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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): 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: % 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: 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 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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