Tag Archives: ustekinumab

Treatments for “Bad” Inflammatory Bowel Disease (Part 1)

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Generally, in my view, “bad” inflammatory bowel disease (IBD) occurs when treatments are not working; though, many would argue that any IBD is bad IBD. Over the next few days, reviewed articles will focus on the problem of IBD that is not responding well to treatment.

A Yerushalmy-Feler et al. JPGN 2022; 75: 717-723. Safety and Potential Efficacy of Escalating Dose of Ustekinumab in Pediatric Crohn Disease (the Speed-up Study): A Multicenter Study from the Pediatric IBD Porto Group of ESPGHAN

In this retrospective study with 69 children with Crohn’s disease (CD) from 25 centers, the authors looked at the effectiveness of ustekinumab (UST) dose escalation which entailed reducing frequency to less than every 8 weeks. Most children were biologic (98.6%)- and immunomodulator (86.8%)- experienced.

Key findings:

  • Clinical response and remission were observed at 3 months after UST escalation in 46 (67%) and 29 (42%) children, respectively.
  • Fecal calprotectin level from 1100 (500–2300) to 515 (250–1469) µg/g (P = 0.012) 3 months post-escalation
  • Endoscopic and transmural healing were achieved in 3 of 19 (16%) and 2 of 15 (13%) patients, respectively

In their discussion, the authors note that UST has not received FDA approval despite the fact that it has become a common second- and third-line biologic therapy for pediatric CD.

My take: This study supports the common practice of escalation of UST for children with active CD despite treatment at every 8 weeks.

Related Ustekinumab Studies:

Related blog posts:

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Improving MRE Utility in Pediatric Crohn’s

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G Focht et al. Gastroenterol 2022; 163: 1306-1320. Open Access! Development, Validation, and Evaluation of the Pediatric Inflammatory Crohn’s Magnetic Resonance Enterography Index From the ImageKids Study

In this prospective study of children (n-240) with Crohn’s disease, the authors utilized ileocolonoscopy and MREs (n=159) and followed for 18 months.

Key findings:

  • 5 MRE findings were identified to generate a PICMI (Pediatric Inflammatory Crohn’s Magnetic Resonance Enterography Index): wall thickness, wall diffusion weighted imaging, ulcerations, mesenteric edema, and comb sign
  • In the validation cohort of 81 MREs, the weighted global PICMI correlated well with the radiologist global assessment (r = 0.85; P < .001) and with the simple endoscopic score in a subsample with ileocolonic disease (r = 0.63; P < .001).
  •  Interobserver and test-retest reliability were high (interclass correlation coefficients, 0.84 and 0.81, respectively; both P < .001)
  • Transmural healing was defined as PICMI ≤10 and response as a change of >20 points with excellent discriminative validity (area under the receiver operating characteristic curve = 0.96

My take: This study identifies a specific MRI index (PICMI) that is reliable for assessing the entire bowel in pediatric CD and does not require intravenous gadolinium or rectal enema. By using a standardized tool, similar to SEMA-CD for ileocolonoscopy, this will improve the usefulness of MREs.

Also noted: Link: Clinical support tool (sponsored by AGA) that provides individualized information on 2nd line therapy effectiveness (ustekinumab and vedolizumab) with regard to probability of achieving clinical remission, how quick to expect a response, and whether therapeutic drug monitoring is needed.

Related blog posts:

IBD Updates: Dietary Patterns and Disease Activity, Ustekinumab in SUSTAIN study, INSPECT Study for Perianal Fistulas

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BN Limketkai et al. Inflamm Bowel Dis 2022; 28: 1627-1636. Open Access! Dietary Patterns and Their Association With Symptoms Activity in Inflammatory Bowel Diseases. This retrospective study with dietary surveys of 691 participants found the following:

  • Compared with WD1 (typical Western Diet), PB2 (Plant-based diet 2) was associated with lower odds of active symptoms for CD (odds ratio [OR], 0.32
  • PB1 (Plant-based diet 1) was associated with lower odds of active symptoms for participants with UC (OR, 0.45; 95% CI, 0.23-0.90) but not for participants with CD (OR, 0.95

Diet PB1 (“Plant-based Diet 1”) was characterized by much higher intake of fruits, vegetables, plant-based proteins, and cooked grains than most other dietary clusters. There was low water intake in favor of juices and other beverages. There was otherwise average intake of added fats and oils, sugars, seafood, and dairy products, and modest intake of meats, eggs, mixed grains, and breads.

Diet PB2 (“Plant-based Diet 2”) was characterized by high intake of fruits, vegetables, plant proteins, and cooked grains and low intake of animal proteins (especially red and cured meats), added fats, sweetened beverages, sweet bakery products, other desserts, eggs, and breads. There was also a reduction of other beverages in favor of water. There was otherwise an average intake of seafood and dairy products.

M Chaparro et al. Inflamm Bowel Dis 2022; 28: 1725-1736. Open Access! Long-Term Real-World Effectiveness and Safety of Ustekinumab in Crohn’s Disease Patients: The SUSTAIN Study In this retrospective study, 97% of the 463 patients had received prior biological therapy.

