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CCFA IBD Update -Conference Notes (part 2)

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As noted in previous blog post, I wanted to share some notes from recent Atlanta CCFA talk.

The fourth lecture by Jeffry Katz discussed optimizing biologic therapy.  Overall this was an excellent review.  He discussed his general preference for combination therapy since the publication of the SONIC study. Also, he highlighted a smaller study that showed better efficacy with combination therapy in ulcerative colitis as well (DDW 2011, Abstract #835).

With regard to withdrawal of therapy when doing well on combination treatment, he indicated that he sometimes reduces (or stops) dosage of immunomodulator after 1 year but tries to avoid stopping anti-TNF agents.  Relapse rates after stopping infliximab in Crohn’s disease are approximately 50% at 1 year and 75% at 5 years.

His talk reviewed antibodies to infliximab and low therapeutic levels. This has been discussed on this blog previously:

He reviewed risks of the IBD medications.  With regard to psoriasis reactions, he stated that developing skin lesions occur in about 5% and this necessitates drug withdrawal in 1%.  As these skin reactions are often a ‘class effect,’ use of an alternative may be needed.  He stated that he had used ustekinumab in this setting (“but this entails a fight with the insurance company”).

The 5th talk by Doug Wolf reviewed pregnancy in IBD.  Much of the information has also been discussed in this blog recently: Anti-TNFs and Pregnancy | gutsandgrowth

His key points:

  • Probably stop infliximab at gestational week 32
  • Likely give adalimumab up until week 34-36
  • If patient in remission, consider stopping stopping drugs earlier
  • In PIANO registry (n=1000), use of anti-TNFs and immunomodulators was not associated with any complication, including prematurity, spontaneous abortion, intrauterine growth retardation or specific birth defects.  However, there was a significant increase in infant infections up to 12 months of life in the combination therapy group.
  • No live virus vaccines (eg. rotavirus) for first 6 months for infants exposed to infliximab

The last talk that I attended was a pediatric case presentation from Cary Sauer. He presented a teenage boy who had mild disease based on bloodwork and endoscopy who had more severe and extensive disease on magnetic resonance enterography (MRE) (More imaging needed? | gutsandgrowth) and video capsule endoscopy.  He argued that small bowel assessment is worthwhile in every patient at the time of diagnosis as more severe findings could influence the choice to start with top-down therapy.

The final aspect worth mentioning were some of the patient-related information:

1. A pediatric, adolescent, and parent support group will have its first meeting April 23rd 6-7:30 pm at Scottish Rite Children’s Hospital (Main auditorium).  Followup meetings are scheduled for August 27, and October 22. All meetings are free.  Contact CCFA mball@ccfa.org or 646-623-4869 (cell) for more information.

2. CCFA also has “Power of Two.”  This contacts patients/parents with peer mentors.  Interested patients can contact mball@ccfa.org or 404-982-0616.

CCFA IBD Update -Conference Notes (part 1)

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I wanted to share some notes from the Atlanta CCFA “Update in Inflammatory Bowel Disease” conference which was held March 23, 2013.

The first talk by Gil Melmed reviewed immunization issues in IBD.  One of the best quotes of the conference was on his first slide:  “The single most important thing a [rheumatologist] can do to optimize care for a [lupus] patient is to act as their internist, yet that is the last thing most [rheumatologists] wish to or feel qualified to do.” (Wallace DJ. Lupus 2008 (17) 91-2.

While trying to manage all aspects of the health care of our patients with chronic disease is an ideal, he also noted that 20-30% of adult IBD doctors do not understand the importance of avoiding live-virus vaccines (a list of these are noted in previous blog: Protecting the most vulnerable | gutsandgrowth).

One of the take-home points from this talk for me was to avoid use of rotavirus vaccine in newborn patients if their mother is receiving Infliximab or Adalimumab.  Another useful point would be to remind family members of immunosuppressed IBD patients to receive the influenza vaccine rather than the live-virus vaccine (flumist).

The second talk by Wallace Crandall focused on improving health care delivery.  The best quote of the day was from his first slide: “Every system is perfectly designed to achieve exactly the results it gets.”  (Donald Berwick).  One of his slides that I found intriguing showed 2007 data on immunomodulator use within the first 3 months of diagnosis from 10 different centers.  The rate varied from 30% to 98%.  He didn’t try to answer how frequent immunomodulator use in this time period should occur but there was no valid reason for this degree of variation.

In Columbus (Ohio), he stated that they are working to transform chronic care from 15-30 minute visits every 3-6 months to a more continuous process.  “Patients receive only 60% of recommended care.” With a better health care delivery system, this could be improved and potentially improve outcomes.

Another obstacle is the lack of evidence to guide decisions.  Recent “ECCO” guidelines for pediatric ulcerative colitis had 48% of recommendations based on level D evidence.

