Category Archives: Gastroenterology

Monotherapy or Combination Therapy with Adalimumab?

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Since the introduction of anti-tumor necrosis factor therapies (anti-TNFs), the benefit of using these agents in combination with immunomodulators or as monotherapy has shifted a few times based on the latest studies.  The most influential recent studies had been SONIC and UC Success which indicated that combination therapy for Crohn’s and Ulcerative Colitis, respectively, was more effective and without more adverse effects than monotherapy. A recent study may create some additional uncertainty in this line of thought (Gastroenterol 2014; 146: 941-49).

The author performed a pooled analysis of data from 1594 patients with Crohn’s disease (CD).  Studies included CLASSIC I and II, CHARM, GAIN, EXTEND, and ADHERE.  In total, these studies provided 3050 patient-years of exposure. For individual patients, the median followup period was 1.5 years.

Key findings:

  • “Those patients receiving combination therapy had an increased risk of malignancy (other than non melanoma skin cancer [NMSC])” with a relative risk of 2.82.
  • Adalimumab monotherapy was not associated with an increased risk of malignancy other than NMSC
  • Combination therapy was associated with relative risk of NMSC of 3.46

In the discussion, the authors state “the data suggest that the increased risk likely is attributed to the immunomodulator therapy.”

A related editorial (884-86) helps dissect the articles strengths/limitations as well as implications.

Strengths:

  • the study captured data from randomized controlled trials.

Limitations:

  • median followup of 1.5 years –may not be long enough to detect a malignancy signal from anti-TNF therapy
  • unclear how many adalimumab monotherapy patients had been on a thiopurine previously

Implications:

  • “Even if Osterman et al are correct, is this information clinically meaningful enough to swing the mono-combo pendulum back to mono therapy?”
  • “The clinical relevance of the increase in absolute cancer risk from 4 in 1000 with adalimumab monotherapy to 10 in 1000 with combination therapy for cancers other than NMSC is unclear”
  • This difference of 6 in 1000 “translates to 167 patients who are treated before seeing 1 excess cancer”
  • “Most (if not all) of the cancer risk is associated with thiopurine exposure…induction therapy is more effective with combination treatment–>”we propose that we should induce patients into remission with combination therapy, and then consider withdrawing thiopurines at some point.“
  • “Consider treating younger males with thiopurines short term, or alternatively with methotrexate.”  Though the authors note that data from rheumatology brings some concern to methotrexate cancer risk (Semin Arthritis Rheum 2014; 43: 489-97). Source Article: Methotrexate Safety | gutsandgrowth
  • “Consider treating elderly patients with anti-TNF monotherapy to decrease their risk of serious infections”

Also noted: “Risk of Cancer in Patients with Inflammatory Bowel Diseases: A Nationwide Population-based Cohort Study with 30 Years of Follow-up Evaluation” (Clin Gastroenterol Hepatol 2014; 13: 265-73). n=13,756 patients with CD and 35,152 with UC. Key findings –among CD patients, the excess risk was largely due to extra-intestinal cancers such as hematological malignancies (SIR 1.9) and smoking-related malignancies (SIR 1.5).  Associations between UC and gastrointestinal/extraintestinal cancers were weaker (both SIRs were 1.1); the risk of gastrointestinal cancers decreased over the course of the study.

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The Latest on EoE and PPI-REE

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A recent study shows similar clinical, endoscopic and histologic findings between eosinophilic esophagitis (EoE) and proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE) (Aliment Pharmacol There 2014; 39: 603-08 -thanks to Seth Marcus for this reference).

The authors used two databases: one from Walter Reed and one from the Swiss EoE database.  All of these patients were >/=18 years.  Response to PPI was defined as achieving less than 15 eos/hpf and a 50% decrease from baseline following at least 6-weeks of PPI treatment.

Demographics: 63 EoE patients, 40 PPI-REE, mean age 40 years (75% male, 89% Caucasian).

Findings:

  • Similar dysphagia 97% vs. 100% (in EoE and  of PPI-REE cohorts)
  • Similar food impaction 43% vs. 35% (in EoE and  of PPI-REE cohorts)
  • Similar heartburn 33% vs. 32% (in EoE and  of PPI-REE cohorts)
  • Similar duration of symptoms: 6.0 years vs 5.8 years (in EoE and  of PPI-REE cohorts)
  • Similar endoscopic findings too: rings 68% in both groups, furrows 70% in both groups, strictures 49% vs 30% (in EoE and  of PPI-REE cohorts)
  • Similar histology: proximal esophagus 39 vs 38 eos/hpf and distal esophagus 50 vs 43 eos/hpf

Take-home message: EoE and PPI-REE are very similar in presentation and indistinguishable without a PPI trial.

