Crohn's Disease: GALAXI, GRAVITI & FORTIFY

Breaking trial data reshaping IBD management

Gastroenterology · Seminar week 6 · released April 27, 2026 · includes a discussion video

Three landmark trials, one disease. How guselkumab and the IL-23 pathway are challenging anti-TNF dominance in Crohn's disease management.

Learning Objectives

1. Analyze the long-term efficacy and safety of guselkumab and risankizumab for moderate-to-severe Crohn's disease using data from the GALAXI, GRAVITI, and FORTIFY trials
2. Differentiate between IL-23p19-selective inhibitors and IL-12/23p40 inhibitors in mechanism of action, dosing protocols, and clinical outcomes
3. Evaluate real-world treatment persistence, healthcare utilization, and comparative effectiveness among biologic therapies for Crohn's disease
4. Interpret induction and maintenance trial data to guide clinical decision-making in biologic-naive and biologic-experienced patients
5. Apply evidence-based treatment algorithms integrating the latest trial data into the management of refractory Crohn's disease

Section 1: Introduction — The IL-23 Revolution in Crohn's Disease

Duration: 10 min | Content Tier: Teaching Point

%%FIG0%% Crohn's disease affects approximately 3 million adults in the United States, with incidence continuing to rise globally (PMID: 37156006). It is a chronic, relapsing inflammatory bowel disease characterized by transmural inflammation that can affect any segment of the gastrointestinal tract. The morbidity is substantial: roughly 50% of patients will require surgery within 10 years of diagnosis, and the disease imposes enormous costs on healthcare systems and quality of life.

Teaching Point: The therapeutic landscape for Crohn's disease has undergone a dramatic transformation over the past two decades. We have moved from a world where corticosteroids and immunomodulators were the mainstay of treatment to one where targeted biologics dominate moderate-to-severe disease management. TNF inhibitors — infliximab, adalimumab, certolizumab — were the first wave, arriving in the late 1990s and early 2000s. The second wave brought the IL-12/23 inhibitor ustekinumab, which targets the shared p40 subunit of IL-12 and IL-23. And now we are in the third wave: selective IL-23p19 inhibitors that target only the p19 subunit unique to IL-23 (PMID: 37751585).

Why does this distinction matter? IL-12 drives Th1 responses and is important for host defence against intracellular pathogens and tumour surveillance. IL-23, by contrast, drives Th17 pathways and is the dominant cytokine in the pathogenesis of Crohn's disease. By selectively blocking IL-23 while preserving IL-12 signalling, p19-selective agents offer a theoretical advantage: potent anti-inflammatory activity with a potentially cleaner safety profile (PMID: 36631182).

Say Out Loud: "We are no longer choosing between TNF inhibitors and ustekinumab. The IL-23p19 agents — risankizumab and guselkumab — have arrived, and the trial data is changing how we sequence therapy."

Two drugs are at the centre of this revolution: risankizumab (Skyrizi), approved for Crohn's disease, and guselkumab (Tremfya), with pivotal Phase III data now available. Tonight we will dissect three landmark trials: GALAXI, GRAVITI, and FORTIFY.

Audience Poll: Which biologic class are you most comfortable prescribing for moderate-to-severe Crohn's disease?

• A) TNF inhibitors (infliximab, adalimumab)
• B) IL-12/23 inhibitor (ustekinumab)
• C) IL-23p19 inhibitors (risankizumab, guselkumab)
• D) Integrin inhibitor (vedolizumab)

Section 2: The IL-23 Pathway — Why Selectivity Matters

Duration: 8 min | Content Tier: MUST ACT

%%FIG1%% MUST ACT: Understanding the IL-23/IL-12 distinction is not merely academic — it directly informs drug selection and counselling. Every clinician managing Crohn's patients needs to explain why a p19-selective agent differs from ustekinumab.

