Tag Archives: Crohn’s disease

Outcomes with Enteral Nutrition

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Notice: At this time, gutsandgrowth intends to post blogs 2-3 times per week rather than daily.

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N Davidson et al. JPGN 2022; 75: 70-75. 6- and 12-Month Outcomes after 90:10 Enteral Nutrition Induction Therapy in Pediatric Crohn’s Disease

In this retrospective study (2013-2018), the authors examined outcomes in 105 children treated with a 90:10 enteral feeds (90% formula).

Key findings:

  • 44/105 (42%) patients completed 8–12 weeks
  • After induction, 18 continued EN maintenance with a 80:20 then 70:30 protocol; however, only 10 remained on EN at 6 months and 4 remained on EN at 12 months

The associated editorial (pg: 1-2) make several points:

  1. While EEN is effective and safe, this study and others have shown poor adherence
  2. It is unclear how exclusive enteral nutrition needs to be in order to be effective. And, many patients instructed to receive 90% of their calories as formula are likely consuming higher amounts of table foods
  3. We still are working out which foods need to be excluded

My take: This study shows that EEN is NOT a practical option for most patients beyond induction. Only 4 patients remained on EEN at 12 months.

Related blog posts:

Ustekinumab Efficacy in Crohn’s Disease With Concurrent Autoimmune Skin Disease

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E Fradkov et al. Inflamm Bowel Dis 2022; 28: 895-904. Efficacy of Ustekinumab in Crohn’s Disease With and Without Concurrent Autoimmune Skin Disease

This retrospective study reviewed 395 CD patients received ustekinumab therapy (79 CD-ASD (autoimmune skin disease), 316 CD-none). ASD included atopic dermatitis, eczema, psoriasis/psoriaform dermatitis and alopecia. The skin disease group also included those with cutaneous manifestations of Crohn’s disease: erythema nodosum, pyoderma gangrenosum, pyostomatitis vegetans, Sweet’s syndrome, granulomatous vasculitis, and leukocytoclastic vasculitis. 55 of the 79 with CD-ASD had psoriatic disease, 20 had eczema, 11 had erythema nodosum, 8 had pyoderma gangrenosum.

Key findings:

  • Ustekinumab had greater efficacy in CD-ASD when evaluated by fecal calprotectin (P = .0337) and CRP (P = .078). For calprotectin, the values decreased by 61% after at least 5 months of therapy (394 to 164) in the CD-ASD group compared to 11% in the group without skin disease (365 to 265)
  • The CD-ASD group also showed better outcomes in Likert scores of endoscopy (P = .016), histopathology (P = .074), and imaging (P = .094). 

My take: Ustekinumab appears to be particularly effective in patients with concurrent skin disease.

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Chattahoochee River near Morgan Falls

Risankizumab Receives FDA Approval for Crohn’s Disease

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Abbvie Press Release: SKYRIZI® (risankizumab-rzaa) Receives FDA Approval as the First and Only Specific Interleukin-23 (IL-23) to Treat Moderately to Severely Active Crohn’s Disease in Adults

– Third approved indication for SKYRIZI (risankizumab-rzaa) is supported by safety and efficacy data from two induction and one maintenance clinical trials evaluating SKYRIZI in moderately to severely active Crohn’s disease, ADVANCE, MOTIVATE and FORTIFY1-4

– As early as week 4 in the induction studies, clinical response and clinical remission were achieved by significantly more subjects treated with SKYRIZI versus placebo, as were co-primary endpoints of endoscopic response and clinical remission at week 12 and week 521-4

About SKYRIZI® (risankizumab-rzaa)
SKYRIZI is an interleukin-23 (IL-23) inhibitor that selectively blocks IL-23 by binding to its p19 subunit.9,10 IL-23, a cytokine involved in inflammatory processes, is thought to be linked to a number of chronic immune-mediated diseases, including Crohn’s disease.10 The approved dose to treat adults with moderately to severely active Crohn’s disease is 600 mg administered by intravenous infusion over at least one hour at week 0, week 4, and week 8, followed by 360 mg administered by subcutaneous injection at week 12, and every 8 weeks thereafter.4 SKYRIZI is also approved in the U.S. to treat moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy, as well as to treat active psoriatic arthritis in adults, and the recommended dosage is 150 mg administered by subcutaneous injection at week 0, week 4, and every 12 weeks thereafter.4 Phase 3 trials of SKYRIZI in psoriasis, Crohn’s disease, ulcerative colitis and psoriatic arthritis are ongoing

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The Curtain or The Box: Therapeutic Dilemmas

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X Roblin et al. Inflamm Bowel Dis 2022; 28: 720-727. Swapping Versus Dose Optimization in Patients Losing Response to Adalimumab With Adequate Drug Levels

Many times, treatment decisions are like on “Let’s Make a Deal.” That is, should I stick with what I’ve got or should I try for something better & sometimes wind up with a goat. In this referenced article, patients were under maintenance therapy with adalimumab (ADA) monotherapy (40 mg every 14 days) and had experienced a secondary loss of response (LOR) despite trough levels > 4.9 μg/mL. In this nonrandomized prospective study, patients were either swapped to vedolizumab (VDZ) or optimized on adalimumab (ADA) treatment.

