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Archana Verma , MD Iowa Digestive Disease Center * What is Inflammatory Bowel Disease ? It is a chronic inflammatory condition of the intestine characterized by remission and relapses caused by dysregulated mucosal immune response to antigens of the normal commensal microbiota that reside within the intestine of a genetically susceptible host. Major subtypes are : Crohn’s disease Ulcerative colitis. Indeterminate ( 5% of cases) Factors leading to IBD IBD How common is IBD ? There are 1 million people with IBD in the US, equally split between UC and Crohn’s disease. The prevalence is 175 -200 per 100,000 people. The incidence/ new cases per year is 3-14 per 100,000 people About 1/3rd patients develop IBD in their teens and twenties , and there is again a bump in the sixties and seventies Women are slightly more prone to IBD Some famous people with IBD Mike Mcready David Garrard President Eisenhower Ben Morrison Shannon Doherty Mary Ann Mobley Factors Leading to IBD – Genetic Genetic Susceptibility to IBD More than 173 genes have been identified using the GWAS – The first gene identified was the NOD2/CARD15 gene o 3 independent mutations are associated with it o One increases risk of Crohn’s by 3 fold , 2 would result in a 1040 fold increase Genes in autophagy / self preservation ( ATG 16 L1) and IRGAM and TH 17 pathway ( IL 23 R) also cause IBD We have candidates but no causal gene No role of genetic testing in diagnosis What does genetic susceptibility really mean ? 3-7 % chance of a child developing IBD one parent has it Increases to 1 in 3 if both parents have it 10-25% that if you have IBD a first degree relative also has it Genetic risk is more in Crohn’s than in UC If your child has IBD, there is high degree of concordance of disease type, behavior and location Genetic anticipation Factors Leading to IBD - Microbiota IBD occurs most commonly in areas of maximum bacterial flora In animal studies , sterile gut do not develop IBD Decrease in Faecalbacterium prausnitzii in ileum increases risk of surgery Initial presentation of IBD may be precipitated by intestinal bacterial infection like E.coli or Campylobacter infection Role of Intestinal Flora Bacteriodes decrease adherence and pathogen invasion Lactobacilli secrete SCFA which promote mucin secretion / IgA Help development of microvilli circulation Control release of cytokines Long term antibiotics disrupt flora and precipitate IBD Probiotics like Saccharomyces boulardii may reduce risk of relapse Probiotics like lactobacillus may be helpful in UC Early studies of usefulness of fecal transplant in UC Pathophysiology of IBD Factors Leading to IBD - Immunology Immunology of IBD Immunology – Therapeutic Implications Target Mechanism Therapeutic Antigen Eliminate pathogenic bacterial stain Antibiotic ( Rifaximin)/ Probiotic(VSL-3 ) and worms ( Trichuris suis) T-cell / APC Interaction Manipulate T-Cell Activation Anti-CD3 ( visilizumab), CTA4lg(abatacept), azathioprine/6-MP Cytokines/ Membrane Receptors Decrease proinflammatory / Increase anti-inflammatory cytokines Anti- TNF ( infliximab, adalimumab, certoluzimab pegol, golimumab), Anti-IL 12 ( ustekinamab ) , Anti – Il 23, Anti-IFN γ, Anti-IL 6R ( Tocilizumab) , IL-10 (LLactis ) Immunology – Therapeutic Implications Target Mechanism Therapeutic Cellular recruitment Block T-cell or endothelial cell addressins Anti-α4β7 ( Natalizumab, Vedolizumab,CCX28-8), Anti MADCAM1, PF-000547659, Abaticept Inflammatory mediators Block Inflammatory Signalling Protease inhibitors, mesalamines, JAK-3 inhibitors ( Tofacitinib) Barrier Function Increase Epithelial and Repair barriers and restitution Epidermal growth factors , Stem cell therapy * No single symptom, physical finding or test result can diagnose IBD * The diagnosis is based on findings obtained from history, physical examination , laboratory , endoscopic , histologic and radiologic studies * A doctor who cannot take a good history and a patient who cannot give one are in danger of giving and receiving bad treatment. ~Author Unknown Signs and symptoms of IBD Crohn’s Disease Ulcerative Colitis Insidious onset Acute onset Abdominal pain and diarrhea – usually non - bloody Overt rectal bleeding and urgency Fever, weight loss Abdominal pain and diarrhea Perianal disease with rectal abcess and Fever with abdominal distension fistula suggests severe disease Obstructive symptoms Extraintestinal manifestations Extraintestinal manifestations r i t i s . j p g Extraintestinal Manifestations Organs Manifestation Eyes Episcleritis , Uveitis , Iritis Oral Aphthous Ulcer Dermatological Erythema nodosum , pyoderma gangrenosum, Sweet syndrome Hepatobiliary Primary sclerosing cholangitis, Cholnagiocarcinoma , Gallstones Musculoskeletal Enterpathic arthropathy, Sacrolitis, Ankylosing spondylitis, Osteopenia/osteoporosis Hematologic Thromboembolic disease Colonoscopy is the mainstay in IBD diagnosis Crohn’s Disease Ulcerative Colitis Effect from mouth to anus – ileum involved Limited to colon Patchy involvement with skip lesions Confluent inflammation from the anal verge extending proximally Deep serpeginous ulcers Diffuse superficial ulcerations Transmural inflammation Mucosal inflammation Extent of disease Crohn’s Disease Frequency Ulcerative Colitis Frequency Ileocolonic 35 % Proctitis 5-10% Small bowel only 28% Distal 44% Colon only 32% Left sided 36% Gastroduodenal 1-4% Pancolitis 18% Perianal 18% Testing for IBD Laboratory Testing Inflammation CBC/CRP/CMP Fecal lactoferrin Stool Calprotectin Malabsorption B-12 Iron studies Fat soluble vitamins Rule out infection C.Diff Cultures O/P CMV Imaging Stage Disease SBFT CT/MR enterography Capsule endoscopy Rule out complication CT scan MRI pelvis EUS Respond intelligently even to unintelligent treatment – Lao Tzu * Goals of IBD Therapy Goal Clinical Parameters Outcomes Response Improved Symptoms Improved quality of life Remission No symptoms Normal labs Decreased hospitalization Deep remission Normal endoscopy Mucosal healing Avoidance of surgery Minimal / no disability Sustained Minimize adverse effects of therapy Step-up versus Top-Down Therapy Step up AZA / MTX Steroids Budesonide 5 ASA /Antibiotics Increasing drug side effects Anti - TNF Increasing efficacy Anti - TNF AZA/MTX Combination Steroids Top Down Maintenance of Clinical remission in Crohn’s at week 54 ACCENT II FDA AdComm 030403 31 Mucosal healing in UC Rutters showed patients with UC with endoscopic healing/ histological remission had lower risk of CRC and approached risk of general population. Inception cohort- moderate to severe UC o Decreased rates of hospitalization 25% vs. 49% o Less use of immunosuppressive 5% vs. 26% o Lower rates of colectomy 3% vs. 18% Colombel showed ACTII post hoc analysis showed week 8 mucosal healing associated with decrease risk of colectomy and need for corticosteroids at week 30 and 54 Decreases risk of colon cancer Decreases need of corticosteroids Decreases risk of colectomy Step-up versus Top-Down Therapy Step up AZA / MTX Steroids Budesonide 5 ASA /Antibiotics Increasing drug side effects Anti - TNF Increasing efficacy Anti - TNF AZA/MTX Combination Steroids Top Down Common IBD Drugs– adverse effects Drug Side effect Pregnancy Category 5 ASA Interstitial nephritis B ( except sulfasalazine causes reversible sterility in men) Antibiotic Ciprofloxacin Flagyl Tendonitis Peripheral neuropathy C B Steroids Moon facies, buffalo hump , acne, sleep disturbance and mood disorders, osteoporosis, aseptic necrosis, myopathy, diabetes, weight gain, adrenal suppression, hypokalemia , opportunistic infections, cataract, glaucoma, growth retardation /C Thiopurines Hepatitis, Bone marrow suppression, Pancreatitis, Increased risk of lymphoma, infections and non-melanoma skin cancer C Common IBD Drugs– adverse effects Drug Side effect Pregnancy Category Methotrexate Mucositis , nausea, pancytopenia, pneumonitis, hepatitis and hepatic fibrosis X Cyclosporine Nephrotoxicity, opportunistic infections, seizures if cholesterol < 100 or hypomagnesaemia C Natalizumab PML - Risk 0 % if JC virus negative, If JC virus positive and drug for < 2 years and no prior immunosuppressant risk is 1 in 2000 If JC virus positive and no prior immunosuppressant duration of therapy > 2 years, risk 1 in 250 If JC virus positive and duration of therapy > 2 years and patient has been immunosuppressed , risk is in 1 in a 100 C Anti-TNF therapy – adverse effects Allergic reaction early : 3.8% -16.5% , delayed reaction:1-7 % Infections serious :3-9.9%, all : up to 25 % , twice as likely to develop especially on steroids with HR 1.98 and opioids 1.57 Hepatosplenic lymphoma – only 36 cases in IBD patients, 90% in people < 35 Combination risk of Concomtant thiopurine and anti TNF 1:22,000 for all ages Risk increases if age is < 35 Risk of thiopurine monotherapy 1:7,204 Risk of combination 1:3,534 Non-Hodgkins lymphoma 6.1 cases per 10,000 vs baseline of 1.9 cases Increased risk of non melenoma skin cancer ( Adalumimab 4.83) Pregnancy category B Benefits outweigh risks for the right patient Therapy for IBD – Pros and Cons Conventional stepup and accelerated step-up Early Top-Down Risks Lower Efficacy Higher risk of infection / mortality with repeated courses of steroids High surgical risk High risk of disease progression Risks Higher Cost, but cost effective Side effect of drugs Benefits Benefits Lower cost Higher efficacy Lower disease related complication Higher rates of mucosal healing Decreased rates of surgery / hospitalization Improvement in growth/bone formation Who should use top-down therapy Crohn’s Disease Ulcerative Colitis Diagnosis made before age 40 Severe initial presentation Ileal disease Need for corticosteroids at presentation Need for corticosteroids early Deep ulcerations on endoscopy Perianal disease Smoker Elevated CRP with low albumin and persistent stooling in spite of 3 days of IV steroids High-risk patients => benefits of top-down therapy outweigh risks Can I be tapered off combination therapy ? If in remission and tapered of inflixamab, risk of relapse is 44% Risk factors for relapse are o o o o o o o Male gender Absence of previous surgery Use of steroids within 6-12 months of infliximab withdrawal WBC >6000 Fecal calprotectin > 300 mg CDEIS > 0 Infliximab trough level > 2 mg / l If less than 2 of these factors exists, risk < 15% and may consider tapering The doctor of the future will give no medicine but will interest his patients in the care of the human frame, in diet and in the cause and prevention of disease. ~Thomas Edison * Cancer Risk and IBD Risk factors Extent of disease Duration of disease Family history of colon cancer Primary sclerosing cholangitis Screening is recommended after 8 years , after every 1-2 years Increased activity of disease Backwash ileitis Younger age of diagnosis Risk increases after 8-10 years of pancolitis by 2% at 10 years 8% at 20 years and 18% at 30 years In left side of colitis risk increases after 15 years Preventive Guidelines for patients with IBD Item Comment Bone density DEXA scan at diagnosis and repeat every 2 years Yearly DEXA scan if on corticosteroids or osteopenia with active disease Check Vitamin D once a year Calcium supplementation Cancer screening Yearly complete dermatological examination. Always use sunscreen. Cervical cancer screening with 6 monthly PAP smear and HPV testing if on AZA Breast cancer screening with yearly mammograms after 40/50 CRC surveillance discussed earlier Mal absorption Especially true in Crohn’s patients Check Vitamin B12, Fe studies and folate once a year Check fat soluble vitamins- Vitamin A and D once a year Vaccination Guidelines for patients with IBD Item Comment General Vaccinate as for general population Except live vaccines in immunosuppressed At diagnosis Varicella vaccine if no history of chicken pox and negative serologies Hepatitis B vaccine if negative serology Pneumococcal vaccine Inactivated influenza vaccine Human papilloma vaccine Annually Influenza vaccine Booster Pneumococcal vaccine in 5 years Discretionary Travel vaccines – Hepatitis A Meningococcal vaccine Family Members Usual vaccination except Rotavirus and live influenza Pregnancy and IBD PIANO registry 1115 women entered who are on immunosupressants or biological agents 896 women have delivered No increased risk of congenital anomalies Increased risk of spontaneous abortions – odds ratio is 2.56 Increased risk of pre-term labor – odds ratio is 1.83 After adjustment for pre-term birth, there was no increased risk of infection in children at 4 , 9 and 12 months “This is not the end, it is not even the beginning of the end. But it is perhaps the end of the beginning.” – Winston Churchill * Advances in medical therapy Drug Trial Outcomes Vedoluzimab In moderate to severe UC who have failed anti TNF, steroids and immunosupressives At 6 weeks CR increased by 21.7% Clinical remission by 11.5% Mucosal healing by 40.9 % Vedoluzimab In responders every 8 week infusion of 300 mg Durable mucosal healing in 42.6% Vedoluzimab Moderate to severe Crohn’s disease failed anti-TNF, immunomodulator and steroids At 10 weeks higher clinical remission, 0.6 % versus 12.1 %, decrease in CDAI 39.2% versus 22.3% Adalimumab Ultra-2 Trial In moderate to severe UC Remission of 18.5% by 8th week 40.8% at 52 weeks Trials through the Iowa IBD center Study Patient Population Drug CONTRIBUTE UC Age 18-75 Mild to moderate UC flare UCDAI>4 and <10 and Mayo score >1 despite being on oral 5ASA/ mesalamine Oral Budesonide MMX 9mg (Uceris) Pfizer A7281009 UC study Moderate to severe UC Mayo endoscopy score >/= 2 Failed/ intolerant to at least 1 conventional therapy: immunosuppressant ,Mesalamine, steroids/ anti TNF PF-00547659 A fully human IgG2 anti human MadCAM monoclonal antibody Pfizer A7281006 Crohn’s Age 18-75 Active moderate to severe Crohn's disease( CDAI 220-450) despite stable doses of mesalamine and immunosuppressant's Ulcerations on endoscopy PF-00547659 A fully human IgG2 anti human MadCAM monoclonal antibody UNITI 2 Crohn’s Age >18 Crohn's disease for 3 months with CRP>3 and fecal calprotectin >250 Ulcerations on colonoscopy Intolerant or failed steroids/immunosuppressive No previous antiTNF exposure A fully human IgG1K monoclonal Ab to IL12/23 p40 which binds to IL12/23 The doctor is often more to be feared than the disease. ~French Proverb *