Best Practices in the Diagnosis and Treatment of Inflammatory Bowel Disease

Best Practices in the Diagnosis and Treatment of Inflammatory Bowel Disease Mark Lazarev, MD Summary Inflammatory bowel disease (IBD) is a complex disease that is costly both in terms of medical costs and quality of life. The major goal of treating IBD is to induce and maintain remission. An evolving goal is to completely heal the intestinal mucosa. There are a variety of effective agents for IBD. Better use of these agents is occurring with the use of top-down therapy and the targeting of those patients most likely to have complications for aggressive therapy. Key Points IBD is a significant, costly disease that impacts quality of life. Ulcerative colitis primarily affects the colon, whereas Crohn s disease can affect the entire GI tract. Treatments include 5-amiosalicylic acid derivatives, thiopurines, TNF inhibitors, and natalizumab. Therapy is moving to a top-down approach with more aggressive therapy being used earlier. Mucosal healing is becoming a goal of treatment. Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract, which affects up to 1.4 million persons in the United States. It is typically divided into ulcerative colitis (UC) and Crohn s disease (CD). IBD generally presents in people in their teens or 20s. A few predisposing factors for developing IBD include genetics, gastrointestinal infections, nonsteroidal anti-inflammatory medication uses, and antibiotics. The prevalence of IBD is 120 to 200 per 100,000 for UC and 50 to 200 per 100,000 for CD in the Western world. 1 The U.S., Canada, and some parts of Europe and Scandinavia have very high rates. It is unclear why the rate is so high in these countries and continues to increase but it may be related to increased recognition, increased use and abuse of antibiotics, heavily processed food diets, and increased hygiene. In non-westernized countries, many people are colonized with helminthes and bacteria that may protect against autoimmune diseases. The direct medical costs for IBD are significant. IBD patients are more likely to have emergency room visits, hospitalizations and surgeries than patients without IBD. Hospital costs make up a significant portion of costs of an IBD patient. This disease also significantly impacts quality of life. UC is a diffuse mucosal inflammation limited to the colon; it almost always affects the rectum, and it may extend proximally in a symmetrical, uninterrupted pattern to involve all or part of the large intestine. 2,3 CD, by contrast, is a patchy, transmural inflammation that may involve any part of the gastrointestinal tract from mouth to anus. Based on population-based and health care claims databases, UC affects approximately 250,000 to 500,000 people in the U.S. Between 7000 and 46,000 persons are newly diagnosed with UC annually. Common symptoms include rectal bleeding, urgency, frequency, and systemic signs of toxicity in more severe disease (fever, weight loss, anemia, elevated inflammatory markers). Most people have moderate symptoms and are controlled by conventional therapies (Exhibit 1). 3,4 UC is associated with frequent outpatient medical visits, hospitalizations, and high drug and hospitalization costs due to relapses in disease activity. Thirty to 40 percent of UC 22 Journal of Managed Care Medicine Vol. 17, No. 1 www.namcp.org

Exhibit 1: Ulcerative Colitis 3,4 100% Fulminant Disease (9%) 80% Patients with UC 60% 40% Moderate to Higher Activity (71%) 20% 0% Low Activity (20%) Disease Activity patients ultimately require colectomy during their disease course, whether for medically refractory symptoms, fulminant colitis or dysplasia/cancer. Crohn s disease is a chronic inflammatory disorder of the entire gastrointestinal tract. The primary symptoms are chronic, occasionally bloody diarrhea and crampy abdominal pain. There are 10,000 to 47,000 new diagnoses annually. Up to 30 percent of patients can develop perianal CD with abscesses, fistulas, and fissures. Traditionally, up to 75 percent of patients will require at least one surgery. IBD is diagnosed based on symptoms, laboratory tests, bowel studies, and bowel biopsies. Exhibit 2 compares the advantages and disadvantages of the various methods for assessing structural features of IBD. In most cases, CD is readily distinguished from UC by clinical, radiologic, endoscopic, and pathologic features. Biomarkers are increasingly being used to distinguish between UC and CD. Autoantibodies and antibody levels against various bacteria can be used to measure the amount of inflammation within the body. Increasing amounts of immune reactivity has been shown to indicate increasing disease complications and more aggressive disease phenotypes in adults and children with CD. 5 Fecal calprotectin, another biomarker which is frequently used, is elevated with increased mucosal inflammation in IBD. Fecal calprotectin represents 40 to 60 percent of cytosolic proteins in neutrophils. The amount of calprotectin in feces is therefore proportional to the neutrophil migration to the gastrointestinal mucosa. It accurately distinguishes IBD from non-ibds such as irritable bowel syndrome and furthermore predicts clinical relapse in IBD patients. It has been found to be more sensitive and specific than other inflammatory