hb 10.5 g/dL, ESR 38 mm/hr, RF 20 IU/mL, CRP 20 mg/dL, and elevated ACPA (> 250 units) Low disease activity (CDAI 9 and RAPID3 1.2) ACPA, anticitrullinated protein antibody; CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; Hb, hemoglobin; RAPID3, Routine Assessment of Patient Index Data 3; RF, rheumatoid factor. Slide credit: clinicaloptions.com

Composite Outcome Measures of RA Disease Activity Response Criterion ACR 20/50/70 DAS28 SDAI CDAI RAPID3 Pt function + Pt pain Pt’s global assessment of disease activity Physician’s global assessment of disease activity No. of tender joints No. of swollen joints ESR or CRP ACR, American College of Rheumatology; CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; DAS28, Disease Activity Score 28; ESR, erythrocyte sedimentation rate; RA, rheumatoid arthritis; RAPID3, Routine Assessment of Patient Index Data 3; SDAI, Simple Disease Activity Index. Yazici Y. Bull NYU Hosp Jt Dis. 2007;65(suppl 1):S25-S28. Zatarain E, et al. Nat Clin Pract Rheumatol. 2006;2(suppl 11):611-618. Pincus T, et al. Rheum Dis Clin North Am. 2009;35(suppl 4):773-778. Slide credit: clinicaloptions.com

RA Disease Activity Score Categories of Disease Activity Instrument Remission Low Moderate High DAS28 < 2.6 ≥ 2.6 to < 3.2 ≥ 3.2 to ≤ 5.1 > 5.1 PAS/PAS-II 0 to 0.25 0.26 to 3.7 3.71 to < 8.0 ≥ 8.0 CDAI ≤ 2.8 > 2.8 to 10.0 > 10.0 to 22.0 > 22.0 RAPID3 0 to 1.0 > 1.0 to 2.0 > 2.0 to 4.0 > 4.0 to 10.0 SDAI ≤ 3.3 > 3.3 to ≤ 11.0 > 11.0 to ≤ 26.0 > 26.0 Continuous measures recommended for use in clinical practice CDAI, Clinical Disease Activity Index; DAS28, Disease Activity Score 28; PAS, Patient Activity Scale; RAPID3, Routine Assessment of Patient Index Data 3; SDAI, Simplified Disease Activity Index. Anderson J, et al. Arthritis Care Res. 2012;64(suppl 5):640-647. Singh JA, et al. Arthritis Care Res. 2016;68(suppl 1):1-25. Slide credit: clinicaloptions.com

ACR Guideline: Early RA Early RA defined as < 6 mos of symptoms/disease, not the length of time since diagnosis Strong recommendation DMARD-naive early RA Conditional recommendation Treat to target (ideally low disease activity or remission) Low disease activity Moderate/ high disease activity ACR, American College of Rheumatology; DMARD, disease-modifying antirheumatic drug; GC, glucocorticoid; RA, rheumatoid arthritis. DMARD monotherapy* DMARD monotherapy* *For flares, consider using short-term GCs (< 3 mos). Singh JA, et al. Arthritis Rheumatol. 2016;68(suppl 1):1-26. Singh JA, et al. Arthritis Care Res. 2016;68(suppl 1):1-25. Slide credit: clinicaloptions.com

ACR Guideline: Early RA After DMARD Monotherapy Failure Moderate/high disease activity after DMARD monotherapy, early RA*† Strong recommendation Combination traditional DMARDs*† or TNF inhibitor ± MTX*† or non-TNF biologic ± MTX*† *For flares, consider using short-term GCs (< 3 mos). †In pts with previous biologic or DMARD failure or when starting DMARDs in pts with moderate/high disease activity, consider using low-dose GCs (≤ 10 mg/day of prednisone or equivalent). Treat to target (ideally low disease activity or remission) Moderate/high disease activity*† ACR, American College of Rheumatology; DMARD, disease-modifying antirheumatic drug; GC, glucocorticoid; MTX, methotrexate; RA, rheumatoid arthritis; TNF, tumor necrosis factor. See established RA algorithm Singh JA, et al. Arthritis Rheumatol. 2016;68(suppl 1):1-26. Singh JA, et al. Arthritis Care Res. 2016;68(suppl 1):1-25. Slide credit: clinicaloptions.com

