Residency · Residency · Gastroenterology

IBD Therapeutics - Biologics and Small Molecules

Treatment Paradigm Evolution

From Step-Up to Top-Down

The treatment paradigm for inflammatory bowel disease has undergone a fundamental shift from the traditional step-up approach, which progressed sequentially from 5-ASA to corticosteroids to immunomodulators and finally to biologics, toward a modern strategy that emphasizes risk stratification at diagnosis and early biologic therapy for moderate-to-severe and high-risk patients. The CALM trial demonstrated that tight control guided by biomarker-driven escalation using CRP and fecal calprotectin was superior to symptom-based management in achieving endoscopic and clinical endpoints. The REACT trial showed that early combined immunosuppression with infliximab and azathioprine reduced disease-related complications. These findings support the concept of a window of opportunity in which early intervention before irreversible structural damage, such as strictures and fistulae, can alter the natural history of the disease.

Treat-to-Target (STRIDE-II)

The STRIDE-II consensus establishes hierarchical treatment targets for both ulcerative colitis and Crohn disease. Clinical remission is defined as resolution of rectal bleeding and normalization of stool frequency in UC, and resolution of abdominal pain and diarrhea in CD. Biomarker normalization includes CRP below 5 mg/L and fecal calprotectin below 150 to 250 mcg/g. Endoscopic healing is defined as a Mayo endoscopic subscore of 0 to 1 in UC and absence of ulceration with SES-CD of 2 or less in CD. Long-term targets include histologic remission in UC, transmural healing in CD, absence of disability, and normal quality of life.

Anti-TNF Agents

Infliximab

Infliximab is a chimeric (mouse/human) IgG1 monoclonal antibody directed against TNF-alpha. The induction regimen consists of 5 mg/kg administered intravenously at weeks 0, 2, and 6, followed by maintenance dosing of 5 mg/kg every 8 weeks. The pivotal trials include ACT-1 and ACT-2 for ulcerative colitis, ACCENT I for Crohn disease maintenance, and ACCENT II for fistulizing Crohn disease. The landmark SONIC trial demonstrated that combination therapy with infliximab plus azathioprine was superior to either agent as monotherapy in Crohn disease, achieving steroid-free remission in 57% of patients compared to 44% with infliximab alone and 30% with azathioprine alone at week 26. The UC SUCCESS trial similarly demonstrated the superiority of combination infliximab and azathioprine over infliximab monotherapy in ulcerative colitis. Multiple biosimilars are available, including CT-P13 (Inflectra/Remsima), SB2 (Renflexis), and ABP 710 (Avsola), and switching from the originator product has been shown to be safe in the NOR-SWITCH trial.

Adalimumab

Adalimumab is a fully human IgG1 anti-TNF monoclonal antibody. The induction regimen is 160 mg subcutaneously at week 0 followed by 80 mg at week 2, with maintenance dosing of 40 mg every 2 weeks. The pivotal trials include CLASSIC I and II for Crohn disease, CHARM for Crohn disease maintenance, and ULTRA 1 and 2 for ulcerative colitis. Multiple biosimilars are available, including Hadlima, Hyrimoz, Cyltezo, and Amjevita.

Certolizumab Pegol

Certolizumab pegol is a PEGylated Fab' fragment of an anti-TNF antibody that lacks an Fc region. This structural distinction is clinically important because the absence of Fc-mediated transport means that certolizumab does not cross the placenta, making it the preferred anti-TNF agent in pregnancy planning. The induction regimen is 400 mg subcutaneously at weeks 0, 2, and 4, with maintenance of 400 mg every 4 weeks. It is approved for Crohn disease only, based on the PRECISE 1 and 2 trials.

Golimumab

Golimumab is a fully human IgG1 anti-TNF monoclonal antibody. Induction dosing is 200 mg subcutaneously at week 0 and 100 mg at week 2, with maintenance of 100 mg every 4 weeks for patients weighing more than 80 kg or 50 mg every 4 weeks for those weighing less than 80 kg. It is approved for ulcerative colitis only, based on the PURSUIT trials.

Anti-TNF Class Effects and Monitoring

Therapeutic drug monitoring is a cornerstone of anti-TNF management. Reactive TDM, in which levels are checked at the time of loss of response, is the established standard, while proactive TDM with routine monitoring is increasingly supported by evidence. Target trough levels for infliximab are 5 to 10 mcg/mL during maintenance and higher than 10 to 15 mcg/mL for perianal Crohn disease. Target trough levels for adalimumab are 7.5 to 12 mcg/mL. The TDM algorithm for loss of response involves four clinical scenarios: a low trough level without antibodies indicates pharmacokinetic failure and warrants dose optimization through increased dose or shortened interval; a low trough with low antibody titers indicates salvageable immunogenicity, managed by adding an immunomodulator and dose optimizing; a low or undetectable trough with high antibody titers indicates non-salvageable immunogenicity, warranting a switch to a different anti-TNF or a switch out of class; and an adequate trough level with loss of response indicates mechanistic failure, requiring a switch out of class entirely.

<image>A therapeutic drug monitoring (TDM) decision algorithm for anti-TNF therapy in IBD. Start at top with "Loss of response to anti-TNF." First step: "Check drug trough level and anti-drug antibodies (ADA)." Branch into four scenarios with corresponding actions: (1) "Adequate trough + no ADA" — labeled "Mechanistic failure" — action: "Switch out of class (vedolizumab, ustekinumab, IL-23 inhibitor, JAK inhibitor)"; (2) "Low trough + no ADA" — labeled "Pharmacokinetic failure" — action: "Dose optimize: increase dose or shorten interval"; (3) "Low trough + low ADA titer" — labeled "Immunogenic, salvageable" — action: "Add immunomodulator + dose optimize; recheck in 4-8 weeks"; (4) "Low/undetectable trough + high ADA titer" — labeled "Immunogenic, non-salvageable" — action: "Switch to different anti-TNF (within class) or switch out of class." Include target trough values in a reference box: infliximab 5-10 mcg/mL, adalimumab 7.5-12 mcg/mL. Use green arrows for dose optimization, blue for within-class switch, red for out-of-class switch. Include a note about proactive vs reactive TDM.</image>

Anti-TNF Safety Concerns

The safety profile of anti-TNF agents requires careful consideration across several domains. Serious infections are increased 2- to 3-fold, and tuberculosis screening with an IGRA or PPD is mandatory before initiation, with treatment of latent TB for at least 1 to 2 months before starting therapy. Opportunistic infections including histoplasmosis, coccidioidomycosis, listeriosis, and the rare but serious progressive multifocal leukoencephalopathy must be considered. Hepatitis B screening with HBsAg, anti-HBc, and anti-HBs is required, with antiviral prophylaxis for patients who are HBsAg-positive or have occult HBV (anti-HBc positive), given the risk of fatal reactivation. The malignancy risk includes hepatosplenic T-cell lymphoma, a rare but typically fatal condition occurring primarily in young males receiving combination anti-TNF and thiopurine therapy, as well as non-melanoma skin cancer (primarily attributed to thiopurines) and a modestly increased lymphoma risk. Anti-TNF agents are contraindicated in NYHA Class III-IV heart failure and demyelinating disease. A lupus-like syndrome with anti-dsDNA antibodies develops in 10 to 15% of patients, though clinical lupus is rare at less than 1%. Paradoxical psoriasiform skin lesions occur in 5 to 10% and may require drug discontinuation.

