#NASPGHAN19 Postgraduate Course (Part 5)

Here are some selected slides and notes from this year’s NASPGHAN’s postrgraduate course.  There may be errors in omission or transcription on my part.

Link to the full NASPGHAN PG Syllabus 2019 (Borrowed with permission)

– Intestinal Inflammation Session

192 David T. Rubin, MD, University of Chicago Positioning the new IBD therapies: Merging experience with evidence

Some key points:

  • Ustekinumab escalation can increase response. Optimization in CD patients with loss of response led to recapture of response in 69% of patients
  • Tofacitinib –given black warning, will likely be used in more refractory patients
  • May be able retry a previous therapy (Chicago protocol in slide below)

As an aside, while Dr. Rubin is an excellent speaker, my view is that there are so many terrific pediatric IBD specialists, I would favor having a pediatric IBD specialist give this talk at our postgraduate course.  (Some might argue that adult IBD specialists would have more experience with emerging therapies.)

204 Anne Griffiths, MD, FRCPC, Hospital for Sick Children Immunosuppressive therapy in IBD: Can we de-escalate therapy?

  • High rate of relapse when biologic therapy is stopped.  Use of an immunomodulator may reduce the relapse rate when stopping an anti-TNF agent

215 Stacy Kahn, MD, Boston Children’s Hospital When it is not IBD … rare forms of intestinal inflammation

  • For patients with milder microscopic colitis, antidiarrheal agents can be given.  For more severe disease, budesonide is effective.

223 Edaire Cheng, MD, UT Southwestern Medical Center  Eosinophilic inflammation beyond the esophagus

 

Disclaimer: NASPGHAN/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. The discussion, views, and recommendations as to medical procedures, choice of drugs and drug dosages herein are the sole responsibility of the authors. Because of rapid advances in the medical sciences, the Society 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. Some of the slides reproduced in this syllabus contain animation in the power point version. This cannot be seen in the printed version.

Ustekinumab for Ulcerative Colitis (UNIFI Trial)

A landmark study (BE Sands et al. NEJM 2019; 381: 1201-14) shows that ustekinumab (Stelara) can be an effective therapy for moderate-to-severe ulcerative colitis (UC); it is already an approved, established therapy for Crohn’s disease. This randomized placebo-controlled study included an 8-week induction trial (n=961) followed by a 44-week maintenance trial (n=523) for patients with response.

Clinical remission was defined as a total socre of ≤2 on the Mayo scale (range 0-12) and no subscore >11 on any of the four Mayo scale components.

Key findings:

  • During induction, there was a similar clinical remission rate between those who received 130 mg fixed intravenous dose compared to those who received 6 mg/kg: 15.6% and 15.5% compared to 5.3% for placebo group.
  • During maintenance, among patients receiving 90 mg every 8 weeks the clinical remission rate at 44 weeks was 43.8%, in those with 90 mg every 12 weeks the rate was 38.4%; placebo group was 24.0%.
  • The response to ustekinumab occurred in those with or without previous treatment failure with biologic agents, though response was lower in both induction and maintenance in those with prior treatment failure.  In both phases, at least 59% of participants had failed either or both anti-TNF agents or vedolizumab.
  • In this study, there were similar serious adverse events with ustekinumab compared to placebo.  In the treatment groups, there were two deaths (one from ARDS, one from esophageal varices) and 7 cases of cancer (3 nonmelanoma skin cancer, two colon cancer, one prostate, one renal).  There was one death from testicular cancer in the placebo group. Also four patients in the ustekinumab group had opportunistic infections including CMV in two, legionella in one and HSV in one.

In terms of dosing, the authors note that there was greater improvement in calprotectin values during induction in the group who received 6 mg/kg compared to those who received 130 mg.  At week 44, using more objective and stringent end points (eg. endoscopic improvement), greater clinical benefit was observed with the every 8 week regimen.

Visual abstract from NEJM Twitter Feed:

The following image depicts patients response during the maintenance phase –the lightest color is placebo, followed by every 8 weeks, and then the darkest color is every 12 weeks.  The x-axis measures (left to right) are clinical remission, maintenance of clinical response at week 44, endoscopic improvement, corticosteroid-free remission, and remission at 44 weeks in those with remission after induction.

My take: Ustekinumab is more effective for placebo in patients with ulcerative colitis.  More experience is needed to understand its long-term safety.

