1. 2016 Annual Scientific Meeting JIA: INACTIVE DISEASE WORKGROUP APRIL 16, 2016 1

2. Goals for today’s session To discuss how CARRA can study: different strategies for reducing, tapering, or stopping systemic medications for inactive JIA factors associated with clinical outcomes after reducing, tapering, or stopping systemic medications for inactive JIA 2

3. Agenda Introduction (9-9:30am) Breakout groups (9:35-10:35am) Break Group presentations and discussion (10:50am- 12pm) 3

4. JIA Inactive Disease Relevant Studies Melissa Mannion 4

5. Brief review Definition of inactive disease Relevant studies on stopping meds ◦Methotrexate trial ◦Observational studies ◦Imaging ◦Biomarkers 5

6. Inactive Disease: Provisional Criteria ◦No joints with active arthritis ◦No fever, rash, serositis, splenomegaly, or generalized lymphadenopathy attributable to JIA ◦No active uveitis (SUN criteria) ◦Physician’s global assessment of disease activity score equals the best possible score ◦ESR or CRP normal (if both tested, both must be normal); if elevated, not attributable to JIA ◦Duration of morning stiffness ≤15 minutes 6 Wallace, Arthritis Care Res 2011.

7. Methotrexate trial Study population: multicenter, 364 with JIA inactive disease ≥3 months on MTX Strategies to stop drugs: MTX for 6 more months vs. 12 more months Main study results: ◦no difference in relapse between groups ◦higher MRP8/14 levels associated with flares 7 Foell, JAMA 2010.

8. Observational studies (1) Study population: single center, 171 with JIA on TNFi; 136 stopped when inactive Strategies to stop drugs: TNFi stopped w/o taper, MTX continued Main study results: ◦50% relapse by 6 mo, 68% by 12 mo ◦relapse not associated with age, sex, JIA category, duration TNFi treatment, duration inactive disease 8 Baszis, Arthritis Rheum 2011.

9. Observational studies (2) Study population: single center, 335 with poly JIA or ERA, 74 on MTX+TNFi Strategies to stop drugs: if on combo, stop MTX first vs. stop TNFi first Main study results: ◦after stopping meds, 63% flared within 1y ◦of those, 63% with flare achieved new inactivity (16% within 6mo), 73% on same regimen ◦flare off meds not associated with JIA category, joint count, taper vs. stop, time of inactive disease 9 Chang, Arthritis Care Res 2015.

10. 10 Study limitations: ◦retrospective ◦small sample ◦only poly/ERA ◦confounding ◦JIA type ◦JIA severity Chang, Arthritis Care Res 2015.

11. Observational studies (3) Study populations: mostly single center, <40 pts, inactive JIA on biologics Strategies to stop drugs: reduce dose, increase interval, and/or stop Main study results: ◦off meds ~1/3 flare within 6m, ~2/3 flare within 1y ◦flare not associated with age, sex, JIA category, duration JIA, duration drug, duration inactivity (except Prince), taper vs. stop (except Prince) 11 Prince, Ann Rheum Dis 2009. Remesal, J Rheum 2010. Can, Rheumatol Int 2013. Postępski, Rheumatol Int 2013. Iglesias, Rheumatol Int 2014.

12. Imaging in clinical inactive disease/remission Subclinical inflammation seen: ◦by ultrasound: 15-56% patients ◦by MRI: 25-63% patients Can subclinical inflammation predict future activity or flare? ◦little evidence so far, mostly in abstract form 12 Rebollo-Polo, Arthritis Care Res 2011. Nielsen, Dan Med J 2013. Hemke, Eur Radiol 2014. Silva V, Rheumatol Int 2014. Colebatch-Bourn, Ann Rheum Dis 2015.

13. Biomarkers High serum S100 protein levels (MRP14/18, S100A12) have been associated with risk of flare, most strongly within 3 months Other potential biomarkers of (in)activity: ◦gene expression ◦epigenetic changes 13 Knowlton, Arthritis Rheum 2009. Foell, JAMA 2010. Ellis, Clin Epigenetics 2012. Gerss, Ann Rheum Dis 2012. Jiang, Arthritis Res Ther 2013. Anink, Arthritis Res Ther 2015.

14. Medication Reduction and Discontinuation in RA Sarah Ringold 14

15. Medication Reduction and Discontinuation in RA Objective ◦To provide a brief overview of studies in RA to stimulate discussion in the small groups. ◦Dr. Keystone will cover this area in more depth 15

16. Patients Diverse patient populations studied include: ◦Early versus late RA ◦Low disease activity (LDA) / remission ◦Disease state maintained for 3 – 12 months 16 Most studies of drug reduction/discontinuation in RA have not been limited to patients in remission.

