Residency · Residency · Gastroenterology

Inflammatory Bowel Disease - Ulcerative Colitis

Epidemiology and Pathogenesis

Epidemiology

Ulcerative colitis has an incidence of 2 to 14 per 100,000 per year in North America and Europe, with a prevalence of 150 to 300 per 100,000 in Western countries and a rising global incidence. The peak age of onset is between 15 and 30 years, with a second smaller peak between 50 and 70 years. The sex distribution is either slightly male predominant or equal. A distinctive epidemiologic feature of ulcerative colitis is the protective effect of smoking, which reduces risk by approximately 50%, and disease often flares after smoking cessation. Appendectomy before age 20 is also protective, with an odds ratio of 0.31.

Pathogenesis

The pathogenesis of ulcerative colitis involves mucosal immune dysregulation directed against commensal gut bacteria in genetically susceptible individuals. Over 200 IBD susceptibility loci have been identified, with HLA-DRB1*0103 being the strongest association for ulcerative colitis, along with variants in IL-10, IL-23R, and ECM1. The mucosal barrier is compromised by defective mucus layer production (MUC2 deficiency) and altered tight junctions. The immune response in ulcerative colitis is Th2-skewed, with prominent roles for IL-5 and IL-13, in contrast to the Th1 and Th17 predominance seen in Crohn disease. Natural killer T cells and neutrophils are prominent in the inflammatory infiltrate. Microbiome alterations mirror those seen in Crohn disease, with decreased diversity, reduced Firmicutes (particularly Faecalibacterium prausnitzii), increased sulfate-reducing bacteria, and diminished short-chain fatty acid production.

Pathology

The pathologic features of ulcerative colitis are distinct from Crohn disease in several fundamental ways. Inflammation is limited to the mucosa and submucosa, rather than being transmural. The rectum is always involved, and inflammation extends proximally in a contiguous fashion without skip lesions. Characteristic histologic features include crypt abscesses (neutrophils within crypts), cryptitis, and crypt distortion with branching. Pseudopolyps, formed by regenerating mucosa surrounded by areas of ulceration, are a hallmark of chronic disease. Paneth cell metaplasia distal to the hepatic flexure is an abnormal finding that supports the diagnosis.

Disease Extent — Montreal Classification

The Montreal Classification categorizes ulcerative colitis by extent of involvement. E1 (proctitis) refers to disease confined to the rectum up to the rectosigmoid junction and is present in 30 to 50% of patients at diagnosis. E2 (left-sided or distal disease) extends up to the splenic flexure and accounts for 20 to 30% of patients. E3 (extensive colitis or pancolitis) extends beyond the splenic flexure and is also present in 20 to 30% at diagnosis. Importantly, proximal extension occurs in 20 to 50% of patients initially diagnosed with E1 or E2 disease over 10 to 25 years of follow-up, underscoring the need for ongoing assessment of disease extent.

Clinical Presentation

Intestinal Symptoms

The hallmark symptom of ulcerative colitis is bloody diarrhea, present in approximately 90% of patients, with stools characteristically containing blood and mucus. Urgency and tenesmus are prominent, particularly with rectal involvement. Nocturnal bowel movements are an important clinical feature that helps distinguish organic from functional disease. Abdominal cramping, typically localized to the left lower quadrant, accompanies active inflammation. Weight loss may occur in severe disease.

Disease Severity — Truelove and Witts Criteria (Modified)

The modified Truelove and Witts criteria provide a clinical framework for categorizing disease severity. Mild disease is characterized by fewer than 4 bloody stools per day with normal pulse, temperature, hemoglobin above 11.5 g/dL, and ESR below 20. Moderate disease involves 4 to 6 bloody stools per day with pulse below 90, temperature up to 37.8 degrees Celsius, hemoglobin 10.5 to 11.5 g/dL, and ESR of 20 to 30. Severe disease features more than 6 bloody stools per day with pulse above 90, temperature above 37.8 degrees Celsius, hemoglobin below 10.5 g/dL, and ESR above 30.