Anti-Integrin Therapy

Vedolizumab

Vedolizumab is a humanized IgG1 monoclonal antibody directed against alpha4-beta7 integrin. Its gut-selective mechanism blocks lymphocyte trafficking to the intestinal mucosa without affecting central nervous system trafficking, thereby eliminating the risk of progressive multifocal leukoencephalopathy that is associated with natalizumab. The induction regimen is 300 mg intravenously at weeks 0, 2, and 6, with maintenance of 300 mg intravenously every 8 weeks, or every 4 weeks for incomplete responders. A subcutaneous formulation at 108 mg every 2 weeks following intravenous induction is available based on the VISIBLE trials. The pivotal GEMINI trials demonstrated efficacy in both UC (GEMINI 1) and CD (GEMINI 2 and 3), with the drug generally being more effective in UC than CD and having a slower onset of action requiring 8 to 14 weeks for maximal effect. The safety profile is excellent, with no increased serious infection risk compared to placebo due to the gut-selective mechanism. TDM targets are emerging, with trough levels of 20 mcg/mL or higher at steady state associated with better outcomes.

Natalizumab

Natalizumab is an anti-alpha4 integrin antibody that blocks both alpha4-beta1 and alpha4-beta7, making it non-gut-selective. It is approved for Crohn disease based on the ENCORE and ENACT trials. However, its clinical use is severely limited by the risk of progressive multifocal leukoencephalopathy from JC virus reactivation, occurring in approximately 1 in 1,000 patients with prolonged use. It requires JCV antibody testing and enrollment in the TOUCH prescribing program. Natalizumab has been largely replaced by vedolizumab due to the PML risk.

Anti-IL-12/23 Therapy

Ustekinumab

Ustekinumab is a fully human IgG1 monoclonal antibody targeting the p40 subunit shared by IL-12 and IL-23. Induction is administered as a weight-based intravenous infusion: 260 mg for patients weighing 55 kg or less, 390 mg for those between 56 and 85 kg, and 520 mg for those above 85 kg. Maintenance dosing is 90 mg subcutaneously every 8 weeks or every 12 weeks. The pivotal trials include UNITI-1 and UNITI-2 plus IM-UNITI for Crohn disease and UNIFI for ulcerative colitis. The safety profile is favorable, with no increased serious infection risk. TDM target troughs are emerging, with levels above 4.5 mcg/mL associated with endoscopic remission.

Selective Anti-IL-23 Therapy (p19 subunit)

Risankizumab

Risankizumab is a humanized IgG1 monoclonal antibody targeting the IL-23 p19 subunit. The induction regimen is 600 mg intravenously at weeks 0, 4, and 8, with maintenance of 360 mg subcutaneously every 8 weeks. The pivotal ADVANCE, MOTIVATE, and FORTIFY trials established its efficacy in Crohn disease, with UC data (INSPIRE, COMMAND) emerging. It is approved for moderate-to-severe Crohn disease and has demonstrated high endoscopic remission rates with maintained efficacy in anti-TNF-experienced patients.

Guselkumab

Guselkumab is a fully human IgG1 anti-IL-23 p19 monoclonal antibody. Induction is 200 mg intravenously at weeks 0, 4, and 8, with maintenance of 100 mg subcutaneously every 8 weeks or 200 mg every 4 weeks. The GALAXI trial for Crohn disease and QUASAR trial for ulcerative colitis were both positive, and the drug is now approved for both indications.

Mirikizumab

Mirikizumab is a humanized IgG4 anti-IL-23 p19 monoclonal antibody. Induction consists of 300 mg intravenously every 4 weeks for 3 doses, with maintenance of 200 mg subcutaneously every 4 weeks. The pivotal LUCENT-1 and LUCENT-2 trials established efficacy in ulcerative colitis, while VIVID demonstrated positive data in Crohn disease. It is currently approved for UC.

