1. The Evolving Diagnostic and Treatment Landscape of Axial Spondyloarthritis This program is supported by educational grants from AbbVie and Novartis Pharmaceuticals Corporation.

2. About These Slides  Please feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patients  When using our slides, please retain the source attribution:  These slides may not be published, posted online, or used in commercial presentations without permission. Please contact permissions@clinicaloptions.com for detailspermissions@clinicaloptions.com Slide credit: clinicaloptions.comclinicaloptions.com

3. Faculty and Disclosures Nigil Haroon, MD, PhD, DM Assistant Professor of Medicine and Rheumatology University of Toronto Clinician Scientist University Health Network Scientist Krembil Research Institute Toronto, Canada Nigil Haroon, MD, PhD, DM, has disclosed that he has received consulting fees from AbbVie, Amgen, Janssen, Novartis, and UCB.

4. Agenda  Diagnosis of axial spondyloarthritis (AxSpA) –Nonradiographic axial spondyloarthritis (nrAxSpA) vs AS  Screening for suspected AxSpA in pts with back pain  Treatment of AxSpA –Guideline recommendations –Use of NSAIDs and TNF inhibitors (TNFis) –Potential concerns for pts undergoing treatment  Beyond TNFis –Secukinumab and emerging agents –Management of pts with TNFi failure Slide credit: clinicaloptions.comclinicaloptions.com

5. Diagnosis of Axial Spondyloarthritis

6. Axial Spondyloarthritis  Form of chronic inflammatory arthritis of the axial skeleton  Characterized by chronic back pain  Subclassification includes –Nonradiographic axial spondyloarthritis –Ankylosing spondylitis  Prevalence estimates, US adults –Chronic low back pain: 19.4% –Axial spondyloarthritis: 1.0% to 1.4% –Ankylosing spondylitis: 0.52% to 0.55% Rudwaleit M, et al. Ann Rheum Dis 2009;68:777-783. Reveille JD, et al. Am J Med Sci. 2013;345:431-436. Slide credit: clinicaloptions.comclinicaloptions.com

7. Calin Inflammatory Back Pain Criteria  Controlled clinical history study (N = 138) –75 controls, 42 pts with AS, 21 pts with mechanical low back pain  Inflammatory back pain if 4/5 of the following criteria present (sensitivity 95%, specificity 85%) –Age at onset: younger than 40 yrs –Duration of back pain > 3 mos –Insidious onset –Morning stiffness –Improvement with exercise Calin A, et al. JAMA. 1977;237:2613-2614. Slide credit: clinicaloptions.comclinicaloptions.com

8. Modified New York Criteria for Ankylosing Spondylitis  Clinical criteria –Low back pain and stiffness for > 3 mos that improves with exercise but is not relieved by rest –Limitation of motion of the lumbar spine in both the sagittal and frontal planes –Limitation of chest expansion relative to normal values corrected for age and sex  Radiologic criterion –Sacroiliitis grade ≥ 2 bilaterally or grade 3/4 unilaterally  Ankylosing spondylitis if radiologic criterion is associated with at least 1 clinical criterion Van der Linden S, et al. Arthritis Rheum. 1984;27:361-368. Slide credit: clinicaloptions.comclinicaloptions.com

9. ASAS Classification Criteria for Axial Spondyloarthritis  Criteria evaluated in pts with back pain (N = 649) –Sensitivity (82.9%), specificity (84.4%) for AxSpA –Imaging alone: sensitivity (66.2%), specificity (97.3%) Rudwaleit M, et al. Ann Rheum Dis 2009;68:777-783. Slide credit: clinicaloptions.comclinicaloptions.com CharacteristicImaging ArmClinical Arm Back pain ≥ 3 mos Age at onset Younger than 45 yrs Sacroiliitis on imaging* YesNo HLA-B27 Negative/positivePositive SpA features † ≥ 1≥ 2 *Acute inflammation on MRI suggestive of sacroiliitis OR definite radiographic sacroiliitis per New York grading. † SpA features: IBP, arthritis, enthesitis, uveitis, dactylitis, psoriasis, Crohn’s/colitis, NSAID response, family history, HLA-B27 positive, elevated CRP.