Related blog posts:

Ustekinumab in Pediatric Clinical Practice

A recent study (JR Dayan et al. JPGN 2019; 69: 61-67) provides some helpful insight into the use of ustekinumab.

Background: The authors conducted a retrospective review of 52 patients (73% younger than 18 years, 27% 18-21 years).

  • Median age at induction was 16.8 years.
  • 10 patients were biologic-naive; 42 had received at least one anti-TNF agent (18 had received two anti-TNFs).
  • 42 of the 52 patients had Crohn’s disease.
  • Of note, 64% of their patients had a normal baseline CRP and they defined “biomarker remission at 52 weeks” as having a normal CRP.  The high rate of normal baseline CRP likely indicates milder disease than many other refractory populations; though nearly half of the patients with Crohn’s disease were receiving steroids when ustekinumab was initiated.
  • Steroid-free remission was defined by Harvey Bradshaw Index ≤4 or partial Mayo Score <2 and off steroids for >4 weeks.

Dosing: 47 (90%) received induction with ustekinumab IV (260 mg if <55 kg, 390 mg if 55-85 kg, 520 mg if >85 kg) followed by 90 mg subcutaneous injections every 8 weeks

Key findings:

  • 75% of patients continued to receive ustekinumab at 52 weeks.
  • 50% of bio-exposed patients were in steroid-free remission
  • 90% of bio-naive were in steroid-free remission
  • 57% received a dose escalation (increased frequency due to inadequate clinical response); such that at 52 weeks, 12 were receiving q4 weeks, 9 were receiving q6-7 weeks, and 15 continued with q8 weeks.
  • With a median f/u of 18 months, the authors reported few serious adverse events: two patients had an anaphylactoid reaction with IV induction (Rx with steroids and epinephrine). One of these two went on to experience arthralgias, fatigue and headaches with maintenance injection and treatment was discontinued. One patient experienced “self-limited paresthesia of bilateral lower extremities at 16 months on therapy” (CHOP experience with 22 patients reported one case of transverse myelitis: #NASPGHAN17 More Abstracts)

Discussion:

  • The authors note low immunogeiecity of ustekinumab and “suggest that ustekinumab monotherapy is possible and preferable in children”
  • Limitations: Lack of better objective markers for response to treatment

My take: This data indicates that ustekinumab therapy was associated with clinical remission in 50% of patients who had received anti-TNF therapy and had higher response in a small sample of biologically-naive patients.  More experience is needed to confirm drug safety with long-term usage

Related blog posts:

Barcelona

 

IBD Briefs: May 2019 (Part 1)

H Khalili et al. Clin Gastroenterol Hepatol 2019; 17: 123-29.  Using data from two prospective Swedish cohort sutdies with 83,042 participants (age 44-83 yrs), the authors determined that there was “no evidence for association between consumption of sweetened beverages and later risk of” Crohn’s disease or Ulcerative Colitis.

WJ Sandborn et al. Gastroenterol 2019; 156: 946-57.  This study published data from 354 patients who received subcutaneous abrilumab, an anti-alpha4beta7 antibody as a treatment for moderate-to-severe colitis. This 8 week treatment increased the odds of remission compared with placebo.

B Wynne et al. Gastroenterol 2019; 156: 935-45. This study showed that a psychological intervention termed “acceptance and commitment therapy (ACT)” was effective in a randomized controlled trial in reducing stress and depression in patients with quiescent or mildly-active IBD (n=122). With ACT, the “primary aim is to encourage subjects to adopt positive life values and to accept adverse experiences, including thoughts, feelings and sensations that are an inevitable consequence of life.”  All program materials are available in article supplement: Full text and supplement: https://doi.org/10.1053/j.gastro.2018.11.030

D Duricova et al. Inflamm Bowel Dis 2019; 25:789-96. This study included 72 consecutive children born to mothers with IBD treated with anti-TNF therapy during pregnancy (2007-16) along with 69 unexposed controls.  Key findings: Anti-TNF therapy exposure in utero was NOT associated with a negative impact on postnatal complications, including infections, allergy, growth, or psychomotor development. Findings are limited by the small number of participants.

