Inflammatory bowel disease

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Inflammatory Bowel Disease Main page

Patient Information

Overview

Causes

Classification

Crohn's disease
Ulcerative colitis

Differential Diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]
Synonyms and keywords: IBD ; Template:Infobox medical condition

Inflammatory bowel disease (IBD) is a group of chronic immune-mediated inflammatory disorders of the gastrointestinal tract characterized by periods of inflammatory activity and remission.

The major disease entities include:

  • Crohn disease (CD).
  • Ulcerative colitis (UC).
  • IBD-unclassified (IBDU).

IBD is a systemic inflammatory disorder with intestinal and extraintestinal manifestations. Inflammation may involve the joints, eyes, skin, and hepatobiliary system.

Disease entities

Ulcerative colitis

Ulcerative colitis is a chronic inflammatory disorder limited primarily to the colon.

Characteristics:

  • Continuous inflammation beginning in the rectum and extending proximally.
  • Primarily mucosal inflammation.
  • Bloody diarrhea and fecal urgency are common.
  • Longstanding colonic inflammation increases colorectal neoplasia risk.

Crohn disease

Crohn disease may affect any portion of the gastrointestinal tract from mouth to anus.

Characteristics:

  • Segmental "skip" lesions.
  • Transmural inflammation.
  • Strictures, fistulas, and abscess formation.
  • Noncaseating granulomas may occur.

Disease behavior is categorized as:

  • Inflammatory.
  • Stricturing.
  • Penetrating.

IBD-unclassified

IBD-unclassified describes patients with clinical, endoscopic, histologic, and radiologic findings that do not allow definitive classification as Crohn disease or ulcerative colitis.

Classification may change over time with longitudinal follow-up.

Etiologic framework

IBD results from inappropriate immune activation against intestinal microbial communities in genetically susceptible individuals.

Disease development reflects interaction between:

  • Host genetics.
  • Intestinal microbiome alterations.
  • Intestinal epithelial barrier dysfunction.
  • Innate and adaptive immune responses.
  • Environmental exposures.

Genetic pathways

Important genetic associations include:

  • NOD2 variants — strongly associated with Crohn disease.
  • ATG16L1 and autophagy pathways.
  • IL-23/Th17 immune axis.

Environmental contributors

Potential contributors include:

  • Westernized dietary patterns.
  • Smoking.
  • Altered microbial diversity.
  • Antibiotic exposure.
  • Urbanization and industrialization.

Epidemiology and disease burden

IBD prevalence continues to increase globally due to:

  • Improved survival.
  • Accumulation of chronic disease burden.
  • Increasing incidence in newly industrialized regions.

Historically high-incidence Western countries show stabilization or decline in incidence, while prevalence continues to rise.

Clinical presentation

Clinical manifestations depend on:

  • Disease location.
  • Inflammatory activity.
  • Presence of complications.

Common symptoms include:

  • Abdominal pain.
  • Chronic diarrhea.
  • Nocturnal diarrhea.
  • Rectal bleeding.
  • Mucus passage.
  • Weight loss.
  • Fatigue.
  • Fever.
  • Anemia.

Features suggesting Crohn disease complications:

  • Postprandial abdominal pain.
  • Vomiting.
  • Abdominal distension.
  • Obstructive symptoms.

Children and adolescents may present with:

  • Growth impairment.
  • Delayed puberty.
  • Nutritional deficiencies.

Extraintestinal manifestations

Extraintestinal manifestations may occur independently of intestinal disease activity.

Musculoskeletal

  • Peripheral arthritis.
  • Axial spondyloarthritis.
  • Sacroiliitis.

Ocular

  • Episcleritis.
  • Uveitis.

Dermatologic

  • Erythema nodosum.
  • Pyoderma gangrenosum.

Hepatobiliary

  • Primary sclerosing cholangitis (PSC).

Diagnosis overview

Diagnosis requires integration of:

  • Clinical history.
  • Physical examination.
  • Laboratory inflammatory markers.
  • Stool biomarkers.
  • Endoscopy with histology.
  • Cross-sectional imaging when indicated.

No single test independently establishes the diagnosis.

Fecal calprotectin should be interpreted according to clinical context and pretest probability.

Biomarker monitoring

Fecal calprotectin

Fecal calprotectin is a neutrophil-derived stool biomarker used to assess intestinal inflammation.

Clinical applications include:

  • Differentiating IBD from functional gastrointestinal disorders.
  • Monitoring inflammatory activity.
  • Supporting treatment decisions.

The AGA framework is based on clinical probability.

