Download DEBATE: What should be our end-points of therapy? Pro: The

DEBATE: What should be our endpoints of therapy?
Pro: The only end-points of therapy
that matter are clinical symptoms
and quality of life
James Markowitz, MD
Professor of Pediatrics
Hofstra North Shore – LIJ School of Medicine
Division of Pediatric Gastroenterology
Cohen Children’s Medical Center of NY
New Hyde Park, NY
Disclosures
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Janssen Pharmaceuticals – Consultant
Abbvie – Consultant
UCB – Consultant
Soligenix – Consultant
Case: P.T.
March 2011
• 13 yo Tanner I boy with short stature (50→10%), referred
from Peds Endo after neg GH testing
– Mild daily cramps, loose nonbloody stools bid
– ESR 22, CRP 0.5, albumin 3.2
• Dx: Mild granulomatous inflammation in TI and cecum on
ileocolonoscopy; small bowel aphthae on VCE
• Rx: Enteral feeds supplying 85% of RDA x 3mos, then prn
• Outcome: Asymptomatic with improved weight gain,
growth, normalization of labs
May 2013 (15 yrs old)
• Asymptomatic, hgt 50%, Tanner IV
• Gluten free, dairy free diet; resumes NG feeds
for episodes of pain or diarrhea
• Routine labs: ESR 15, CRP 0.3, albumin 3.8,
calprotectin 1380
• VCE: scattered aphthous ulcerations
throughout the small bowel
How to treat?
• Primarily small bowel CD in an asymptomatic
adolescent
– 5ASA
• No significant benefit
– Antibiotics
• Mom afraid – mat GF had been hospitalized with severe C diff
– Immunomodulators, Biologics
• Parents very worried about cancer
• Parents and patient not interested in issues related
to mucosal healing and its role in potentially
decreasing risk of future complications
• Opted to accept no new therapy
The only end-points of therapy
that matter…..
Matter To Whom??
Patient/Parent Concerns
Day to day symptoms
1. Loss of energy
2. Loss of control
3. Body image
4. Isolation and fear
5. Not reaching full
potential
6. Feeling dirty
Casati J, et al. Dig Dis Sci 2000 Jan;45(1):26-31
Drug induced toxicities
1. Infection
2. Cancer
3. Fertility
4. Teratogenicity
PROs: Patient Reported Outcomes
Measures
• Recognized as a critical, necessary and now
required aspect of new drug development
• The patient perspective: “How does it make
me feel?”
– FDA: always relevant and should be assessed in all
pivotal clinical trials
– Recognizes that biologic effects alone are not
adequate to judge the overall effect of a
treatment
http://www.fda.gov/downloads/Drugs/Guidances/UCM193282.pdf
Basch E. Value in Health 2012;15(3):401-3
Psychological factors influence health-related
quality of life in outpatients with IBD
• 72 adults with IBD
• Standardized survey: Rating Form of IBD Patients'
Concerns (RFIPC)
Results
• HRQOL affected at least as much by psychological
characteristics as by IBD activity
• “Depressive coping” associated with:
– more psychological distress
– worse self-rated health status
– increased somatic complaints nonspecific to IBD
Mussell M, et al. Eur J Gastroenterol 2004;16(12):1273-80
Potential mechanisms by which stress
can worsen tissue inflammation and
clinical course of IBD
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Increase gut permeability
Promote immune reactivity
Affect luminal flora
Promote maladaptive behaviors
– Sleeplessness
– Smoking
– Adherence to medical regimens
Soderholm JD, et al. Am J Physiol Gastrointest Liver Physiol 2001; 280:G7–G13
Qiu BS, et al. Nat Med 1999; 5:1178–1182
Lyte M, et al. J Lab Clin Med 1996; 128:392–398
Nigro G. et al. J Clin Gastroenterol 2001; 32:66–68
Do we change the natural history of
IBD with medical therapies?
Corticosteroid free
maintenance
Change from B1 → B2 or B3
Risk of 1st surgery
Post-operative recurrence
Growth
Thiopurines
+++
Anti-TNF
+++
+
+
+
0
++
++
++
+
Striving for mucosal healing may
increase toxicity risk
Opportunistic infections
Malignancy
Lymphoma
Skin
Immunogenicity/
Autoimmunity
Thiopurines
+
Anti-TNF
+
+
+
Nonmelanoma Melanoma
0
+