Tag Archives: Crohn’s disease

Proactive Therapeutic Drug Monitoring and Better Outcomes in Pediatric Crohn’s Disease (2024)

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S Ali et al. Clinical Gastroenterology and Hepatology, Volume 22, Issue 10, 2075 – 2083.e1. Characterization of Biologic Discontinuation Among Pediatric Patients With Crohn’s Disease

Methods:  Prospective ImproveCareNow registry data (n=823, from 7 centers) were supplemented with medical record abstraction. 

Treatment/Monitoring:

  • 86% started biologics (78% infliximab, 21% adalimumab, <1% others)
  • Twenty-six percent used concomitant immunomodulators for ≥12 months
  • Most (85%) measured TDM including 47% induction, 69% proactive, and 24% reactive

Key findings:

  • Twenty-nine percent discontinued their first biologic after median 793 days because of inefficacy (34%), anti-drug antibodies (8%), adverse events (8%), or non-adherence (12%)
  • Proactive TDM and concomitant immunomodulators were associated with 60% and 32% reduced biologic discontinuation
  • Half of patients discontinued biologics without trial of high-dose therapy and 14% without any evaluation
  • Among patients started with infliximab therapy, 62% of patients started at a dose of <6 mg/kg, 18% stared at a dose >8 mg/kg. 67% of patients underwent dose escalation. This is agreement with other studies indicating that as many as 80% of children need doses in excess of ‘standard’ dosing (5 mg/kg every 8 weeks)
  • In patients with anti-TNF medication inefficacy with TDM availability, 36% had infliximab or adalimumab levels below 5 mcg/mL. and 20% had levels between 6-8 mcg/mL.
  • Among patients who discontinued anti-TNF medications, 60% had serum trough levels less than 10 mcg/mL.
  • The rate of biologic durability was lower for those (n=61) receiving a 2nd biologic who had rates of remaining on agent of 56% at 1 yr, 28% at 2 yrs, and 10% at 4 yrs. In contrast, the first biologic had durability of 90% at 1 year, 79% at 2 years, and 66% at 4 yrs.

My take: This study strongly supports the use of proactive therapeutic drug monitoring. In addition, the authors make a compelling argument to optimize a therapy and evaluate carefully before switching to a new medication/biologic. Finally, the use of concomitant immunomodulators can improve medication durability; it is particularly important if needing to switch from one anti-TNF agent to another due to anti-drug antibodies.

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Pitt Street Bridge (Mt Pleasant, SC)

Moving Away From Placebo-Controlled Trials in Crohn’s Disease

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Din, Shahida et al. The Lancet Gastroenterology & Hepatology; 2024: DOI: 10.1016/S2468-1253(24)00264-4.  Open Access! Harms with placebo in trials of biological therapies and small molecules as induction therapy in inflammatory bowel disease: a systematic review and meta-analysis

Background: “Placebo-controlled trials are especially important during the early phases of drug development, as use of placebo aids early detection of efficacy or futility.”

Methods: The authors performed a systematic review which identified 47 trials including 20,987 patients (14 267 [68·0%] receiving active drug and 6720 [32·0%] receiving placebo) were eligible. The studies involved multiple RCTs of biologics and small molecules in IBD.

Key findings:

  • The risks of worsening of IBD activity (Active treatment vs placebo: 563/13,473 [4·2%] vs 530/6252 [8·5%];RR 0·48)
  • Withdrawal due to adverse event (Active treatment vs placebo: 401/13 363 [3·0%] vs 299/6267 [4·8%]; RR 0·62)
  • Serious adverse event (Active treatment vs placebo: 682/14,267 [4·8%] vs 483/6720 [7·2%]; RR 0·69)
  • Serious infection (Active treatment vs placebo: 140/14 ,194 [1·0%] vs 91/6647 [1·4%]; RR 0·67)
  • Serious worsening of IBD activity (Active treatment vs placebo: 187/11,271 [1·7%] vs 189/5056 [3·7%]; RR 0·4)
  • VTEs (Active treatment vs placebo: 13/7542 [0·2%] vs 12/2981 [0·4%]; RR 0·45)
  • All of these adverse outcomes were significantly lower with active drug than placebo. 

My take: Now that there are proven medications that are effective for moderate-to-severe Crohn’s disease, head-to-head trials of novel drugs against existing drugs with proven efficacy, rather than placebo-controlled trials, should be prioritized.

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Windy day at Isle of Palms, SC. There streams of sand flowing over the beach.

How Quickly Does Upadacitinib Work for Crohn’s Disease Symptoms?

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JF Colombel. et al. Clin Gastroenterol Hepatol 2024; 22: 1668-1677. Open Access! Upadacitinib Reduces Crohn’s Disease Symptoms Within the First Week of Induction Therapy

This study was a post hoc analysis included pooled data from 2 phase 3, multicenter, double-blind, 12-week induction trials (U-EXCEL and U-EXCEED) and 1 maintenance trial (U-ENDURE). The study included 1021 patients with Crohn’s disease (CD) (n = 674 UPA45; n = 347 PBO).

Key findings:

  • Upadacitinib 45 mg taken once daily resulted in rapid relief from CD symptoms within 5 to 6 days of treatment initiation and improved clinical outcomes starting at week 2.
  • The present analysis demonstrates symptomatic relief as early as day 5 to 6 for patients receiving UPA, with 16.7% of patients experiencing daily SF/APS clinical remission by day 5. 
  • The first achievement of daily stool frequency/abdominal pain score (SF/APS) clinical remission occurred earlier with UPA45 (median, 13 d) vs PBO (median, 32 d)
  • Patients treated with UPA45 showed improved rates of SF/APS clinical remission (21.1% UPA45 vs 8.9% PBO) and clinical response (58.8% UPA45 vs 37.9% PBO) starting at week 2 (both P ≤ .01).

In their discussion, the authors note that time to response to treatment with upadacitinib compares favorably to other advanced therapies:

“Vedolizumab resulted in symptomatic improvement within 2 to 4 weeks of treatment initiation16; ustekinumab led to clinical response and remission at week 3 or 6, depending on the dose.17 Similarly, of the time points analyzed, clinical response and/or clinical remission was observed as early as week 2 for risankizumab, 5 infliximab,18 and certolizumab pegol,19 and as early as week 1 for adalimumab.20,21“

My take: The rapid response seen in many patients indicate that upadacitinib can be a steroid-sparing therapy in patients with Crohn’s disease.

Unrelated article: E Louis et al. JAMA 2024; doi:10.1001/jama.2024.12414. Risankizumab for Ulcerative Colitis: Two Randomized Clinical Trials

Key findings:  Among the 975 patients with moderate to severe ulcerative colitis, analyzed in the induction trial, 1200 mg of risankizumab significantly increased the rates of clinical remission at 12-week follow-up compared with placebo (20.3% vs 6.2%, respectively). Among 548 patients included in the primary efficacy analysis for the maintenance trial, 180 mg of risankizumab and 360 mg of risankizumab significantly increased the rates of clinical remission (40.2% and 37.6%, respectively) compared with placebo (25.1%).

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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

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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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