Ulcerative colitis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahad Hasan, M.D.[2], Tarek Nafee, M.D. [3], Usama Talib, BSc, MD [4] Omar Soliman, M.D.[5]

Synonyms and keywords: Colitis ulcerosa; distal colitis; ulcerative proctitis

Overview

Ulcerative colitis (UC) is a chronic, immune-mediated inflammatory bowel disease characterized by continuous mucosal inflammation of the colon, typically beginning in the rectum and extending proximally to a variable extent. Its course is characterized by periods of active disease and remission. Clinical presentation and disease severity vary substantially among patients.

Clinical Presentation

Common symptoms include:

• Bloody diarrhea.
• Increased stool frequency and urgency.
• Tenesmus and rectal discomfort.
• Abdominal cramping or pain.

Systemic symptoms, including fatigue, fever, and weight loss, may occur in more severe disease. Extraintestinal manifestations can involve the joints, skin, eyes, hepatobiliary system, and other organs. Severe presentations may include substantial bleeding, dehydration, systemic toxicity, and complications such as toxic megacolon.

Diagnosis

Diagnosis is based on the combination of clinical presentation, laboratory assessment, stool testing, endoscopy, and histopathology. No single finding independently establishes the diagnosis in every patient.

• Laboratory assessment: Complete blood count, inflammatory markers, electrolytes, renal function, and albumin can help assess inflammation, anemia, dehydration, and disease severity.
• Stool testing: Infectious causes of colitis, particularly Clostridioides difficile, should be evaluated when appropriate.
• Endoscopy and histopathology: Colonoscopy with biopsies, when clinically appropriate, helps establish the diagnosis, define disease extent, and assess inflammatory activity. In acute severe colitis, the timing and extent of endoscopic evaluation depend on clinical stability and safety.
• Objective monitoring: Symptoms should be assessed alongside biomarkers, including fecal calprotectin, and endoscopic findings when indicated. Fecal calprotectin below 125 µg/g is a STRIDE-II intermediate treatment target used as a surrogate marker of inflammatory control; interpretation depends on clinical context and the overall assessment.

Classification and Risk Stratification

UC is classified by disease extent, activity, and clinical severity. Disease extent is commonly described using the Montreal classification:

• E1 — Ulcerative proctitis: Inflammation limited to the rectum.
• E2 — Left-sided UC: Inflammation extends proximally from the rectum but does not extend beyond the splenic flexure.
• E3 — Extensive UC: Inflammation extends proximal to the splenic flexure.

Severity assessment incorporates stool frequency, rectal bleeding, systemic features, laboratory findings, endoscopic activity, and the need for hospitalization or treatment escalation. Acute severe UC is a medical emergency requiring prompt assessment and treatment. Classification systems and severity indices support clinical decision-making but do not replace individualized assessment.

Management Overview

Treatment aims to induce and maintain steroid-free clinical remission, control inflammation, improve quality of life, and reduce complications. Treat-to-target management integrates symptom assessment with objective measures of inflammation, including biomarkers and endoscopic healing when appropriate.

Mild-to-Moderate UC

5-aminosalicylates (5-ASAs), particularly oral and/or rectal mesalamine according to disease extent and severity, are standard initial treatments for many patients with mild-to-moderate UC. Treatment selection and optimization depend on disease distribution, activity, response, and tolerability.

Moderate-to-Severe UC

Guidelines recommend induction therapy with anti-TNF agents (infliximab, adalimumab, or golimumab), vedolizumab, ustekinumab (an IL-12/23p40 antibody), IL-23p19 inhibitors (guselkumab, mirikizumab, or risankizumab), JAK inhibitors (tofacitinib or upadacitinib), or S1P receptor modulators (ozanimod or etrasimod). The 2025 ACG guideline makes strong recommendations supported by moderate-quality evidence for these advanced-therapy options, with high-quality evidence for infliximab and upadacitinib. Choice of therapy depends on disease severity, prior treatment exposure and response, patient characteristics, safety considerations, and patient preferences.

Systemic corticosteroids may be used for induction in selected patients but should not be used for maintenance therapy. Patients with inadequate response to optimized treatment may require escalation to advanced therapy or surgical assessment.

Acute Severe UC

Acute severe UC generally requires hospitalization, intravenous corticosteroids, close monitoring, and assessment for complications. Patients who do not respond adequately to intravenous corticosteroids may require rescue therapy, such as infliximab or cyclosporine, or colectomy when medically indicated. Surgical consultation should not be delayed when deterioration or complications warrant it.

Natural History, Complications, and Prognosis

UC is a chronic relapsing disease. Relapse is common, and a proportion of patients eventually require colectomy despite medical treatment. Published estimates vary by cohort, treatment era, disease extent, and duration of follow-up; a 2023 review reported colectomy in approximately 7% of patients by 5 years, while other reviews report higher cumulative estimates over longer follow-up.

Important complications include acute severe colitis, toxic megacolon, significant bleeding, colorectal cancer, and extraintestinal manifestations. UC causes significant morbidity but has a low rate of disease-specific mortality.

Colorectal cancer (CRC) risk is increased in some patients with longstanding colonic inflammatory bowel disease. CRC surveillance is generally initiated 8–10 years after symptom onset in colonic IBD. In patients with concurrent primary sclerosing cholangitis (PSC), annual surveillance should begin at the time of PSC diagnosis, regardless of disease duration.

Key Clinical Principles

• Confirm the diagnosis using clinical, laboratory, endoscopic, and histopathological evidence while evaluating for infectious mimics.
• Document disease extent and assess activity and severity at diagnosis and during follow-up.
• Use symptoms and objective inflammatory measures to guide treat-to-target management.
• Select treatment according to disease severity, prior therapy, safety, and patient preferences.
• Avoid systemic corticosteroids as maintenance therapy.
• Recognize acute severe UC as a potentially life-threatening condition requiring urgent assessment.
• Assess colorectal cancer surveillance needs, including the need for annual surveillance from the time of PSC diagnosis.

Classification

Ulcerative colitis (UC) is classified according to anatomic extent and disease activity/severity. The Montreal classification describes both extent (E) and clinical severity (S). Clinical activity indices and endoscopic scores provide complementary assessments; acute severe ulcerative colitis (ASUC) is a distinct, potentially life-threatening category defined by modified Truelove and Witts criteria.

Classification by Anatomic Extent: Montreal Classification

The Montreal classification categorizes UC according to the maximum documented extent of colonic involvement. Extent may change over time and should be reassessed during follow-up.

Classification	Disease extent	Anatomic boundary
E1: Proctitis	Rectum only	Inflammation limited to the rectum, with the proximal margin distal to the rectosigmoid junction (operationally ≤15 cm from the anal verge per ACG 2025)
E2: Left-sided colitis	Rectum and colon distal to the splenic flexure	Disease does not extend proximal to the splenic flexure
E3: Extensive colitis	Disease extending proximal to the splenic flexure	May involve the entire colon (pancolitis)

Extent informs prognosis and treatment planning but should not, by itself, restrict therapeutic options. Proctitis can still be associated with clinically significant or moderate-to-severe disease activity.

Montreal Classification by Clinical Severity

The Montreal classification also includes a clinical severity axis (S), used alongside the extent classification. The categories are remission, mild, moderate, and severe disease.

Montreal severity class	Description
S0	Clinical remission; asymptomatic
S1	Mild disease
S2	Moderate disease
S3	Severe disease

Classification by Clinical Activity and Severity

Truelove and Witts Criteria

The Truelove and Witts criteria classify clinical activity using stool frequency and systemic manifestations. They are particularly useful for identifying severe disease but do not incorporate endoscopic activity or several important patient-reported symptoms, including urgency and nocturnal bowel movements.

Severity	Clinical and laboratory features
Mild	Fewer than 4 bowel movements/day, with no systemic toxicity; temperature and pulse are normal, hemoglobin is greater than 11 g/dL, and ESR is less than 20 mm/h.
Severe	Six or more bloody bowel movements/day with systemic toxicity, such as fever, tachycardia, anemia, or elevated ESR.

Moderate disease is generally considered intermediate between mild and severe disease. The original Truelove and Witts criteria have limitations as a comprehensive or longitudinal measure of disease activity and should be interpreted alongside endoscopic findings, inflammatory burden, disease course, and patient-reported outcomes.

Mayo Score and Related Clinical Indices

The Mayo score is a composite measure used in clinical practice and clinical trials. Its full version includes four components, each scored from 0 to 3, for a total score of 0-12.

Component	Assessment
Stool frequency	Frequency relative to the patient's normal pattern
Rectal bleeding	Degree of visible rectal bleeding
Endoscopic findings	Endoscopic severity of mucosal inflammation
Physician global assessment (PGA)	Overall physician assessment of disease activity

Related indices include:

• Partial Mayo score: Excludes the endoscopic component.
• PRO2: Uses stool frequency and rectal bleeding as patient-reported outcomes.
• Modified Mayo score: Regulatory trial versions may exclude the physician global assessment.

The Mayo score should not be interpreted in isolation when determining overall disease severity.

Lichtiger Index

The Lichtiger index is an eight-item clinical activity index with a maximum score of 21, used particularly in ASUC. A score greater than 10 indicates severe disease in the cited framework. Clinical response has been defined as a score below 10 on two consecutive days in the relevant acute severe UC assessment context.

Pediatric Disease Activity

The Pediatric Ulcerative Colitis Activity Index (PUCAI) is a validated clinical activity index used to assess disease severity in children with UC. Detailed pediatric thresholds are outside the scope of this adult-focused classification section.

Classification by Endoscopic Severity

Endoscopic severity should be documented separately from clinical symptoms because symptoms may not accurately reflect mucosal inflammation. The Mayo Endoscopic Score (MES) and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) are established systems for classifying endoscopic activity.

Feature	Mayo Endoscopic Score (MES)	UCEIS
Assessment domains	Vascular pattern, erythema, friability, erosions or ulcers, and bleeding	Vascular pattern, bleeding, and erosions or ulcers
Score range	0-3	0-8
Grade 0	Normal or inactive mucosa	Combined domain score
Grade 1	Mild disease	Combined domain score
Grade 2	Moderate disease	Combined domain score
Grade 3	Severe disease	Combined domain score

The MES is widely used and accepted in clinical trials but has limitations in formal validation and interobserver agreement. UCEIS is a validated quantitative index that excludes friability as a separate domain and can support more reproducible assessment of endoscopic severity. Formal UCEIS cutoffs distinguishing mild, moderate, and severe disease have not been definitively established, in contrast to the MES bands.