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Marriage, Divorce and Separation with Anti-TNF Therapy

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This review article (Inflamm Bowel Dis 2014; 20: 757-66) examines the question of whether and when anti-tumor necrosis factor (anti-TNF) agents can be stopped in Crohn’s disease (CD) patients in remission.  This topic is particularly helpful since this comes up frequently in clinical practice.

As recently as a few years ago, one expert advised me that starting an anti-TNF agent (like infliximab or adalimumab) was like getting married.  Once you committed, you stayed in that relationship indefinitely.  Of course, it is well-known that individuals get divorced.  In medical terms, I guess that would be the equivalent of developing antibodies to the anti-TNF agent or other adverse reactions.  Switching from one anti-TNF to another would be equivalent to marital infidelity.

So what does this review article say about all of this?  The article examines nine studies with a little more than 500 patients.  “Current evidence suggests that a group of CD patients, possibly 30% to 40% in clinical remission while on IM (immunomodulators) and infliximab can stop the latter and maintain clinical remission for a relatively long interval.  It seems that, if followed long enough, virtually all patients (including those on IM) will eventually develop clinical recurrence.”

If tempted to separate but not divorce anti-TNF therapy, the authors recommend, in addition to clinical remission, “normal colonoscopy (and/or normal surrogate markers of disease activity) should be adopted as a criterion when stopping therapy and during follow-up….As of today, many authors do not recommend to routinely stop anti-TNF agents in patients responding to this therapy and in the absence of other issues.  Others propose to stop them after a minimum of 2 years of clinical and endoscopic remission or longer if only clinical remission can be documented…

If costs or other issues are present, we suggest to cautiously stop anti-TNF agents only in patients on combination therapy with profound (clinical, biochemical, and endoscopic) and long lasting (>1 year) remission and continuing the IM.  Such patients should be closely followed by serial determinations of fecal calprotectin and inflammatory indices, and the medication immediately restarted in the presence of a flare. When in doubt, colonoscopy should be performed.”

Take-home message: Most patients are better off staying married to their anti-TNF therapy.

Also noted: Inflamm Bowel Dis 2014; 20: 742-56.  Clinical Utility of Fecal Biomarkers for the Diagnosis and Management of Inflammatory Bowel Disease.  This is a useful review with 103 references.

Brief Updates on Colorectal Cancer

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“Low-Dose Aspirin Use After Diagnosis of Colorectal Cancer Does Not Increase Survival: A Case-Control Analysis of a Population-Based Cohort”  Gastroenterol 2014; 146: 700-08.  The authors performed a nested case-control analysis of a cohort of 4794 patients diagnosed with colorectal cancer.  “There was no association between low-dose aspirin usage and colon cancer-specific mortality.”  These study findings contradict previous studies.  More trials are underway.

“Reduced Risk of Colorectal Cancer Up to 10 Years After Screening, Surveillance, or Diagnostic Colonoscopy” Gastroenterol 2014; 146: 709-17.  Conclusion: “In a population-based case-control study, the risk of CRC was strongly reduced up to 10 years after colonoscopy for any indication. Risk was particularly low after screening colonoscopy, even for cancer in the right colon.”  The odds ratio for CRC after screening colonoscopy was 0.09.

NEJM 2014; 370: 1287-97.  Multitarget Stool DNA Testing for Colorectal-Cancer Screening.  Among 9989 average-risk participants, this stool DNA assay identified more cancers than a fecal immunochemical test (FIT) but had more false positives.

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How Common is Eosinophilic Esophagitis?

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There have been numerous epidemiologic studies regarding eosinophilic esophagitis.  A recent summary of a recent study (Clin Gastroenterol Hepatol 2014; 12: 589-96) has been posted on the AGA Journals Blog.  Here’s the link to the full summary:  EoE Prevalence AGA Journal Blog

Here’s an excerpt:

Eosinophilic esophagitis (EoE), which was barely recognized 20 years ago, affects at least 150,000 people in the United States, with three-quarters being adults, report Evan Dellon et al. in the April issue of Clinical Gastroenterology and Hepatology.