The Biology

IL-23 is a heterodimeric cytokine composed of two subunits: p19 (unique to IL-23) and p40 (shared with IL-12). IL-23 binds to its receptor on Th17 cells, innate lymphoid cells, and gamma-delta T cells, driving the production of IL-17, IL-22, TNF, and other pro-inflammatory mediators. This pathway is central to the chronic mucosal inflammation that characterises Crohn's disease (PMID: 36631182).

IL-12, by contrast, shares the p40 subunit but pairs it with p35. The IL-12 receptor complex signals through STAT4 to promote Th1 differentiation and IFN-gamma production — critical for defence against intracellular pathogens (mycobacteria, Salmonella) and tumour immune surveillance.

Teaching Point: Ustekinumab blocks p40, thereby inhibiting both IL-12 and IL-23. Risankizumab and guselkumab block only p19, inhibiting IL-23 while leaving IL-12 intact. Genome-wide association studies have identified IL-23R polymorphisms as among the strongest genetic risk factors for Crohn's disease, reinforcing the primacy of the IL-23 axis in disease pathogenesis (PMID: 37751585).

Decision Point: Does selective IL-23 blockade translate into better clinical outcomes compared to dual IL-12/23 blockade? The answer from GALAXI is yes — guselkumab achieved numerically higher rates of clinical remission than ustekinumab at both 12 and 48 weeks, with the ustekinumab arm included as a reference (PMID: 37751585). While not powered for direct comparison, these data are provocative and clinically relevant.

Nuance: One important consideration: blocking IL-12 could theoretically impair host defence against intracellular infections and affect tumour surveillance. In practice, the safety profiles of ustekinumab and the p19-selective agents have been reassuringly similar in trials. However, the theoretical advantage of preserving IL-12 may become more relevant in long-term real-world use, particularly in immunocompromised or elderly patients.

Section 3: The GALAXI Trial — Guselkumab for Crohn's Disease

Duration: 15 min | Content Tier: MUST ACT

%%FIG2%% MUST ACT: The GALAXI programme is the pivotal trial programme for guselkumab in Crohn's disease. Every gastroenterologist needs to know these results because guselkumab represents a new treatment option with a distinct dosing strategy.

Trial Design — GALAXI 1

GALAXI 1 was a Phase II/III, randomised, double-blind, placebo-controlled, active-comparator (ustekinumab) trial in adults with moderately to severely active Crohn's disease defined by a Crohn's Disease Activity Index (CDAI) of 220-450 and endoscopic evidence of active inflammation (Simple Endoscopic Score for Crohn's Disease [SES-CD] >= 6) (PMID: 37751585).

Patients were randomised to one of four guselkumab induction regimens, ustekinumab (as active reference), or placebo:

• Guselkumab 200 mg IV at weeks 0, 4, 8
• Guselkumab 600 mg IV at weeks 0, 4, 8
• Guselkumab 1200 mg IV at weeks 0, 4, 8
• Guselkumab 200 mg IV + 100 mg SC combination dosing
• Ustekinumab standard dosing (active reference arm)
• Placebo

Approximately 43% of patients had prior biologic failure, making this a mixed population of biologic-naive and biologic-experienced patients.

Key Results — Induction (Week 12)

The primary endpoint was clinical response (CDAI decrease >= 100 points) at week 12:

All guselkumab doses were superior to placebo (p<0.001). Notably, the 200 mg IV dose showed numerical superiority over ustekinumab for clinical remission (44.4% vs 42.4%), and the higher doses demonstrated dose-dependent improvements.

Teaching Point: The dose-response relationship was clear — higher induction doses yielded better outcomes. This led to the selection of higher intravenous doses for Phase III and informed the subsequently approved induction regimen. The inclusion of ustekinumab as an active reference was particularly valuable, allowing indirect benchmarking within the same trial population.

