Tag Archives: Crohn’s disease

FDA Gives Ustekinumab (Stelara) Approval for Crohn’s

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Here’s a link summarizing FDA approval: Medscape: FDA Clears Ustekinumab (Stelara) for Crohn’s Disease

An excerpt:

The US Food and Drug Administration (FDA) has approved ustekinumab (Stelara, Janssen Biotech, Inc) for the treatment of moderately to severely active Crohn’s disease in patients aged 18 years or older.

Specifically, the interleukin-12/23 inhibitor is indicated for Crohn’s patients who have failed or were intolerant to immunomodulator or corticosteroid therapy but who never failed treatment with a tumor necrosis factor (TNF) blocker or who failed or were intolerant to treatment with one or more TNF blockers, according to a company news release.

Ustekinumab is already approved in the United States for treatment of patients with plaque psoriasis and psoriatic arthritis…The clinical development program for ustekinumab for Crohn’s disease included more than 1300 patients across three pivotal phase 3 studies, which served as the primary basis for FDA approval.

In clinical studies of patients who were either new to, experienced with, or failed anti-TNF therapy, between 34% and 56% of patients experienced symptom relief in the 6 weeks after receiving a one-time intravenous induction dose of ustekinumab. “Noticeable improvement was observed as early as 3 weeks,” the company said.

Most patients who responded to induction dosing and who continued ustekinumab treatment with subcutaneous maintenance doses every 8 weeks were in remission at the end of 44 weeks (52 weeks from initiation of the induction dose), the company said.

Full prescribing information and a medication guide are available online.

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Small Pediatric IBD Studies …Briefly Noted

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G Wahbeh et al. JPGN 2016; 63: 348-51.  This retrospective case series with 4 children  (aged 12-17 years) indicated that 2 had a ‘clinical response’ to ustekinumab therapy, though one of these had ongoing elevation of CRP.  The dosing may have been too low: 90 mg at week 0 and 4, then every 8 weeks.  My take: This study shows that ustekinumab’s use in pediatric IBD seems to be a ‘shot in the dark’ given the lack of coherent data.

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L Zimmerman et al. JPGN 2016; 63: 352-56. Among a cohort of 123 children who had underwent a bowel resection, from 1977-2011, the overall postoperative complication rate was 13%.  This included 3 of 24 who had prior infliximab and 9 of 99 who had not received infliximab. It is noteworthy that the infliximab group had more corticosteroid exposure. The authors concluded that preoperative infliximab was not associated with increased complications but noted that their sample size was small. My take: Studies of adults with Crohn’s disease have yielded conflicting results on whether preoperative infliximab increases the risk of complications.  This study shows that children likely have a lower rate of postsurgical complications and more pediatric specific data are needed.

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From KT Park’s Twitter Feed:

calprotectin

4-week-ada-trough-ktparj

Lower Fiber Intake May Increase Risk of Crohn’s Flare

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According to a recent study, lower fiber intake was associated with an increased risk of a flare of Crohn’s disease over a 6-month period (CS Brotherton et al. Clin Gastroenterol Hepatol 2016; 1130-36).

This study examined dietary surveys from 1619 participants (Crohn’s disease in 1130, Ulcerative colitis in 489).  All participants were considered to be in remission at baseline. The key endpoint was disease flare at 6 months which was defined as a disease activity index score exceeding remission cutoff values.

Key finding: “Compared with those in the lowest quartile of fiber consumption, participants with Crohn’s disease in the highest quartile were less likely to have a flare” (adjusted odds ratio 0.58). There was no significant association with ulcerative colitis.

The associated editorial (1137-39) notes that “among 12 RCTs that enrolled patients with Crohn’s disease, fiber did not influence disease activity in studies of induction (flare to remission) or maintenance (remission to flare)…most RCTs had small sample size.”

My take (borrowed from editorial): “A high fiber diet is likely safe in patients with IBD [in the absence of a known stricture/obstructive symptoms] and may impart a weak benefit.”  Overall, dietary approaches are gaining traction and careful evaluation of competing claims will likely be of great benefit.

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This is where I was completely soaked. Grinnell Trail

This is where (moments later) I was completely soaked. Grinnell Trail

More on Ustekinumab, plus Allopurinol Study

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More data emerging that indicates that subcutaneous ustekinumab will be useful for refractory Crohn’s disease: S Khorrami et al. Inflamm Bowel Dis 2016; 22: 1662-69.

  • This open-label cohort of 116 patients identified a clinical response (Harvey-Bradshaw Index) in 97 (84%) after loading dose, and clinical benefit in 58% at 12 months of followup.
  • Perianal disease improved in 11 of 18 (61%).
  • This cohort had refractory disease with almost 90% had failed or were intolerant to 2 or more anti-TNFs.

