Clinical Management of Ulcerative Colitis

By Gary R. Lichtenstein, Robert B. Stein and MD

Provides detailed clinical guidance on the management of ulcerative colitis by disease severity. Clinical presentation and diagnosis criteria are presented along with epidemiology, etiopathogenesis and environmental risk factors. The book contains the 2019 American College of Gastroenterology Ulcerative Colitis Treatment Guidelines. Disease management based on disease severity with separate chapters are devoted to each class of medications including aminosalicylate, corticosteroids, immunomodulators, and biologics. Comorbidities are reviewed in detail as is health maintenance for the ulcerative colitis patient.

• Language: English
• Publisher: Professional Communications, Inc
• Release date: Oct 13, 2023
• ISBN: 9781545756928

Book preview

CHAPTER 1

Epidemiology

Inflammatory bowel disease (IBD) consists of two closely related, and possibly overlapping, disease processes: ulcerative colitis (UC) and Crohn’s disease (CD). The hallmark of IBD is chronic uncontrolled inflammation of the intestinal mucosa. In contrast to CD, which can affect any part of the gastrointestinal tract, the inflammation of UC is limited to the colon. The segment of colon involved with UC varies; however, the inflammation usually begins in the rectum and extends proximally. Disease can be limited to the rectum (ulcerative proctitis) or involve more proximal regions, possibly involving the entire colon (pancolitis). Typically presenting in the second or third decade of life, UC usually presents with bloody diarrhea, urgency, and abdominal cramps.¹,²

The clinical course of UC is most commonly characterized by periods of flares and remission, occurring either spontaneously or in response to treatment. Although chronic inflammation can occur in the healthy gastrointestinal tract, such as in response to potential pathogens, the healthy gastrointestinal tract eventually returns to a normal uninflamed state. In patients with IBD, there is an inability to downregulate these inflammatory responses, so the mucosal immune system remains activated, thus the intestine remains chronically inflamed.¹ The exact cause of aberrant inflammation in patients with UC is unclear, but genetic, dietary, and environmental risk factors are all proposed to play important roles.

Incidence and Prevalence in North America

A recent study that analyzed the 2015 National Health Interview Survey (NHIS) estimated that 3.1 million US adults (1.3%) have received a diagnosis of IBD.³ The study found that IBD was more prevalent among certain population subgroups, including adults aged ≥45 years, Hispanics, non-Hispanic whites, and adults with less than a high school level of education, not currently employed, born in the US, living in poverty, or living in suburban areas. The prevalence of IBD did not differ by sex, current marital status, health insurance coverage type, or region of residence. The study did not specify the proportion of adults with UC or CD. In more developed nations, the prevalence of UC and CD is often similar, in contrast to what has been observed in less developed nations, where UC is generally more common than CD.⁴

In North America, the incidence of IBD increased during the latter half of the 20th century.⁵ Since the 1990s, most studies find that the incidence of both UC and CD has stabilized or even decreased.⁶ A 2017 systematic review of population-based studies found the incidence and prevalence of IBD to vary greatly by geographic region. In North America, the lowest incidence estimate for UC was 8.8 per 100,000 person-years (in Olmsted County, USA) and the highest was 23.14 per 100,000 person-years (in Nova Scotia, Canada). The lowest prevalence estimate for UC was 139.8 per 100,000 persons (in Quebec, Canada) and the highest was 286.3 per 100,000 persons (in Olmsted County, USA). The same study provided similar estimates for other global regions.⁶ A study of nine million American health insurance claims found a lower prevalence of UC in the South compared with the Northeast, Midwest, and West.⁷ This finding is consistent with global patterns, where the risk of UC is increased in persons living at higher latitudes.⁴

A 2019 study estimated the lifetime total and incremental costs by age at diagnosis for patients with CD or UC compared with matched control subjects using a large health care claims database. For UC, the lifetime incremental cost was $369,955 among patients who received their diagnosis at 0-11 years, and $132,396 for individuals ≥70 years, averaging $230,102 for a diagnosis at any age. Lifetime total cost was $405,496, consisting of outpatient ($163,670), inpatient ($123,190), pharmacy ($105,142), and ER ($13,493) costs. Overall, the population of patients with UC in the United States in 2016 was expected to incur lifetime total costs of $377 billion.⁸