Maintenance Phase — Through Week 48

After 12-week induction, responders were re-randomised to maintenance with guselkumab 100 mg SC or 200 mg SC every 4 or 8 weeks. At week 48:

• Clinical remission rates ranged from 55-65% across guselkumab maintenance arms
• Endoscopic response was sustained or improved in the majority of responders
• Ustekinumab reference arm: clinical remission ~48%

Say Out Loud: "GALAXI tells us two critical things: first, guselkumab works — robustly — for Crohn's disease. Second, it appears to perform at least as well as, and possibly better than, ustekinumab. That changes the treatment algorithm."

Audience Poll: A patient with moderate-to-severe Crohn's disease has failed adalimumab. Based on GALAXI data, what would be your preferred next step?

• A) Switch to another TNF inhibitor
• B) Start ustekinumab
• C) Start guselkumab
• D) Start vedolizumab

Section 4: The GRAVITI Trial — Subcutaneous Induction with Guselkumab

Duration: 10 min | Content Tier: Teaching Point

Teaching Point: While GALAXI evaluated intravenous induction, the GRAVITI trial addressed a practical clinical question: can guselkumab be given subcutaneously for induction, improving convenience and potentially enabling outpatient initiation?

GRAVITI Design

GRAVITI was a Phase III, randomised, double-blind trial comparing subcutaneous guselkumab induction regimens in adults with moderately to severely active Crohn's disease. The trial evaluated:

• Guselkumab 400 mg SC at weeks 0, 4, 8 (higher SC dose to achieve comparable exposure to IV dosing)
• Guselkumab 200 mg SC at weeks 0, 4, 8
• Placebo

The patient population was similar to GALAXI: CDAI 220-450, endoscopic evidence of active disease, with a substantial proportion having prior biologic exposure.

Results

The primary endpoint of clinical response at week 12 was met:

• Guselkumab 400 mg SC achieved clinical remission rates comparable to the IV induction arms in GALAXI
• Both SC doses were superior to placebo (p<0.001)
• Endoscopic improvement rates mirrored those seen with IV induction at the higher SC dose

Nuance: The clinical significance of GRAVITI lies not in demonstrating a novel mechanism but in validating a subcutaneous route for induction. This has practical implications: SC induction can be performed in outpatient settings, avoids the need for infusion centres, and may improve access for patients in community practice settings. In an era where healthcare systems are under pressure to reduce infusion suite capacity, a fully subcutaneous regimen is a major logistical advantage.

Decision Point: When would you choose SC versus IV induction? Consider IV induction when you want rapid drug exposure in a severely ill patient (e.g., hospitalised, failing corticosteroids). Choose SC induction when outpatient initiation is preferred, when infusion access is limited, or when patient preference favours self-injection. The key principle: the higher SC doses appear to achieve comparable efficacy to IV, so this is a conversation about convenience, not about sacrificing outcomes.

Section 5: The FORTIFY Trial — Long-Term Risankizumab Efficacy

Duration: 12 min | Content Tier: MUST ACT

%%FIG3%% MUST ACT: The FORTIFY study provides the longest-term data we have for any IL-23 inhibitor in Crohn's disease. Understanding these results is critical because Crohn's disease is a lifelong illness, and patients need assurance that their medication will continue to work years, not just months, into the future.

Background

Risankizumab (Skyrizi) was approved for moderate-to-severe Crohn's disease based on the ADVANCE, MOTIVATE (induction), and FORTIFY (maintenance) trials. The FORTIFY long-term extension (LTE) has now reported data through 276 weeks — over five years of continuous follow-up (PMID: 38778769).

FORTIFY Design

FORTIFY enrolled patients who achieved clinical response to risankizumab induction (600 mg IV at weeks 0, 4, 8) in the ADVANCE or MOTIVATE trials. Responders at week 12 were re-randomised to:

• Risankizumab 180 mg SC every 8 weeks
• Risankizumab 360 mg SC every 8 weeks
• Placebo (withdrawal)

The primary endpoint was clinical remission (CDAI < 150) at week 52. The LTE continued risankizumab through week 276.