17. Review of RA Activity Measures DAS = 0.54 x sqrt(53TJC) + 0.065(44SJC) + 0.33 x ln(ESR) + 0.0072 x PGH DAS28 = 0.56 x sqrt(28TJC) + 0.28 x sqrt(28SJC) + 0.36 x ln(ESR) + 0.014 x PGH + 0.96 SDAI = 28SJC + 28TJC + PGA + PhGA + CRP CDAI = 28SJC + 28TJC + PGA + PhGA 17

18. RA Remission ≠ JIA Inactive Disease 18 Ringold, Arthritis Care Res 2010.

19. Approaches Medications ◦Methotrexate, etanercept, adalimumab, abatacept Study Designs ◦RCT > Observational ◦Drug discontinuation ◦Decreased dose (etanercept) ◦Disease activity-targeted dose reduction ◦One incorporated dose reduction ◦Non-inferiority compared with usual care or full dose drugs 19

20. Outcomes Primary ◦∆ DAS ◦Sustained remission or low disease activity Secondary ◦Rate of flare ◦Functional outcomes ◦Radiographic progression Most studies with 6-12 months follow-up 20

21. Results Higher proportion of patients maintained on biologic (same dose OR decreased dose) had sustained remission or low disease activity. Medication discontinuation led to increase disease activity/flare in 34-83%. Factors associated with improved outcomes: ◦Lower disease activity ◦Earlier treatment ◦Male sex ◦ACPA negative 21

22. Summary Populations studied in RA have been diverse, often not limited to patients in remission. Remission in RA does not necessarily translate well to inactive disease or remission in JIA. Outcomes usually better with full or reduced drug doses rather than drug discontinuation. Some clinical factors have been described in connection with sustained remission. 22

23. CARRA Inactive Disease Survey Daniel Horton 23

24. Survey methods Objective: To assess attitudes and strategies used to taper and discontinue medications for children with JIA in clinical inactive disease ◦non-systemic JIA, assuming no history of uveitis, psoriasis, or inflammatory bowel disease ◦survey open to CARRA members for 4 weeks in November-December 2015 24

25. Survey completion Started survey: 138/405 (34%) Completed survey: 127/405 (31%) ◦121 (95%) reported taking clinical care of children with JIA 25

26. 26 Characteristics of survey respondentsTotal (%), N = 121 Role Attending Fellow NP 105 (87%) 13 (11%) 3 (2%) Years since training (excluding fellows) <5 years 5-9 years ≥10 years 26 (21%) 23 (19%) 59 (49%) Clinical expertise Pediatric only Pediatric and adult 105 (87%) 16 (13%) Clinical time as percentage of total ≥50% <50% 88 (73%) 33 (27%) JIA committee membership Yes No 61 (50%) 60 (50%)

27. Rating of top factors used to decide to stop meds 27 ItemN Median rank IQR Time spent in inactive disease10411, 3 Medication toxicity9231, 4 Patient/family preference6732, 5 History of JIA-related damage6232, 4 JIA category6032, 4 No. of meds needed to achieve inactive disease4542, 5 History of sacroiliitis or TMJ disease2943, 5 Total duration of disease2742, 5 Other1722, 3 Medication adherence1643.5, 5

28. Factors that made people reluctant to stop meds 28 What factor(s), if present, would make you reluctant or hesitant to taper/stop methotrexate or a biologic drug? % History of erosive joint disease 81 Asymptomatic joint(s) with abnormalities on imaging 72 Failure of multiple prior DMARDs/biologics 64 Presence of brief morning stiffness (< 15 minutes) 19 Intermittent joint pain with normal joint exam 11 History of prior flares upon drug discontinuation 4

29. Minimum time JIA should be inactive to taper/stop meds 29

30. Strategies used to reduce/taper/stop meds 30

31. Preferences on stopping combination drugs 31 If a patient has inactive disease on combination methotrexate/biologic therapy, which do you prefer to taper/stop first? % Methotrexate 63 Biologic 10 Depends 27

32. Preferences on stopping combination drugs 32 If a patient has inactive disease on combination methotrexate/biologic therapy, which do you prefer to taper/stop first? % Methotrexate 63 Biologic 10 Depends History of toxicity or intolerance Patient/family preference Relative impact on disease control Cost of or access to drug 27 10 5 2

33. Use of imaging to make decisions about tapering/stopping 33 Use of imaging (not including TMJ) % Often 9 Sometimes 36 Seldom 44 Never 12

34. Use of imaging to make decisions about tapering/stopping 34 Use of imaging (not including TMJ) % Often 9 Sometimes 36 Seldom 44 Never 12 Imaging studies used % MRI 72 Ultrasound 31 X-ray 23

35. Use of patient report to make decisions to taper/stop 35 Patient-reported outcomes% Any patient-reported outcome 25 Patient/parent global score 21 Patient pain score 15 Functional score (e.g., CHAQ) 12 Quality of life score (e.g., PRQL) 2

36. People are interested in studying this topic collaboratively 36 Interest in a future study% Prospective observational study 87 Clinical trial 81

37. Perspectives of patients and parents on stopping meds Melanie Kohlheim 37

38. Breakout groups 1. Study designs/target population 2. Reducing/tapering/stopping strategies 3. Outcomes 4. Role of imaging 38