1. Other Major Side Effects to Immunomodulators and/or Biologics in Our IBD Patients Edward V. Loftus, Jr., M.D. Professor of Medicine Mayo Clinic Rochester, Minnesota, USA

2. Loftus Disclosures Research/grant support –AbbVie –UCB –Janssen –Takeda –Amgen –Genentech –Pfizer –GlaxoSmithKline –Bristol-Myers Squibb –Santarus –Robarts Clinical Trials Consulting –AbbVie –UCB –Janssen –Takeda –Immune Pharmaceuticals

3. Overview Thiopurines –Adverse events and drug interactions –Liver disease Methotrexate Calcineurin inhibitors Anti-TNF –Infusion/injection site reactions –Arthralgias and drug-induced lupus –Demyelination –Cardiomyopathy

4. AZA/6MP Adverse Events in Crohn’s RCTs: Cochrane Meta-Analysis AZA vs. Placebo –Study withdrawal due to AE1.7 (0.9-3.1) –Serious AE2.6 (0.9-7.1) AZA vs. 5-ASA –Study withdrawal due to AE1.0 (0.4-2.5) –Serious AE11.3 (0.6-205) AZA vs. IFX –Study withdrawal due to AE1.5 (0.96-2.2) –Serious AE1.1 (0.8-1.6) Chande N et al, Cochrane Database Syst Rev 2013;(4):CD000545.

5. “Real World” Experiences With AZA/6MP in 2002-4 Setting N% Withdrawal Due to AE Olmsted Co, MN102 25% Canterbury, NZ216 26% Oxford, UK622 28% Groningen, NL318 23% Nijmegen, NL 50 22% Loftus CG et al, Am J Gastroenterology 2003 abstract Gearry et al, Pharmacoepidemiol Drug Safety 2004;13:563-7 Fraser AG et al, Gut 2002;50:485-9 Weersma RK et al, Aliment Pharmacol Ther 2004;20:843-50 deJong DJ et al, Eur J Gastroenterol Hepatol 2004;16:207-12

6. Azathioprine/6-Mercaptopurine Toxicity Nausea Allergic reactions Pancreatitis Bone marrow depression Drug hepatitis

7. Blood Dyscrasias Are an Important SAE for 5-ASA Agents--More Likely with Sulfasalazine Fatalities after developing a blood dyscrasia: Sulfasalazine 5% (7/129) Mesalamine 9% (5/51) Ransford RAJ. Gut 2002;51:536-539.

8. Drug Interactions with AZA/6-MP: 5-ASA AZA and 6-MP may interact with 5-ASAs, potentially causing leukopenia –5-ASA reversibly inhibits TPMT –Low levels of TPMT causes accumulation 6-TGN, active metabolite –Increased 6-TGN leads to a decrease in WBC –Patients with low baseline levels of TPMT who are taking a combination of AZA/6-MP and 5-ASAs are at risk of clinically significant leukopenia Lowry P et al, Gut 2001; 49: 656

9. Concurrent 5 ASA & Immunomodulator Use May Increase Myelosuppression: 8-Week Non- Randomized Parallel Group Study Lowry PW, et al. Gut 2001;49:656-664.

10. Drug Interaction Between Thiopurines and Anti-TNF? Infliximab may cause transient increase in 6TGN metabolites in first few weeks, with transient leukopenia, which normalizes No effect of adalimumab on thiopurine metabolites over 12 weeks in 12 patients Roblin X et al, Aliment Pharmacol Ther 2003;18:917-25. Wong DR et al, J Crohns Colitis 2013 Online early

11. Hepatotoxicity with AZA/6MP Common cause of drug-induced liver injury (DILI)(>3x ULN) –3 rd most common cause of DILI in Iceland 2010-11 (4% of all cases, tied with infliximab) –Absolute risk of DILI was 1 in 133 with AZA Spanish nationwide database of AZA safety (n=3,931) –4% developed hepatotoxicity (>2x ULN) –Dose-related Bjornsson ES et al, Gastroenterology 2013;144:1419-26.

12. p < 0.05 Median 6-MMP (pmol/8x10 8 RBC) 6-MMP and Hepatotoxicity 2213 5463 n=157 Absent n=16 Present HEPATOTOXICITY Dubinsky MC et al, Gastroenterology 2002;122(4):904-15.