markers such as erythrocyte sedimentation rate (ESR). Currently, there is no cure for CD. The only cure for ulcerative colitis is taking out the colon. Thus, all but the patients with the mildest of disease will need to be on chronic, lifelong therapy. Because these are chronic conditions, medication adherence can be an issue. Once patients are feeling well, they are less likely to continue their medications, which can lead to a disease flare-up. The goals of therapy are to induce and maintain a clinical remission, avoid complications of the disease, achieve a good quality of life, and minimize short- and long-term toxicity. The medications for IBD include 5-aminosalicylic acid (ASA) agents, corticosteroids, thiopurines, anti-tnf agents, and natalizumab. Each class has benefits and risks in treating IBD. The 5-ASA agents are considered the safest agents for IBD. They have been used for decades. They are anti-inflammatory but are not immunosuppressives. They are effective for induction and maintenance of remission of mild to moderate ulcerative colitis. These come in multiple different forms including oral tablets and rectal topicals. Oral agents include sulfasalazine [Azulfidine ] and mesalamine [Pen- www.namcp.org Vol. 17, No. 1 Journal of Managed Care Medicine 23

Exhibit 2: Methods for Assessing Structural Features in IBD Ileocolonoscopy Advantages Validated, widely available Sensitive to changes Prognostic value Disadvantages Limited to luminal structures Incomplete examinations 20% Small Bowel follow through Widely available Detection penetrating/stricturing complications Patient tolerance Radiation exposure Bowel transit time No information about extraenteric disease, misses mild disease CT MRI Widely available, reproducible Less interobserver variation Fast study Extraenteric structures High sensitivity & specificity Reproducible over time Extraenteric structures No radiation Better for perianal disease Radiation exposure and overuse Misses mild disease Limited availability Heterogeneity in image acquisition and interpretation Have to lie still for appropriate breath-holding sequences Misses mild disease Wireless Capsule Endoscopy Detects more small bowel lesions than cross-sectional imaging Widely available Heterogeneity in interpretation Lower specificity for Crohn s disease Capsule retention tasa, Asacol, Lialda, Apriso ]. Rectal topicals include mesalamine enema [Rowasa ] or suppository [Canasa ]. Often, combination therapy with oral and rectal 5-ASA works better than oral alone. For proctitis, topical ASA can be used alone. The 5-ASA agents are generally very safe and well tolerated. With some formulations, there is a need to take up to 12 pills a day. A minority of patients will actually get worse on this class of medications. Interstitial nephritis can rarely be caused by 5-ASA agents and thus kidney function needs to be monitored at least once a year. Corticosteroids are effective in the induction, but not maintenance of remission in both CD and UC. The most commonly used steroids are prednisone and budesonide [Entocort ]. In UC, steroids are usually used with active flare-ups when 5-ASAs are not working. This usually involves starting prednisone at 40mg a day, and tapering over eight to 10 weeks. In CD involving the small intestines and right colon (the most common locations), budesonide is preferred over prednisone. Budesonide has fewer systemic side effects because of the way it is metabolized. The long-term risks of steroids are well known and significant. They include diabetes, hypertension, increased risk of infection, osteopenia and osteoporosis, avascular necrosis of the hip, weight gain, cataracts, skin thinning and bruising, hormonal imbalance, and anger, anxiety or other psychiatric effects. Overall, 55 percent of patients on corticosteroids will have an adverse event and will have to discontinue therapy. Historically, patients with CD on corticosteroids have a high likelihood of becoming steroid dependent or requiring surgery. Because of the risks, long-term treatment of IBD with steroids is inappropriate and should be avoided. Thiopurines (azothioprine [Imuran ], 6-mercaptopurine) are steroid-sparing oral agents. They are purine-antagonist anti-metabolites that interfere with nucleic acid synthesis in white blood cells, especially in T-lymphocytes, which are important in the production of inflammatory mediators. Thiopurines are effective in maintaining remission in CD and UC in about 50 percent of patients. They are usually started when 5-ASAs are not enough to control moderate to severe symptoms or for steroid dependence. They have no role for inducing a remission because it takes two to four months for maximum effectiveness. The thiopurines are usually combined with a steroid taper to initiate therapy. Thiopurines can cause some significant adverse 24 Journal of Managed Care Medicine Vol. 17, No. 1 www.namcp.org

Exhibit 3: ACG Guidelines for CD (2009) Mild to moderate disease - Sulfasalazine at 3-6g/d for colonic disease - Budesonide for ileal/right colon disease Moderate to severe disease - Prednisone for induction - Azathioprine for maintenance of remission - Anti-TNFs for patients with inadequate response with steroids, immunomodulators Infliximab and infliximab/azathioprine more effective than azathioprine alone - Natalizumab for patients with inadequate response to anti-tnf Exhibit 3: ACG Guidelines for UC (2010) 7,8 Mild to moderate disease - Sulfasalazine at (4-6g/d) 5-ASAs - Thiopurines for patients who don t respond to steroids - Infliximab for patients steroid refractory or dependent who have failed thiopurine Moderate to severe disease - 5-ASAs effective in reducing relapses - Thiopurines for maintenance of remission - Infliximab effective for induction and maintenance events, including leukopenia, increased risk for infection, elevated liver function tests, pancreatitis, allergic reaction, and fatigue. One adverse effect of major concern is the increased risk for lymphoma. The risk of non-hodgkin s lymphoma with longterm use of thiopurines is about four to five times that of the general population. 6 The chances of getting lymphoma in the general population is two out of 10,000. The risk with thiopurines is nine out of 10,000, but the absolute risk is still low. This risk has to be compared with the risk of not taking the medication and achieving remission. Patients will have to be closely monitored especially when a thiopurine is first started. Overall, about 10 percent of patients will need to stop the medication because of an adverse event. Tumor necrosis factor (TNF) levels are elevated in the serum, stool, and intestinal tissues of patients with inflammatory bowel diseases, and it may play a pivotal role in the pathogenesis of CD. The anti-tnf biologic agents are approved for induction and maintenance of remission for CD (infliximab [Remicade ], adalimumab [Humaria ], certolizumab [Cimzia ]) and UC (infliximab, adalimumab, golimumab [Simponi ]). They are usually started when 5-ASAs or thiopurines are not enough to control moderate to severe symptoms, or for steroid dependence. Anti-TNF agents are the most effective therapy available for perianal fistulizing disease. The anti-tnf agents have some well-known, adverse events including immediate or delayed infusion or injection site reaction and increased risk for infection. The risk of lymphoma related to these agents is unknown. Overall, about 10 percent of patients will have an adverse event, but only one in 250 events will be serious. Because of the risk of significant immunosuppression, caution must be taken in combining these medications with steroids for an extended period. Additionally, up to 50 percent of patients will lose response to anti-tnf agents over time. In this case, a switch to another anti-tnf agent can be made, but the second agent is usually less effective. Natalizumab [Tysabri ] is a humanized monoclonal antibody against the cell adhesion molecule α4- integrin. The drug is believed to work in IBD by reducing the ability of inflammatory immune cells to attach to and pass through the cell layers lining the intestines. It is effective in inducing and maintaining remission in CD. This agent is administered as a once- monthly infusion. It is usually started in patients who have failed an anti-tnf agent and for whom surgery is not a good option. Patients must be off all immunosuppressants other than steroids before starting this agent. The potential adverse effect of most concern with www.namcp.org Vol. 17, No. 1 Journal of Managed Care Medicine 25

Exhibit 4: AGA IBD QI Measures 2012 PQRS 1. Document disease activity and severity 2. Recommend steroid-sparing therapy after 60 days 3. Assess bone health if steroid-exposed 4. Recommend influenza vaccine 5. Recommend pneumococcal vaccine 6. Document recommendation for cessation of smoking 7. Assess for HBV status pre-anti-tnf 8. Assess for latent TB pre-anti-tnf Exhibit 4: CCFA Process Measures 9,10 Test for TB before anti-tnf therapy Test for C. difficile in flares Flex sig. for CMV in steroid-refractory hospitalized UC Check TPMT before starting thiopurines Recommend steroid-sparing agents if >4m steroids Recommend colectomy or close surveillance for low-grade dysplasia in colitis Recommend smoking cessation if smoker with CD Educate patients regarding vaccinations HBV = Hepatitis B virus; TB = Tuberculosis; CMV = Cytomegalovirus; TPMT = Thiopurine S-methyltransferase (ability to metabolize thiopurines) Steroid-free clinical remision Days lost from work/school Days hospitalized ED visits Malnutrition Anemia Normal health related QOL Narcotic use Nighttime BMs or leakage Incontinence Exhibit 4: CCFA Outcome Measures natalizumab is progressive multifocal leukoencephalopathy (PML). There is a one in 1000 risk of developing PML while on natalizumab. It is a concerning event because it is very often fatal or debilitating if acquired. The major risk factors for developing PML are John Cunningham (JC) virus exposure, prior immunosuppressives, and natalizumab use greater than 24 months. Patients on natalizumab need close monitoring with neurologic exams. If it does not work in the first three months, it should be discontinued. Exhibit 3 outlines the A level recommendations for CD and UC from the American College of Gastroenterology guidelines. 7,8 Additionally, the American Gastroenterological Association (AGA) and Crohn s and Colitis Foundation of America (CCFA) have published quality and process measures in IBD which can be used to assess care for these patients (Exhibit 4). 9,10 Traditionally, when a patient was diagnosed, the least toxic agents were started and then therapy would be moved forward once failure occurred. Top-down therapy refers to starting with the most aggressive therapy rather than the least. This method is most applicable to CD and refers to starting an anti-tnf agent, often with a thiopurine agent, as initial therapy. New data are emerging that combination therapy may be most effective early in the course of disease. The hope is that early aggressive treatment will decrease complication, hospitalization and surgery rates. There is a need to weigh the benefits and risks of combination therapy. It is important to try to predict at diagnosis those patients who will have an aggressive course with complications. Currently, this prediction is made based on severity of disease based on initial presentation, level of immune markers, and bowel study findings. Increasingly, the management of IBD is moving toward mucosal healing as a goal of therapy. Studies are now using mucosal healing as a marker of medication efficacy. There is evidence that patients in clinical remission who also achieve mucosal healing are less likely to flare over time. Clinical remission of symptoms does not always mean that mucosal healing has occurred. Currently our medications do an overall poor job at achieving mucosal healing. There is no clear consensus as to how we should strive to achieve mucosal healing as a goal of therapy. 26 Journal of Managed Care Medicine Vol. 17, No. 1 www.namcp.org

An area of frequent concern for patients is whether anti-tnf or thiopurine therapy can be stopped. In most cases, therapy cannot be safely stopped without a significant risk of relapse. In patients on an anti-tnf agent in combination with a thiopurine agent, a subset of patients may be able to stop the thiopurine. In order to stop a medication, patients should have clinical and endoscopic remission, as well as have no elevated markers of inflammation and mucosal healing. We are only now learning which factors predict the ability to come off medication. Sometimes medical therapy is inappropriate. Examples include patients with recurrent obstructive episodes from scarred down stricture that is best approached with surgery, extensive fistulizing disease or abscess within the abdomen which needs surgery (followed by medical therapy). It is important to address these situations with surgery. There is a growing push to use more biologic agents in IBD. Biologics have been shown to decrease the rate of hospitalization and surgery. A recent systematic review in Crohn s disease, found that infliximab and adalimumab were cost effective when given as induction therapy followed by episodic therapy for five years. 11 It is unclear if biologics are still cost effective when given as maintenance therapy. Episodic therapy is only using the agent when the patient is having a flare-up, but this strategy is not as effective as maintenance therapy nor is it recommended by any guidelines. A few new agents are under development for IBD. Vedolizumab, similar to natalizumab but without the risk of PML, is being studied for both UC and CD. Tofacitinib is an oral agent beginning Phase III study for UC. Ustekinumab is in Phase III trials for CD. Conclusion IBD is a complex, heterogeneous condition that affects patients for many decades. It causes significant morbidity and associated costs to society. Effective medications are available, but can be very expensive and thus need to be used wisely. Mark Lazarev, MD is an Assistant Professor of Medicine at the Johns Hopkins University School of Medicine. References 1. Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology. 2011;140(6):1785-94. 2. Loftus CG, Loftus EV Jr, Harmsen WS, et al. Update on the incidence and prevalence of Crohn s disease and ulcerative colitis in Olmsted County, Minnesota, 1940-2000. Inflamm Bowel Dis. 2007;13(3):254-61. 3. Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology. 2004;126(6):1504-17. 4. Langholz E, Munkholm P, Nielsen OH, et al. Incidence and prevalence of ulcerative colitis in Copenhagen county from 1962 to 1987. Scand J Gastroenterol. 1991;26(12):1247-56. 5. Dubinsky MC, Lin YC, Dutridge D, et al. Serum immune responses predict rapid disease progression among children with Crohn s disease: immune responses predict disease progression. Am J Gastroenterol. 2006;101(2):360-7. 6. Siegel CA. Review article: explaining risks of inflammatory bowel disease therapy to patients. Aliment Pharmacol Ther. 2011;33(1):23-32. 7. Lichtenstein GR, Hanauer SB, Sandborn WJ, et al. Management of Crohn s disease in adults. Am J Gastroenterol. 2009;104(2):465-83. 8. Kornbluth A, Sachar DB; Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010;105(3):501-23. 9. AGA. Adult Inflammatory Bowel Disease Physician Performance Measures Set. 2011. Available at http://www.gastro.org/practice/quality-initiatives/ IBD_Measures.pdf 10. Melmed GY, Siegel CA, Spiegel BM, et al. Quality indicators for inflammatory bowel disease: development of process and outcome measures. Inflamm Bowel Dis. 2013;19(3):662-8 11. Tang DH, Harrington AR, Lee JK, et al. A systematic review of economic studies on biological agents used to treat Crohn s disease. Inflamm Bowel Dis. 2013;19(12):2673-94. www.namcp.org Vol. 17, No. 1 Journal of Managed Care Medicine 27