  • At week 16, 56% had remission, 70% had response
  • 26.1% required dose escalation or intensification
  • After a median follow-up of 15 months, 356 (77%) patients continued treatment.
  • Previous intestinal surgery and concomitant steroid treatment were associated with higher risk of ustekinumab discontinuation.
  • Neither concomitant immunosuppressants nor the number of previous biologics were associated with ustekinumab discontinuation risk

J Panes et al. Inflamm Bowel Dis 2022; 28: 1737-1745. Open Access! INSPECT: A Retrospective Study to Evaluate Long-term Effectiveness and Safety of Darvadstrocel in Patients With Perianal Fistulizing Crohn’s Disease Treated in the ADMIRE-CD Trial

Background: The current chart review study evaluated the longer-term effectiveness and safety of darvadstrocel (expanded allogeneic adipose-derived mesenchymal stem cells).; n=43 treated patient and n=46 controls.

Key findings:

  • At 52, 104, and 156 weeks posttreatment, clinical remission was observed in 29 (67.4%) of 43, 23 (53.5%) of 43, and 23 (53.5%) of 43 darvadstrocel-treated patients, compared with 24 (52.2%) of 46, 20 (43.5%) of 46, and 21 (45.7%) of 46 control subjects, respectively.

SEAVUE: Head-to-Head Ustekimumab vs. Adalimumab

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BE Sands et al.Lancet 2022; 399: 2200-2211. Ustekinumab versus adalimumab for induction and maintenance therapy in biologic-naive patients with moderately to severely active Crohn’s disease: a multicentre, randomised, double-blind, parallel-group, phase 3b trial

Methods: This was  “a randomised, double-blind, parallel-group, active-comparator, phase 3b trial (SEAVUE) at 121 hospitals or private practices in 18 countries. We included biologic-naive patients aged 18 years or older with moderately to severely active Crohn’s…Eligible patients were randomly assigned (1:1; via an interactive web response system) to receive ustekinumab (approximately 6 mg/kg intravenously on day 0, then 90 mg subcutaneously once every 8 weeks) or adalimumab (160 mg on day 0, 80 mg at 2 weeks, then 40 mg once every 2 weeks, subcutaneously) through week 56. Study treatments were administered as monotherapy and without dose modifications.”

386 patients were enrolled.

Key findings:

  • 29 (15%) of 191 patients in the ustekinumab group and 46 (24%) of 195 in the adalimumab group discontinued study treatment before week 52
  • At week 52, 124 (65%) of 191 patients in the ustekinumab group versus 119 (61%) of 195 in the adalimumab group were in clinical remission (CDAI <150)
  • Endoscopic remission at week 52: ustekinumab 29% and for adalimumab 29%
  • Endoscopic response at week 52: ustekinumab 42%and for adalimumab 37%
  • Rapid onset of clinical response was seen with both therapies with improvement noted as early as week 2 assessment
  • Antidrug antibodies were less frequent with ustekinumab compared to adalimumab: 2% vs 74%.
  • Infections were reported in 65 (34%) of ustekinumab group compared to 79 (41%) of adalimumab group. Serious infections were reported in four (2%) of 191 patients in the ustekinumab group and five (3%) of 195 in the adalimumab group.
  • No deaths occurred through week 52 of the study.

My take:

  1. Both medications had a high similar response rate. Ustekinumab had fewer patients discontinue medication and lower immunogenicity which could improve efficacy/duration of response in an extended study.
  2. It is good to see a well-designed head-to-head study rather than a placebo-control arm. Placebo-based studies are hard to justify given the availability of multiple effective agents.

Near Denali, AK

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

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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.

Related blog posts:

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Can You Give Ustekinumab Subcutaneously After IV Reaction?

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J Sunny et al. JPGN Reports: May 2022 – Volume 3 – Issue 2 – p e205 Open Access: Hypersensitivity Reaction to Ustekinumab in Pediatric and Young Adult Inflammatory Bowel Disease Patients: A Case Series

This is a case series of six pediatric patients and young adults who developed hypersensitivity reactions during intravenous infusion with ustekinumab (UST).

Key findings:

  • Hypersensitivity reactions during intravenous (IV) induction dose of UST, ranging from mild allergic reactions to anaphylaxis, with no antibodies detected in the two who had testing
  • Reactions occurred 0-30 minutes after start of infusion
  • Management was with methylprednisolone in 5 of 6 patients, diphendyramine in 3 of 6, and epinephrine in 1. One patient was managed with IV diphenhydramine alone.
  • Four of six continued with UST subcutaneously without reactions. ***Change of formulation of UST from IV to subcutaneous was done in a controlled hospital-based setting. The other two 33% were switched to another biologic due to physician preference and were never exposed to the subcutaneous formulation
  • Although the exact pathogenesis of this infusion reaction remains unknown, it has been attributed to EDTA

My take: It appears that patients with UST hypersensitivity reactions can be changed to SC formulation. The authors recommend to trial a subcutaneous dose of UST in a controlled setting; in addition, they suggest testing with skin prick testing or specific IgE levels to EDTA done by allergy and immunology.

Related blog posts:

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

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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.