The third talk by Douglas Drossman was probably the most helpful.  He discussed pain management in IBD.  He reviewed a lot of recent data on irritable bowel syndrome (IBS) and discussed similarities between post-infectious IBS and many patients with treated IBD.

He also discussed central pain aspects and alluded to changes in the brain that happen with chronic treatment (Pain changes brain | gutsandgrowth).  He noted that antidepressants have the potential to reverse brain changes due to chronic pain but that regrowth of neurons can take a long time.  As such, he noted that agents like imipramine are needed for at least one year. Use of imipramine, he noted, has been shown to improve cognitive function in mice with traumatic brain injury (J Neurotrauma 2011; 28: 995).

With regard to IBD, Dr. Drossman noted a wide variability in pain response among patients.  Some who have very significant mucosal disease do not experience significant pain, likely due to downregulation of some central pathways.  He outlined his treatment model for pain in IBD.

  1. Effective communication improves clinical outcomes
  2. Just as there is a “treatment pyramid” for IBD, with IBS the treatment pyramid ncludes the following: motility agents, antispasmodics, antidepressants, psychological intervention, and central augmentation.
  3. With regard to antidepressants, he highlighted the differences between tricyclics, SSRIs, and SNRIs. He noted that SSRIs like citalopram, escitalopram, fluoxetine, paroxetine, and sertraline are not effective at reducing pain but can help anxiety/depression.
  4. Tricyclic antidepressants are effective at reducing pain and are inexpensive.  Side effects can include sedation, dry mouth, dizziness, and constipation.  Desipramine and nortriptyline have fewer side effects.
  5. SNRIs including duloxetine, venlafaxine, desvenlafaxine, and minacipran are effective at reducing pain and fewer side effects.  However, they are considerably more expensive.  Nausea, though, is not infrequent.
  6. Psychologic treatments: cognitive behavioral, psychotherapy, hypnosis, and relaxation training.  When to refer? moderate-severe symptoms, maladaptive coping (eg. “catastrophizing”), and motivated patient.
  7. What is central augmentation? If an antidepressant is not effective, augmentation is adding an agent that may target a different brain receptor.  Potential augmenters include pharmacologic and non-pharmacologic approaches.  Pharmacologics could include added gabapentin, added atypical antipsychotic (e.g.. quetiapine [Ability]), added clonidine, added buspirone, or added mirtazepine (e.g. remeron).  Most practitioners will need the help of a psychiatrist to manage these medications.

Thiopurine Metabolite Testing -NASPGHAN Consensus Recommendations

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The inflammatory bowel disease committee of NASPGHAN has published a review and recommendations for the use of thiopurine metabolite testing (JPGN 2013; 56: 333-40).

The effectiveness of thiopurines is reviewed with a few key points:

  • Cochrane reviews have shown that azathioprine and 6-mercaptopurine are effective in inducing remission in Crohn’s disease.  For active disease the overall response rate has been reported as 54% compared with 33% for placebo.
  • For ulcerative colitis, a Cochrane analysis deemed the methodologic quality of 4 of the 6 studies as unsatisfactory and that all studies were small.  “The reviewers concluded that azathioprine may be effective treatment for patients with ulcerative colitis.”

The review covers the potential adverse effects of the thiopurines: myelosuppression, pancreatitis, elevated transaminases, susceptibility to infection, and malignancy.  The review suggests that the risk of non-Hodgkin lymphoma is probably increased up to 4-fold. Though, it is difficult to determine how much of the risk is truly due to the usage of thiopurines or other confounding factors.  The studies about the risk of non-melenoma skin cancer are not discussed.

Other covered topics: advantages of thiopurine metabolite testing (6-thioguanine [6-TGN] and 6-methylmercaptopurine[ 6-MMP]), potential disadvantages of metabolite testing (e.g.. cost), use of genotype versus phenotype (phenotypic testing is generally preferred), thiopurine metabolism, devising target levels, use of allopurinol, and misinterpretation of metabolite testing.

Specific Consensus Recommendations:

  • Obtain thiopurine methyltransferase (TPMT) testing prior to initiation of thiopurines.
  • Avoid use of thiopurines in individuals with extremely low TPMT activity or who are homozygous recessive for TPMT activity
  • TPMT testing does not predict all cases of leukopenia.  All individuals receiving thiopurines should have routine monitoring with CBCs.  “Most adverse effects from thiopurines are not directly related to 6-TGN or 6-MMP levels.”
  • Metabolite testing can help determine adherence to therapy
  • Metabolite testing may be helpful in guiding dose adjustment and/or adding allopurinol treatment
  • Routine and repetitive testing of metabolites is not recommended in patients who are doing well on an acceptable thiopurine dosage.

Related blog posts:

Anti-TNFs and Pregnancy

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While pregnancy does not occur commonly while patients are in a pediatric gastroenterology practice, the possibility of becoming pregnant certainly influences our choice of medications.  With inflammatory bowel disease (IBD), I rarely recommend methotrexate in young women due to its teratogenicity.  With regard to the anti-TNF agents, there is less data available.   Two recent studies add some insight into this issue.

