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

Pro: The only end-points of therapy that matter are clinical symptoms and

quality of life

James Markowitz, MDProfessor of Pediatrics

Hofstra North Shore – LIJ School of MedicineDivision of Pediatric GastroenterologyCohen Children’s Medical Center of NY

New Hyde Park, NY

Disclosures

• 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 symptoms1. Loss of energy2. Loss of control3. Body image4. Isolation and fear5. Not reaching full

potential6. Feeling dirty

Drug induced toxicities1. Infection2. Cancer3. Fertility4. Teratogenicity

Casati J, et al. Dig Dis Sci 2000 Jan;45(1):26-31

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.pdfBasch 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

• 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–G13Qiu BS, et al. Nat Med 1999; 5:1178–1182Lyte M, et al. J Lab Clin Med 1996; 128:392–398Nigro G. et al. J Clin Gastroenterol 2001; 32:66–68

Do we change the natural history of IBD with medical therapies?

Thiopurines Anti-TNFCorticosteroid free maintenance

+++ +++

Change from B1 → B2 or B3 + ++Risk of 1st surgery + ++Post-operative recurrence + ++Growth 0 +

Striving for mucosal healing may increase toxicity risk

Thiopurines Anti-TNFOpportunistic infections + +Malignancy

Lymphoma + +Skin Nonmelanoma Melanoma

Immunogenicity/Autoimmunity 0 +