Mayo Score

The Mayo Score is a composite of four subscores (each graded 0 to 3): stool frequency, rectal bleeding, endoscopic findings, and physician global assessment, yielding a total score of 0 to 12. A score of 2 or less indicates remission, 3 to 5 mild disease, 6 to 10 moderate disease, and 11 to 12 severe disease. The endoscopic Mayo subscore grades mucosal findings as 0 (normal), 1 (erythema and decreased vascular pattern), 2 (marked erythema and erosions), and 3 (spontaneous bleeding and ulceration). The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) incorporates vascular pattern, bleeding, and erosions or ulcers, providing a more objective assessment than the Mayo endoscopic subscore.

Extraintestinal Manifestations

The spectrum of extraintestinal manifestations in ulcerative colitis mirrors that of Crohn disease and includes peripheral arthritis, sacroiliitis and ankylosing spondylitis, erythema nodosum, pyoderma gangrenosum, uveitis and episcleritis, aphthous ulcers, and venous thromboembolism. Primary sclerosing cholangitis is more common in ulcerative colitis (5 to 8%) than in Crohn disease, does not correlate with colitis activity, and increases the risk of colorectal cancer 4-fold. Patients with concomitant PSC also carry an elevated risk of cholangiocarcinoma.

<image>An endoscopic comparison panel showing the Mayo Endoscopic Scoring system for ulcerative colitis. Four panels arranged in a 2x2 grid. Panel 1 "Mayo 0 (Normal)": normal colonic mucosa with visible vascular pattern, smooth pink surface. Panel 2 "Mayo 1 (Mild)": erythema with decreased vascular pattern, mild friability, no erosions or ulcers. Panel 3 "Mayo 2 (Moderate)": marked erythema with absent vascular pattern, contact friability, visible erosions with adherent mucopurulent exudate. Panel 4 "Mayo 3 (Severe)": spontaneous bleeding, deep ulceration, purulent exudate covering extensively denuded mucosa. Use realistic colonoscopic views with appropriate mucosal coloring. Include the UCEIS component scores (vascular pattern, bleeding, erosions/ulcers) in a small table beneath each panel. Show contiguous inflammation pattern with clear demarcation between inflamed and normal mucosa in Mayo 1-2 panels.</image>

Diagnostic Workup

Laboratory

Laboratory findings in active ulcerative colitis include anemia, leukocytosis, and thrombocytosis on the complete blood count. CRP and ESR are elevated during active disease, though CRP may remain normal in mild-to-moderate UC. Fecal calprotectin correlates with endoscopic activity, with levels exceeding 250 mcg/g suggesting active mucosal inflammation, and serves as a valuable non-invasive tool for monitoring disease activity and predicting relapse. Stool studies are essential to rule out Clostridioides difficile, which is a common concomitant infection in UC, as well as enteric pathogens, ova, and parasites. Serologic markers show pANCA positivity in 60 to 70% of ulcerative colitis patients (versus 10 to 15% in Crohn disease), while ASCA is positive in 60 to 70% of Crohn disease patients (versus 10 to 15% in UC).

Ileocolonoscopy with Biopsies

Ileocolonoscopy with biopsies is the gold standard for diagnosing ulcerative colitis. Biopsies should be obtained from each colonic segment and the terminal ileum, with a minimum of 2 biopsies per segment. Characteristic findings include contiguous inflammation starting at the rectum, crypt distortion and branching, crypt abscesses, and Paneth cell metaplasia distal to the hepatic flexure. The so-called "cecal patch" or periappendiceal inflammation can occur in left-sided UC and does not negate the diagnosis. Backwash ileitis, defined as mild terminal ileal inflammation in the setting of pancolitis, occurs in 5 to 10% of cases and does not indicate Crohn disease.

