Treating the Challenging Inpatient with Complicated IBD: Case Studies Peter D.R. Higgins, MD, PhD, MSc University of Michigan

Today’s Cases Difficult inpatients 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 a bit of science

Complicated Crohn’s DIsease CASE 1 Complicated Crohn’s DIsease

Case 1: Crohn’s Disease 23 year old male with CD x 4 years Ileal and segmental colonic location Failed 5-ASA x 8m, Aza x 3 years, now referred after starting IFX monotherapy x 4m Slowly worsening RLQ pain, fevers x 2 months CT Scan ordered Admitted with CRP 4.3, ESR 78, Albumin 2.2, Prealbumin 3 after scan result.

Long arrows: Active inflammatory TI stricture Short yellow arrow: retroperitoneal abscess cavity medial to the cecum

Coronal images Long arrows: Active inflammatory TI stricture Short yellow arrows: retroperitoneal abscess cavity medial to the cecum

Consultant Notes Radiology: 2.6 cm abscess medial to cecum, adjacent to long (15 cm) TI stricture with active inflammation. Unable to drain safely. Upstream SB dilated to 3.6 cm. Surgery: No emergent indication for surgery. Recommend maximize medical therapy to eliminate inflammation and eradicate all infection before elective surgery. Follow up in surgery clinic in 8 weeks.

Options? Continue anti-TNF? What are the anti-inflammatory options? Anti-microbial therapy? Surgical therapy? Will this situation recur? Will this damaged bowel be responsive to therapy? Discuss…

Medical Therapies Anti-TNF Systemic steroids Topical steroids Entocort Immunomodulators Methotrexate Azathioprine Abscess fertilizers

Anti-microbial therapy Drainage Would be optimal, not always possible 60-84% can be drained in case series with 2+ attempts Antibiotics Cover gut bugs broadly Consider iv for best bioavailability Consider early re-image (3-5d) if incomplete drainage Long term, re-image in 4-6 weeks Waljee, Chapter 135, Advanced Therapy of IBD text, ed. Bayless and Hanauer Feagins, Kane, et al, CGH 2011:842

Is Surgery Avoidable? Usually not Penet rating complications occur close to strictures Increased pressure within and upstream Inflammation weakens walls Likely to recur unless stricture fixed There are exceptions – inflammatory strictures Can you drain and start anti-TNF? 31% recur @5y N=55 Goal is generally to get patient to ELECTIVE surgery Nguyen, Sandborn, et al. CGH 2012: 400-4

Goals for pre-op visit Eradicate infection Control mucosal inflammation Even better, control transmural inflammation Limit/reduce length of resection “neoadjuvant” anti-TNF therapy? Prevent new fistulas, abscesses Boost nutritional status – Prealb, Alb Boost functional status – “Pre-hab”

Treating the challenging inpatient with complicated IBD: Case studies Hans Herfarth, MD, PhD University of North Carolina at Chapel Hill Chapel Hill, North Carolina

Case 2 27 yo female patient, hospitalized for refractory ulcerative colitis PMHx: Diagnosis of ulcerative pancolitis 2.5 years ago Initial therapy with steroids and 5-ASA without improvement, start of infliximab. Allergic reaction with shortness of breath, chest pain during maintenance therapy Start of 6-MP, remission for 18 months until 3 weeks before hospitalization. 2 weeks before hospitalization start of oral steroids (40 mg prednisolone) without success

Case 2 (cont'd) Time of consult: 8-10 bloody bowel movements/day, no fever Physical exam: Abdomen soft, non-tender Medication: Start of 60 mg methylprednisolone iv yesterday. Labs: WBC 11.9 x10 9th/L, HGB 8.9 g/dl, platelets 550,000 x10 9th/L, CRP 9.4 mg/dl.

Sigmoid Colon Rectum

Case 2 (cont'd)

Case 2 (cont'd) Therapeutic options in the setting of no response to steroids in active UC and pregnancy: Infliximab Adalimumab Golimumab Cyclosporine Colectomy with ileostomy

Cyclosporine Therapy of UC in Pregnancy 3 case reports, 3 case series with 2, 5 and 8 patients 8 patients 7-Pan-UC 1 Left sided UC Pregnancy week 6-27 Iv cyclosporine for 5-17 days (1 patient oral), then switch to oral cyclosporine (2 patients + AZA 7/8 patients with response to therapy. One patient after 17 days switch to IFX with response (later on Dx of CD) 7/8 pregnancies conducted to term. 1 death at week 22 (cyclosporine started week 10; mother with protein-S defect). Two newborns premature. Branche et al. 2009

Surgical management of Therapy Refractory UC in Pregnancy 11 case reports with 1 or 2 patients, 4 case series with 4, 5, 7 and 9 patients Case series before 2000 , especially around the 1970’s significant mortality of mothers or infants Case series Mayo 2006 (Dozois et al. 2006): 5 patients with UC. All with subtotal colectomy at first (1), second (3) and third trimester (1) No complications after surgery or during delivery.

