1. Can Rheumatoid Arthritis treatment ever be stopped? Robert L. DiGiovanni, DO, FACOI Program Director Largo Medical Center Rheumatology Fellowship robdsimc@tampabay.rr.com

2. I have no financial relationship in regard to the content of this presentaion.

3. “Do not pour strange medicines into your patients.” Sir William Osler

7. New treatment paradigm Recognize RA as a heterogenous group of diseases. Identify patients with aggressive disease. Early window of opportunity to achieve remission Use best therapies up front. MTX as anchor. Treat to a pre-identified target (DAS28 < 2.6). Maintain tight control of the disease. Can treatment be stopped at any point? Can remission be maintained with fewer Rx?

8. Traditional DMARDS Methotrexate Hydroxychloroquine Sulfasalazine Azathioprine Gold Salts D-penicillamine

9. Can the traditional synthetic DMARDs induce sustained remission? Six RCT of RA patients on DMARD monotherapy published prior to 2000 were reviewed by Scott, et. al. in Clin. Exp. Rheumatology in a 2013 supplement. Total 501 patients deemed under good control evaluated Flares occurred in 43/248 (17%) of patients who continued DMARDS vs. 117/253 (46%) of patients who discontinued DMARDS. Risk of flare 3x greater in those that stopped DMARDs Restarting DMARDs was usually successful.

10. Step down therapy Scott further evaluated 4 RCT of step down combination therapy compared to monotherapy COBRA: early RA patients; group I aggressive treatment with high dose prednisilone tapered over 28 weeks + MTX 7.5mg for 40 weeks and sulfasalazine as the anchor Rx. Group II was sulfasalazine monotherapy. Aggressive group had superior clinical and radiographic response that was maintained.

11. Step down therapy (continued) BeSt (Behandel Strategieen) study: 508 patients in four treatment groups with early RA One group was DMARD monotherapy, next was a Step-up protocol, next was a step-down based on COBRA and last was a MTX + infliximab group. The last two groups did the best as one might predict When patients achieved DAS remission, DMARDS were tapered and stopped and patients followed for 5 years

12. Step Down therapy (continued) 23% of patients had drug free remission during the five year period of study observation Subsequently, 46% of these had to go back on a DMARD The results were similar across all the four initial treatment groups. Hence, this data suggests that DMARD-free remission is rare. The best predictors of disease reactivation in Scott’s review were IgM-RF and ACPA-positivity

13. Further data from BeSt Groups 1,2,3 were allowed to go on infliximab later on if they failed 77/120 (64%) of the initial infliximab group (4) were able to stop infliximab compared to only 27/109 (25%) of the delayed infliximab start (groups 1-3) After D/C infliximab, 59% of groups 1-3 and 44% of group 4 suffered a flare with DAS>2.4 and had to restart infliximab. Median time off infliximab was 17 months (range 3-47 months)!

14. Further BeSt data (continued) Restarting Infliximab resulted in DAS28 < 2.4 in all patients and no radiographic progression. Therefore, inflixamab discontinuation was possible in 1 in 4 patients following 6 months of LDA. If MTX is continued, 50% could permanently stop infliximab. Hmmmmmmm!

15. Biologicals TNF target: etanercept, adalimumab, infliximab, certulizumab pegol, golimumab Co-stimulatory inhibitor: abatacept Interleukin-6 target: tocalizumab B-cell depletion: rituximab Jak inhibitor: tofacitanib Interleukin-17 target: on its way

16. Biologicals Revolutionized the treatment of Rheumatoid Arthritis Often used in combination with methotrexate Can we use a cancer chemotherapy model of “induction” followed by maintenance with fewer medication? Then re- treat if disease activity flares? Problem: inflammatory disease is due to “dysregulation” of the immune system. Can the biologicals “re-boot” the immune system to a more normal status?

17. Studies OPTIMA: Optimal Protocol for Treatment Initiation with Methotrexate and Adalimumab ORION: Orencia Remission Induction and Outcome Navigation DREAM: Drug-free REmission/low disease activity after cessation of tocilizumab (Actemra) Monotherapy IDEA: Infliximab as in-Duction therapy in Early rheumatoid Arthritis

18. Studies (continued) HIT HARD: High Induction THerapy with Anti- Rheumatic Drugs PRESERVE: Maintain low disease activity (LDA) with reduced doses or withdrawal of entanercept in patients with moderately active RA despite MTX. CERTAIN, PRIZE, HONOR, RRR, TNF-20

19. PRESERVE 604 patients with moderate RA disease activity while taking MTX (MTX-IR) All received etanercept 50mg/week in an open phase for 9 months More than 80% achieved LDA with DAS28 < 2.6 They were maintained on therapy for 6 months further If they maintained LDA (DAS28 < 3.2), they were further randomized in a double-blinded fashion.

20. PRESERVE (continued) Three groups: MTX + full dose etanercept, MTX + reduced etanercept (25mg), MTX + placebo One year later: 57% of MTX monotherapy lost their LDA state compared to 18% on full dose etanercept and 21% on the half dose of etanercept Progression of joint damage did not occur on either etanercept dose. Some of the MTX monotherapy patients had progression of joint damage radiographically.

21. PRESERVE (continued) Thus, in patients with established RA, withdrawal of an anti-TNF agent following good control usually led to disease flare However, 90% of the reduced dose patients maintained LDA status Results are essentially confirmed by the CERTAIN (certolizumab pegol) study wherein patients with established RA (MTX-IR) flared with withdrawal of the biological

22. OPTIMA Early RA patients (mean duration of disease 3.9 months) MTX-naïve Over 1,000 patients randomized to MTX + adalimumab vs. MTX + placebo Former group had better outcomes in terms of DAS, structural damage, etc. Of the 466 patients with stable LDA at 24 weeks on MTX + adalimumab, 207 were randomized to MTX + continued adalimumab vs. MTX + placebo

23. OPTIMA (continued) At week 78, 86% of the combination group and 66% of the MTX/placebo group maintained DAS28 remission. (<2.6) LDA was maintained in 91% of the combination group and 81% of the MTX monotherapy group (adalimumab-free) Work productivity was better in the group that continued on adalimumab Similar results in the German study of MTX-naïve early RA (mean 1.7 months) with MTX + adalimumab HIT HARD

24. Some differences between PRESERVE and OPTIMA Early RA vs. established RA MTX-IR vs. MTX-naïve MOA of the anti-TNF medication: Soluble TNF-receptor vs. Monoclonal Antibody Can the monoclonal antibody “re-boot” the regulation of the immune response in the MTX-naïve early RA patient? It appears to be the case in a subset of patients.

25. DREAM STUDY Patients on tocilizumab monotherapy for a mean of 4 yrs who met DAS28 remission criteria (previous MTX-IR) at the time the biological was discontinued LDA maintained without DMARDS was 35% at 24 weeks and 13.4% at 52 weeks Remission (DAS28 criteria) without DMARDS was 9.1% at 52 weeks Comparable to the anti-TNF meds for true drug-free remission

26. Official Recommendations EULAR: (2012) After remission has been maintained for 12 months, gradual dosage reduction of the biological should be attempted (van den Broek, et al) ACR: No official recommendations on withdrawal of biologicals

27. Possible strategy for a “Drug Holiday” Early aggressive treatment with MTX + biological to a target (DAS28) LDA/remission for 6 months; consider tapering dose of the biological. (Tanaka, et. al.) Patient should be brought into this decision. I say remission not LDA. Once biological stopped, continue to monitor for disease activity and radiographic joint progression Resume biological as soon as it appears RA is relapsing

28. Personal practice experience over 30 years In the case of RA, the disease is far worse than the treatment. The consequences of unchecked systemic inflammtion include structural damage, disability, extra-articular organ involvement (e.g., pulmonary, ASHD, SAA amyloid) Select carefully patients you believe can retain LDA off biologics but follow them very closely for increase in DAS28 or radiographic/ultrasound progression. Low disease activity is, after all, still smoldering disease activity. Don’t hesitate to resume biologics if need be. We have never had better treatments for RA as we do now.

29. “The desire to take medicine is perhaps the greatest feature which distinguishes man from animals.” Sir William Olser

30. “One of the first duties of the physician is to train the masses not to take medicine” Sir William Osler

31. References Tanaka et al, Discontinuation of biologics in patients with rheumatoid arthritis, Clin Exp Rheumatol. 2013, 31 supp 78 Kavanaugh et al, The when and how of biologic agent withdrawal in rheumatoid arthritis, Clin Exp Rheumatol. 2013, 31 supp 78 Yoshida et al, Use of data from multiple registries in studying biologic discontinuation, Clin Exp Rheumatol. 2013, 31 supp 78 Pincus, et al, Possible discontinuation of therapies in inflammatory rheumatic diseases. Scott, et al, Can we discontinue synthetic disease-modifying anti- rheumatic drugs in rheumatoid arthritis? Clin Exp Rheumotol. 2013, 31 supp 78 American College of Rheumatology: Image bank

32. Accordion players squeeze better