1. Treating the Inpatient with Severe Crohn’s Disease: Case Studies Peter D.R. Higgins, MD, PhD, MSc University of Michigan Hans H. Herfarth, MD, PhD, FACG, AGAF University of North Carolina

2. Today’s Cases Difficult inpatients with Crohn’s disease The kind that are NOT eligible for clinical trials Limited, if any, RCT data available There are frequently NO right answers Management through general principles, art, analogy, and the limited science available

3. COMPLICATED CROHN’S DISEASE CASE 1

4. Crohn’s Disease 49 year old female with CD x 5 years (2009) – Initial Sx intractable nausea and wt loss Gastric, duodenal, jejunal and and ileal disease Failed 5-ASA x 6m, did well on Aza x 3 years 2013 seizure, R burning facial pain, HA – MRI – leptomeningeal lesion, Bx: cerebral vasculitis Rx with 80 prednisone qd, pain and seizures continue – Progression on MRI, pain 8/10, Keppra no effect Neurologist wants to start Cytoxan Jan 2014.

5. Options Continue Aza (controlling CD) with Cytoxan? Stop Aza during Cyclophosphamide, then resume Aza? Stop Aza during Cyclophosphamide, then new Rx? – Options for new Rx?

6. Case Continued Cytoxan with some benefit (5 cycles) – Off Aza, covered with entocort 9 mg po daily – Fewer seizures, continued R facial pain/numbness August admitted to hospital – Periumbilical and RUQ/RLQ pain, 10 loose BM qd – Rising WBC (20K), CRP 82 mg/L, fatigue and fever – Alk Phos 487, AST 82, ALT 58, Tbil 2.3 – Worsening edema in arms and legs (albumin 1.6) – Neurology – no more Cytoxan

7. Evaluation? Labs? Scopes? Scan?

8. Workup CTE – inflammation in stomach, D, J, I, and rectosigmoid Upper – ulcerations of antrum and D2 with granulomas FS – acute colitis, suggestive of EHEC MRCP – PSC with hilar stricture – ERCP dil. – Pip/tazo for cholangitis/ ? EHEC

9. Chronic IBD/Vasculitis Therapy? Short term (post Abx) – Prednisone (lots of side effects) – Dual BUdesonide? Maintenance Options? – Aza (but onset of Vasculitis through Aza) – Anti-TNF? – Vedo (what about vasculitis?) – Mycophenolate and/or MTX? – Natalizumab? (treat both??)

10. Latest update Prednisone taper, IFX/Aza (2 infusions) – CD Sx returning, Alb 2.7 New LE weakness, continued R facial pain – Trileptal and Keppra combo not helping

11. Hans Herfarth, MD, PhD University of North Carolina at Chapel Hill Chapel Hill, North Carolina Case 2 Severe Indeterminate Colitis

12. Case 32 year old female, dx of indeterminate Colitis (based on mild non-specific histologic inflammation in TI) 5 years ago. HPI: 20 bloody bm’s/day, oral steroids for 10 days, no improvement, hospitalization, steroid iv. Course of the disease: Initially 5 years ago steroid dependent disease course. Start of azathioprine with long term remission. Patient self-discontinued azathioprine 2 years ago while feeling well. Labs: WBC 3.4 (diff: lymphocytes 500), HGB 8.1, CRP 3. C. diff. negative. Physical exam: Tender abdomen, fever 39.1°C

13. Endoscopy: Severe colitis to transverse colon (more compatible with UC) and normal terminal ileum and ascending colon. Histology: severe colitis (H&E), no granuloma. Suspicion of CMV colitis Case

14. CMV Colitis– Clinical and Laboratory Features Diarrhea Bloody Diarrhea Fever Toxic Megacolon Leukopenia Lymphopenia LFT’s Ulcerative colitis >> Crohn’s disease

15. Immunohistochemistry for CMV CMV – serologies (IgG and IgM) CMV –PCR using colonic biopsies Qualitative Quantitative CMV PCR plasma What test do you perform to diagnose CMV colitis?