10. Other Key Differences Between AS and nrAxSpA: Cohort Studies VariableAS vs nrAxSpA Age at onset Similar Sex AS: males more frequently afflicted (up to 3:1 vs females) nrAxSpA: similar rates; may be slightly more likely in females HLA-B27 positive Similar CRP Higher for pts with AS Pain scores Similar BASDAI Similar BASFI Higher for pts with AS BASMI Higher for pts with AS TNFi response Similar* *Similar TNFi response if CRP elevation or MRI positive. TNFi response in normal CRP, MRI-negative nrAxSpA similar to placebo. Baraliakos X, et al. RMD Open. 2015;1:e000053. Kiltz U, et al. Arthritis Care Res. 2012;64:1415-1422. Rudwaleit M, et al. Arthritis Rheum. 2009;60:717-727. Wallman JK, et al. Arthritis Res Ther. 2015;17:378. Callhoff J, et al. Ann Rhem Dis. 2015;74:1241-1248. Sieper J, et al. Ann Rheum Dis. 2013;72:815-822. Slide credit: clinicaloptions.comclinicaloptions.com

11. Progression From nrAxSpA to AS: Longitudinal Studies  0 to 2 yrs from nrAxSpA diagnosis: 8% to 12% progress to AS  2 to 9 yrs from nrAxSpA diagnosis: 16% to 52% progress to AS  Ranges represent data from multiple sources (N = 23 to 210) –Variable methodology and disease definitions were used in these studies –Most studies mixed axial and peripheral disease at baseline –No study used ASAS criteria for AxSpA Sampaio-Barros P, et al. J Rheumatol. 2010;37:1195-1199. Poddubnyy D, et al. Ann Rheum Dis. 2011;70:1369-1374. Schattenkirchner M, et al. Clin Rheumatol. 1987;6(suppl 2):83-86. Sany J, et al. Arthritis Rheum. 1980;23:258-259. Mau W, et al. J Rheumatol. 1988;15:1109-1114. Oostveen J, et al. J Rheumatol. 1999;26:1953-1958. Bennett A, et al. Arthritis Rheum. 2008;58:3413-3418. Slide credit: clinicaloptions.comclinicaloptions.com

12. 1. Huerta-Sil G, et al. Ann Rheum Dis. 2006;65:642-646. 2. Poddubnyy D, et al. Ann Rheum Dis. 2011;70:1369-1374. 3. Bennett A, et al. Arthritis Rheum. 2008;58:3413-3418. 4. Sampaio-Barros P, et al. J Rheumatol. 2010;37:1195-1199. 5. Machado P, et al. Arthritis Rheum. 2011;63(suppl 10):1650. 6. Poddubnyy D, et al. ACR 2011. Abstract 0777. Factors Associated With Progression to AS  Baseline low-grade x-ray sacroiliitis [1,2]  Baseline MRI inflammation [3]  Elevated CRP [2]  Additional potential factors –HLA-B27 positivity inconsistent between studies [2,3] –Male sex predictive for nrAxSpA but protective for AS [2] –Buttock pain [4] –Smoking [5,6] Slide credit: clinicaloptions.comclinicaloptions.com

13. Screening for Axial Spondyloarthritis in Pts With Back Pain

14. Typical Course of Back Pain in AxSpA  Pts with AxSpA often diagnosed late in disease course  Chronic back pain frequent in the general population but only ~ 5% with chronic back pain have AxSpA  Strategies needed for earlier recognition of possible AxSpA and referral to specialty care  Studies have focused on referrals for younger pts with IBP or HLA-B27 positivity or a combination of risk factors –33% to 45% of those referred were subsequently diagnosed with AxSpA Rudwaleit M, et al. Nat Rev Rheumatol. 2012;8:262-268. Slide credit: clinicaloptions.comclinicaloptions.com

15. Age at Onset and Time of AS Diagnosis  Study assessed disease timing in HLA-B27–positive pts with AS Van der Linden S, et al. Arthritis Rheum. 1984;27:241-249. Age at disease onset Age at diagnosis Males (n = 135) Females (n = 30) 100 80 60 40 20 0 010203040506070 Age in Yrs Pts (%) Slide credit: clinicaloptions.comclinicaloptions.com

