#NASPGHAN17 Annual Meeting Notes (Part 2): Year in Review

This blog entry has abbreviated/summarized this presentation. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

This first slide shows the growth in NASPGHAN membership:

Year in Review

Melvin Heyman  Editor, JPGN

This lecture reviewed a number of influential studies that have been published in the past year.  After brief review of the study, Dr. Heyman summarized the key take-home point.

 

CCFA Conference Notes 2016 (part 4) –Pregnancy and IBD

Pregnancy and IBD –Dr. Doug Wolf

Dr. Wolf reviewed infertility, pregnancy issues, and PIANO registry. This topic has been covered elsewhere in this blog (IBD and Pregnancy | gutsandgrowth). Vedolizumab is a FDA category B; thus far, it is considered fairly safe. Thiopurines are category D but overall thought to be low risk.

This blog entry has abbreviated/summarized this terrific presentation. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

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Biosimilars -Position Statement

Briefly noted:

“Use of Biosimilars in Paediatric Inflammatory Bowel Disease” Position Statement. JPGN 2015; 61: 503-08.  Conclusions:

  • “IBD Porto group advocates giving high priority to performing paediatric trials with long-term followup to support” the use of biosimilars (97% agreement)
  • “Treatment of a child with sustained remission on a specific medication should not be switched to a biosimilar until clinical trials in IBD are available to support the safety and efficacy of such a change” (94% agreement)
  • “Postmarketing surveillance…in children with IBD should be a mandatory requirement.” (100% agreement)

My take: Keep this reference handy.  The lower expected costs (>30% reduction) could create pressure to change treatment before the safety/efficacy is proven.

Atlanta Botanical Gardens

Atlanta Botanical Gardens

IBD Incidence Increasing: 30 Years of Data from Manitoba

A recent study (JPGN 2014; 59: 763-66) shows a steady trend of increased incidence of IBD in Manitoba. This figure is available online:

 

Increasing IBD Incidence in Children

Increasing IBD Incidence in Children from JPGNonline

Abstract:

Objectives: The aim of this study was to describe the incidence and prevalence of inflammatory bowel disease (IBD) in children <17 years of age in 30 years from 1978 to 2007.

Methods: From January 1, 1978, to December 31, 2007, the sex- and age-adjusted annual incidence and prevalence of pediatric IBD per 100,000 population were calculated based on the pediatric IBD database of the only pediatric tertiary center in the province. The annual health statistics records for the Province of Manitoba were used to calculate population estimates for the participants. To ensure validity of data, the University of Manitoba IBD Epidemiology Database was analyzed for patients <17 years of age from 1989 to 2000.

Results: The sex- and age-adjusted incidence of pediatric Crohn disease has increased from 1.2/100,000 in 1978 to 4.68/100,000 in 2007 (P < 0.001). For ulcerative colitis, the incidence has increased from 0.47/100,000 in 1978 to 1.64/100,000 in 2007 (P < 0.001). During the same time period, the prevalence of Crohn disease has increased from 3.1 to 18.9/100,000 (P < 0.001) and from 0.7 to 12.7/100,000 for ulcerative colitis (P < 0.001). During the last 5 years of the study the average annual incidence of IBD in urban patients was 8.69/100,000 as compared with 4.75/100,000 for rural patients (P < 0.001).

Conclusions: The incidence and prevalence of pediatric IBD are increasing. The majority of patients were residents of urban Manitoba, confirming the important role of environmental factors in the etiopathogenesis of IBD.

Unrelated: As a bonus for those who made it to the bottom of this post : there’s a new Bristol Stool App for iPhones.  Here’s the link: http://www.bristol-stool-scale.com (from John Pohl’s twitter feed)

 

Vedolizumab -another new IBD treatment

Occasionally a parent will express concern that their child may run out of effective treatments for inflammatory bowel.  At this time, there are a limited number of effective therapies. If a patient develops reactions or antibodies to medications and/or does not have a clinical response, then the options become quite limited.

Against this backdrop, it is encouraging that new medical treatments are being tested, including Vedolizumab (Inflamm Bowel Dis 2012; 18: 1470-79).

