IBD CasesStephen B. Hanauer, MDProfessor of MedicineFeinberg School of MedicineMedical Director, Digestive Health Center

24 year old female

States that she is “fatigued”

2-4 bloody, loose stools with urgency and cramping daily for 3 weeks

No weight loss

24 year old female

Past Medical History Unremarkable

Family History No family history of IBD

Social History No recent foreign travel, non-smoker

Review of Systems Unremarkable

Medications None

Allergies None

24 year old female

Vital SignsBP: 110/60, P=80, afebrileWt = 65 kg (no change from baseline)

AbdomenBS-present, soft nontender, no guarding or rebound tenderness and normal perianal examination

Laboratory Findings

Hematologic: • WBC = 8.9/mm3

• Hgb = 11.2 g/dL• Plt = 433/µL

Renal and liver function: Normal

Stool studies: • Enteric pathogens - Negative• Ova & parasites x 3 - Negative• C difficile toxin (A & B) - Negative

24 year old female

DX: Moderate active left sided ulcerative colitis

What options are available for treatment of this patient ?

Management Algorithm

Admit + IV steroids 3-5

days

IFX therapy or cyclosporine

+/- AZA

Surgery

SEVERE

Unable to taperprednisone

Steroid dependent

5ASA +/- prednisone

MODERATE

Respond to 1-2 rounds of steroid tapered over 6-8

weeksContinue 5-ASA

Fail 2-4

weeks

MILD

Oral 5-ASA/ SASP +/- topical 5-ASABudesonide MMX

Modified from Panaccione R, et al. Aliment Pharmacol Ther. 2008;28:674-88.

Ulcerative Colitis

Steroid refractory

2-4 weeks

No response

No responseSASP=sulfasalazine

IFX=infliximabADA=adalimumabGOL=golimumab

AZA/6MP aloneor IFX/ ADA/GOLor IFX/ ADA/GOL and AZA/6MP

evaluate after 12 weeks

FailAZA/6MP

alone

IFX/ADA/GOL +/-AZA/6MP

evaluate after 12 weeks

24 year old female

Treatment

Mesalamine 2.4 g/dNo significant improvement at 2 wksMesalamine dose escalated to 4.8 g/dDue to persistent symptoms at 4 wks Budesonide MMX 9mg one po qd added

Follow-up at 6 weeks

Symptoms slightly improved some days

24 year old female

For 2 months On mesalamine and Budesonide MMX (for 4 weeks)

Symptoms Transiently better but now continues to worsen

Chief Complaint 4 to 6 stools per day with occasional bleeding

What should be done at this point ?

1. Continue current therapy for 4 more weeks2. Stop Budesonide MMX and treat with prednisone3. Add 6MP or Azathioprine after checking TPMT4. Switch Budesonide MMX to Budesonide EC

What are her options?

24 year old female

Treated with prednisone 40 mg/day for 1 week durationStool frequency decreased to one formed BM a day with no fecal urgency

Began to taper prednisone at 5mg/day every week

At a dose of 20 mg a day of prednisone disease she had recurrence of diarrhea (6 BM/day) with minimal bleeding, fecal urgency and tenesmus

Steroid-Dependent Ulcerative Colitis: Treatment Choices

Treatment choices in the steroid-

dependent ulcerative colitis patient Biologic therapy?

Surgery?

Immunomodulator therapy?

Continue steroids?

Steroid-Dependent Ulcerative Colitis: Treatment Choices

Continue steroids?

Surgery?

Treatment choices in the

medically refractory or

severe ulcerative

colitis patient

Immunomodulator therapy?

Continue steroids?

Biologic therapy?

Surgery?

Steroid-Dependent Ulcerative Colitis: Treatment Choices

Continue steroids?

Immunomodulator therapy?

Surgery?

Treatment choices in the medically

refractory or severe ulcerative colitis

patient Biologic therapy?

Steroid-Dependent Ulcerative Colitis: Treatment Choices

Surgery?

Treatment choices in the medically

refractory or severe ulcerative colitis

patient

Surgery?

Biologic therapy?

Immunomodulator therapy?

Continue steroids?

Who should NOT be offered continued medical therapy?

• Emergent indications for surgery‒ Fulminant disease activity unresponsive to maximal

medical therapy‒ Toxic megacolon‒ Colonic perforation ‒ Massive hemorrhage

• Elective indications for surgery‒ Disease activity refractory to medical therapy‒ Mucosal dysplasia‒ Diagnosis of carcinoma‒ Colonic stricture‒ Growth retardation in children

Ford D; American Society of Colon & Rectal Surgeons. Ulcerative colitis. Available at http://www.fascrs.org/physicians/education/core_subjects/2005/ulcerative_colitis/ Cyma RR, et al. Arch Surg. 2005;140:300-310.

Colectomy for UC

• Delay in surgery more important predictor of poor outcome than hospital volume

• OR for death 2.12 (1.1-3.9) if colectomy after 6 days of hospitalization

• OR increases to 2.89 (1.4-5.9) if colectomy after 11 days • Emergently admitted patients 5 times more likely to die

compared to electively

Kaplan G. Gastroenterology. 2008;134:680-687.