13. Allopurinol Therapy for Preferential 6-MMP Metabolism Pre-allopurinol Post-allopurinol Sparrow MP et al. Aliment Pharmacol Ther. 2005;22:441. Allopurinol 100 mg added; 6-MP/AZA dose reduced to 25% to 50% of baseline

14. 20 6MP/AZA nonresponders with high 6MMP levels (12 CD, 6 UC, 2 IC) Mean AZA = 200 mg 6MP = 87 mg Treatment Decrease AZA/6MP to 25-50% original dose Allopurinol = 100 mg/day Allopurinol + AZA/6MP: Clinical Outcome Sparrow MP et al. Clin Gastroenterol Hepatol 2007;5:209-214

15. Allopurinol Plus AZA/6MP Might prevent non-hepatic adverse events as well (nausea, myalgia, fatigue): 88% success in one small study Needs to be done with extreme vigilance –100 mg allopurinol –Dose reduce to 25% of original dose –Weekly CBC for 4 weeks then monthly –Periodic metabolites Ansari A et al, Aliment Pharmacol Ther 2010;31:640-7. Gearry RB et al, J Gastroenterol Hepatol 2010;25:649-56.

16. Long-Term AZA/6MP Hepatotoxicity Much less common but much more serious: Nodular regenerative hyperplasia: 1.2% at 10 years of AZA (but there may be a baseline of NRH in thiopurine-naïve IBD Veno-occlusive disease of liver DeBoer NK et al, Scand J Gastroenterol 2008;43:604-8 Seksik P et al, Inflamm Bowel Dis 2011;17:565-72. Male gender and extensive SB resection may be risk factors Much higher incidence of these events with high-dose thioguanine (>40 mg/day) Watch for thrombocytopenia Reticulin stain

17. Nausea Only with AZA: Switch to 6MP! If nausea with AZA is the rate-limiting side effect, it’s worth trying 6-MP; many will tolerate Olmsted County 1940-2001 –102 patients treated with thiopurines –73 treated with AZA 12 of 24 who stopped AZA were treated with 6-MP, and exactly 50% tolerated it Edinburgh: 149 pts intolerant of AZA treated with 6MP –Overall 58% tolerated –More likely to tolerate if AZA issue was GI symptom or LFTs compared to flu-like Loftus CG et al, Am J Gastroenterol 2003;9 (Suppl):S242. Kennedy NA et al, Aliment Pharmacol Ther 2013;38:1255-66.

18. Pregnancy Outcome in Crohn’s Disease for Women Treated with Thiopurines: Cohort from the CESAME Study 215 pregnancies (204 women) in the CESAME cohort 3/04 -12/07. 3 exposure groups compared: –TP (TP only or associated with another treatment: 5-ASA, CS or anti-TNF) –A drug other than TP –No medication Conclusions TP use is not associated with increased risk of congenital abnormalities Increased incidence of LBW and prematurity under TP was not significant and may correlate to the underlying disease Coelho J, Gut 2011; 60:198-203. IBD treatment Outcome TPs (n=86) Others (n=84) None (n=45) Births, n (%) 55 (64%) 56 (66.6%) 27 (60%) Prematurity, n (%)* 12 (21.8%) 9 (16.0%) 4 (14.8%) Low birth weight under 2500g, n (%)* 8 (14.5%) 7 (12.5%) 2 (7.4%) Congenital abnormalities, n (%)* 2 (3.6%) 3 (5.3%) 1 (3.7%)

19. Methotrexate Toxicity Rash, alopecia Nausea, mucositis, diarrhea –Folate mitigates much of this –Ondansetron before MTX injections Bone marrow suppression Hypersensitivity pneumonitis Increased LFTs Hepatic fibrosis/cirrhosis

20. MTX Hepatotoxicity Risk factors: –Obesity –Alcohol –Diabetes Screen for HBC/HCV Monitor LFTs, adjust dose accordingly Khan N et al, Inflamm Bowel Dis 2012;18:359-67. Steatosis, steatohepatitis, hepatic fibrosis Fortunately, risk of hepatotoxicity is low (0.9-1.4 per 100 person-months)

21. MTX Pulmonary Toxicity Approximately 1-8% of treated patients Various forms –Hypersensitivity pneumonitis –BOOP –Interstitial pneumonia –Pleuritis/effusion Risk factors –Age>60 –RA with pulmonary –Low albumin –Diabetes Can present as culture negative pneumonia Subacute dry cough with dyspnea Up to 50% have peripheral eosinophilia Abnl PFTs in subacute presentation: restrictive pattern, ↓DLCO Sometimes BAL ± lung bx needed Rx: hold MTX, consider steroids

