Clinical Management of Inflammatory Bowel Disease (IBD)

Clinical Management of Inflammatory Bowel Disease (IBD): Crohn's Disease and Ulcerative Colitis

Instructor: Negin Sazgar, PharmD

Objectives

  • Compare and contrast the presentation and complications of ulcerative colitis (UC) and Crohn’s Disease (CD).

  • Explain the initial workup for patients with suspected IBD.

  • Describe the treatment strategies for ulcerative colitis (UC) and Crohn’s Disease (CD).

  • Evaluate patient-specific factors in selecting IBD treatment.

  • Assess therapies for UC and CD in patient case scenarios.

What is Inflammatory Bowel Disease?

  • Definition: Inflammatory Bowel Disease (IBD) is an umbrella term that encompasses two main conditions:

    • Ulcerative Colitis (UC):

    • A mucosal inflammatory condition confined to the rectum and colon.

    • Crohn’s Disease (CD):

    • A transmural inflammation of the gastrointestinal (GI) tract that can affect any part from the mouth to the anus.

Epidemiology

  • IBD is most prevalent in Western countries, with the highest rates in:

    • North America

    • Northern Europe

    • Great Britain

  • There is an increasing incidence worldwide, especially in Western and newly industrialized countries.

  • Both sexes are affected equally overall:

    • 20%-30% more females are affected with CD.

    • 60% more males are affected with UC.

  • Higher incidence in Jewish populations. The incidence among Black, Asian, and White patients is similar.

Presentation

  • Bimodal Distribution:

    • Both CD and UC show a bimodal distribution in their presentation:

    • First peak:

      • CD: Second decade (ages 10-19)

      • UC: Third decade (ages 20-29)

    • Second peak:

      • Both conditions peak again at 60-70 years of age.

Etiology

  • Uncertain and multifactorial: The exact etiology is unknown and likely involves a combination of:

    • Infectious Factors:

    • Presence of more pro-inflammatory bacteria in the gut.

    • Genetic Factors:

    • First-degree relatives of patients with IBD have a 20-fold increased risk.

    • Genes associated with the interleukin pathway system may be involved.

    • Immunologic Factors:

    • May play a role in affecting the stability of the intestinal barrier (through lymphocytes and epithelial cells).

    • Psychological Factors:

    • Possible correlation with disease flare-ups.

    • Lifestyle, Dietary, and Drug-Related Factors:

    • Various theories suggest refined sugars, animal fats, and increased proteins may affect gut microbiota.

    • Smoking is protective in UC but can worsen CD; cessation is advised regardless.

Pathophysiology

  • The extent and distribution of inflammation in the GI tract include:

    • Depth of involvement:

    • If the disease affects the mucosal, submucosal layers up to deep transmural involvement, it implies different disease states.

  • Indeterminate Colitis:

    • If it’s unclear which type of IBD a patient has, it can be classified as “indeterminate colitis.”

Clinical Features of Ulcerative Colitis

  • Extent and Distribution:

    • Confined to the rectum and colon.

  • Depth of Involvement:

    • Mucosal and submucosal layers affected.

  • Appearance:

    • Characterized by continuous inflammation.

  • Specific Types:

    • Proctitis, Left-sided disease (proctosigmoiditis), Extensive disease (pancolitis).

Complications of Ulcerative Colitis

  • Possible complications include:

    • Hemorrhoids, anal fissures, perirectal abscesses.

    • Toxic Megacolon:

    • Urgent medical or surgical treatment required.

    • Symptoms include:

      • Blood diarrhea, systemic toxicity signs (fever, tachycardia, distended abdomen, elevated WBC).

      • Dilated colon >6 cm noted on X-ray.

    • Colonic perforation, colonic strictures, and colonic dysplasia leading to colorectal carcinoma (2-6x higher risk vs. the general population).

Clinical Features of Crohn's Disease

  • Extent and Distribution:

    • Can affect any part of the GI tract; most common site is the terminal ileum.

  • Depth of Involvement:

    • Transmural, affecting all layers of the bowel wall.

