Choosing the Right Treatment at the Right Time for Children with Inflammatory Bowel Disease

Table of Contents

• Introduction: The Treatment Challenge in Pediatric IBD
• The Right Time: Early Effective Therapy
• Treating a Progressive Disease
• The Problem with Step-Up Therapy
• Benefits of Early Therapy in Crohn's Disease
• Benefits of Early Therapy in Ulcerative Colitis
• Debating the Definition of "Early"
• The Right Patient: Predicting Disease Course
• Clinical Factors Affecting Prognosis
• Clinically Available Protein Markers
• Future Predictive Biomarkers
• The Right Drug: Sequencing and Treatment Choices
• Choosing First-Line Therapy
• Does Treatment Order Matter?
• Combination Therapy Approaches
• Conclusion and Recommendations
• Source Information

Introduction: The Treatment Challenge in Pediatric IBD

Despite having more treatment options than ever before, inflammatory bowel disease (IBD) still faces a significant treatment ceiling. In clinical trials, response to therapy typically doesn't exceed 30% of patients. Many patients only find the right treatment after failing multiple medications, which can be disabling, psychologically stressful, and cause permanent damage to the bowel wall.

The solution to this problem lies in precision medicine—selecting the right patient, right therapy, right time, right dose, and right monitoring strategy. This article focuses on the critical process of pairing the right patient with the right therapy at the right time, with particular attention to pediatric IBD where specific data is often lacking compared to adult studies.

The Right Time: Early Effective Therapy

The timing of treatment initiation plays a crucial role in managing IBD effectively. The approach has shifted from traditional "step-up" therapy (starting with less effective medications first) to "early effective" therapy (using more potent treatments upfront for appropriate patients).

Treating a Progressive Disease

IBD, which includes Crohn's disease and ulcerative colitis, is a progressive chronic disease that causes irreversible bowel wall injury. Current treatments focus on reducing inflammation but cannot reverse existing damage to the bowel wall. This natural progression often leads to complications that require surgery.

In Crohn's disease, fibrosis (scar tissue formation) is a well-known complication that leads to strictures (narrowing) affecting one-third of patients at some point. Pediatric-onset Crohn's disease typically has a more severe phenotype than adult-onset disease, suggesting children may benefit even more from early aggressive therapy to prevent damage from chronic inflammation over their longer disease duration.

Ulcerative colitis has only recently been recognized as progressive. Over half of UC patients will experience disease extension, and a small proportion develop colonic fibrotic strictures. Disease duration, severity, and activity have all been associated with increasing colorectal cancer risk.

The Problem with Step-Up Therapy

Historically, IBD was treated with "step-up" therapy, requiring failure of less effective medications like mesalamine and thiopurines before starting biologics, even for patients with moderate-to-severe disease. Evidence now shows this approach causes patients to miss an important "window of opportunity" to permanently alter their disease course by quickly controlling inflammation.

Despite this understanding, step-up therapy remains common. A large US claims database study (28,119 UC patients and 16,260 CD patients) from 2008-2016 found that less than 1% of UC patients and less than 5% of CD patients received first-line biologics. Instead, 61% of UC patients started on 5-aminosalicylic acid monotherapy, and 42% of CD patients started on corticosteroid monotherapy.

Insurance companies often mandate step therapy against providers' advice. A 2016 Crohn's and Colitis Foundation survey found that 40% of patients were forced by their insurance company to follow step therapy against their provider's recommendation.

Benefits of Early Therapy in Crohn's Disease

Multiple studies demonstrate clear benefits of early effective therapy for Crohn's disease:

• PRECiSE 2 study: Patients treated within a year of diagnosis had 90% response rate versus 57% for those diagnosed 5+ years prior
• CHARM trial: Patients with disease duration less than 2 years had 43% remission rate versus 30% (2-5 years) and 28% (>5 years)
• CALM trial: Early-diagnosed patients achieving deep remission had 81% decrease in adverse outcomes at 3 years
• VICTORY consortium: CD patients with disease duration ≤2 years had improved response to vedolizumab
• LOVE-CD study: Early CD patients (<2 years) showed significantly better endoscopic remission (45% vs 15%) and combined steroid-free clinical remission with endoscopic remission (47% vs 16%) with vedolizumab

Prospective randomized controlled trials also support early therapy. One trial randomized newly-diagnosed CD patients to either early combination therapy (infliximab + thiopurine) or thiopurine alone. Early infliximab therapy led to 62% achieving clinical remission at 1 year versus 42% on thiopurine alone.

The REACT-1 cluster RCT (n=1,982) showed that accelerated step-up therapy reduced serious complications and need for hospital admission or surgery.

