Category Archives: inflammatory bowel disease

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 (part 2) and a Few Mentions

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Another study (K Papamichael et al. Clin Gastroenterol Hepatol 2016; 14: 543-9) examined therapeutic drug levels with regard to infliximab induction and mucosal healing.

In this retrospective study with 101 patients with ulcerative colitis, 54 (53.4%) achieved mucosal healing between weeks 10-14, defined by a Mayo endoscopic score of 0 or 1.  97% of patients were treated with 5 mg/kg infusions.

Key finding:

  • Infliximab threshold concentrations of 28.3 mcg/mL at week 2, 15 mcg/mL at week 6, and 2.1 mcg/mL at week 14 were associated with mucosal healing.

My take: While this study provides information on what type of levels to expect at 2, 6, and 14 weeks, what is really important is figuring out which patients need higher doses of infusions from the start.

Unrelated, briefly noted:

R Yadlapati et al. Clin Gastroenterol Hepatol 2016; 14: 535-42. In this prospective blinded cohort study of 59 subjects, oropharyngeal pH testing (Restech Dx-pH) and salivary pepsin analysis was not able to distinguish between healthy volunteers and subjects with a combination of laryngeal and reflux symptoms.

M Moris et al. Clin Gastroenterol Hepatol 2016; 14: 585-93. This study reports increasing findings of small pancreatic cysts with more (and better) MRI imaging.

Y Kawamura et al. Clin Gastroenterol Hepatol 2016; 14: 597-605. This retrospective study shows, among almost 10,000 patients with fatty liver disease, that alcohol consumption of ≥40 g/day is an independent risk factor for hepatocellular carcinoma.

Strongloides

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

Oral Cancer and Inflammatory Bowel Disease

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A recent study (KH Katsanos et al. Clin Gastroenterol Hepatol 2016; 14: 413-20) shows an increased risk of oral cancers in patients with inflammatory bowel disease (IBD). Because these cancers are infrequent, the absolute risk remains low.  However, this study provides some further insight into why other cancers may occur more often in IBD as well.

This retrospective study collated data on 7294 patients with IBD seen at a single New York center (2000-2011).  Key findings:

  • 11 patients (7 male) developed biopsy-proven oral cancer, most commonly of the tongue (n=6).  The overall oral cancer age-adjusted standardized incidence ration (SIR) was 9.77 and the SIR for tongue was 18.91.  These numbers could be influenced by a referral bias.
  • The average age for oral cancer in this study was 44 years.
  • Prior treatment for IBD had occurred in 7 patients, including 4 with a thiopurine, 1 with infliximab, and 3 with combination therapy.
  • One patient died.

Discussion:

  • Traditional risk factors for oral cancer: tobacco exposure (smoking, oral tobacco) and alcohol consumption.
  • The authors speculate that in their population that acquiring oncogenic HPV virus may have contributed to increased risk.  This is clearly a risk with cervical cancer which has been reported as increased in IBD populations as well.

Related blog post: Cancers Complicating Inflammatory Bowel Disease | gutsandgrowth

Gibbs Gardens

Gibbs Gardens

Varicella and Zoster Infections in Children with Inflammatory Bowel Disease

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A recent study (DJ Adams, CM Nylund. J Pediatr 2016; 171: 140-5) looked at a large database (1997-2012) with nearly 9 million admissions.  In this retrospective cohort, there were 4434 admissions related to varicella and 4488 due to herpes zoster.

  • Children with Crohn’s disease had a greater increased risk: Varicella OR 12.75, and Zoster OR 7.9 compared to the general population.
  • Children with ulcerative colitis had increased risk compared to general population but less compared to children with Crohn’s disease: Varicella OR 4.25, and Zoster OR 3.9
  • Overall, the risk of these infections improved among all groups over the 15 year study period

One significant limitation of this study is that children with IBD may have been hospitalized more readily out of concern for their vulnerability.  It is noted that there were no deaths due to these infections in the children with IBD.

My take (from the authors):  the increased risk of Varicella and Zoster “were comparable with that observed in children with HIV, malignancy, and primary immune deficiency.”  Given the difficulty of immunizing children on immunosuppressive treatments, at the very least, immunizing household contacts needs to take place.

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Fox Theatre on a Tuesday

Fox Theatre (Atlanta) on a Tuesday

Vitamin D and IBD, More Data

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Another large study (Kabbani TA, et al. Am J Gastroenterol. 2016;doi:10.1038/ajg.2016.53) links low vitamin D status with worse outcomes in IBD.

An excerpt from summary from HealioGastro: (Low vitamin D linked to higher morbidity, disease severity in IBD)

Binion and colleagues identified 965 IBD patients (61.9% Crohn’s disease; 38.1% ulcerative colitis; 52.3% women; mean age, 44 years) with up to 5 years of follow-up data in University of Pittsburgh Medical Center’s longitudinal IBD natural history registry…

At enrollment, 8.9% of patients were vitamin D deficient and 33.1% had vitamin D insufficiency vs. 4.9% and 23.6%, respectively, at the conclusion of the study period. Among patients who received vitamin D supplements, 67.9% achieved normal levels by the end of the study…

Overall, patients with low vitamin D levels required significantly more steroids, biologics, narcotics, computed tomography scans, emergency department visits, hospital admissions and surgeries compared with those who had normal mean vitamin D levels (P < .05). They also had worse pain, disease activity scores and quality of life (P < .05).

