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Miguel Regueiro, M.D. Professor of Medicine Associate Chief, Education

What adverse reactions to immunomodulators and biologics: 1) mandate discontinuation of therapy and 2) when can medications be continued?. Miguel Regueiro, M.D. Professor of Medicine Associate Chief, Education Clinical Head and Co-Director, IBD Ctr University of Pittsburgh Medical Ctr.

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Miguel Regueiro, M.D. Professor of Medicine Associate Chief, Education

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  1. What adverse reactions to immunomodulators and biologics:1) mandate discontinuation of therapy and2) when can medications be continued? Miguel Regueiro, M.D. Professor of Medicine Associate Chief, Education Clinical Head and Co-Director, IBD Ctr University of Pittsburgh Medical Ctr

  2. Very little to no evidenced based data on this subject, so… I called some friends for help.

  3. Corey Siegel – after 1 minute of laughter, “I was asked to give this talk and turned it down…good luck!”

  4. David Rubin – “What are you kidding me?!?!”

  5. Asher Kornbluth – “I’m sorry, I can’t hear you.”

  6. Ed Loftus – Clearly has gone over his own cliff…….

  7. Jean Fred Colombel – yelled something in French about the color blue being sacred, the rest I couldn’t understand.

  8. So, with no help from my “friends”

  9. I will give you my opinion on what to do with IMMs/antiTNFs when an AE occurs. We need to individualize this decision based on severity of IBD and AE. I look forward to further discussion and opinion in the panel session.

  10. What are the main side-effects of 6MP/Azathioprine? Siegel CA, et al. APT 2005 (weighted average); Siegel CA, et al. CGH 2009; Beaugerie L, et al. Lancet 2009.

  11. Adverse Events Associated with anti-TNF Treatment Siegel CA.. The inflammatory bowel disease yearbook, volume 6. 2009; Infliximab package insert; Vermeire, Gastro 2003; Cush, Ann Rheum Dis 2005; Lenercept study group, Neurology 1999; ATTACH trial 2003

  12. Continue or Stop Rxent?Focus on three adverse event categories – cases from my clinic • Infections • Malignancy • Skin Complications • Thank you Drs Siegel, Rubin, Loftus, Kornbluth, and Colombel for your slides

  13. Infections - Continue or Stop? • 33 yo CD IFX/AZA recently relocated from Louisville to Pittsburgh. • For the past month he had cough, myalgias, weight loss, and low grade fevers. • PPD/Quantiferon negative, but CXR shows……..

  14. CXR – Reticulonodular infiltrate

  15. Bronchoscopy – what is the dx?

  16. Histoplasmosis • Urine antigen also positive for Histoplasmosis • Stop AZA/IFX and rx ketoconazole • Would you restart IFX/AZA after infxn clears?

  17. Increased Risk of Opportunistic Infections (Mayo) – AZA/antiTNF Toruner M et al, Gastroenterology 2008; 134:929-36.

  18. Older Age Is Associated with Opportunistic Infections Age at IBD diagnosis: Odds Ratio (per 5 years), 1.1 (1.1-1.2) Age at first Mayo visit: 0 – 23 1.0 (reference) 24 – 36 1.2 (0.5 – 2.8) 37 – 49 1.1 (0.5 – 2.5) ≥ 50 3.0 (1.2 – 7.2) Toruner M et al, Gastroenterology 2008; 134:929-36.

  19. The type of infections more prevelant with anti-TNFs (granulomatous) • Bacterial • Tuberculosis • Atypical mycobacterial infection • Listeriosis • Invasive Fungal • Histoplasmosis • Coccidioidomycosis • Candidiasis • Aspergillosis • Pneumocystosis Lee JH et al. Arthritis Rheum. 2002;46:2565-70 Velayos FS et al. Inflamm Bowel Dis. 2004;10:657-60 Bergstrom L et al. Arthritis Rheum. 2004;50:1959-66

  20. Case - Stop or Continue? • 27 yo male with a h/o severe Crohn’s ds who is in remission for 4 years on 6MP 1 mg/kg. • Over the past year he has had recurrent “bumps” over his hands and arms. • Not painful, but aesthetically displeasing and affecting social life

  21. What is the diagnosis?

  22. Warts (likely papillomavirus) • Despite treatment he continues to have problems with warts. • The 6MP is lowered but it is not until 6MP is stopped that his warts resolve. • Can 6MP be started again in the future?

  23. Thiopurines Increase the Incidence of Certain Viral Infections - Warts Prospective study (n=230) NS * 20 18 16 14 12 10 8 6 4 2 0 NS 2.0 1.5 1.0 0.5 0 * Patients (%) Infection/patient-year AZA+ AZA– AZA+n=169 AZA–n=61 AZA+ AZA– AZA+n=169 AZA–n=61 Appearance of increased number of warts Warts at the entryin the study Upper respiratory tract infections Herpes virus flare-ups Seksik P et al. Aliment Pharmacol Ther 2009;29:1106-13. NS = not significant

  24. Case - Continue or Stop? • 58 yo in remission on IFX monotx for 5yrs (first 1.5 yrs on 6MP as well). • Due for IFX infusion in 3 weeks. • 1 wk ago developed severe pain along back, “thought kidney stone” • 4 days ago developed “blisters” along back (very painful)

  25. Diagnosis? Give IFX in 3 weeks?

  26. Does Zoster mandate stopping? • If pt due for antiTNF and active zoster, I wait for blisters to “dry/scab” • In this case she received IFX on schedule as her lesions resolved • Side Note: Shingles vaccine is live and contraindicated in immunosuppressed patients

  27. Case - Continue or Stop? • 41 yo UC in remission on Adalimumab 40mg qow and 6MP 50mg/d for 3 yrs • 2 weeks ago worsening diarrhea – no bleeding, but “feels like flare” • Colonoscopy shows……..

  28. What is your dx and would you change the ADA/6MP?

  29. Clostridium difficile Infection and IBD Increasing number of hospitalizations in IBD patients with C. diff Increasing percentage of C. diff infections are IBD patients • Classic risk factors disappearing • Pseudomembranes usually not present • Low threshold for checking in IBD patients with flares • Should you stop immunosuppression? Conflicting data Issa M, et al. Clin Gastroenterol Hepatol 2007; 5: 345-51.

  30. Infections: Stop or Continue?What I do….Consult with ID..then..

  31. Infections: Stop or Continue?What I do….

  32. Infections: Stop or Continue?What I do….

  33. Infections: Stop or Continue?

  34. Infections: Stop or Continue?What I do….

  35. Infections: Stop or Continue?What I do….

  36. Malignancy Lymphoma Solid Tumors

  37. Case – Stop or Continue? • 39 yo male CD in remission on 6MP/IFX for 8 yrs. • Now with weight loss, sweats, and low grade fevers

  38. Large periaortic LNs involving left renal cortex – diagnosis?

  39. Non-Hodgkin’s Lymphoma • What do you do now? • Stop IFX and continue 6MP? • Stop 6MP and continue IFX? • Stop both?

  40. In contrast: Hepatosplenic T cell lymphoma – enlarged spleen, otherwise nonspecific

  41. AZA/6-MP are probably related to Lymphoma (Meta-analysis): SIR 4.06 SIR = 4.06, 95% CI 2.01 – 7.28 Kandiel A et al. Gut. 2005:54:1121-25

  42. CESAME – 6MP/AZA OnlyLymphoma: HR 5.3 Beaugerie L. Lancet 2009 DOI:10.1016/S0140-6736(09)61302-7

  43. Risk of NH Lymphoma with anti-TNF + IM treatment for Crohn’s Disease: A Meta-Analysis • 8905 patients representing 20,602 pt-years of exposure • 13 Non-Hodgkin’s lymphomas  • Mean age 52, 62% male • 10/13 exposed to IM* (really a study of combo Rx) 6.1 per 10,000 pt-years Siegel et al, CGH 2009;7:874. *not reported in 2

  44. CESAME – Combo 6MP/AZA and antiTNF: SIR = 10.2 Beaugerie L. Lancet 2009 DOI:10.1016/S0140-6736(09)61302-7

  45. Case Continue or Stop? • 58 yo female with severe UC who has been on IFX/6MP (50mg/d) for past 1yr • Just diagnosed with intraductal breast CA (T1N0MX) • Strong FHx breast CA, pt opts for bilateral mastectomy • After consultation with oncology, the decision is to cont meds

  46. No clear association between thiopurines/antiTNFs and solid tumors in IBD …..but DO seem associated with increased risk of skin cancers and lymphoma

  47. Malignancy: Stop or Continue? What I doConsult with Oncology and then.….

  48. Malignancy: Stop or Continue? What I doConsult with Oncology and then.….

  49. Malignancy: Stop or Continue? What I doConsult with Oncology and then.….

  50. Malignancy: Stop or Continue? What I doConsult with Oncology and then.….

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