16. Screening and Referral for Potential AxSpA  Pts with the following factors should be referred to a specialist for further assessment of potential AxSpA 1.Chronic back pain > 3 mos AND 2.Age of onset: younger than 45 yrs AND 3.Presence of inflammatory back pain (Calin/ASAS criteria) OR HLA-B27 positivity  Optional identifying factors –Suspected sacroliitis after imaging (radiography/CT, MRI, scintigraphy) Rudwaleit M, et al. Nat Rev Rheumatol. 2012;8:262-268. Slide credit: clinicaloptions.comclinicaloptions.com

17. Summary: Screening and Diagnosis  AxSpA (nrAxSpA and AS) affects young male and female pts in their most productive yrs and is often unrecognized for yrs  AxSpA occurs in pts younger than 45 yrs of age with back pain ≥ 3 mos –AS: late stage of the disease; sacroiliitis observable on imaging –nrAxSpA: early stage of the disease; no radiographic evidence of disease but IBP  Pts with nrAxSpA and AS have similar signs and symptoms –Disease severity as measured by BASDAI, pain levels, pt and physician global assessment of disease activity are similar –BASFI and BASMI are higher in AS pts vs nrAxSpA pts  Referral should be considered in the nonspecialist setting for younger pts with chronic inflammatory back pain and/or HLA-B27 positivity Slide credit: clinicaloptions.comclinicaloptions.com

18. Treatment of Axial Spondyloarthritis

19. ACR/SAA/SPARTAN Recommendations for Active AS Ward MM, et al. Arthritis Rheumatol. 2016;68:282-298. Slide credit: clinicaloptions.comclinicaloptions.com SettingRecommendationConsiderations First-line NSAIDs*  No preferred NSAID  Use continuously if active  Nonresponder: lack of response to ≥ 2 NSAIDs over 1 mo or incomplete response to ≥ 2 NSAIDs over 2 mos Physical therapy*  Active vs passive  Land-based vs aquatic Not recommended: systemic GCs  Consider if peripheral arthritis, pregnancy, or IBD flare Active AS despite NSAIDs TNFi*  No preferred agent  Recurrent iritis: IFX or ADA  IBD: TNFi monoclonal If TNFi contraindication: SAARD  Non-TNFi biologic not recommended If isolated sacroiliitis, peripheral arthritis, enthesitis: local GC Active AS despite TNFiAlternative TNFi † *Strongly recommended. † Conditionally recommended.

20. *In pts with complete set of radiographs (n = 150). NSAID Therapy in AS: Radiographic Progression  Open-label, randomized trial  AS pts treated with continuous or on-demand NSAIDs for 2 yrs (N = 215) –All pts initiated treatment with celecoxib (could switch NSAID if discontinued celecoxib) –Mean daily dose of celecoxib –Continuous-treatment group: 243 mg –On-demand group: 201 mg –Dose difference: 42 mg; P =.0001 Radiographic Progression After 2 Yrs* 2.0 1.5 1.0 0.5 0 1.5 0.4 P =.002 mSASSS (Mean Change) Continous NSAIDs On-demand NSAIDs Slide credit: clinicaloptions.comclinicaloptions.com Wanders A, et al. Arthritis Rheum. 2005;52:1756-1765.

21. ENRADAS: Effects of NSAIDs on Radiographic Progression in AS  Multicenter, randomized phase III trial  Primary endpoint: spinal radiographic progression (change in mSASSS)  Mean daily dose: continuous tx, 113 mg; on-demand tx, 66 mg Pts with AS, back pain ≥ 4/10 (N = 167) Continuous Diclofenac 150 mg/day (N = 85) On-Demand Diclofenac 75 mg/pill (N = 82) Treatment to 2 yrs or lost to follow-up Treatment to 2 yrs or lost to follow-up Stratified by time period between radiographic exam and trial inclusion. Sieper J, et al. Ann Rheum Dis. 2015. Slide credit: clinicaloptions.comclinicaloptions.com

22. Sieper J, et al. Ann Rheum Dis. 2015. 14 12 10 8 6 4 2 0 -2 -4 -6 -8 020406080100 Cumulative Probability (%) Change From Baseline in mSASSS Treatment Continuous NSAIDs On-demand NSAIDs Slide credit: clinicaloptions.comclinicaloptions.com ENRADAS: Radiographic Progression

23. NSAIDs for Treating AS: Conclusions  NSAIDs have no disease-modifying effect  NSAIDs should be used for symptom modification in AS  ACR/SAA/SPARTAN: conditionally recommend continuous NSAID treatment vs on-demand treatment for active AS  If pts are stable on TNFi, NSAID continuation is not warranted Slide credit: clinicaloptions.comclinicaloptions.com

24. TNFis: Response Rates for Treating AS 1. van der Heijde D, et al. Arthritis Rheum. 2005;52:582-591. 2. Davis J, et al. Ann Rheum Dis. 2005;64:1557-1562. 3. van der Heijde D, et al. Arthritis Rheum. 2006;54:2136-2146. 4. Inman RD, et al. Arthritis Rheum. 2008;58:3402-3412. 5. Landewé R, et al. Ann Rheum Dis. 2014;73:39-47. ASAS40 Response After 24 Wks* *Independent trials; no head-to-head comparisons between TNFis. † 50 mg Q4W. ‡ 400 mg Q4W. Placebo 100 80 60 40 20 0 ASAS40 Response (%) Placebo Etanercept [2] Infliximab [1] Adalimumab [3] Golimumab †[4] Certolizumab ‡[5] 47 12 45 14 39 13 44 15 49 18 Slide credit: clinicaloptions.comclinicaloptions.com

25.  Post hoc analysis of ASSERT and GO- RAISE trials –TNFi-naive pts with active AS despite NSAID or DMARD tx treated with TNFi or placebo (N = 635)  Objective: Create a model to select AS pts who would benefit from TNFi therapy Vastesaeger N, et al. Ann Rheum Dis. 2011;70:973-981. Predicting Response to TNFi Therapy Slide credit: clinicaloptions.comclinicaloptions.com 81% 5% Continue NSAID ± DMARD Add TNFi Therapy CRP > 2.0 CRP 0.6-2.0 CRP < 0.6 no yes no yes no yes no yes no yes no yes ≤40 >40 ≤40 >40 ≤40 >40 Enthesitis >6.5 4.5- 6.5 ≤4.5 >6.5 4.5- 6.5 ≤4.5 HLA-B27 neg. HLA-B27 pos. HLA-B27 neg. HLA-B27 pos. >6.5 4.5- 6.5 ≤4.5 >6.5 4.5- 6.5 ≤4.5 HLA-B27 neg. HLA-B27 pos. HLA-B27 neg. Enthesitis BASFI Age ≥ 40% 20% to 39% 10% to 20% < 10% BASDAI50 Response Rate

26. AdalimumabInfliximab Radiographic Progression: TNFi vs Historical Controls in Longitudinal Studies  2-yr mSASSS data from AS pts treated with TNFi in 24- wk, randomized, placebo-controlled trials with open-label extensions compared with that from historical control cohort with TNFi-naive pts (OASIS) 1. van der Heijde D, et al. Arthritis Rheum. 2008;58:1324-1331. 2. van der Heijde D, et al. Arthritis Rheum. 2008;58:3063-3070. 3. van der Heijde D, et al. Arthritis Res Ther. 2009;11:R127. *OASIS: historical AS control group with no TNFi therapy over 2 yrs. For all comparisons, P value = NS. 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0 EtanerceptOASIS* All OASIS* Meeting Study Entry Criteria OASIS* all OASIS* Meeting Study Entry Criteria 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0 OASIS* All OASIS* Meeting Study Entry Criteria 0.91 0.95 1.27 Etanercept [1] 0.9 1.0 1.2 Infliximab [2] 0.8 0.9 Adalimumab [3] mSASSS Change 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0 Slide credit: clinicaloptions.comclinicaloptions.com

