ENTERPRISE Study: Vedolizumab for Perianal Fistulizing Crohn’s Disease

DA Schwartz et al. Clin Gastroenterol Hepatol 2022; 20: 1059-1067. Open Access: Efficacy and Safety of 2 Vedolizumab Intravenous Regimens for Perianal Fistulizing Crohn’s Disease: ENTERPRISE Study

Methods: “Patients with moderately to severely active CD and 1–3 active perianal fistulae (identified on magnetic resonance imaging [MRI]) received vedolizumab 300 mg intravenously at weeks 0, 2, 6, 14, and 22 (VDZ) or the same regimen plus an additional vedolizumab dose at week 10 (VDZ + wk10)… Enrollment was stopped prematurely because of recruitment challenges”

Key findings:

  • “Rapid and sustained fistula closure was observed; 53.6% (VDZ, 64.3%; VDZ + wk10, 42.9%) and 42.9% (VDZ, 50.0%; VDZ + wk10, 35.7%) of patients achieved ≥50% decrease in draining fistulae and 100% fistulae closure, respectively, at week 30”
  • “MRI healing, defined as the disappearance of T2 hyperintensity signal and absence of gadolinium contrast enhancement,3 was not reached in this study…gadolinium contrast enhancement showed improvement at week 30…MRI studies have shown that internal fistulae healing lags behind clinical remission by a median of 12 months”
Figure 1
Figure 2 B

The study findings are limited by relatively small size and lack of control group (eg. placebo or seton/antibiotic group). However, the rate of response in this study is significantly higher than placebo studies which have shown “~1 in 6” who experienced fistula closure.

My take: Vedolizumab is another option for treating Crohn’s disease with perianal fistula. Both regimens in this study were associated with response, though the additional 10-week dose (in one group) did not improve outcomes.

Related blog posts:

IBD Shorts: Pediatric Colonic CD, UC Colectomy Risk Factors, Ustekimumab for 5 years

TD Berger et al. JPGN 2022; 74: 258-266. Clinical Features and Outcomes of Paediatric Patients With Isolated Colonic Crohn Disease

This study focused on 94 with isolated colonic Crohn’s disease (L2). Key findings: Response to enteral nutrition (78.3%) was comparable to those with L1 disease (82.4%) (n=104). Skp lesions and granulomas, identified in 65% and 36% in those with L2 disease was similar to those with L1 disease.

JS Hyams et al. Inflamm Bowel Dis 2022; 28: 151-160. Open Access: Clinical and Host Biological Factors Predict Colectomy Risk in Children Newly Diagnosed With Ulcerative Colitis

Key findings:

  • 25/428 (6%) children with recently diagnosed UC underwent colectomy at ≤1 year, 33 (9%) at ≤2 years, and 35 (13%) at ≤3 years. 
  • An initial PUCAI ≥ 65 was highly associated with colectomy (P = 0.0001)
  • A  pretreatment rectal gene expression panel showed that patients who had colectomy had significantly higher values for this genetic signature in comparison with those who did not require colectomy

WJ Sandborn et al. Clin Gastroenterol Hepatol 2022; 20: 578-590. Open Access: Five-Year Efficacy and Safety of Ustekinumab Treatment in Crohn’s Disease: The IM-UNITI Trial

Key findings:

  • Using an intent-to-treat analysis of all patients randomized to ustekinumab at maintenance baseline, 34.4% of patients in the every-8-weeks group and 28.7% in the every-12-weeks group were in clinical remission at week 252. In the 8 week group in the long-term extension portion of the study the rate was 54.9%
  • Adverse effect profile (per 100 patient-years): generally were similar in the placebo and combined ustekinumab groups for all adverse events (440.3 vs 327.6), serious adverse events (19.3 vs 17.5), infections (99.8 vs 93.8), and serious infections (3.9 vs 3.4).
White Sands (actually gypsum) at White Sands National Park, NM

SERENE Study: Does a Higher Induction Dose of Adalimumab Help for Crohn’s Disease?