JAK Inhibitors (Small Molecules)

Tofacitinib

Tofacitinib is a pan-JAK inhibitor with preferential activity at JAK1 over JAK3 and JAK2. The induction dose is 10 mg orally twice daily for 8 to 16 weeks, followed by maintenance at 5 mg twice daily or 10 mg twice daily as needed. It is approved for ulcerative colitis only, based on the OCTAVE trials. A key advantage is its rapid onset of action, measured in days to weeks. Safety concerns are dose-dependent and include herpes zoster (patients should be screened and vaccinated with Shingrix before initiation), venous thromboembolism, major adverse cardiovascular events (FDA boxed warning based on the ORAL Surveillance trial in rheumatoid arthritis patients over 50 with cardiovascular risk factors), malignancy (boxed warning), and lipid elevations. Tofacitinib is contraindicated in patients with active serious infection, severe hepatic impairment, and pregnancy.

Upadacitinib

Upadacitinib is a selective JAK1 inhibitor. The induction dose is 45 mg orally daily for 8 weeks, used for both UC and CD, with maintenance of 15 or 30 mg daily. The pivotal trials include U-ACHIEVE and U-ACCOMPLISH for UC and U-EXCEL, U-EXCEED, and U-ENDURE for CD. It is approved for both ulcerative colitis and Crohn disease. Its higher JAK1 selectivity may confer an improved safety profile compared to pan-JAK inhibition, though the same boxed warnings for VTE, MACE, malignancy, and infection apply. Herpes zoster risk necessitates Shingrix vaccination at least 2 to 4 weeks before initiation. Acne is a relatively common side effect, occurring in 10 to 15% of patients.

Filgotinib

Filgotinib is a selective JAK1 inhibitor approved in Europe and Japan for ulcerative colitis based on the SELECTION trial at a dose of 200 mg orally daily. It has not been approved in the United States, where the FDA requested additional safety data.

<image>A comparative mechanism of action diagram showing the major IBD drug classes and their targets in the inflammatory cascade. Central image: intestinal epithelium with underlying lamina propria showing immune cells. Illustrate the following pathways with drug intervention points: (1) TNF-alpha pathway: macrophage releasing TNF, blocked by infliximab/adalimumab/certolizumab/golimumab (red X marks). (2) Lymphocyte trafficking: T cell with alpha4-beta7 integrin approaching MAdCAM-1 on gut endothelium, blocked by vedolizumab (blue X). (3) IL-12/IL-23 pathway: dendritic cell releasing IL-12 (p40+p35) and IL-23 (p40+p19), with ustekinumab blocking p40 (green X) and risankizumab/guselkumab/mirikizumab blocking p19 specifically (purple X). Show downstream Th1 (from IL-12) and Th17 (from IL-23) differentiation. (4) JAK-STAT pathway inside a T cell: cytokine receptor activating JAK1/JAK2/JAK3/TYK2, with tofacitinib blocking pan-JAK (orange X) and upadacitinib selectively blocking JAK1 (yellow X). (5) S1P receptor on lymphocyte: ozanimod/etrasimod blocking S1P1 receptor, preventing lymphocyte egress from lymph node (pink X). Label all drug names next to their targets. Use a clean, educational style with pastel colors for different cell types and bold colors for drug intervention points.</image>

S1P Receptor Modulators

Ozanimod

Ozanimod modulates the S1P1 and S1P5 receptors. It requires a dose titration over 7 days, starting with 0.23 mg on days 1 through 4, increasing to 0.46 mg on days 5 through 7, and reaching the maintenance dose of 0.92 mg daily thereafter. It is approved for ulcerative colitis based on the TRUE NORTH trial, with investigation ongoing for Crohn disease. The mechanism of action involves sequestering lymphocytes within lymph nodes, thereby reducing gut-homing inflammatory cells. The safety profile includes specific considerations: first-dose cardiac monitoring is not required (unlike fingolimod), but macular edema necessitates ophthalmologic examination at baseline and at 3 to 4 months, bradycardia risk precludes use with beta-blockers, calcium channel blockers, or Class Ia/III antiarrhythmics, hepatotoxicity requires liver function test monitoring, and lymphopenia is an expected pharmacologic effect. Contraindications include recent myocardial infarction, unstable angina, stroke or TIA within 6 months, Mobitz type II or higher atrioventricular block, and severe hepatic impairment. An ECG must be checked before initiation.