Key findings:

  • At 24 months, 11 out of 70 patients (16%) in the swap group discontinued treatment compared with 36 out of 61 (59%) patients in the optimization group (P < 0.001)
  • In the optimization group, treatment discontinuation was positively associated with baseline fecal calprotectin >500 μg/g (HR, 3.5)
  • In patients selected for optimization, 56% (34/61) remained on ADA at 1 year and 41% (25/61) at 2 years

In their discussion, the authors state “current guidelines recommend switching to another class of biologics in case of LOR to ADA with therapeutic drug levels.” However, the authors note that their therapeutic level cut-off of >4.9 mcg/mL is lower than the latest recommendations. In addition, in their conclusion, they note that due to limited biologic options, “ADA optimization strategy might be considered” in a subgroup.

My take: Despite better results in the patients that swapped to VDZ in this study, I think it is important to assure adequate drug levels before choosing a new drug class. For ADA, expert recommendations have suggested a level of 8-12 as therapeutic and to avoid discontinuation if ADA level is less than 10. In this study, more than 40% remained on ADA two years after LOR in those with dosing optimization.

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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.

Panoramic View -Sandia Mountain, NM

IBD -Briefly Noted: Intestinal U/S and Anxiety/Depression Not Worsening Pediatric IBD Activity

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EA van Wassenaer et al. Inflamm Bowel Dis 2022; 28: 783-787. Open Access PDF: Intestinal Ultrasound in Pediatric Inflammatory Bowel Disease: Promising, but Work in Progress

Key points from this review:

  • Research has shown that IUS has the potential to be a valuable additional point-of-care tool to guide treatment choice and to monitor and predict treatment response, although evidence of its accuracy and value in clinical practice is still limited
  • The utility may be operator-dependent as well

My take: Due to low upfront costs, IUS would be appealing adjunct to current monitoring. However, one could envision IUS leading to more downstream studies (& costs), especially if its sensitivity and specificity are not very high.

EJ Brenner et al. Inflamm Bowel Dis 2022; 28: 728-733. Anxiety and Depressive Symptoms Are Not Associated With Future Pediatric Crohn’s Disease Activity

In this internet-based cohort of 9-17 yr olds (n=159, 96% white), the authors found no association between baseline PROMIS Pediatric anxiety score and subsequent sCDAI (change in sCDAI for 3-point change in PROMIS Pediatric −0.89; 95% CI −4.81 to 3.03). This study is in contrast to studies in adults which have shown a bidirectional relationship between anxiety/depression and IBD activity.

My take: It is difficult to know with certainty whether anxiety/depression may trigger IBD activity; more studies are needed. Treatment of mental health is important regardless of its effects on IBD activity.

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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:

Sandia Mountain, near Albuquerque

Guselkumab: Expanding the GALAXI of Treatments for Crohn’s Disease

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WJ Sandborn et al. Gastroenterol 2022; 162: 1650-1664. Open Access: Guselkumab for the Treatment of Crohn’s Disease: Induction Results From the Phase 2 GALAXI-1 Study

Background: Guselkumab, a selective p19 interleukin-23 antagonist, is approved for the treatment of plaque psoriasis and psoriatic arthritis.

Methods: GALAXI-1, a phase 2, double-blind, placebo-controlled study, randomized patients with moderate to severe Crohn’s disease 1:1:1:1:1 to intravenous guselkumab 200 mg, 600 mg, or 1200 mg at weeks 0, 4, and 8; intravenous ustekinumab approximately 6 mg/kg at week 0 and 90 mg subcutaneously at week 8; or placebo. n=309 with ~50% having disease refractory to prior biologics

Key findings:

  • At week 12, significantly greater reductions in Crohn’s Disease Activity Index from baseline (least squares means: 200 mg: –160.4, 600 mg: –138.9, and 1200 mg: –144.9 vs placebo: –36.2; all, P < .05) and significantly greater proportions of patients achieved clinical remission in each guselkumab group vs placebo
  • Improvement compared to placebo was evident as early as week 4
  • Safety event rates were generally similar across treatment groups

My take: This is an exciting time for practitioners taking care of patients as there are an increasing number of pharmacologic and dietary treatments for inflammatory bowel disease. With guselkumab, there may be an overlapping mechanism with ustekinumab which targets IL-12/23.

Related blog post: Emerging Data on Risankizumab for Crohn’s Disease

ENTERPRISE Study: Vedolizumab for Perianal Fistulizing Crohn’s Disease

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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.

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

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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?

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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.

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