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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.

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Presentation on theme: "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."— Presentation transcript:

1 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

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

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

4 WHEN IT IS WORKING BUT ASSOCIATED WITH TOXICITY When Do We Stop Anti-TNF Therapy?

5 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 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 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

6 WHEN IT IS STILL WORKING When Do We Stop Anti-TNF Therapy?

7 Why Stop? Significant cost Side effect profile

8 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

9 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 Waugh AWG, et al, Aliment Pharmacol Ther 2010;32:1129-34 50% relapse at 15 months 35% long term remission

10 115 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 Louis E, et al. Gastroenterology 2012;142:63-70 Risk of Relapse Upon Stopping Anti-TNFα Therapy and Continuing IM 39% relapse by 1 yr ~50% by 2 yrs

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

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

13 Predicting the Likelihood of Relapse after Discontinuing Anti-TNF Therapy WBC < 6x10 9 /L hsCRP < 5 mg/L Calprotectin <300 µg/g Hemoglobin >145 g/dl Louis et al. Gastroenterology 2012;142:63

14 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)

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16 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

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

18 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

19 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

20 When should we stop anti-TNF therapy? Continue Anti-TNF Active disease – Clinical – Biologic ↑CRP, ↑calprotectin No mucosal healing Recent dose escalation Short duration remission Ongoing growth impairment, delayed puberty 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

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

22 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

23 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.

24 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


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