Clinical scenario Threshold Interpretation Action
Symptomatic remission with low probability of inflammation Approximately ≤150 µg/g Suggests absence of active inflammation Avoid routine endoscopy
Moderate-to-severe symptoms with high probability >150–250 µg/g Supports active inflammation Treatment decisions may proceed without routine endoscopy
Mild symptoms with intermediate probability Any cutoff Accuracy insufficient Perform endoscopy

In established ulcerative colitis for detection of Mayo endoscopic subscore 2–3:

  • 50 ± 50 µg/g:
    • Sensitivity approximately 78%.
    • Specificity approximately 57%.
  • 150 ± 50 µg/g:
    • Sensitivity approximately 71%.
    • Specificity approximately 69%.
  • 250 ± 50 µg/g:
    • Sensitivity approximately 67%.
    • Specificity approximately 73%.

ACG guideline interpretation:

  • Pooled sensitivity for endoscopic inflammation: approximately 87%.
  • Pooled specificity: approximately 77%.
  • Fecal calprotectin around 321 µg/g during clinical remission predicts relapse risk at 6 and 12 months.

A normal fecal calprotectin does not exclude active disease when clinical suspicion remains high.

Treat-to-target strategy

Symptoms correlate poorly with inflammatory burden.

Approximately:

  • 50% of asymptomatic patients with Crohn disease.
  • 15% of asymptomatic patients with ulcerative colitis.

may have ongoing objective inflammation.

Treatment decisions should integrate:

  • Symptoms.
  • CRP.
  • Fecal calprotectin.
  • Endoscopy.
  • Imaging when appropriate.

STRIDE-II treatment targets

The STRIDE-II framework defines treatment targets according to time horizon.

Immediate targets

  • Clinical response.
  • Improvement in symptoms.

Short- to intermediate-term targets

  • Clinical remission.
  • Normalization of CRP when previously elevated.

Intermediate targets

  • Reduction in inflammatory biomarkers.
  • Fecal calprotectin reduction toward approximately 100–250 µg/g.
  • Endoscopic response in Crohn disease.

Long-term targets

  • Endoscopic healing.
  • Absence of disability.
  • Restoration of quality of life.
  • Normal growth in pediatric patients.

Additional prognostic markers:

  • Transmural healing in Crohn disease.
  • Histologic improvement in ulcerative colitis.

These provide prognostic information but are not mandatory formal STRIDE-II targets.

Endoscopic definitions

Crohn disease

Endoscopic response:

  • >50% decrease in SES-CD or CDEIS.

Endoscopic remission:

  • SES-CD ≤2.
  • CDEIS ≤3 according to validated definitions.

Ulcerative colitis

Endoscopic healing refers to resolution of visible inflammatory mucosal lesions.

STRIDE-II defines endoscopic remission as:

  • Mayo Endoscopic Score (MES) 0.
  • UCEIS ≤1.

Endoscopic response:

  • Reduction in MES by ≥1 point.
  • Reduction in UCEIS by ≥2 points.

Endoscopic improvement, commonly reported in trials, generally refers to MES 0 or 1.

Treat-to-target trial evidence

CALM trial — biomarker-driven tight control

CALM was an open-label phase 3 randomized trial evaluating biomarker-driven escalation compared with symptom-driven management in patients with active Crohn disease.

Eligibility criteria included:

  • CDEIS >6.
  • CDAI 150–450.
  • No previous immunomodulator or biologic exposure.

Tight-control escalation triggers included:

  • Fecal calprotectin ≥250 µg/g.
  • CRP ≥5 mg/L.
  • CDAI ≥150.
  • Recent corticosteroid requirement.

The primary endpoint was mucosal healing defined as:

  • CDEIS <4.
  • Absence of deep ulcerations.

Results:

Primary endpoint

Mucosal healing:

  • Tight control:
    • 56/122 patients (46%).
  • Clinical management:
    • 37/122 patients (30%).

CMH-adjusted risk difference:

  • 16.1%.
  • 95% CI 3.9–28.3.
  • p=0.010.

Secondary endpoints

Deep remission:

  • Risk difference 14.5%.
  • 95% CI 2.9–26.0.
  • p=0.014.

Biologic remission:

  • Risk difference 14.5%.
  • 95% CI 4.1–25.0.
  • p=0.006.

Treatment-emergent adverse events:

  • 86% versus 82%.
  • No treatment-related deaths.

Clinical implication:

Biomarker-driven monitoring has randomized evidence supporting improved objective outcomes in early active Crohn disease.

Limitations:

  • Open-label design.
  • Site-read endoscopy.
  • Short follow-up duration.

STARDUST trial — endoscopy-driven escalation of ustekinumab

STARDUST evaluated endoscopy-driven treat-to-target escalation compared with standard management in Crohn disease patients responding to ustekinumab induction.

Primary endpoint:

  • Endoscopic response at week 48.

Results:

Endoscopic response:

  • 38% versus 30%.
  • Not statistically significant.

Endoscopic remission:

  • 11% versus 15%.
  • Not statistically significant.

Clinical remission:

  • 62% versus 70%.
  • Not statistically significant.

Important limitation:

The maintenance strategy included every-12-week ustekinumab dosing, which differs from FDA-approved every-8-week dosing in the United States.