Pediatric-specific data strongly supports early biologic therapy:

• RISK cohort (n=1,813): Early anti-TNF treatment was superior to early immunomodulator treatment for achieving remission at 1 year (85.3% vs 60.3%; Relative Risk: 1.41)
• South Korean study (n=31): Relapse rates improved with infliximab started just after diagnosis versus after failing conventional therapy (21% improvement in relapse-free rates at 3 years)
• European multicenter trial (n=100): First-line infliximab improved short-term endoscopic remission at 10 weeks (59% vs 17%), long-term remission without escalation at 52 weeks (41% vs 15%), and growth outcomes

Benefits of Early Therapy in Ulcerative Colitis

In contrast to Crohn's disease, the data does not compellingly support early effective therapy for ulcerative colitis:

• Murthy et al study (n=213): Longer disease duration was associated with higher 1-year steroid-free remission (adjusted OR=2.1 per 10-year increase) and lower colectomy risk (adjusted HR=0.49 per 10-year increase)
• Mandel et al study (n=42): No benefit of early anti-TNF exposure (within 3 years from diagnosis)
• VICTORY consortium: No improvement in vedolizumab response in UC patients with shorter disease durations
• LOVE-UC Study: No difference in remission rates at week 26 between early (<4 years) and late (>4 years) UC patients (49% vs 43%)

Pediatric data is nearly non-existent on this topic. One study of 121 children with UC compared outcomes with early versus late azathioprine initiation and found no differences in surgery rates, hospitalization, treatment escalation, disease extension, or acute severe colitis episodes.

The available literature is retrospective and primarily adult, but consistently shows no clear benefit for early therapy in UC. An active European prospective trial (SPRINT) aims to examine early therapy benefits in adult UC, but pediatric trials remain needed.

Debating the Definition of "Early"

There remains disagreement about what constitutes "early" IBD. Some experts suggest 2 years from diagnosis, but this differs from other diseases like rheumatoid arthritis where much shorter intervals (3 months) are described. The long delays in IBD diagnosis further complicate this definition, as 2 years after diagnosis may translate to 5 years after disease onset.

The Right Patient: Predicting Disease Course

To pair the right therapy with the right patient immediately, defining the patient's prognosis is critical. Current practice combines clinical factors with traditional laboratory markers, with growing research expanding these prognostic tools.

Clinical Factors Affecting Prognosis

In pediatrics, younger age at diagnosis is associated with increased risk of relapses and recurrences in both UC and CD. Disease location/extent also affects outcomes:

• Crohn's disease: Perianal, ileocolonic, and upper tract disease phenotypes associate with more severe courses
• Ulcerative colitis: Extensive colitis carries higher colectomy risk
• Progressive disease (complications in CD, extension in UC) predicts negative outcomes

Extraintestinal manifestations (EIM) and concomitant immune-mediated inflammatory diseases (IMIDs) also indicate worse prognosis. A systematic review of 93 studies found patients with IBD and another IMID had higher risk for extensive colitis/pancolitis (RR 1.38) and IBD-related surgeries (RR 1.17). Another study found pre-existing IMID was a poor prognostic factor (OR 3.71 for surgical risk).

Clinically Available Protein Markers

Two classic IBD markers are C-reactive protein (CRP) and fecal calprotectin (FC). While primarily markers of disease activity, they also relate to disease prognosis:

• CRP elevations associate with increased need for surgery in both CD and UC, even during clinical remission in CD
• Fecal calprotectin improves upon CRP's limitations for detecting intestinal inflammation
• Serial FC measurements can predict disease progression/relapse

Serologic responses to enteric pathogens and autoantigens also show predictive value:

• Anti-Saccharomyces cerevisiae antibody (ASCA)
• Antibody to flagellin (CBir1)
• Granulocyte-macrophage colony-stimulating factor (GMCSF) autoantibodies
• Perinuclear antineutrophil antibody (pANCA)

In a large prospective pediatric CD study, positivity for more antimicrobial antigens associated with faster progression to complicated disease. High GMCSF autoantibody expression associates with complicated CD, and these antibodies may rise before disease diagnosis.

Future Predictive Biomarkers

Numerous predictive markers are under development across various 'omic fields:

• RISK cohort (pediatric CD): Identified extracellular matrix tissue transcriptomic signature predicting stricturing within 3 years
• PROTECT cohort (pediatric UC): Identified two predictive gene signatures for severity and therapeutic response
• Validated blood test: CD8+ T cell gene expression profiling panel categorizes patients into low- and high-risk groups (note: steroid use may affect results)

Genomic studies have identified four loci linked to prognosis distinct from susceptibility loci. Polygenic risk scores and NOD2 polymorphisms have been examined, though neither associated with stricturing or fistulizing behavior in pediatric CD in the RISK cohort.

Microbiome, metabolomic, and glycomic signatures are being developed to inform prognosis. Network-based methods can integrate multi-omic data to identify personalized disease subtypes and ideal therapies.

The Right Drug: Sequencing and Treatment Choices

Making data-driven decisions about first-line therapy has been historically difficult due to lack of head-to-head comparative trials, though this is changing.

Choosing First-Line Therapy

Recent head-to-head trials provide valuable comparison data:

• VARSITY trial (n=769 UC patients): Vedolizumab showed superior 1-year outcomes versus adalimumab (clinical remission: 39% vs 23%; endoscopic improvement: 40% vs 28%)
• SEAVUE trial (n=386 CD patients): No significant differences between ustekinumab and adalimumab, though trend toward improved endoscopic response with ustekinumab
• Other recent trials: No significant differences between etrolizumab and infliximab, or between adalimumab and comparators
• Guselkumab vs ustekinumab: IL-23 blocker compared to IL-12/23 blocker showed no significant differences, possibly due to power issues

Does Treatment Order Matter?

As new therapies enter the IBD treatment options, understanding the impact of therapy sequence becomes increasingly important. Response to first-line therapy remains relatively low—approximately one-third of patients remain on their first-line biologic during follow-up, while two-thirds change to another therapy.

Most data on newer therapies examines their effect after anti-TNF failure. Second-line and beyond therapies commonly show decreased effectiveness, underscoring the importance of first-line therapy choice.

Studies examining vedolizumab and ustekinumab after anti-TNF failure show mixed results:

• Two studies supported ustekinumab superiority over vedolizumab after anti-TNF failure
• One study reported no significant difference when used third-line after anti-TNF and then either vedolizumab or ustekinumab

Anti-IL23 medications (risankizumab, mirikizumab, guselkumab) may not have diminished effectiveness after prior biologic failure. Anti-TNF non-responders show upregulation of IL23p19, IL23R, and IL17A, suggesting a biological explanation for these observations.

Children with early CD show significantly higher levels of IL12p40 and IL12Rb2 messenger RNA and INF-g production by T cells compared to late CD, suggesting IL-12 may be an important pathway in early disease and anti-TNF refractory disease.

JAK inhibitors (tofacitinib, upadacitinib) maintain effectiveness after biologic failure, possibly due to different clearance mechanisms than biologic therapies. However, other small molecules (S1P receptor modulators) don't fare as well after multiple biologic failures.

Combination Therapy Approaches

Rational early use of combination therapies may enhance response and remission rates by targeting complementary biological pathways. The SONIC study famously described the superiority of thiopurine + anti-TNF combination, though this has fallen out of favor as optimized monotherapy allows avoidance of thiopurine adverse effects.

Observational data exists on other combination approaches in both adults and pediatrics. The VEGA trial (n=214) compared golimumab + guselkumab combination to monotherapy for moderate-to-severe UC. Endoscopic improvement was more likely with combination therapy, without higher adverse events. The EXPLORER study examined vedolizumab + adalimumab + methotrexate combination.

Conclusion and Recommendations

The evidence strongly supports early effective therapy for pediatric Crohn's disease, with multiple studies showing significantly improved outcomes including higher remission rates (85.3% vs 60.3% with conventional therapy), better growth, and reduced complications. The benefits appear less clear for ulcerative colitis, where the data doesn't compellingly support early aggressive treatment.

Predicting which patients need early aggressive therapy involves assessing clinical factors (age at diagnosis, disease location, extraintestinal manifestations) and available biomarkers (CRP, fecal calprotectin, serologic markers). Emerging 'omic technologies promise improved prognostication capabilities.

Treatment sequencing matters, with first-line therapy choice being particularly important as subsequent therapies often show reduced effectiveness. Head-to-head trials are increasingly providing data to inform these decisions, though more pediatric-specific research is needed.

For families navigating pediatric IBD treatment decisions, this research emphasizes:

1. Early assessment of disease severity and prognosis is critical
2. Crohn's disease often benefits from earlier biologic therapy
3. Insurance barriers to appropriate therapy remain a significant challenge
4. Treatment sequencing decisions should consider long-term outcomes
5. Ongoing monitoring and adjustment of therapy is essential

Source Information

Original Article: "Choosing the Right Therapy at the Right Time for Pediatric Inflammatory Bowel Disease: Does Sequence Matter" by Elizabeth A. Spencer, MD, MSc

Publication: Gastroenterology Clinics of North America, Volume 52, 2023, Pages 517-534

Note: This patient-friendly article is based on peer-reviewed research and maintains the full content and data from the original scientific publication while making it accessible to patients and families affected by inflammatory bowel disease.