Endoscopic Remission and Improvement

The STRIDE-II treatment-target framework distinguishes endoscopic remission from improvement and response.

Endpoint	Definition
Endoscopic remission	MES 0 or UCEIS ≤1
Endoscopic improvement	MES 0 or 1
Endoscopic response	Reduction in MES by at least 1 point or reduction in UCEIS by at least 2 points

Composite measures such as the DUBLIN score (MES multiplied by Montreal extent), the Modified Mayo Endoscopic Score (MMES), and the panMayo score incorporate disease extent into estimates of total inflammatory burden. These measures are not yet standard replacements for established classification systems.

Acute Severe Ulcerative Colitis

Acute severe ulcerative colitis (ASUC) is a potentially life-threatening presentation requiring hospital assessment. It is defined using the modified Truelove and Witts criteria rather than endoscopic severity alone.

ASUC is defined by:

• At least 6 bloody bowel movements in 24 hours; and
• At least one marker of systemic toxicity:
  • Pulse greater than 90 beats/min.
  • Temperature greater than 37.8°C.
  • Hemoglobin less than 10.5 g/dL.
  • ESR greater than 30 mm/h.

The ECCO framework additionally incorporates CRP greater than 30 mg/L as a systemic inflammatory marker in the relevant criteria.

The Oxford criteria help assess response to intravenous corticosteroids on day 3 of treatment. They identify a high-risk group when there are at least 8 stools/day, or 3-8 stools/day with CRP greater than 45 mg/L. The latter threshold has historically been associated with a high risk of colectomy in the studied population.

In suspected ASUC, infection should be excluded before attributing the presentation solely to UC activity.

Multidimensional Assessment of Disease Severity

Contemporary severity assessment extends beyond a single symptom score. The 2025 ACG guideline describes four domains that should inform classification and treatment decisions:

• Patient-reported outcomes: Stool frequency, rectal bleeding, urgency, and other relevant symptoms.
• Inflammatory burden: Endoscopic findings and inflammatory markers, including fecal calprotectin, CRP, and albumin.
• Disease course: Hospitalization, corticosteroid requirement, and treatment failure.
• Disease impact: Effects on quality of life and daily functioning.

Moderate-to-severe disease in clinical trials is commonly defined using a combination of clinical activity, endoscopic inflammation, corticosteroid dependence or refractoriness, and risk of complications or colectomy. A Mayo score of 6-12 with an endoscopic subscore of 2-3 is a commonly used trial framework, although operational definitions vary by study and guideline.

Clinical Considerations and Limitations

• Document both Montreal extent and clinical and endoscopic activity at diagnosis and reassessment.
• Do not classify disease severity by symptoms alone; clinical symptoms and mucosal inflammation may be discordant.
• Do not use anatomic extent as a ceiling on therapeutic options.
• Recognize that Truelove and Witts criteria have not been prospectively validated as a comprehensive severity index.
• Recognize that MES remains widely used despite limitations in validation and interobserver reproducibility.
• No single composite severity index is currently endorsed as a universal replacement for multidimensional clinical assessment.

Pathophysiology

Pattern of Mucosal Inflammation

• Inflammation is confined to the mucosa. It begins in the rectum and extends proximally in a continuous pattern to a variable length of the colon.

Pathogenic Model

UC is a multifactorial disorder with four interacting domains:

• Genetic susceptibility
  • Genome-wide association studies have identified more than 200 IBD risk loci. These loci are enriched for genes involved in intestinal barrier function and T-cell immunity.
  • Known risk variants explain only about 19–26% of IBD heritability.
  • Genotyping therefore does not predict disease onset or phenotype and has no routine clinical role.
• Environmental triggers
  • Smoking has a distinctive relationship with UC. Current smoking is associated with a lower risk, while former smokers and recent quitters have a higher risk.
  • Other modifiers include appendectomy, NSAIDs, antibiotics, enteric infections, and diet. Many of these act by reshaping the microbiome.
• Epithelial barrier dysfunction is an early and possibly primary event (see below).
• Immune dysregulation consists of aberrant innate and adaptive responses to luminal microbial antigens.

Epithelial Barrier Dysfunction

Barrier failure is detectable early in the disease. It is increasingly viewed as a primary driver rather than only a consequence of inflammation.

• Mucus layer defects: reduced mucin 2 (MUC2) synthesis and goblet cell depletion make the mucus barrier thinner and more permeable.
• Tight junction disruption: downregulation of occludin, claudins, and tricellulin increases paracellular permeability.
• Pre-clinical changes:
  • Foci of epithelial apoptosis appear before endoscopic disease.
  • Unaffected first-degree relatives show increased intestinal permeability.
• Epithelial stress pathways: two mechanisms link genetic and environmental hits to epithelial inflammation.
  • Reduced colonocyte PPAR-γ expression. PPAR-γ normally restrains NF-κB.
  • Unresolved endoplasmic reticulum stress, for example through the XBP1 pathway.
• Once the barrier fails, luminal microbial antigens reach immune cells in the lamina propria. This sets up a self-reinforcing cycle of inflammation and further barrier injury.

Microbial Dysbiosis

• Characteristic changes in the UC microbiome:
  • Reduced microbial diversity.
  • Depletion of commensals that produce short-chain fatty acids (SCFAs), such as Faecalibacterium prausnitzii.
  • Expansion of facultative pathobionts, including Escherichia coli and other Enterobacteriaceae and Proteobacteria.
• No single causative organism: no pathogen reproducibly causes UC. Disease reflects altered proportions of normally resident taxa and opportunistic pathobionts.
• Dysbiosis is both cause and consequence:
  • The inflamed mucosa is rich in oxygen and nitrate, which favors aerotolerant Proteobacteria and perpetuates inflammation.
  • The direction of causality remains unresolved.
• Functional consequences: loss of SCFAs (colonocyte fuel and inducers of regulatory T cells) and activation of toll-like receptor–NF-κB signaling amplify release of pro-inflammatory cytokines.

Dysregulated Immune Response

Innate Immunity

• After antigens cross the epithelium, dendritic cells, macrophages, and neutrophils are activated.
• A hallmark of UC is mucosal neutrophil accumulation with neutrophil extracellular traps (NETs). NETs amplify TNF and IL-1β signaling.
• Dendritic cells shift to a pro-inflammatory, less tolerogenic phenotype and induce fewer regulatory T cells.

Adaptive Immunity

• Atypical Th2 response: non-classic NKT cells produce IL-5 and IL-13.
  • IL-13 is directly cytotoxic to epithelial cells.
  • It induces apoptosis and disrupts tight junctions.
• Th9 cells: these PU.1⁺ cells are induced by epithelial IL-33 and produce IL-9.
  • They are more enriched in UC mucosa than in Crohn's disease.
  • They impair epithelial proliferation and barrier function.
• Th17 cells: these RORγt⁺ cells are driven by IL-23 and produce IL-17, IL-21, and IL-22. They are present in both UC and Crohn's disease.
• Effector:regulatory T-cell imbalance: impaired regulation by IL-10 and TGF-β sustains inflammation.
  • Loss-of-function mutations in IL-10 or its receptor cause severe early-onset colitis.
• T-cell plasticity: T cells can change phenotype, for example Th17 cells converting to Th1 cells or mixed FOXP3⁺IL-17⁺ cells appearing. Together with redundancy in the cytokine network, this helps explain why blocking a single cytokine often fails.

T-cell subsets in UC versus Crohn's disease

T-cell subset	Inducing signal	Signature cytokines	Predominant disease
Atypical Th2 (NKT-driven)	—	IL-5, IL-13	UC
Th9	IL-33	IL-9	UC
Th1	IL-12	IFN-γ, TNF, IL-6	Crohn's disease
Th17	IL-23	IL-17, IL-21, IL-22	Both
Treg (reduced Treg:effector ratio)	—	IL-10, TGF-β	Both

Adapted from Neurath 2017 and Neurath 2019.

Pathogenic Targets of Approved Therapies

Pathogenic target	Mechanism	Representative agents
TNF	Neutralizes a dominant pro-inflammatory cytokine	Infliximab, adalimumab, golimumab
α4β7 integrin–MAdCAM-1	Blocks gut-selective lymphocyte trafficking	Vedolizumab
IL-12/IL-23 (p40); IL-23 (p19)	Inhibits the Th17/IL-23 axis	Ustekinumab; mirikizumab
JAK–STAT signaling	Oral inhibition of multiple cytokine pathways	Tofacitinib, filgotinib, upadacitinib
S1P receptor	Retains lymphocytes in lymph nodes	Ozanimod, etrasimod

Table sources: Gros 2023, Le Berre 2023, Neurath 2019.

Each agent blocks only one node of a redundant inflammatory network. As a result, only about 30–60% of patients respond to any given advanced therapy. This explains primary non-response and supports sequencing or combining mechanisms.

Causes

Genetic susceptibility

UC is a polygenic disorder involving susceptibility loci associated with epithelial barrier function, immune regulation, cytokine signaling, antigen presentation, and host–microbiome interactions.

• HLA/MHC region: The human leukocyte antigen (HLA) region within the major histocompatibility complex (MHC) is a major UC susceptibility locus with disease-specific association patterns. HLA-DRB1*01:03 is a strongly replicated UC-associated allele, with reported associations with extensive and severe colitis and colectomy risk. HLA-DRB1*15:01 has also been implicated. HLA associations differ between UC and Crohn's disease, supporting distinct contributions of antigen presentation to disease susceptibility.
• IL-23 signaling: Variants involving IL23R, IL12B, STAT3, and JAK2 implicate dysregulated cytokine signaling and type 17 immune responses.
• Immune tolerance: Impaired IL-10 signaling can cause severe early-onset intestinal inflammation, illustrating the importance of regulatory pathways in maintaining mucosal homeostasis.
• Barrier and microbial interactions: Genetic variation affecting epithelial integrity and microbial recognition may increase susceptibility to inflammation.

Unlike Crohn's disease, UC does not have the same characteristic association with NOD2 and autophagy-related susceptibility pathways. However, genetic susceptibility alone does not determine disease development or clinical phenotype.

Adaptive immunity and cytokine signaling

UC involves overlapping immune pathways rather than a single dominant T-cell phenotype.

• Atypical type 2 immune response: UC has historically been associated with an atypical Th2-like response, including IL-13 production by nonclassical, CD1d-restricted type II natural killer T cells, implicated in epithelial cytotoxicity and barrier dysfunction. However, the extent to which this pathway dominates human UC remains debated, and some studies have not demonstrated increased mucosal IL-13. Anti-IL-13 antibodies, including anrukinzumab and tralokinumab, did not demonstrate significant clinical benefit in trials of moderate-to-severe UC, illustrating the distinction between a plausible disease mechanism and a clinically validated therapeutic target.
• IL-23/Th17 axis: IL-23 supports inflammatory type 17 immune responses involving cytokines such as IL-17A, IL-17F, and IL-22. This pathway contributes to the inflammatory network, although individual cytokines may also support mucosal defense. IL-22 has context-dependent effects: it can promote epithelial repair and barrier protection but may also contribute to inflammation. Increased expression of IL-22-regulated genes has been associated with resistance to anti-IL-12/23p40 therapy in some studies.
• Other inflammatory mediators: TNF, IL-1β, and IL-6 contribute to inflammatory signaling and tissue injury. IL-9 has also been implicated in epithelial dysfunction and mucosal inflammation.
• Regulatory pathways: Impaired immune tolerance and inadequate regulatory responses permit persistent reactions to intestinal antigens.

The traditional distinction of UC as a pure Th2 disease and Crohn's disease as a pure Th1 disease is an oversimplification. Both conditions involve overlapping immune pathways, although their characteristic tissue patterns and genetic associations differ.

Clinical pearl: Although IL-23/Th17 signaling contributes to UC pathogenesis, direct IL-17 blockade is not an established UC treatment and can precipitate or exacerbate inflammatory bowel disease. Clinical development of IL-17 inhibitors in IBD was limited by lack of efficacy and worsening disease in clinical studies. Postmarketing pharmacovigilance has identified disproportionate reporting of IBD with IL-17 inhibitors, and observational population data have investigated an increased risk of new-onset IBD with these agents. IL-17A also contributes to mucosal defense and epithelial barrier integrity, including regulation of tight-junction function. These findings illustrate why involvement of a cytokine in disease pathogenesis does not automatically make its direct inhibition therapeutically beneficial.

Differentiating Ulcerative colitis from other Diseases

Ulcerative colitis (UC) has no single gold-standard diagnostic test. Diagnosis requires a compatible clinical history, endoscopic findings, supportive histology, and exclusion of infectious and other mimics. Typical symptoms include bloody diarrhea, urgency, and tenesmus. The diagnostic assessment addresses two questions: whether the patient has UC or Crohn disease (CD), and whether the colitis represents inflammatory bowel disease (IBD) or a non-IBD condition.

The principal diagnostic assessment combines colonoscopy with terminal ileal intubation, biopsies from affected and normal-appearing segments, and small-bowel evaluation when CD is suspected. Some patients remain classified as IBD-unclassified (IBD-U) when clinical, endoscopic, histologic, and imaging findings do not establish a definitive subtype.

Ulcerative Colitis versus Crohn Disease

The most useful discriminators are the distribution and depth of inflammation, terminal ileal and perianal involvement, endoscopic morphology, and histologic pattern. No individual feature is invariably diagnostic.

Feature	Ulcerative colitis	Crohn disease
Distribution	Typically continuous inflammation beginning in the rectum and extending proximally	Segmental inflammation with skip areas; rectal sparing may occur
Rectum	Usually involved, although exceptions occur	May be spared
Terminal ileum	Usually normal; short-segment backwash ileitis may accompany extensive colitis	Ileitis may occur independently of colonic disease and may include ulcers or strictures
Depth of inflammation	Primarily mucosal	Transmural inflammation
Endoscopic appearance	Diffuse erythema, loss of vascular pattern, friability, and superficial ulceration	Aphthous or deep linear ulcers, cobblestoning, and intervening normal mucosa may occur
Strictures and fistulae	Unusual; a stricture warrants assessment for CD or malignancy	More characteristic, reflecting transmural disease
Perianal disease	Uncommon	More characteristic, particularly fistulae and abscesses
Histology	Diffuse chronic mucosal inflammation, crypt architectural distortion, basal plasmacytosis, and cryptitis or crypt abscesses	Patchy chronic inflammation; non-cryptolytic granulomas, when present, support CD

Endoscopic discriminators

The pretreatment index examination is particularly valuable because therapy can cause patchiness, rectal sparing, or uneven healing that complicates differentiation. Features favoring UC include continuous inflammation from the rectum, diffuse friability, loss of vascular pattern, and superficial ulceration. Features favoring CD include skip lesions, deep or serpiginous ulcers, cobblestoning, terminal ileal disease, strictures, fistulae, and perianal disease. Interpret findings in combination rather than relying on any one feature.

Recognized UC patterns that can mimic Crohn disease

• Backwash ileitis: Mild inflammation of a short, contiguous segment of terminal ileum may accompany extensive colitis. This finding alone does not establish CD. Discrete ileal ulcers, strictures, patchy ileal inflammation, or ileitis disproportionate to the colonic disease should prompt further evaluation for CD.
• Cecal or periappendiceal patch: Localized periappendiceal inflammation can occur alongside distal UC despite otherwise normal-appearing intervening colon. This pattern alone does not establish CD.

Histology

Obtain biopsies from multiple colonic segments, including the rectum and endoscopically normal-appearing mucosa; sample the terminal ileum when appropriate. A commonly used sampling approach is at least two biopsies from each of five or more colonic sites, including the rectum, together with ileal biopsies when indicated.

Basal plasmacytosis and diffuse crypt architectural distortion support chronic IBD and help distinguish it from acute self-limited infectious colitis. Cryptitis and crypt abscesses indicate active inflammation but are not specific to UC. Early biopsies may lack established architectural distortion, so a nondiagnostic early specimen does not exclude UC.

Granulomas away from ruptured crypts support CD in the appropriate clinical context. However, crypt rupture can produce cryptolytic granulomas in UC; granulomas must therefore be interpreted with their location, associated crypt injury, and the broader clinical picture. Reliable assessment of transmural inflammation generally requires a surgical resection specimen rather than superficial mucosal biopsies.

Serology: limited diagnostic role

Perinuclear antineutrophil cytoplasmic antibodies (pANCA) have an association with UC, while anti-Saccharomyces cerevisiae antibodies (ASCA) are associated with CD. These tests have insufficient sensitivity and overall diagnostic performance to establish IBD or routinely distinguish UC from CD in adults. A pANCA-positive/ASCA-negative pattern may be relatively specific in selected populations, but a negative result does not exclude either disease, and colonic CD can share the UC-associated pattern. Serology has a limited potential role in selected pediatric IBD-U cases, but it should not replace clinical, endoscopic, histologic, and imaging assessment.

Ulcerative Colitis versus Non-IBD Colitides

Infection and other mimics should be assessed before attributing colitis to UC. The appropriate workup depends on symptom pattern, exposure history, immune status, medications, age, and endoscopic distribution.

Mimic	Distinguishing features	Diagnostic approach
Infectious colitis	Acute or subacute diarrhea; exposure or outbreak history; may produce bloody diarrhea and endoscopic inflammation	Stool pathogen testing guided by presentation, including Clostridioides difficile testing. Consider parasites based on travel and exposure. Investigate cytomegalovirus (CMV) in severe or treatment-refractory colitis when clinically indicated.
Sexually transmitted proctitis	Rectal pain, discharge, tenesmus, or bleeding; relevant sexual exposure; inflammation may be limited to the rectum	Exposure-informed testing for Neisseria gonorrhoeae, Chlamydia trachomatis including lymphogranuloma venereum when relevant, herpes simplex virus, syphilis, and mpox as indicated
Ischemic colitis	Often abrupt pain and hematochezia in patients with vascular risk factors or relevant medication exposure; rectal sparing is common	Clinical assessment and appropriate imaging/endoscopy, considering disease severity and distribution
Microscopic colitis	Chronic watery, usually non-bloody diarrhea with normal or near-normal endoscopic appearance	Colonic biopsies; histology identifies lymphocytic or collagenous colitis
Segmental colitis associated with diverticulosis (SCAD)	Inflammation in a diverticular segment, usually the sigmoid colon, with rectal sparing	Colonoscopy and biopsies documenting the distribution and excluding other causes
Drug-induced colitis	Temporal relationship to medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) or immune checkpoint inhibitors; appearances may overlap with IBD	Medication history, clinical context, endoscopy, and histology
Radiation proctocolitis	History of pelvic radiotherapy; rectal or distal colonic symptoms according to the radiation field	Treatment history and endoscopic assessment
Other conditions	Consider colorectal malignancy, Behçet disease, vasculitis, graft-versus-host disease, and immunodeficiency-associated colitis. Celiac disease, irritable bowel syndrome, and food intolerance may explain diarrhea but do not ordinarily cause chronic inflammatory colitis	Directed testing based on clinical presentation, risk factors, and biopsy findings

Infectious evaluation

• Test for C. difficile at diagnosis and during acute diarrheal flares. Exclude CDI before diagnosing UC and test patients hospitalized with acute severe UC. Test patients with established IBD who develop an acute diarrheal flare or new or worsening diarrhea, especially with colonic involvement.
• Use a two-step CDI testing algorithm when appropriate. A strategy incorporating glutamate dehydrogenase (GDH) and toxin testing, or nucleic acid amplification testing (NAAT/PCR) with toxin testing, helps distinguish toxin-mediated infection from colonization. PCR positivity alone can overdiagnose CDI because asymptomatic colonization, including PCR-positive/toxin-negative results, occurs in IBD.
• Use stool pathogen testing according to symptom severity, epidemiology, travel, exposure, and local testing protocols.
• Investigate CMV, usually with tissue-based testing, in severe or corticosteroid-refractory colitis or otherwise unexplained deterioration.
• In isolated proctitis, elicit a history of receptive anal intercourse and use the exposure history and clinical presentation to direct testing for sexually transmitted infections, including N. gonorrhoeae, C. trachomatis (including lymphogranuloma venereum when relevant), herpes simplex, syphilis, and mpox.

Clinically Actionable Diagnostic Approach

1. Obtain a focused history, including symptom duration, bleeding, urgency, pain, travel, infectious exposures, sexual exposures where relevant, medication use, prior pelvic radiotherapy, and family history.
2. Perform appropriate laboratory and stool testing to assess inflammation and exclude infection, including C. difficile testing before diagnosing UC and during acute diarrheal flares.
3. Perform ileocolonoscopy with segmental biopsies, including samples from normal-appearing mucosa, when safe and clinically appropriate. In acute severe colitis, limited flexible sigmoidoscopy with biopsies may be safer than full colonoscopy.

Epidemiology and Demographics

UC affects millions of people worldwide, with estimates suggesting approximately 5 million prevalent cases in 2023. The burden of inflammatory bowel disease varies geographically, and incidence continues to rise in some newly industrialized countries despite stabilization in parts of Western Europe and North America.

In the United States, a 2023 population-based analysis estimated UC incidence at 6.3 cases per 100,000 person-years and approximately 1.253 million prevalent cases. A separate review estimated North American inflammatory bowel disease prevalence at approximately 0.4%, corresponding to roughly 1.5 million people; estimates differ by study population, methodology, and the inflammatory bowel disease definition used and should not be considered directly interchangeable.

UC can present at any age, with a predominant peak of onset in the second to fourth decades of life; the 2025 ACG guideline specifically identifies the third decade as a peak. Diagnoses among people older than 60 years are increasing, and this group accounts for up to approximately 20% of new diagnoses.

Risk Factors

Ulcerative colitis (UC) develops through interactions among polygenic susceptibility, environmental exposures, the intestinal microbiome, epithelial barrier function, and mucosal immunity. Genome-wide association studies explain only a minority of disease variance; estimates include approximately 7.5% to 8.2%, depending on the study and analytical approach. These estimates should not be interpreted as a definitive measure of the total heritable contribution to UC. Most environmental associations derive from observational studies and should not automatically be interpreted as causal or clinically actionable.

Non-Modifiable Risk Factors

Family history and genetic susceptibility

A positive family history of inflammatory bowel disease (IBD) is the strongest established risk marker for UC. First-degree relatives of patients with UC have an adjusted incidence rate ratio of approximately 4–10 compared with the general population, although estimates vary by population and study design. Offspring of a parent with UC have an estimated absolute lifetime IBD risk of approximately 6%, compared with approximately 9% when the affected parent has Crohn disease. Risk increases with a greater number of affected relatives, younger age at the relative's diagnosis, and a Crohn disease rather than UC proband. Sibling risk exceeds parent-to-offspring risk in reported cohorts.

Monozygotic twin concordance for UC is approximately 15–19%, compared with approximately 30–50% for Crohn disease. Dizygotic twin concordance for UC is approximately 4–6%. The incomplete concordance supports a substantial but partial genetic contribution alongside environmental and other influences.

• More than 240 IBD-associated genetic risk loci have been identified. UC-associated pathways include HLA-mediated immunity, epithelial barrier function, and T-cell/IL-23 signaling.
• Current genetic risk scores are not sufficiently predictive to guide routine screening or risk stratification in asymptomatic individuals.

Ethnicity and geography

Historically, UC incidence has been higher in populations of European ancestry, including Ashkenazi Jewish populations. However, incidence has risen in multiple newly industrialized regions, including Asia, the Middle East, and South America. These trends support an important contribution from changing environmental exposures and healthcare ascertainment rather than a fixed ethnic predisposition alone.

Modifiable and Environmental Risk Factors

The table summarizes selected reported associations. Effect estimates are approximate and may differ by study design, population, exposure definition, and whether the outcome was UC specifically or IBD overall. The strength of evidence is not uniform, and an observed association does not establish causation.

Factor	Reported association with UC onset	Approximate effect estimate	Evidence and interpretation
Family history of IBD	Increased risk	OR approximately 3.6–3.9 in an East-West meta-analysis	Consistent association; magnitude varies across populations and family relationships.
Former smoking	Increased risk compared with current smoking in many studies	OR approximately 1.6–1.8 in an East-West meta-analysis	Association is reported across populations; estimates depend on comparator and smoking history.
Current smoking	Lower observed risk	OR approximately 0.58 in a cited meta-analysis	One of the most consistent environmental associations, but causality is uncertain and smoking is harmful.
Appendectomy, particularly for appendicitis at a young age	Lower observed risk	OR approximately 0.31 in a cited review	Association is strongest in some Western populations and attenuated or absent in some Asian cohorts; not an indication for preventive surgery.
Vitamin D deficiency	Increased risk reported	OR approximately 2.0 in an East-West meta-analysis	Association reported in different regions; whether deficiency is causal or reflects preclinical disease remains uncertain.
Oral contraceptive use	Slightly increased risk reported	OR approximately 1.18 in an IBD-focused analysis	Modest association; not proof of causality or a reason by itself to avoid contraception.
Antibiotic exposure	Increased risk reported for IBD overall; UC-specific findings are inconsistent	OR approximately 1.40 in an IBD-focused analysis	Association varies with age, antibiotic class, dose, timing, and geography; some studies have reported no UC-specific association or a protective association in developing-country cohorts.
Urban living	Modestly increased risk in some Western populations	OR approximately 1.22 in a cited meta-analysis	Not a universal association across populations.
Cesarean delivery	Slightly increased risk reported	OR approximately 1.17 in an East-West meta-analysis	Observational association; causality and UC-specific applicability remain uncertain.
Soft drinks and high-sugar dietary patterns	Increased risk reported	No single estimate provided	Reported in an umbrella review; dietary evidence is heterogeneous.
Breastfeeding	Lower risk of IBD reported	No single estimate provided	Evidence relates primarily to IBD overall and does not establish a specific preventive effect against UC.
Tea consumption	Lower risk of UC reported	No single estimate provided	Reported in an umbrella review; does not establish tea as a preventive intervention.
Higher total energy or n-6 polyunsaturated fatty acid intake	Increased risk reported in some Western cohorts	OR approximately 1.2–1.25 in cited analyses	Observational evidence; dietary definitions and results vary across studies.
Helicobacter pylori infection	Lower observed risk of UC/IBD in some studies	No single estimate provided	Epidemiologic association only; it is not a reason to retain or acquire infection.

Smoking

Smoking has a paradoxical epidemiologic association with UC: current smoking is associated with lower UC incidence, whereas former smoking is associated with increased risk compared with current smoking in many observational studies. Disease onset or worsening may occur after smoking cessation, but this does not establish smoking as a causal preventive factor or a treatment.

Smoking initiation must never be recommended to prevent UC. Smoking substantially increases cardiovascular, pulmonary, and cancer risks. People who smoke should be supported in quitting; the overall health benefits of cessation far outweigh any possible UC-specific association. Mendelian randomization studies have not consistently confirmed a causal relationship between smoking and UC, leaving residual confounding as a concern.

Appendectomy

Appendectomy, particularly for confirmed appendicitis at a young age, has been associated with lower subsequent UC risk in some Western populations. The association is weaker or absent in some Asian populations, and its mechanism remains uncertain.

Appendectomy should not be performed to prevent UC. Appendectomy after UC diagnosis is a separate clinical question and should not be inferred to have the same association with disease onset; surgery is not a routine preventive or treatment strategy for UC.

Diet, medications, and microbiome-related exposures

• Dietary patterns high in total energy, some fats, processed foods, food additives, or sugar-sweetened drinks have been associated with IBD or UC in observational research. Plant-rich dietary patterns and tea consumption have also been associated with lower risk in some studies. Evidence is insufficient to prescribe a specific diet as proven primary prevention.
• Antibiotic exposure has been associated with increased IBD risk in some studies, with reported differences by dose, recency, age, and geography. A proposed explanation is alteration of the intestinal microbiome. However, the increased-risk estimate cited above is primarily for IBD overall; the Lancet review reported that antibiotic exposure was not consistently associated with UC specifically, and some developing-country cohorts have reported protective associations. These findings support appropriate antibiotic stewardship, not withholding clinically indicated antibiotics.
• Prior enteric infection, including infections caused by Salmonella, Shigella, or Campylobacter, has been associated with increased subsequent UC risk in observational studies. The association does not prove that infection directly causes UC.
• Perfluoroalkyl substances, herbicides, and dietary emulsifiers are under investigation as potential environmental exposures. Current evidence is not sufficient to use these exposures for individual clinical risk prediction or to make specific prevention recommendations.

Clinically Actionable Recommendations

• Document family history of IBD when evaluating patients with possible UC. Family history changes clinical suspicion but does not justify routine genetic testing or screening of asymptomatic relatives with current tools.
• Counsel against smoking initiation and support smoking cessation. Explain that observed UC-specific associations do not outweigh the established harms of smoking and do not justify nicotine or tobacco as therapy.
• Do not perform appendectomy solely to prevent or treat UC.
• Assess and correct vitamin D deficiency when clinically indicated, without presenting supplementation as proven UC primary prevention.
• Use antibiotics judiciously while prescribing them when medically indicated; epidemiologic associations are not a reason to delay or withhold necessary treatment.
• Avoid promising that dietary modification, tea consumption, breastfeeding, or avoidance of a single exposure will prevent UC; evidence for primary prevention remains limited.

Information Removed / Older Teaching to Avoid

• Urbanization as a universal risk factor: available evidence suggests a modest, population-dependent association rather than a consistent effect worldwide.
• Psychological stress as an established cause of UC onset: the supplied reviews do not establish stress as a validated independent cause of incident UC. Stress may affect symptoms or disease experience after diagnosis, which is outside this microchapter's scope.
• Breastfeeding or specific diets as proven UC-prevention interventions: reported associations are not equivalent to demonstrated causation or evidence of an effective preventive intervention.
• Smoking as a recommended preventive measure: the inverse association with UC onset does not justify smoking or nicotine treatment.
• Generic autoimmune or allergic explanations without evidence grading: risk factors should be described according to the strength and limitations of available epidemiologic evidence.

Important Updates Compared with Older Teaching

• Genetic susceptibility is substantial but incomplete; currently available genetic risk scores are not clinically useful for predicting UC onset in asymptomatic individuals.
• Environmental associations may differ between Eastern and Western populations. In particular, reported associations involving smoking, appendectomy, and antibiotic exposure should not be assumed to generalize uniformly across regions.
• Research increasingly examines preclinical IBD, the microbiome, and environmental exposures. These developments have not yet established a validated exposure-based strategy for primary prevention in otherwise healthy individuals.

Areas of Uncertainty or Controversy

• Association versus causation: many reported risk factors come from observational studies vulnerable to confounding, recall bias, and reverse causation.
• Smoking paradox: the mechanisms behind the inverse association between current smoking and UC onset remain uncertain, and genetic causal-inference studies have not consistently confirmed the relationship.
• Vitamin D: it remains uncertain whether deficiency contributes to disease development or is partly a marker of preclinical inflammation or other factors.
• Dietary prevention: high-quality prospective and interventional evidence establishing specific diets or foods as effective primary prevention is lacking.
• Geographic variation: differences between Eastern and Western studies may reflect environmental exposures, genetics, study methods, healthcare access, and changing disease ascertainment; the contribution of each remains incompletely resolved.

High-Yield Clinical Pearls

• A positive family history of IBD is the strongest established risk marker for UC. First-degree relatives have an adjusted UC incidence rate ratio of approximately 4–10, but most relatives will not necessarily develop disease.
• Monozygotic twin concordance is approximately 15–19% for UC, compared with approximately 30–50% for Crohn disease.
• Current smoking has an inverse epidemiologic association with UC onset; this must never be translated into advice to smoke.
• Appendectomy has been associated with lower UC incidence in some populations, particularly when performed for appendicitis at a young age, but it is not a preventive intervention.
• Environmental risk estimates derived from Western cohorts may not apply directly to Asian or Middle Eastern populations.
• Antibiotic, dietary, and vitamin D associations are not proof of causation and do not independently establish a UC-prevention strategy.

Common Pitfalls

• Interpreting an observational association as proof that an exposure causes or prevents UC.
• Advising smoking or nicotine use because of the inverse association between current smoking and UC onset.
• Recommending appendectomy or unnecessary dietary restriction for primary prevention.
• Ordering genetic testing or using genetic risk scores to screen asymptomatic relatives without a validated clinical indication.
• Withholding necessary antibiotics because of observational associations between antibiotic exposure and IBD.
• Applying East-West population estimates as if they were universal.
• Presenting an IBD-overall antibiotic effect estimate as an established UC-specific association.

Natural History, Complications and Prognosis

Ulcerative colitis (UC) is a lifelong, relapsing–remitting inflammatory disease with a variable clinical course. Disease activity is often greatest near diagnosis, followed by periods of remission and relapse. Most patients have a mild-to-moderate course, while approximately 10–17% develop an aggressive course. In the modern therapeutic era, colectomy rates have declined and colorectal cancer (CRC) risk has decreased. Reported all-cause mortality in UC ranges from no excess to a modest increase (hazard ratios approximately 1.0–1.4 across population-based cohorts); the most recent biologic-era matched data suggest mortality similar to that of the general population.

Disease Activity Patterns

Population-based cohorts have described four longitudinal activity patterns:

• Remission or mild activity after an initially active period: approximately 55%.
• Chronic intermittent symptoms: approximately 37%.
• Chronic continuous symptoms: approximately 6%.
• Initially low activity followed by increasing activity: approximately 1%.

The cumulative risk of relapse is approximately 70–80% at 10 years. An aggressive course requiring advanced therapy or surgery occurs in approximately 10–17% of patients. During a flare, assess for potentially contributing factors, including enteric infection (particularly Clostridioides difficile), nonsteroidal anti-inflammatory drug exposure, smoking cessation, and medication nonadherence.

Disease Extension

Disease extent can change over time and does not invariably progress proximally. Proximal extension occurs in approximately 10–30% of patients during follow-up, with estimates of 10–19% by 5 years and up to 28% by 10 years. Longer-term studies have reported progression to extensive colitis in up to 46% of patients initially diagnosed with proctitis and 70% of those with left-sided colitis. Estimates vary geographically; a meta-analysis reported proximal extension in approximately 37.8% of North American cohorts versus 19.6% of European cohorts. Persistent symptoms or inadequate response to topical treatment should prompt reassessment of disease extent.

Hospitalization

Hospitalization is common during the disease course. Approximately 20% of patients are hospitalized within 5 years of diagnosis, and nearly half may require UC-related hospitalization over longer follow-up. Among patients hospitalized once, the 5-year risk of rehospitalization is approximately 50%. Previous UC-related hospitalization is an adverse prognostic marker and predicts an increased risk of subsequent colectomy.

After restorative proctocolectomy with ileal pouch–anal anastomosis (IPAA), pouchitis is a common long-term complication, with a reported prevalence of approximately 31% (about 18% acute and 13% chronic). Pouch failure requiring permanent diversion or ileostomy occurs in approximately 6% of patients. Detailed surgical options and pouch complication management belong in the surgery microchapter.

Colectomy

Contemporary cumulative risk

A meta-analysis of population-based cohorts reported cumulative colectomy risks of 4.0% at 1 year, 8.8% at 5 years, and 13.3% at 10 years overall. In cohorts diagnosed in the 21st century, the corresponding risks were lower: 2.8%, 7.0%, and 9.6%, respectively. These estimates are substantially below figures from older cohorts.

The decline in colectomy has been driven largely by lower elective colectomy rates, while emergency colectomy rates have remained relatively stable. The downward trend began in some populations before widespread biologic use, suggesting that multiple factors contribute.

A 2026 English population-based study reported a continuing decline in elective colectomy across diagnostic eras from 2003 to 2020.

Indications and predictors

Major indications for colectomy include medically refractory disease, corticosteroid dependence, UC-associated neoplasia, and complications of acute severe UC. Features associated with a more aggressive course or increased colectomy risk include:

• Extensive colitis at diagnosis.
• Younger age at diagnosis, particularly younger than 30 years.
• Deep endoscopic ulceration.
• Need for systemic corticosteroids.
• Elevated inflammatory markers, including C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR).
• Previous UC-related hospitalization.
• Male sex, reported as a risk factor in some cohorts.

Genetic and serologic markers have limited predictive value and are not recommended for routine prognostication. Prognostic factors should be interpreted together rather than as deterministic predictors for an individual patient.

Acute Severe Ulcerative Colitis

Acute severe ulcerative colitis (ASUC) is a high-risk presentation associated with substantial morbidity, colectomy, and mortality. Approximately 15–25% of patients experience an episode during their disease course, and a substantial proportion of episodes occur at initial presentation. A systematic review reported an episode-associated colectomy rate of approximately 13%; 3-month and 12-month mortality estimates were 0.84% and 1.01%, respectively. Delayed surgery and older age are associated with worse outcomes.

In a contemporary US multicenter prospective cohort, 22.3% of hospitalized patients with ASUC underwent colectomy within 1 year, including 12% during the index admission. Admission features associated with inpatient colectomy included body mass index below 21.5 kg/m², Simple Clinical Colitis Activity Index (SCCAI) greater than 8, and serum albumin below 2.4 g/dL. These cohort-specific predictors should not be treated as universally validated decision thresholds.

Complications

Major complications include:

• Toxic megacolon, perforation, and severe hemorrhage: Potentially life-threatening complications, particularly in ASUC, requiring urgent assessment and early surgical involvement.
• Venous thromboembolism (VTE): Inflammatory bowel disease is associated with an approximately threefold increased VTE risk, which is highest during active disease and hospitalization. Pharmacologic thromboprophylaxis is recommended for hospitalized patients with active UC, including those with ASUC, unless contraindicated.
• Superimposed infection: C. difficile and cytomegalovirus (CMV) can complicate severe or refractory colitis and should be considered when assessing poor response to treatment.
• Colonic stricture: A new colonic stricture requires evaluation for malignancy and reconsideration of the diagnosis, including Crohn disease.
• Functional complications: Colonic dysmotility and anorectal dysfunction may contribute to persistent bowel symptoms.

Extraintestinal manifestations

Extraintestinal manifestations (EIMs) occur in a substantial minority of patients and can affect morbidity, prognosis, and treatment decisions. Manifestations include peripheral arthritis, axial arthropathy, uveitis, episcleritis, scleritis, erythema nodosum, and pyoderma gangrenosum. Primary sclerosing cholangitis (PSC) is particularly important prognostically: PSC-associated UC may have less prominent luminal symptoms despite extensive colitis and carries a substantially increased risk of colorectal neoplasia.

Colorectal Cancer Risk

Long-standing colonic inflammation increases CRC risk, but population-based estimates have declined over recent decades. Risk varies with disease duration, extent, inflammatory burden, and individual risk factors; it is not uniform across all patients with UC. CRC and cholangiocarcinoma are important causes of disease-associated mortality and contribute to the cause-specific mortality signal reported in some cohorts.

Risk factors for colorectal neoplasia include:

• Longer disease duration and greater colonic extent.
• Persistent or severe endoscopic or histologic inflammation.
• Concomitant PSC.
• Family history of CRC.
• Previous dysplasia, colonic stricture, or extensive pseudopolyposis.

Surveillance implications

For UC extending beyond the rectum, surveillance colonoscopy generally begins 8 years after symptom onset. Patients with PSC should begin surveillance at PSC diagnosis and generally undergo annual colonoscopy, regardless of UC duration. Subsequent surveillance intervals are individualized according to risk factors and prior findings, with recommendations varying among professional societies. High-definition white-light endoscopy or chromoendoscopy with targeted biopsies is used in contemporary surveillance. Isolated proctitis without proximal extension carries little or no excess colitis-associated CRC risk.

Detailed surveillance techniques, dysplasia management, and society-specific interval recommendations belong in the relevant screening and diagnostic-study microchapters.