RA Undertreatment 2011 study: Nearly 40% of Medicare pts with RA received no DMARD over a period of 4 yrs[1] 2015 study: 28% of an insured cohort of incident RA pts received only symptomatic therapy during a minimum follow-up of 1.75 yrs[2] DMARD, disease-modifying antirheumatic drug; RA, rheumatoid arthritis. 1. Schmajuk G, et al. JAMA. 2011;305(suppl 5):480-486. 2. Crane MM, et al. Arthritis Care Res. 2015;67(suppl 12):1646-1655. Slide credit: clinicaloptions.com

ACR Guideline: Early RA Disease Activity Previous Therapy Recommendation(s) Evidence Strength Any NA Use treat-to-target strategy Low Strong No DMARDs Use DMARD monotherapy (MTX preferred) over double or triple therapy Moderate/ high Use DMARD monotherapy over double or triple therapy Moderate/high Conditional DMARD monotherapy ± GCs Use combination DMARDs, TNF inhibitor, or non-TNF biologic ± MTX DMARDs Use TNF inhibitor ± MTX over tofacitinib ± MTX DMARDs or biologics Add low-dose GCs Low/ moderate Flares Add short-term GCs at lowest possible dose for shortest possible duration Very low ACR, American College of Rheumatology; DMARD, disease-modifying antirheumatic drug; GC, glucocorticoid; MTX, methotrexate; NA, not applicable; TNF, tumor necrosis factor. Singh JA, et al. Arthritis Rheumatol. 2016;68(suppl 1):1-26. Singh JA, et al. Arthritis Care Res. 2016;68(suppl 1):1-25. Slide credit: clinicaloptions.com

Recognizing Treatment Failure in Early Rheumatoid Arthritis and Established Rheumatoid Arthritis

Case Study: Presentation Woman 42 yrs of age with 2 mos of symmetric involvement of hands, wrists, knees, and feet and 3 hrs of generalized morning stiffness Screening for hepatitis, TB, and CXR all WNL Started on prednisone 10 mg QD, hydroxychloroquine 200 mg QD, oral methotrexate rapidly advancing to 15 mg QW High disease activity at baseline (DAS28 6.2, CDAI 46, RAPID3 22) CDAI, Clinical Disease Activity Index; CXR, chest x-ray; DAS28, Disease Activity Score 28; QD, once daily; QW, once weekly; RAPID3, Routine Assessment of Patient Index Data 3; SDAI, Simple Disease Activity Index; TB, tuberculosis; WNL, within normal limits. Slide credit: clinicaloptions.com

Case Study: Presentation After 6 mos on therapy, with regular follow-up and taper off prednisone, disease activity is moderate Disease Activity Score Before DMARD After 6 Mos of DMARD DAS28 6.2 4.4 CDAI 46 19 RAPID3 22 3.9 CDAI, Clinical Disease Activity Index; DAS28, Disease Activity Score 28; DMARD, disease-modifying antirheumatic drug; RAPID3, Routine Assessment of Patient Index Data 3. Slide credit: clinicaloptions.com

ACR Guideline: Established RA After Monotherapy or in DMARD-Naive Pts Disease Activity Previous Therapy Recommendation(s) Evidence Type Any NA Use treat-to-target strategy Moderate Strong Low No DMARDs Use DMARD monotherapy (MTX preferred) over TNF inhibitor Moderate/ high Use DMARD monotherapy (MTX preferred) over tofacitinib or combination DMARDs Moderate/high Conditional DMARD monotherapy Use combination DMARDs or add TNF inhibitor, non-TNF biologic, or tofacitinib, all ± MTX Very low/ moderate TNF inhibitor, no DMARDs Add 1 or 2 DMARDs to TNF inhibitor High TNF inhibitor monotherapy Use non-TNF biologic ± MTX over another TNF inhibitor ± MTX or tofacitinib ± MTX low Non-TNF biologic monotherapy Use another non-TNF biologic ± MTX over tofacitinib ± MTX Very low ACR, American College of Rheumatology; DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; TNF, tumor necrosis factor. Singh JA, et al. Arthritis Rheumatol. 2016;68(suppl 1):1-26. Singh JA, et al. Arthritis Care Res. 2016;68(suppl 1)1-25. Slide credit: clinicaloptions.com

