Managing. Inflammatory Bowel Disease. Slide 1. Slide 2. Slide 3. Disclosures. Vijay Yajnik, MD., PhD 01/25/14. None relevant to this talk

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1 Slide 1 Managing Inflammatory Bowel Disease Vijay Yajnik, MD., PhD 01/25/14 Slide 2 Disclosures None relevant to this talk 2 Slide 3 Inflammatory Bowel Disease Topics Covered My friend called me and she thinks her daughter has Crohn s disease? What is the best way to diagnose IBD? Key Concepts in managing IBD Overview of drugs Post op patient Pregnant patient 3

2 Slide 4 Key observations in IBD Prevalence differs among ethnic groups Maternal twins (44%) Fraternal twins(3.8%) Genetics Immune Cytokine Imbalance System Down regulating immune system can be effective therapy Link to genetically susceptible hosts IBD Microbiome Environment Microbial community structure metagenome Gut-microbe interactions Antigen Trigger (food Ag, or toxins) Hygiene or Urban Areas Smoking 4 Slide 5 Case #1 29 year old male with diarrhea- Workup at MGH/North Shore General: normal appearing male Physical exam shows mild abdominal tenderness and normal rectal exam with occult bleeding Investigations Anemia, with both Iron and B12 deficiency, Liver and pancreatic tests are normal Stool culture is negative and microscopy shows many White blood cells Patient was booked for a CT scan with emphasis to investigate small bowel. CT shows inflammation of ileum and descending colon Slide 6 When to suspect IBD Common Symptoms Bleeding Diarrhea Abdominal Pain Constipation Bowel obstruction Extra intestinal Manifestation Malnutrition Iron and B12 deficiency Anemia Loss of Weight

3 Slide 7 Pattern of Mucosal Injury Cobblestone Ulcers (punched) Ulcers (linear) Swollen mucosa Pseudopolyps 7 Slide 8 IBD: Anatomic Classification Ulcerative Colitis: starts in the rectum and extends proximal Proctitis (rectal involvement only, with a maximal extent of 10cm from the anal verge) Proctosigmoiditis (inflammation is limited to the rectum and sigmoid) Left sided ulcerative colitis (inflammation does not extend proximal to the splenic flexure) Pancolitis (inflammation extends proximal to the splenic flexure) Crohn s disease: can involve any part of the GI tract Crohn s ileitis (only small bowel) Crohn s colitis (only the colon involved) Crohn s ileocolitis (both the small bowel and large bowel are involved) Slide 9 IBD: Pathology Ulcerative Colitis Acute and chronic inflammation limited to mucosa and the sub mucosa Diminished quantity of goblet cells and many crypt abscesses Diseased segment of the colon is continuous and starts at the rectum Crohn s Disease Patchy disease with normal bowel present between affected areas. Trans mural inflammation with sub-mucosal edema, lymphoid aggregation resulting in fibrosis, perforation and fistula formation Sub mucosal inflammation has a cobblestone appearance Hallmark epitheliod granuloma, found anywhere from mouth to anus 9

4 Slide 10 Extra-intestinal Manifestations Peripheral arthritis -type 1 (more common) asymmetric oligoarticular arthritis affecting large joints (knees, ankles, wrists, elbow); normal plain film; self limited and follows course of IBD -type 2 more chronic and symmetric poly arthritis (similar to RA but RF negative) ; activity follows CD activity; Hematologic disease -Anemia (B12, Fe, folic acid deficiency) -Thrombosis: 1-39% (DVT or PE, UC > Crohn s Slide 11 Extra-intestinal Manifestations Dermatologic Disease Erythema nodosum: 10-20% of IBD patients, correlates well with bowel disease activity Pyoderma gangrenosum: 1-10% of IBD patients, UC>CD, independent of IBD activity Psoriasis: 10% frequency in CD Sweet s syndrome (acute febrile neutrophilic dermatosis), rare, parallels disease activity Aphthous and angular stomatitis Erythema multiforme: 25% of patients have CD Metastatic CD: granulomas at extra-gi sites Slide 12 Extra-intestinal Manifestations Erythema nodosum Pyoderma Gangrenosum Metastatic Crohn s Disease

5 Slide 13 Extra-intestinal Manifestations Ophthalmic diseases - 2-5% of UC and 3-6% of CD Episcleritis: no loss of vision, parallels bowel activity - The condition is characterized by increased redness and tenderness of the eye. On occasion, there is tenderness upon moving the eyes from side to side and/or up and down. Uveitis: may progress to blindness without Rx, independent of bowel activity Symptoms of uveitis include: - light sensitivity - blurring of vision - eye pain (often described as an aching sensation) - redness of the eye. Slide 14 UC Symptom Summary characterized by exacerbations and remission Onset may be insidious or abrupt Rectal bleeding with mucous is the most common symptoms Severe disease may evoke abdominal pain with distention, fever, tachycardia, elevated WBC. This is a medical emergency. Extra-intestinal symptoms in up to 36% of patients Slide 15 Crohn s Symptom Summary characterized by exacerbations and remission Onset may be insidious or abrupt Disease location determine symptoms but overall rectal bleed is not common. Abdominal pain with distention, loss of weight, iron and B12 deficiency Extra-intestinal symptoms and fistula are often present at time of diagnosis.