Key Results

52-Week Maintenance (FORTIFY Core):

Both risankizumab doses were superior to withdrawal (p<0.001 for endoscopic endpoints).

Long-Term Extension Through 276 Weeks (PMID: 38778769):

• Clinical remission was sustained in approximately 80% of patients who continued risankizumab
• Endoscopic response was maintained or improved in the majority
• Deep remission (clinical remission + endoscopic remission) was achieved by approximately 47% of patients at the latest assessment
• No new safety signals emerged through 276 weeks of exposure
• The safety profile remained consistent with earlier reports, with low rates of serious infections

Teaching Point: The FORTIFY LTE is transformative because it demonstrates something clinicians and patients desperately need: durability. In a disease where loss of response is the rule with many biologics — approximately 30-40% of TNF inhibitor responders lose response within 12 months — seeing sustained efficacy over five years is remarkable. The rate of deep remission (clinical + endoscopic) remaining stable is particularly important, as mucosal healing is associated with reduced hospitalisation, surgery, and long-term disability (PMID: 38778769).

Say Out Loud: "When a patient asks me 'will this drug still be working in five years?', FORTIFY gives me the data to say 'based on what we've seen in over five years of follow-up, the answer is very likely yes.' That is a conversation we couldn't have had with this level of evidence even three years ago."

Safety Through 276 Weeks

The safety data from FORTIFY LTE deserves specific attention:

• Serious infections: The rate remained low and stable over time, with no increase in opportunistic infections
• Malignancy: Rates were consistent with the background population risk for Crohn's disease patients
• Hepatic safety: No signal for hepatotoxicity
• Injection site reactions: Mild and infrequent with SC administration
• Upper respiratory tract infections and headache were the most common adverse events, consistent with the induction trial data

Nuance: One limitation of long-term extension data is the inherent selection bias — patients who continue in LTE studies are those who responded initially and tolerated the drug. Patients who failed or experienced adverse events are not captured. Real-world registries will be essential to complement these findings and provide effectiveness data in broader populations.

Audience Poll: How long does a biologic need to demonstrate sustained efficacy before you feel confident recommending it for long-term use?

• A) 1 year
• B) 2 years
• C) 3-5 years
• D) I want lifetime data

Section 6: Comparative Analysis — Positioning IL-23 Inhibitors in the Treatment Algorithm

Duration: 10 min | Content Tier: Teaching Point

%%FIG4%% Teaching Point: With three classes of advanced therapies now available — TNF inhibitors, IL-12/23 inhibitors, integrin inhibitors, and IL-23p19 inhibitors — the question is no longer "should I use a biologic?" but "which biologic, and when?"

Head-to-Head and Network Meta-Analysis Data

No large head-to-head trials comparing IL-23 inhibitors to TNF inhibitors have been completed. However, network meta-analyses and indirect comparisons provide useful guidance:

• IL-23 inhibitors (risankizumab, guselkumab) show comparable or superior endoscopic outcomes to TNF inhibitors in biologic-experienced populations
• In biologic-naive patients, TNF inhibitors (particularly infliximab) remain highly effective for induction, though IL-23 inhibitors are emerging as alternatives
• Real-world data suggest superior treatment persistence with risankizumab compared to adalimumab and ustekinumab in some registries (PMID: 37156006)
• Healthcare utilisation data show reduced emergency department visits and hospitalisations among patients on IL-23 inhibitors compared to historical TNF inhibitor cohorts

The Emerging Treatment Paradigm

Decision Point: How should we position these agents?

Nuance: The question of whether IL-23 inhibitors should be used first-line (before TNF inhibitors) in biologic-naive patients is one of the most active debates in IBD. Proponents argue that IL-23 inhibitors have superior durability and safety, which should matter more than marginally higher short-term response rates with TNF inhibitors. Opponents note the decades of real-world experience with TNF inhibitors, their proven efficacy in fistulizing disease, and cost considerations. The answer may ultimately depend on patient-specific factors: age, comorbidities, disease phenotype, and payer access.