Incidence and Prevalence Worldwide

The incidence and prevalence of IBD are greatest in more industrialized regions,⁴ such as North America, the United Kingdom, Northern Europe, Australia, and New Zealand (Figure 1.1 and 1.2). In these regions, the incidence rates for UC and CD have plateaued or decreased in recent decades.⁶ In developing countries, such as those in Latin America, Asia, and Eastern Europe, incidence rates vary greatly between nations, ranging from 0.5 to 31.5 cases per 100,000 person-years, depending on the study population.⁹ As developing nations become more industrialized, the incidence of IBD increases,¹⁰ a pattern mirroring the experience in the west more than 50 years ago.¹¹ The cause of this trend is unknown but is likely in part due to environmental factors, such as microbial exposure and diet. In addition to an industrialization gradient, the incidence of UC increases with increasing latitude, with higher incidence rates in Northern countries and lower rates in Southern countries.¹²,¹³

Morbidity and Mortality

UC is a chronic condition that commonly requires a lifetime of care and can cause significant morbidity. In the United States, IBD constitutes about 0.1% of all emergency department visits. Between the years of 2006 and 2014, the rate of IBD emergency department visits per 100,000 persons rose significantly, from 75.7 per 100,000 to 100.1 per 100,000, a 32.2% increase.¹⁴ Patients with UC accounted for less than half as many emergency department visits as those with CD. The rate of IBD-related in-patient admissions from the emergency room was 52.6% in 2014. Compared to UC patients, those with CD are significantly less likely to be admitted from the emergency department. Other factors associated with a higher IBD in-patient admission rate include older age, current or former smoking, and having private insurance or high income.

The risk of surgery in IBD patients has decreased over the past several decades. Current estimates for the cumulative-risk of surgery among UC patients are 4.9%, 11.6%, and 15.6% after 1, 5, and 10 years following diagnosis, respectively. This compares to a higher cumulative-risk in CD patients: 16.3%, 33.3%, and 46.6% over the same time periods.¹⁵

In the 1980s, the mortality rate of patients with UC was higher than the general population.¹⁶ However, current studies find that patients with UC have mortality rates similar to, or only slightly higher than, the general population when properly managed,¹⁷,¹⁸ possibly due to increased use of immune modulator and biologic therapy and the refinement of surgical techniques.

Certain populations, including newly diagnosed patients and patients with more extensive colitis, are at greater risk of mortality. A Danish study of 36,080 patients with UC found that the overall risk of dying of any cause was higher compared with the general population in the first year following diagnosis (HR = 2.43), but then rapidly declined to approximately 1.1 after 2 years.¹⁹ The long-term risk of death from certain causes remained significantly higher in patients with UC, including infectious diseases (HR=1.64), gastrointestinal disorders other than colorectal cancer (HR=1.47), gastrointestinal disorders other than UC (HR=1.26), and cardiovascular disease (HR=1.11).

Age

In North America, older estimates for the mean age of diagnosis for UC ranged from 40 to 45 years, compared with an earlier diagnosis for CD of 33 to 45 years.²⁰,²¹ More recent estimates place the peak age of onset of UC between the ages of 30 and 40 years.²² According to a population-based study in Olmsted County, Minnesota, the median age of UC diagnosis was 34.9 years (Figure 1.3), compared with 29.5 years for CD.²³

UC is less common in children and adolescents, but studies have found that its incidence is increasing in these age groups. In a recent systematic review of pediatric IBD studies, of the 63 studies focused on UC, 29 (46%) reported a significant increase, 29 (46 %) reported no significant changes, and 5 (8%) reported a significant decreasing trend in UC.²⁴ Like in the adult population, the incidence of UC in children and adolescents appears to have reached a plateau in the Western world, but is increasing in other parts of the world, most prominently in Southern Europe, Eastern Europe, Oceania.²⁴,²⁵

Racial and Ethnic Disparity

IBD affects people of all races and ethnic groups. Although UC appears to be more common in whites and people of Ashkenazi Jewish origin, racial and ethnic gaps are narrowing, with an increasing incidence in African Americans and second-generation Asians who have migrated to more industrialized countries.²⁶,²⁷ Some older studies concluded that IBD was more aggressive and had earlier onset in African American patients²⁸; however, several subsequent studies found such disparities in disease severity to be due to economic inequalities, rather than genetic factors.²⁹