6 Slide 16 Laboratory studies May be normal in mild disease but check CBC with differential counts, LFTs, Chemistry and markers of inflammation ESR and CRP. Acute phase reactants- ESR and CRP are helpful in identifying response to medication and disease exacerbations. Fecal Calprotectin and Lactoferrin are sensitive but not routinely accepted. Serology available through Prometheus labs can be useful. Slide 17 Serology in IBD Antibody Antigen Crohn s UC ASCA Mannose of S cerevisciae + - ANCA Neutrophils UC like CD + PAB Pancreas + + ompc Outer Membrane Porin Pseudomonas fluorescence + - CBir1 Flagilin + - ACCA Glycan (chitobioside) + - ALCA Glycan (laminariboside) + - AMCA Glycan (mannobioside) + - Slide 18 Diagnosis: CT scan

7 Slide 19 Colonoscopy Diagnosis Colonoscopy with or without EGD Intubation of terminal ileum Biopsy of ileum and colon Slide 20 Diagnosis Colonoscopy with ulcers in ileum and descending colon Slide 21 Long term effects of Crohn s disease Cumulative probability of remaining free of symptoms (%) Inflammatory n=2002 Patients with Crohn s disease since diagnosis of the disease Penetrating Stricturing

8 Induction therapy Maintenance Therapy Follow up care Slide 22 Goals of Medical Therapy in IBD Reduce signs and symptoms of disease within 4-6 weeks Suppress disease activity and restore bowel function by sustained mucosal healing Focus is to prevent long term complications such as stricture, fistula, malnutrition and cancer 22 Slide 23 Advances in IBD Radiology Surgery Small Bowel CT Low Radiation scanners MR imaging Laparoscopy 23 Slide 24 Strategies to induce remission 5ASA Steroids Biologics 24

9 Slide 25 Strategies to maintain remission 5ASA Immune modulators Biologics 25 Slide 26 5 Aminosalicylates (5-ASA) Common drugs Dosing Efficacy Safety Asacol Delzichol Colazol Apriso Lialda Canasa 3x day but once daily options available Rectal formulations for proctitis Data in Ulcerative colitis Less effective in Crohn s Well tolerated Used in pregnancy There can be side effects 26 Slide 27 Steroids Common drugs Dosing Efficacy Safety Prednisone Budesonide for ileal disease MMX budesonide (UCERIS) 1x day b Rectal formulations for proctitis available as foam and suppository Effective in UC and CD Indicated for short term induction therapy Well tolerated Used in pregnancy Acute side effects Contraindicated for long term use 27

10 Slide 28 Immune Modulators Common drugs Dosing Efficacy Safety Imuran or azathioprine Mercaptopurine or 6MP 1x day Weight based Genetic test can help define the dose of the drug Effective in UC and CD Indicated for maintenance therapy as it takes 6 weeks to take effect Well tolerated Not Used in pregnancy Risk of liver, pancreas, bone marrow dysfunction Lymphomas 28 Slide 29 Advances in Medical Therapy 5-ASA Steroids Immune modulators Safety Sustained release Budesonide MMX Budesonide Drug monitoring 29 Slide 30 Biologics: 4 generations of Anti-TNF Remicade Humira Cimzia Simponi Antibody raised in mice Infused every other month Humanized antibody Self inject every other week Antibody fragment that has PEG Self inject once a month New anti TNF Humanized Monthly self injections 30

11 Slide 31 Biologics: Indications Moderate to severe CD CD with fistula UCremicade,,humira and simponi Efficacy Effective in CD Less effective in UC Safety Well tolerated >10 years of safety data Safe in pregnancy TB Lymphomas 31 Slide 32 Biologics: Treatment approach Biologics Immune modulators 5-ASA 32 Slide 33 Biologics Top Down therapy Biologics Immune modulators 5-ASA 33