ACR Guideline: Established RA After DMARD Monotherapy Failure Moderate/high disease activity after DMARD monotherapy, established RA*† Strong recommendation Conditional recommendation Combination traditional DMARDs*† or anti-TNF or non-TNF biologic ± MTX*† or tofacitinib ± MTX Treat to target (ideally low disease activity or remission) *For flares, consider using short-term GCs (< 3 mos). †In pts with previous biologic or DMARD failure or when starting DMARDs in pts with moderate/high disease activity, consider using low-dose GCs (≤ 10 mg/day of prednisone or equivalent). Moderate/high disease activity*† ACR, American College of Rheumatology, DMARD, disease-modifying antirheumatic drug; GC, glucocorticoid; MTX, methotrexate; RA, rheumatoid arthritis; TNF, tumor necrosis factor. If single TNF inhibitor failure: Non-TNF biologic ± MTX or TNF inhibitor ± MTX If single non-TNF biologic failure: Another non-TNF biologic ± MTX Singh JA, et al. Arthritis Rheumatol. 2016;68(suppl 1):1-26. Singh JA, et al. Arthritis Care Res. 2016;68(suppl 1):1-25. Slide credit: clinicaloptions.com

Comparative Durability of TNF Inhibitors in RA Adjusted HR (95% CI): IFX vs ETN: 0.98 (0.85-1.13) IFX vs ADA: 0.95 (0.78-1.15) ADA vs ETN: 1.04 (0.88-1.22) Similar risk of discontinuation observed with infliximab, adalimumab, or etanercept in RA pts during first 9 yrs of use 1.0 Infliximab Adalimumab Etanercept Drug n (%) Median Durability, Yrs (95% CI) Infliximab 620 (21) 3.68 (2.88-4.95) Adalimumab 474 (16) 3.33 (2.63-4.10) Etanercept 1829 (63) 3.78 (3.31-4.32) 0.8 0.6 Persistence Probability ADA, adalimumab; ETN, etanercept; IFX, infliximab; RA, rheumatoid arthritis. 0.4 0.2 Log-rank P = .2342 2 4 6 8 Yrs Slide credit: clinicaloptions.com Fisher A, et al. PLoS One. 2014;9(suppl 8):e105193.

New Standard of Care: Treat to Target Up to 30% of pts respond suboptimally to current treatment and continue to experience active disease, including pain, joint stiffness, disability, and progressive joint damage[1] Fewer than one half of RA pts received care consistent with guidelines recommendations[2] Australian study: many rheumatologists fail to treat to target or adjust DMARD therapy[3] Biologics, which are recommended after MTX failure, are prescribed in just 15% of pts[4] DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; RA, rheumatoid arthritis. 1. Kelly JC. Medscape news, 2015. 2. Harrold LR, et al. Arthritis Rheum. 2012;64(suppl 3):630-638. 3. Tymms K, et al. Arthritis Care Res. 2014;66(suppl 2):190-196. 4. Montag K, et al. Intern Med J. 2011;41(suppl 6):450-455. Slide credit: clinicaloptions.com

Treat-to-Target RA Algorithm Main Target Adapt therapy according to disease activity Adapt therapy if state is lost Remission Sustained remission Active RA Use a composite measure of disease activity every 1-3 mos Assess disease activity about every 3-6 mos Low disease activity RA, rheumatoid arthritis. Sustained low disease activity Adapt therapy according to disease activity Adapt therapy if state is lost Alternative Target Reproduced from Ann Rheum Dis, Smolen JS, et al., 69:631-637, 2010 with permission from BMJ Publishing Group Slide credit: clinicaloptions.com

Tight Control of Rheumatoid Arthritis (TICORA) RA pts with < 2 yrs of disease activity randomized into 2 treatment groups: Routine care Intensive care: monthly clinic visits coupled with additional treatments based on DAS28 score Routine care Intensive care 6 DAS28 5 4 3 2 1 DAS28, Disease Activity Score 28; RA, rheumatoid arthritis. 3 6 9 12 15 18 Mos Slide credit: clinicaloptions.com Grigor C, et al. Lancet. 2004;364(suppl 9430):263-269.