The cited study reports the experience of using Vedolizumab in a randomized controlled phase 2 dose-ranging study in 46 patients (9 placebo, 37 vedolizumab).

Vedolizumab is “a gut-selective monoclonal antibody that antagonizes α4β7 integrin on select subsets of leukocytes binding to MAdCAM-1 on gut vascular endothelium.”  Many have considered vedolizumab to be similar to natalizumab, except it is considered  gut-specific and therefore should not increase the risk of progressive multifocal leukoencephalopathy (PML).  By altering the immune surveillance/lymphocyte tracking of the GI tract and not the brain, theoretically there should not be an increased risk of PML.

Another previous limitation of vedolizumab in small studies was the development of human antihuman antibodies (HAHA) –no joke!  HAHA occurred in up to 44% of patients in previous studies and were associated with reduced efficacy.  As a consequence, a new formulation of vedolizumab has been developed with presumably reduced  immunogenicity.

In the cited study, patients between 18-70 were recruited to receive one to three doses of vedolizumab (2, 6, or 10 mg/kg) or placebo.

Results:

  • Over 50% of vedolizumab-treated patients maintained a clinical response between days 29-253 whereas placebo response ranged between 22-33%.
  • This study was not powered for efficacy; however, the treated patients did have reduced fecal calprotectin.  At baseline, the calprotectin in the treatment groups averaged 405 μg/g and by day 113 had reduced to 54 μg/g.  In contrast, placebo group started with calprotectin of 310 μg/g and dropped to 192 μg/g during same time period.
  • HAHA were detected in 4 (11%)

According to a presentation at DDW (GEMINI I trial), more than 2500 patients have been treated in trials with vedolizumab.  None has developed PML. Encouraging results for efficacy (dosing 300mg IV q4weeks) were also noted; 1 year clinical remission noted in 45% of treated patients compared with 14% of placebo group. Digestive Disease Week 2012 – Vedolizumab Scores on Safety …)

Results of vedolizumab for Crohn’s disease are expected soon as well.

Related blog entries:

Quantifying Risk of PML with Natalizumab

Tofacitinib –a JAK Inhibitor for UC

Abatacept for IBD?

Doesn’t work (Gastroenterology 2012; 143: 62-69).  While this study indicates that Abatacept was not effect for either Crohn’s disease (CD) or ulcerative colitis (UC), it was useful nevertheless.

In brief, the study examined four placebo-controlled trials of abatacept for induction and maintenance therapy in both CD and UC.  The induction studies included 451 CD patients and 490 UC patients.  The maintenance studies had 90 CD and 131 UC patients.

Results for induction:

  • CD: Clinical response: 17%, 10%, 15% for abatacept dosing of 30, 10, and 3 mg/kg.  Placebo 14%
  • UC: 21%, 19%, 20%  for abatacept dosing of 30, 10, and 3 mg/kg.  Placebo 29.5%

Results for maintenance:

  • CD: 24% abatacept vs 11% placebo
  • UC: 12.5% vs 14% placebo

The premise of this study was that T-cell activation requires co-stimulatory signaling via T cell CD28 and CD80 or CD86 on the antigen-presenting cell.  Abatacept (CTLA4-Ig) which is effective for psoriasis, rheumatoid arthritis, and juvenile idiopathic arthritis was thought to have potential; it blocks costimulation pathways involved in T-cell activation which was shown to be helpful in animal model of colitis.

So why did it not work?  The editorial in the same volume (pages 13-16) suggests the following possibilities:

  • Abatacept would be more likely to work when naive T cells are actively recruited into inflammation rather than memory T cells which are predominant in IBD
  • CD28-related pathways may not be important in IBD pathogenesis
  • Abatacept may have impeded Treg function in addition to preventing T-cell activation (explained in Fig 1D)
  • Blockade of CD28 pathways could have resulted in unfavorable changes in cytokine profiles from T-cell differentiation (Th1 vs Th2)

The implication of this study is that not all T-cell mediated inflammatory disease respond to the same treatment approaches.  The complexity of intestinal immune responses necessitates ongoing clinical studies to determine which promising therapies will be useful.