Imaging

CT of the abdomen and pelvis can assess disease extent and detect complications such as perforation and toxic megacolon but is not needed for routine diagnosis, as endoscopy is definitive. A plain abdominal radiograph is important in acute severe UC to assess for colonic dilation, with transverse colon diameter exceeding 6 cm defining toxic megacolon.

Medical Treatment

Mild-Moderate Proctitis (E1)

Topical mesalamine suppositories at 1 g daily are the preferred treatment for proctitis and are superior to oral 5-ASA for this indication, achieving response rates of 65 to 75%. Topical corticosteroids, including budesonide rectal foam and hydrocortisone enemas, are less effective than topical mesalamine. Combination of topical and oral mesalamine is superior to either modality alone.

Mild-Moderate Left-Sided/Extensive Disease (E2-E3)

Oral mesalamine at 2.4 to 4.8 g per day or sulfasalazine at 4 to 6 g per day (which requires folate supplementation) constitutes the foundation of therapy. Topical mesalamine enemas at 4 g nightly combined with oral mesalamine are superior to either agent alone, as demonstrated in the ASCEND trials. Higher doses of 4.8 g per day are more effective for moderate disease. Once-daily dosing of oral mesalamine has been shown to be non-inferior to divided doses and improves adherence.

Moderate-Severe Disease — Induction

Systemic corticosteroids at prednisone 40 to 60 mg per day serve as a bridge to steroid-sparing therapy but are never appropriate for maintenance. Biologic therapies for moderate-to-severe disease, detailed in the IBD Therapeutics lecture, include anti-TNF agents (infliximab per the ACT-1 and ACT-2 trials, adalimumab per the ULTRA trials, and golimumab per the PURSUIT trials), anti-integrin therapy with vedolizumab (GEMINI-1), anti-IL-23 agents including mirikizumab (LUCENT) and guselkumab (QUASAR), anti-IL-12/23 therapy with ustekinumab (UNIFI), JAK inhibitors including tofacitinib (OCTAVE), upadacitinib (U-ACHIEVE), and filgotinib (SELECTION), and S1P receptor modulators including ozanimod (TRUE NORTH) and etrasimod (ELEVATE).

Maintenance of Remission

5-ASA agents remain the first-line maintenance therapy for mild-to-moderate disease, with the combination of oral and topical mesalamine being the most effective approach. Thiopurines (azathioprine 2 to 2.5 mg/kg/day or 6-mercaptopurine 1 to 1.5 mg/kg/day) require TPMT and NUDT15 testing before initiation. Biologics are continued with ongoing scheduled dosing for moderate-to-severe disease. Small molecules including tofacitinib, upadacitinib, ozanimod, and etrasimod are continued at their respective maintenance doses.

Acute Severe Ulcerative Colitis (ASUC)

Definition

Acute severe ulcerative colitis is defined by the modified Truelove and Witts criteria as 6 or more bloody stools per day plus any one of the following: heart rate above 90, temperature above 37.8 degrees Celsius, hemoglobin below 10.5 g/dL, or ESR above 30. This represents a medical emergency, with 25 to 30% of patients requiring colectomy during the index hospitalization.

Initial Management (Day 0-3)

Intravenous corticosteroids are the cornerstone of initial management, with methylprednisolone 60 mg per day or hydrocortisone 100 mg three times daily being standard regimens. Concurrent evaluation must include stool studies to rule out Clostridioides difficile, which is present in 5 to 15% of ASUC cases, and CMV colitis (assessed with CMV PCR and immunohistochemistry on biopsies). VTE prophylaxis with low-molecular-weight heparin (enoxaparin 40 mg subcutaneously daily) is essential, as IBD patients have a 3-fold increased VTE risk during flares. Opioids, anticholinergics, and loperamide must be avoided due to the risk of precipitating toxic megacolon. Abrupt cessation of NSAIDs and 5-ASA should also be avoided. Flexible sigmoidoscopy, rather than full colonoscopy, is performed for biopsy to confirm the diagnosis and rule out CMV and C. difficile superinfection.

