Between Crohn’s Disease and Ulcerative Colitis with Emphasis on Evidence-Based Treatment Recommendations

Continuing Education Information:

Target Audience: pharmacists

Learning Objectives:

1.Describe key similarities and distinctions between the clinical presentation of Crohn’s disease and ulcerative colitis. 2.Discuss evidencebased treatment recommendations for the management of moderate to severe Crohn’s disease and ulcerative colitis. 3.Identify the difference between the initial management of Crohn’s disease and ulcerative colitis.

Spot the Difference:

Outlining the Key Distinctions Between Crohn’s Disease and Ulcerative Colitis with Emphasis on Evidence-Based Treatment Recommendations

Lena Kan, PharmD Desert Oasis Healthcare, Palm Springs, CA

Ndidi Precious Alino, PharmD, MS Banner Ocotillo Medical Center, Chandler, AZ

Conflict of Interest The authors declare that there are no conflicts of interest.

Funding This research was not funded.

Crohn’s disease (CD) and ulcerative colitis (UC) are two of the most common chronic idiopathic inflammatory disorders of the gastrointestinal (GI) tract. CD can affect the entire GI tract and is characterized by a discontinuous pattern with skip lesions. UC is limited to the colon with a continuous pattern that originates in the rectum. Both share similarities in clinical presentation, use of nonspecific laboratory markers for diagnosis, and treatment, which can lead to confusion on how to appropriately manage each disease state. CD and UC share the same medication classes used for treatment, but initial therapy will vary depending on the disease state and severity of illness. The management of CD and UC has evolved, as seen by changes in the way existing treatments are used and the inclusion of additional classes into the guidelines. This article aims to highlight primary distinctions between CD and UC while providing evidence-based treatment strategies for acute illness in both disease states. Mildly active UC, which is limited to the colon, is initially treated using oral or rectal 5-aminosalicylates. In contrast, 5-aminosalicylates are less effective in mildly active CD because of its inability to have a widespread effect within the GI tract. Corticosteroids can be used in moderate to severe UC or CD, but only recommended for short-term use in induction of remission. Anti-tumor necrosis factor (anti-TNF) agents may be useful for induction and maintenance of remission in severe cases; however, specific agents and doses vary depending on the disease state being treated. Crohn’s disease (CD) and ulcerative colitis (UC) are two of the most common chronic idiopathic inflammatory disorders of the gastrointestinal (GI) tract.1 Both Crohn’s disease and ulcerative colitis are marked by an abnormal response by the body’s immune system and may share similar initial symptoms, such as bloody diarrhea, abdominal pain, and weight loss. The primary distinctions between the two disease states are the location within the gastrointestinal tract, pattern of illness, and response to treatment.1 Since both disease states are inflammatory GI conditions with variable severity, patients may present with a wide range of symptoms and are diagnosed based on a broad differential. Similarities in clinical presentation and use of nonspecific laboratory markers for diagnosis can lead to confusion and impact the appropriate management of Crohn’s disease or ulcerative colitis. Due to the availability of additional therapeutic classes for treatment and changes in the way existing treatments are used, the management of these idiopathic inflammatory disorders has rapidly evolved to optimize therapy for individuals with CD or UC.2 These changes can become a challenge for providers in selecting the appropriate management strategy based on the disease state and severity of illness. The purpose of this article is to highlight the primary distinctions between CD and UC while providing evidence-based management strategies for both disease states.

Crohn’s Disease

Crohn’s disease is an idiopathic inflammatory disorder of unknown etiology with genetic, immunologic, and environmental influences. Hallmark symptoms include abdominal pain, diarrhea, nausea, vomiting, and weight loss. It can affect the entire gastrointestinal tract and is characterized by a discontinuous pattern with skip lesions, which are diseased sections of bowel adjacent to uninvolved sections in the small intestine and colon. Rectal involvement is typically spared, yet perianal disease, fistulas, and strictures are relatively common in this population.1 The diagnosis of CD is established by clinical presentation, presence of inflammatory markers, and the patient’s history. Risk factors for CD include a history of inflammatory bowel disease (IBD), chronic use of nonsteroidal antiinflammatory medications, and cigarette smoking. An elevation in nonspecific inflammatory markers are likely to be seen in a patient with CD, such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fecal calprotectin, and lactoferrin. However, there are no specific laboratory markers to detect CD. The combination of a colonoscopy and imaging of the small bowel are important to detect the location and severity of illness to confirm a CD diagnosis.1

