What are the contraindications and precautions for the inflammatory bowel disease biologic and small‑molecule agents—including infliximab (Remicade), adalimumab (Humira), golimumab (Simponi), vedolizumab (Entyvio), ustekinumab (Stelara), risankizumab (Skyrizi), ozanimod (Zeposia), tofacitinib (Xeljanz), and upadacitinib (Rinvoq)—and can they be continued during active infections?

Contraindications and Precautions for IBD Biologics and Small Molecules

All IBD biologics and small molecules are contraindicated in patients with active tuberculosis, sepsis, or opportunistic infections, and should be stopped if severe infection develops. 1

Universal Contraindications and Screening Requirements

Absolute Contraindications

• Active tuberculosis (TB)
• Active sepsis
• Opportunistic infections (including Clostridium difficile, invasive fungal infections)
• Known hypersensitivity to the specific agent 2, 3, 4

Pre-Treatment Screening (All Agents)

Before initiating any biologic or small molecule therapy:

• Screen for latent TB and treat before starting therapy 1, 5
• Screen for hepatitis B virus (HBV) - monitor carriers during and several months after therapy 2
• Update vaccinations - complete before starting treatment where possible 1
• Assess for active infections - defer treatment until resolved 1

Agent-Specific Contraindications and Precautions

Anti-TNF Agents (Infliximab, Adalimumab, Golimumab)

Specific Warnings:

• Demyelinating disease - exacerbation or new onset may occur 2
• Heart failure - worsening or new onset possible; use caution in NYHA Class III/IV 2
• Hepatitis B reactivation - monitor HBV carriers closely 2
• Malignancy risk - incidence greater than controls 2
• Lupus-like syndrome - discontinue if develops 2

Monitoring:

• Cytopenias/pancytopenia - advise patients to seek immediate attention if symptoms develop 2

JAK Inhibitors (Tofacitinib, Upadacitinib)

FDA Boxed Warnings - Highest Risk Profile:

Tofacitinib/Upadacitinib specific risks:

• Serious infections including TB, bacterial, invasive fungal, viral, and opportunistic infections 3
• Increased mortality (all-cause) 3
• Malignancies including lymphoma and lung cancer 3
• Major adverse cardiovascular events (MACE) - myocardial infarction, stroke 3
• Thrombosis - pulmonary embolism, deep vein thrombosis, arterial thrombosis 3
• Herpes zoster - significantly increased risk 6, 7

Laboratory Thresholds for Interruption: Avoid initiation or interrupt if 3:

• Absolute lymphocyte count <500 cells/mm³
• Absolute neutrophil count <1000 cells/mm³
• Hemoglobin <8 g/dL

Monitoring Requirements:

• Complete blood counts and liver function tests at baseline and during therapy 3
• Lipid levels before and after initiation 3

Special Populations:

• Adults ≥65 years: Increased risk of serious infections, malignancy, MACE - use only if no suitable alternatives 6
• Smokers/former smokers: Higher risk of malignancy and MACE 3
• Cardiovascular risk factors: Increased MACE risk 3

Vedolizumab

Favorable Safety Profile:

• Gut-selective mechanism - lowest systemic immunosuppression 1, 6
• Progressive multifocal leukoencephalopathy (PML): Monitor for neurological symptoms (rare with other integrin antagonists) 1
• No increased infection risk compared to other biologics 1, 6

Contraindications:

• Active TB, sepsis, opportunistic infections including gut infections (C. difficile) 1

Ustekinumab (IL-12/23 Inhibitor)

Favorable Safety Profile:

• Lower infection risk compared to anti-TNF agents 6
• Theoretical risk: Serious infections from mycobacteria, salmonella, BCG vaccinations (based on genetic IL-12/23 deficiency data) 4

Specific Warnings:

• Posterior Reversible Encephalopathy Syndrome (PRES) - if suspected, discontinue immediately 4
• Noninfectious pneumonia - interstitial pneumonia, eosinophilic pneumonia, cryptogenic organizing pneumonia reported; discontinue if confirmed 4

Contraindications:

• Active TB, sepsis, opportunistic infections 1

Risankizumab (IL-23 Inhibitor)

Favorable Safety Profile:

• Similar to ustekinumab with selective IL-23 inhibition 6
• Lower infection and malignancy risk 6

Ozanimod (S1P Receptor Modulator)

Cardiac Precautions:

• First-dose monitoring required in specific populations 7
• Cardiac events - bradycardia, AV conduction delays 6, 7
• Macular edema - ophthalmologic evaluation if visual symptoms 6, 7

Monitoring:

• Baseline ECG and heart rate monitoring 7
• Ophthalmologic examination if visual changes 7

Management During Active Infections

General Principle

Do NOT stop or reduce IBD medications without discussing with the IBD team - risk of disease flare requiring steroids or hospitalization outweighs most infection concerns 8

Specific Infection Scenarios

Severe Infections:

• Stop biologic/small molecule therapy until infection resolves 1, 2, 3, 4
• Definition: Infections requiring hospitalization or IV antibiotics

Non-Severe Infections (e.g., upper respiratory tract infections, uncomplicated UTI):

• Continue therapy - no evidence of increased COVID-19 or routine infection risk with most agents 8
• Exception: Consider holding JAK inhibitors given higher infection risk 3

COVID-19 Specific Guidance:

• Continue biologics and small molecules during COVID-19 infection unless severe 8
• No current evidence of increased COVID-19 infection risk for any IBD biologic 8

Clostridium difficile Infection (CDI):

• Screen at every disease flare, especially in immunosuppressed patients 9
• Treat CDI appropriately; biologics contraindicated during active CDI 1
• Can resume after CDI treatment completion

Herpes Zoster:

• Particularly relevant for JAK inhibitors (highest risk) 3, 6, 7
• Treat infection; temporarily hold therapy during active infection
• Consider zoster vaccination before initiating JAK inhibitors 5

Key Clinical Pitfall

Immunosuppressive effects persist for weeks to months after stopping therapy - stopping medication during mild infections provides no immediate benefit but risks disease flare 8

Combination Therapy Considerations

Not Recommended:

• JAK inhibitors with other JAK inhibitors, biologic DMARDs, or potent immunosuppressants (azathioprine, cyclosporine) 3
• Multiple biologics simultaneously (except in refractory cases under specialist supervision) 10

Combination with Immunomodulators:

• Discuss risk-benefit carefully, especially in older patients (>60 years) 8
• Consider in biologic-naïve patients to reduce immunogenicity 1

Summary Algorithm for Active Infection Management

1. Assess infection severity:

   • Severe (hospitalization/IV antibiotics needed) → STOP biologic/small molecule
   • Non-severe (outpatient management) → CONTINUE therapy (except consider holding JAK inhibitors)

2. Specific infections requiring therapy cessation:

   • Active TB
   • Sepsis
   • Opportunistic infections (fungal, C. difficile, etc.)
   • Severe bacterial infections

3. Resume therapy when:

   • Infection clinically resolved
   • Appropriate antimicrobial course completed
   • Patient clinically stable

The risk of IBD flare from stopping therapy often exceeds the risk of continuing therapy during non-severe infections. 8