Gender

Although the mechanism is not understood, the age of onset of IBD varies with gender. In a recent pooled analysis of 112,004 incident cases of UC among over 478 million people in the Western world, the rates of UC incidence were found to be 22% higher for females in early childhood (5-9 years of age), similar for males and females between the ages of 10 and 44, and subsequently 13% to 32% lower for females until the age of 70-74.²⁹ This pattern contrasts with the incidence of CD, which according to the same analysis is less common in females until the age of 10-14, but is more common in all subsequent age groups.²⁹

REFERENCES

1.Kappelman MD, Rifas-Shiman SL, Kleinman K, et al. The prevalence and geographic distribution of Crohn’s disease and ulcerative colitis in the United States. Clin Gastroenterol Hepatol. 2007;5(12):1424-1429.

2.Hanauer SB. Inflammatory bowel disease: epidemiology, pathogenesis, and therapeutic opportunities. Inflamm Bowel Dis. 2006;12(suppl 1):S3-S9.

3.Dahlhamer JM, Zammitti EP, Ward BW, et al. Prevalence of inflammatory bowel disease among adults aged ≥18 years – United States, 2015. MMWR Morb Mortal Wkly Rep. 2016;65(42):1166-1169.

4.Talley NJ, Abreu MT, Achkar JP, et al. An evidence-based systematic review on medical therapies for inflammatory bowel disease. Am J Gastroenterol. 2011;106(suppl 1):S2-S25.

5.Kaplan GG, Ng SC. Understanding and preventing the global increase of inflammatory bowel disease. Gastroenterology. 2017;152:313-321.

6.Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2018;390(10114):2769-2778.

7.Kappelman MD, Rifas-Shiman SL, Kleinman K, et al. The prevalence and geographic distribution of Crohn’s disease and ulcerative colitis in the United States. Clin Gastroenterol Hepatol. 2007;5(12):1424-1429.

8.Lichtenstein GR, Shahabi A, Seabury SA, et al. Lifetime economic burden of Crohn’s disease and ulcerative colitis by age at diagnosis [published online ahead of print July 18, 2019]. Clin Gastroenterol Hepatol. 2019. doi: 10.1016/j.cgh.2019.07.022.

9.Burisch J, Munkholm P. Inflammatory bowel disease epidemiology. Curr Opin Gastroenterol. 2013;29:357-362.

10.Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2011;142:46.

11.Kaplan GG, Ng SC. Globalisation of inflammatory bowel disease: perspectives from the evolution of inflammatory bowel disease in the UK and China. Lancet Gastroenterol Hepatol. 2016;1:307-316.

12.Shivananda S, Lennard-Jones J, Logan R, et al. Incidence of inflammatory bowel disease across Europe: is there a difference between north and south? Results of the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD). Gut. 1996;39:690-697.

13.Sonnenberg A, McCarty DJ, Jacobsen SJ. Geographic variation of inflammatory bowel disease within the United States. Gastroenterology. 1991;100:143-149.

14.Ballou S, Hirsch W, Singh P, et al. Emergency department utilisation for inflammatory bowel disease in the United States from 2006 to 2014. Aliment Pharmacol Ther. 2018;47(7):913-921.

15.Frolkis AD, Dykeman J, Negrón ME, et al. Risk of surgery for inflammatory bowel diseases has decreased over time: a systematic review and meta-analysis of population-based studies. Gastroenterology. 2013;145(5):996-1006.

16.Gyde S, Prior P, Dew MJ, et al. Mortality in ulcerative colitis. Gastroenterology. 1982;83:36-43.

17.Jess T, Gamborg M, Munkholm P, et al. Overall and cause-specific mortality in ulcerative colitis: meta-analysis of population-based inception cohort studies. Am J Gastroenterol. 2007;102:609-617.

18.Manninen P, Karvonen AL, Huhtala H, et al. Mortality in ulcerative colitis and Crohn’s disease. A population-based study in Finland. J Crohns Colitis. 2012;6:524-528.

19.Jess T, Frisch M, Simonsen J. Trends in overall and cause-specific mortality among patients with inflammatory bowel disease from 1982 to 2010. Clin Gastroenterol Hepatol. 2013;11:43-48.