“More importantly, correction of vitamin D deficiency was associated with overall improvement in clinical status,” Binion said.

My take: Vitamin D levels are often low when patients are acutely ill and can improve without supplements in many; this accounts for some of the association with worsened outcomes.  True vitamin D deficiency and insufficiency does have negative physiologic effects and should be treated.

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Gibbs Gardens

Gibbs Gardens

 

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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Should Medical Marijuana Get a Free Pass?

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In many states, including Georgia, medical marijuana has bypassed the rigorous Food and Drug Administration (FDA) approval process via state laws permitting its usage.  A recent editorial (J Koliani-Pace, CA Siegel. Am J Gastroenterol 2016; 111: 161-62 -thx to Ben Gold for this reference) highlights the dilemma facing physicians with medical marijuana with regard to providing advice/approval for this treatment.

Key points:

  • 12% of people aged 12 years or older report using cannabis in the past year.
  • For gastrointestinal illnesses, there is scant evidence effectiveness.  There is some data indicating that it makes you feel better, but no data proving that there is objective improvement in conditions like Crohn’s disease.
  • Adverse effects require more research.  “Approximately 9% of people who experiment with marijuana will become addicted.”  Other concerns: increased car accidents, altered memory/judgment, hyperemesis syndrome, and respiratory effects.  With increasing availability and increasing THC concentrations, there have been in an increase in emergency department visits related to usage.
  • Lack of quality control: various concentrations of THC and cannabinoids, different administration routes, contaminants.

My take: At least with GI illnesses, more studies are needed to determine whether medical marijuana should be recommended.

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Gibbs Gardens

Gibbs Gardens

Here’s Why Biologic Therapy for Crohn’s Helps Adolescents Grow

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It is well-recognized that Crohn’s disease is associated with delays in the onset and progression of puberty with the potential for stunted growth, impaired bone accrual, and diminished quality of life.

Now, a study (MD DeBoer et al. J Pediatr 2016; 171: 146-52) shows that initiation of anti-tumor necrosis factor α (anti-TNFα) treatment results in a rapid increase in sex hormone and gonadotropin levels.

In 72 adolescents, this observational study followed levels of sex hormones, gonadotropin levels, dual-energy x-ray absorptiometry, along with cytokine/inflammatory markers at initiation of anti-TNFα therapy, at 10 weeks and at 12 months.

Key findings:

  • By week 10 , testosterone z scores in males increased from a median of -0.36 to 0.40 (P<0.05)
  • By week 10 , estradiol z scores in females increased from a median of -0.35 to -0.02 (P<0.01)

My take (from the authors): This study suggests that “systemic inflammation suppresses gonadotropin-stimulated production of sex hormones” and that treatment of this inflammation with anti-TNFα agents allows rapid resumption normal production.

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Law Quad, Univeristy of Michigan

Law Quad, Univeristy of Michigan

CCFA Conference Notes 2016 (part 5) -Emerging Therapies

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This blog entry has abbreviated/summarized this terrific presentation; most of the material has been covered in this blog in prior entries (can use search function to find additional relevant material) but still this was a useful review. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

Emerging Therapies in IBD –Dr. Gary Lichtenstein

Background: This lecture started with a review of current therapies. We have learned how to use our current therapies better. There still remain a large number of patients that face surgery with IBD; though there has been improvement (?50% reduction).

Issues with thiopurines were reviewed. May take 2-6 months to take effect, though monotherapy with thiopurines are fairly ineffective for Crohn’s disease as initial therapy.

Leukocyte Trafficking Agents:

  • Natalizumab
  • Vedolizumab
  • AJM300 –oral agent. Initial safety data were fine.
  • AMG 181
  • Etrolizumab (Vermeire S Lancet 2014) –low rates of endoscopic healing, but better than placebo

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PF-00547,659

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S1P Modulators:

Fingolimod

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Ozanimod (RPC1063) (oral agent, fairly rapid onset) causes S1P-r on lymphocytes to be internalized –more selective than Fingolimod. Good safety has been noted thus far.  No notable cardiac problems. Infrequent elevations of transaminases; this issue will need to be followed.

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Tofacitinib oral Janus Kinus (JAK) Inhibitor (Sanborn WJ et al. NEJM 2012; 367: 616-24). Dr. Lichtenstein thinks 10 mg will be recommended dose. Follow lipids. For UC

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Mongerson related post: Mongerson -Phase II Data Available in NEJM | gutsandgrowth

 

Ustekinumab

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Related article from GI & Hep News: Ustekinumab for complex Crohn’s from ECCO conference/UNITI-1 Study (n=741)

FMT.  Further studies are needed

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