Real-World Outcomes When Rheumatologists Consistently Measure Mean CDAI at final evaluation > 10 P = .0001 Initial proportion of pts in each CDAI state Final proportion of pts in each CDAI state 45 P = .0001 42% 40 39% 35% 35 32% 30 P = .0001 25 Pts (%) 20 19% P = .0001 15 14% CDAI, Clinical Disease Activity Index. 12% 10 7% 5 High (> 22) Moderate (10.1-22) Low (2.9-10) Remission (≤ 2.8) CDAI Slide credit: clinicaloptions.com Craig G, et al. ACR 2013. Abstract 2300.

Evidence for How Long to Wait to Determine Inadequate Clinical Responses 3 mos is generally sufficient in most cases based on available data[1,2] Approximately 15% to 20% of pts may need longer than 3 mos to reap the near-maximal benefit of TNF inhibitor therapy[3,4] Follow-up intervals should vary based on the needs of the pt and the physician’s experience TNF, tumor necrosis factor. 1. Smolen JS, et al. Ann Rheum Dis. 2014;73(suppl 3):492-509. 2. Gaujoux-Viala C, et al. Joint Bone Spine. 2014;81(suppl 4):287-297. 3. Curtis JR, et al. Arthritis Care Res. 2012;64(suppl 5):658-667. 4. Kavanaugh A, et al. Ann Rheum Dis. 2008;67(suppl 10):1444-1447. Slide credit: clinicaloptions.com

Addressing Comorbidities/ High-Risk Conditions

ACR Guideline: Specific Populations High-Risk Condition Recommendation(s) Evidence Type Congestive heart failure, including worsening on current TNF inhibitor Use combination DMARDs, non-TNF biologic, or tofacitinib over new or additional TNF inhibitor Very low/ moderate Conditional Hepatitis B, receiving/received ARVs Same recommendations as in pts without hepatitis B Very low Strong Hepatitis C, receiving/received ARVs Same recommendations as in pts without hepatitis C Hepatitis C, not receiving/requiring ARVs Use DMARDs over TNF inhibitor ARV, antiretroviral; DMARD, disease-modifying antirheumatic drug; TNF, tumor necrosis factor. Singh JA, et al. Arthritis Rheumatol. 2016;68(suppl 1):1-26. Singh JA, et al. Arthritis Care Res. 2016;68(suppl 1):1-25. Slide credit: clinicaloptions.com

ACR Guideline: Specific Populations High-Risk Condition Recommendation(s) Evidence Type Treated/untreated skin cancer Use DMARDs over biologics or tofacitinib Very low Conditional Treated lymphoproliferative disorder Use rituximab over TNF inhibitor Use combination DMARDs, abatacept, or tocilizumab over TNF inhibitor Strong Treated solid organ malignancy Same recommendations as in pts without this malignancy Previous serious infection Use combination DMARDs or abatacept over TNF inhibitor ACR, American College of Rheumatology; DMARD, disease-modifying antirheumatic drug; TNF, tumor necrosis factor. Singh JA, et al. Arthritis Rheumatol. 2016;68(suppl 1):1-26. Singh JA, et al. Arthritis Care Res. 2016;68(suppl 1):1-25. Slide credit: clinicaloptions.com

Take-Home Lessons 2015 ACR guideline designed to provide practical advice In early RA, implement a treat-to-target strategy Re-evaluate regularly, adjust according to disease activity measurements, and recognize treatment failure Each pt may have individual needs Personalize therapy by addressing comorbidities/high- risk conditions ACR, American College of Rheumatology; RA, rheumatoid arthritis. Slide credit: clinicaloptions.com

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