Category Archives: inflammatory bowel 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

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Latest on Tofacitinib for Refractory Ulcerative Colitis

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From Gastroenterology & Endoscopy News July 2016: Tofacitinib Effective in Refractory and Severe UC

An excerpt:

Tofacitinib (Pfizer), an oral agent already approved for certain patients with rheumatoid arthritis, can induce clinical remission in up to 25% of individuals with moderate to severe, refractory ulcerative colitis (UC) and clinical response in as many as 60% of these patients.

The results, based on two placebo-controlled trials involving more than 1,100 patients, showed the drug also increased the risk for serum lipid elevations but was otherwise safe. Researchers presented the data at the 2016 annual meeting of the European Crohn’s and Colitis Organization (ECCO; oral presentation 019)…

The new data are from the OCTAVE Induction 1 and Induction 2 trials, identically designed, randomized, double-blind and placebo-controlled Phase III studies…In the OCTAVE 1 trial, 476 patients received 10 mg of tofacitinib orally twice daily for eight weeks and 122 received an oral placebo. In OCTAVE 2, 429 and 112 patients were randomized to receive the two regimens, respectively.

Screenshot from gastroendonews.com

Screenshot from gastroendonews.com

Also from Gastroenterology & Endoscopy News August 2016: Update on Diagnosis and Treatment for Ulcerative Colitis  This article provides a succinct summary regarding diagnosis and treatments of ulcerative colitis; treatments discussed include emerging therapies like tofacitinib.

 

Pediatric Experience with Vedolizumab

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N Singh et al. Inflamm Bowel Dis 2016; 22: 2121-25.  Abstract:

Background: Though vedolizumab has received regulatory approval for the treatment of Crohn’s disease (CD) and ulcerative colitis (UC) in adults, there is increasing off-label use in children.

Aims: To describe the experience with vedolizumab in pediatric inflammatory bowel disease (IBD) patients at 3 tertiary IBD centers and examine predictors of remission.

Methods: A retrospective review identified pediatric IBD patients (age < 18 yrs) receiving vedolizumab. Data on demographics, disease behavior, location, activity, and previous treatments/surgeries were collected. Disease activity was assessed using the weighted pediatric CD activity index or pediatric UC activity index. Primary outcome was week 14 remission, defined as pediatric UC activity index <10 or weighted pediatric CD activity index <12.5. Descriptive statistics and univariate analyses were performed to examine associations of clinical characteristics with efficacy.

Results: Fifty-two patients, 58% CD and 42% UC, initiated vedolizumab between June 2014 and August 2015. Median age at vedolizumab initiation was 14.9 (range 7–17) years. Ninety percent had failed ≥1 anti-tumor necrosis factor (TNF) agent. Week 14 remission rates for UC and CD were 76% and 42%, respectively (P < 0.05). Eighty percent of anti–TNF-naive patients experienced week 14 remission. At week 22, anti–TNF-naive patients had higher remission rates than TNF-exposed patients (100% versus 45%, P = 0.04). There were no infusion reactions or serious adverse events/infections.

Conclusions: Our results suggest that vedolizumab is efficacious and safe in pediatric IBD patients, with UC patients experiencing earlier and higher rates of remission than CD patients. Anti–TNF-naive patients experienced higher remission rates than those with anti-TNF exposure. Controlled clinical trial data are needed to confirm these observations.

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Glacier Natl Park

Glacier Natl Park

How helpful are serologies in pediatric inflammatory bowel disease?

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For quite some time, I have been unimpressed with the utility of serologies in distinguishing Crohn’s disease and Ulcerative Colitis.  While some of these tests claim some usefulness, when one excludes the obvious cases of Crohn’s disease (eg. perianal disease, fistulizing disease, small bowel disease), these claims seem quite dubious  Another study backs up my interpretation: L Birimberg-Schwartz et al. Inflamm Bowel Dis 2016; 22: 1908-14

This longitudinal report from the IBD Porto Group examined a multicenter retrospective cohort of 406 children with isolated colonic disease.  These children had a mean age of 10.5 years.  117 had Crohn’s colitis, 143 had ulcerative colitis, and 146 had IBD-unclassified (IBDU).

Key findings:

  • Among those with IBDU, the most prevalent serologic profile was pANCA neg/ASCA neg (41%).  34% had pANCA pos/ASCA neg, and 17% and pANCA neg/ASCA pos.
  • ANCA+: present in 43% of patients with IBDU, 64% of patients with UC, and 30% of patients with Crohn’s.
  • ASCA+ (IgA or IgG): present in 26% of  patients with IBDU, 6% of patients with UC, and 40% of patients with Crohn’s.
  • pANCA neg/ASCA pos did help differentiate Crohn’s colitis versus IBDU with 83% specificity, 96% positive predictive value; however the sensitivity was only 33% and the negative predictive value was only 13%.
  • pANCA neg/ASCA pos also differentiated Crohn’s colitis compared with ulcerative colitis with 97% specificity, and 90% positive predictive value however the sensitivity was only 33% and the negative predictive value was only 40%.
  • pANCA pos/ASCA neg did NOT differentiate well.  For IBDU versus UC, the specificity was 66%, the positive predictive value was 94%; the sensitivity was 65% and the negative predictive value was 38%.

In short, these tests generally have poor sensitivity.  If ASCA antibodies are present, which occurred in only 23%, the serology performs better but still usually not well-enough to help with big decisions. The presence of positive serology was associated with an increased likelihood of more severe disease.

Before you order IBD serology, you may want to consider whether you might use the money for this costly test in a better way.

My take (borrowed from authors): “Serology cannot routinely be recommended for differentiating between IBDU versus CC or UC as a sole diagnostic criterion given its low diagnostic utility.”

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Trail to Iceberg Lake, Glacier Natl Park

Trail to Iceberg Lake, Glacier Natl Park

Biologic Exposure Prenatally and Perinatally

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The widespread use of anti-TNF therapy for inflammatory bowel disease has improved clinical outcomes including fewer surgeries, hospitalizations, and complications.  One consequence of this usage has been the exposure of infants to biologics due to their usage by their mothers during pregnancy.  A recent study (M Julsgaard et al. Gastroenterol 2016; 151: 110-19) explores this topic further.

In this study, the authors prospectively followed 80 pregnant women: 36 received adalimumab & 44 infliximab. In addition, 39 received concomitant thiopurine therapy.

Key findings:

  • The time from last exposure to anti-TNF agent correlated inversely with the concentration of these drugs in the umbilical cord and in mothers at the time of birth.
  • Median ratio for infant: mother drug concentration at birth was 1.21 for adalimumab and 1.97 for infliximab.
  • Mean time for drug clearance: 4.0 months for adalimumab and 7.3 months for infliximab. Drugs were not detected after 9 months of life for adalimumab and after 12 months of life for infliximab.
  • No increased risk of adverse pregnancy outcomes were identified; preterm birth was low (n=3 or 3.8%). 48% of women experienced a disease relapse during pregnancy.
  • In this small study, the relative risk for infection was 2.7 in infants exposed to combination therapy.  Benign courses of viral infections were noted in 16 (20%) of the entire cohort and of bacterial infections in 4 (5%).

The authors recommend avoidance of live virus vaccines in biologically-exposed infants for up to 1 year unless drug clearance has been documented. Currently, this would affect only rotavirus vaccination.

My take (borrowed from editorial pgs 25-26): “For now, the sum of evidence seems to support continued use of anti-TNF therapy in pregnancy when clinically indicated and, despite measureable levels in offspring, there does not seem to be a significant clinical consequence.”

Related study: “Adverse Pregnancy Outcomes among women with inflammatory bowel disease: a population-basd study from England” Inflamm Bowel Dis 2016; 22: 1621-30. The authors identified 1969 pregnancies from a total of 364,363 singleton pregnancies.  Women with Crohn’s had increased preterm births with an Odd ratio of 1.42, babies with low birth weight (OR 1.39); women with ulcerative colitis had only a small increase risk in preterm birth (absolute risk <2.7%).

