Ulcerative colitis: diagnosis and management

Ulcerative colitis: diagnosis and management Word count: 3,367 Abstract word count: 140 Tables and Figures included: 4 1

Abstract Ulcerative colitis is an inflammatory bowel disease that affects approximately 500,000 individuals in the United States. The highest incidence rates are found in northern Europe, the United Kingdom, and North America, but the burden of ulcerative colitis is increasing in areas such as Japan, South Korea, and Latin American. Individuals with ulcerative colitis typically present with bloody diarrhea along with other symptoms such as tenesmus and rectal urgency. Symptoms can be severe and even life threatening, resulting in colectomy in 20-30% of patients. Patients with ulcerative colitis are also at increased risk of colorectal cancer later in life. First line treatment of mild to moderate ulcerative colitis is with oral and/or topical (rectal) aminosalicylates such as mesalamine or balsalazide. In severe disease, systemic corticosteroids or surgery may be required. This article reviews the epidemiology, diagnosis, and treatment of ulcerative colitis. 2

INTRODUCTION Ulcerative colitis is an inflammatory bowel disease that affects approximately 500,000 individuals in the United States 1. This chronic condition is characterized by mucosal inflammation of the colon that begins at the rectum and extends proximally to varying lengths 2. The relapsing and remitting disease course is often unpredictable, and acute flares of inflammation can result in significant personal suffering 3. Ulcerative colitis can also lead to life-threatening complications which must be recognized by healthcare providers. This article reviews the epidemiology, diagnosis, and treatment of ulcerative colitis. EPIDEMIOLOGY AND BACKGROUND Worldwide the highest incidence and prevalence rates of ulcerative colitis are found in northern Europe, the United Kingdom, and North America 4. Incidence rates appear to have stabilized in westernized regions, but rates are increasing in areas such as Japan, South Korea, and Latin America 5,4. In the United States, the incidence varies between 9 and 12 per 100,000, with a prevalence as high as 238 per 100,000 6,1. The peak age of onset is 30-40 years, although ulcerative colitis can occur at any age 5,7. At the time of diagnosis, approximately one third of patients present with proctitis (inflammation limited to the rectum), one third with left-sided colitis (inflammation distal to the splenic flexure), and a final third with extensive colitis (inflammation extending proximal to the splenic flexure) 5. Over time inflammation spreads proximally, and after 20 years approximately 50% of patients have pancolitis 5. For many patients, disease 3

activity decreases over time following an initial severe flare, while some patients may experience continuous or worsening symptoms 3. The overall mortality of patients with ulcerative colitis is not greater than that of the general population 5. However, there is a slight increase in mortality seen during the first two years following diagnosis 8. Similarly, colectomy rates are highest during the first year following diagnosis, approaching ten percent 5. Overall, colectomy rates vary widely, but are thought to be approximately 20-30% after 25 years 5. The precise etiology of ulcerative colitis is unknown, but it is thought that mucosal inflammation is the result of an abnormal colonic immune response and interactions between genetics, colonic gut flora and other environmental factors 4. Twin studies have shown fairly low concordance for ulcerative colitis 4, yet individuals who have a first degree relative with ulcerative colitis or Crohn s disease have a 10-fold risk of developing the disease compared to the general population 9. Factors associated with decreased risk of ulcerative colitis include cigarette smoking and appendectomy 4. Furthermore, individuals who quit smoking appear to be at increased risk of developing ulcerative colitis compared to non-smokers 4. CLINCAL PRESENTATION Individuals with ulcerative colitis typically present with a history of bloody diarrhea and frequent bowel movements 2,10. Patients also commonly describe rectal urgency, tenesmus, passage of mucus, and colicky abdominal pain 8. Some patients with distal colitis may present with formed or hard stools, but bloody stools are nearly universal. In 4

