ibd cases
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IBD Cases. Stephen B. Hanauer, MD Professor of Medicine Feinberg School of Medicine Medical Director, Digestive Health Center. What options are available for treatment of this patient ?. Management Algorithm. Ulcerative Colitis. MODERATE. MILD. SEVERE. 5ASA +/- prednisone. - PowerPoint PPT PresentationTRANSCRIPT
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