I nflammatory Bowel Disease: Ulcerative Colitis and Crohn’s Disease Update

1. Inflammatory Bowel Disease:Ulcerative Colitis and Crohn’s Disease Update Dr. Shelley Rahn October 13, 2017

2. Topics We Will Cover - IBD Etiology Similarities and differences Treatment update Underwriting concerns Cases

3. –Spastic colitis Mucous Colitis What we will not cover IBS - IrritableBowelSyndrome

4. Common Features • Inflammatory bowel diseases • Cause mostly not understood • Genetic predisposition • Autoimmune component • Multifactorial • Symptoms • Gastrointestinal bleeding • Ulceration • Abdominal cramps/pain • Diarrhea • Weight loss • Relapse/remission • Extraintestinal manifestations • Increased cancer risk in affected large intestine after 8-10 years since disease onset • Treatment

5. Extraintestinal manifestations Bold = more common in UC than Crohn’s, R = more common in Crohn’s

6. Common Laboratory Manifestations

7. Clinical Evaluation – Imaging/Endoscopy

8. Microsocpic: Granulomas Microsocpic: No Granulomas Complications: Abscesses Fistulas Strictures Complications: No abscesses No fistulas Toxic megacolon Stricture only if there is cancer Celgene.com

9. Crohn’s and Ulcerative Colitis Endoscopic Images

10. Crohn’s

11. Ulcerative Colitis Images

12. UC VS Crohn’s Ulcerative Colitis Crohn’s

13. Crohn’s vs Ulcerative Colitis

14. Crohn’s vs Ulcerative Colitis (cont’d)

15. ULCERATIVE COLITIS

16. Treatment • Historical perspective • Crohn’s and Ulcerative Colitis can be chronic, frequently disabling diseases • Relapsing/remitting course • Surgical intervention • Poor quality of life • Often starts in younger ages causing years of low productivity (although there is a second peak onset in older women ages 60-70) • Steroid dependence

17. Treatment • Steroids (immune suppressants) prednisone budesonide • 5-ASA preparations – sulfasalazine, mesalamine • Antibiotics – metronidazole, rifaxamin, cipro • Non-Steroidal Immunosuppressants • Non-biologics • Biologics

18. Nonsteroidal immunosuppressants: • Non biologics – oldies, ? goodies • Methotrexate (MTX) • 6-mercaptopurine -6MP (Purinethol) • Azathioprine (Imuran) • Cyclosporine, tacrolimus • Biologics – relatively new kids on the block, very effective • Tumor necrosis factor (TNF) inhibitors • Anti -integrins or Integrin inhibitors

19. Biologics • TNF inhibitors (Anti TNFs) • infliximab (Remicade) • adalimumab (Humira) • certolizumab (Cimzia) • ustekinumab (Stelara) • golimumab (Simponi) • Integrin inhibitors (Anti-integrins) • natalizumab (Tysabri) – rarely causes white matter disease of the brain • vedolizumab(Entyvio) no adverse brain effect – does not cross blood brain barrier • etrolizumab

20. Biologics • What makes them biologic? • They are “manufactured” in living cells – yeast, bacteria or human cell lines • They are antibodies • If they work so well, why aren’t they used as first line drug? • Life long commitment thus far • Expensive • Infusion or injected • Side effect profile

21. Biologics: What’s New? • Biologics are being used more commonly and earlier in disease course • No longer reserved for severe disease only • Side effect profile better understood and less frightening • Infection risk and possible lymphoma risk – probably similar to non-biologics - small risk, worse if combined with non-biologicsand/or steroids • Newer anti integrin – vedoluzimab (Entyvio)-safer

22. Adverse Effects of Biologics • Injection site reactions • Infusion reactions (immediate and delayed) • Joint aches, muscle aches, fatigue, fever • Serious infection • Tuberculosis (screen with PPD) • “Opportunistic infections” (legionella, listeria, fungal) • Activation of Hepatitis B or C • Demyelinating disease? (relationship not established) • Heart failure/pulmonary disease (no clear evidence) • Malignancy

23. Biosimilars – the future • New formulations of biologics • Nearly identical to “reference” or “originator” biologic • Same clinical activity, safety profile, purity • Different inactive components • Theoretically cheaper

24. FDA Approved Biosimilars

25. Malignancy • The only malignant condition for which a clear relationship has been established is non-melanotic skin cancer

26. Case #1 • 28 y o female attorney: • a)Life - $1 million of term and • b)Disability- $3000/month benefit, 90 day elimination period, to age 65 benefit period, future insurability rider (extra cost to allow additional monthly benefit with financial underwriting only) • On application • Colitis diagnosed 7 years ago • Last visit one year ago • Meds: Imuran, Asacol (mesalamine preparation – 5-ASA)

27. What do you want to know? • What disease does she have? Crohn's or UC • What has been the clinical course? • If Crohn’s: • Other parts of GI tract involved • Abscess, fistula, surgery • Perianal disease