one study, 96% of patients with active colitis reported passing stools with blood and mucus every day 10. Signs and symptoms usually reflect the physical extent and degree of inflammation, and disease activity is commonly classified as mild, moderate, severe, or fulminant (table 1) 3,2. Patients with mild to moderate disease experience less than six stools daily and show minimal signs of systemic illness. Around 90% of patients present with mild or moderate disease 11. Patients presenting with severe disease have greater stool frequency and increased signs of toxicity such as fever, tachycardia, or an elevated erythrocyte sedimentation rate (greater than 30 mm in one hour) 2,12. Fulminant disease may necessitate blood transfusions and can lead to perforation or toxic megacolon 2. Extraintestinal symptoms may be present in up to 30% of patients 5. These manifestations include sacroilitis, ankylosing spondylitis, sclerosing cholangitis, erythema nodosum, episcleritis, and uveitis 4. COMPLICATIONS Toxic megacolon is a rare but life-threatening condition which results from severe colonic inflammation and paralysis, and it is typically defined as colonic dilation exceeding 6 cm on radiographs 13. Although it was once viewed solely as a complication of ulcerative colitis, other causes of colonic inflammation such as Crohn s disease and Clostridium Difficile colitis can also lead to toxic megacolon. Symptoms may include severe abdominal pain and distention, constipation, decreased bowel sounds, and signs of systemic toxicity. However, because patients are often receiving large doses of 5

corticosteroids, signs of perforation or systemic toxicity may be masked. Clinicians should also be aware that perforation can occur without preceding colonic dilation 13. Colorectal cancer affects approximately 3.7% of patients with ulcerative colitis 4, and cumulative risk is commonly reported to be 2% at 10 years, 8% at 20 years, and 18% at 30 years based on a meta-analysis by Eaden and colleagues 14. Risk is dependent upon the duration and extent of disease, as well as the presence of microscopic inflammation 2. Other factors associated with increased risk include the presence of backwash ileitis, primary sclerosing cholangitis, and family history of sporadic colon cancer. In contrast to the typical adenoma-to-cancer sequence typically observed with colon cancer, cancers associated with colitis tend to arise from flat mucosa. These cancers are also more likely to be multiple, broadly infiltrating, and anaplastic 2. Patients with ulcerative colitis should be followed closely to ensure appropriate screenings are performed. DIAGNOSIS The differential diagnosis for patients presenting with features of ulcerative colitis includes Crohn s disease, infectious colitis, irritable bowel syndrome (IBS), diverticulitis, and radiation colitis (Table 3) 2,15. In patients presenting with rectal bleeding and formed stools, symptoms may be incorrectly attributed to hemorrhoids 4. The diagnosis of ulcerative colitis is made based on clinical features, endoscopic findings, and lack of infectious causes 2. Patients should be asked about recent travel, antibiotic use, family history, and smoking history 8. History and physical examination 6

should also be directed at determining disease severity and the presence of systemic illness. Patients presenting with persistent bloody stools or diarrhea should receive colonoscopy or sigmoidoscopy with biopsies. Stool examination for parasites and testing for Clostridium difficile toxin are important for ruling out infection, and other laboratory tests may include ESR to assess systemic inflammation, complete blood count to identify anemia, and metabolic profile to look for electrolyte disturbances caused by persistent diarrhea 15. Distinguishing ulcerative colitis from Crohn s disease is sometimes challenging. Patients with Crohn s disease can present with a wide range of symptoms including chronic diarrhea, abdominal pain, fever, and rectal bleeding 16. Table 2 compares characteristic features of both inflammatory bowel conditions. When the diagnosis is still in question following endoscopic and histologic evaluation, tests for certain perinuclear antineutrophil cytoplasmic antibodies (panca) may help make the distinction 2. Around 5% of patients cannot be classified initially because they share features of both inflammatory bowel conditions 8. TREATMENT Treatment of ulcerative colitis is directed at inducing and maintaining remission of active disease 2. Recently, mucosal healing has become an important marker for disease remission, and it has been suggested that mucosal healing reduces the risk of malignancy, colectomy rates, and long-term remission rates 17. However, it is usually not necessary to confirm endoscopic remission in patients who achieve clinical remission 2. 7

Medical therapy Aminosalicylates (5-ASA) have been used as first line treatment of ulcerative colitis for decades 11. They can be given orally or administered topically as rectal suppositories or enemas. Although the exact mechanism of action is unclear, 5-ASA are thought to act directly on the gut lumen 11. Oral 5-ASA include sulfasalazine, mesalamine, balsalazide, and olsalazine (table 4). These compounds are readily absorbed and inactivated by small intestinal epithelium, and various delivery methods have been developed to maximize the amount of active drug reaching the colon. Mesalamine is available in timed release (Pentasa), ph-dependent (Asacol, Apriso), and MMX multi-matrix release (Lialda) formulations. Sulfasalazine, balsalazide, and olsalazine (Dipentum) are prodrugs in which 5-ASA is bound to a carrier molecule. After the drug is delivered to the colon, the bond is split by colonic bacteria and active 5-ASA is released. Oral aminosalicylates generally have few side effects, but they may not be tolerated in up to 15% of patients. Sulfasalazine is the least expensive of the oral 5-ASA, but causes the most side effects due to its sulfa group 2,18. Olsalazine has been associated with a high incidence of diarrhea, and it is typically avoided unless other 5-ASA preparations are not well tolerated 18. Acute intolerance of any 5-ASA may occur in up to 3% of patients, leading to bloody diarrhea that often resembles an acute flare of disease activity 19. In rare instances, 5-ASA may lead to renal impairment which is thought to be reversible with early discontinuation of therapy 20. Patients with pre-existing renal impairment are at higher risk for nephrotoxicity 19. Current guidelines suggest measuring serum creatinine 8

prior to beginning 5-ASA treatment and periodically thereafter. A reasonable monitoring schedule may consist of checking levels every 3-6 months for the first year followed by annual measurements, although the optimal monitoring frequency is yet to be determined 2. Corticosteroids are used to induce remission in patients who do not respond to 5-ASA therapy or are systemically ill 2. Rectal suppositories, enemas, and 10% hydrocortisone foam can be used for topical treatment 2. Because enemas require a large volume of fluid (100 ml), foams are generally better tolerated 19. Immunosuppressive agents include thiopurines (6-mercaptopurine and azothioprine) and cyclosporine. Thiopurines can be used for maintenance in steroid dependent or steroid refractory patients, and they have been shown to reduce the rate of steroid dependence 2,21. Cyclosporine may be tried as rescue therapy for hospitalized patients with severe colitis with a response seen in around 85% of patients 21. Infliximab is a monoclonal antibody to tumor necrosis factor-α (TNF- α) that can be used to induce and maintain remission in patients not responding to corticosteroids or thiopurines 2. Like cyclosporine, infliximab is also used as rescue therapy in severely ill patients 21. Side effects of infliximab include increased risk of TB and other opportunistic infections. 9

Probiotics such as VSL # 3 have shown some efficacy in treating and maintaining remission in ulcerative colitis. One preparation, E coli Nissle 1917, has similar efficacy rates as 5-ASA for maintaining remission 8. Management by disease extent and severity Distal Mild to Moderate Colitis In mild to moderate disease limited to the rectum or sigmoid colon, treatment plans may be guided largely by patient preferences. Some patients may wish to rely solely on oral 5- ASA, while others might prefer suppositories or enemas to avoid taking pills several times per day 2. Other advantages of topical preparations include decreased systemic absorption and often a quicker response to treatment. Treatment options are also guided by disease extent. Suppositories deliver adequate doses of drug approximately 10 cm, hydrocortisone foams are effective up to 15-20 cm, and enemas may be effective as far as the splenic flexure 2. Current guidelines suggest that topical mesalamine is more effective than either topical corticosteroids or oral 5-ASA preparations for inducing remission in active ulcerative colitis 2. In one recent meta-analysis comparing oral 5-ASA to topical ASA, remission was achieved in 41% of patients taking oral 5-ASA and in 50% using topical 5-ASA 22. Furthermore, patients may see maximum benefit through combined used of topical and oral 5-ASA. In the same meta-analysis, 63% of patients using combined therapy achieved remission compared to 45% of patients using oral 5-ASA alone. In the patients using combination therapy, remission was also achieved more quickly 22. 10

Some experts suggest escalating therapy if rectal bleeding continues beyond 10-14 days, although a longer trial period (3-4 weeks) is suggested for patients with mild disease 21. These recommendations are based on a study which shows the median time to remission of moderate colitis is 9 days for patients taking 4.8 grams of oral mesalamine 21. Other evidence shows longer durations of 5-ASA treatment may be worthwhile in patients who initially do not respond to 5-ASA 23. In a study examining extended therapy with MMX mesalamine, patients who had failed to achieve clinical remission during the first 8 weeks of MMX mesalamine therapy were given high dose (2.4g twice daily) MMX mesalamine for 8 more weeks. During the additional 8 weeks 60% of patients achieved complete remission, bringing the total from 44% (after the first 8 weeks) to 79% 11. The authors of this study suggest that patients might continue 5-ASA treatment for up to 16 weeks before declaring treatment failure. When treatment with 5-ASA is not effective at inducing remission, topical corticosteroids, oral corticosteroids, or infliximab may be used 2. Extensive Mild to Moderate Colitis In patients with extensive disease, oral 5-ASA therapy is required. Up to 80% of patients achieve remission within 4 weeks of starting oral sulfasalazine, but patients may prefer to start a newer 5-ASA agent to avoid potential side effects. There is also evidence to suggest the newer compounds are slightly more effective than sulfasalazine 2. Even in extensive disease combined treatment with topical mesalamine and oral 5-ASA can help increase remission rates and achieve symptom relief more quickly. In a randomized 11

controlled trial of 127 patients, participants received 2g of oral mesalamine twice daily for 8 weeks and either a hydrocortisone or placebo enema during the first 4 weeks of treatment. During the 8 week trial, 73% of patients receiving enema treatment experienced cessation of bleeding compared to 38% in the placebo group. Similarly, 64% of patients in treatment group achieved remission compared to 43% in the placebo group 24. Severe Colitis Severe colitis should be treated with corticosteroids 19. Oral prednisone shows a dose response, with 60 mg/day having greatest efficacy but also more side effects. Usually 40-60mg/day is given until clinical improvement is seen, and then the dose is gradually tapered 2. Although initial outcomes with steroid treatment are favorable, around half of steroid treated patients will need additional therapy within 1 year, and as many as 22% will develop steroid dependence 19. Chronic treatment with steroids should not be used to maintain remission, so patients who respond to steroids should be placed on 5-ASA for maintenance 2. Patients who do not respond to oral steroids or who become steroid dependent can be treated with 6-mercaptopurine, azothiaprine, or infliximab for maintenance of remission 2. Patients with signs of systemic toxicity should be hospitalized and treated with intravenous steroids, typically with a dose equivalent to 300mg of hydrocortisone daily 2. If significant improvement is not seen within 3 to 5 days of maximal medical therapy, patients should be referred to surgery or treated with a trial of IV infliximab or 12

cyclosporine 2. Concomitant infection with C. difficile is becoming more frequent and should be ruled out in hospitalized patients 2. In immunocompromised patients CMV infection should also be considered 8. Toxic megacolon is managed in a manner similar to severe colitis, and some experts recommend performing surgery within 72 hours if significant improvement is not observed 2. Others suggest expectant management may be appropriate in cases of mild dilation if the patient does not show signs of toxicity 2,8. However, any signs of deterioration while on medical therapy are absolute indications for colectomy. Patients with toxic megacolon should be kept nil per os (NPO), and hypokalemia or hypomagnesmia should be corrected because they can worsen colonic dilation. Instructing patients to assume a knee-elbow position may help evacuate bowel gas 2. Maintenance of remission Once remission is achieved, most experts recommend that patients adopt a permanent maintenance regimen 2. Newer 5-ASA preparations are equally effective compared to sulfasalazine at maintaining remission. Mesalamine is usually given at doses of 1.2 grams to 2.4 grams daily, and balsalazide is given at 4.5 grams daily 8. Combined oral and topical 5-ASA therapy is more effective than oral 5-ASA alone, and in a recent metaanalysis, 42% of patients receiving combined therapy experienced a relapse while 73% of patients experienced a relapse on oral 5-ASA alone 22. Thiopurines and infliximab can be used for maintenance in steroid dependent patients, but maintenance on corticosteroids is never appropriate 2. Surgery should be considered when steroids cannot be withdrawn 8. 13

The success of maintenance therapy relies heavily on patient adherence to prescribed medications. A prospective study of 99 patients in remission found that patients who were adherent to therapy had a 89% chance of maintaining remission for 2 years compared to a 39% chance in nonadherent patients (p=0.001) 25. Several once daily dosing regimens, such as 2.4 grams of MMX mesalamine, appear to be effective and improve adherence 4,11. For patients with proctitis, a mesalamine suppository given 3 times weekly has been shown to be effective in clinical trials 19. Surgical Therapy Indications for emergency surgery include massive hemorrhage, perforation, and severe colitis or toxic megacolon unresponsive to maximal IV medical therapy 26. Carcinoma or dysplasia are absolute indications for an elective total proctocolectomy. In addition to these life-threatening scenarios, the most common reason surgery is performed is for chronic symptoms unresponsive to medical therapy and for patients that cannot be treated medically due to side effects. These chronic refractory symptoms can result in diminished quality of life, and in severe cases ongoing symptoms may result in physical debility and psychosocial dysfunction 2. Patients requiring elective surgery usually undergo total proctocolectomy with either permanent ileostomy or an ileoanal pouch anastomosis (IPAA) procedure 8. The IPAA (sometimes referred to as J-pouch surgery) is the most common operation for ulcerative colitis, and it can be performed in one or multiple stages based on the patient s clinical 14

status and the surgeon s preferences 2. The IPPA procedure is technically demanding and mortality risk is increased twofold at low volume centers 2. British guidelines recommend this procedure be performed at centers performing at least 10 cases per year 8. When emergency surgery must be performed, the initial procedure of choice is most often a subtotal colectomy with ileostomy and preservation of the rectum. The remaining rectal stump is either over-sewn (Hartmann s pouch) or brought out as a mucous fistula 26. It is not usually recommended for patients to undergo an IPAA procedure at this stage because they are often acutely ill, have low albumin, and are receiving high dose steroids 8. Once the patient is well enough for another operation, a total colectomy with permanent ileostomy or ileoanal pouch is performed 26. However, if the subtotal colectomy was performed for bleeding a restorative procedure is recommended 2. Although total proctocolectomy is considered curative, patients may still suffer from frequent bowel movements, bowel incontinence, or infertility (in females) following the procedure 3. Pouchitis, resulting from idiopathic inflammation, may occur in up to 60% of patients undergoing IPAA. Pouchitis is treated primarily with metronidazole, and VSL #3 can be used for prevention and maintenence 2. Cancer Surveillance Cancer screening recommendations from the American College of Gastroenterologists (ACG) suggest annual or biannual colonoscopies with biopsies beginning 8-10 years following diagnosis 2. However, it has been reported as many as 20% of ulcerative colitis 15

related cancers are detected within 8 years following diagnosis 2. Patients with disease limited to the sigmoid colon or a lesser extent do not appear to be at increased cancer risk, although the ACG does not feel there is sufficient evidence to recommend separate guidelines based on disease extent 2. Findings of high grade dysplasia in flat mucosa must be treated with a total colectomy. Low grade dysplasia carries a 9-fold increase in cancer risk and colectomy is usually advised 2. British guidelines also recommend beginning screening colonoscopies around 10 years following diagnosis. However, disease extent is considered, and patients are stratified as low, intermediate, or high risk. Low risk patients with left-sided colitis or who had no histological active disease at last biopsy receive colonoscopy every 5 years. Intermediate risk patients with mild histological inflammation on last biopsy or post-inflammatory polyps receive colonoscopy every 3 years, and high risk patients receive yearly colonoscopy. These guidelines also recommend the use of chromoendoscopy and targeted biopsies 8. There is some evidence which suggests treatment with 5-ASA reduces colon cancer risk in individuals with ulcerative colitis 11,2. Studies examining this question have primarily been retrospective, although animal studies have demonstrated that 5-ASA inhibits carcinogenesis 11. Also, it is thought the increased cancer risk may be due to colonic mucosal inflammation, and aggressive treatment with 5-ASA seems to result in improved mucosal healing 17. However, this relationship remains controversial, as investigators in a recent population based study found no apparent chemoprotective effect of 5-ASA 27. 16

CONCLUSION Ulcerative colitis is a chronic condition with increasing prevalence worldwide. Active disease is associated with miserable symptoms and significant morbidity, including colectomy rates as high as 30% 8. Aggressive treatment aimed at achieving remission of symptoms and mucosal healing should be balanced with patient preferences and medication side effects. By encouraging patients to adhere to maintenance regimens and cancer screening guidelines, healthcare providers can help patients with ulcerative colitis increase their time spent in remission and reduce the risk of serious complications. 17

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FIGURES Table 1 Classification of disease severity based on criteria from Truelove and Witts 28. Mild Moderate Severe Fulminant Stools/day <4 4-6 >6 >10 Bleeding Intermittent --- Frequent Continuous Hemoglobin Normal --- Anemia Transfusion needed Clinical Signs No systemic toxicity (Information from references 2, 12, 28) Minimal systemic toxicity Fever, tachycardia, abdominal tenderness Fever, tachycardia, abdominal tenderness and distention Table 1 Characteristics of ulcerative colitis and Crohn s disease. Ulcerative Colitis Crohn s Disease Cardinal symptoms Bloody diarrhea Presence of Uncommon anal fistulae Pathologic Continous, mucosal features inflammation Location Limited to bowel, possible backwash ileitis (Information from references 2, 15, 29) Chronic or nocturnal diarrhea, abdominal pain, fever, weight loss, rectal bleeding Common, may precede bowel symptoms Focal, transmural inflammation Any part of GI tract, ileum and colon are most common sites 23

Table 2 Comparison of 5-ASA preparations at maximum daily dose. Trade name Daily dose Pills per day 30 day cost* Oral Mesalamine Ph-dependent ASACOL 2.4 grams 6 (2 tid) $ 350 Timed release PENTASA 4 grams 8 (2 qid) $ 647 MMX LIALDA 4.8 grams 4 (qd) $ 697 Granules** APRISO 1.5 grams 4 (qd) $ 270 Balsalazide 6.75 grams 9 (3 tid) $ 106 Olsalazine DIPENTUM 1 gram 4 (2 bid) $ 667 Sulfasalazine 4 grams 12 (4 tid) $ 62 Rectal Mesalamine Enema 4 grams/60ml $ 3,519 Suppository CANASA 1 gram $ 518 *Price excluding insurance from http://cashcard.lc.healthtrans.com/pages/drugsearch.aspx granules in delayed release (ph-dependent) and extended release capsule dose given is indicated for maintenance of remission Table 4 - Differential Diagnosis Crohn's disease Infectious colitis Clostridium difficile Parasitic infections CMV or herpetic colitis (immunocompromised patients) Noninfectious colitis Radiation colitis Drug-induced colitis Microscopic colitis Solitary rectal ulcer syndrome Diverticulitis Irritable Bowel Syndrome (Information from references 2,15) 24