Mortality and Long-Term Morbidity

Population-based evidence on all-cause mortality in UC is mixed. Several large cohorts report a modest excess, with hazard ratios approximately 1.17–1.4, whereas the most recent biologic-era matched cohort found no significant difference from controls (HR 1.03, 95% CI 0.97–1.10). Where excess mortality exists, it appears concentrated in older-onset and long-duration disease and is driven partly by cause-specific deaths, including colorectal cancer and cholangiocarcinoma, rather than a uniform increase across all patients. Despite generally favorable survival, UC can cause substantial long-term morbidity, including fatigue, impaired health-related quality of life, and disability.

Clinically Actionable Prognostic Principles

• Assess disease extent, age at onset, endoscopic severity, inflammatory markers, corticosteroid requirement, and previous hospitalization when estimating the likelihood of an aggressive course.
• Aim for objective control of inflammation rather than symptom improvement alone; persistent inflammation is associated with adverse outcomes.
• Provide VTE prophylaxis to hospitalized patients with active UC unless contraindicated.
• Consider C. difficile and CMV in severe or refractory disease, according to the clinical context.
• Initiate CRC surveillance at the recommended time for colonic disease and at PSC diagnosis for patients with PSC.
• Do not use genetic or serologic markers alone to estimate an individual patient's prognosis.
• In ASUC, recognize clinical deterioration and avoid delaying necessary surgical assessment.

Important Updates Compared With Older Teaching

• Contemporary 10-year colectomy risk in cohorts diagnosed in the 21st century is approximately 9.6%, substantially lower than historical estimates.
• UC extent can change over time but does not invariably progress proximally.
• CRC risk has declined in many populations; the degree of residual excess risk varies by patient and disease characteristics.
• All-cause mortality estimates in UC are inconsistent, ranging from no excess to a modest increase; the most recent biologic-era matched cohort suggests mortality may be approaching that of the general population.
• Histologic remission may provide prognostic information beyond endoscopic remission, although the strength and generalizability of evidence depend on the population and treatment context.

Areas of Uncertainty

• The relative contributions of biologics, earlier diagnosis, improved disease monitoring, and changing surgical thresholds to declining colectomy rates remain uncertain.
• Whether contemporary therapies modify the long-term natural history of UC, rather than delaying adverse outcomes, remains unresolved.
• Optimal CRC surveillance intervals and the balance between targeted and random biopsies vary across guidelines and clinical contexts.
• The magnitude of residual CRC risk in patients with well-controlled inflammation receiving modern surveillance remains uncertain.
• The magnitude of any excess all-cause mortality in UC remains uncertain and may differ by age at onset, disease duration, geography, and therapeutic era.

High-Yield Clinical Pearls

• Relapse is common even after remission.
• Contemporary 10-year colectomy risk is approximately 10% in cohorts diagnosed in the 21st century.
• All-cause mortality in UC is at most modestly increased in many population-based cohorts and may be approaching that of the general population in the biologic era; morbidity remains substantial.
• PSC-associated UC carries increased CRC risk; surveillance begins at PSC diagnosis.
• A new colonic stricture in UC requires evaluation for malignancy.
• Hospitalized patients with active UC generally require pharmacologic VTE prophylaxis unless contraindicated.
• Delayed surgery in deteriorating ASUC can worsen outcomes.

Common Pitfalls

• Quoting historical colectomy or CRC estimates as though they represent current population risk.
• Assuming that UC extent always progresses proximally.
• Relying on symptoms alone without assessing ongoing inflammation.
• Withholding VTE prophylaxis solely because a hospitalized patient has rectal bleeding, without assessing the overall bleeding and thrombosis risks.
• Attributing severe or refractory colitis solely to UC without considering superimposed infection.
• Applying routine surveillance timing to patients with PSC instead of starting surveillance at PSC diagnosis.

Diagnosis

History and Symptoms | Physical Examination | Laboratory Findings | Abdominal X Ray | CT | Other Imaging Findings | Other Diagnostic Studies

Diagnosis of Ulcerative Colitis

Ulcerative colitis (UC) has no single diagnostic gold standard. Diagnosis integrates a compatible clinical history, exclusion of infectious causes and other mimics, endoscopic findings, and histologic confirmation. Typical symptoms include bloody diarrhea, urgency, and tenesmus. Typical endoscopic findings include continuous mucosal inflammation beginning in the rectum. Histology supports chronic inflammatory bowel disease and helps distinguish established UC from acute infectious colitis.

Clinical History and Initial Evaluation

UC should be suspected in patients with bloody diarrhea, mucus, increased stool frequency, bowel urgency, tenesmus, and abdominal cramping. The history should document stool frequency, nocturnal bowel movements, visible blood, abdominal pain, weight loss, and possible extraintestinal manifestations involving the joints, skin, eyes, mouth, or hepatobiliary system.

Ask about recent travel, food and water exposures, antibiotic use, infectious contacts, nonsteroidal anti-inflammatory drug use, and smoking cessation. These factors can influence the differential diagnosis and interpretation of symptoms.

Exclusion of Infection

Infectious colitis must be excluded at initial presentation and reconsidered during disease flares, because infection may mimic UC or complicate established disease.

• Clostridioides difficile: Test at diagnosis and when symptoms worsen or recur. Use an appropriate stool-based testing algorithm, such as a nucleic acid amplification test and/or toxin assay according to local laboratory protocols.
• Other enteric pathogens: Stool culture or multiplex molecular testing may be appropriate according to clinical presentation, travel, exposure history, and local epidemiology. Consider pathogens such as Salmonella, Shigella, Campylobacter, Shiga toxin-producing Escherichia coli, Yersinia, and parasites when indicated.
• Cytomegalovirus (CMV): Consider tissue-based assessment in severe or treatment-refractory colitis, particularly in patients receiving immunosuppressive therapy.

Laboratory Evaluation

Routine laboratory tests support assessment of inflammation, anemia, nutritional status, and disease severity but cannot independently establish or exclude UC.

• Complete blood count and iron studies: Assess for anemia, iron deficiency, leukocytosis, and thrombocytosis.
• C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR): May be elevated with active inflammation but can be normal in mild disease and in some patients with endoscopically active UC. Establishing a baseline CRP can aid subsequent assessment.
• Serum albumin: A low concentration may indicate systemic inflammation, nutritional compromise, or more severe disease.
• Additional tests should be guided by the clinical presentation and potential alternative diagnoses.

Fecal Biomarkers

Fecal calprotectin (FC) is the preferred noninvasive biomarker for identifying intestinal inflammation and helping determine which patients require endoscopic evaluation. It is elevated in many inflammatory and infectious gastrointestinal conditions and is not specific for UC.

• For UC, a cited pooled analysis reported sensitivity of approximately 0.88 and specificity of approximately 0.79; estimates vary by population, assay, and threshold.
• A meta-analysis evaluating adults with inflammatory bowel disease (IBD) versus irritable bowel syndrome (IBS) reported sensitivity of 83.1% and specificity of 83.3% for UC.
• A low FC concentration, often around 40–50 µg/g or lower depending on the assay and clinical setting, reduces the likelihood of IBD and may help avoid unnecessary endoscopy in patients with a low pretest probability. It does not absolutely exclude IBD, particularly when clinical suspicion is high.
• In a prospective UK primary-care cohort of symptomatic young adults, FC was useful for excluding IBD, including in patients without alarm symptoms. Interpretation still depends on clinical context and the assay used.
• FC cannot distinguish UC from Crohn disease or infectious colitis and should not be used as a standalone diagnostic test. CRP may be normal despite active intestinal inflammation.

Serologic Markers

Perinuclear antineutrophil cytoplasmic antibodies (pANCA) and anti-Saccharomyces cerevisiae antibodies (ASCA) have limited sensitivity and specificity for distinguishing UC from Crohn disease. Although certain antibody patterns have been associated with UC, they are not sufficiently accurate to establish or exclude the diagnosis.

pANCA/ASCA testing is not recommended for routine diagnosis or subtyping of UC in adults. Diagnosis should instead rely on the clinical presentation, exclusion of infection, endoscopy, and histology.

Endoscopy and Histology

Ileocolonoscopy with biopsies is the principal diagnostic investigation for suspected UC when clinically safe. It assesses the distribution and severity of inflammation, permits histologic confirmation, and evaluates the terminal ileum.

In acute severe colitis, limited flexible sigmoidoscopy with biopsies is generally preferred initially because full colonoscopy may increase procedural risk. The extent of examination should be determined by clinical stability and endoscopic safety.

Endoscopic Features

Typical UC shows continuous, circumferential mucosal inflammation beginning in the rectum and extending proximally. Findings may include:

• Loss of normal vascular markings.
• Erythema and mucosal granularity.
• Friability and contact bleeding.
• Erosions or ulceration, including deep ulcers in severe disease.

Rectal sparing or patchy inflammation may occur, particularly after treatment, and should not alone be taken as proof of Crohn disease.

Biopsy Strategy and Histology

Biopsies should be obtained from multiple colonic segments, including both inflamed and endoscopically normal-appearing mucosa. Submit samples by segment when feasible to allow the pathologist to assess distribution and chronicity. Include the rectum and proximal colon because histologic inflammation may extend beyond visibly abnormal mucosa and can affect disease-extent assessment.

Histologic findings supporting UC include:

• Chronic architectural abnormalities, such as crypt distortion and irregular crypt spacing.
• Basal plasmacytosis.
• Active inflammation, including cryptitis and crypt abscesses.

The combination of chronic mucosal injury and a compatible clinical and endoscopic pattern supports the diagnosis. Histology must be interpreted in clinical context, since early UC may not yet show all chronic features and infection can produce overlapping findings.

Recognized Endoscopic Patterns

A periappendiceal or cecal patch and short-segment backwash ileitis in extensive colitis may occur in UC. Neither finding independently establishes Crohn disease. Rectal sparing or a proximal-predominant pattern may also be observed in some patients, including those with primary sclerosing cholangitis. Interpret these patterns alongside the full clinical, endoscopic, and histologic assessment.

Role of Upper Endoscopy and Small-Bowel Imaging

Routine upper endoscopy is not generally required to diagnose UC in adults. It may be indicated for upper gastrointestinal symptoms or when another diagnosis is suspected. Pediatric diagnostic evaluation may differ from adult practice.

Small-bowel imaging, including magnetic resonance or computed tomography enterography, is not routinely necessary when the terminal ileum is normal and the presentation is typical of UC. Consider imaging when symptoms suggest small-bowel disease, Crohn disease remains a concern, the proximal extent cannot be adequately assessed, or additional anatomic information is needed for management planning.

Intestinal ultrasound is an emerging noninvasive method for assessing intestinal inflammation. Its role in the initial diagnostic evaluation depends on clinical context, availability, and operator expertise; it does not replace histologic assessment when tissue confirmation is needed.

Pre-Treatment Screening

Before initiating immunosuppressive or advanced therapy, complete the relevant infection-screening and prevention assessment. This is a prerequisite to safe treatment rather than a test that establishes the diagnosis of UC.

• Screen for latent tuberculosis using an interferon-gamma release assay or tuberculin skin test, as appropriate.
• Assess hepatitis B status and evaluate hepatitis C and HIV according to current treatment guidance, patient-specific risk factors, and local protocols.
• Review vaccination status and identify indicated vaccinations before immunosuppression when feasible.

Clinically Actionable Diagnostic Approach

1. Take a focused history, including stool frequency, visible blood, urgency, nocturnal symptoms, abdominal pain, weight loss, relevant exposures, medication use, and extraintestinal manifestations.
2. Obtain a complete blood count, iron studies, CRP and/or ESR, and serum albumin; use additional tests according to the clinical context.
3. Test for C. difficile and other enteric pathogens when indicated. Use FC to assess the likelihood of intestinal inflammation and help triage the need for endoscopy.
4. Perform ileocolonoscopy with segmental biopsies, including affected and normal-appearing mucosa, when safe. In acute severe colitis, use limited flexible sigmoidoscopy with biopsies initially.
5. Integrate endoscopic distribution and histologic findings with the clinical presentation and infection testing to establish the diagnosis.
6. Do not use pANCA/ASCA serology for routine diagnosis or subtyping. Reserve upper endoscopy and small-bowel imaging for specific clinical indications.
7. Complete infection screening and vaccination review before initiating immunosuppressive or advanced therapy.

Important Updates Compared With Older Teaching

• Fecal calprotectin is a triage biomarker, not a UC-specific diagnostic test. It can help identify intestinal inflammation and reduce unnecessary endoscopy when the pretest probability of IBD is low.
• pANCA/ASCA serology should not be used routinely to establish or exclude UC or to subtype adult IBD.
• Biopsy both visibly inflamed and normal-appearing colonic mucosa, including the rectum and proximal colon, to assess histologic chronicity and distribution.
• Avoid full colonoscopy in acute severe colitis when limited sigmoidoscopy is safer.
• Routine upper endoscopy and small-bowel imaging are not required in every adult with suspected UC; use them when symptoms or diagnostic uncertainty warrant further evaluation.
• Pre-treatment infection screening and vaccination review are important safety steps before advanced therapy, but they do not establish the diagnosis of UC.

Areas of Uncertainty or Controversy

• Optimal FC cutoff: thresholds vary by assay, clinical setting, and pretest probability; no single threshold is appropriate for every patient.
• Early or treated disease: endoscopic and histologic patterns may be less typical, and diagnosis may require integration of follow-up findings.
• IBD-unclassified: some patients cannot initially be classified confidently as UC or Crohn disease; classification may change as additional clinical, endoscopic, imaging, or histologic information becomes available.
• Intestinal ultrasound: it is increasingly used for noninvasive assessment of intestinal inflammation, but its role in establishing the initial diagnosis depends on local expertise and clinical context.

High-Yield Clinical Pearls

• UC has no single diagnostic test; diagnosis integrates symptoms, infection exclusion, endoscopy, and histology.
• A low FC can make IBD less likely in an appropriate low-risk presentation but does not definitively exclude it.
• Test for C. difficile at diagnosis and reconsider infection when symptoms flare.
• Biopsy normal-appearing proximal colon and rectum because histologic inflammation may exceed visible endoscopic disease.
• A normal CRP does not exclude active UC.
• Rectal sparing or patchiness, especially after treatment, does not by itself establish Crohn disease.
• Use limited flexible sigmoidoscopy with biopsies rather than full colonoscopy initially in acute severe colitis when clinically appropriate.
• Do not use pANCA/ASCA serology to diagnose or routinely subtype UC.

Common Pitfalls

• Treating FC or CRP as a standalone diagnostic test.
• Assuming a normal CRP excludes active inflammation.
• Failing to test for infection, especially C. difficile.
• Sampling only visibly inflamed mucosa and thereby underestimating histologic extent.
• Interpreting rectal sparing, patchiness, a cecal patch, or backwash ileitis as independently diagnostic of Crohn disease.
• Performing full colonoscopy in acute severe colitis when limited sigmoidoscopy is safer.
• Ordering routine upper endoscopy or small-bowel imaging in every adult with suspected UC without a specific indication.

Treatment

Medical Therapy | Surgery | Alternative Treatments | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies

Treatment of Ulcerative Colitis

Medical treatment of ulcerative colitis (UC) is selected according to disease activity, anatomic extent, prior treatment exposure, comorbidities, and patient preferences. The goals are steroid-free clinical remission, endoscopic healing, improved quality of life, and prevention of hospitalization and complications. Treatment includes induction and maintenance of remission. Moderate-to-severe disease generally warrants timely use of advanced therapy rather than prolonged stepwise escalation.

This microchapter covers medical therapy and treatment-monitoring decisions. See Ulcerative colitis classification for disease severity and Ulcerative colitis surgery for operative management.

Goals of Therapy and Treat-to-Target

Treatment should target objective control of inflammation, not symptom improvement alone. STRIDE-II identifies clinical remission and endoscopic healing as principal treatment targets; biomarkers help assess response between endoscopic examinations.

• Short-term targets: Resolution of rectal bleeding and normalization of bowel habits; improvement or normalization of inflammatory biomarkers, including C-reactive protein (CRP) and fecal calprotectin.
• Long-term target: Endoscopic healing, generally defined as a Mayo endoscopic subscore (MES) of 0 or 1, alongside sustained clinical remission and improved quality of life.
• Reassessment: Reassess disease activity during induction and after treatment changes, commonly within approximately 3 months, using symptoms and biomarkers and endoscopy when indicated.

Histologic remission is associated with favorable outcomes but is not yet a universally required treatment target. Treatment escalation should integrate symptoms, biomarkers, endoscopic findings, prior response, and treatment risks.

Mild-to-Moderately Active UC

5-aminosalicylates (5-ASA) are first-line therapy for most patients with mild-to-moderately active UC. Route and dose depend on disease extent. For distal disease, rectal therapy improves local drug delivery; combining oral and rectal 5-ASA is generally more effective for left-sided disease than oral treatment alone.

Disease extent	Induction	Maintenance
Proctitis	Rectal mesalamine, usually 1 g/day as a suppository	Rectal mesalamine, usually 1 g/day
Left-sided colitis	Rectal mesalamine (at least 1 g/day) plus oral mesalamine (at least 2 g/day)	Oral mesalamine; rectal treatment may be continued according to response and preference
Extensive colitis	Oral mesalamine, at least 2 g/day	Oral mesalamine, generally at least 1.5 g/day

• Once-daily and divided 5-ASA dosing are both reasonable; choose a regimen that supports adherence.
• Patients with moderate activity may benefit from higher-dose oral mesalamine (up to 4.8 g/day).
• For inadequate response, first confirm adherence, dose, and appropriate rectal therapy. Do not repeatedly switch 5-ASA formulations in a patient who has failed adequately optimized treatment.
• Budesonide MMX 9 mg/day can be used to induce remission when optimized 5-ASA is inadequate.
• Systemic corticosteroids may be used for induction when disease does not respond to 5-ASA or when disease activity warrants faster control. Prednisone 40–60 mg/day is a commonly used starting range, followed by an individualized taper.
• Corticosteroids must not be used for maintenance. Recurrent steroid requirement or failure of appropriate induction should prompt steroid-sparing treatment and reassessment of disease severity.

Moderate-to-Severely Active UC

Moderate-to-severe UC generally requires advanced therapy, sometimes with a short corticosteroid bridge. Treatment choice should account for prior biologic or small-molecule exposure, speed of onset, extraintestinal manifestations, safety, route, comorbidities, and patient preference. The 2024 AGA living guideline supports choosing among advanced therapies according to comparative efficacy and prior exposure rather than requiring every patient to progress through a rigid step-up sequence.

Advanced therapies

Class	Agents	Practical considerations
Anti-tumor necrosis factor (anti-TNF)	Infliximab, adalimumab, golimumab	Infliximab has an established role in moderate-to-severe disease and in rescue treatment for ASUC. Combination with a thiopurine may improve efficacy and reduce immunogenicity.
Anti-integrin	Vedolizumab	Gut-selective mechanism; an option for induction and maintenance.
IL-12/23 p40 inhibitor	Ustekinumab	Intravenous induction followed by subcutaneous maintenance.
IL-23 p19 inhibitors	Mirikizumab, risankizumab, guselkumab	Options for induction and maintenance; comparative head-to-head evidence among these agents is limited.
Janus kinase (JAK) inhibitors	Tofacitinib, upadacitinib	Oral small molecules with relatively rapid onset; consider infection, malignancy, cardiovascular, and thromboembolic risks and applicable regulatory restrictions.
Sphingosine-1-phosphate (S1P) receptor modulators	Ozanimod, etrasimod	Oral options; assess cardiac history, drug interactions, and agent-specific monitoring requirements.

Agent availability, approved indications, and preferred sequencing may vary by jurisdiction and evolve as evidence and regulatory labeling change.

Positioning by prior treatment exposure

• Advanced-therapy-naive patients: Consider agents with higher comparative efficacy in guideline evidence syntheses, including infliximab, vedolizumab, selected JAK inhibitors, selected S1P modulators, and selected IL-23 inhibitors. Selection remains individualized.
• Prior advanced-therapy exposure, especially anti-TNF failure: Consider the mechanism and reason for failure. After primary nonresponse, switching mechanism is often appropriate; after secondary loss of response, assess adherence, drug concentrations, and antidrug antibodies when relevant before deciding whether to optimize or switch.
• In anti-TNF-exposed patients, comparative evidence syntheses generally favor upadacitinib, tofacitinib, and ustekinumab over some alternatives for induction; however, rankings rely substantially on indirect comparisons and should not be treated as definitive head-to-head superiority. In the United States, JAK inhibitor use for UC is restricted by FDA labeling to patients with inadequate response or intolerance to one or more TNF blockers.

Combination and conventional immunomodulator therapy

• In appropriate patients starting infliximab, combination with a thiopurine can improve treatment efficacy and reduce immunogenicity compared with infliximab alone. Balance potential benefit against infection, malignancy, and other patient-specific risks.
• Thiopurine monotherapy is not appropriate for induction because onset is slow, but it may be used for maintenance in selected patients.
• Methotrexate monotherapy is not an effective standard induction or maintenance treatment for UC.
• Once a patient escalates to an effective advanced therapy, review the need for continued 5-ASA rather than assuming it must always be continued.
• Maintain remission with an effective steroid-sparing regimen. Systemic corticosteroids are not maintenance therapy.

Acute Severe Ulcerative Colitis

Acute severe ulcerative colitis (ASUC) is a medical emergency requiring hospitalization, close monitoring, pharmacologic treatment, and early colorectal surgical consultation. The conventional definition is at least six bloody stools per day plus at least one marker of systemic toxicity.

Initial inpatient management

1. Test for Clostridioides difficile and assess for other infection when clinically indicated.
2. Start intravenous corticosteroids, such as methylprednisolone 60 mg/day or hydrocortisone 100 mg three to four times daily.
3. Give pharmacologic venous thromboembolism (VTE) prophylaxis unless contraindicated. Rectal bleeding alone is not a reason to withhold prophylaxis.
4. Monitor stool frequency, rectal bleeding, vital signs, abdominal findings, hemoglobin, electrolytes, albumin, CRP, and other clinically indicated laboratory tests.
5. Avoid routine broad-spectrum antibiotics unless there is a suspected or documented infection or another specific indication. Total parenteral nutrition should not be used solely for bowel rest when enteral nutrition is feasible.
6. Involve colorectal surgery early, particularly if there is deterioration, suspected toxic megacolon or perforation, uncontrolled hemorrhage, or failure to respond to medical treatment.

Assessing response and rescue therapy

Assess response to intravenous corticosteroids by approximately day 3. The Oxford criteria identify a high risk of treatment failure when stool frequency is greater than 8 per day, or when stool frequency is 3–8 per day with CRP greater than 45 mg/L. These criteria support risk assessment but should not replace overall clinical judgment.

For steroid-refractory ASUC, recommended medical rescue options include infliximab or cyclosporine. Short-term efficacy is broadly comparable; selection depends on previous treatment, contraindications, local expertise, and the intended maintenance plan.

• Infliximab: If response is achieved, continue infliximab as maintenance. Individualize dose and induction strategy; evidence does not support assuming that intensified dosing is necessary for every hospitalized patient.
• Cyclosporine: An induction/rescue option that requires drug-level and toxicity monitoring. A commonly recommended intravenous dose is 2 mg/kg/day, preferred over 4 mg/kg/day because efficacy is similar and adverse events are fewer; target a blood concentration of 200–400 ng/mL. Patients who achieve remission should transition to maintenance with a thiopurine or vedolizumab. Cyclosporine is induction/rescue therapy, not long-term maintenance.
• Failure of rescue therapy or clinical deterioration: Do not delay colectomy when medical treatment fails or complications arise. Surgery is covered in Ulcerative colitis surgery.
• JAK inhibitors have been studied as rescue or salvage treatment in selected ASUC cases, but this use should not be presented as established routine standard care without specialist assessment and recognition of evidence limitations.

Monitoring and Therapeutic Drug Monitoring

Monitoring should establish whether treatment is controlling inflammation, detect toxicity, and guide optimization or switching.

• Assess symptoms and adherence during induction and maintenance; use CRP and fecal calprotectin as objective markers when appropriate.
• Use endoscopy when needed to establish mucosal response, clarify discordance between symptoms and biomarkers, or guide treatment decisions.
• Reactive therapeutic drug monitoring (TDM): In patients receiving anti-TNF therapy who have active disease or loss of response, drug and antidrug antibody levels can help distinguish inadequate exposure from mechanistic failure and guide dose optimization versus switching.
• Proactive TDM: Evidence and guideline support vary by clinical setting; it is not universally recommended for every patient on every biologic.
• For thiopurines, monitor blood counts and liver tests and consider metabolite measurement in selected situations, such as inadequate response or suspected toxicity. Assay interpretation and detailed metabolite targets belong in the laboratory-monitoring microchapter.

Safety and Pretreatment Assessment

Before starting advanced immunosuppressive therapy, review infection risk, vaccination status, comorbidities, medication interactions, and agent-specific monitoring requirements. Screening commonly includes latent tuberculosis and hepatitis B; assess hepatitis C and HIV according to clinical context and local protocols. Update indicated vaccines before immunosuppression when feasible. Recombinant zoster vaccination is advised before JAK inhibitor or S1P modulator initiation when indicated and feasible.

JAK inhibitors

Tofacitinib and upadacitinib carry important warnings regarding serious infections, herpes zoster, malignancy, major adverse cardiovascular events, venous thromboembolism, and mortality. In the United States, FDA labeling restricts their use for UC to patients with an inadequate response or intolerance to one or more TNF blockers. Assess individual cardiovascular, thrombotic, malignancy, and infection risk, with particular caution in older adults, current or former smokers, and patients with relevant comorbidities. Obtain baseline and follow-up laboratory testing as required by the specific product label, including blood counts, liver enzymes, and lipids where indicated.

S1P receptor modulators

Ozanimod and etrasimod may increase herpes zoster risk. Before initiation, review the specific product label for contraindications, drug interactions, vaccination requirements, and monitoring. Obtain a baseline ECG and assess cardiac history; these agents may be contraindicated in selected conduction disorders, including high-degree atrioventricular block. Monitor blood pressure, particularly with etrasimod, and assess for macular edema risk; ophthalmologic assessment is indicated when specified by the agent label or patient risk factors.

Special Populations

Pregnancy and conception

Maintaining disease control before conception and throughout pregnancy is a central treatment priority because active IBD can adversely affect pregnancy outcomes. Medication decisions should be individualized with gastroenterology and obstetric input. Do not stop effective maintenance therapy without assessing the risk of relapse.

• Continue when clinically indicated: 5-ASA, thiopurines, anti-TNF agents, vedolizumab, ustekinumab, and the IL-23 inhibitors mirikizumab, risankizumab, and guselkumab. Patients taking sulfasalazine should receive folic acid 1 mg twice daily.
• Methotrexate: Contraindicated in pregnancy; discontinue before conception, generally at least 1–3 months beforehand according to the 2026 ACG consensus and individualized clinical guidance.
• JAK inhibitors: Avoid during pregnancy. The 2026 ACG consensus recommends discontinuing tofacitinib, upadacitinib, and filgotinib at least 4 weeks before conception.
• S1P receptor modulators: Avoid during pregnancy. Discontinue ozanimod at least 3 months before conception and etrasimod 1–2 weeks before conception, in accordance with the 2026 ACG consensus.
• Corticosteroids may be used when necessary to control a flare, with attention to maternal and fetal risks. If a medication must be discontinued, establish an effective alternative plan to avoid loss of disease control.

Older adults

Treatment should account for frailty, comorbidity, polypharmacy, infection risk, malignancy risk, and cardiovascular or thromboembolic risk. Thiopurines and JAK inhibitors require particular risk assessment in older patients. Select therapy individually rather than assuming a single advanced agent is safest for all older adults.

Clinically Actionable Recommendations

• Use a treat-to-target approach that combines clinical assessment with biomarkers and endoscopic evaluation when indicated.
• For mild-to-moderate UC, select oral and/or rectal 5-ASA according to disease extent; consider budesonide MMX or systemic corticosteroids for induction when appropriate.
• Do not use systemic corticosteroids, budesonide MMX, or topical corticosteroids for maintenance.
• For moderate-to-severe UC, consider advanced therapy early and choose the agent according to prior exposure, comparative evidence, safety, and patient preference.
• In hospitalized ASUC, test for C. difficile, administer intravenous corticosteroids and VTE prophylaxis unless contraindicated, reassess response by day 3, and promptly plan rescue therapy or surgery when indicated.
• Before advanced therapy, screen for relevant infections, review vaccinations, and arrange agent-specific safety monitoring.

Important Updates Compared With Older Teaching

• Moderate-to-severe disease is not required to progress through every conventional step before advanced therapy is considered.
• Treatment decisions increasingly use objective inflammatory markers and endoscopic healing rather than symptom control alone.
• The advanced-therapy landscape now includes IL-23p19 inhibitors, newer JAK inhibitors, and S1P receptor modulators in addition to anti-TNF agents, vedolizumab, and ustekinumab.
• In the United States, tofacitinib and upadacitinib are labeled for UC after inadequate response or intolerance to one or more TNF blockers.
• ASUC requires timely response assessment and rescue planning; prolonged ineffective intravenous corticosteroid treatment can delay necessary escalation.

Areas of Uncertainty

• Comparative rankings of advanced therapies are based substantially on indirect comparisons; direct head-to-head evidence remains limited for many agents.
• The optimal sequencing of newer IL-23 inhibitors and other advanced therapies is not established for every clinical scenario.
• The role of proactive TDM, intensified infliximab induction in ASUC, and JAK inhibitors as ASUC rescue therapy remains incompletely defined.
• Histologic remission is prognostically informative but is not yet a universally mandated treatment target.

Common Pitfalls

• Using corticosteroids for maintenance or repeatedly relying on them instead of establishing steroid-sparing control.
• Delaying advanced therapy in persistent moderate-to-severe disease because of a rigid step-up sequence.
• Treating ASUC without pharmacologic VTE prophylaxis when no contraindication exists.
• Continuing ineffective intravenous corticosteroids without timely reassessment, rescue planning, and surgical consultation.
• Starting advanced immunosuppressive therapy without appropriate infection screening, vaccination review, and agent-specific safety assessment.

Case Studies

Case #1

Related Chapters

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