Medical Management of Inflammatory Bowel Disease Freddy Caldera D.O. Assistant Professor Division of Gastroenterology Objectives Discuss Crohn s disease and Ulcerative Colitis Discuss Medications for Inflammatory Bowel Disease Treatment goals for Inflammatory Bowel Disease Review appropriate Vaccination for IBD population. Inflammatory Bowel Disease Inflammatory Bowel Disease Conditions characterized by chronic or relapsing immune activation and inflammation within the gastrointestinal tract. Crohn's disease and ulcerative colitis (UC) are the two major forms of idiopathic IBD Less common, but increasingly recognized, are the microscopic colitis primarily collagenous colitis and lymphocytic colitis Is NOT An Allery An immune deficiency Is Inflammatory active immune system in the intestinal tract Chronic last a long time (maybe lifetime) Treatable Current Etiologic Hypothesis for IBD Microbial flora Inflammatory Bowel Disease (IBD) Approximately 1.4 million Americans have IBD 70,000 new cases each year Lack of infections (Hygiene Hypothesis) 58 1
Incidence IBD < 1960 Incidence 1980-2008 Epidemiology of IBD Onset of IBD Wisconsin study: incidence for CD 4.56 (95% CI, 3.77-5.35) incidence for UC 2.14 (95% CI, 1.6-2.68) Mean age at diagnosis 12.5 y Only 11% had a family Hx of IBD 6% 4% 2% 0.5% 6% 4% 2% 2% 87% 86% Wisconsin New IBD Diagnosis Wisconsin Pediatric Population Kugathasan et al. J Pediatr 2003;143:525-31. What is Ulcerative Colitis? Ulcerative colitis location and extent Inflammatory bowel disease involving the large intestine (colon and rectum) Variable extent of large bowel involvement Almost always starts in the rectum and may involve more bowel or progress proximally Major symptoms usually come from the inflamed rectum Disease is characterized in most patients by active inflammation alternating with periods of quiescence (remission) Cause remains unknown, triggers of onset are usually not identifiable. 28% 25% 47% 58 2
Presentation of UC Symptoms depending on extent and severity of inflammation Bloody diarrhea Abdominal cramping Tenesmus fecal urgency Systemic symptoms, fever, decreased stamina, weight loss Natural history of UC Disease progress in 54% of patients within 5 years of diagnosis Complications highest among pancolitis patients 20-38% ultimate require proctocolectomy Increased risk of colon cancer Ulcerative Colitis Disease Activity What is Crohn s disease? Inflammatory bowel disease involved the entire GI tract (mouth to anus) Disease is characterized in most patients by patchy inflammation which alternates between periods of active disease and periods of quiescence. Inflammation is full-thickness Fistulas and strictures occur Symptoms depend on extent and severity of disease Crohn s disease location and extent Clinical presentation of Crohn s disease Ileocecal disease: abdominal pain, diarrhea, fever Colonic disease: bloody diarrhea, weight loss, fever Perianal disease: pain, fistulae, fissures 58 3
Clinical Criteria for Crohn s Disease Activity Mild to moderate disease Ambulatory, no abdominal tenderness, painful mass, or obstruction Moderate to severe disease Unresponsive to treatment for mild to moderate disease with prominent fever, weight loss, anemia, abdominal pain and tenderness or intermittent nausea or vomiting Severe fulminant disease Persistent symptoms on corticosteroids or with high fever, rebound tenderness, cachexia or abscess What is clinical remission? A) Getting rid of all inflammation B) Achieving symptom relief C) Curing the disease D) Decrease symptoms What drug classes are available for treatment? Aminosalycilates Immunomodulators Biologics Non-TNF Biologics Steroids Induction Therapy Induction Achieve quick treatment response and clinical remission Decided based on severity of disease Options Aminosalycilates Steroids Anti-TNF Agents (Biologics) Maintenance Therapy Maintenance Prevents relapses and maintains long term clinical remission Therapy depends on severity of disease Corticosteroid sparing therapy Options Aminosalycilates Immunomodulators Anti-TNF Agents (Biologics) Non-TNF Biologics Goals of Therapy Establish and maintain symptom control (clinical remission) Control inflammation Prevent flare-ups of disease (maintain remission) Reduce complications Reducing the need for surgery Improve quality of life In children facilitating normal growth 58 4