EoE, also known as allergic esophagitis, is an allergic inflammatory disease characterized by increased numbers eosinophils in the esophagus. Symptoms include difficulty swallowing, food impaction, and heartburn…

They found that despite its relatively recent description, EoE is frequently diagnosed in the US, with an estimated prevalence of 56.7/100,000 persons. The mean age of patients, surprisingly, was 33.5 years; 65% were male, 55.8% had dysphagia, and 52.8% had at least 1 other allergic condition. Prevalence peaked in men 35–39 years old (see figure).

EoE Prevalence by Age

Dellon et al. identified patients based on the International Classification of Diseases (ICD), 9th revision code for EoE (530.13). They state that this prevalence could be an underestimate, because knowledge of the code and recognition of EoE are increasing…

Take home point: This study shows that EoE in adults and in children is much more common in males than females, especially in those with other allergic diseases.  Given the frequency of those with mild symptoms, the prevalence data are likely to be huge underestimates.

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Adenoma Detection Rate: Life or Death Quality Measure

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Many physicians bristle at numerous quality measures due to concerns that they may have little relevance to clinical practice or that they are not representative since they measure only a tiny fraction of their work.  For adult gastroenterologists, adenoma detection rate may become a quality measure that will be more difficult to dismiss (NEJM 2014; 370: 1298-306).

Background: In this study, the authors evaluated 314,872 colonoscopies by 136 gastroenterologists by using data from an integrated health care delivery organization.  They determined associations between adenoma detection rate and the risks of colorectal cancer/cancer-related deaths diagnosed 6 months to 10 years after colonoscopy.  Estimates of attributable risk were adjusted for the demographics of the patients, indications for colonoscopy, and coexisting conditions.

Key Results:

  • The adenoma detection rate varied considerably, from 7.4% to 52.5%.
  • 712 colorectal adenocarcinomas were identified during followup, including 255 advanced-stage cancers.
  • 147 deaths from interval colorectal cancer occurred.
  • Among patients of physicians with adenoma detection rates in the highest quintile, compared with patients of physicians in the lowest quintile, the adjusted hazard ratio for any interval cancer was 0.52; it was 0.43 for advanced-stage interval cancer and 0.38 for fatal interval cancer.
  • For each 1% increase in the adenoma detection rate, there was an associated decrease in the risk of cancer by 3%.

Bottomline: Previous studies have shown that spending longer than 6 minutes on a screening colonoscopy increases detection rates.  This study shows that doing a high quality colonoscopy really does alter the outcome.

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How Colonoscopy & Preps are Indicative of Patient Activation and Health Care Decision-Making

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I found two recent studies on bowel preps interesting primarily because of how they help us understand problems with utilization and problems with patient motivation.

The first study (Clin Gastroenterol Hepatol 2014; 12: 443-50) utilized a 5% random national sample of Medicare claims data.  The authors determined that among 57,597 Medicare beneficiaries 66 years and older that underwent screening colonoscopy (not therapeutic) 24.8% of these procedures were performed in individuals with a life expectancy <10 years.  Given the nature of the study (eg. relying on administrative data), there were several limitations.  However, the implication of the study is that there are a lot of unnecessary colonoscopies.  That is, screening colonoscopies are intended to interrupt a sequence of adenoma to adenocarcinoma that can take years; even when cancer is present, it can take several years before the onset of clinical symptoms.  Currently, the US Preventive Services Task Force (USPSTF) recommends against routine screening in those aged 75-84, precisely because the benefits of screening may be outweighed by the risks of screening.”  The authors note that “people with multiple comorbidities (and therefore lower life expectancy) are more likely to visit multiple providers, which increases the chances of receiving testing.”

The second study (Clin Gastroenterol Hepatol 2014; 12: 451-57) showed that patients with lower “patient activation” are much more likely to have a poor colonoscopy preparation.  Patient activation is defined as “an individual’s knowledge, skill, and confidence for managing his/her own health and health care.”  The author’s note that the “Patient Activation Measure (PAM) is a validated scale developed…to measure this construct.” This cross-sectional study took place in Chicago between 2008-2010 at either an academic practice or a ‘federally qualified health center.’ Key findings:

  • One-third of patients (n=134/462 adults) had suboptimal quality of bowel preparations. Of these, 15% (n=62) were fair quality and 17% (n=72) were poor quality.
  • After multivariable analysis and adjustments, patient activation (OR 2.12) and diabetes (OR 2.45) were independent predictors of suboptimal bowel preparation quality.
  • Health literacy (a measure of cognitive skill) was not correlated with patient activation (a measure of patient engagement).