Another strategy for managing inflammatory bowel disease is using allopurinol which can help low-dose azathioprine achieve therapeutic levels.  In the largest cohort to date, Pavlidis et al (Inflamm Bowel Dis 2016; 22: 1639-46) showed that at the end of followup (median 19 months after treatment initiation) 113/164 (69%) of patients with Crohn’s disease and 83/136 (61%) with ulcerative/unclassified colitis had a clinical response; 52% and 54% respectively were in remission. The azathioprine dose was 25% of weight-based monotherapy dose adjusted based on TPMT status; thus, for normal/high TPMT activity, azathioprine was dosed at 0.5 mg/kg whereas for heterozygous/intermediate activity, azathioprine was dosed at 0.25 mg/kg.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  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.

Vickery Creek, Sandy Springs

Vickery Creek, Sandy Springs

Disease extent and need for higher infliximab dosing

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A recent study (JM Shapiro et al. JPGN 2016; 62: 867-72) reviewed 98 pediatric patients treated with infliximab (2012-2014) with inflammatory bowel disease (IBD).

The authors divided their patients into three groups, mainly based on extent of colonic involvement.  In those with limited colonic involvement, they were labelled “limited” disease (n=53).  In those with patchy inflammation involving the entire colon, they were considered to have “moderate” disease (n=27).  In contrast, those with continuous pancolitis were ascribed to have “extensive” disease (n=18).  Overall, Crohn’s disease accounted for 85 patients (87%),  ulcerative colitis for 11 patients (11%), IBDU for 2 patients (2%).  Interestingly, the majority (9 of 11) of those patients without Crohn’s disease were considered to have extensive disease.

Key findings:

  • “Patients with moderate and extensive disease, started taking 5 mg/kg per dose, showed statistically significant shorter times to escalation that those with limited disease.”
  • 70% of those with extensive disease required dose escalation, compared with 58.3% of those with moderate disease and 26.4% of those with limited disease.
  • The authors note that patients (n=8) with extensive disease who started with 10 mg/kg dosing  “exhibited longer treatment durability;” all 8 patients who started on 10 mg/kg dosing remained on this dose at the study’s conclusion.  Among the 10 patients that started on 5 mg/kg dosing, only 7 were on IFX therapy at the study conclusion–3 remained on 5 mg/kg, 4 were escalated to 10 mg/kg; there were 3 patients who stopped IFX therapy (1 infusion reaction, 2 with nonresponse).

My take: This is a small study. Yet, the implication is that early optimal dosing of IFX is likely  helpful, especially in the setting of extensive disease.

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Chattahoochee River

Chattahoochee River

 

Identifying IBD Years Before Symptoms

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A while back there was a movie called “Minority Report.”  The movie’s premise was that crimes could be predicted and stopped before they occurred.  A recent study (P Lochhead et al. Clin Gastroenterol Hepatol 2016; 14: 818-24) presents intriguing data suggesting a similar scenario for inflammatory bowel disease (IBD).

The authors used a prospective, nested case control study of participants in the Nurses’ Health Study I and II. Median age of patients with Crohn’s disease (CD) (n=83) and ulcerative colitis (UC) (n=90) was 52.7 years and 50.4 years respectively. Key findings:

  • Median prediagnostic hsCRP levels (mg/L) were 2.3 in CD, 2.2 in UC and 1.5 in controls (n=344).
  • Median prediagnostic IL6 levels (pg/mL) were 1.7 in CD, 1.2 in UC, and 1.0 in controls.
  • Median time interval between blood collection and diagnosis was 6.6 years for CD and 6.8 years for UC.
  • There was increased odds for developing disease even after adjustment for potentially confounding variables like smoking.  This analysis held up even when excluding disease that developed within 2 years of sampling.

Overall, this study suggests that there is a significant population of patients with subclinical IBD which precedes the diagnosis by several years.  This report adds to a number of other studies showing potential “preclinical phase” of many diseases including rheumatoid arthritis and type 1 diabetes.

My take: It is fascinating that bloodwork can be abnormal years before clinical symptoms. However, as in “Minority Report” the problem will be with identifying a crime/disease that might never occur.

Unrelated –Chart Depicting Car Temps:

car temp

IBD School Videos for Patients and Families

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While these “IBD School” YouTube videos have been around for several years, I only became aware of them in the past few months.  I think they are good patient education resources.

Here are some links to a few of them:

There are a lot of these videos including the following:

My take: these videos are generally ~4 minutes and a good way to get a lot of information on IBD pretty quickly.

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Extent of Disease: Microscopic or Endoscopic Classification?

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Several recent articles highlight the divergence between microscopic and endoscopic classification of disease.

  • Verstraete et al. JPGN 2016; 62: 242-5.
  • Asthon et al. JPGN 2016; 62: 246-51.
  • Pashankar et al. JPGN 2016; 62: 314-16.