Crohn s Disease: 1960 s historical perspective We have come along way. Treatment limited to sulfasalazine and prednisone. No need for algorithm, because limited options available Principles of IBD Treatment Since it s an autoimmune condition most cases are treated with immunosuppressant. Mild cases can be treated with nonimmunosuppressant's. Steroids are temporary and do not make inflammation better. Serious Potential Adverse Effects From Prolonged Corticosteroid Therapy Adverse effect Infection Hypertension Diabetes Osteonecrosis Osteoporosis Myopathy Cataracts Glaucoma Psychosis Use of corticosteroids in IBD should always have an effective exit strategy. Lichtenstein GR et al. ACG 2008;Abstract 14 Sandborn WJ. Can J Gastroenterol. 2000;14(suppl C):17C-22C 28 Aminosalycilates Sulfasalazine initially developed to treat rheumatoid arthritis by Swedish physician Nana Svartz in 1938 Effective in inducing and maintain clinical remission: Mild to moderate Ulcerative Colitis Mild Crohn s disease affecting Colon Immunomodulators Two commonly used are Methotrexate and Azathioprine Steroid sparing agents 6MP/Azathioprine Developed in the late 50 and early 60 By George Hitchings and Gertrude Elison Used in Childhood leukemia and Organ transplantation Used since the 1980 Methotrexate Used in rheumatoid arthritis Evidence that its effective in Crohn s disease 58 5
6MP/Azathioprine Efficacy Effective in moderate Crohn s and Ulcerative Colitis Can take 3-4 months to work Maintenance Therapy Remission rates 30-40% Methotrexate Efficacy Effective in maintain clinical remission in moderate Crohn s disease Delivered SQ or IM Folate supplementation is needed Not PO (like used by rheumatologist) Maintenance Medication Effective 30-40% of the time Infliximab Biologics Adalimumab Certolizumab Pegol TNF inhibitors Mechanism of Action IgG 1 Chimeric monoclonal antibody (75% human IgG 1 isotype) IgG 1 Human recombinant antibody (100% human IgG 1 isotype) PEG VL No Fc PEG VH CH 1 Humanized Fab fragment (95% human IgG 1 isotype) Interfere with body inflammatory response targeting specific cytokines Targeted treatment as opposed to corticosteroids provide more general suppression Work by binding and preventing activity of tumor necrosis factor alpha (TNF-alpha) TNF cytokine promotes inflammation in intestine and other organs. Mouse Human PEG, polyethylene glycol. TNF inhibitor Efficacy Effective in inducing and maintaining clinical remission in severe Ulcerative Colitis and Crohn s disease. SQ or IV One year maintenance rates of 40-50% Anti-integrin integrin Mainly acts by affecting white blood cell migration Natalizumab efficacious for Crohn s disease and Multiple sclerosis Rare side effect of PML limits it use Vedolizumab Gut specific No Risk of PML FDA approved for Crohn s and Ulcerative Colitis 58 6
Selective anti-adhesion molecules : Rationale Conventional and evolving treatment strategies in CD leukocyte vercirnon CCR9 integrins Brain Bone marrow natalizumab α 4 β 1 Gut α 4 β 7 natalizumab Vedolizumab, rhumab-beta7 addressins PF-00547659 VCAM-1 MadCAM-1 endothelium Ordás I et al. Gut 2011 Early top-down biologic therapy vsconventional management of Crohn s disease CDAI <150 AND no steroids AND no surgery Remission With No Corticosteroid Therapy Top-Down vs Step-Up 80 Top-Down P < 0.001 P = 0.006 P = 0.03 Step-Up P = 0.80 P = 0.43 Patients (%) * * ** Patients in Remission (%) 60 40 20 *p<0.01 **p<0.05 Weeks D Haens G, et al. Lancet 2008;371:660-7. 0 Week 14 Week 26 Week 52 Week 78 Week 104 D Haens GD, et al. Lancet. 2008;371:660 667. Early promotion of mucosal healing to prevent complications Weighing the Value of Top-Down Therapy Benefits Evidence of 6-MP/AZA and infliximab promoting mucosal healing Serious side effects Development of antibodies (biologics) Cost Disadvantages Majority of patients do not require more potent treatments initially Percent of patients (%) 100 80 60 40 20 The impact of CE studies: SONIC: Corticosteroid-Free Clinical Remission at Week 50 22.7 Patients with CRP 0.8 mg/dl andlesions on Baseline Endoscopy* P=.016 P=.002 41.5 P=.354 50.0 0 17/75 27/65 32/64 AZA+ placebo IFX + placebo IFX + AZA * Patients who did not enter the study extension were treated as nonresponders Lichtenstein GR et al. Inflamm Bowel Dis. 2004;10:S2 S10. Caprilli R et al. Digestive Liver Dis. 2005;37:973 979. AZA=azathioprine; IFX=infliximab Colombel JF, et al. N Engl J Med. 2010 58 7