More on IBD medicine risks

As noted in a recent post (Assessing and discussing risk of lymphoma in IBD), diagrams can be useful to convey the absolute risks for IBD medicines; this risk is often poorly understood by patients and their families. Two articles add additional insight that may help with counseling. (Thanks to Ben Gold for forwarding these articles.)

  • Am J Gastroenterol 2012; 107: 964-70.
  • Am J Gastroenterol 2012; 107: 1051-63.

The first article reviews the risk of lymphoma with regard to inflammatory bowel disease treatment decisions.  Important points in this article include the following:

1. Relative risks may appear large while absolute risk may be quite low.  The estimate for absolute risk for lymphoma:

  • For azathioprine or 6-mercaptopurine: 1 additional case for every 4357 persons treated
  • For anti-TNF (infliximab, adalimumab, certolizumab): 1 additional case for every 2380 persons treated between ages 20-29.

2. Framing the discussion with regards to risk of continued active disease, continued exposure to steroids, and potential need for surgery can be helpful:

  • “It would take only three patients discontinuing their azathioprine to cause one additional relapse of IBD per year”
  • Seven patients stopping anti-TNF therapy would result in an additional hospitalization each year and 14 patients stopping anti-TNF therapy would result in an additional abdominal surgery each year
  • While the ‘relative risks of lymphoma associated with these medications may sound inappropriately large…A more appropriate comparison is the absolute risk of lymphoma versus the absolute risk of active/untreated disease or corticosteroid therapy.’  An example: if 2000 patients with IBD took one of these medications (eg. anti-TNF agent), probably one patient will develop a lymphoma; however, if none of those patients took an anti-TNF agent, it would result in more than 100 hospitalizations and nearly 60 surgeries.

3. “Patients can also be very sensitive to numerators and pay relatively insufficient attention to denominators.” This has been called “anchoring and adjustment” or “base-rate neglect.”  This issue has to do with “numeracy;” this is defined as the basic math skill needed for health-related activities. To help families, consider the following:

  • avoid labels such as “very low” when describing risk
  • use absolute risk data
  • use similar denominators when comparing risks
  • use visual aids

The second study cited is a pooled analysis of infections, malignancy, and mortality risks associated with infliximab and immunomodulator treatment in adult IBD patients.  This study collected safety data from 10 previous trials.  Five of these trials were randomized, controlled studies.  Table 3 and Table 4 detail extensive safety data for immunomodulators (eg. azathioprine) and for infliximab respectively.

With regard to immunomodulators, the combined studies enrolled 947 on immunomodulators in comparison to 1170 without immunomodulators.  With ulcerative colitis (UC) patients but not with Crohn’s disease (CD), immunomodulator use increased the risk of infections (120/100 patient years versus 92.5 among placebo-treated patients).  CD patients, but not UC patients, had an increased risk of malignancy with immunomodulator use (1.84/100 patient years compared with 0/100 patient years in the control group).  With the exception of the SONIC study, use of immunomodulator was not randomly assigned.  So, some of the increased risk in these patients could be due to having more severe IBD rather than due to the medication.

With regard to infliximab, and in contradiction to the previous article’s estimated risks, infliximab treatment did not appear to affect the incidence of infection, mortality, or malignancy.  This study and several others have not demonstrated an increased risk of malignancy with infliximab. This could be that even with this pooled data it is difficult to detect a rare adverse outcome.  More prospective studies and more long-term followup will be needed to truly determine the risk.

While it is known that these agents may increase the risk of some infections, the limited increase in infections which was detected only with immunomodulator use in UC is likely due to a lowered risk of infection when active inflammatory bowel disease is controlled.  A much bigger risk factor for infection is the use of corticosteroids.  When effective IBD medications are administered, this helps control inflammation and allows tapering of corticosteroids.

Related posts:

TNF-α antagonists and infections

Disease modifying treatment in IBD

Only one chance to make first impression