Risk-Benefit Ratio of Surgery in UC

• Probably reduces rate of mortality

in the sickest patients• Considered “cure” for UC• Subtotal colectomy during acute

phase– IPAA– Permanent ileostomy

• Post-surgical complications– Infection– Small bowel obstruction– Sepsis– Leak– Pouch dysfunction– Irritable pouch

• Pouchitis/Cuffitis• Crohn’s disease• Reduced female fertility• Risk male erectile dysfunction

Benefit Risk

Case 2

- 40-Yr-Old Man With Long-Standing Ileocolonic Crohn’s Disease

- s/p 2 ileocecal resections- Recurrent disease in small and large bowel despite

steroids and azathioprine 2.5 mg/kg with therapeutic 6-TGN levels

Case 2 Treatment History- Treated with single infusion of infliximab

• Excellent response lasting ~6 mo- Second infliximab infusion

• Complicated by an acute infusion reaction• Response lasted ~8 wk

- Third infliximab infusion• Pretreated with prednisone, diphenhydramine, and

acetaminophen • Flushing and headache• Response lasted ~4 wk

- Fourth infliximab infusion• Pretreated as above and increased dose to 10 mg/kg• Headache and flushing• Benefits lasted only 12 wk

What is the mechanism for his loss of response?

Case 2

Comments on Biologics

•Despite “humanness” they are all immunogenic

-Immunogenicity is reduced by Immune suppressants…..

•Anticipate dose adjustment with all•There will be diminishing returns with 2nd and/or 3rd agent

-Duration of Disease-Refractory Disease-Immunogenicity

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Adalimumab 160 mg (day 1), 80 mg (day8)and 40 mg every two weeks Adalimumab 40 mg every two weeks

Infliximab 5 mg/kg at day 1, day 15, day 43 and every 8 weeksInfliximab 3 mg/kg at day 1, day 15, day 43 and every 8 weeks

Theoretical threshold

Subtherapeutic

Therapeutic Levels for Anti-TNF Agents

Implications of Low Drug (trough) Levels

•Disease Recurs- No longer maintenance but re-treatment

•Development of anti-drug antibodies- Eventual loss of response

Factors that Influence the Pharmacokinetics of Biologics

Impact on Pharmacokinetics

Presence of Anti-Drug Antibodies(ADAs)

Decreases drug concentration Increases clearanceWorse clinical outcomes

Ordas I et. al. Clin Gastroenterol Hepatol. 2012; 10:1079-1087. 24

Impact on Pharmacokinetics

Concomitant use of immunosuppressives Reduces ADA formationIncreases drug concentrationDecreases drug clearanceBetter clinical outcomes

Ordas I et. al. Clin Gastroenterol Hepatol. 2012; 10:1079-1087. 25

Factors that Influence the Pharmacokinetics of Biologics

Impact on Pharmacokinetics

Low serum albumin concentration Increases drug clearanceWorse clinical outcome

High baseline CRP concentration Increase drug clearance

High baseline TNF concentration May decrease drug concentration by increasing clearance

Ordas I et. al. Clin Gastroenterol Hepatol. 2012; 10:1079-1087. 26

Factors that Influence the Pharmacokinetics of Biologics

Impact on Pharmacokinetics

High body size May increase drug clearance

Sex Males have higher clearance

Ordas I et. al. Clin Gastroenterol Hepatol. 2012; 10:1079-1087. 27

Factors that Influence the Pharmacokinetics of Biologics

Case 2 Continued

• How should loss of response in this patient be assessed?

• What are your current options to treat him?

Algorithm for loss of response to Anti-TNF

Is there active disease?

YesMeasure Drug Level and Anti-

Drug Antibodies Undetectable Drug &

undetectable ADA

Suboptimal Dosing

Increase Drug dose or frequency

Undetectable Drug &Detectable ADA

Loss of response due to ADA

Switch within sameDrug Class

Therapeutic Levels

IBD refractory to anti-TNF

Alternative Class(e.g. vedolizumab)

No IBS SBBOBile-acid diarrheaStrictures

Case 2 continued

• Patient was prescribed adalimumab• 160 mg at wk 0; 80 mg at wk 2; and then

40 mg EOW

• He initially responded with resolution of diarrhea and abdominal pain

• He then developed recurrent abdominal pain and loose stools

Case 2 Continued

• How should loss of response in this patient be assessed?

• What are your current options to treat him?

Case 2 Summary

• Several mechanisms can lead to loss of response to a biologic- For patients who respond to anti-TNF therapy and then

lose response or become intolerant, switching within the anti-TNF class is a reasonable option• Absolute likelihood of response to second anti-TNF agent is lower than response in naïve patients

- Loss of response requires• Evaluation for active inflammation (eg, CRP, imaging, endoscopy)

• Exclusion of inflammatory and non-inflammatory complications