27. Radiographic Progression With TNFi in Prospective Cohort Study  Analysis of spinal radiographic progression in AS pts in prospective cohort study (N = 334) –Pts had ≥ 2 sets of radiographs –Pts received standard treatment, including NSAIDs/TNFi  Baseline characteristics –76.7% male, 83.4% HLA-B27 positive –60% had received previous TNFi –Mean age: 40.7 yrs; age of onset: 24.2 yrs; disease duration: 16.4 yrs –Mean baseline mSASSS score: 9.6 ± 14.5 –Baseline BASDAI: TNFi naive, 3.61; prior TNFi treatment, 4.64 (P =.001)  Progressors (change of ≥ 1 mSASSS unit/yr): 30.5% Haroon N, et al. Arthritis Rheum. 2013;65:2645-2654. Slide credit: clinicaloptions.comclinicaloptions.com

28. Factors Associated With AS Progression  Regression analysis in all study pts (N = 334) Haroon N, et al. Arthritis Rheum. 2013;65:2645-2654. P Value Variable Odds Ratio (95% CI) Univariable Analysis Multivariable Analysis (All Variables) Baseline mSASSS1.07 (1.05-1.09)<.001 Baseline ESR, mm/hr1.02 (1.01-1.04)<.001.005 Baseline BASDAI1.10 (0.98-1.20).09.15 Smoking, no. of pack-yrs1.06 (1.02-1.09).002.03 Male vs female1.52 (0.78-2.97).22.25 Age of onset1.02 (0.99-1.05).07.02 Disease duration1.01 (0.99-1.03).26.08 HLA-B271.08 (0.54-2.17).82.58 TNFi use0.52 (0.30-0.88).02.03 NSAID index1.01 (0.99-1.01).15.71 Multivariable analysis (only variables significant in the unvariable analysis) Baseline mSASSS1.06 (1.04-1.08)--<.001 Baseline ESR, mm/hr1.02 (1.01-1.04)--.004 Baseline BASDAI1.10 (0.95-1.25)--.09 Smoking, no. of pack-yrs1.05 (1.01-1.09)--.009 Age of onset1.03 (0.99-1.06)--.07 TNFi use0.47 (0.24-0.94)--.03 Slide credit: clinicaloptions.comclinicaloptions.com

29. Slower Rate of Progression When TNFi Started Within 10 Yrs of Disease Onset Haroon N, et al. Arthritis Rheum. 2013;65:2645-2654. 60% 20% 14 12 10 8 6 4 2 0 020406080100 Rate of mSASSS Progression TNFi early* TNFi late † Cumulative Probability (%) Slide credit: clinicaloptions.comclinicaloptions.com *Treated within 10 yrs of symptom onset. † Treated > 10 yrs after symptom onset.

30. When do you assess treatment response after starting treatment with a TNFi? A.2 wks to 1 mo B.1-3 mos C.3-6 mos D.1-2 yrs

31. ACR/SAA/SPARTAN Recommendations for Use of Specific TNFi  For pts with active AS, no TNFi is recommended over another, EXCEPT when the pt has one of the following comorbidities –IBD: strongly recommend use of TNFi monoclonal antibodies (eg, infliximab, adalimumab) over etanercept –Recurrent iritis: conditionally recommend use of infliximab or adalimumab over etanercept Ward M, et al. Arthritis Rheum. 2016;68:282-298. Slide credit: clinicaloptions.comclinicaloptions.com

32. Managing Possible Safety Concerns in AS Pts Treated With TNFis AEConsiderations Infection (general)  TNFi tx carries increased risk of developing serious infections  Do not start TNFi if active infection; pts should be monitored closely during and after tx; tx should be stopped if serious infection develops TB  TNFi tx can cause reactivation of latent TB; pts should be evaluated for TB risk factors and tested for latent infection prior to initiating TNFi and periodically during tx  Consider anti-TB tx for pts with latent TB or TB risk factors prior to TNFi tx HBV  TNFi tx may increase risk of HBV reactivation in chronic carriers  Pts should be evaluated for HBV infection prior to TNFi tx and monitored during tx; treatment should be stopped if active HBV infection develops Malignancy  Lymphoma and other cancers reported for pts receiving TNFi  Assess risks/benefits for pts with history of malignancy Neurologic disorders  TNFi tx rarely associated with exacerbation or onset of CNS demyelinating disorders, including multiple sclerosis References in slidenotes. Slide credit: clinicaloptions.comclinicaloptions.com