28. What do you want to know? (cont’d) • If either Crohn’s or UC: • Degree of severity with flares weight loss, bleeding, anemia • Responsiveness to treatment • Specific medications • Extraintestinal manifestations – joints, back, skin, biliary disease • Degree of adequate follow up – most recent colonoscopy • History of surgery and type of surgery • Current labs – albumin, liver enzymes

29. Underwriting considerations - UC Favorable • Disease stability • Sulfasalazine or other 5 ASA medication or no treatment • Disease limited to proctitis • Routine colonoscopy for disease ≥8-10 years • Currently asymptomatic • Symptoms mild with flares • Normal LFTs especially alkaline phosphatase– no sclerosing cholangitis • No extracolonic symptoms • No current anemia (when data available) • Normal serum albumin (when data available) • No dysplasia or colon cancer

30. Underwriting considerations - UC Unfavorable • Recent diagnosis (within past 6 months to a year) • Immunosuppressant medications • Disease beyond the rectum • Inadequate surveillance colonoscopy • Current symptoms • Severe symptoms with disease flares • Abnormal LFTs- particularly Alkphos and GGT • Extracolonic symptoms • Current anemia Hgb ≤ 10.5 (when data available) • Serum albumin <3.8 (when data available) • Dysplasia or colon cancer

31. Crohn’s Disease UW ConsiderationsFavorable • Diagnosis older than age 25 • Mild symptoms • BMI ≥ 18 • No anemia • Serum albumin ≥ 3.8 - 4.0 • No surgery • No prolonged steroid use • No immunosuppressant use • Diagnosis more than 3-5 years ago • Mild or no extra-intestinal manifestations • Adequate follow up

32. Underwriting Considerations – Crohn’s Unfavorable • Moderate to severe symptoms • BMI <18 • Anemia • Serum albumin < 3.8 - 4.0 • Immunosuppressant other than occasional steroids or methotrexate • History of surgery, abscess, stricture, fistula • Diagnosis less than 5 years ago • Inadequate follow up

33. APS information • Crohn’s colitis and terminal ileitis diagnosed 9 years ago – abdominal cramps, bloody diarrhea. Not hospitalized • Diagnosed by colonoscopy with skip lesions, terminal ileum involvement, granulomas on biopsy • No extraintestinal manifestations • Initially treated with prednisone and mesalamine • Improved but relapsed whenever prednisone was tapered • Started Imuran about 7 years ago and has been stable since • Current labs normal • BMI 22- stable • No history of surgery • Last colonoscopy 7 years ago

35. Severity of disease/Mortality and Morbidity Risk • Mild, Moderate or Severe • Flares easily controlled but requires immunosuppressant therapy • Otherwise stable Moderate Crohn’s (not the same as mortality risk) • Assess based on mortality/morbidity associated with • Underlying disease – risk of progression, complications including colon cancer • Treatment – risk of medications – infection, malignancy

36. Mortality Risk • Mortality risk has been studied in populations – • Some studies indicate similar to population (not the same as an insured population) • Other studies find 50% increase mortality over standard population • So how do we assess mortality • Have to assess on an individual basis as those with complications have a higher mortality • Poorly responsive to medication, fistulas, abscesses, multiple surgeries, recurrent infections

37. “What ifs?” • What if she was 11 years since diagnosis with no colonoscopy in 5 years? • risk of colorectal cancer increases by 0.5-1% per year. • What if she had a recent colonoscopy with finding of pseudopolyps? • What if she had a recent colonoscopy with low grade dysplasia? • Incidence of cancer is 2-3/100 person years • What if her labs showed alkaline phosphatase of 210/GGT 150?

38. What if she was a trial attorney? • Beware of stress related comments in the APS • Be aware of occupation limiting access to bathroom facility

39. Case #2 • 28 y o female attorney: • a)Life - $1 million of term and • b)Disability- $3000/month benefit, 90 day elimination period, to age 65 benefit period, future insurability rider (extra cost to allow additional monthly benefit with financial underwriting only) • On application • Crohn’s colitis diagnosed 7 years ago • Last visit one year ago • Meds: Remicade (infliximab), Asacol (mesalamine preparation – 5-ASA) Does this alter risk assessment?

40. Case #3 - What if she was not on immunosuppressants? • 28 y o female attorney: • a)Life - $1 million of term and • b)Disability- $3000/month benefit, 90 day elimination period, to age 65 benefit period, future insurability rider (extra cost to allow additional monthly benefit with financial underwriting only) • On application • Crohn’s colitis diagnosed 7 years ago • Last visit one year ago • Meds: Asacol (mesalamine preparation – 5-ASA) Does this alter risk assessment?

41. What if she told us on the application that she had colitis since 2001, on dicyclomine? • Need to determine if this is IBD or IBS (inflammatory bowel disease or irritable bowel syndrome) • Dicyclomine (Bentyl) - not usually for IBD, mostly used for IBS

42. Summary • Complicated diseases with many factors to consider • Mortality risk – devil is in the details – can be low to uninsurable • Morbidity risk – can truly be disabling but motivation, occupation can play a major role • Biologics have been miracle drugs and have changed the course of the disease • More drugs surely to come • Better screening for colon cancer risk will come eventually

43. Questions