Subgroup findings remain hypothesis-generating.

REACT-2 trial — endoscopic versus symptom-based management

REACT-2 was a cluster-randomized trial comparing enhanced care targeting ulcer healing with standard symptom-based management.

It was not an early-combination-therapy trial.

Results:

  • No significant difference in the primary endpoint.
  • No consistent improvement in endoscopic outcomes.

Post hoc analyses suggested possible benefit in selected patients with:

  • Elevated CRP.
  • Baseline ulceration.

These findings are hypothesis-generating.

AGA pooled analysis

Pooling STARDUST and REACT-2:

No significant difference was demonstrated between endoscopic targets and symptom-based targets for clinical remission.

Clinical remission:

  • 63.2% versus 57.3%.
  • RR 1.04.
  • 95% CI 0.78–1.39.

Practical interpretation of treat-to-target evidence

Current evidence supports:

  • Objective monitoring rather than symptom assessment alone.
  • Biomarker-guided escalation in selected Crohn disease populations.
  • Endoscopic reassessment when clinically indicated.

However:

  • The incremental benefit of mandatory endoscopic escalation over clinical plus biomarker monitoring remains unproven.

Early effective therapy and risk stratification

Treatment intensity should be individualized according to risk of disease progression.

High-risk Crohn disease features

  • Young age at diagnosis.
  • Extensive small bowel involvement.
  • Deep ulcerations.
  • Perianal disease.
  • Stricturing phenotype.
  • Penetrating phenotype.
  • Need for corticosteroids.

Patients with mild, non-progressive disease may not require aggressive escalation.

Early combination therapy evidence

PROFILE trial

PROFILE evaluated early infliximab plus immunomodulator therapy compared with conventional step-up treatment.

Findings:

Symptomatic remission at 1 year:

  • RR 1.12.
  • 95% CI 0.98–1.30.
  • Not statistically significant.

Steroid-free, surgery-free remission:

  • 79% versus 15%.

Clinical interpretation:

The 79% versus 15% finding should not be presented as the primary clinical remission outcome.

REACT-1 trial

Pragmatic trial evaluating accelerated treatment strategies.

Findings:

  • No significant difference in steroid-free remission.
  • Lower disease-related adverse events:
    • HR 0.73.
    • 95% CI 0.62–0.86.

AGA meta-analysis

Across 3 trials including 2497 patients:

Clinical remission:

  • 66.4% versus 60.6%.
  • RR 1.18.
  • 95% CI 0.96–1.46.

Overall:

  • Benefit for steroid-free and endoscopic outcomes is more consistent than benefit for clinical remission alone.

Therapeutic classes

Treatment selection depends on:

  • Disease severity.
  • Disease location.
  • Disease behavior.
  • Prior treatment exposure.
  • Risk of progression.
  • Patient preference and safety considerations.

The therapeutic goal is sustained steroid-free remission with control of objective inflammation.

5-aminosalicylates

5-aminosalicylates (5-ASA) are primarily used in ulcerative colitis.

Clinical considerations:

  • Effective for mild ulcerative colitis induction and maintenance.
  • Oral mesalamine is not recommended for induction or maintenance of moderate-to-severe Crohn disease.
  • Mesalamine is not recommended as postoperative prophylaxis for Crohn disease.

Corticosteroids

Corticosteroids are induction therapies only.

They should not be used for maintenance because of:

  • Osteoporosis.
  • Infection risk.
  • Hyperglycemia and metabolic complications.
  • Adrenal suppression.
  • Other cumulative steroid toxicities.

Budesonide

Controlled ileal-release budesonide:

  • Dose: 9 mg daily.
  • Used for selected patients with mild-to-moderate ileocecal Crohn disease.
  • Induction therapy only.

Steroids should generally be tapered and discontinued within approximately 3 months whenever possible.

Acute severe ulcerative colitis

Acute severe ulcerative colitis (ASUC) is a medical emergency requiring hospitalization, intravenous corticosteroids, close monitoring, and early colorectal surgical involvement.

Approximately 20–30% of hospitalized patients with ASUC eventually require colectomy.

Initial evaluation and admission bundle

Initial assessment should include:

  • Stool frequency.
  • Rectal bleeding.
  • Abdominal pain.
  • Fever.
  • Signs of systemic toxicity.

Laboratory evaluation:

  • Complete blood count.
  • C-reactive protein (CRP).
  • Electrolytes.
  • Albumin.
  • Renal function.
  • Other inflammatory markers as clinically indicated.

Additional evaluation:

  • Stool testing for infectious causes, particularly Clostridioides difficile infection.
  • Flexible sigmoidoscopy with biopsies when appropriate.