Early top-down therapy with azathioprine is not more effective than placebo or conventional therapy RAPID AZTEC Discontinuation of Infliximab in Stable Remission on Combination Therapy (azathioprine maintained) n=52 relapses/115 patients Median follow-up 28+/- 2 months STORI Median time to relapse: 16.4 months Cosnes J et al. Gastroenterology 2013;145: 758-65 Panes J et al. Gastroenterology 2013;145: 766-74 Louis E et al. Gastroenterology. 2012;142:63-70. Mucosal Healing and Time to Colectomy in Infliximab- treated Patients: Endoscopy Subscore 0 1 2 3 The Natural Course of Postop CD Recurrence is clinically silent initially 1 Proportion without colectomy or commercial IFX use 0.75 0.5 0 10 20 30 40 50 Time to colectomy or commercial IFX use (use) 0 = NORMAL 1 = MILD 2 = MODERATE 3 = SEVERE Histologic Within 1 week Endoscopic 70-90% by 1 yr Radiologic Clinical Surgical Tissue damage 30% 3 yr 60% 5 yr 50% by 5 yrs Surgery Colombel JF, Sandborn WJ, et al. Gastroenterology 2011;141:1194-1201. [1] D Haens G, Geboes K, Peeters M, et al. Gastroenterology 1998;114:262-267. [2] Olaison G, S medh K, Sjodahl R. Gut 1992;33:331-335. [3] Rutgeerts P, Geboes K, Vantrappen G, et al Gastroenterology 1990;99:956-983. [4] Sachar DB. Med Clin North Am 1990;74:183-188. >70% of Patients have i2,3,4 Recurrence 1 Year i1 after Surgery i0 i2,i3,i4 and i1 recurrence remission -low Likely likelihood progression of progression to another surgery Rutgeerts et al Gastro 1990 Preventive care Recommended? 26yo with newly diagnosed Crohn s disease with ileal and perianal disease starting TNF therapy What preventive measures would you recommend? i,3 i4 i2,i3,i4 recurrence Likely progression to another surgery 58 8
Why do does it matter? Many patients with IBD are young and do not have comorbid illnesses Patients with IBD receive less preventive health services than the general primary care patients Risk of Infection in IBD Infections are the most common significant adverse event among immunosuppressed patient with IBD Risk of serious infection increases with the number of immunosuppressive therapies Steroids Many infections are preventable with routine preventive immunizations. Selby Inflamm Bowl Dis 2008:14: 253-58 Serious Infection Risk with TNF-αvs. non-biologics Grijalva et al JAMA 2011 306(21):2331-2339 Vaccination Goal: prevent infections in a population that is often immunocompromised Influenza and pneumococcal pneumonia are the most common vaccine preventable illnesses in adults Standard recommended immunization scheduled for adults should be adhered to At diagnosis, all adults should have review of immunization history, with catch up vaccination given as needed Exceptions Live virus vaccines Contraindicated with immunosuppression Sands et al: IBD 2004;10: 677-92 Patients with IBD are under-vaccinated 169 patients surveyed at Tertiary IBD Center 98% reported current or past immunosuppressant use 28% received regular influenza shots 9% had pneumococcal vaccination 45% tetanus vaccine in past 10 years Most common reason for non-immunization Lack of awareness (49%) Immunization of IBD Patients All patients should get influenza vaccination All patient should get vaccinated with pneumococcal vaccine Patient on Immunosuppression should receive new 13 serotype followed by 23 serotype vaccine Young males and females vaccinated for HPV. Melmed Am J gastroenterol 2006;101:1834-40 1. Sands BE, et al. Inflamm Bowel Dis 2004;10:677-692 54 58 9
Increased risk of Pneumonia in IBD Retrospective national cohort 108, 604 IBD vs. 434,416 non IBD Smoking Cessation in IBD Patients Crohn s and UC patient should be counseled to quit. Increased prevalence of Crohn s disease in smokers Crohn s disease patients who are smokers More severe ileal disease, more frequent flares, an increased need for steroids and Immunomodulator and higher rates of surgery Long, M. Am J Gastroenterol 2013 108: 240-48 Cutting back or Quitting Helps Smoking cessation is crucial aspect in the management of Crohn s patients that if often overlooked Decreased risk of relapse Decreases need for steroids or Immunomodulator Summary: Take Home Points Steroids are temporary medication for IBD Medical treatment of IBD goals to achieve prolonged clinical remission. We are never going to prevent all infections But, we have an opportunity to prevent serious infectious complications by thoughtful patient selection and vaccination Advise smokers to quite smoking THANK YOU Questions? fcaldera@medicine.wisc.edu New Multi-Disciplinary IBD clinic complicated patients seen by IBD specialist Colorectal Surgeon. Ostomy nurse 58 10