AW Gridnal et al. Inflamm Bowel Dis 2019; 25:642-45.  The authors examined the frequency of financial conflicts of interest (FCOI) among authors of 11 relevant clinical practice guidelines for IBD in the US,  the UK, Canada, and Europe. Key finding: FCOI were frequently present with 19% prevalence among US authors, 56% in UK, 84% in Canada, and 94% in Europe.

KN Weaver et al. Inflamm Bowel Dis 2019; 25:767-74. This retrospective study examined the efficacy of ustekinumab for Crohn’s disease of the pouch in 56 patients; 73% had previously been treated with anti-TNF therapy, vedolizumab or both. Key finding: 83% demonstrated a clinical response 6 months and 60% with endoscopic improvement after induction with ustekinumab. Clinical response was defined as “any improvement in symptoms …including a decrease in bowel movements, pain, or fistula drainage.”

Retiro Park, Madrid
Thanks to Jennifer

 

Most Popular GutsandGrowth Posts from Past Year

These five posts were the most popular (most views) in the past year:

This is a bike path from Canmore to Banff. I had a chance to ride an electric bike which was a lot of fun.

IBD Shorts June 2018

AL Granstrom et al. JPGN 2018; 66: 398-401. Using a nationwide Swedish registry, the authors determined that patients with a Hirschsprung disease had an increased risk of receiving a diagnosis of IBD (OR 4.99).  In total 20 of 739 HD patients, developed IBD.

T Card et al. Inflamm Bowel Dis 2018; 24: 953-9.  This article questions the ‘what is the risk of progressive multifocal leukoencephalopathy ..with vedolizumab?  The authors are not certain.  But they state that after reviewing 54,619 patient-years “there have been no cases of PML reported in association with vedolizumab use.”

LCT Buer et al. Inflamm Bowel Dis 2018; 24: 997-1004. This case report of 10 patients describes combination therapy with anti-TNF therapy with vedolizumab. “At the end of follow-up, all patients were in clinical remission, and 8 patients could discontinue anti-TNF treatment.”

OJ Adedokun et al. Gastroenterol 2018; 154: 1660-71. This study examined pharmocokinetics and response of ustekinumab in patients with Crohn’s disease from 701 patients in phase 3 studies..  “Trough concentrations was approximately threefold higher in patients given ustekinumab at 8-week intervals compared with 12-week intervals…Trough concentrations of 0.8 (or even up to 1.4 mcg/mL) or greater were associated with maintenance of clinical remission.”  Also, “concentrations of ustekinumab did not seem to be affected by cotreatment with immunomodulators.”

View from Pine Mountain

Predicting Response to Vedolizumab and Ustekinumab for Inflammatory Bowel Disease

A recent review (A Barre, JF Colmbrel, R Ungaro. Alim Pharm Ther 2018 DOI: 10.1111/apt.14550) discusses predictors of response to vedolizumab and ustekinumab for inflammatory bowel disease (IBD). Thanks to Ben Gold for this reference.

Background:

  • “Vedolizumab is a humanised monoclonal gut-selective antibody against α4β7 integrin and inhibits the trafficking of inflammatory cells to the intestine.”
  • From Vedolizumab GEMINI trials, , “primary response to vedolizumab was typically evaluated at week 14 after induction with rates of clinical remission and clinical response ranging between 24%-36% and 49%-64% in CD, and 23%-39% and 43%-57% in UC, respectively”
  • “Ustekinumab is a monoclonal IgG1 antibody against the p40 subunit of interleukin-12 (IL-12) and interleukin-23 (IL-23) that targets both the T-helper 1 and T-helper 17 pathways involved in the pathogenesis of CD.”
  • With Ustekinumab, “in real-world observational studies, patients were treated off-label and received highly variable induction and maintenance dosing, thus limiting the generalizability of results. The rates of response were reported to be as high as 84% and remission rates as high as 35% at end of induction, with loss of response in around one-third of patients during maintenance”

Key points:

  • Patients with severe disease (by clinical activity and inflammatory biomarkers), and prior anti-TNF exposure are less likely to respond to vedolizumab.
  • Ileocolonic disease, no prior surgery and uncomplicated phenotype were associated with better responses to ustekinumab in CD

With ustekinumab, in particular, there is still very limited data on its effectiveness and long-term outcomes and this is even more the case in pediatrics. This review does a good job in compiling the current available data.

My take: While this is a nice review, it does not help me much with developing an algorithm for how I will use these relatively new medications for IBD.

Related blog posts:

Bright Angel Trail