1. Crohn’s Disease Daniel Ustinov Nathan Hann Dylan Innamorati PHM142 Fall 2015 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

2. What is Crohn’s Disease?  Crohn’s disease is an autoimmune disorder that manifests in the GI tract of a patient  Characterized by severe inflammation in the GI tract, specifically large tracts of the upper GI, colon and/or the ileum  Not completely sure of the mechanism behind the immune response but what is certain is that there has been an increase in cases over the past several decades D Baumgart, W Sandborn (2012). Crohn‘s Disease. Lancet; 380: 1590–1605 R Sartor (2006). Mechanisms of Disease: pathogenesis of Crohn’s disease and ulcerative colitis. Nature; 3: 390-407

3. D Baumgart, W Sandborn (2012). Crohn‘s Disease. Lancet; 380: 1590–1605

4. Causes of Crohn’s  Environmental  Smoking  Diet  Genetic  Immune response  Familial Connections  Important genes include NOD2 and MUC1  Important to note that there is also evidence that reduced bacterial diversity influences Crohn’s D Baumgart, W Sandborn (2012). Crohn‘s Disease. Lancet; 380: 1590–1605 F Shanahan (2002). Crohn‘s Disease. Lancet; 359: 62-69

5. D Baumgart, W Sandborn (2012). Crohn‘s Disease. Lancet; 380: 1590–1605

7. Symptoms of Crohn’s Disease  diarrhea  abdominal cramping and pain  weight loss  fatigue  nausea  loss of appetite  fever  anemia Crohn's & Colitis Foundation of America. (2011, April 30). Crohn's & Colitis. Retrieved October 1, 2015.

8. Diagnosis of Crohn’s Disease  medical and family history  blood tests  Upper GI series (x rays)  lower GI series (x rays)  stool tests  computerized tomography (CT) scan  intestinal endoscopy (flexible sigmoidoscopy and colonoscopy) NIH Publication No. 14–3410. (2014, September 3). Crohn's Disease. Retrieved October 1, 2015. NIH Publication No. 12–5774. (2013, July 10). What I need to know about Crohn's Disease. Retrieved October 1, 2015.

9. Name of testIndication C-reactive protein (CRP)Non-specific inflammation erythrocyte sedimentation rate (ESR) Non-specific inflammation Complete Blood Count (CBC)Anemia, infection, inflammation perinuclear anti-neutrophil antibody (pANCA) Distinguishes UC from CD anti-Saccharomyces cervisiae antibody (ASCA) Distinguishes CD from UC anti-flagellin antibody (CBir1)Indicative of Crohn’s disease anti-OmpC antibody (OmpC)Indicative of Crohn’s disease NIH Publication No. 14–3410. (2014, September 3). Crohn's Disease. Retrieved October 1, 2015. NIH Publication No. 12–5774. (2013, July 10). What I need to know about Crohn's Disease. Retrieved October 1, 2015. Papadakis, K., Yang, H., Ippoliti, A., Mei, L., Elson, C., Hershberg, R.,... Targan, S. (2007). Anti-flagellin (CBir1) phenotypic and genetic Crohn ʼ s disease associations. Inflammatory Bowel Diseases, 524-530. Retrieved October 20, 2015, from http://www.ncbi.nlm.nih.gov/pubmed/17260364http://www.ncbi.nlm.nih.gov/pubmed/17260364 Rump, J., Schölmerich, J., Gross, V., Roth, M., Helfesrieder, R., Rautmann, A.,... Peter, H. (1990). A New Type of Perinuclear Anti-Neutrophil Cytoplasmic Antibody (p-ANCA) in Active Ulcerative Colitis but not in Crohn's Disease. Immunobiology, 406-413. Retrieved October 20, 2015, from http://www.ncbi.nlm.nih.gov/pubmed/2099908http://www.ncbi.nlm.nih.gov/pubmed/2099908 Zholudev, A., Zurakowski, D., Young, W., Leichtner, A., & Bousvaros, A. (2004). Serologic Testing with ANCA, ASCA, and Anti-OmpC in Children and Young Adults with Crohn's Disease and Ulcerative Colitis: Diagnostic Value and Correlation with Disease Phenotype. The American Journal of Gastroenterology Am J Gastroenterology, 2235-2241. Retrieved October 20, 2015, from http://www.ncbi.nlm.nih.gov/pubmed/15555007

10. Treatments  Naturopathic  special diet, smoking cessation, nutritional supplements or parenteral nutrition  may help to alleviate some of the symptoms  AVOID: alcohol or high-fibre foods  Surgery  Bowel resection, stricturoplasty, colectomy, proctocolectomy  Last line of defense after pharmaceutics/diet  Recurrence after surgery is high

11. Treatments  Corticosteroids  such as prednisone and adrenocorticotropic hormone (ACTH)  70% success for induction of remission but not maintenance  Prednisone-type: reduce tissue inflammation and thereby relieve symptoms such as rectal bleeding, abdominal pain, and fever  Adverse effects  sulfasalazine-type drugs  Contains 2 ingredients: sulfapyridine and 5-aminosalicylic acid (5-ASA)  Limited benefit, induction of remission in mild cases prednisone Sulfapyridine 5-ASA Steinhart AH, Ewe K, Griffiths AM et al. Corticosteroids for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev 2003;(4):CD000301. Summers RW, Switz DM, Sessions JT et al. National Cooperative Crohn's Disease Study: results of drug treatment. Gastroenterology 1979;77(4 Pt 2):847-69.

12. Treatments  Antimetabolites/Immunosuppresants  6-mercaptopurine (6-MP) + azathioprine  Methotrexate (minimal effect)  Infliximab (Remicaide)  Adalimumab (Humira)  [certolizumab pegol (Cimzia)]  No Canadian approval for CD Colombel JF, Sandborn WJ, Reinisch W et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med 2010;362(15):1383-95. http://www.webmd.com/drugs/2/drug-144769/humira-pen-subcutaneous/details#images http://www.webmd.com/drugs/2/drug-150396/cimzia-subcutaneous/details#images http://www.webmd.com/drugs/2/drug-16554/remicade+intravenous/details#images

13. Mechanism of action  Humira  Recombinant human immunoglobulin (IgG1) monoclonal antibody (MW=148 kD)  Specificity to human tumour necrosis factor alpha (TNFα)  A rapid decrease in CRP levels is observed in patients with Crohn's disease  Remicaide  Chimeric immunoglobulin (IgG1κ) monoclonal antibody (MW=149 kD)  Specificity to human tumour necrosis factor alpha (TNFα)  ASIDE: TNFα biological activities  Induction of pro-inflammatory cytokines such as interleukins  Enhancement of leukocyte migration  Activation of neutrophil and eosinophil functional activity  Induction of acute phase reactants and other liver proteins Canadian Pharmacists Association, 2015.

14. Mechanism of action http://www.haderermuller.com/portfolio-item/inflammatory-bowel-disease/

15. Adverse Effects  Serious infections  Allergic reactions  Neurologic events  demyelinating disorders  Malignancies  Infusion-related reactions  dyspnea, flushing, headache and rash Canadian Pharmacists Association, 2015

16. Summary  Crohn’s is a disease where a good portion of the GI tract can become inflamed due to an improper immune response  Important factors in contracting Crohn’s Disease include environmental factors (diet and smoking) as well as genetic factors (genetic inheritance and mutations)  Genetic factors can be wide ranging from mutations in the mucosal membrane to improper responses to percieved bacterial infection (examples include NOD2, MUC1, and gap junction proteins)  Physical exam, imaging tests and basic blood tests used to check for inflammation  anti-flagellin antibody (CBir1) and anti-OmpC antibody (OmpC) indicative of Crohn’s  anti-Saccharomyces cervisiae antibody (ASCA) specific and sensitive in distinguishing Crohn’s from other IBDs  Naturopathic, pharmacological, and surgical (prn)  Initial inducement of remission with steroids, followed by maintenance of remission by immunosuppresants (primarily acting on TNF-alpha)  Low incidence of adverse events with immunosuppresants  Highest incidence associated with ROA, not drug