GR D’Haens et al. Gastroenterol 2022; DOI:https://doi.org/10.1053/j.gastro.2022.01.044. Open Access: Higher vs Standard Adalimumab Induction Dosing Regimens and Two Maintenance Strategies: Randomized SERENE CD Trial Results

Methods: In this phase 3, randomized, double-blind, multicenter trial, eligible adults were randomized to higher induction regimen (adalimumab 160 mg at weeks 0, 1, 2, and 3; n = 308) or standard induction regimen (adalimumab 160 mg at week 0 and 80 mg at week 2; n = 206) followed by 40 mg every other week from week 4 onward. Endoscopic results were interpreted by a central reviewer.

Key Findings:

  • Similar proportions of patients receiving higher induction regimen and standard induction regimen achieved clinical remission at week 4 (44% in both; P = .939) and endoscopic response at week 12 (43% vs 39%, respectively, P = .462).
  • There was a high proportion of patients (>70%) who achieved corticosteroid-free clinical remission after an early corticosteroid taper beginning at week 4
  • Week 56 efficacy was similar between clinically-adjusted (CA) and therapeutic drug monitoring (TDM).  28% of patients in the CA group and 39% of TDM had their dose escalated.
  • Safety profiles were comparable between dosing regimens.

In the discussion, the authors wade into the topic of TDM for adalimumab:

Results from the exploratory SERENE CD study suggesting there is no clinical benefit of a proactive TDM strategy over a CA strategy for optimizing adalimumab maintenance dosing align with the results from previous studies evaluating TDM of anti–tumor necrosis factor therapies in adult patients with inflammatory bowel disease. In the TAXIT study, proactive TDM was not superior to CA dose optimization for achieving remission at 1 year in patients with CD or ulcerative colitis.24 Similarly, in the TAILORIX study of patients with CD, proactive TDM failed to improve clinical and endoscopic remission rates over a CA approach.25 In contrast, proactive TDM led to a higher clinical remission rate than did reactive TDM among pediatric patients with CD in the PAILOT trial, but this trial was nonblinded and lacked endoscopic assessments.26

My take: This study shows that standard induction performed as well as higher dose induction in adults with Crohn’s disease. Also, this study found that TDM did not improve response at 56 weeks in adults. Due to differences in body size and metabolism, the exact role for TDM in pediatric patients needs further study.

Related blog posts:

HIR =high dose induction regimen, SIR =standard induction regimen

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

IBD and Chronic Recurrent Multifocal Osteomyelitis: Paradoxical Association with anti-TNF Therapy in Some Cases

MJ Dushnicky et al. JPGN 2021; 73: 626-629. Pediatric Patients with a Dual Diagnosis of Inflammatory Bowel Disease and Chronic Recurrent Multifocal Osteomyelitis

This article describes a retrospective review of seven patients with a dual diagnosis of inflammatory bowel disease (IBD) and chronic recurrent multifocal osteomyelitis (CRMO). In their cohort 4 of 6 were receiving anti-TNF therapy at the time of CRMO diagnosis. Misleading statements from this article:

  1. The triad of IBD, CRMO and psoriasis has not been reported previously to their knowledge
  2. “It seems unlikely that anti-TNF-alpha therapy would promote its [CRMO] development”

In JPGN Reports (not available on pubmed), Cordesse et al (JPGN Reports; November 2020 – Volume 1 – Issue 2 – p e007) identified the association of IBD, CRMO and psoriasis; in addition, they identified a paradoxical reaction to anti-TNF-alpha therapy; in this case series of three patients, anti-TNF-alpha therapy triggered CRMO and stopping anti-TNF-alpha therapy led to resolution of CRMO in two of the cases.

In a response to a letter to the editor (Hochman JA. JPGN 2022; DOI: 10.1097/MPG.0000000000003407. Faulty Information Regarding CRMO and IBD), Dushnicky et al (DOI: 10.1097/MPG.0000000000003433) note that JPGN Reports is not available on Pubmed; however, the articles that have described this association are near the top of a google search if one looks for “IBD, CRMO and Psoriasis.” Interestingly, in their response to the letter to the editor, the authors did not amend their claim that anti-TNF therapy is unlikely to promote CRMO despite being furnished with information showing that it can. In my view, the situation with CRMO is similar to psoriasis which can be treated with anti-TNF therapy and can paradoxically be caused by anti-TNF agents as well.

My take:

  1. CRMO is important to recognize due to its association with IBD and to realize that antibiotics are not an effective treatment.
  2. Anti-TNF-alpha agents can cause CRMO in some patients.
  3. In 2022, a web browser search (eg Google), in addition to Pubmed, is probably worthwhile when claiming that this is the first case of xyz ‘to our knowledge.’
Bahamas (from a friend)

Early Antibiotics -Minimal Risk for Crohn’s Disease

Previous studies have shown an association between the early use of antibiotics and an increased risk of inflammatory bowel disease. A recent study examined all the children born in Denmark from 1995-2009 and followed them up to 2013 via a prospectively maintained database.

A Mark-Christensen et al. Inflamm Bowel Dis 2022; 28: 415-422. Early-Life Exposure to Antibiotics and Risk for Crohn’s Disease: A Nationwide Danish Birth Cohort Study 

During a median 9.5 years (9.3 million total person-years), CD was diagnosed in 208 of 979,039 children.

Key findings:

  • Antibiotic use in the first year of life was associated with a higher risk of CD (adjusted hazard ratio, 1.4)…with the highest risk with ≥6 courses of antibiotics (adjusted hazard ratio, 4.1)
  • The cumulative risk of CD at the 11th birthday for children exposed to antibiotics in their first year of life was 0.16% compared to 0.11% for children unexposed to antibiotics in their first year of life. 

My take: This study indicates that antibiotics (and/or serious infections) are associated with an increased the risk of pediatric Crohn’s disease but the absolute risk is very low. We still have a lot to learn about how environmental exposures, including diet, infections, antibiotics, and pollution, contribute to the increasing prevalence of inflammatory bowel disease.

Related blog posts:

From Atlanta Botanical Gardens -Thanks to Jennifer for this picture

What is An Emulsifier and Are They Safe in Our Diets?

Two recent articles examine emulsifiers and their potential impact on the GI tract and beyond.

Levine et al provide a good overview of the topic of emulsifiers. Key points:

  • Emulsifiers allow “the mixing of water and and water-soluble agents with fats and fat-soluble agents that is they possess both hydrophilic and lipophilic properties”
  • The FDA “has been responsible for approving the use of all direct food additives” (n=~3000) and “for regulatory purposes, [the FDA excluded] some substances that were generally regarded as safe (GRAS) (n=~450)…Precisely how some emulsifiers gained GRAS status is unclear.
  • “Lecithin” is derived from the Greek name for egg yolk (lekithos). “Over the years the use of the term “lecithin” has been taken to include various mixtures of different phospholipids” (not just phosphatidylcholine).
  • Lecithin can provide the substrate “for the production of trimethylamine N-oxide (TMAO)…linked to cardiac events and cardiovascular inflammation.”
  • “The list of emulsifiers that are widely used, but not considered GRAS, most notably include polysorbate 80 (p80), carboxymethylcellulose (CMC) and carrageenan…these emulsifiers have been linked to the disruption of the microbiota and gut mucosal lining…In addition, low-grade inflammation [has been] associated with consumption of emulsifying agents such as CMC and p80” [in mouse models].
  • The International Organization for the Study of Inflammatory Bowel Disease (IOIBD) has recommended that IBD patients “limit consumption of certain commonly encountered synthetic emulsifiers, specifically carboxymethylcellulose (E466/cellulose gum) and polysorbate 80 (E433) [which] are present in many processed foods, such as ice cream. The group also recommends a decrease in foods containing carrageenan”

In the second study by Chassaing et al with 16 healthy adults, the authors studied the effects of CMC in those with an emulsifier-free diet (n=9) or an identical diet enriched with CMC (n=7).

Key findings:

  • Relative to control subjects, CMC consumption modestly increased postprandial abdominal discomfort and perturbed gut microbiota composition in a way that reduced its diversity
  • CMC-fed subjects exhibited changes in the fecal metabolome, particularly reductions in short-chain fatty acids and free amino acids
  • 2 subjects consuming CMC who exhibited increased microbiota encroachment into the normally sterile inner mucus layer, a central feature of gut inflammation, as well as stark alterations in microbiota composition

My take: The dramatic increase in the prevalence of IBD over the past 50 years indicates a strong influence of environment factors, particularly diet. Determining which of these factors are most important will be challenging. These articles indicate that some emulsifiers could be contributing to GI tract inflammation and non-GI tract inflammation as well.

The challenges with identifying dietary factors relate to difficulties with using randomized controlled trials (especially eliminating delicious foods) to assess the impact over a long period of follow-up.

Related blog posts:

New Therapy for Crohn’s Disease: Mirikizumab

Because our office is one of the centers participating in a mirikizumab study for adolescents, I was particularly interested in seeing the published results of a phase 2 study in 191 adults.

BE Sands et al. Gastroenterol 2022; 162: 495-508. Open Access: Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Crohn’s Disease

Summary Video Link (worth a watch!): Summary of Mirikizumab Study (4:25 minutes)

Background: “Mirikizumab (LY3074828) is a humanized immunoglobulin G4 (IgG4)–variant monoclonal antibody that binds specifically to the p19 subunit of IL23 and has demonstrated efficacy in psoriasis and ulcerative colitis, and is currently in phase 3 testing for psoriasis, ulcerative colitis, and CD. We evaluated the efficacy and safety of mirikizumab for the treatment of patients with moderately-to-severely active CD”

Methods: Patients (N = 191) were randomized (2:1:1:2) to receive placebo (PBO), 200, 600, or 1000 mg mirikizumab, administered intravenously (IV) every 4 weeks. Patients who received mirikizumab and achieved ≥1 point improvement in Simple Endoscopic Score-CD at Week 12 (rerandomized maintenance cohort) were rerandomized to continue their induction IV treatment (combined IV groups [IV-C]) or receive 300 mg mirikizumab subcutaneously (SC) every 4 weeks. Nonrandomized maintenance cohort included endoscopic nonimprovers (1000 mg) and PBO patients (PBO/1000 mg) who received 1000 mg mirikizumab IV from Week 12. The primary objective was to evaluate superiority of mirikizumab to PBO in inducing endoscopic response (50% reduction from baseline in Simple Endoscopic Score-CD) at Week 12.

**approximately two thirds of participants had received biologic therapy and approximately half of all patients in this trial having experienced at least 1 biologic failure

Key findings:

  • At Week 12, endoscopic response was significantly higher for all mirikizumab groups compared with placebo (PBO) (200 mg: 25.8%, P = .079; 600 mg: 37.5%, P = .003; 1000 mg: 43.8%, P < .001; PBO: 10.9 %). 
  • Endoscopic response at Week 52 was 58.5% (24/41) and 58.7% (27/46) in the IV-C (combined IV groups) and SC (subcutaneous) groups , respectively. See 4th and 6th slides below which show that those with response at 12 weeks continued with response at 52 weeks.
In the Non-Randomized group which included non-improvers and placebo, they received
the highest dose, 1000 mg. A significant number of non-improvers responded at week 52.

My take: In this study of adults, with moderate to severe Crohn’s disease, Mirikizumab showed good efficacy and safety at both 12 weeks and 52 weeks. Because about half of the participants were biologic failures, this indicates that this agent shows promise in those with refractory disease.

NASPGHAN 2021 Nutrition Highlights

Thanks to Kipp Ellsworth for forwarding this link:

Nutrition for IBD website: NASPGHAN 2021 Nutritional Highlights

On this website: “Four presentations/lectures were released at the Nutritional Therapy for IBD Virtual Booth that provide a comprehensive review and update of the latest information regarding the use of EEN and therapeutic diets in the management of IBD”

Why Do We Need Dietary Therapies for IBD

Presenter: Lindsey Albenberg, DO

Dr. Lindsey Albenberg, a clinician and researcher from Children’s Hospital of Philadelphia, describes the rapidly increasing incidence of IBD and its relationship to diet, microbiome and the immune system. She reviews the rationale and science supporting the use of dietary therapy to compliment drug therapy as an avenue to potentially achieve higher, more sustainable and possibly safer levels of remission long term in pediatric patients.

The Crohn’s Disease Exclusion Diet Updates: December 2021

Presenter: Rotem Sigall Boneh, RD. Rotem Sigall Boneh, RD, a primary researcher and developer of CDED, provides an overview of the accumulating data with CDED in combination with PEN, including the newly published results of adult data with important endoscopic findings and further shares real world experience and application of nutritional therapy.

IBD Anti-inflammatory Diet or IBD-AID: Proof of Concept

Presenter Ana Maldonado-Contreras, MSc, PhD. Dr. Ana Maldonado-Contreras, a lead researcher in IBD-AID explains the relationship between diet, microbiome and immune function with the design and rational of IBD-AID to manipulate the microbiome. She shares the recently published data of the impact of IBD-AID on the microbiome and cytokine levels specific to food components.

Nutritional Therapy: Perioperative + Complicated Crohn’s Disease

Presenter Andrew S. Day, MB, ChB, MD, FRACP, AGAF

At the NTforIBD Nutritional Symposium prepared for NASPGHAN2021, Professor Day provides insight into the important role of EEN, an underutilized option to both induce remission and improve outcomes in complicated and peri-operative patients.

IBD Shorts: Fecal Calprotectin in UC & Medication Withdrawal, Outcome of Biosimilar Reverse Switches, Vedolizumab after Anti-TNF Therapy

TW Stevens et al. Inflamm Bowel Dis 2021; 19: 2333-2342. Open Access. Diagnostic Accuracy of Fecal Calprotectin Concentration in Evaluating Therapeutic Outcomes of Patients With Ulcerative Colitis

Key finding: A post hoc analysis of data from a phase 4 trial (the MOMENTUM trial) found that, even in patients (n=593 at week 8, n=305 at week 52) with complete endoscopic healing of UC, FC concentration can be used to discriminate patients with ongoing microscopic inflammation from patients with histologic remission.  The optimal FC cut-off concentrations for identification of patients with histologic remission were 75 μg/g at week 8 and 99 μg/g at week 52.

A Cassinotti et al. Clin Gastroenterol Hepatol 2021; 19: 2293-2301. Noninvasive Monitoring After Azathioprine Withdrawal in Patients With Inflammatory Bowel Disease in Deep Remission

Key finding: In this prospective study, 57 patients in deep remission stopped azathioprine after a median of 7 years. 26 (46%) relapsed within a median of 15 months. Fecal calprotectin (FC) levels were >50 mcg/g in all patients with relapse (FC specificity 100%) but the sensitivity was only 50%. Thus, having a normal FC does not preclude relapse but elevated FC is associated with relapse.

S Mahmmod et al. Inflamm Bowel Dis 2021; 27: 1954-1962. Outcome of Reverse Switching From CT-P13 to Originator Infliximab in Patients With Inflammatory Bowel Disease

In this retrospective study, 75 patients, 9.9% of all patients, who had been changed from originator infliximab to a biosimilar had clinical worsening. Key finding: Improvement of reported symptoms was seen in 73.3% of patients after reverse switching back to originator infliximab; alsor 7 out of 9 patients (77.8%) with loss of response regained response

J Kim et al. Inflamm Bowel Dis 2021; 27: 1931-1941. Clinical Outcomes and Response Predictors of Vedolizumab Induction Treatment for Korean Patients With Inflammatory Bowel Diseases Who Failed Anti-TNF Therapy: A KASID Prospective Multicenter Cohort Study

Key finding: Clinical remission rates with vedolizumab among patients with CD (n=80) and patients with UC (n=78) were 44.1% and 44.0%. Among patients with UC, the endoscopic remission rate was 32.4%