Etrasimod

Etrasimod modulates S1P1, S1P4, and S1P5 receptors. It is administered at 2 mg orally daily without the need for dose titration. It is approved for ulcerative colitis based on the ELEVATE UC-52 and ELEVATE UC-12 trials. The safety profile is similar to ozanimod, with first-dose cardiac monitoring recommended for patients with certain cardiac conditions.

Immunomodulators

Thiopurines (Azathioprine, 6-Mercaptopurine)

Azathioprine is dosed at 2 to 2.5 mg/kg/day and 6-mercaptopurine at 1 to 1.5 mg/kg/day. These agents have a slow onset of action of 3 to 6 months and are not appropriate for induction therapy. TPMT and NUDT15 genotyping is mandatory before initiation. Heterozygous TPMT carriers require a 50% dose reduction, while homozygous TPMT-deficient patients must never receive thiopurines due to the risk of severe myelosuppression. NUDT15 variants are especially relevant in East Asian populations. Metabolite monitoring targets a 6-TGN level of 230 to 400 pmol per 8 times 10 to the eighth red blood cells, while 6-MMP levels above 5,700 are associated with hepatotoxicity. For metabolic shunters who produce high 6-MMP and low 6-TGN, allopurinol co-therapy at 100 mg daily combined with a reduced thiopurine dose (25 to 33% of standard) can redirect metabolism toward the therapeutic 6-TGN pathway.

Side effects include myelosuppression, hepatotoxicity, pancreatitis (idiosyncratic, occurring in 3 to 7%), nausea, and infections. The malignancy risk encompasses lymphoma (absolute risk low at 5 per 10,000 patient-years), non-melanoma skin cancer (mandating sun protection counseling), and cervical dysplasia (requiring HPV screening). The risk of hepatosplenic T-cell lymphoma, primarily affecting young males on combination anti-TNF and thiopurine therapy, has led some clinicians to favor methotrexate as an alternative immunomodulator in this population.

Methotrexate

Methotrexate is administered at 25 mg subcutaneously or intramuscularly weekly for induction over 16 to 25 weeks, followed by maintenance at 15 mg subcutaneously weekly. The subcutaneous route is preferred over oral due to variable oral bioavailability. Folic acid supplementation at 1 mg daily (except on methotrexate day) or leucovorin is given concurrently. The METEOR trial was negative for methotrexate in Crohn disease, though it was possibly underpowered. Methotrexate is more commonly used as a combination therapy partner with anti-TNF agents to reduce immunogenicity. Side effects include hepatotoxicity (with particular caution in patients who use alcohol or have obesity or diabetes, due to the risk of methotrexate-related steatohepatitis and fibrosis), myelosuppression, and pneumonitis. Methotrexate is absolutely contraindicated in pregnancy and requires a washout period of 3 to 6 months before conception for both sexes.

Positioning and Sequencing

First-Line Biologic Selection Considerations

The choice of first-line biologic agent requires consideration of multiple factors. Anti-TNF agents offer the longest track record and most extensive data and are preferred for fistulizing Crohn disease and acute severe UC rescue, with the risk of immunogenicity mitigated by combination therapy. Vedolizumab offers an excellent safety profile, is more effective in UC than CD, has a slower onset, and is preferred for older patients, those prone to infection, or those with a malignancy history. IL-23 inhibitors are increasingly used as first-line agents, demonstrating high efficacy in both anti-TNF-naive and experienced patients with an excellent safety profile, and are particularly favored in Crohn disease. JAK inhibitors provide rapid onset and oral convenience and are useful for anti-TNF failures, but safety concerns regarding VTE and MACE limit first-line use in some patient populations. S1P receptor modulators offer oral administration and a good safety profile with moderate efficacy, currently approved for UC only.

Combination Therapy Considerations

Combination therapy with an immunomodulator is best established for anti-TNF agents, supported by the SONIC and UC SUCCESS trials. Vedolizumab is generally used as monotherapy, with limited data supporting combination with an immunomodulator. IL-23 inhibitors are typically used as monotherapy given their low immunogenicity. JAK inhibitors and S1P modulators are small molecules used as monotherapy.

Advanced Combination Therapy (Dual Biologic/Targeted Therapy)

Advanced combination therapy using two biologic or targeted agents is an emerging approach for refractory patients. Studied combinations include vedolizumab plus anti-TNF, vedolizumab plus tofacitinib, and vedolizumab plus ustekinumab, supported by case series and small studies. The VEGA trial demonstrated that the combination of guselkumab plus golimumab was superior to either agent alone for UC induction. Safety data for dual targeted therapy remain limited, and intensive infection monitoring is essential.

Special Populations

Pregnancy

Most biologics are IgG1 antibodies that cross the placenta during the third trimester via active FcRn-mediated transport. Certolizumab, which lacks an Fc region, does not cross the placenta and is preferred when initiating biologic therapy periconceptionally. For patients on infliximab or adalimumab who are in stable remission, the last dose is generally administered at weeks 30 to 32 with resumption postpartum. Thiopurines are continued during pregnancy, as their benefits outweigh their risks as a low-risk teratogen. Methotrexate is absolutely contraindicated and must be stopped 3 to 6 months before conception. Tofacitinib and upadacitinib are contraindicated in pregnancy. The overarching principle is that active disease during pregnancy poses a greater risk to both mother and fetus than the medications used to control it.

Vaccinations

All vaccinations should ideally be completed before starting immunosuppression. Live vaccines are contraindicated in patients on biologics or immunomodulators, including MMR, varicella, live zoster (Zostavax), yellow fever, oral typhoid, and BCG. Shingrix (recombinant, non-live) is safe and recommended, particularly before JAK inhibitor initiation. Annual influenza and COVID-19 vaccination, pneumococcal vaccination (PCV20 or PCV15 plus PPSV23), and hepatitis B vaccination for non-immune patients are all recommended. Infants exposed to biologics in utero should avoid live vaccines for the first 6 to 12 months of life.

Key Clinical Pearls

• SONIC trial: combination infliximab + azathioprine is superior to either monotherapy for CD — informs combination therapy decisions
• Therapeutic drug monitoring is essential for anti-TNF agents — adequate trough with loss of response indicates mechanistic failure requiring class switch
• IL-23 selective inhibitors (risankizumab, guselkumab, mirikizumab) represent the most rapidly growing class with excellent efficacy and safety profiles
• JAK inhibitors offer rapid onset (days) and oral convenience but carry boxed warnings for VTE/MACE/malignancy — risk-benefit discussion essential
• Certolizumab pegol does not cross the placenta — preferred anti-TNF agent in pregnancy planning
• TPMT/NUDT15 genotyping is mandatory before starting thiopurines — homozygous deficient patients should NEVER receive thiopurines
• Shingrix vaccination should be administered before JAK inhibitor initiation due to high herpes zoster risk
• Dual biologic/targeted therapy is emerging for refractory IBD — VEGA trial supports guselkumab + golimumab in UC

References

1. Feuerstein JD, et al. AGA Clinical Practice Guidelines on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn's Disease. Gastroenterology. 2021;160(7):2496-2508.
2. Colombel JF, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease (SONIC). N Engl J Med. 2010;362(15):1383-1395.
3. Sandborn WJ, et al. Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA). Lancet Gastroenterol Hepatol. 2023;8(4):307-320.
4. Papamichael K, et al. Role of therapeutic drug monitoring in inflammatory bowel diseases: an AGA clinical practice update. Gastroenterology. 2024.
5. Mahadevan U, et al. Inflammatory Bowel Disease in Pregnancy Clinical Care Pathway: A Report from the American Gastroenterological Association IBD Parenthood Project Working Group. Gastroenterology. 2019;156(5):1508-1524.

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