22. AgentPublished Guidelines For Monitoring CBC Oral 5 ASA AgentsPackage insert sulfasalazine: Q2 wk x 1 st 3 mo, then qmo x 3 mo, then q3mo ThiopurinesAGA & ACG: TPMT Q2 wk “while adjusted” then ≤3 mo Package insert Q1 wk x 1 mo, q2wk x3 mo, the “then monthly or more frequently if dosage alterations or other therapy changes are necessary” MethotrexateAGA “routine” CBC RA patientsACR recommends CBC q 4-8 wk for RA patients Package insert & Internal Recommendations Monthly Anti-TNF RA patientsBritish Society of Rheumatology recommends “regular monitoring” in RA patients

23. Cyclosporine and Tacrolimus Toxicity Nephrotoxicity: –Acute azotemia, usually reversible/dose- related –Rarely chronic progressive Hypertension: may require Ca ++ channel blocker Neurotoxicity –Tremor common –Seizures rare (more common with low lipids) ↓K +, ↓Mg ++, ↑glucose

24. Adverse Events with Anti-TNF Therapies Neurologic Cardiac Hepatic Rheumatologic Infusion reactions Injection site reactions –Usually minor

25. Neurologic Side Effects: Demyelination Confusing since there is a baseline association between IBD and multiple sclerosis (Olmsted, Manitoba, GPRD) –MS is between 50% more and 3 times more common in IBD than general population Lenercept caused increased MS exacerbations in a group of MS patients Over 150 cases of demyelination after anti-TNF therapy reported to FDA AERS (2000-09) –Optic neuritis, MS-like presentation Spanish registry of anti-TNF therapy estimates incidence at 0.2 per 1000 p-y for IFX and 1 per 1000 p- y for ADA Kimura K et al, Mayo Clin Proc 2000; Bernstein CN et al, Gastroenterology 2005; Gupta G et al, Gastroenterology 2005; Lenercept MS Study Group, Neurology 1999; Deepak P et al, Aliment Pharmacol Ther 2013; Ramos-Casals M et al, Autoimmune Rev 2010.

26. Other Neurologic Side Effects Reported with Anti-TNF Therapy Guillain-Barre syndrome Peripheral neuropathy Aseptic meningoencephalitis Leukoencephalopathy Transverse myelitis Chronic inflammatory demyelinating polyneuropathy Progressive multifocal leukoencephalopathy Posterior reversible encephalopathy syndrome Singh S et al, Inflamm Bowel Dis 2013; 19:864-72.

27. Congestive Heart Failure and Anti-TNF Therapy Etanercept trials to treat CHF were negative Infliximab trial of CHF: highest mortality rate in IFX 10 mg/kg arm Adalimumab: event rate of CHF <0.26 per 1000 p-y Use with caution in patients with CHF or reduced LVEF IFX contraindicated at doses >5mg/kg in NYHA Class III/IV Consider ECHO ± Cards consult in those with suspected CHF Mann DL et al, Circulation 2004; Chung ES et al, Circulation 2003; Schiff MH et al, EULAR 2005; Kent JD et al, ACR 2005.

28. Hepatotoxicity with Anti-TNF Most commonly described with infliximab but has been describe with all –PI contains warning –Hepatocellular > cholestatic injury, often with autoimmune characteristics –Slowly improves after drug cessation –Rare cases of hepatic failure/liver transplant Ghabril M et al, Clin Gastroenterol Hepatol 2013;11:558-64.

29. Lupus-Like Reactions with Anti-TNF Most are women Virtually all have arthritis/arthralgias Rash is common Serositis ANA positive Anti-ds-DNA often positive Don’t forget to check anti- histone Treatment is anti-TNF cessation Sometimes steroids needed, rarely hydroxychloroquine Recurrence with a 2 nd anti-TNF is relatively low One study from U of C suggested cumulative 5- yr incidence over 10% in women on anti-TNF Wetter DA & Davis MDP. Mayo Clin Proc 2009;84:979-84. Subramanian S et al, Inflamm Bowel Dis 2011;17:99-104. Yanai H et al. Inflamm Bowel Dis 2013;19:2778-86.

30. Infliximab Infusion Reactions Acute infusion reactions –Associated with antibodies to infliximab –Mild reactions treated with acetaminophen, diphenhydramine and slowing of infusion rate –Severe reactions require cessation, steroids, or epinephrine Delayed hypersensitivity reactions –Not necessarily associated with ATI –Arthralgias 1 to 5 days after infusion –Sometimes require steroids –More common on monotherapy episodic

31. Natalizumab: Adverse Events Beyond PML Headache Infusion reactions, generally mild Hepatotoxicity –Rare but severe cholestatic liver injury reported

32. Conclusions A wide variety of side effects can occur with our commonly used medications for IBD Regular monitoring necessary for many agents