GI Pharmacology · Module 4 of 8

IBD Pharmacology Part 2: Biologics and Small Molecules

Anti-TNF biologics · JAK inhibitors · Gut-selective biologics · Therapeutic drug monitoring

Four anti-TNF biologics for IBD differ in structure and indications: infliximab (chimeric IgG1, IV, most immunogenic, most clinical data, biosimilars available); adalimumab (fully human IgG1, SC q2wk, lower immunogenicity, biosimilars); certolizumab (PEGylated Fab’, no Fc → no placental transfer → preferred in pregnancy, CD only in most markets); golimumab (fully human IgG1, SC monthly, UC only); combining anti-TNF + azathioprine (as in SONIC trial) reduces anti-drug antibody formation and improves outcomes but increases infection risk and rare hepatosplenic T-cell lymphoma risk in young males.
Pre-biologic screening mandatory before every anti-TNF start: TB (TST or IGRA + CXR) — treat latent TB ≥4 weeks before starting; hepatitis B (HBsAg + anti-HBc + anti-HBs) — surface antigen-positive patients need antiviral prophylaxis; hepatitis C; varicella immunity; update all vaccines before starting (live vaccines contraindicated once biologic is active); document in medical record.
Vedolizumab (anti-alpha-4-beta-7 integrin): gut-selective — blocks gut-homing lymphocyte trafficking without affecting systemic immunity; no TB screening required; no increase in systemic serious infections; preferred in elderly and high-infection-risk patients; slower onset in CD (response by week 10–14); approved for both UC and CD. Ustekinumab (anti-p40, blocks IL-12 + IL-23): excellent safety profile, no TB reactivation risk; IV induction then SC q8–12wk maintenance; approved UC and CD; effective for extraintestinal manifestations. Risankizumab (anti-IL-23 p19 selective): spares IL-12 → preserves antiviral/antimycobacterial immunity; IV induction then SC q8wk; approved UC and CD.
JAK inhibitors (tofacitinib JAK1/3, upadacitinib JAK1-selective): oral, rapid onset within days, no immunogenicity; 2022 FDA black box warning (MACE, VTE, malignancy) — use only after inadequate response to TNF inhibitor; avoid in age ≥50 with CV risk factors, active malignancy, prior VTE; vaccinate against herpes zoster before starting; monitor LDL (mild elevation occurs); upadacitinib approved for both UC and CD.
Loss of response to anti-TNF — measure trough and anti-drug antibodies (ADA) before deciding: low trough + low ADA (pharmacokinetic failure) → dose escalate; low trough + high ADA (immunogenic failure) → switch anti-TNF or switch class; adequate trough + loss of response (pharmacodynamic failure) → switch class, do not dose escalate; primary non-response (no benefit within 8–14 weeks) → switch class; certolizumab preferred in pregnancy (no placental Fc transport); infants born after maternal infliximab/adalimumab after week 22 should not receive live vaccines until 6 months of age.

ADA = anti-drug antibody · CD = Crohn’s disease · CXR = chest X-ray · HBsAg = hepatitis B surface antigen · IBD = inflammatory bowel disease · IGRA = interferon-gamma release assay · IL = interleukin · JAK = Janus kinase · MACE = major adverse cardiovascular events · MAdCAM-1 = mucosal addressin cell adhesion molecule-1 · TDM = therapeutic drug monitoring · TNF = tumor necrosis factor · TST = tuberculin skin test · UC = ulcerative colitis · VTE = venous thromboembolism

Anti-Tumor Necrosis Factor Biologics

Agent	Structure	Route	Key Advantage	Key Consideration
Infliximab	Chimeric IgG1 (25% murine)	IV q8wk	Most clinical trial data; biosimilars widely available and equivalent	Most immunogenic of the class; anti-drug antibodies form against murine component; primary mechanism of secondary loss of response
Adalimumab	Fully human IgG1	SC q2wk	Self-injection; lower immunogenicity than infliximab; biosimilars available	Anti-drug antibodies still form; co-immunosuppression with thiopurine reduces ADA
Certolizumab	PEGylated Fab’ — no Fc region	SC monthly	No placental transfer (no neonatal Fc receptor transport) — preferred in pregnancy; approved for CD	Approved for CD only (not UC) in most markets
Golimumab	Fully human IgG1	SC monthly	Monthly maintenance dosing; convenient	Approved for UC only (not CD)

Gut-Selective and IL-23 Targeted Biologics

Vedolizumab

Alpha-4-Beta-7 Integrin Blocker

Blocks alpha-4-beta-7 integrin on gut-homing lymphocytes → prevents binding to MAdCAM-1 on intestinal vascular endothelium → blocks mucosal trafficking
Gut-selective: systemic immunity preserved; no TB screening required; no increase in systemic serious infections vs. IBD baseline
Preferred in elderly and high-infection-risk patients
Slower onset in CD (response by weeks 10–14); does not treat extraintestinal manifestations reliably
Approved: UC and CD; IV induction then SC or IV maintenance

