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

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

CASE 1

COMPLICATED CROHN’S DISEASE

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.

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?

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

• • • Labs?

Scopes?

Scan?

Evaluation?

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

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??)

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

Case 2 Severe Indeterminate Colitis

Hans Herfarth, MD, PhD University of North Carolina at Chapel Hill Chapel Hill, North Carolina

• 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

Case • 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

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

What test do you perform to diagnose CMV colitis?

• Immunohistochemistry for CMV • CMV – serologies (IgG and IgM) • CMV –PCR using colonic biopsies • Qualitative • Quantitative • CMV PCR plasma

Tests, Costs and Problems in the Detection of CMV Infection

Test Sensitivity Specificity Cost Problem

Histology (H&E) 10-87% 92-100% $ Sampling error Histology (IHC) CMV culture CMV -DNA CMV IgM CMV IgG CMV antigen 78-93% 45-78% 65-100% 100% 98-100% 60-100% 92-100% 89-100% 40-92% 99% 96-99% 83-100% $$ Sampling error $$ $$$ 1-3 week incubation $$ $$ May be not present in immunocompromised patients 4x increase between two separate titers $ Blood & cerbrospinal fluid, semiquantitative Kandiel and Lashner 2006

Predictive Model for CMV Disease in IBD Predictive variable Refractory disease* IM exposure OR 4.24

1.95

95% CI 2.21-8.11

1.05-3.62

p value

<.001

<0.34

Score component 14 7 Risk category for CMV • ≥24 high risk Age 31-53y 2.26

1.02-5.03

<0.35

8 • Moderate risk ≥ 14<24 Age ≥ 54y 2.69

1.20-6.02

10 • Low risk < 14 CS exposure 2.05

0.94-4.48

Fever 2.02

0.84-4.87

Sensitivity and specificity >85% Endoscopic ulcer UC 1.37

0.73-2.59

*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.

McCurdy et al. 2014

Detection of CMV-DNA in Stool and Colon Biopsy and Plasma – Quantitative PCR 1000000 100000 10000 1000 100 10 1 0 1 2 4 5 6 Biopsy Stool Plasma Patient No. 1, 2 CMV DNA plasma, stool <500 copies, No. 4 stool test solidified, No. 5 Plasma test not done.

Herfarth et al. 2010

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

100% CMV DNA Copies in Colonic Biopsies and Risk of Colectomy in the Following 6 Months p<0.03

p<0.04

100,0% 87,5% 80% 60% 50,0% 40% 36,4% 20% 0% n=7 n=4 All IBD<2000 copies/ml All IBD >2000 copies/ml n=6 UC <2000 copies/ml n=4 UC >2000 copies/ml Onyah et al. DDW 2014

Case • CMV DNA PCR mucosal biopsy positive.

CMV DNA PCR plasma: positive.

H&E and immunohistochemistry (IHC) for CMV negative.

What now?

CMV-Colitis Therapy in IBD Ganciclovir 5 mg/kg intravenously every 12 h after 3–5 days, switch to oral to 3-wk.

valganciclovir for a total of 2 Review in Am J Gastroenterol by Kandiel and Lashner 2006 Literature is equivocal about need for therapy, Meta-analysis does not show effect. (Kopylov et al. 2014) Problems: No prospective studies.

Do we treat the reason of the exacerbation or only a “innocent” bystander

Case • 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.

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

CASE 3

PENETRATING CROHN’S DISEASE

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 infusions in June 2013 – Low trough -> To q 6 week Rx wk between

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 – Anti-IFX Ab 56 ng/mL (REF <0.4) (REF <22)

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

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

Fistula Options?

• • • • • Change anti-inflammatory meds? Antibiotics?

Setons?

Local Rx (doxycycline, APC)?

Diversion?

Case 4 Pain in Crohn’s Disease

Hans Herfarth, MD, PhD University of North Carolina at Chapel Hill Chapel Hill, North Carolina

Case 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 Psychiatric diagnosis 4.3

2.2

1.2 – 15.6

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: • • • • 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.

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 and total drug dose be 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 (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 Grunkemeier et al. 2007

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