Durability of Biologics in Children with Inflammatory Bowel Disease

JL Kaplan et al. JPGN 2023; 76: 567-575. Open Access! Use, Durability, and Risks for Discontinuation of Initial and Subsequent Biologics in a Large Pediatric-Onset IBD Cohort

Methods: The authors analyzed pediatric inflammatory bowel disease (IBD) data from the ImproveCareNow Network registry (n= 17,649) between May 2006 and September 2016, including time to biologic initiation, choice of first subsequent biologics, biologic durability, and reasons for discontinuation

Key findings:

  • 7585 (43%) were treated with a biologic agent before age 18. 50% of children with Crohn’s disease (CD) received a biologic compared to 25% of children with ulcerative colitis (UC)
  • First biologic agents for all patients were anti-tumor necrosis factor agents (88% infliximab, 12% adalimumab)
  • Probability of remaining on first biologic in patients with CD: 93% at 6 months, 85% at 12 months, 79% at 24 months, and 74% at 36 months
  • Probability of remaining on first biologic in patients with UC: 84% at 6 months, 75% at 12 months, 66% at 24 months, and 55% at 36 months
  • First biologics were discontinued because of loss of response (39%), intolerance (23%), and nonresponse (19%).

My take: This is an important study that shows that anti-TNF therapy durability was 79% in patients with CD and 66% in patients with UC at 2 years. This pediatric-specific information will help with counseling families when starting biologic therapy. There was improvement in durability after 2013 compared to prior -so perhaps perhaps even better durability is occurring in 2023. It is a little ironic that this study is from ImproveCareNow given that the results are quite dated. There have been a lot of changes in the last seven years. These include the widespread use of dose optimization/therapeutic drug levels and the approval of several new classes of targeted medications.

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Tucson Botanical Gardens

Is There An Increased Risk of Infections with Anti-TNF Therapy?

J Holmgren et al. Inflamm Bowel Dis 2023; 29: 339-348. Open Access! The Risk of Serious Infections Before and After Anti-TNF Therapy in Inflammatory Bowel Disease: A Retrospective Cohort Study 

Methods: Retrospective study with 980 patients at 5 centers participating in the Swedish IBD Quality Register. Serious infections, defined as infections requiring in-patient care, the year before and after the start of anti-TNF treatment were evaluated.

A decline in the incidence rate can first be seen beyond 1 year of treatment with anti-TNF, with an incidence rate of 1.22 (95% CI, 0.90-1.66) events per 100 person year compared with 2.19 (95% CI, 1.43-3.36) events per 100 person year the year before treatment. This is a significant reduction of infections, with an incidence rate ratio of 0.56 (95% CI, 0.33-0.95; P = .030).

Key findings:

  • A 72.0% reduction in the incidence rate of perianal abscesses and intra-abdominal abscesses during treatment with anti-TNF was found compared with before treatment.
  • Figures 2 & 3 show than most infection rates decreased with treatment. CMV infection did not change significantly with 0.10 per 100 person-years prior to treatment and 0.14 per 100 person-years after starting anti-TNF therapy
  • ” In the current study, patients younger than 20 years old experienced a substantial decrease of infection incidence rate ratio (0.11) with the introduction of anti-TNF treatment. The results could be explained by the fact that young patients have a more active disease with increased risk of infection before treatment with anti-TNF.”
  • “The most common type of infection after anti-TNF treatment was pneumonia. The high incidence of pneumonia confirms earlier data.9,36,37” However, the authors show that the rate of pneumonia dropped from 0.51 to 0.27 per 100 person-years after starting anti-TNF therapy.

The authors note that a prior study by “Zabana et al showed that patients with IBD had an increased risk for serious infection after starting immunosuppressive treatment compared with before treatment (median follow-up 3 years before and 5 years after)… the discrepancy in the result may be explained by selection bias. We included all patients starting anti-TNF treatment. However, Zabana et al included only patients who suffered from infections during immunosuppressive treatment and retrospectively examined the risk of infection before start of treatment.24

Limitations of study: several other important factors affecting infections were not captured in this study including steroid exposure and nutritional status.

My take (from authors): “The incidence rate of serious infection among IBD patients did not increase with anti-TNF therapy. Instead, serious infections seemed to decrease more than 1 year after initiation of anti-TNF treatment.”

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Kids Are Different: Therapeutic Drug Monitoring

NH Nguyen et al. Gastroenterol 2022; 163: 937-949. Open Access! Proactive Therapeutic Drug Monitoring Versus Conventional Management for Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis

Key finding:

  • On meta-analysis of 9 RCTs (8 RCTs in adults, and focusing on maintenance phase), there was no significant difference in the risk of failing to maintain clinical remission in patients who underwent proactive TDM (267/709; 38%) vs conventional management (292/696; 42%) (relative risk [RR], 0.96)

The discussion in this paper makes some important points, as there are some populations in which proactive TDM is more likely to be beneficial.


“The impact of proactive TDM in pediatric patients also merits further consideration. This concept may be particularly important in pediatrics due to the variability in size of patients, which may not be adequately addressed by weight-based dosing.33 This is especially important in younger children, where it has been shown that standard TNFα antagonist regimens and trough levels may not be applicable in this age group, and may require more frequent escalation of therapy.34,35 In the PAILOT trial, proactive TDM in children with clinical response to adalimumab was associated with higher rates of maintaining sustained corticosteroid-free clinical remission at all visits from week 8–72, compared with reactive TDM in which physicians were informed of trough concentration only after loss of response.”

Induction Dosing (Adults and Children):

“It is possible that the early measurement of biologic drug concentrations, to identify patients who may have accelerated clearance, and optimization of a subset of these patients early in the course of therapy may offer benefit.1,30 …Ongoing trials such as OPTIMIZE (NCT04835506) and TITRATE (NCT03937609) in which infliximab is optimized during the induction phase through a pharmacokinetic dashboard in patients with Crohn’s disease and acute severe ulcerative colitis will shed further light on this.”

My take: So far, studies in adults have not shown that proactive therapeutic drug monitoring has been effective in improving clinical outcomes. This may change particularly if studies focus on patients on monotherapy who are at increased risk of subtherapeutic levels. No matter what happens in adults, there is sufficient data showing that proactive therapeutic drug monitoring is essential in children. This is especially important as ‘routine” dosing of infliximab in children may be subtherapeutic in nearly 80%.

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What Happens When Infliximab is Stopped in Patients in Deep Remission Plus One

S Buhl et al. NEJM 2022; DOI:https://doi.org/10.1056/EVIDoa2200061. Discontinuation of Infliximab Therapy in Patients with Crohn’s Disease

Design: This was a multicenter, randomized, double-blind, placebo-controlled withdrawal study of infliximab in patients (n=115) with Crohn’s disease who were in clinical, biochemical, and endoscopic remission after standard infliximab maintenance therapy for at least 1 year. Patients were randomly assigned 1:1 to continue infliximab therapy or to receive matching placebo for 48 weeks.

Key finding:

  • At the end of the trial at week 48, relapse-free survival was 100% in the infliximab-continuation group and 51% in the infliximab-discontinuation group

My take (borrowed from authors): Discontinuation of infliximab for patients with Crohn’s disease receiving long-term infliximab therapy and in clinical, biochemical, and endoscopic remission leads to a considerable risk of relapse

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Figure from NEJM Evidence Twitter Feed

S Sassine et al. AJG 2022; Volume 117 – Issue 4 – p 637-646. doi: 10.14309/ajg.0000000000001650. Risk Factors of Clinical Relapses in Pediatric Luminal Crohn’s Disease: A Retrospective Cohort Study

Key findings–The following variables were associated with clinical relapse:

  • female sex (adjusted hazard ratio [aHR] = 1.52, P = 0.0007)
  • exposure to oral 5-ASA (aHR = 1.44, P = 0.04),
  • use of immunomodulatory agents compared with tumor necrosis factor-alpha inhibitors (methotrexate aHR = 1.73, P = 0.003; thiopurines aHR = 1.63, P = 0.002)
  • presence of granulomas (aHR = 1.34, P = 0.02)
  • increased eosinophils on intestinal biopsies (aHR = 1.36, P = 0.02)
  • high levels of C-reactive protein (aHR = 1.01, P < 0.0001)
  • fecal calprotectin (aHR = 1.08, P < 0.0001)
  • low serum infliximab levels (<7 mcg/mL) (aHR = 2.32P = 0.001).