Ustekinumab

Anti-IL-12/23 p40

Blocks p40 subunit shared by IL-12 (Th1 → IFN-γ) and IL-23 (Th17 → IL-17/IL-22) → suppresses both mucosal inflammatory pathways
IV weight-based induction; SC maintenance q8–12 weeks
Excellent safety profile; no TB reactivation risk; infection profile comparable to vedolizumab
Effective for extraintestinal manifestations (arthritis, skin)
Approved: UC and CD; biosimilar available

Risankizumab

Selective Anti-IL-23 p19

Blocks IL-23 p19 only — spares IL-12; rationale: IL-23/Th17 is dominant IBD pathway; IL-12-dependent antiviral and antimycobacterial immunity preserved
IV induction (weeks 0, 4, 8) then SC maintenance q8wk
Favorable infection and malignancy profile; no unexpected safety signals in trials
Approved: UC and CD

JAK Inhibitors in IBD

Advantages Over Biologics

Oral, Rapid, Non-Immunogenic

Oral bioavailability — no injection or IV infusion required
Rapid onset: measurable clinical response within days (vs. weeks for biologics)
No immunogenicity — not foreign proteins; no anti-drug antibodies
Tofacitinib (JAK1/3): approved for moderate-severe UC
Upadacitinib (selective JAK1): approved for UC and CD; superior or comparable to adalimumab in trials

2022 FDA Black Box Warning

MACE, VTE, Malignancy

Use only after inadequate response or intolerance to at least one TNF inhibitor
Avoid in age ≥50 with cardiovascular risk factors, active malignancy, or prior VTE when alternatives exist
Vaccinate against herpes zoster before starting (Shingrix) — zoster reactivation rate higher than with biologics
Monitor LDL: mild elevation occurs; manage per CV risk reduction principles
Screen for TB and HBV as for all immunosuppressants before starting

Loss of Response: Use TDM to Guide Next Step

Mechanism	Trough Level	Anti-Drug Antibodies	Management
Pharmacokinetic failure	Low	Low / absent	Dose-escalate or shorten dosing interval
Immunogenic failure	Low	High	Switch to different anti-TNF agent or switch biologic class; adding thiopurine does not reliably reverse established immunogenicity
Pharmacodynamic failure	Adequate	Low / absent	Switch biologic class — TNF is no longer the dominant driver; do NOT dose-escalate
Primary non-response	Any	Any	Switch biologic class immediately — do not dose-escalate the failing agent

Pre-Biologic Screening — All Anti-TNF Agents

TB screening (TST or IGRA + chest X-ray) is mandatory before every anti-TNF start; TNF is essential for granuloma integrity and its neutralization releases viable mycobacteria from quiescent granulomas. Latent TB must be treated for at least 4 weeks before starting the biologic, with the full 9-month course continued concurrently. Hepatitis B serology (HBsAg + anti-HBc + anti-HBs) is mandatory; surface antigen-positive patients require antiviral prophylaxis (entecavir or tenofovir) before and throughout therapy. Screen for hepatitis C. Confirm varicella immunity and vaccinate before starting if non-immune (live vaccine contraindicated once biologic is active). Update all recommended vaccines before initiation. Document all screening in the medical record at each biologic start.

Suggested References

Author / Source	Title	Publication
Katzung BG, ed.	Basic and Clinical Pharmacology, 15th ed. — Chapter on Gastrointestinal Pharmacology	McGraw-Hill; 2021
Brunton L, Knollmann B, Hilal-Dandan R, eds.	Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14th ed.	McGraw-Hill; 2023
Colombel JF et al.	Infliximab, azathioprine, or combination therapy for Crohn’s disease (SONIC trial)	N Engl J Med. 2010;362(15):1383–1395
Rahier JF et al.	Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in IBD	J Crohns Colitis. 2014;8(6):443–468
Ytterberg SR et al.	Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis (ORAL Surveillance)	N Engl J Med. 2022;386(4):316–326
Feagan BG et al.	Vedolizumab as induction and maintenance therapy for ulcerative colitis	N Engl J Med. 2013;369(8):699–710
Feagan BG et al.	Ustekinumab as induction and maintenance therapy for Crohn’s disease	N Engl J Med. 2016;375(20):1946–1960
D’Haens G et al.	Risankizumab as induction therapy for Crohn’s disease (ADVANCE and MOTIVATE)	Lancet. 2022;399(10340):2015–2030
Papamichael K et al.	Therapeutic drug monitoring of biologics in inflammatory bowel disease: unmet needs and future perspectives	Lancet Gastroenterol Hepatol. 2022;7(2):171–185
Lichtenstein GR et al.	ACG clinical guideline: management of Crohn’s disease in adults	Am J Gastroenterol. 2018;113(4):481–517