Management includes:

  • Intravenous corticosteroids.
  • Pharmacologic venous thromboembolism (VTE) prophylaxis unless contraindicated.
  • Avoidance of routine broad-spectrum antibiotics in uncomplicated ASUC.
  • Avoidance of total parenteral nutrition solely for bowel rest.
  • Preference for enteral nutrition when tolerated.

Corticosteroid induction

Common regimens:

  • Methylprednisolone approximately 60 mg/day intravenously.
  • Hydrocortisone 100 mg intravenously three to four times daily.

Clinical response should be assessed after approximately 3 days.

Failure to improve requires evaluation for:

  • Rescue therapy.
  • Surgical intervention.

Predicting corticosteroid failure

The Oxford criteria identify patients at increased risk of colectomy.

High-risk criteria:

  • Stool frequency >8 bowel movements/day.

OR

  • Stool frequency 3–8 bowel movements/day with CRP >45 mg/L.

Patients meeting these criteria require early escalation planning.

Rescue therapy

For corticosteroid-refractory ASUC:

Infliximab

Advantages:

  • Effective rescue therapy.
  • Can continue as maintenance therapy.

Infliximab remains one of the best-established rescue therapies, particularly in patients without contraindications to anti-TNF therapy.

Cyclosporine

Advantages:

  • Rapid immunosuppressive effect.
  • Alternative rescue option.

Limitations:

  • Nephrotoxicity.
  • Hypertension.
  • Infection risk.
  • Drug interactions.

After cyclosporine-induced remission, transition to maintenance therapy is required.

Options include:

  • Thiopurines.
  • Vedolizumab.
  • Other advanced therapies.

Tofacitinib and newer rescue strategies

Tofacitinib salvage therapy has demonstrated encouraging results in observational studies; however, randomized evidence remains insufficient for routine first-line rescue use in ASUC.

Selection of rescue therapy should consider:

  • Prior biologic exposure.
  • Comorbidities.
  • Safety profile.
  • Need for long-term maintenance strategy.

Cytomegalovirus colitis in ASUC

CMV reactivation may occur in a substantial proportion of patients with corticosteroid-refractory severe colitis.

Active CMV infection is associated with severely inflamed mucosa and poorer outcomes.

Diagnosis

Important principles:

  • Biopsies obtained from ulcer bases provide the highest diagnostic yield.
  • Hematoxylin-eosin staining has limited sensitivity.
  • Immunohistochemistry, rapid viral culture, or tissue PCR are preferred diagnostic methods.

Treatment

Treatment options:

  • Intravenous ganciclovir followed by oral therapy.
  • Typical treatment duration approximately 14 days.
  • Valganciclovir in selected patients.

Clinical principles:

  • Antiviral therapy has not demonstrated benefit in patients responding to intravenous corticosteroids.
  • Colectomy should not be delayed solely to complete antiviral therapy in patients failing medical management.

Surgical management in ASUC

Urgent colectomy is indicated for:

  • Perforation.
  • Toxic megacolon.
  • Massive hemorrhage.
  • Progressive clinical deterioration.

Colectomy should be considered when:

  • No meaningful improvement occurs after approximately 3–7 days of appropriate medical therapy.
  • Rescue therapy fails.

Surgical consultation should occur early during hospitalization rather than after multiple failed medical interventions.

Venous thromboembolism prevention

Patients with IBD have increased risk of venous thromboembolism (VTE), especially during:

  • Active inflammation.
  • Hospitalization.
  • Corticosteroid exposure.

The risk of VTE remains elevated even in patients with active intestinal bleeding.

Thromboprophylaxis recommendations

Pharmacologic thromboprophylaxis should be provided during hospitalization for:

  • IBD-related admissions.
  • Non-IBD-related admissions in patients with IBD.

Inflammatory rectal bleeding alone should not prevent prophylactic anticoagulation.

Studies have not demonstrated increased:

  • Major bleeding.
  • Minor bleeding.
  • Blood transfusion requirements.

Preferred agents include standard inpatient pharmacologic prophylaxis regimens unless contraindicated.

Risk reduction strategies

Important measures:

  • Achieving inflammatory remission.
  • Minimizing corticosteroid exposure.
  • Smoking cessation.
  • Individualized thrombotic risk assessment before JAK inhibitor therapy.

Preventive care and vaccination

Patients with IBD require preventive care according to:

  • Age.
  • Disease status.
  • Medication exposure.
  • Immunosuppression intensity.

General principles:

  • Inactivated vaccines are safe and do not increase IBD activity.
  • Live vaccines should generally be avoided during significant immunosuppression.
  • Vaccinations should ideally be completed before immune-modifying therapy when feasible.
  • Appropriate IBD therapy should not be delayed solely because vaccination is incomplete.

Include:

  • Annual influenza vaccination.
  • COVID-19 vaccination according to recommendations.
  • Pneumococcal vaccination when indicated.
  • Recombinant zoster vaccine when eligible.

Herpes zoster vaccination

All adults aged ≥19 years receiving or planning to initiate immune-modifying therapy should receive recombinant zoster vaccine (RZV).

Key points:

  • RZV is non-live.
  • RZV is not associated with increased IBD flare risk.
  • It is preferred in immunosuppressed patients.

Risk of herpes zoster is increased with:

  • Thiopurines.
  • Anti-TNF therapy.
  • JAK inhibitors.
  • Corticosteroids.

Other preventive measures

Patients receiving immunosuppressive therapy require:

  • Bone mineral density assessment after prolonged systemic corticosteroid exposure (≥3 months at ≥7.5 mg prednisone equivalent daily).
  • Annual skin examination in patients receiving thiopurines, methotrexate, or anti-TNF therapy.
  • Cervical cancer screening according to recommended guidelines, with consideration of increased surveillance in immunosuppressed women.

Before advanced therapies, evaluate for:

  • Tuberculosis.
  • Hepatitis B.
  • Hepatitis C.
  • HIV when clinically indicated.

Additional assessment may be required before:

  • JAK inhibitors.
  • S1P receptor modulators.

Natural history and surgery

Contemporary surgical rates are substantially lower than historical pre-biologic estimates.

Time after diagnosis Ulcerative colitis Crohn disease
1 year ~2.8% ~12.3%
5 years ~7.0% ~18.0%
10 years ~9.6% ~26.2%

The above estimates represent modern all-era pooled estimates rather than historical cohorts.

Earlier pooled estimates across all treatment eras reported:

  • Ulcerative colitis:
    • 4.0% at 1 year.
    • 8.8% at 5 years.
    • 13.3% at 10 years.
  • Crohn disease:
    • 18.7% at 1 year.
    • 28.0% at 5 years.
    • 39.5% at 10 years.

A genuinely pre-biologic estimate reported approximately 46.6% cumulative Crohn disease surgery by 10 years.

Declining surgery rates likely reflect multiple factors, including:

  • Earlier diagnosis.
  • Improved monitoring.
  • Better multidisciplinary care.
  • Modern medical therapy.
  • Changes in surgical practice.

Surgery is not curative for Crohn disease.

Following first intestinal resection:

  • Approximately 17.7% require a second resection within 5 years.
  • Approximately 31.3% require a second resection within 10 years.

Postoperative Crohn disease

Risk factors for postoperative recurrence include:

  • Active smoking.
  • Penetrating disease.
  • Prior intestinal resection.
  • Extensive small bowel disease.
  • Perianal disease.

Low-risk patients

Characteristics:

  • Nonsmoker.
  • No penetrating phenotype.
  • No previous resection.

Management:

  • Observation may be appropriate.
  • Ileocolonoscopy approximately 6 months after surgery.

Intermediate-risk patients

Management options:

  • Thiopurine therapy.
  • Thiopurine plus short-course metronidazole.

Escalate therapy when Rutgeerts score is ≥i2b.

High-risk patients

Examples:

  • Previous resection within 10 years.
  • Multiple prior resections.
  • Active smoking.

Preferred therapy:

  • Anti-TNF therapy.
  • Consider combination immunomodulator.

Repeat ileocolonoscopy approximately 6 months postoperatively.

Rutgeerts score

Score Findings
i0 No lesions
i1 ≤5 aphthous ulcers
i2 >5 aphthous ulcers with normal intervening mucosa or lesions confined to the anastomosis
i3 Diffuse aphthous ileitis
i4 Diffuse inflammation with large ulcers, severe lesions, or narrowing

Key evidence

POCER

  • Colonoscopy-guided treatment escalation reduced postoperative endoscopic recurrence.

REPREVIO

  • Early postoperative vedolizumab reduced severe endoscopic recurrence compared with placebo.

Mesalamine is not recommended for postoperative prophylaxis.

Colorectal cancer surveillance

Patients with longstanding colonic inflammatory bowel disease have increased risk of colorectal cancer (CRC).

Surveillance applies to:

  • Ulcerative colitis extending beyond the rectum.
  • Crohn colitis with substantial colonic involvement.

Average-risk colorectal cancer screening applies to:

  • Isolated small bowel Crohn disease.
  • Isolated ulcerative proctitis.

When to begin surveillance

Routine surveillance:

  • Approximately 8 years after onset of colonic disease.

Patients with primary sclerosing cholangitis (PSC):

  • Begin surveillance at the time PSC is diagnosed regardless of IBD duration.

Patients with a first-degree relative diagnosed with colorectal cancer before age 60:

  • Begin surveillance 10 years before the relative's age at diagnosis or 8 years after IBD onset, whichever occurs first.

Surveillance intervals

Risk stratification determines surveillance frequency.

High-risk patients:

  • Annual colonoscopy.

Intermediate-risk patients:

  • Every 2–3 years.

Selected low-risk patients:

  • Longer intervals may be appropriate, although many guidelines recommend intervals no longer than 3 years.