The first two references describe histology in comparison to endoscopic extent of disease in pediatric Crohn’s and the 3rd reference provides information on the finding of “duodenitis.”

Verstraete et al selected 60 patients  randomly from their cohort for retrospective review.  Two physicians independently reviewed the patients.  In describing extent of disease, the extent of disease (Paris Classification) was discordant in 34 (56.6%) when comparing  macroscopic disease (imaging and endoscopy) to macroscopic/microscopic combined.  In addition, there was high interobserver variability of the physicians when the physicians reviewed just macroscopic findings (κ= 0.53).

Asthton et al examined data from 172 pediatric patients with inflammatory bowel disease.  They found that histologic disease was more extensive than endoscopic findings.  For example, among those with ileal biopsies, 49% had endoscopic findings compared with 71.3% having histologic disease.

Currently, the Paris classification relies on endoscopic findings; however, together these two studies suggest that the microscopic findings need to be considered as well. How often areas with microscopic disease will eventually develop endoscopic lesions is not clear.

Pashankar et al, reviewed pathology reports over a 5-year periods with 2772 children (mean age 10.6 years).  They identified duodenitis in 352 with a prevalence rate of 12.7%. Gastritis was seen in 64% of children with duodenitis. Interestingly, 63% of the cases with histologic duodenitis had normal endoscopic appearance. Reported reasons for duodenitis:

  • Celiac disease 32%
  • Crohn’s disease 13%
  • Ulcerative colitis 3%
  • Helicobacter pylori infection 6%
  • Functional dyspepsia 7%

The remaining children (36%) were considered to have nonspecific duodenitis.  The authors state: “this finding is similar to the high percentage of nonspecific duodenitis (60%) in adults.”

My take: It is difficult to know how important microscopic findings are in many cases.  With inflammatory bowel disease, whether/how to incorporate microscopic findings in classification is unclear.  With regard to the finding of microscopic duodenitis, when a specific etiology has not been identified, this leads to lots of questions:

  • How important is this finding?
  • How should this be treated?
  • How much additional workup and followup is needed?
  • How helpful is your pathologist –is the threshold for abnormality too low histologically?

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marriage colonoscopy

More on Anti-TNF Drug Levels

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B Ungar et al (Clin Gastroenterol Hepatol 2016; 14: 550-7) report median serum levels of infliximab (n=78) or adalimumab (n=67) in correlation with mucosal healing.

In this retrospective cross-sectional study of adult patients with IBD (median age ~35 years), the authors found a correlation with higher drug troughs and mucosal healing.

“Levels of infliximab above 5 mcg/mL…and levels of adalimumab above 7.1 mcg/mL identified patients with mucosal healing with 85% specificity. Increasing levels of infliximab above 8 mcg/mL produced only minimal increases in the rate of mucosal healing, whereas the association between higher level of adalimumab and increased rate of mucosal healing reached a plateau at 12 mcg/mL”

The authors propose a “therapeutic window” of 6-10 for infliximab and 8-12 for adalimumab.

Clin Gastro Trough Levels

Remarks from DDW

Remarks from DDW

What happens when anti-TNF therapy is stopped

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Another study (NA Kennedy et al. Aliment Pharmacol Ther 2016; 43: 910-23) has examined the issue of outcomes after anti-TNF therapy withdrawal among patients with inflammatory bowel disease.

This study included 166 UK patient cohort (117 with Crohn’s disease [median 31 yrs], 19 with ulcerative colitis [median 40 years]) as part of a retrospective observational study and a meta-analysis incorporating 11 further cohorts totalling 746 patients (624 with Crohn’s dissease, 122 with ulcerative colitis).

Key findings:

  • In the UK cohort, relapse rates were 36% at year and 56% at 2 years for Crohn’s disease
  • In the UK cohort, relapse rates were 42% at year and 47% at 2 years for ulcerative colitis
  • Increased relapse rates were noted for those with a diagnosis prior to age 22 years (hazard ratio (HR) 2.78), calprotectin >50 mcg/g (HR 2.95).
  • In meta-analysis, 1-year relapse rates were 39% for CD and 35% for UC/IBDU patients
  • Retreatment with anti-TNF was successful in 88% for CD and 76% of UC/IBDU patients

To understand this study, it is important to note some of the study criteria.  In the UK cohort, inclusion criteria required the patient to have had at least 12 months of ant-TNF therapy and be in corticosteroid-remission for at least 6 months.  In addition, the relapse rate is likely to be underestimated due to using a definition of relapse that required either commencement of steroids, immunomodulator or anti-TNF therapy.  The meta-anlaysis cohort studies also used clinical relapse rather than endoscopic or other objective markers.

My take: Relapse of clinical symptoms occur in about 40% after withdrawal in highly-selected groups who were doing well prior.  Significantly higher rates of endoscopic relapse are likely.  This study provides strong reasons for not interrupting therapy when it is working.

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