Audience Poll: In a 28-year-old newly diagnosed with moderate-to-severe ileocolonic Crohn's disease (biologic-naive), what would be your first-line advanced therapy?

• A) Infliximab
• B) Adalimumab
• C) Risankizumab
• D) Vedolizumab

Clinical Cases

Case 1: The Biologic-Naive Young Adult — Choosing a First-Line Agent

Presentation: A 24-year-old male university student presents with 6 months of worsening abdominal pain, bloody diarrhoea (6-8 stools/day), weight loss of 8 kg, and fatigue. Colonoscopy reveals deep serpiginous ulceration in the terminal ileum and ascending colon with skip lesions. SES-CD score is 14. MR enterography shows mural thickening and enhancement in the terminal ileum without stricture or fistula. CRP is 42 mg/L, faecal calprotectin > 1800 mcg/g. He is started on budesonide for bridging but clearly needs advanced therapy. He works part-time and wants minimal disruption to his schedule.

Decision Point: What biologic should we choose for this biologic-naive patient?

The traditional answer would be a TNF inhibitor — infliximab has decades of data and strong efficacy in induction. However, this patient has several features that make an IL-23 inhibitor attractive:

• He is young and will need decades of therapy — durability matters
• He has inflammatory (non-fistulising, non-stricturing) disease — the phenotype where IL-23 inhibitors perform best
• He values convenience — SC self-injection every 8 weeks is more compatible with his lifestyle than infusion-centre visits

Based on GALAXI and FORTIFY data, either guselkumab or risankizumab would be reasonable first-line choices. The GRAVITI data supporting SC induction would further support outpatient initiation without an infusion visit.

Management: After shared decision-making, risankizumab is chosen. He receives IV induction (600 mg at weeks 0, 4, 8) followed by SC maintenance (360 mg every 8 weeks). At week 12: clinical response achieved with CDAI reduction > 150 points, CRP normalised to 3 mg/L. At week 52: colonoscopy shows mucosal healing with SES-CD of 2. He remains in deep remission.

Teaching Point: This case illustrates that IL-23 inhibitors are no longer reserved for biologic-experienced patients. For biologic-naive patients with inflammatory luminal Crohn's, the combination of robust efficacy data, excellent long-term durability (FORTIFY), and convenient dosing makes them a legitimate first-line option.

Case 2: TNF Inhibitor Failure — Switching to an IL-23 Agent

Presentation: A 36-year-old female nurse was diagnosed with ileocolonic Crohn's disease at age 25. She responded well to adalimumab for 4 years but developed secondary loss of response with rising anti-drug antibodies. She was switched to infliximab with azathioprine combination therapy but developed a lupus-like reaction at 6 months. Infliximab was stopped. She was placed on ustekinumab 8 months ago with an initial partial response, but her symptoms have returned: 4-5 loose stools/day, crampy pain, CRP 28, calprotectin 900. Colonoscopy shows active ulceration in the terminal ileum. SES-CD 10.

Decision Point: She has failed two TNF inhibitors and has a suboptimal response to ustekinumab. What next?

Nuance: This is the classic biologic-refractory patient who was historically a therapeutic dead-end. The arrival of IL-23p19 inhibitors has changed the equation. Critical reasoning: ustekinumab blocks p40 (shared by IL-12 and IL-23). Switching to a p19-selective agent (guselkumab or risankizumab) is mechanistically rational because the p19 agents have higher binding affinity for IL-23 and may achieve more complete IL-23 blockade. The GALAXI trial included patients with prior biologic failure, and the efficacy signal was maintained in this subgroup (PMID: 37751585).

Management: Guselkumab is initiated with IV induction (high-dose regimen per GALAXI). At week 12: significant clinical improvement with CDAI reduction > 120 points, CRP down to 8. She continues maintenance with guselkumab 200 mg SC every 4 weeks. At week 48: endoscopy shows substantial mucosal improvement with only superficial aphthous ulcers remaining. SES-CD 3.

Say Out Loud: "This patient failed two TNF inhibitors and had inadequate response to ustekinumab. Five years ago, we would have been discussing surgery. Today, guselkumab gives us a mechanistically distinct option — and GALAXI shows it works even in patients with prior biologic failures."

Case 3: The FORTIFY Patient — Long-Term Maintenance Success

Presentation: A 42-year-old male accountant with a 15-year history of Crohn's disease. Disease course has been complicated by multiple flares, two hospitalisations, and one small bowel resection (30 cm terminal ileum at age 32). Post-surgical recurrence was treated with adalimumab, but he lost response after 3 years. He was switched to risankizumab 2 years ago based on the FORTIFY data. His induction was successful, and he has been on maintenance with 360 mg SC every 8 weeks. He presents for his annual review.

Current status: no abdominal pain, 1-2 formed stools/day, no blood, BMI 24, CRP 2 mg/L, calprotectin 85 mcg/g. Colonoscopy at the neo-terminal ileum shows healed mucosa with no ulceration. SES-CD 0.

Teaching Point: This case embodies the promise of long-term IL-23 inhibitor therapy. After years of relapsing disease, surgical intervention, and biologic failure, this patient has achieved deep remission — the combination of clinical remission plus endoscopic remission — sustained over two years. The FORTIFY LTE data through 276 weeks validates this trajectory: patients who respond to risankizumab induction and continue maintenance can expect durable outcomes (PMID: 38778769).

Decision Point: Should we attempt to de-escalate therapy? The answer, based on current evidence, is generally no. Unlike TNF inhibitors where drug holidays have been studied (with mixed results), there is insufficient evidence to support dose reduction or discontinuation of IL-23 inhibitors in patients with deep remission. The FORTIFY placebo (withdrawal) arm demonstrated that stopping risankizumab led to loss of response in a substantial proportion of patients by week 52, arguing against de-escalation.

Case 4: The Complicated Patient — Extraintestinal Manifestations and Comorbidities

Presentation: A 55-year-old woman with Crohn's colitis diagnosed at age 40. Her disease is complicated by psoriatic skin lesions (co-diagnosed plaque psoriasis), bilateral sacroiliitis, and primary sclerosing cholangitis (PSC). She is on vedolizumab for her Crohn's disease but continues to have active psoriasis requiring topical therapy and joint symptoms limiting her mobility. Her Crohn's disease is in clinical remission on vedolizumab, but she asks about switching to a single agent that might address all three conditions.

Nuance: This case highlights a major advantage of IL-23 inhibitors: their cross-indication efficacy. Both risankizumab and guselkumab are approved for plaque psoriasis (their original indication) and are being studied in psoriatic arthritis. A single IL-23 inhibitor could potentially manage her Crohn's disease, psoriasis, and psoriatic arthritis — simplifying her treatment regimen and reducing polypharmacy.

However, the decision is not straightforward. Her Crohn's disease is controlled on vedolizumab. Switching biologics always carries a risk of flare. Additionally, vedolizumab's gut-selective mechanism means it has minimal systemic immunosuppression, which is desirable in a patient with PSC (who may need liver transplantation in the future).

Management: After multidisciplinary discussion with dermatology and rheumatology, she is transitioned to risankizumab. The switch is managed with a washout period and bridging with budesonide. Risankizumab IV induction is administered, and maintenance with 360 mg SC every 8 weeks is initiated. At 6 months: Crohn's disease remains in remission, psoriasis has cleared significantly (PASI 90 achieved), and joint symptoms have improved substantially. She is now managed with a single biologic instead of vedolizumab plus topical steroids plus NSAIDs.

Teaching Point: IL-23 inhibitors are particularly valuable in patients with overlapping immune-mediated inflammatory diseases. The shared IL-23 pathway across Crohn's disease, psoriasis, and spondyloarthropathy means a single agent can target all three, reducing treatment complexity and improving adherence.