Preferred surveillance technique

Preferred approach:

  • High-definition colonoscopy with chromoendoscopy and targeted biopsies.

If chromoendoscopy is unavailable:

  • High-definition white-light colonoscopy.
  • Targeted biopsies.
  • Four-quadrant random biopsies approximately every 10 cm.

Surveillance should ideally be performed during remission.

Colonic strictures require careful evaluation because malignancy may coexist.

Pouchitis and inflammatory pouch disorders

Inflammatory disorders of the ileal pouch occur after restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA).

Diagnosis requires:

  • Endoscopic confirmation of inflammation.
  • Exclusion of alternative causes.

AGA guidance consists primarily of conditional recommendations based on low-certainty evidence.

Management

Intermittent pouchitis

Management:

  • Antibiotics.

Recurrent antibiotic-responsive pouchitis

Management:

  • Consider probiotics to reduce recurrence.

Chronic antibiotic-dependent pouchitis

Options include:

  • Chronic antibiotics.
  • Advanced therapies when long-term antibiotics are undesirable or ineffective.

Chronic antibiotic-refractory pouchitis

Management:

  • Advanced immunosuppressive therapy.
  • Corticosteroids may be considered in selected patients.

Crohn-like disease of the pouch

Management:

  • Corticosteroids.
  • Advanced biologic or targeted therapy.

Cuffitis

Initial treatment:

  • Topical 5-ASA.
  • Topical corticosteroids.

Current evidence has not demonstrated clear superiority of one advanced therapy class over another.

Pregnancy

Women with IBD should ideally conceive while disease is in documented remission.

Active disease is associated with increased:

  • Maternal complications.
  • Preterm birth.
  • Low birth weight.
  • Disease-related complications.

Continue during pregnancy

Generally appropriate when clinically indicated:

  • 5-ASA agents.
  • Sulfasalazine.
  • Thiopurines.
  • Anti-TNF therapy.
  • Vedolizumab.
  • Ustekinumab.
  • Corticosteroids when necessary.

Avoid or discontinue

Avoid:

  • Methotrexate.
  • JAK inhibitors.
  • S1P receptor modulators.

Methotrexate should be discontinued at least 6 months before conception.

Ozanimod should be discontinued at least 6 months before conception.

Thiopurines and methotrexate should not be newly initiated during pregnancy.

Practical considerations

  • Sulfasalazine requires folic acid supplementation.
  • Infliximab and adalimumab cross the placenta after approximately 20 weeks.
  • Infants exposed to biologics during late pregnancy should avoid live vaccines during the first 6 months of life.
  • Certolizumab has minimal placental transfer.
  • MRI without gadolinium is preferred over CT when imaging is required.
  • Cesarean delivery is recommended for active perianal Crohn disease or previous rectovaginal fistula.

Anemia and nutritional deficiencies

Anemia is one of the most common systemic complications of inflammatory bowel disease.

Iron deficiency and/or iron deficiency anemia occur in up to 90% of patients during the disease course.

Common causes include:

  • Chronic intestinal blood loss.
  • Active inflammation with impaired iron utilization.
  • Reduced dietary intake.
  • Malabsorption.
  • Previous intestinal surgery.

Screening

Assessment should include:

  • Complete blood count.
  • Ferritin.
  • Transferrin saturation.
  • C-reactive protein (CRP).

Monitoring frequency:

  • Every 6–12 months during remission or mild disease.
  • Approximately every 3 months during active disease.

Ferritin is an acute-phase reactant; therefore, normal or elevated ferritin does not exclude iron deficiency during active inflammation.

Additional nutritional assessment should include:

  • Vitamin B12.
  • Folate.
  • Vitamin D.
  • Other micronutrients when clinically indicated.

Iron replacement

Treatment principles:

  • Optimize control of intestinal inflammation.
  • Correct iron deficiency in all patients with iron deficiency anemia.

Intravenous iron is preferred in:

  • Active IBD.
  • Hemoglobin <10 g/dL.
  • Significant anemia.
  • Oral iron intolerance.
  • Failure of oral iron therapy.
  • Extensive intestinal disease.

Randomized trials demonstrate that intravenous iron is associated with:

  • Greater likelihood of hemoglobin increase ≥2 g/dL.
  • Lower treatment discontinuation rates than oral iron.

ECCO recommends intravenous iron as first-line therapy for active disease and clinically significant anemia.

Vitamin B12 deficiency

Risk factors include:

  • Terminal ileal Crohn disease.
  • Ileal resection.
  • Extensive ileal involvement.

Management:

  • Screen patients with ileal disease or previous ileal resection.
  • Replace vitamin B12 when deficiency is identified.

Folate deficiency

Risk factors:

  • Poor nutritional intake.
  • Malabsorption.
  • Methotrexate therapy.

Management:

  • Replace folate deficiency.
  • Supplement when clinically indicated.