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Art at Big Creek Greenway, Alpharetta

Art at Big Creek Greenway, Alpharetta

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

Gold Medal Winner: Infliximab (anti-TNF competition)

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According to a recent retrospective study, (S Singh et al. Clin Gastroenterol Hepatol 2016; 14: 1120-29), infliximab outperformed its rivals.  In the spirit of the recent olympics, we’ll give infliximab a gold medal in the anti-TNF category.

Here’s the play-by-play:

This study used an administrative claims database with more than 100 million US enrollees.  In total, there were 3205 biologic-naive patients with Crohn’s disease (CD) with a mean age of 41 years.  All of the participants had not received a biologic agent for at least 12 months prior to their first study dose (between 2006-2014). In addition, the authors excluded patients who had a concomitant diagnosis which could necessitate a biologic, including rheumatoid arthritis, ankylosing spondylitis, and psoriasis.

Race details:

  • Compared to adalimumab-treated patients, inlfiximab-treated patients had a lower risk of CD-related hospitalization (aHR [adjusted Hazard Ratio] 0.80), abdominal surgery (aHR 0.76), and corticosteroid use (aHR 0.85)
  • Compared to certolizumab pegol-treated patients, infliximab-treated patients had a lower risk of hospitalization (all-cause) (aHR 0.70), and CD-related hospitalization (aHR 0.59).
  • All agents had comparable risk of serious infections

Post-race analysis:

Was this a fair race (ie study)? Definitely.  If anything, this study may have underestimated the benefit of infliximab.  Due to trouble with confounders across retrospective studies, it may be that infliximab was chosen preferentially among sicker patients.

My take: There is limited data on comparative effectiveness of anti-TNF agents.  This retrospective study  indicates that infliximab is likely superior to its competitors.  Definitive proof would necessitate a head-to-head live-action (prospective) competition.

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4 Points for C diff in Inflammatory Bowel Disease

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A nice review: K Rao, PDR Higgins. Inflamm Bowel Dis 2016; 22: 1744-54.

Many aspects of Clostridium difficile with and without coexisting inflammatory bowel disease has been reviewed on this blog.  This review adds a few additional points:

  1. C difficile testing in patients with IBD, “start with enzyme immunoassay-based tests with a reflex to PCR test for discordant enzyme immunoassay results.”  Rationale: “PCR is quite sensitive for the presence of toxigenic C difficile, it may increase the detection of asymptomatic colonization and shedding.”
  2. Don’t test for C difficile in patients in clinical remission. “Clayton et al evaluated outpatients with IBD who were in clinical remission and had no recent exposure to antimicrobials, corticosteroids, immunomodulatory agents, or hospitalizations.  These patients had toxigenic C difficile carriage rates of 8.2%.”
  3. What to do when IBD patients test positive for C difficile infection (CDI) -treat which one or both? The authors recommend, that “if there is no response to the treatment for CDI after 48 hours, then concurrent immunologic therapy can be started/escalated.”
  4. Safety of FMT with IBD. “There may be additional risk incurred in the IBD population…[in a recent study] 14% of the subgroup of patients with IBD experienced adverse events including IBD flare, requiring hospitalization in some instances.” Overall, there is not enough data to “risk stratify patients in terms of these adverse outcomes.”

In addition to these pointers, advice on treatment based on severity and whether CDI is recurrent is listed on Table 1.

  • For primary CDI (nonsevere): metronidazole, vancomycin or fidaxomicin.
  • For primary CDI (severe): vancomycin or fidaxomicin.
  • For primary CDI (severe & complicated*): vancomycin at highest dose and IV metronidazole and (if ileus present) vancomycin rectally
  • Recurrent CDI: 1st recurrence — same as initial Rx, 2nd recurrence -same as initial Rx, then use either vancomycin pulsed and/or tapered regimen of 6 or more weeks

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View from Grinnell Glacier Trail, Glacier Nat'l Park

View from Grinnell Glacier Trail, Glacier Nat’l Park

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.