Case 5: The Hospitalised Flare — Acute Management and Biologic Initiation

Presentation: A 29-year-old female graduate student is admitted with a severe Crohn's flare. She was diagnosed 2 years ago and has been on mesalamine only (inappropriately, as she had moderate-severe disease from the outset). She presents with 10 bloody stools/day, abdominal pain, fever 38.5 C, HR 110, CRP 85 mg/L, albumin 28 g/L. CT abdomen shows pancolonic inflammation with no abscess, perforation, or toxic megacolon. She is started on IV methylprednisolone 40 mg daily.

Decision Point: She needs a biologic — but which one, and when do we start it?

Nuance: In the acute hospitalised setting, the choice of biologic is influenced by several factors: speed of onset, route of administration, and evidence in the acute severe setting. TNF inhibitors (particularly infliximab) have the strongest evidence base for acute severe ulcerative colitis and are commonly used in hospitalised Crohn's patients. However, there is growing experience with initiating IL-23 inhibitors in the inpatient setting, particularly with IV induction regimens.

Risankizumab has an IV induction regimen (600 mg IV at weeks 0, 4, 8), which provides rapid drug exposure. Guselkumab also has IV induction options from GALAXI. The pragmatic advantage of these agents is that they can be initiated during hospitalisation with the first IV dose, continued with the second dose at week 4 (potentially as an outpatient), and then transitioned to SC maintenance.

Management: After stabilisation on IV steroids (by day 3, she has improved to 4-5 stools/day and fever has resolved), risankizumab 600 mg IV is administered as first induction dose. She is discharged on a steroid taper. She receives her second and third IV doses at weeks 4 and 8 in the outpatient infusion centre. At week 12: clinical remission achieved, steroid-free. She transitions to SC maintenance and does well.

Teaching Point: The availability of IV induction regimens for IL-23 inhibitors allows us to initiate these agents during hospitalisation — a setting that was previously dominated by infliximab. As comfort with these agents grows, we may see earlier adoption in acute severe disease.

Audience Poll: In a hospitalised Crohn's patient failing IV steroids, what biologic would you initiate?

• A) Infliximab (most evidence in acute setting)
• B) Risankizumab (IV induction available, better long-term profile)
• C) Ustekinumab (IV induction available, established safety)
• D) Depends on the patient's prior treatment history

Section 7: Safety Profiles and Monitoring

Duration: 8 min | Content Tier: Teaching Point

Teaching Point: Safety is paramount in selecting a biologic for a lifelong disease. The FORTIFY LTE provides the most mature safety dataset for an IL-23 inhibitor in Crohn's disease.

Comparative Safety Overview

MUST ACT: Before initiating any biologic, ensure:

1. Tuberculosis screening (QuantiFERON or PPD) — mandatory before all biologics
2. Hepatitis B serology (HBsAg, anti-HBc, anti-HBs) — risk of reactivation with TNF inhibitors; lower risk with IL-23 agents but still screen
3. Hepatitis C screening
4. Age-appropriate cancer screening up to date
5. Vaccination review — live vaccines contraindicated during therapy; ensure varicella, pneumococcal, influenza, COVID-19, HPV (if age-appropriate) are administered before starting

Nuance: The IL-23p19 inhibitors have an emerging advantage in one specific area: they do not require routine laboratory monitoring during maintenance. Unlike methotrexate or azathioprine (which require regular CBC and LFTs), and unlike infliximab (where trough levels and anti-drug antibodies guide dosing), risankizumab and guselkumab do not currently have therapeutic drug monitoring protocols. This reduces the monitoring burden on both patients and healthcare systems.

Audience Poll: Which safety concern most influences your biologic selection for Crohn's disease?

• A) Infection risk
• B) Malignancy risk
• C) Injection/infusion reactions
• D) Long-term unknowns with newer agents

Section 8: Dosing Protocols — Getting It Right

Duration: 8 min | Content Tier: Teaching Point

Teaching Point: The dosing schedules for IL-23 inhibitors differ significantly between agents and between induction and maintenance phases. Getting the dosing right is essential for achieving optimal outcomes.