Also noted in same journal issue: Clin Gastroenterol Hepatol 2014; 12: 470-77.  “In a supervised setting, nurse endoscopists perform colonoscopies (after a minimum of 100) according to quality and safety standards that are comparable with those of physician endoscopist and can substantially reduce costs.”

Take-home messages:

  1. Poor bowel preparations are common.  In studies of adult patients, split-dose preparations can help.  The associated editorial (pg 458-462) recommends delaying case and considering further oral prep or enemas for patients arriving with stool that is not clear or yellow.
  2. Colonoscopies are performed too frequently in some patients and not frequently enough in others.  Thus, something as simple as a colonoscopy is not so simple.

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Probiotics For Fatty Liver Disease

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Probiotics and alterations in the microbiome are being examined for a range of ailments.  However, as noted in previous blog posts, the current evidence shows only a limited number of disorders where probiotics have been proven effective.  There is more evidence, now, that probiotics may be beneficial for nonalcoholic fatty liver disease (NAFLD).

  • Am J Clin Nutr 2014; 99: 425-6. editorial
  • Am J Clin Nutr 2014; 99: 535-42.

The referenced article examined 52 nondiabetic patients with fatty liver disease in a double-blind, randomized, placebo-controlled trial. Patients were considered to have NAFLD on the basis of an ultrasonography and an alanine aminotransferase value >60 U/L.  Those who received a probiotic were compared with a placebo group and followed for 28 weeks.

In this study, rather than a probiotic, technically, the treatment group received a synbiotic because it contained fructooligosaccharides (FOS) which are non digestible oligosaccharides in addition to a probiotic mixture.  FOS can stimulate the growth of intestinal bacteria.  The probiotic mixture included Lactobacillus case, Lactobacillus rhamnosus, Streptococcus thermopiles, Bificobacterium breve, Lactobacillus, acidophilus, B. longum, and Lactobacillus bulgaricus.

Key findings:

  • There were improvements in ALT values and in baseline mild fibrosis (estimated by Fibroscan).
  • There were decreased levels of circulating TNF-α and decreased nuclear transcription factor κβ in circulating mononuclear leukocytes –both consistent with decreased systemic inflammation

Limitations: 

  1. Study did not include liver histology (biopsy).  In addition, in nearly all subjects, the fibroscans were near normal, both before and after the intervention.  Thus, the reduction in liver stiffness is not clear cut.
  2. Small number of participants.
  3. Short study period.

Bottomline: This study along with several others points towards a potential role for modulating the microbiome to improve NAFLD along with metabolic syndrome more broadly.

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What is Evidence-Based Medicine for Helicobacter Pylori?

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Full article (Clin Gastroenterol Hepatol 2014; 12: 177-86): http://ow.ly/sPKbi 

My take on the most important parts of this Helicobacter pylori (HP) article:

  • Success defined: curing HP ≥95% =excellent, curing HP ≥90% =good, acceptable ≥85%, and unsatisfactory <85%.
  • “Because clarithromycin-containing triple therapy and 10-day sequential therapy are now only effective in special populations, they are considered obsolete.”
  • The “preferred choices for Western countries” are the following
  1. 14-day concomitant therapy: PPI, amoxicillin 1 g, clarithromycin 500 mg, metronidazole -all twice daily
  2. 14-day bismuth quadruple therapy: PPI BID, bismuth BID, tetracycline 500 mg QID, metronidazole 500 mg TID
  3. 14-day hybrid sequential-concomitant therapy: 7 days of PPI-amoxicillin 1 g, followed by amoxicillin 1 g, clarithromycin 500 mg, metronidazole 500 mg for 7 days-all BID

Other useful points:

  • Tetracycline is not available in many parts of the world and generally doxycycline is not an adequate substitute for tetracycline.
  • Triple therapies are extremely sensitive to resistance of the third drug (eg. clarithromycin and metronidazole).  The increase in resistance is making these regimens ineffective
  • An online calculator can help predict which therapy to choose: https://hp-therapy.biomed.org/tw/ (need to know local resistance)
  • Poor compliance is the other factor besides resistance that can undermine a well-constructed treatment regimen. Spending ample time educating patients about the need to  take all of their medicines is crucial.
  • Figure 1 on page 178 outlines the recommended treatment approach.  Unfortunately, availability of susceptibility testing has been quite limited.

Take-home message: The authors emphasize using regimens that work locally and using the evidence that we have to choose the best treatments.  However, given the resistance patterns, working on collaborating with laboratories to culture HP for susceptibility/resistance would be worthwhile to increase the likelihood of excellent outcomes.

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Also noted:  full text article online (from Kipp Ellsworth twitter feed): http://goo.gl/dD2ooF “Intestinal Transplantation: An Unexpected Journey”  This is a succinct overview of intestinal transplantation’s progress and potential.

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

Why an ERCP Study Matters to Pediatric Care

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While there are pediatric patients who undergo endoscopic retrograde cholangiopancreatography (ERCP), this is a relatively infrequent occurrence. Nevertheless, a recent study has a couple useful clinical pearls that may have broader application.

  1. Clin Gastroenterol Hepatol 2014; 12: 303-07.
  2. Clin Gastroenterol Hepatol 2014; 12: 308-10 Associated editorial
  3. Gastroenterol 2014; 146: 581-82. Associated summary

Key points/Implications:

  • Aggressive hydration may prevent post-ERCP pancreatitis. In the study, the treatment group received an average of 3290 mL over the 9-hour period compared with 945 mL in the standard infusion group.
  • Implication: The speculation from the study and the editorials is that improved pancreatic perfusion will result in better oxygenation and reduce the likelihood of  pancreatitis. In the 2nd reference, the author states that his practice is to administer “at least 3 L of crystalloid in recovery to young, healthy patients who have undergone high-risk ERCP and an additional 3 to 5 L within the first 12 hospital hours to those admitted with postprocedure pain”
  • The best fluid (for post-ERCP and acute pancreatitis) may be lactated Ringer’s (LR).
  • Implication: The lactate in LR may help reduce pancreatitis by avoiding acidosis which could promote zymogen activation and pancreatic inflammation. A previous small trial (n=40) of acute pancreatitits from any cause showed lesser degrees of systemic inflammatory response with LR in compared with normal saline (Clin Gastroenterol Hepatol 2011; 9: 710-17e1).
  • This study adds aggressive IVFs as another intervention to prevent ERCP.  Rectal indomethacin and prophylactic stent placement (in high-risk patients) are other accepted treatments.

Study details:

This pilot study randomly assigned 39 patients to aggressive hydration and 23 to standard hydration; all patients were inpatients who were not at risk for fluid overload. The aggressive group received 3 mL/kg/h during the procedure, a 20 mL/kg bolus after the procedure, and then continued on 3 mL/kg/hr for 8 hours.  In contrast, the standard group received LR at 1.5 mL/kg/h during and for 8 hours afterwards.

Demographics: The average age was 43 years in the aggressive hydration group and 45 years in the standard group. 78% were hispanic.  The ERCP procedures were mostly “average risk.”  74% had ERCP for choledocholithiasis.  Only 2 subjects needed precut sphinterotomy (3%).

Results:

  • No patients in the aggressive hydration group developed acute pancreatitis compared with 4 (17%) in the standard hydration group
  • Elevated amylase (23% vs. 39%) and epigastric pain (8% vs 22%) were also less frequent in the aggressive hydration group.

Numerous Limitations: This was a small pilot study with an atypical population; thus, the findings are difficult to generalize.  A false-positive (type 1 error) can easily occur due to the small numbers, especially as the standard hydration group had a rate of acute pancreatitis that was about double from previous studies. In addition, this study was not blinded and could have been susceptible to bias.  Furthermore, the authors defined acute pancreatitis differently than in previous studies.  In this study, the authors required enzyme increases 2 or 8 hours after ERCP with new abdominal pain; in previous studies, the definition of acute pancreatitis relied on enzyme increases for at least 24 hours after the ERCP.

Take-home message for those not doing ERCPs: Think about using lactated ringer’s and aggressive hydration in otherwise-well patients who present with acute pancreatitis.

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