Management of CD Biological Agents

1. APDW IBD-Working Party Crohns Disease Consensus Statements 2011 Management of CDBiological Agents Associate Professor Rupert WL Leong Director of Endoscopy, Concord Hospital University of New South Wales, Sydney Australia

2. Quality of Evidence • Major publication(s) • Cochrane/ systematic reviews • Current guidelines/ recommendations • BSG Guidelines 2004 • AGA Position Statement 2006 • ECCO Consensus 2 2010 • Asia-Pacific studies • Quality of evidence – mostly Western • assumption: similar efficacy • note pharmacogenomics egthiopurines • infectious diseases

3. Management Statement 12 Statement rationale: biological agents - indications

4. There are no data that internal fidtulae respond to biologis - these need surgical treatment • Numbering would help. • Surgery adjustment to anti-TNF "Too many substatements here too....may be we should vot for substetements example: ""Biologialagenst should be cosindiered: a. failure of 2nd line medical treatment b. presence of fistulizingdiesases (and a quailifyingstteemtn about fibritic strictures...not been responsive)

6. Maintenance of Remission

7. EIM Pyoderma gangrenosum 3 months Etanercept can precipitate uveitis Hewitt et al Austral J Derm 2007

9. Management Statement 12 The indications for anti-TNF biological agents include failure of conventional therapy in luminal disease [I-A], as well as fistulizing CD [I-A] and some extra-intestinal manifestations [II-3,B] of CD. to • conventional steroids • with or without immunomodulators • maintenance of remission • EIM • fistulas • strictures Perianal fistulizing CD in addition to appropriate surgical management. Text: Anti-TNF therapy may have limited efficacy in the treatment of internal fistulas. Fixed fibrotic strictures do not respond well to anti-TNF.

10. Management 13 Statement rationale: monotherapy or combined

11. I would not use the word synergism here. It implies a phaarmacologic interaction. Also, the benefits of combined treatment are only present for infliximab in very specific ircumstances. The COMMIT study showed no benefit from infliximab plus methotrexate • The statement of efficacy should be clarified completely, then state reversed event. • "substatements: (voting separately_ • Combined therapy with infliximab and azathioprine, is useful • Combined therapy is safe"

13. Median serum trough IFX IFX + AZA IFX + placebo

15. Immunomodulator Withdrawal • withdrawal of IM at 6 mth • maintenance infliximab q2mth Rescue anti-TNF Cease anti-TNF Van Assche Gastroenterol 2008

16. Azathioprine/ 6MP Withdrawal CRP: favours continuing immunomodulator infliximab trough level: favours continuing immunomodulator Van Assche Gastroenterol 2008

18. Hepatosplenic T Cell Lymphoma Mackey J Pediatr Gastroenterol Nutr 2007

19. Hepatosplenic T Cell Lymphoma Little data from Asia

20. Hepatosplenic T Cell Lymphoma • ?increased recognition following concern regarding anti-TNF causing lymphoma • ?anti-TNF reduces threshold of developing HSTCL with thiopurines & Crohn’s disease • ?independent to anti-TNF

21. MTX • no synergism with IFX (COMMIT) • CD active disease induced with steroids and IFX • 50 week steroid-free remission • IFX + placebo: 56% • IFX + MTX: 57% (ns) • abstract

22. Management 13 • infliximab and thiopurine • HSTCL Combined infliximab and thiopurine is more effective than either alone in thiopurine-naïve patients. [I-A] The risk-benefit balance including lymphoma-risk and opportunistic infections need to be considered. [II-3, B] MTX in text no data with ADA

23. Management 14 Statement rationale: dosing, other biologics

24. 80mg SC then 2 weekly thereafter. • 8-weekly? • "Should be 2 weekly therefore for Adalimumabs. • Certouzumis should be mentioned as well " • About adalimab, "then 8-weekly" is wrong. It should be corrected to "40mg sc bi-weekly". • Certoluzimab and natalizumab have been adopted by US FDA • Adalimumab need 2 weekly • Infiximab and adalimumab are the only 2 clically useful biological agents (doses given inthe paragraph belw as qualifying statements...not for voting!

25. Mod-severe Crohn’s disease % Infliximab (Remicade) Certolizumab (Cimzia) Adalimumab (Humira) Hanauer et alLancet 2002 Schreiber et al NEJM 2007 Colombel et al Gastroenterol 2007

26. Biologics • 4 commercially available: • infliximab (Remicade) • adalimumab (Humira) • certolizumab (Cimzia) – further phase 3 • natalizumab (Tysabri) – limited use • others under trial • vedolizumab • ustekinumab (Stelara) etc • small molecule: CCR9 receptor blocker

27. induction: • ineffective: etanercept, CDP571 • ?certolizumab

28. maintenance

29. Natalizumab vessel wall vascular cell adhesion molecule (VCAM) • leukocyte trafficking • blocks migration of lymphocytes to inflamed tissue • monotherapy • reactivation of JC virus in brain • monitor for neuroSx • 7 cases • plasma exchange lymphocyte alpha-4 integrin progressive multifocal leukoencephalopathy (PML) Adelman NEJM 2005, Yousry NEJM 2006

31. alpha-4-beta-7 integrin inhibitor (Vedolizumab) • monoclonal Ab • targets only a4b7 integrin: • GI tract-specific • ligand = MAdCAM (mucosal addressin cell adhesion molecule) – expressed on intestinal vascular endothelium • increased expression in inflamed gut

32. Management 14 • IFX • ADA • other biologics 2 Infliximab etc [I-A] Remove other biologics

33. Management 15 • Screening and treatment for active/ latent TB and any form of sepsis should be carried out prior to commencing anti-TNF treatment.

34. Tuberculin skin tests rather than IGRA may still be acceptable due to cost constraints • IGRA is not available in some countries like us • TB culture/PCR not done under to high supervision • "This shoud be the stetemtn.....""Active and latent tuberculosis and other infectious colitides must be excluded prior to treatment with anti-TNF therapy"" • Others as clarifying statements" • Should we say that when ever IGRA is not available, an alternative may be the mantoux test?

35. Tuberculosis TB reporting rate per 1,000 patients

36. Tuberculosis • PPD not helpful: BCG, immunosuppressed • individual risk assessment:

37. serious infections: • randomised studies: no increase in infections

39. Exposure history, examination • IGRA • CXR • mucosal biopsies: TB culture, PCR

40. Opportunistic Infections • Japan: RA date; n = 646 anti-TNF vs 498 on DMARDs

41. Revised Management 15 • Screening and treatment for active/ latent TB and any form of sepsis should be carried out prior to commencing anti-TNF treatment.[II-3,B]

42. Management 16 Statement rationale: HBV screening

43. Cost may be an issue in developing countries. Which vaccine souhld be carried out also not established. (the adult vaccine schedule is very extensive). Live vaccines (eg varicella) BEFORE treatment may not be feasible in patients requiring prompt treatment. • Prior to immunomoderator, stewia, and biologics. • Whether anti-viral prophylaxis with immunomodulator? • this is mainly for rheumatological diseases....makes sense to reccommend but I dont know the incidence of reactivation • Is there any evidence for screening for Hepatitis C although there is no vaccine or single effective anti-viral therapy?

44. alive alive died • HBV Screening subfulminant hepatitis Tx LAM Tx LAM Tx LAM died Tx LAM Tx LAM Tx LAM

45. HBV • majority HBsAg+patients • some HBsAg−, anti-HBcAb + • variable manifestations • TNF-α central mediator of anti-HBV responses • reactivation (increased viral loads with or without increased transaminases) • some fatal hepatitis

46. HBV Strategies • 1. monitor HBV, ALT: reactivation not in everyone • 2. prophylactic LAM/ anti-viral therapy: reactivation unpredictable and risk of death • prophylaxis for 3-6 mths after cessation of anti-TNF

47. HCV • TNF-α in HCV infection differ to HBV • serum TNF levels predict failure of interferon therapy • liver inflammation perpetuated • favourable short-term safety profile • longer term safety remains to be proven • ECCO: screening not routine

48. ECCO 2009

49. Management 16 • ?which HBV serologies • ?HCV, VZV, HIV • ?prophylaxis Screening for HBV is recommended prior to initiation of immunosuppressive agents. Anti-viral prophylaxis should be considered in HBV-positive individuals receiving biological agents or steroids. Patients with HBV on immunomodulator therapy requires monitoring for HBV reactivation and commencement of anti-viral therapy for reactivation. Patients should be up-to-date with specific vaccinations. Live virus vaccinations are to be avoided for at least 3 weeks prior to commencement of biological agents and 3 months after the last dose of biological agents

50. Management 17 Statement rationale: contraindications