20.Loftus EV, Silverstein MD, Sandborn WJ, et al. Crohn’s disease in Olmsted County, Minnesota, 1940-1993: incidence, prevalence, and survival. Gastroenterology. 1998;114(6):1161-1168.

21.Loftus EV, Silverstein MD, Sandborn WJ, et al. Ulcerative colitis in Olmsted County, Minnesota, 1940-1993: incidence, prevalence, and survival. Gut. 2000; 46(3):336-343.

22.Ungaro R, Mehandru S, Allen PB, et al. Ulcerative colitis. Lancet. 2017;389(10080):1756-1770.

23.Loftus EV, Shivashankar R, Tremaine WJ, et al. Updated incidence and prevalence of Crohn’s disease and ulcerative colitis in Olmsted County, Minnesota (1970-2011). ACG 2014 Annual Scientific Meeting. October 2014.

24.Sýkora J, Pomahačová R, Kreslová M, et al. Current global trends in the incidence of pediatric-onset inflammatory bowel disease. World J Gastroenterol. 2018;24(25):2741-2763.

25.Ng SC, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2017;390(10114):2769-2778.

26.Carr I, Mayberry JF. The effects of migration on ulcerative colitis: a three-year prospective study among Europeans and first- and second-generation South Asians in Leicester (1991-1994). Am J Gastroenterol. 1999;94:2918-2922.

27.Loftus EV, Sandborn WJ. Epidemiology of inflammatory bowel disease. Gastroenterol Clin North Am. 2003;31:1-20.

28.Goldman CD, Kodner IJ, Fry RD, et al. Clinical and operative experience with non-Caucasian patients with Crohn’s disease. Dis Colon Rectum. 1986;29(5):317-321.

29.Shah SC, et al. Sex-based differences in incidence of inflammatory bowel diseases-pooled analysis of population-based studies from western countries. Gastroenterology. 2018;155(4):1079-1089.e3.

CHAPTER 2

Etiopathogenesis

UC is a systemic, chronic, idiopathic, inflammatory disorder characterized by relapsing-remitting mucosal inflammation, starting in the rectum and extending to proximal segments of the colon. The exact etiopathogenesis of UC remains unknown; however, studies have implicated genetic factors, environmental triggers, and immunoregulatory dysfunction as contributing factors.

Genetic Factors

Family History

A family history of IBD is present in approximately 8% to 14% of patients with UC, with first-degree relatives being at four times greater risk for developing the disease.¹ In families with a high incidence of IBD, approximately 75% are concordant, that is, affected members have either UC or CD. The remaining 25% are not concordant, with certain family members having UC and others having CD.² Heritability studies have found a higher concordance rate among monozygotic twins compared to dizygotic twins for both UC and CD; however, concordance rates for UC are lower than for CD, suggesting that the genetic contribution in CD is more pronounced. In CD, concordance rates range from 37% to 58% in monozygotic twins compared to 3.9% to 12% in dizygotic twins.³-⁵ In UC, concordance rates range from 6% to 17% and 0% to 5% in monozygotic and dizygotic twins, respectively. These findings indicate that genetic factors do contribute to the pathogenesis of IBD, particularly CD; however, the low concordance rates indicate that other factors play important roles as well.

In a 5-year population-based cohort study of 454 patients with UC, no significant differences in medical therapy outcomes, indications for colectomy, or disease extent were found between patients with and without a family history of UC. However, the study did find that relapse rates were greater in familial cases.⁶ In an analysis of 46114 UC cases, Kuwahara and colleagues found that although the age of onset was lower in patients with a family history of UC, the clinical course of patients was not affected.⁷ Similar results were found in a retrospective study of 411 children with IBD, 244 of whom had UC.⁸

Susceptibility Loci

Recent advances have been made in genetic testing and DNA sequencing, thus permitting genome-wide association studies in IBD. One study of more than 75,000 patients with IBD and controls identified 163 susceptibility loci for IBD, with 110 contributing to both UC and CD phenotypes, 30 unique to CD, and 23 unique to UC.⁹ UC and CD are therefore hypothesized to be heterogenous polygenic disorders sharing many, but not all, susceptibility loci. Human leukocyte antigen variants appear