12 Slide 34 Adverse Events on anti TNF Infusion reactions Acute 3.8% Delayed 2.8% Infection (8.2% overall, 4% serious) Autoimmune phenomena ANA (57%) anti-ds/ssdna, anti-histone Ab Lupus-like syndrome (0.6%) Demyelinating disease (0.2%) Worsening of CHF Hepatic failure Cancer/ Lymphoma Slide 35 How effective is anti TNF therapy? Within a few weeks of starting treatment of an anti-tnf drug 40% do not have improvement in their symptoms 60% do have improvement in their symptoms Continued anti-tnf or placebo For those who improve, after 1 year of either continued treatment with the anti-tnf medication or placebo, this is what happens: Anti-TNF Placebo How many people were free from symptoms and off of prednisone? 29% 7% Slide 36 When Biologics Fail Re-evaluate Surgery Clinical trials Is there an infection? Is this cancer? Should we use steroids or immune modulators? Good option in certain cases Disease may not be treatable by surgery Ustekineumab Tofacitinib Vedolizumab 36

13 Slide 37 Advances in Medical Therapy Anti TNF Natalizumab Drug level UC indication JCV safety 37 Slide 38 Indications for Surgery in IBD Ulcerative Colitis Crohn s Disease Disease failing medical therapy Patient unwilling to take lifelong immune Rx Colitis associated colon cancer Disease failing medical therapy Narrowing or stricture formation Abscess or perforation Fistula to the bladder, vagina and in some cases to the skin Dysplasia or cancer 38 Slide 39 Loss of anti TNF response leading to surgery Laporoscopy 23 cm of disease Ileum removed with Reconnection

14 Slide 40 Post op assessment Discuss the operation with surgeon Define the risk for repeat surgery Smoker Number of surgeries How did the pathology lab grade the diseased bowel: Scarred with narrowing vs fistula vs deep fissures with abscess Genetics 40 Slide 41 Risk factors for Crohn s Disease recurrence after surgery Penetrating disease Multiple surgeries Active smoking Was active disease left behind Ist surgery at an early age 41 Slide 42 Treatment approach: Risk stratification Low Risk Endoscopy to evaluate surgical anastamosis at 6 months Treat > 6 ulcers High Risk Aggressive medical therapy Rx with anti TNF 2 weeks after surgery 42

15 Slide 43 Risk stratification at 6 month colonoscopy Anastamosis Small Bowel A Normal Healthy bowel B 43 Stricture Healthy bowel beyond stricture Following balloon dilation Slide 44 Risk stratification at 6 month colonoscopy Anastamosis Small Bowel Inflammation with >6 ulcers Treat the patient 44 Slide 45 Efficacy of Medical therapy after surgery in Crohn s disease Low Good Excellent Mesalamine Select Antibiotics 6 MP azathioprine Remicade Humira Cimzia 45

16 Slide 46 Symptoms in patients with J pouch Irritable pouch pouchitis Cuffitis Crohn s Disease 46 Slide 47 Strategies to treat J pouch issues Irritable pouch Anti spasmodics Pouchitis antibiotics Cuffitis 5-ASA steroids Crohn s Steroids immune modulators and Biologics 47 Slide 48 Pregnancy and IBD Normal fertility in inactive Crohn s disease and UC; decreased in women with active disease J-pouch decreases fertility significantly (70%), course of pregnancy is shortened For women with IBD in remission before pregnancy, 2/3 remain in remission through pregnancy and postpartum Flares occur most commonly during the first trimester and postpartum Controlled vaginal delivery is an option Increase risk of preterm delivery

17 Slide 49 Pregnancy and IBD Endoscopy is safe but we all are reluctant to do it Biologic therapy is overall safe Third Trimester issues Imuran may be OK as recent data is supportive Methotrexate is toxic to embryo, therapeutic abortion is recommended Slide 50 Immune suppressed patients Office visit with PCP, nursing encounter in endo or infusion suite Interval History Discuss that disease (UC and Crohn s) and ongoing medical therapy Discuss alarm symptoms Labs with focus on bone marrow, liver, pancreas, vitamin levels Discussion of Colonoscopy for surveillance. Cancer Prevention Surveillance: PAP smears, PSA, Mamogram Bone density scan Yearly TB testing Hepatitis screen Skin check- basal and squamous cell cancers Slide 51 Vaccines for immune suppressed patients Avoid live vaccines. BCG MMR Smallpox Varicella Zoster Yellow Fever Adenovirus Typhoid live (polysaccharide OK) Cholera live (killed, use with caution) Tick-borne encephalitis (use with caution) Influenza

18 Slide 52 Discuss IBD patients 32 y/o female with new onset Crohn s disease and prei anal fistula 32 year old female on infliximab for 3 years complains of a rash, muscle aches, joints stiffness 32 year old female with steroid dependent ulcerative colitis, pancreatitis on 6MP and SOB after 2 doses of remicade 52