  • Appearance:

    • Discontinuous disease with “cobblestone appearance” (deep mucosal ulcerations with nodular submucosal thickening).

Complications of Crohn's Disease

  • Complications include:

    • Small bowel strictures requiring surgery.

    • Fistula formations (more common than in UC):

    • Types include enterocutaneous (GI to skin), enteroenteric (GI to GI), enterovesicular (GI to bladder/vagina).

    • Nutritional deficiencies (folate, vitamin B12, iron, etc.) due to several factors: decreased food intake, intestinal losses, malabsorption, hypermetabolic state, drug-nutrient interactions, TPN (Total Parenteral Nutrition).

  • Less risk of bleeding and carcinoma vs. UC.

Comparison Between UC and CD


  • Clinical Features Comparison:

    Feature

    Crohn's Disease

    Ulcerative Colitis

    Clinical malaise

    Common

    Uncommon

    Rectal bleeding

    Common

    Common

    Abdominal tenderness

    Common

    May be present

    Abdominal mass

    Common

    Absent

    Abdominal pain

    Common

    Unusual

    Internal fistulas

    Common

    Absent

    Distribution

    Discontinuous

    Continuous

    Aphthous or linear ulcers

    Common

    Rare


  • Pathologic Features Comparison:

    Feature

    Crohn's Disease

    Ulcerative Colitis


    Rectal involvement

    Rare

    Common


    Ileal involvement

    Very common

    Rare


    Strictures

    Common

    Rare


    Fistulas

    Common

    Rare


    Transmural involvement

    Common

    Rare


    Crypt abscesses

    Rare

    Very common


    Granulomas

    Common

    Rare


    Linear clefts

    Common

    Rare


    Cobblestone appearance

    Common

    Absent

    Extraintestinal Manifestations of IBD

    • General Definition: Manifestations that refer to symptoms and organ involvement outside of the GI tract.

    • Types of Complications:

      • Hepatobiliary Complications:

      • MASLD, pericholangitis, primary sclerosing cholangitis, cholangiocarcinoma.

      • Joint Complications:

      • Peripheral and axial arthropathies (sacroiliitis, ankylosing spondylitis).

      • Ocular Complications:

      • Dry eye and uveitis.

      • Dermatologic and Mucocutaneous Complications:

      • Aphthous ulceration, pyoderma gangrenosum.

      • Hematologic, Coagulation, Pulmonary, and Metabolic Abnormalities:

      • Anemia, venous thromboembolism (VTE), osteopenia.

    Clinical Presentation of IBD

    • Symptoms in Patients:

      • Abdominal cramping and abdominal pain.

      • Diarrhea/loose stools with or without blood.

      • Increased frequency of bowel movements (BM), urgency to pass BM.

      • Intermittent bouts of illness after varying intervals of remission (flares).

    Worse Disease Outcomes in Ulcerative Colitis

    • Certain features may predict an aggressive disease course:

      • Age younger than 40 years at diagnosis.

      • Extensive disease.

      • Severe endoscopic activity (presence of deep ulcers).

      • Extra-intestinal manifestations present.

      • Elevated inflammatory markers.

    • Patients with these features may require more aggressive initial therapy or rapid intensification of therapy.

    Diagnosis of IBD

    • Diagnosis is primarily based on clinical suspicion and symptom presentation, which may include extraintestinal symptoms as well.

    • Investigative procedures may include:

      • Colonoscopy or Sigmoidoscopy:

      • To assess the distribution and extent of disease, presence of any fistulae and granulomas versus abscess.

      • Biopsy:

      • Pathology report is essential for diagnosis.

      • Tests for Inflammation:

      • Blood tests including C-reactive protein (CRP) and Erythrocyte Sedimentation Rate (ESR) - nonspecific inflammatory markers.

      • Stool tests for fecal calprotectin.

    Scoring Disease Severity in Ulcerative Colitis

    • Mayo Clinic Score Classification:

      • Points are allocated across four categories: stool frequency, rectal bleeding, endoscopic findings, and physician global assessment.