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Ustekinumab vs Adalimumab: Head-to-Head Study

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From Gastroenterology & Endoscopy News: Head-to-Head Trial Shows Similar Efficacy and Safety With Ustekinumab and Adalimumab

An excerpt:

The first head-to-head trial comparing ustekinumab and adalimumab has found the two drugs are similarly safe and effective in patients with moderate to severe Crohn’s disease…

Dr. Scherl and her co-investigators in the SEAVUE trial randomly assigned 386 biologic-naive patients with Crohn’s disease to receive one year of treatment with either ustekinumab or adalimumab at standard on-label doses, with no dose escalation throughout the study period and no concomitant immunomodulators...

The findings, which were presented at the 2021 annual meeting of the European Crohn’s and Colitis Organisation (oral presentation OP02), showed that after one year of treatment, 65% of patients who received ustekinumab and 61% of those who received adalimumab achieved clinical remission, defined as a CDAI below 150...[And] similar additional outcomes, including clinical response at one year (72.3% for ustekinumab vs. 66.2% for adalimumab), corticosteroid-free remission at one year (60.7% vs. 57.4%, respectively), endoscopic remission at one year (28.5% vs. 30.7%) 

My take: This study indicates that ustekinumab likely has similar safety and efficacy as adalimumab (though the study did not allow dose escalation or immunomodulators); thus, it could be positioned as a first-line treatment. It is administered less frequently as well.

Related blog posts:

Ustekinumab in Pediatric Patients and More on VTE Prophylaxis

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FS Kim et al. JPGN 2021; 73: 610-614. Open Access (PDF): Experience Using Ustekinumab in Pediatric Patients With Medically Refractory Crohn Disease

In this retrospective study with 38 pediatric patients with Crohn’s disease, 34% had stricturing or penetrating disease. Key findings:

  • At time of last follow-up, 84.2% of patients remained on UST for a median duration on UST of 62.1 weeks, and 60.5% achieved clinical remission
  • 89.5% of patients had no significant adverse events
  • Sixteen (of 38, 42.1%) patients required dose escalation, to every 4 weeks (n= 15 of these 16, 93.8%) or every 6 weeks (Nn=1 of 16, 6.3%)

My take: Ustekinumab had good efficacy in this group of refractory pediatric patients.

Related blog posts:

E Story et al. JPGN 2021; 73: 604-609. Safety of Venous Thromboprophylaxis With Low-molecular-weight Heparin in Children With Ulcerative Colitis

In this retrospective study with 218 inpatient pediatric patients with active ulcerative colitis, the key findings:

  • Use of enoxaparin did not result in a greater fall in hemoglobin among those with acute severe colitis (initial PUCAI ≥65) during the week following admission and there was not an increased risk of needing a transfusion
  • VTE occurred in 2 of 130 in control group and 1 of 88 in enoxaparin group (enoxaparin group was sicker)

My take: The absolute risk of VTE is low in the pediatric population. This study shows that enoxaparin prophylaxis is NOT associated with increased issues with blood loss. In those with active disease, the presence of CVC and use of steroids are known risk factors and require consideration of, at minimum, nonpharmacologic interventions.

Related blog posts:

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Encouraging Safety Data for Ustekinumab & ESPGHAN Obesity Position Paper

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WJ Sandborn et al. Inflamm Bowel Dis 2021; 27: 994-1007. Full text: Safety of Ustekinumab in Inflammatory Bowel Disease: Pooled Safety Analysis of Results from Phase 2/3 Studies

Methods: Data from 6 ustekinumab phase 2/3 CD and UC studies were pooled, and safety was evaluated through 1 year; this included 2574 patients (1733 patient-years of follow-up)

Key Safety findings –Events per 100 patient years -placebo vs ustekinumab respectively:

  • Adverse events: 165.99 [95% CI, 155.81–176.67] vs 118.32 [95% CI, 113.25–123.55])
  • Serious AEs: 27.50 [95% CI, 23.45–32.04] vs 21.23 [95% CI, 19.12–23.51])
  • Infections 80.31 [95% CI, 73.28–87.84] vs 64.32 [95% CI, 60.60–68.21])
  • Serious infections: 5.53 [95% CI, 3.81–7.77] vs 5.02 [95% CI, 4.02–6.19])
  • Malignancies excluding nonmelanoma skin cancer: 0.17 [95% CI, 0.00–0.93] vs 0.40 [95% CI, 0.16–0.83])
  • Major cardiovascular events were rare with 2 in placebo group 0.34 and 2 in the ustekinumab group 0.12

More key findings:

  • No cases of progressive multifocal leukoencephalopathy or reversible posterior leukoencephalopathy
  • Antibodies to ustekinumab were identified in 3.6% of patients

My take: This study showed similar safety between ustekinumab and placebo, but is limited by short followup. The authors note that 5-year data from ustekinumab’s use with psoriasis has found no safety signals for malignancy.

Related blog posts:

Unrelated article: E Verduci et al. JPGN 2021; 72: 769-783: Full text: Role of Dietary Factors, Food Habits, and Lifestyle in Childhood Obesity Development: A Position Paper From the European Society for Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition