Tag Archives: Crohn’s disease

Pediatric Data for Ustekinumab Therapy in Crohn’s Disease

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D Turner et al. JPGN 2024; 79:315–324. Ustekinumab in paediatric patients with moderately to severely active Crohn’s disease: UniStar study long-term extension results

Dosing: “Patients were randomised 1:1 and stratified by body weight (<40 or ≥40 kg) to receive a single induction dose of lower- or higher-dose IV ustekinumab (lower dose: 3 mg/kg [<40 kg] and 130 mg [≥40 kg]; higher dose: 9 mg/kg [<40 kg] and 390 mg [≥40 kg]). Doses specified as higher were selected to deliver ustekinumab exposure comparable to a reference adult population with CD.7, 12 At Week 8, patients received a single SC maintenance dose of ustekinumab (2 mg/kg [<40 kg]; 90 mg [≥40 kg]).”

Key findings:

  • Of the 34 patients who entered the LTE, 25 patients with evaluable data completed Week 48, and 41.2% (14/34) achieved clinical remission at Week 48
  • Efficacy and PK through 1 year in ustekinumab-treated paediatric patients were comparable to those previously reported in adults. No new safety or immunogenicity signals were reported through 4 years of ustekinumab treatment.

My take (borrowed in part from authors): “Overall, long-term data support the SC dose regimens of 90 mg as maintenance therapy for the treatment of CD for a paediatric population with ≥40 kg body weight. A phase 3 study of ustekinumab (ClinicalTrials.gov Identifier: NCT04673357) is ongoing to further evaluate dose regimens for paediatric patients <40 kg and ≥40 kg.” This type of data is essential to support the use of advanced therapies like ustekinumab until they receive specific regulatory approval for children (often 8-10 years after approval in adults).

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Risankizumab Outperforms Ustekinumab

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L Peyrin-Biroulet et al. NEJM 2024; 391:213-223. Risankizumab versus Ustekinumab for Moderate-to-Severe Crohn’s Disease

Background: “Interleukin-23 is a heterodimeric proinflammatory cytokine comprising a p40 subunit shared with interleukin-12 and a unique p19 subunit that plays a key role in skin, joint, and gastrointestinal inflammation.16 Ustekinumab and risankizumab are humanized IgG1 monoclonal antibodies; ustekinumab selectively binds p40, and risankizumab selectively binds p19…In head-to-head trials directly comparing their efficacy in psoriasis, risankizumab was superior to ustekinumab, which suggests greater efficacy with p19 blockade than with p40 blockade.”

This “SEQUENCE” trial was a phase 3b, multicenter, open-label, randomized controlled trial with 527 patients with moderate-to-severe Crohn’s disease who either had an inadequate response or had intolerance to anti-TNF agents, received either risankizumab or ustekinumab.

Key Findings:

  • A higher percentage of patients in the risankizumab group than in the ustekinumab group completed all the assigned treatment (90.2% [230 of 255 patients] vs. 72.8% [193 of 265 patients]).  The primary reason for discontinuation of risankizumab was an adverse event (3.1% [8 of 255 patients]), and the primary reason for discontinuation of ustekinumab was lack of efficacy (13.2% [35 of 265 patients]
  • Clinical remission at 48 weeks was 60.8% with risankizumab and 40.8%% with ustekinumab (P<0.001); there were similar rates of glucocorticoid-free clinical remission, 60.8% vs 40.4% respectively. Endoscopic response at 48 weeks was 45.1% and 21.9% respectively.

My take: These head-to-head results showed the superiority of risankizumab over ustekinumab across numerous clinical and endoscopic end points, including glucocorticoid-free clinical remission and endoscopic remission. However, it is still concerning to me that endoscopic remission rates were only 32% at 1 year and that less than half had an endoscopic response.

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Crohn’s Disease: Risankizumab Real-World Data

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A Zinger et al. Clin Gastroenterol Hepatol 2024; 22: 1336-1338. Risankizumab Effectiveness and Safety in Crohn’s Disease: Real-world Data From a Large Tertiary Center

In a group of 80 patients with Crohn’s disease with evidence of active disease, the authors examined the effectiveness of risankizumab with prospectively-collected data. Patients received 600 mg intravenously at 0, 4, and 8 weeks. Only 6 patients (8%) were unexposed to prior advanced therapy; 44 patients (55%) had prior ustekinumab (UST) therapy.

Key findings:

  • Clinical remission was 78% in patients without prior ustekinumab therapy and 64% in those with prior ustekinumab therapy
  • Steroid-free clinical remission was 75% and 52%, respectively in patients without and with prior ustekinumab therapy. Overall, 63% of patients achieved a steroid-free clinical remission

My take: This study shows that risankizumab, a selective IL23 inhibitor, has good effectiveness, even in patients previously treated with a IL12/23 inhibitor. It highlights our need to better understand the reasons why a more selective agent is able to work after patients failed to respond to UST treatment.

Unrelated article: KA Chien et al. JPGN 2024; 79: 10-17. (Kudos to the authors including my partner Dr. Ben Gold). This article detailed the median work RVUs target for practices and composition of healthcare team to provider ratios: Nursing 0.80, MA 0.29, dietician 0.29, social worker 0.14, and psychologist 0.13. The article reviews salary structure/incentives and wellness initiatives as well.

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Should Vedolizumab Be Used as a First Line Agent for Crohn’s Disease?

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B Bokemeyer et al. Inflamm Bowel Dis 2024; 30: 746-756.

Methods: 3277 adult biologically-unexposed CD patients starting therapy with VEDO or anti-TNF were consecutively enrolled in 45 IBD centers across Germany (2017-202). This was a non-randomized, observational study with prospectively collected data.

Findings:

  • Anti-TNF agents had higher induction clinical remission rates compared to vedolizumab: 73.9% 56.3% vs, P < .05
  • Vedolizumab (VEDO) had higher long-term clinical remission rates: clinical remission after 2 years was significantly better for VEDO compared with anti-TNF, 74.2% vs 44.7%; P < .05. This was associated with a much better treatment persistent rate. The switch rate for VEDO was 17% compared with 44% for anti-TNF agents.
  • Among week 14 responders, VEDO 2-year clinical remission rates were 88.6% compared to 45.8% (P < .00001) for anti-TNF agents

The discussion describes the strengths and limitations of this study. As it is not a randomized control trial, there can still be selection bias and confounding even with propensity scoring that was done in this study. The authors note that in a prior analysis of RCTs comparing infliximab to vedolizumab in CD patients, that infliximab had higher efficacy for induction and maintenance, though the clinical remission rates were only modestly improved at 1 year. (L Peyrin-Biroulet et al. BMC Gastroenterol 2022; 22: 291).

Recent expert guidance (2024) has favored infliximab and risankizumab over other advance therapies in CD patients who have not had previous biologic therapies (see: Comparative Evidence and Positioning Advance Therapies for Inflammatory Bowel Disease).

My take: This study shows that vedolizumab is a good advanced therapy for patients with Crohn’s disease without prior therapy. Among those with a clinical response at 14 weeks, the treatment durability was particularly impressive in this cohort.

It would be great to see an RCT in children with CD comparing IFX to VEDO. Treatment persistence is even more important in younger patients.

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IBD Updates: Insurance Barriers Hindering Care, Guselkumab vs Ustekinumab, IBD Pain Management Guidelines

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B Constant et al. AJG 2024;  DOI: 10.14309/ajg.0000000000002851. Insurer-Mandated Medication Utilization Barriers are Associated With Decreased Insurance Satisfaction and Adverse Clinical Outcomes: An Inflammatory Bowel Disease Partners Survey

Key findings: In this longitudinal survey with 2017 patients, 72% experienced an insurer-mandated barrier, most commonly prior authorizations (51%). Fifteen percent were denied an IBD medication by their insurer, 22% experienced an insurance-related gap in therapy, and 8% were forced by their insurer to switch from an effective medication.  Several insurance barriers were linked to negative downstream clinical outcomes, including prior authorizations associated with corticosteroid rescue (odds ratio [OR] 2.24]), forced medication switches associated with continued disease activity (OR 3.28), and medication denials associated with IBD-related surgery (OR 8.92).

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S Danese et al. Lancet Gastroenterol Hepatol 2024; 9: 133-146. Efficacy and safety of 48 weeks of guselkumab for patients with Crohn’s disease: maintenance results from the phase 2, randomised, double-blind GALAXI-1 trial

In this phase 2 randomised, multicentre, double-blind trial with 309 adults, the authors report on the safety and efficacy of subcutaneous guselkumab maintenance regimens to week 48 in the GALAXI-1 study. Key findings:

  • “At week 48, the numbers of patients with CDAI clinical remission were 39 (64%) in the guselkumab 200→100 mg group, 46 (73%) in the guselkumab 600→200 mg group, 35 (57%) in the guselkumab 1200→200 mg group, and 37 (59%) in the ustekinumab group.”
  • “Eendoscopic remission was seen in 11 (18%), 11 (17%), 20 (33%), and four (6%) patients, respectively.”

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L Keefer et al. Gastroenterology 2024; 166: 1182-1189. AGA Clinical Practice Update on Pain Management in Inflammatory Bowel Disease: Commentary

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

IBD Updates: Diagnosis Change in Pediatric IBD

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H Duarte et al. JGPN 2024; 78: 623–633. Diagnosis change in pediatric inflammatory bowel disease

This was a retrospective study using the ICN registry. Key findings:

  • Overall, 6.1% of 18,055 patients aged 1–20 years changed diagnosis.
  • Ulcerative colitis was reclassified in 347/4758 (7.3%).
  • Crohn’s disease was reclassified in 257/12,178 (2.1%)
  • IBD-U was reclassified in 495/1119 (44.2%)

My take: This study showed that a change in diagnosis to Crohn’s disease was the most common reclassification. While the study did not find that a younger age specifically increased the risk of a diagnosis change, it is noted that IBD-U diagnosis was utilized more frequently in children less than 11 years of age.

Of course, this study will be useless when we no longer utilize the terms Crohn’s disease and Ulcerative Colitis. ‘”‘The concept of IBD as two diseases, Crohn’s disease and UC, is flawed; there are more than 200 susceptibility genes for inflammatory bowel disease'”‘ (see post: Dr. Joel Rosh: Positioning Therapies for Pediatric Ulcerative Colitis)

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View Near Arches National Park

IBD Updates: Reducing Postoperative Crohn’s Disease, How Effective is IFX after Adalimumab, UST vs VDZ in Pediatric UC

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C Hernandez-Rocha et al. J Crohns Colitis 2024: 18: 615–627. Clinical Predictors of Early and Late Endoscopic Recurrence Following Ileocolonic Resection in Crohn’s Disease

Prospective Study n=365 adult patients with post-operative Crohn’s disease. Findings: At first colonoscopy, 109 [29.9%] had recurrence. Male gender (odds ratio [OR] = 1.95), non-White ethnicity [OR = 2.48], and postoperative smoking [OR = 2.78] were associated with recurrence, while prophylactic anti-TNF reduced the risk [OR = 0.28]. Postoperative anti-TNF prophylaxis had a protective effect on anti-TNF experienced patients but not on anti-TNF naïve patients. Among patients without recurrence at first colonoscopy, Rutgeerts score i1 was associated with subsequent recurrence [OR = 4.43]

A Lecoutour et al JPGN 2024; 78:1116–1125. Efficacy of infliximab after loss of response of/intolerance to adalimumab in pediatric Crohn’s disease: A retrospective multicenter cohort study of the “GETAID pédiatrique”

Key findings: In this retrospective study, 27 of 32 patients (84.4%) were still on IFX at 12 months of the switch. Among them, 13 had discontinued ADA because of a LOR, 12 for insufficient response and 2 due to primary nonresponse. At 1 year, 22 patients were in corticosteroid free clinical remission (68.7%).

PV Patel et al. JPGN 2024; 78:1126–1134. Real‐world effectiveness of ustekinumab and vedolizumab in TNF‐exposed pediatric patients with ulcerative colitis

Using the ICN registry, this observational study had 262 anti-TNF refractory patients receiving VDZ and 74 patients receiving UST. Key finding: At 6 months, 28.3% of patients on VDZ and 25.8% of those on UST achieved CFCR (p= 0.76)

Orchid, Atlanta Botanical Gardens

Comparative Evidence and Positioning Advance Therapies for Inflammatory Bowel Disease

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PS Dulai et al. Gastroenterol 2024; 166: 396-408. Open Access! Integrating Evidence to Guide Use of Biologics and Small Molecules for Inflammatory Bowel Diseases

“In this review, we provide a framework for clinicians and researchers to understand key differences in sources of evidence, how different methodologies are applied to study the comparative effectiveness of advanced medical therapies in IBD, and considerations for how these sources of evidence can be used to better integrate current guideline recommendations.”

This article explains the use of randomized controlled trials, “real-world evidence”/observational comparative studies, network meta-analysis, and post-hoc comparisons from randomized studies.

“The authors advocate for “”Given the rapidity with which new advanced medical therapies are becoming available in IBD, which quickly make current guidelines obsolete, living guidelines may offer a unique consideration to ensure applicability to routine care.”

My take: This article provides a useful update of current advanced therapies and information in positioning these advanced therapies. It would be a great service if the IBD community could create something similar to HCVguidelines.org. The latter was a coordinated effort by the AASLD and IDSA to help provide expert advice during a deluge of amazing advances in HCV. And just like HCVguidelines, it is important to address “special” populations including pediatric patients and patients with very early onset IBD.

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Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Modest Benefits of Early Advanced Therapies in IBD?

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R Lujan, R Buchuk et al. Gastroenterol 2024; 166: 815-825.Early Initiation of Biologics and Disease Outcomes in Adults and Children With Inflammatory Bowel Diseases: Results From the Epidemiology Group of the Nationwide Israeli Inflammatory Bowel Disease Research Nucleus Cohort

Methods: All patients diagnosed with CD or UC in Israel (2005–2020) were included in the Epidemiology Group of the Israeli Inflammatory Bowel Disease Research Nucleus cohort. The authors compared disease duration at biologics initiation (ie, 0–3 months, >3–12 months, >1–2 years, and >2–3 years) using the cloning, censoring, and weighting by inverse probabilities method to emulate a target trial, adjusting for time-varying confounders and selection bias.


Of the 34,375 included patients (of whom 5240 [15%] were children), 7452 of 19,264 (39%) with CD and 2235 of 15,111 (15%) with UC received biologics. To attempt to adjust for patient characteristics, “essentially, each patient was cloned 4 times and 1 clone was assigend to each treatment strategy at baseline…[they were removed] subsequently if they did not receive the biologic within the acceptable time window.” Key findings:

  • In CD, by 10 years postdiagnosis, the probability of CD-related surgery decreased gradually but modestly with earlier initiation of biologics; a significant difference was noted between >2–3 years (31%) and 0–3 months (18%; P = .02; number needed to treat, 7.7)
  •  In CD, the 10-year probability of steroid dependency for the 0–3-month period (19%) differed both from the >2–3-year (31%; P < .001) and 1–2-year periods (37%; P < .001).
  •  In UC, no significant differences in colectomy or steroid dependency rates were observed between the treatment initiation periods.
  • Similar trends were noted in the pediatric population.

Thus, overall, the study found that early initiation of biologics was associated only with a modest reduced risk of surgery and steroid dependency for Crohn’s disease. It was not found to reduce risk of colectomy or steroid dependency in UC.

My take: In my view, this study probably underestimates the benefits of early biologic therapy. Even though, lead time bias can skew interpretation, inadequately-treated disease likely leads to long-term damage. The associated editorial (pg 728) by Murphy notes that despite the sophisticated statistical methodology, all observational studies cannot fully control for unmeasured confounders.

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Colorado River Near Moab, UT

This past weekend there were two fun events in Atlanta -Porchfest (Virginia Highlands) and Midtown Garden Stroll. Porchfest featured more than 50 local bands.

Here’s a couple photos from the Midtown Garden Stroll: