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When Should We Stop Anti-TNF Therapy and How Do We Then Treat the Patient?

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.

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When Should We Stop Anti-TNF Therapy and How Do We Then Treat the Patient?

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

  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 • GuillainBarre • 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 Ther2013;38:388–96 Seror R, et al. Rheum2013;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

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

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

  10. 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

  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 < 6x109/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)

  15. 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

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

  17. 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

  18. 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 ileocolonoscopyand Bx • Deep remission • No clinical symptoms AND • No endoscopic activity • SES-CD = 0-2 • Mayo endosubscore 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

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

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

  21. 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

  22. Trough Levels and Antidrug Antibodies Predict Safety and Success of Restarting Infliximab After a Long Drug HolidayBaert 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.

  23. 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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