When Should We Stop Anti-TNF Therapy and How Do We Then Treat the Patient? James Markowitz, MD Professor of Pediatrics Hofstra North Shore – LIJ School of Medicine Division of Pediatric Gastroenterology Cohen Children’s Medical Center of NY New Hyde Park, NY

Disclosures Janssen Pharmaceuticals – Consultant Abbvie – Consultant UCB – Consultant Soligenix – Consultant

When Do We Stop Anti-TNF Therapy? When it stops working When it is working but associated with toxicity When it is still working

When it is working but associated with toxicity When Do We Stop Anti-TNF Therapy? When it is working but associated with toxicity

Toxicities Requiring Discontinuation of Anti-TNF Rx (Probable Class Effect) Severe psoriasis Autoimmune disease Autoimmune hepatitis Agranulocytosis ?Opportunistic infection Histoplasmosis Coccidiomycosis Blastomycosis Lymphoma Demyelinating disease Multiple sclerosis Chronic inflammatory demyelinating polyneuropathy Guillain Barre Interstitial pneumonitis Cassaday RD, et al. Clin Lymphoma Myeloma Leuk. 2011;11:289–292 Flynn AD, et al. IBD 2013;19(5):E69-70 Deepak P, et al. Aliment Pharm Ther 2013;38:388–96 Seror R, et al. Rheum 2013; 52(5): 868-74 Villeneuve E, et al. J Rheum 2006;33(6):1-5 Sherlock ME, et al. JPGN 2013;56: 512–518 Doyle A, et al. J Crohn's Colitis 2011;5:253–5 Sebastian S, et al. J Crohn's Colitis 2012;6:713–6 Ordonez ME, et al. IBD 2013;19:2490–2500

When it is still working When Do We Stop Anti-TNF Therapy? When it is still working

Why Stop? Significant cost Side effect profile

Do Patients Want to Stop? Before starting anti-TNF Rx, many express concern regarding possible long term effects In UK, National Institute for Health and Clinical Excellence (NICE) recommends use of anti-TNF until it fails, or for 12 months At 12 months, reassess for ongoing need of Rx 21 adults with CD on anti-TNF ≥12 months 8 (38%) agreed to reassessment: afraid of lymphoma, infections, demyelinating disease 13 (62%) refused: afraid of possible relapse, lost wages, possible need for surgery if disease relapsed Blackmore L, Harris A. Clin Med 2012;12(3):235-8

High Rate of Relapse Following Infliximab Withdrawal 48 adults on maintenance IFX CS free clinical remission 67% on AZA/6MP/MTX Median # infusions: 8 (2-51) Median duration IFX: 15.6 mos (1-67.3) No clinical predictors for long term remission identified 50% relapse at 15 months 35% long term remission Waugh AWG, et al, Aliment Pharmacol Ther 2010;32:1129-34

Risk of Relapse Upon Stopping Anti-TNFα Therapy and Continuing IM 115 GETAID patients with luminal disease ≥ 1 yr of anti-TNF + IM Stable CS free remission for at least 6 months IM maintained throughout observation period (median 28 months) Median disease duration at withdrawal of IFX = 7.8 yrs 39% relapse by 1 yr ~50% by 2 yrs Louis E, et al. Gastroenterology 2012;142:63-70

Factors Associated With Relapse Louis et al. Gastroenterology 2012;142:63

Increasing Number of Risk Factors are Associated with Greater Likelihood of Relapse Louis et al. Gastroenterology 2012;142:63

Predicting the Likelihood of Relapse after Discontinuing Anti-TNF Therapy WBC < 6x109/L hsCRP < 5 mg/L Calprotectin <300 µg/g Hemoglobin >145 g/dl Louis et al. Gastroenterology 2012;142:63

In Hungary, anti-TNF must be stopped after 1 yr of Rx Can be restarted for relapse 121 CD adults discontinued anti-TNF 87 IFX, 34 ADA 85% concomitant 6MP/AZA 45% resume anti-TNF by 1 yr Median time to resumption: 6 months (IQR: 3.75-12 mos)

EPACT-II Update Objective: To rate the appropriateness of stopping anti-TNF therapy in CD patients in remission Methods: RAND/UCLA Appropriateness Method Withdrawing anti-TNF monotherapy: After 2 yrs of clinical and endoscopic remission After 4 yrs of clinical remission Withdrawing anti-TNF from combo Rx: After 2 yrs of clinical remission Pittet V, et al. J Crohns Colitis 2013;7:820-6

“If It Ain’t Broke, Don’t Fix It” Clarke K, Reguerio M. IBD 2012;18:174-9

When should we stop anti-TNF therapy? OK to Consider Stopping Anti-TNF Deep remission Clinical Biologic No recent need for dose escalation ?Low/absent trough levels Longer duration of remission (2-4 yrs ??) Normal growth; Tanner IV-V Willing to consider alternative maintenance Rx

How Common is a Deep Remission in Patients Treated with anti-TNF Rx? 252 pts with IBD (Finland) 183 CD, 62 UC, 7 IBD-U 177 IFX, 75 ADA Minimum duration 11 mos Concomitant IM CD 69%, UC 82%, IBD-U 86% Reassessed clinically and with ileocolonoscopy and Bx Deep remission No clinical symptoms AND No endoscopic activity SES-CD = 0-2 Mayo endo subscore 0-1 Results 168 (67%) clinical remission 64% CD, 75% UC 122 (48%) deep remission 43% CD, 62% UC 99/122 (81%) also with histologically inactive Molander P, et al. J Crohn's Colitis 2013;7:730–735

When should we stop anti-TNF therapy? OK to Consider Stopping Anti-TNF Continue Anti-TNF Deep remission Clinical Biologic No recent need for dose escalation ?Low/absent trough levels Longer duration of remission (2-4 yrs ??) Normal growth; Tanner IV-V Willing to consider alternative maintenance Rx Active disease Clinical Biologic ↑CRP, ↑calprotectin No mucosal healing Recent dose escalation Short duration remission Ongoing growth impairment, delayed puberty

How do we treat after stopping anti-TNF Rx? To maintain remission Immune modifiers 6MP, Azathioprine, Methotrexate Enteral feeds Nothing???

How do we treat after stopping anti-TNF Rx? If the patient relapses Restart anti-TNF Alternative biologic with a different mechanism of action IL-12/23 inhibitor Anti-adhesion molecule Rx

Trough Levels and Antidrug Antibodies Predict Safety and Success of Restarting Infliximab After a Long Drug Holiday Baert FJ, et al. DDW 2013, Abstract 492 128 patients in whom IFX had been stopped because of LOR, remission, pregnancy, or infusion reaction. Mean duration off IFX = 15 months. Bottom line: IFX successful re-start in 85% at week 14, 70% at year 1, 61% at last f/u. Infusion reaction in 25/128 (19.5%), 16/128 had to stop IFX. Predictors of course: Reason for stopping first course (remission better), concomitant IM at re-start (better), TL (higher better) and absence of ATI (better) were predictors of response and absence of infusion reaction.

How do we treat after stopping anti-TNF Rx? If the patient relapses Restart anti-TNF Alternative biologic with a different mechanism of action IL-12/23 inhibitor Anti-adhesion molecule Rx