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There are similarities in the variety of medical therapies offered as treatment options for CD and UC. For instance, the first line agents used are similar, but strength and doses may vary depending on the disease state and severity of illness. In the 2018 American College of Gastroenterology guidelines on CD, therapy is stratified based on mild symptoms versus moderate to severe symptoms.3 Mild symptoms typically require less aggressive initial therapy using a step-up approach. The first line agent for mildly severe disease is oral sulfasalazine, a 5-aminosalicylate, 3-6 grams per day in divided doses. The mechanism of action of sulfasalazine is currently unknown but thought to be an oral agent acting locally within the GI tract to modulate mediators of the inflammatory response. The oral 5-aminosalicylate, mesalamine, has not consistently shown efficacy for induction of remission and should not be used to treat active CD.3 A Cochrane review of twenty studies including 2,367 patients with mild to moderately active Crohn’s disease was conducted to investigate whether 5-aminosalycylic acid derivatives induce remission or alleviate symptoms in comparison to steroids.4 Sulfasalazine was shown to be less effective than corticosteroids and inferior to combination therapy with corticosteroids (RR 0.64, 95% CI 0.47 to 0.86), with 43% of patients entering remission at 18 weeks. There was no difference between low dose mesalamine (1-2 grams per day) and placebo (RR 1.33, 95% CI 0.91 to 1.96), and no difference between high dose mesalamine (3-4 grams per day) and placebo (95% CI -46.2 to 6.7).4 In conclusion, researchers found that sulfasalazine provides modest benefit for mild-moderate disease, while mesalamine formulations were not effective for inducing remission. Moderate to severe symptoms require more aggressive initial therapy using a top-down approach. Oral corticosteroids at doses equivalent to prednisone 40-60 mg per day serve as first line agents to alleviate signs and symptoms for the first three months of therapy. The anti-tumor necrosis factor (anti-TNF) agents, infliximab, adalimumab, or certolizumab pegol, are effective in the treatment of CD in those who inadequately responded to corticosteroid treatment.3

Ulcerative Colitis

Ulcerative colitis is a chronic immune-mediated inflammatory condition affecting the large intestine. Common symptoms include abdominal pain, rectal bleeding, and inflamed rectum and diarrhea. In contrast to CD, UC is limited to the colon with a continuous pattern that originates in the rectum and progresses proximally. Unlike CD, rectal involvement is common but perianal disease, fistulas, and stricture are uncommon.1 The pattern of disease is characterized by intermittent periods of relapse and remission, but if inadequately managed it can increase the risk of dysplasia and colorectal cancer.2 The diagnosis of UC is similar to that of CD, with the use of nonspecific serology laboratory markers for inflammatory bowel disease (IBD) in addition to assessing the clinical presentation. Anemia and elevations in CRP and ESR are commonly seen and stool studies must be conducted to rule out Clostridioides difficile. To confirm a diagnosis of UC, a colonoscopy with intubation of the ileum, accompanied by biopsies must be performed unless there is a risk of perforation. Endoscopic findings include loss of vascular markings, erosions, ulcerations, or spontaneous bleeding.2 Disease severity is categorized by stool frequency or urgency, presence of blood in the stool, anemia, and degree of ESR elevation. Patients with mild flares typically have less than 4 stools per day, intermittent blood in the stool, and an ESR less than 30 mm/hr. Moderate to severe illness is typically categorized as greater than 6 stools per day, frequent blood found in the stool, a decrease in hemoglobin (Hgb) less than 75% of normal, and an ESR greater than 30 mm/hr.2 First line treatment for mildly active UC is an oral or rectal 5-aminosalicylate, such as mesalamine or sulfasalazine, at 1-2 grams per day for induction of remission. Oral or intravenous (IV) systemic corticosteroids are used for moderate to severely active UC or for failure to induce remission with 5-aminosalicylates. Induction agents should be continued for at least 6 weeks to assess the clinical response before a corticosteroid-free maintenance regimen is established.2 In severe cases requiring hospitalization, IV corticosteroids at a dose equivalent to methylprednisolone 60mg/day should be used short term for induction of remission only.2 A systematic review of 32 studies included 1,948 adults hospitalized for acute severe UC who received IV methylprednisolone on varying doses of at least 40 mg per day. Results showed a clinical response rate of 67% with a sub-group analysis revealing there was no benefit to doses higher than methylprednisolone 60 mg per day (R2 < 0.01, p=0.98).5 The 2019 ACG guidelines on ulcerative colitis recommend infliximab 5mg/kg or cyclosporine 2-4mg/kg per day if no clinical response is observed within 3-5 days of systemic steroids. The selection of agent should be based on provider experience with