Vitamin D deficiency and bone health

Vitamin D deficiency is particularly common in Crohn disease.

Potential consequences:

  • Reduced bone mineral density.
  • Osteopenia.
  • Osteoporosis.
  • Increased fracture risk.

Management:

  • Assess vitamin D status in at-risk patients.
  • Replace deficiency.
  • Minimize corticosteroid exposure whenever possible.

Perianal Crohn disease

Perianal Crohn disease represents an aggressive phenotype associated with significant morbidity.

Evaluation should include:

  • Pelvic MRI.
  • Examination under anesthesia when appropriate.

Abscess management

Drainage of abscess is mandatory before initiation of immunosuppressive therapy.

Management may include:

  • Surgical drainage.
  • Seton placement for complex fistulas.

Medical therapy

Anti-TNF therapy remains the best-established biologic treatment.

Infliximab has the strongest evidence for:

  • Fistula closure.
  • Durable fistula healing.

Persistent fistulizing disease requires multidisciplinary management involving:

  • Gastroenterology.
  • Colorectal surgery.
  • Radiology.

Therapeutic drug monitoring

Therapeutic drug monitoring (TDM) measures serum drug concentration—usually trough concentration—together with antidrug antibodies.

It is most established for TNFα antagonists.

Rationale

Exposure–response relationship

Across ACT, PURSUIT, GEMINI, UNIFI, FORTIFY, PREVENT, ADVANCE, and MOTIVATE studies:

  • Patients in the lowest drug-concentration quartile achieved clinical remission and endoscopic outcomes nearly identical to placebo.

Variability in clearance

Drug clearance varies because of:

  • Immune-mediated mechanisms:
    • Neutralizing antidrug antibodies.
  • Nonimmune-mediated mechanisms:
    • High inflammatory burden.
    • Protein loss.

Mechanistic failure

Adequate drug exposure may still fail when the targeted inflammatory pathway is not the principal driver of disease.

Reactive TDM

Reactive TDM is performed in patients with:

  • Clinical evidence of inflammation.
  • Biochemical activity.
  • Radiologic inflammation.
  • Endoscopic inflammation.

It is supported for:

  • Primary nonresponse.
  • Secondary loss of response.
Drug concentration Antidrug antibodies Interpretation Management
Low Absent or low titer Underexposure Dose intensification or interval shortening
Low High titer Immunogenic failure Switch therapy; consider adding immunomodulator
Adequate Any Mechanistic failure Switch mechanism of action

Concentration threshold before declaring failure

Infliximab or adalimumab should not be considered mechanistically ineffective until trough concentrations of approximately:

10–15 µg/mL

have been achieved.

Stopping therapy below this threshold risks misclassifying underdosing as treatment failure.

Thiopurine monitoring

Target:

  • 6-thioguanine nucleotide concentration of 230–450 pmol/8 × 10⁸ red blood cells.

Proactive TDM — unresolved

Proactive TDM involves routine measurement regardless of disease activity.

Current evidence remains conflicting.

Evidence against routine use:

  • Meta-analysis of 9 randomized trials found no improvement in clinical remission.
  • Increased therapy escalation occurred without reduction in antidrug antibody formation.

Evidence supporting proactive monitoring:

  • Meta-analysis of 8 studies found reduced treatment failure, although evidence was mainly observational.

Expert consensus:

  • A modified Delphi panel supported proactive anti-TNF monitoring after induction and at least once during maintenance.

Current society position:

  • AGA and ECCO consider proactive TDM a knowledge gap and make no recommendation for or against routine use.

Practical principles

  • Reactive TDM is established practice for loss of response and primary nonresponse.
  • Proactive TDM should be individualized.
  • Do not abandon infliximab or adalimumab below 10–15 µg/mL trough concentrations.
  • Drug concentrations should always be interpreted with symptoms, CRP, fecal calprotectin, endoscopy, and imaging.

Common pitfalls

  • Treating symptoms without confirming objective inflammatory control.
  • Using corticosteroids as maintenance therapy.
  • Presenting PROFILE secondary outcomes as the primary remission outcome.
  • Describing REACT-2 as an early-combination therapy trial.
  • Applying STARDUST every-12-week ustekinumab dosing to U.S. clinical practice.
  • Applying all-era pooled surgery estimates as historical pre-biologic cohorts.
  • Describing filgotinib as FDA-approved.
  • Withholding pharmacologic VTE prophylaxis solely because of inflammatory rectal bleeding.
  • Omitting recombinant zoster vaccination before immune-modifying therapy when indicated.
  • Delaying colectomy solely to complete antiviral therapy in corticosteroid-refractory CMV colitis.

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Causes

While the causes of inflammatory bowel disease is unknown, several possibly interrelated studies have been suggested following causes:

Common causes

Genetic factors

  • Mutations in the CARD15 gene (also known as the NOD2 gene) are associated with Crohn's disease.
  • Mutations of the transporter proteins such as OCTN1 and OCTN2 and scaffolding proteins such as the MAGUK family are believed to cause ulcerative colitis.