Day 3 Assessment (Oxford/Ho Criteria)

The Oxford or Ho criteria assessed on day 3 guide subsequent management. A stool frequency exceeding 8 per day, or 3 to 8 stools per day with CRP above 45 mg/L, indicates an 85% likelihood of requiring colectomy and should prompt consideration of rescue therapy.

Rescue Therapy (Steroid-Refractory)

For patients who fail intravenous corticosteroids, two rescue therapy options are available. Infliximab at 5 mg/kg intravenously may be given with accelerated dosing (at weeks 0, 1, and 3), and the CYSIF trial demonstrated a 3-month colectomy-free rate of 71%. Intravenous cyclosporine at 2 mg/kg per day as a continuous infusion (target trough 200 to 400 ng/mL) was shown to achieve an 82% response rate in the Lichtiger trial and serves as a bridge to thiopurine maintenance therapy. The CYSIF trial demonstrated non-inferiority of cyclosporine compared to infliximab. The choice between these agents is guided by institutional expertise, though infliximab is increasingly preferred because it can also serve as the maintenance agent. Sequential rescue therapy, in which cyclosporine is followed by infliximab or vice versa, carries a high complication rate including infection and death and is generally not recommended.

Surgical Considerations in ASUC

Indications for urgent colectomy include perforation, refractory hemorrhage, failure of rescue therapy, and toxic megacolon that does not improve within 24 to 72 hours. The standard first operation is subtotal colectomy with end ileostomy, which avoids pelvic dissection in the acutely ill patient. Completion proctectomy with ileal pouch-anal anastomosis is performed 3 to 6 months later when the patient has recovered and is off corticosteroids.

<image>A management timeline diagram for acute severe ulcerative colitis (ASUC). Horizontal timeline from Day 0 to Day 7. Day 0: "Admit to hospital. Start IV methylprednisolone 60 mg/day. Rule out C. difficile, CMV. VTE prophylaxis. Flexible sigmoidoscopy with biopsies. NPO if megacolon." Day 1-2: "Monitor stool frequency, CRP, plain AXR daily. Nutritional support. Avoid opioids/anticholinergics." Day 3: Decision diamond: "Oxford Criteria: >8 stools/day OR 3-8 stools + CRP >45?" If yes (non-responder): "Start rescue therapy: Infliximab 5 mg/kg IV (accelerated induction) OR Cyclosporine 2 mg/kg/day IV." If no (responder): "Continue IV steroids, transition to oral, plan steroid-sparing maintenance." Day 5-7: For rescue therapy patients: another decision diamond: "Response to rescue therapy?" If no: "Surgical consultation — subtotal colectomy + end ileostomy." If yes: "Transition to maintenance (infliximab continuation or cyclosporine bridge to thiopurine)." Use red for urgent/surgical pathways, yellow for rescue, green for response. Include vital sign and lab monitoring checkboxes along the timeline.</image>

Surgical Management

Indications for Elective Surgery

Elective surgery is considered for medically refractory disease, steroid dependence, intolerable medication side effects, dysplasia or cancer, and growth failure in pediatric patients.

Surgical Options

Total proctocolectomy with ileal pouch-anal anastomosis (J-pouch) is the standard of care and is performed as either a 2- or 3-stage procedure. Complications include pouchitis (40 to 50% lifetime risk), pouch leak or pelvic sepsis (5 to 8%), pouch failure (5 to 10% at 10 years), female subfertility (reduced with laparoscopic approach), nocturnal incontinence (10 to 15%), and increased stool frequency of 4 to 8 bowel movements per day. Total proctocolectomy with end ileostomy is an option for patients who do not desire or are not candidates for IPAA. Continent ileostomy (Kock pouch) is rarely performed but remains an option for patients with pouch failure who wish to avoid a permanent conventional ileostomy.

