Treating the Inpatient with Severe Crohn’s Disease: Case Studies

Peter D.R. Higgins, MD, PhD, MScUniversity of Michigan

Hans H. Herfarth, MD, PhD, FACG, AGAFUniversity 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

COMPLICATED CROHN’S DISEASECASE 1

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

Evaluation?

• Labs?• Scopes?• Scan?

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

Hans Herfarth, MD, PhDUniversity of North Carolina at Chapel Hill

Chapel Hill, North Carolina

Case 2Severe Indeterminate Colitis

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

• 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

CMV Colitis– Clinical and Laboratory Features

• Diarrhea

• Bloody Diarrhea

• Fever

• Toxic Megacolon

• Leukopenia

• Lymphopenia

• LFT’s

Ulcerative colitis >> Crohn’s disease

• 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?

Test Sensitivity Specificity Cost Problem

Histology (H&E) 10-87% 92-100% $ Sampling error

Histology (IHC) 78-93% 92-100% $$ Sampling error

CMV culture 45-78% 89-100% $$ 1-3 week incubation

CMV -DNA 65-100% 40-92% $$$

CMV IgM 100% 99% $$ May be not present in immunocompromised patients

CMV IgG 98-100% 96-99% $$ 4x increase between two separate titers

CMV antigen 60-100% 83-100% $ Blood & cerbrospinal fluid, semiquantitative

Tests, Costs and Problems in the Detection of CMV Infection

Kandiel and Lashner 2006

*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

OR 95% CI p value Score component

Refractory disease*

4.24 2.21-8.11 <.001 14

IM exposure 1.95 1.05-3.62 <0.34 7

Age 31-53y 2.26 1.02-5.03 <0.35 8

Age ≥ 54y 2.69 1.20-6.02 10

CS exposure 2.05 0.94-4.48

Fever 2.02 0.84-4.87

Endoscopic ulcer UC

1.37 0.73-2.59

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

0 1 2 3 4 5 61

10

100

1000

10000

100000

1000000

BiopsyStoolPlasma

Patient No.

CM

V [

Cop

ies/

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

Roblin et al. 2011

Relationship Between Cytomegalovirus (CMV) DNA Load in Inflamed Colonic Tissue and Therapeutic Outcome

Cutoff 250 copies/mg of tissue

All IBD<2000 copies/ml

All IBD >2000

copies/ml

UC <2000 copies/ml

UC >2000 copies/ml

0%

20%

40%

60%

80%

100%

36.4%

87.5%

0.5

1

n=7 n=4 n=6 n=4

p<0.03 p<0.04

CMV DNA Copies in Colonic Biopsies and Risk of Colectomy in the Following 6 Months

Onyah et al. DDW 2014

• CMV DNA PCR mucosal biopsy positive.

CMV DNA PCR plasma: positive.

H&E and immunohistochemistry (IHC) for CMV

negative.

Case

What now?

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

CMV-Colitis Therapy in IBD

Literature is equivocal about need for therapy, Meta-analysis does not show effect. (Kopylov et al. 2014)

• 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

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

PENETRATING CROHN’S DISEASECASE 3

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) 7th wk between

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

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)

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 weekAdded 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?

Hans Herfarth, MD, PhDUniversity of North Carolina at Chapel Hill

Chapel Hill, North Carolina

Case 4Pain in Crohn’s Disease

40 yo female patient

• Diagnosis of Crohn‘s disease (CD) at age 24Intermittent 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

• 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)

• Flare

• Stricture, Abscess

• Infection (e.g. C. diff, CMV)

• Bacterial overgrowth

• Narcotic Bowel Syndrome

• IBS

Possible Reasons for Recurrent IBD Symptoms

(Pain, Diarrhea)

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:

• Flare

• Stricture, Abscess

• Infection (e.g. C. diff, CMV)

• Bacterial overgrowth

• Narcotic Bowel Syndrome

• IBS

Possible Reasons for Recurrent IBD Symptoms

(Pain, Diarrhea)

Risk Factors for Inpatient Narcotic UseOdds ration 95% confidence

interval [CI]Narcotics prior to admission 5.4 1.5 – 19.0Smoking 4.3 1.2 – 15.6Psychiatric diagnosis 2.2 0.4 – 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

• 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

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)

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

• 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

Narcotics discontinued

n=22

Narcotics continued

n=17Medically adherent 100 % 53 %Surgically adherent 100 % 94 %Mod/severe pain 27 % 82 %None/mild clinical symptoms 80 % 24 %

Outcome after Discontinuation of Narcotics in IBD

Hanson et al. 2009