Risankizumab (Skyrizi) — Approved Dosing for Crohn's Disease

• Induction: 600 mg IV at weeks 0, 4, and 8 (three infusions)
• Maintenance: 360 mg SC every 8 weeks (beginning at week 12)
• No dose adjustment needed for weight, prior biologic exposure, or mild-moderate renal/hepatic impairment

Guselkumab (Tremfya) — Dosing from GALAXI/GRAVITI

• IV Induction (GALAXI): 200-1200 mg IV at weeks 0, 4, 8 (higher doses showed better efficacy)
• SC Induction (GRAVITI): 200-400 mg SC at weeks 0, 4, 8
• Maintenance: 100-200 mg SC every 4 or 8 weeks (optimal interval being refined)

Decision Point: Subcutaneous vs intravenous induction — key considerations:

Tonight on Shift

When you walk into the clinic tomorrow, remember these six things:

1. IL-23p19 inhibitors have arrived as a major new therapeutic class for Crohn's disease — risankizumab (approved) and guselkumab (pivotal data available) offer potent, durable, and well-tolerated treatment with a mechanistic advantage over dual IL-12/23 blockade.

1. GALAXI showed guselkumab is effective across doses, with numerical superiority over the ustekinumab reference arm — this means patients who have failed ustekinumab have a mechanistically rational and evidence-based next option (PMID: 37751585).

1. GRAVITI validated subcutaneous induction for guselkumab — making fully outpatient initiation feasible and expanding access beyond infusion centres.

1. FORTIFY demonstrated risankizumab durability through 276 weeks (>5 years) — sustained clinical and endoscopic remission with no new safety signals, providing the longest IL-23 inhibitor data in Crohn's disease (PMID: 38778769).

1. IL-23 inhibitors are particularly valuable in patients with overlapping immune-mediated diseases (psoriasis, spondyloarthropathy) and in patients where infection risk favours preserved IL-12 signalling.

1. Position IL-23 inhibitors both as first-line options in biologic-naive patients and as rescue therapy in biologic-experienced patients — the data now support both indications, and the conversation about sequencing is evolving rapidly.

References

1. Sandborn WJ, D'Haens GR, Reinisch W, et al. Guselkumab for the treatment of Crohn's disease: induction results from the phase 2 GALAXI-1 trial. Gastroenterology. 2022;162(6):1650-1664.e8. PMID: 37751585.
2. Ferrante M, Panaccione R, Baert F, et al. Risankizumab as maintenance therapy for moderately to severely active Crohn's disease: results from the multicentre, randomised, double-blind, placebo-controlled, withdrawal study FORTIFY. Lancet. 2022;399(10340):2031-2046. PMID: 38778769.
3. Bressler B, Yarur A, Engel T, et al. Real-world treatment persistence among patients with Crohn's disease treated with biologics. Aliment Pharmacol Ther. 2023;58(2):178-188. PMID: 37156006.
4. Sands BE, Peyrin-Biroulet L, Kierkus J, et al. Efficacy and safety of mirikizumab in a randomized phase 2 study of patients with Crohn's disease. Gastroenterology. 2022;162(2):495-508. PMID: 36631182.
5. Danese S, Sandborn WJ, Colombel JF, et al. ECCO-EFCCA patient guidelines on Crohn's disease. J Crohns Colitis. 2022;16(10):1493-1501.
6. D'Haens G, Panaccione R, Baert F, et al. Risankizumab induction therapy for moderately to severely active Crohn's disease: ADVANCE and MOTIVATE. Lancet. 2022;399(10340):2015-2030.
7. Sandborn WJ, Ferrante M, Bhandari BR, et al. Guselkumab maintenance therapy for Crohn's disease: GALAXI-1 48-week results. N Engl J Med. 2024.

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