Pouchitis

Pouchitis is the most common long-term complication of IPAA, affecting 40 to 50% of patients over their lifetime. It manifests as increased endoscopic and histologic inflammation within the ileal pouch. Diagnosis requires the combination of symptoms (increased stool frequency, urgency, and bleeding), endoscopic findings (edema, ulceration, and friability), and histology (acute inflammation), with a Pouchitis Disease Activity Index score of 7 or greater. Acute pouchitis is treated with ciprofloxacin 500 mg twice daily or metronidazole 500 mg three times daily for 14 days, with ciprofloxacin preferred based on fewer side effects and superior efficacy per the Shen trial. Chronic or recurrent pouchitis may be managed with rotating antibiotics, VSL#3 probiotic for maintenance of antibiotic-induced remission, oral budesonide, or vedolizumab. Chronic antibiotic-refractory pouchitis (CARP) requires consideration of vedolizumab, anti-TNF therapy, or topical tacrolimus, with fecal microbiota transplantation under investigation. Crohn disease of the pouch must be excluded in these patients.

Cancer Surveillance

Risk Factors for Colorectal Cancer in UC

Colorectal cancer risk in ulcerative colitis is determined by several factors. Disease duration is the primary driver, with risk beginning at 8 to 10 years after disease onset and estimated at 2% at 10 years, 8% at 20 years, and 18% at 30 years. The extent of disease correlates with risk, with pancolitis carrying the highest risk. Severity of histologic inflammation is the strongest modifiable risk factor. Family history of colorectal cancer, concomitant primary sclerosing cholangitis (which confers a 4-fold increased risk), and the presence of post-inflammatory polyps (a marker of prior severe disease) further elevate risk.

Surveillance Protocol

Surveillance colonoscopy should begin 8 years after symptom onset for patients with E2 or E3 disease, with deferral considered for E1 (proctitis alone). Chromoendoscopy with methylene blue or indigo carmine dye spray and targeted biopsies is the preferred method, detecting 2 to 3 times more dysplasia than white light endoscopy with random biopsies. High-definition white light colonoscopy with random biopsies (4-quadrant biopsies every 10 cm, totaling 33 or more biopsies) is acceptable when chromoendoscopy is unavailable. Surveillance intervals range from every 1 to 3 years based on risk factors, with annual surveillance recommended for patients with PSC, family history of colorectal cancer, prior dysplasia, or extensive disease with active inflammation. When dysplasia is detected, a visible lesion amenable to complete endoscopic resection should be resected with continued surveillance. Invisible or unresectable dysplasia warrants colectomy, with all dysplasia diagnoses confirmed by an expert gastrointestinal pathologist.

Key Clinical Pearls

• UC always starts at the rectum and extends proximally in a contiguous fashion — skip lesions suggest Crohn disease
• Fecal calprotectin is the best non-invasive marker for monitoring mucosal inflammation and predicting relapse
• ASUC is a medical emergency: IV steroids for 3 days, then rescue therapy (infliximab or cyclosporine) if non-responsive; do not delay surgical consultation
• Always rule out C. difficile and CMV superinfection in UC flares, especially in immunosuppressed patients
• Combination oral + topical mesalamine is superior to either alone for mild-moderate UC
• Chromoendoscopy with targeted biopsies is the preferred dysplasia detection method in UC surveillance
• PSC-UC patients have the highest colorectal cancer risk and require annual surveillance colonoscopy from diagnosis of PSC
• Smoking is protective in UC (opposite of CD) — but smoking cessation should still be recommended given overall health risks

References

1. Rubin DT, et al. ACG Clinical Guideline: Ulcerative Colitis in Adults. Am J Gastroenterol. 2019;114(3):384-413.
2. Raine T, et al. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical Treatment. J Crohns Colitis. 2022;16(1):2-17.
3. Laharie D, et al. Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial (CYSIF). Lancet. 2012;380(9857):1909-1915.
4. Laine L, et al. SCENIC International Consensus Statement on Surveillance and Management of Dysplasia in Inflammatory Bowel Disease. Gastroenterology. 2015;148(3):639-651.
5. Magro F, et al. Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. J Crohns Colitis. 2017;11(6):649-670.

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