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each drug. Cyclosporine is used less frequently due to the necessity of monitoring trough concentrations. A randomized controlled trial of 45 patients with acute severe UC refractory to IV corticosteroids received either a single infusion of infliximab 5mg/ kg or placebo. An inadequate response to therapy was defined as the need for a colectomy at 3 months. The study showed a 71% response rate in those treated with infliximab, as they did not require a colectomy at 3 months (p=0.0017), indicating that infliximab is an effective and safe rescue therapy in this population.6

Conclusion

Crohn’s disease and ulcerative colitis share a similar initial presentation, and both use nonspecific serological IBD laboratory markers for diagnosis, making it difficult for providers to distinguish between varying gastrointestinal disease states. Once diagnosed with CD or UC, initial treatment is guided by the severity of disease, but is slightly variable in each. Oral sulfasalazine, a 5-aminosalicylate, is recommended as first line therapy for mildly active CD as it has been proven to have a modest benefit in this population, whereas mesalamine has shown ineffectiveness. In contrast, either oral/rectal sulfasalazine or mesalamine can be used as first line therapy in mildly active UC. Oral or IV systemic corticosteroids can be used for moderate to severe active disease in both CD and UC but should only be used as short-term therapy during induction of remission. The 2019 ACG guidelines recommend treatment with an anti-TNF agent, such as infliximab, if no clinical response is seen with corticosteroids in both disease states. 

REFERENCES

1. Cheifetz, A. Management of active Crohn Disease. JAMA. 2013;309(20): 2150-2158. 2. Rubin D, Ananthakrishnan A, Siegel C, et al. ACG clinical guideline: ulcerative colitis in adults. Am J Gastroenterol. 2019;114(3): 384-413. 3. Lichtenstein G, Loftus E, Isaacs K, et al. ACG clinical guideline: management of Crohn’s disease in adults. Am J

Gastroenterol. 2018;113(4): 481-517. 4. Lim W, Wang Y, MacDonald J, Hanauer S. Aminosalicylates for induction of remission or response in Crohn’s disease.

Cochrane Database. 2016. 5. Turner D, Walsh C, Steinhart H, Griffiths A. Response to corticosteroids in severe ulcerative colitis: a systematic review of the literature and a meta-regression. Clin

Gastroenterol Hepatol. 2007;5(1): 103-10. 6. Jarnerot G, Hertervig E, Friis-Liby I, et al. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study.

Gastroenterology. 2005;128(7): 1805-11.

CE Questions

1.According to the 2019 American College of Gastroenterology guidelines on ulcerative colitis in adults, which of the following medication class is considered first line treatment for a moderate-severe acute flare? a. 5-aminosalicylic acid derivatives b. Thiopurines c. Corticosteroids d. Anti-TNF inhibitors

2.True or False: In Crohn’s Disease, corticosteroids can be effectively used to both induce and maintain remission.

3.How long must an induction agent be used before switching to maintenance treatment in ulcerative colitis? a. ≥ 3 weeks b. ≥ 6 weeks c. ≥ 3 months d. ≥ 6 months

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