33. Extra-Articular Manifestations Associated With AS  AS pts can experience extra-articular disease manifestations, including –Uveitis –IBD –Psoriasis –Cardiovascular issues  Recognition and referral to specialty care for these comorbidities is essential Elewaut D, et al. Rheumatology. 2009;48:1029-1035. El Maghraoui A. Eur J Intern Med. 2011;22:554-60. Zarco P, et al. Rheumatol Clin. 2015;11:83-89. Slide credit: clinicaloptions.comclinicaloptions.com

34. Beyond TNF Inhibitors

35. Beyond TNFi  New agents –Secukinumab  Emerging agents –Tofacitinib –Ustekinumab  Other options –Rituximab –Bisphosphonates –SI joint injections  TNFi failure Slide credit: clinicaloptions.comclinicaloptions.com

36. Secukinumab  Human monoclonal antibody to IL-17A  Recently FDA approved for the treatment of adult pts with active AS  Recommended dosing –With a loading dose: 150 mg at Wks 0, 1, 2, 3, and 4 and then every 4 wks –Without a loading dose: 150 mg every 4 wks  MEASURE 1 and 2: randomized, placebo-controlled phase III trials assessing efficacy and safety of secukinumab for treating AS Secukinumab [package insert]. January 2016. Baeten D, et al. N Engl J Med. 2015;373:2534-2548. Braun J, et al. ACR/ARHP 2015. Abstract 974. Slide credit: clinicaloptions.comclinicaloptions.com

37. Managing Possible Safety Concerns in AS Pts Treated With Secukinumab AEConsiderations Infection (general)  Treatment may increase risk of infections  Caution necessary when considering for pts with history of recurrent infection or chronic infection; tx should be stopped if serious infection develops TB  Pts should be evaluated for TB before tx; tx of latent TB should occur prior to secukinumab tx  Monitor pts for active TB during secukinumab tx IBD  Pts should be monitored for IBD; secukinumab may cause exacerbations of existing IBD and new onset IBD Secukinumab [package insert]. January 2016. Slide credit: clinicaloptions.comclinicaloptions.com

38. MEASURE 1 and 2: Secukinumab for Active AS  Randomized, double-blind, placebo-controlled phase III trials Baeten D, et al. N Engl J Med. 2015;373:2534-2548. Adult AS pts with active disease despite NSAIDs; TNFi naive or IR to 1 TNFi (MEASURE 1: N = 371; MEASURE 2: N = 219) Secukinumab 150 mg SC* (n = 125/72) Placebo SC (n = 122/74) Secukinumab 75 mg SC* (n = 124/73) Wk 16 Pts could continue to receive MTX, SSZ, prednisone, or NSAIDs during the trial. *MEASURE 1: both dosage groups received 10 mg/kg IV at baseline, Wk 2, and Wk 4, then SC dosing every 4 wks starting at Wk 8. MEASURE 2: SC dosing occurred at baseline and Wks 1-4, then every 4 wks. Slide credit: clinicaloptions.comclinicaloptions.com

39. Outcome, Wk 16 MEASURE 1MEASURE 2 SECU 150 mg (n = 125) SECU 75 mg (n = 124) PBO (n = 122) SECU 150 mg (n = 72) SECU 75 mg (n = 73) PBO (n = 74) ASAS20, %*61 † 60 † 2961 † 4128 ASAS40, %42 † 33 † 1336 † 2611 BASDAI score, mean ∆ from BL -2.32 † -2.34 † -0.59-2.19 † -1.92-0.85 D/c for AE, %1‡1‡ 45§5§ 5 Serious AE, %2‡2‡ 46§6§ 4 Infection/infestation, %30 ‡ 1232 § 27 Candida infection, %< 1 ‡ 0< 1 § 0 Crohn’s disease, %< 1 ‡ 0< 1 § 0 Major cardiac event, %0‡0‡ 0< 1 § 0 Grade 3/4 neutropenia, %0‡0‡ 00§0§ 0 MEASURE 1 and 2: Key Findings Baeten D, et al. N Engl J Med. 2015;373:2534-2548. *Primary endpoint. † P <.001 vs placebo. ‡ Pooled data (n = 249). § Pooled data (n = 145). Slide credit: clinicaloptions.comclinicaloptions.com