In-Hospital Management and Birth Outcomes in Pregnancy in 2 Tertiary Care Centers (Mount Sinai, NYC, Chicago) Time period 1989-2001: 11 patients with UC, 6 patients with CD, 1 patient with IC Hospitalization and treatment with hydrocortisone n=18, cyclosporine n=5, start of 6-MP/AZA n=3. 15 pat. 83% response to medical therapy, 3 (17%) colectomy. 1 patient in cyclosporine group spontaneous abortion week 15. Average weight (g) p<0.0001 p<0.0001 Reddy et al. 2008

Outcome case UC pregnancy Start of cyclosporine 2 mg/kg bw . Aim trough level >200 <400 ng/ml. Continuation of 6-MP Continuation of iv steroids Patient improved after 2 days with decrease of bowel movements. Switch to oral steroid taper on day 3. Switch on day 7 to oral cyclosporine (6 mg/kg body weight). Continuation of oral cyclosporine + 6-MP for 3 months, then continuation of 6-MP only Uncomplicated vaginal delivery week 36, baby with normal weight

Severe ulcerative colitis CASE 3 Severe ulcerative colitis

Case 3: Severe Ulcerative Colitis 19 year old female with UC x 4 months 3 m on 5-ASA, various types and doses 1 m on Aza 2.5 mg/kg TPMT 13.2 C diff infection found 3 weeks ago Flagyl x 10 days, better on days 5-10 Then worsened 22 bloody BM daily, low-grade fevers

Admitted CDTOX negative WBC 12.2, ESR 33, CRP 9.2 HR 95, BP 122/78 IV methylprednisolone 60 mg daily Small improvements Day 2 scope - severe UC, no CMV End of day 3: 15 BM/day, CRP 6.9

Options? Prognosis? What are the rescue therapy options? How to dose/frequency of dosing? Where will drug go? How to monitor levels? Implications of surgery on fertility? What are long-term risks/benefits? Discuss….

An Extreme Paucity of Data… A fair amount of trial and error Trial and failure, learn from your mistakes IFX can leak out of colon into stool in surprisingly large amounts CRP is invariably high, and falls with therapy Retrospectively developed prognostic indices help If steroids are not working by day 3, will not work In the CYSIF trial, IFX ~ Cyclo at 90 days

What Various IBD Centers Do Operate at Day 4 Rescue with Cyclosporine (decreasing) Rescue with IFX Dose high (10 mg/kg) Dose often (5 mg/kg q 72h until CRP <1) Hybrids of these UM protocol: http://www.med.umich.edu/ibd/docs/UMSevereUCProtocol.2.5.pdf

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

Case 4 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 2 (cont'd) 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

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

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

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

Use of Narcotics in Hospitalizations for IBD 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 Risk Factors for Inpatient Narcotic Use Odds ration 95% confidence interval [CI] Narcotics prior to admission 5.4 1.5 – 19.0 Smoking 4.3 1.2 – 15.6 Psychiatric diagnosis 2.2 0.4 – 11.6 Long et al. 2012

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

Detoxification Protocol for Narcotic Bowel Syndrome (1) 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 (2) 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 using an appropriate calculator and the 24 hours total drug dose reduced by 10-33% q 24 hours. In inpatients setting administration of morphine as continuous infusion (not PRN). Grunkemeier et al. 2007

Detoxification Protocol for Narcotic Bowel Syndrome (3) Start of TCA (e.g. desipramine, nortriptyline @25-150 mg/qhs) or SNRI (e.g. duloxetine 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 (e.g. lorazepam 1 mg q 6 hours) For constipation e.g. PEG 3350 17 g bid Grunkemeier et al. 2007

Narcotics discontinued Outcome after Discontinuation of Narcotics in IBD Narcotics discontinued n=22 Narcotics continued n=17 Medically adherent 100 % 53 % Surgically adherent 94 % Mod/severe pain 27 % 82 % None/mild clinical symptoms 80 % 24 % Hanson et al. 2009