      • Total points calculated provide an overall score:

      • Higher scores indicate more severe disease.

      • Maximum score is 12:

        • Mild = 0-5 points

        • Moderate = 6-10 points

        • Severe = 11-12 points.

    Scoring for Disease Activity in Ulcerative Colitis

    • Mild-Moderate UC:

      • <4-6 bowel movements per day.

      • Mild-moderate rectal bleeding.

      • Absence of constitutional symptoms.

      • Low overall inflammatory burden.

      • Higher frequency/frequency of bowel movements or bleeding along with other factors indicates moderate disease; low-risk factors for colectomy are present.

    • Moderate to Severe:

      • Patients may be dependent on or refractory to steroids.

      • Severe endoscopic disease (ulceration).

      • High risk of colectomy.

      • Young age at diagnosis (<40 years).

      • Extensive disease with large and/or deep ulcers.

      • Mayo Clinic Score of 6-12 with endoscopic subscore of 2 or 3.

    Acute Severe Ulcerative Colitis

    • Defined as a life-threatening medical emergency characterized by:

      • Blood diarrhea and systemic inflammation.

      • Complications may lead to toxic megacolon or bowel perforation.

    • Treatment regimens are outlined in AGA guidelines.

    Scoring Disease Severity in Crohn's Disease

    • Crohn’s Disease Activity Index (CDAI):

      • Includes 8 variables: number of stools, abdominal pain, general well-being, extraintestinal complications, antidiarrheal agents used in the previous 7 days, abdominal mass palpation, hematocrit, and body weight.

      • Total score ranges from 0 to 600:

      • <150 = remission

      • 150-219 = mildly active

      • 220-450 = moderately active

      • >450 = severe disease.

    • A decrease greater than 100 points reflects a clinical response.

    Goals of Treatment

    • Primary Goals:

      • Achieve remission (absence of disease activity).

      • Note that remission is not strictly defined by the American Gastroenterology Association (AGA).

    • Considerations Include:

      • Clinical scoring (Mayo Score in UC, CDAI in CD).

      • Symptoms do not always correlate with underlying inflammation in Crohn’s Disease.

      • Importance of addressing potential complications: strictures, fistulas, abscesses, colorectal cancer, and alleviation of extraintestinal manifestations.

      • Induction and Maintenance:

      • Mucosal healing and endoscopic remission should be targeted (absence of ulceration).

      • Resolution of acute inflammatory processes measured via ESR, CRP, fecal calprotectin (FC).

      • Avoid repeated courses of corticosteroids; consider escalation of therapy early.

    Glossary of Terms

    • Tumor Necrosis Factor (TNF) antagonists:

      • Adalimumab

      • Certolizumab

      • Golimumab

      • Infliximab

    • Thiopurines:

      • Purine antimetabolites that block nucleic acid synthesis and lymphocyte proliferation.

      • Azathioprine (AZA), 6-Mercaptopurine (6MP).

    • Immunomodulator:

      • Includes thiopurines, methotrexate (MTX), cyclosporine (CSA).

    • Immunogenicity:

      • The process of producing antibodies against biologic agents.

    • Primary Nonresponder:

      • Lack of response during initial treatment period (induction period).

    • Secondary Nonresponder:

      • Initial response but loss of efficacy during maintenance therapy.

    Treatment of Ulcerative Colitis

    • Treatment Options:

      • Guideline-directed therapy per AGA recommendations:

      • Mild to moderate UC (2019).

      • Moderate to severe UC (2020).

      • Possible surgeries include Proctocolectomy (removal of colon and rectum).

    • Mild to Moderate UC:

      • Induction of Remission and Maintenance:

      • Proctitis: Offer rectal therapy (mesalamine suppositories).

      • Proctosigmoiditis: Mesalamine enemas or rectal corticosteroids.

      • Left-sided disease: Mesalamine enemas or suppositories over oral (PO) mesalamine.

      If refractory:

      • Add rectal mesalamine to PO 5-ASA.

      • Consider rectal corticosteroids.

      • For extensive disease: Mesalamine 2-3 g/day, diazo-bonded 5-ASA once daily.

      • If suboptimal response → add rectal mesalamine, increase dosage of mesalamine (>3g/day) with rectal mesalamine.

      • For patients on sulfasalazine (SSZ) in remission or those with arthritic symptoms, can use SSZ 2-4 g/day.

      • If refractory to optimized therapy: Add prednisone or budesonide.

    Treatment Mild-Moderate Ulcerative Colitis Clinical Decision Support Tool

    • Patient Parameters:

      • Mild to moderate disease activity (<4-6 bowel movements/day).

      • Mild-moderate rectal bleeding, absence of constitutional symptoms, low overall inflammatory burden.

    • Induction:

      • Anatomical extent of inflammation evaluates treatment options like standard mesalamine at once daily dosing, with various options for rectal or oral therapy considered based on specific localization.

    • Ongoing Disease Activity:

      • Assessment in approximately 4 weeks, adjusting therapy based on response (including the addition of corticosteroids if needed).

    5-Aminosalicylic Acid Derivatives

    • Mesalamine (5-ASA):

      • Mechanism of Action (MOA): Not completely understood; may involve scavenging of free radicals; inhibiting leukocyte motility.

      • Common side effects include abdominal pain, constipation, burping, headache.

    • Formulations:

      • Oral: Asacol HD (pH-dependent), Pentasa (slow release), Apriso (enteric-coated), Lialda (multi-matrix system).

      • Suppository: Canasa.

      • Enema: Rowasa.

    Sulfasalazine (SSZ)

    • Description: Originally for arthritis; a combination of sulfapyridine and mesalamine joined by a diazo bond, activated in the gut.

    • Usual Dose: 4-6 g/day.

    • Side Effects: Loss of appetite, headache, nausea, etc.

    • Contraindications/Warnings: Intestinal or urinary obstruction, porphyria, hypersensitivity.

    • Monitoring: CBC with differential and liver function tests (LFTs) at various intervals.

    Corticosteroids

    • Reserved for patients with symptoms refractory to optimized 5-ASA.

    • Types/Examples:

      • Budesonide (9 mg/day), Uceris (controlled release), Hydrocortisone formulations.

    • Short-term use recommended, as long-term may not prevent flares and lead to serious side effects.

    • Side effects include increased appetite, weight gain, diabetes risk, etc.

    Biologic Therapy for Moderate-Severe Ulcerative Colitis

    • Considered in adult outpatients meeting specific severity parameters:

      • High risk of colectomy; Mayo Clinic Score 6-12 with endoscopic subscore 2 or 3.

    • Encourage early use of biologics rather than step-up approach after failure of medical therapy.

    • Recommended agents include infliximab, adalimumab, golimumab, vedolizumab, tofacitinib.

    • Specific recommendations regarding drug selection based on prior treatment responses or resistance patterns.

    Treatment of Moderate-Severe Disease

    • Induction of Remission and Maintenance:

      • Initiate prompt treatment with suggested biologics for induction.

      • Specifically, biologics-naïve patients should consider infliximab or vedolizumab over adalimumab.

      • Strategies for those who have previously failed anti-TNFα therapy.

    • Ongoing Monitoring:

      • Follow-up strategies for assessing patient response to treatment, including possible modifications or escalations in therapy depending on effectiveness or chronicity of disease progression.

    Summary of Treatment Options

    • Biologic Agents Acknowledgment: Varying recommendations exist based on response rates, noting the potentially high effectiveness of combination therapy with thiopurines or methotrexate.

    • Surgical Considerations: Cases necessitating surgery when medical therapy fails or complications arise (proctocolectomy for UC, bowel resection for CD).

    Conclusion and Future Directions

    • Recognize that while treatment options for IBD have significantly advanced, ongoing management of both UC and CD continues to evolve with longitudinal follow-up for potential solutions and reminders about monitoring.

    • Thank You!

    • For questions: nsazgar@usc.edu