16. TestSensitivitySpecificityCostProblem Histology (H&E)10-87%92-100%$Sampling error Histology (IHC)78-93%92-100%$$Sampling error CMV culture45-78%89-100%$$1-3 week incubation CMV -DNA65-100%40-92%$$$ CMV IgM100%99%$$ May be not present in immunocompromised patients CMV IgG98-100%96-99%$$ 4x increase between two separate titers CMV antigen60-100%83-100%$ Blood & cerbrospinal fluid, semiquantitative Tests, Costs and Problems in the Detection of CMV Infection Kandiel and Lashner 2006

17. *Refractory disease required minimal or no improvement in symptoms after 14 days of oral CS, 7 days of intravenous CS, 2 induction doses of a TNF antagonist, or after escalated dosing of a TNF antagonist. Predictive variable OR95% CIp valueScore component Refractory disease* 4.242.21-8.11<.00114 IM exposure1.951.05-3.62<0.347 Age 31-53y2.261.02-5.03<0.358 Age ≥ 54y2.691.20-6.0210 CS exposure2.050.94-4.48 Fever2.020.84-4.87 Endoscopic ulcer UC 1.370.73-2.59 Risk category for CMV ≥24 high risk Moderate risk ≥ 14<24 Low risk < 14 Sensitivity and specificity >85% Predictive Model for CMV Disease in IBD McCurdy et al. 2014

18. Patient No. CMV [Copies/ml] Patient No. 1, 2 CMV DNA plasma, stool <500 copies, No. 4 stool test solidified, No. 5 Plasma test not done. Detection of CMV-DNA in Stool and Colon Biopsy and Plasma – Quantitative PCR Herfarth et al. 2010

19. Roblin et al. 2011 Relationship Between Cytomegalovirus (CMV) DNA Load in Inflamed Colonic Tissue and Therapeutic Outcome Cutoff 250 copies/mg of tissue

20. n=7 n=4 n=6n=4 p<0.03p<0.04 CMV DNA Copies in Colonic Biopsies and Risk of Colectomy in the Following 6 Months Onyah et al. DDW 2014

21. CMV DNA PCR mucosal biopsy positive. CMV DNA PCR plasma: positive. H&E and immunohistochemistry (IHC) for CMV negative. Case

22. What now?

23. Ganciclovir 5 mg/kg intravenously every 12 h after 3–5 days, switch to oral valganciclovir for a total of 2- to 3-wk. Review in Am J Gastroenterol by Kandiel and Lashner 2006 Problems: No prospective studies. Do we treat the reason of the exacerbation or only a “innocent” bystander Problems: No prospective studies. Do we treat the reason of the exacerbation or only a “innocent” bystander CMV-Colitis Therapy in IBD Literature is equivocal about need for therapy, Meta-analysis does not show effect. (Kopylov et al. 2014)

24. Start valganciclovir 900 mg bid + steroid taper, valganciclovir stop after 10 days due to leukopenia (1.6) 4 months later, clinical remission, but surveillance colonoscopy shows still active inflammation and low grade dysplasia on biopsy. Patient decides for colectomy and 2 stage IPAA. Case

25. IBD not responding to steroids after 2-3 days - Suspicion of CMV colitis Flexible sigmoidoscopy with biopsies H&E, IHC, CMV-DNA PCR biopsy qualitative, +plasma CMV DNA PCR qualitative and quantitative Therapy if H&E and/or IHC + CMV-DNA PCR biopsy and plasma + ? Therapy if only biopsy CMV PCR+ only plasma CMV + but low replication Diagnostic and Therapeutic Algorithm for CMV- Colitis at UNC

26. PENETRATING CROHN’S DISEASE CASE 3

27. Penetrating CD 22 year old female with CD since 2010 Presented with Abd pain, bloody stool – Dx severe UC, colectomy/J pouch 2011 2012 first labial abscess (of several) – Ileal biopsies with chronic ulcerating inflammation – Extends >30 cm proximal to pouch Started IFX monotherapy – Breakthrough Sx (bloody diarrhea) 7 th wk between infusions in June 2013 – Low trough -> To q 6 week Rx

28. 2014 - Losing Response Fatigue, increasing diarrhea CDTOX negative, CRP 2.8 Active ulceration on scope, CMV negative Esoterix IFX level/Ab: – IFX 36 mcg/mL (REF <0.4) – Anti-IFX Ab 56 ng/mL (REF <22)

29. Options? Increase or decrease IFX dose? Decrease IFX interval? Add an immunomodulator? Switch TNF inhibitor? Change drug class? Switched to ADA 160/80, 40 mg q week Added Aza Switched to ADA 160/80, 40 mg q week Added Aza

30. Worsening fistulas 2 weeks later: recurrent Sx, 4T MR: V-shaped tract extending from the inferior aspect of the internal anal sphincter anteriorly to the skin of both labia. How to treat fistulas? – Short term? – Longer term

31. Fistula Options? Change anti-inflammatory meds? Antibiotics? Setons? Local Rx (doxycycline, APC)? Diversion?

32. Hans Herfarth, MD, PhD University of North Carolina at Chapel Hill Chapel Hill, North Carolina Case 4 Pain in Crohn’s Disease

33. 40 yo female patient Diagnosis of Crohn‘s disease (CD) at age 24 Intermittent treatment with steroids and 5-ASA for 10 years CD flares up with severe colitis, steroid refractory. Initiation of infliximab and 6-MP. Remission after 2nd infusion of infliximab. 3 months later diagnosis of fibromyalgia. No effects of pregabalin, start of pain management by outside pain clinic. Case

34. Now admission with increased diarrhea (8-10 BMs daily), non- bloody and severe abdominal pain (10 out of 10). Previous medication before admission: -For CD: Infliximab q 8 weeks, last infusion 4 weeks ago and 6- MP (1.2 mg/kg bodyweight). -For fibromyalgia: Fentanyl patch 25 mcg/hr and oxycodone/acetaminophen 7.5 mg/325 mg 3-4 tablets daily as needed. Physical exam: No fever, abdomen soft, diffusely tender on deep palpation, no rebound tenderness. After admission: Patient is on hydromorphone 4 mg iv q 4 hours Case 2 (cont'd)

35. Flare Stricture, Abscess Infection (e.g. C. diff, CMV) Bacterial overgrowth Narcotic Bowel Syndrome IBS Possible Reasons for Recurrent IBD Symptoms (Pain, Diarrhea)

36. Workup Laboratory: CBC, CRP, calprotectin normal CT-abdomen with oral contrast: Normal, no dilated loops, no abscess Case 2 (cont'd) Upper-GI endoscopy and colonoscopy:

38. Flare Stricture, Abscess Infection (e.g. C. diff, CMV) Bacterial overgrowth Narcotic Bowel Syndrome IBS Possible Reasons for Recurrent IBD Symptoms (Pain, Diarrhea)

39. Risk Factors for Inpatient Narcotic Use Odds ration95% confidence interval [CI] Narcotics prior to admission5.41.5 – 19.0 Smoking4.31.2 – 15.6 Psychiatric diagnosis2.20.4 – 11.6 117 patients with IBD (exclusion of postoperative pat. (up to 1 month) and pat. with abscesses. 70. 1% receiving pain medications at admission ( median 12 mg in first 24 hours, median daily later on 7.5 mg/day. 7.7 % PCA pump Long et al. 2012 Use of Narcotics in Hospitalizations for IBD

40. Pain worsens or incompletely resolves with continued or escalating dosages of narcotics. Marked worsening of pain when the narcotic dose wanes and improvement when narcotics are re-instituted (soar and crash). Progression of the frequency, duration, and intensity of pain episodes. Nature and intensity of the pain not explained by a current or previous GI diagnosis. Chronic or frequently recurring abdominal pain that is treated with acute high-dose or chronic narcotics and all of the following: Diagnostic Criteria for Narcotic Bowel Syndrome Grunkemeier et al. 2007

41. Reduction of morphine dose Treatment of anxiety Treatment of withdrawal symptoms Start of medications for long term control of abdominal pain Physician – Patient Relationship Days 1 2 3 4 5 6 7 8 9 10……….. Grunkemeier et al. 2007 Detoxification Protocol for Narcotic Bowel Syndrome (1)

42. Effective communication with the patient is essential.  Explanation of rationale/benefit of stopping the narcotics  Explanation of the withdrawal program.  Affirmation of the patient’s pain and an explanation of the underlying pathophysiology of NBS (i.e. altered motility and/or visceral hypersensitivity). Total narcotic daily dose should be converted to morphine equivalents and total drug dose be reduced by 10-33% q 24 hours. In inpatients setting administration of morphine as continuous infusion (not PRN). Detoxification Protocol for Narcotic Bowel Syndrome (2) Grunkemeier et al. 2007

43. Start of TCA (25-150 mg/qhs) or SNRI (30-90 mg. qd) for immediate and long terms pain control and to help manage psychological comorbidities. Mirtazepine (15-30 mg. qhs) can be considered instead of or in addition to a TCA or SNRI if nausea is a prominent feature. For withdrawal symptoms clonidine (start with 0.1 mg bid) For anxiety benzodiazepine (1 mg q 6 hours) For constipation e.g. PEG 3350 17 g bid Detoxification Protocol for Narcotic Bowel Syndrome (3) Grunkemeier et al. 2007

44. Narcotics discontinued n=22 Narcotics continued n=17 Medically adherent100 %53 % Surgically adherent100 %94 % Mod/severe pain27 % 82 % None/mild clinical symptoms 80 %24 % Outcome after Discontinuation of Narcotics in IBD Hanson et al. 2009