Environmental factors

  • Alterations in normal bacterial flora of the intestinal tract is responsible for Crohn's disease.
  • Smoking: Unlike Crohn's disease, ulcerative colitis has a lesser prevalence in smokers than non-smokers.
  • Use of NSAIDs
  • Stress
  • Red meat consumption

Rare causes

Classification

Inflammatory bowel disease can be classified into Crohn's disease and ulcerative colitis.

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inflammatory Bowel Disease
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Crohn's Disease
 
 
 
 
 
 
 
 
 
 
 
 
 
Ulcerative colitis
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Based on Region involved
 
 
 
 
 
 
 
 
 
Based on Severity
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ileocolic Crohn's disease
 
Crohn's ileitis
 
Crohn's colitis
 
Stricturing disease
 
Penetrating disease
 
Inflammatory disease
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Based on Region involved
 
 
 
 
 
 
 
Based on Severity
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Distal UC
 
 
 
Proximal UC
 
Mild
 
Moderate
 
Severe
 
Flumiant

Differential diagnosis

Inflammatory bowel disease must be differentiated from other diseases that present with abdominal pain, fever and diarrhea which include appendicitis, diverticulitis, Whipple's disease, mesenteric ischemia, Tropical sprue, hepatitis and spontaneous bacterial peritonitis.

Disease Clinical manifestations Diagnosis Comments
Symptoms Signs
Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo-

tension

Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging
Inflammatory bowel disease Diffuse ± − − ± − + + + − − − Normal or hyperactive

Extra intestinal findings:

Acute appendicitis Starts in epigastrium, migrates to RLQ + Positive in pyogenic appendicitis + − − ± − − Positive in perforated appendicitis + + Hypoactive
  • Ct scan
  • Ultrasound
  • Positive Rovsing sign
  • Positive Obturator sign
  • Positive Iliopsoas sign
Acute diverticulitis LLQ + ± + − + ± − + Positive in perforated diverticulitis + + Hypoactive
  • CT scan
  • Ultrasound
Whipple's disease Diffuse ± − − ± − + + − ± − − N Endoscopy is used to confirm diagnosis.

Images used to find complications

Extra intestinal findings:
Toxic megacolon Diffuse + − − − − + − − + ± + Hypoactive CT and Ultrasound shows:
  • Loss of colonic haustration
  • Hypoechoic and thickened bowel walls with irregular internal margins in the sigmoid and descending colon
  • Prominent dilation of the transverse colon (>6 cm)
  • Insignificant dilation of ileal bowel loops (diameter >18 mm) with increased intraluminal gas and fluid
Tropical sprue Diffuse + − − − − + + − − − − N Barium studies:
  • Dilation and edema of mucosal folds
Infective colitis Diffuse + − ± − − + − + Positive in fulminant colitis ± ± Hyperactive CT scan
  • Bowel wall thickening
  • Edema
Viral hepatitis RUQ + − + + − Positive in Hep A and E + − Positive in fulminant hepatitis Positive in acute + N
  • Abnormal LFTs
  • Viral serology
  • US
  • Hep A and E have fecal-oral route of transmission
  • Hep B and C transmits via blood transfusion and sexual contact.
Liver abscess RUQ + + + + − ± + − + + ± Normal or hypoactive
  • US
  • CT
Spontaneous bacterial peritonitis Diffuse + − − Positive in cirrhotic patients − + − − ± + + Hypoactive
  • Ascitic fluid PMN>250 cells/mm³
  • Culture: Positive for single organism
  • Ultrasound for evaluation of liver cirrhosis
Mesenteric ischemia Periumbilical Positive if bowel becomes gangrenous − + − − + + + Positive if bowel becomes gangrenous Positive if bowel becomes gangrenous − Hyperactive to absent CT angiography
  • SMA or SMV thrombosis
  • Also known as abdominal angina that worsens with eating
Acute ischemic colitis Diffuse + ± + − − + + + + + + Hyperactive then absent Abdominal x-ray
  • Distension and pneumatosis

CT scan

  • Double halo appearance, thumbprinting
  • Thickening of bowel
  • May lead to shock

Abbreviations: RUQ= Right upper quadrant of the abdomen, LUQ= Left upper quadrant, LLQ= Left lower quadrant, RLQ= Right lower quadrant, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, IV= Intravenous, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CXR= Chest X ray, IgA= Immunoglobulin A, IgG= Immunoglobulin G, IgM= Immunoglobulin M, CT= Computed tomography, PMN= Polymorphonuclear cells, ESR= Erythrocyte sedimentation rate, CRP= C-reactive protein, TS= Transferrin saturation, SF= Serum Ferritin, SMA= Superior mesenteric artery, SMV= Superior mesenteric vein, ECG= Electrocardiogram

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