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

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

Mucous Colitis –Spastic colitis What we will not cover IBS - Irritable Bowel Syndrome

Inflammatory bowel diseases Cause mostly not understood 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

Extraintestinal manifestations Improve with improved IBD Independent of activity of IBD Arthritis – pauciarticular asymmetric, less than 5 large joints, migratory Arthritis polyarticular, symmetric, 5 or more small joints Episcleritis Ankylosing spondylitis Sacroiliitis Aphthous ulcers Uveitis Erythema nodosum Primary sclerosing cholangitis (PSC) Pyoderma gangrenosum Bold = more common in UC than Crohn’s, R = more common in Crohn’s

Common Laboratory Manifestations Iron deficiency anemia Low serum albumin Elevated sedimentation rate (ESR) Elevated C reactive protein (CRP) Fecal calprotectin Serologic testing – pANCA, ASCA – Prometheus testing

Clinical Evaluation – Imaging/Endoscopy Upper GI series with small bowel follow through CT scan CT enterography MR enterography Upper endoscopy Colonoscopy with evaluation of the terminal ileum Small bowel enteroscopy

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

Crohn’s and Ulcerative Colitis Endoscopic Images

Crohn’s

Ulcerative Colitis Images

UC VS Crohn’s Ulcerative Colitis Crohn’s

Crohn’s vs Ulcerative Colitis CROHN’S ONLY ULCERATIVE COLITIS ONLY Entire GI tract Colon only Rectum always Skip lesions Continuous – no skip areas Intestinal narrowing (strictures) Strictures only if cancer present Abscess formation Fistulas (bowel to bowel, skin, or GU tract Granulomas on micro exam

Crohn’s vs Ulcerative Colitis (cont’d) CROHN’S ONLY ULCERATIVE COLITIS ONLY Perianal disease Rare Toxic megacolon rare Toxic megacolon rare but more common than Crohn’s Surgery not curative Proctocolectomy curative

ULCERATIVE COLITIS

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

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

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

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 Add in biosimliars

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

Biologics are being used more commonly and earlier in disease course 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-biologics and/or steroids Newer anti integrin – vedoluzimab (Entyvio)-safer

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

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

FDA Approved Biosimilars Date of Biosimilar FDA Approval Biosimilar Product Original Product March 6, 2015 filgrastim-sndz/Zarxio filgrastim/Neupogen April 5, 2016 infliximab-dyyb/Inflectra infliximab/ Remicade August 30, 2016 etanercept-szzs/Erelzi etanercept/Enbrel September 23, 2016 adalimumab-atto/Amjevita adalimumab/ Humira April 21, 2017 infliximab-abda/Renflexis August 25, 2017 adalimumab-adbm/Cyltezo September 14, 2017 bevacizumab-awwb/Mvasi bevacizumab/Avastin

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

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)

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

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

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

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 Alk phos and GGT Extracolonic symptoms Current anemia Hgb ≤ 10.5 (when data available) Serum albumin <3.8 (when data available) Dysplasia or colon cancer Add in dysplastic associated mass lesions

Crohn’s Disease UW Considerations Favorable 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

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

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

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

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

“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?

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

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?

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?

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

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

Questions