Head-to-Head (Sort of): Infliximab vs Ustekinumab for Crohn’s Disease

N Narula et al. Clin Gastroenterol Hepatol 2022; 20: 1579-1587. Comparative Efficacy and Rapidity of Action for Infliximab vs Ustekinumab in Biologic Naïve Crohn’s Disease

Using a post hoc analysis of 2 large Crohn’s disease (CD) trial with 420 biologic-naive adult patients, the authors found the following Key Findings:

  • At week 6, a comparable number of patients achieved clinical remission with infliximab compared with patients treated with ustekinumab (44.9% vs 37.9%; adjusted odds ratio [aOR], 1.22)
  • At week 6 the clinical response rates were not significantly different (58.4% infliximab vs 54.9% ustekinumab; aOR, 1.25)
  • At week 6, 42.3% infliximab vs 34.7% ustekinumab had fecal calprotectin level less than 250 mcg/L in those with increased values at baseline

My take: A true head-to-head trial, rather than a post-hoc analysis, would more definitively determine relative efficacy and relative time to response. This study indicates that both agents have similar efficacy by week 6.

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Biologics in Children with Very Early Onset Inflammatory Bowel Disease

B Kerur et al. JPGN 2022; 75: 64-69. Utilization of Antitumor Necrosis Factor Biologics in Very Early Onset Inflammatory Bowel Disease: A Multicenter Retrospective Cohort Study From North America

In this retrospective study, 120 of 294 children with VEO-IBD (diagnosed 2008 and 2013, PRO-KIDS network) received anti-TNF therapy (96% infliximab). 101 of these 120 had adequate data recorded. It is noted that additional data on this cohort has been previously published (IBD Updates: Outcomes of VEO-IBD, PIANO Study Update, and Insurance-Disparity Relationship). Key findings:

  • Anti-TNF durability was 90% at 1 year, 75% at 3 years, and 55% at 5 years
  • Patients with Crohn’s disease had better durability than those with UC/IBD-U (Hazard ratio 0.17)
  • The most common reason for discontinuation of anti-TNF were loss of response in 24 (57%) children
  • 67 (66%) received combined therapy with an immunomodulator and this was associated with improved anti-TNF durability (Hazard ratio 0.30). However, authors note this was in era preceding widespread therapeutic drug monitoring.
  • The majority of children in the current study did not undergo testing for monogenic mutations

My take: Data for use of anti-TNF agents in this age group (< 6 yrs) has been limited. This study suggests similar effectiveness of anti-TNF agents in VEO-IBD compared to older groups. Given this groups increased risk for monogenic mutations, it is still a good idea, if feasible, to test for these disorders.

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IBD Shorts: Pediatric Cost Savings with Biosimilars and Multiple Biosimilar Switch Data

GA Morris et al. Inflamm Bowel Dis 2022; 28: 531-538. Increasing Biosimilar Utilization at a Pediatric Inflammatory Bowel Disease Center and Associated Cost Savings: Show Me the Money

Key findings:

  • Biosimilar utilization initiation increased from a baseline of 1% in June 2019 to 96% by February 2021 among eligible patients; 20% of all patients (n-98) had insurance which preferred originator product
  • Estimated cost savings over the project duration were nearly $381,000 (average sales price) over the 20 month study

My take: The introduction of biosimilars have resulted in huge cost savings. In addition, for infliximab, the originator product price has also dropped substantially (more than 60% in some locations)

J Hanzel et al. Inflamm Bowel Dis 2022; 28: 495-501. Open Access: Multiple Switches From the Originator Infliximab to Biosimilars Is Effective and Safe in Inflammatory Bowel Disease: A Prospective Multicenter Cohort Study 

Methods: This was a prospective multicenter cohort study of adult IBD patients (n=176) who underwent 2 switches from the originator IFX to CT-P13 to SB2 (group 1), 1 switch from CT-P13 to SB2 (group 2), and 1 switch from the originator IFX to CT-P13 (group 3).

Key findings:

  • At 12 months after the most recent switch 76.9% (40 of 52, group 1), 65.7% (46 of 70, group 2) and 76.9% (20 of 26, group 3) of patients were in clinical remission. Treatment persistence at 12 months was 85.0%, 87.0%, and 70.1%, respectively.
  • There were no significant differences in the rate of clinical, CRP, FC remission, or treatment persistence at 12 months between the 3 groups.

My take: This study did not identify detrimental effects from multiple successive switching and switching between biosimilars of IFX. Longer followup and more clinical experience will be needed to confirm these findings.

Here’s Why Therapeutic Drug Monitoring Should Work

RC Ungaro et al. Inflamm Bowel Dis 2022; 28: 649-651. Impact of Thiopurine Exposure on Immunogenicity to Infliximab Is Negligible in the Setting of Elevated Infliximab Concentrations

Background: Whether proactive therapeutic drug monitoring (pTDM) is superior to reactive TDM (rTDM) is not entirely clear, though some studies have shown better outcomes with pTDM. Additionally, Colombel et al (Clin Gastroenterol Hepatol 2019; 17: 1525-32) showed that antidrug antibodies during combination therapy were detected only in those with the lowest quartile of infliximab trough levels; this suggests that optimized monotherapy should be similarly effective to combination therapy.

Methods: The authors retrospectively analyzed a commercial laboratory database (Prometheus) with 3970 patients and paired 6-thioguanine (6-TGN) levels with infliximab (IFX) and antibodies to infliximab (ATIs)

Key findings:

  • “Those with higher levels of IFX had negligible benefit from concomitant thiopurine treatment in preventing ATIs.”
  • ATIs were detected in 9.9% of all patients. IFX level of >5 mcg/mL were associated with a very low risk of ATI (OR 0.05). “Immunogenicity was negligible (<3%) in the presence of IFX concentrations greater than 5 mcg/mL.”
  • 6-TGN levels (>125) were associated with lower risk of ATI, OR 0.42; though, this effect had a significant impact, only for those with with IFX <5 mcg/mL.
  • The authors note the prospective OPTIMIZE study (NCT04835506) should help determine the effectiveness of pTDM.

My take: In patients with IFX levels >5 mcg/mL, there does not appear to be much benefit for most patients from the addition of a thiopurine; this may not be true for those who are switching to a 2nd anti-TNF agent due to antidrug antibodies. This study supports pTDM to assure adequate IFX levels.

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IBD Shorts: Ustekinumab in Kids, Subcutaenous Infliximab, Nutrition Highlights

MT Dolinger et al. J Crohns Colitis 2022.  doi: 10.1093/ecco-jcc/jjac055. Online ahead of print. Outcomes of Children With Inflammatory Bowel Disease Who Develop Anti-Tumor Necrosis Factor Induced Skin Reactions

In this retrospective study, among those who developed skin reactions to anti-TNF agents, 71 (64%) continued anti-TNF and 40 (36%) switched to ustekinumab (UST). Key findings:

  • Switching to UST had a higher rate and odds of resolution of skin findings (29/40 (73%) vs. 24/71 (34%); p <0.0001) and combined remission (21 (52%) vs. 22 (31%); p=0.03) vs. continuing anti-TNF at 6 months

PJ Smith et al. J Crohns Colitis, jjac053, https://doi.org/10.1093/ecco-jcc/jjac053 Open Access: Efficacy and Safety of Elective Switching From Intravenous to Subcutaneous Infliximab (Ct-P13): A Multi-Centre Cohort Study

Patients (n=181) on established maintenance IV infliximab who switched to SC CT-P13 were included in this retrospective multi-centre cohort study. Key findings:

  • Treatment persistence rate was high (N=167, 92.3%) and only 14 patients (7.7%) stopped treatment during the follow-up period. There were low rates of immunogenicity with no change in clinical disease activity indices or biomarkers

Link: Crohn’s and Colitis Congress 2022 Nutritional Highlights (Nutritional Therapy for IBD Website). This website has a summaries, and links to extensive information (videos/posters) from recent IBD meeting.

Sunrise in Sandy Springs (4/9/22) -no filter

Dietary Therapy for Adults with Crohn’s Disease

H Yanai et al. The Lancet 2021; The Crohn’s disease exclusion diet for induction and maintenance of remission in adults with mild-to-moderate Crohn’s disease (CDED-AD): an open-label, pilot, randomised trial https://doi.org/10.1016/S2468-1253(21)00299-5

In this open-label trial of adults with mild-to-moderate biologic naive Crohn’s disease, key findings:

  • At week 6, 13 (68%) of 19 patients in the CDED plus partial enteral nutrition group and 12 (57%) of 21 patients in the CDED group had achieved clinical remission (p=0·4618)
  • Among the 25 patients in remission at week 6, 20 (80%) were in sustained remission at week 24 (12 patients in the CDED plus partial enteral nutrition group and eight in the CDED alone group)
  • 14 (35%) of 40 patients were in endoscopic remission at week 24 (eight patients in the CDED plus partial enteral nutrition group and six in the CDED alone group)

My take: Dietary therapy may be effective option for motivated adult patients with Crohn’s disease.

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