40. Tofacitinib for Biologic-Naive AS Pts  Tofacitinib: oral JAK inhibitor  Phase II trial: biologic-naive adult AS pts with IR or intolerance to NSAIDs randomized to tofacitinib 2, 5, 10 mg BID or placebo (N = 208) van der Heijde D, et al. ACR/ARHP 2015. Abstract 5L. Wk 12, % Tofacitinib 2 mg (n = 52) Tofacitinib 5 mg (n = 52) Tofacitinib 10 mg (n = 52) Placebo (n = 51) ASAS20 response (E max model)*56.063.067.440.1  Difference vs placebo (95% CI) 15.8 (5.0-30.3) 22.9 (8.4-37.7) 27.3 (10.7-43.4) -- ASAS20 (observed)51.980.8 † 55.841.2 BASDAI5046.2 ‡ 42.3 ‡ 23.5 D/c for AE01.9 5.9 TEAEs44.253.851.943.1 Serious AEs01.9 3.9 *Primary endpoint. † P <.001 vs placebo. ‡ P <.05 vs placebo. Slide credit: clinicaloptions.comclinicaloptions.com

41. TOPAS: Ustekinumab for Active AS  Ustekinumab: IL-12/23 inhibitor (SC)  Phase II trial: pts with active AS and IR or intolerance to NSAIDs treated with ustekinumab 90 mg SC at BL, Wk 4, and Wk 16 (N = 20) van der Heijde D, et al. ACR/ARHP 2015. Abstract 5L. OutcomeWk 24, % AEs95 Serious AEs5 100 80 60 40 20 0 75 65 55 ASAS20ASAS40BASDAI50 Pts (%) Slide credit: clinicaloptions.comclinicaloptions.com

42. 100 Song I, et al. Arthritis Rheum. 2010;62:1290-1297. Rituximab for Active AS  Rituximab: targets CD20+ B cells  Open-label phase II trial in which pts with active AS were treated with rituximab 1000 mg at BL and Wk 2 (N = 20) 80 60 40 20 0 Wk 24 Responders (%) TNFi Naive (n = 10) TNFi Failures (n = 10) ASAS20 ASAS40 BASDAI50 Slide credit: clinicaloptions.comclinicaloptions.com

43. Treating AS in Pts With TNFi Failure  Lack of evidence supporting treatment approaches for these pts  ACR/SAA/SPARTAN recommendations [1] –Treat with a different TNFi over adding a SAARD treating with a non-TNFi biologic –Recommendation based on “very low-quality evidence”  Secukinumab may be an option Slide credit: clinicaloptions.comclinicaloptions.com 1. Ward M, et al. Arthritis Rheum. 2016;68:282-298.

44. Summary: Treatment  Treatment for active AS typically begins with NSAIDs  Pts with active disease despite NSAIDs may receive TNFi or secukinumab –If pt is stable on TNFi, NSAIDs not warranted  TNFi most effective if started < 10 yrs of disease onset, making early diagnosis essential  Pts receiving TNFi should be monitored for general infection, TB, HBV, malignancy, and neurologic disorders; pts receiving secukinumab should be monitored for general infection, TB, and IBD  Investigational agents tofacitinib and ustekinumab show promise in clinical trials for treating active AS Slide credit: clinicaloptions.comclinicaloptions.com

45. Go Online for More CCO Coverage of Axial Spondyloarthritis! Interactive Virtual Presentation featuring streaming narration of these slides and case studies illustrating essential considerations for diagnosing and treating pts with axial spondyloarthritis ClinicalThought™ expert faculty commentaries on key considerations in axial spondyloarthritis management clinicaloptions.com/immunology