The first study ((Clin Gastroenterol Hepatol 2013; 11: 318-21) followed 31 pregnancies in 28 women with IBD (2006-2011).  18 patients received infliximab (IFX) and 13 adalimumab (ADA).  Most were receiving lower doses; only one IFX patient was receiving 10 mg/kg/dose and only two ADA patients were receiving weekly dosing.  Levels of anti-TNF agents were measured from cord blood from 18 newborns (12  IFX, 6 ADA).

Results:

  • 28 live births.  3 miscarriages (1 IFX, 2 ADA).  No congenital malformations were noted.
  • Mean cord IFX level was 6.4 mcg/mL.  A level of 2.8 mcg/mL was noted in the early discontinuation group –stopping 10 weeks prior to delivery .
  • Mean ADA level was 1.7 mcg/mL in five infants.  One infant had an undetectable level. All mothers had stopped ADA at gestational week 22.

In the second study (Clin Gastroenterol Hepat 2013; 11: 286-92) there were 31 pregnant patients. Anti-TNF treatment: Certolizumab (CZP) (n=10), IFX (n=11), ADA (n=10).  Serum levels were measured at birth in the mother, infant, and in cord blood. Then, levels were followed monthly until undetectable.  Among women receiving IFX, two were receiving 10 mg/kg/dose.  Women were identified through the Crohn’s Colitis Foundation of America Pregnancy IBD and Neonatal Outcomes (PIANO) Registry.

Results:

  • IFX was detectable for 2-7 months postpartum (median interval prior to delivery and last dose was 35 days).  Median IFX level in the cord was 160% that of the mother.
  • ADA was detectable for at least 11 weeks in infant’s circulation (median interval prior to delivery and last dose was 5.5 weeks). Median ADA in the cord was 153% of the mother.
  • Median CZP in the cord was 3.9% that of the mother.
  • No congenital anomalies or complications were reported in any of the infants.

Bottomline from these studies:

Stopping these drugs after the second trimester lowers the level of these medications in the infant.  This likely results in a lower likelihood of the infant developing an opportunistic infection but also results in a low risk for the mother of an IBD flareup.  Certolizumab pegol has very low levels of placenta transfer.

Related references:

  • -J Am Acad Dermatol 2011; 65: 870.  Death noted in infant whose mother took IFX after BCG vaccination.
  • -J Crohns Colitis 2011; 5: 555-8.  Low levels of IFX detected in infants from nursing mothers with IBD  (1/200th of the maternal level in serum 2 to 3 days after infusion).
  • -Clin Gastroenterol & Hep 2010; 8: 509. n=2377. Crohn dz assoc w prematurity but not birth defects.
  • -Gastroenterol 2003;124: 9-17. Safety of 6-MP in pregnancy. n=155, at least 1 pregnancy. No adverse effect noted.
  • -Clin Gastroenterol & Hepatology; 2006: 4: 1255.  Infliximab crosses placenta but was not detected breastmilk.

Trends in Adolescent Bariatric Surgery

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Despite increased numbers of obese adolescents, the number of inpatient bariatric surgery cases has plateaued (JAMA Pediatr 2013; 167: 126-32).  Thanks to Ben Gold for sharing this reference.

In this retrospective cross-sectional study using an administrative dataset (Healthcare Cost and Utilization Project Kids’ Inpatient Database), the authors documented the following bariatric surgery rates:

  • In 2000: 0.8 per 100,000 (328 procedures)
  • In 2003: 2.3 per 100,000 (987 procedures)
  • In 2006: 2.2 per 100,000 (925 procedures)
  • In 2009: 2.4 per 100,000 (1009 procedures)

The other observations in this study were that procedures were predominantly performed on females (75%), the prevalence of comorbidites increased (49% in 2003 vs. 59% in 2009), and complications rates were low.  68.3% had private insurance.

Take-home points:

The number of adolescents who would qualify for bariatric surgery has increased but the rates have not changed.  Why?

  1. Societal barriers.  Obesity is more common in lower socioeconomic groups with lower educational levels.  Yet, the rates of bariatric procedures is the same in low-income and high-income populations.
  2. Insurance coverage.  In many states, medicaid does not cover bariatric surgery.
  3. Physicians limiting access.  After initial enthusiasm (2000-2003), published guidelines to identify appropriate patients and to highlight recommendations prior to surgery may have led to more cautious referral patterns.

Over the past decade, there are increased numbers of qualified surgeons and there has been more use of laparascopic techniques.  The Roux-en-Y gastric bypass (RYGB) was the most common bariatric procedure in this population, accounting for 67.6% of cases in 2009 (60.6% were laparascopic, 7% were open).  Laparascopic adjustable gastric banding (LAGB) accounted for the remaining 32.1% of cases.

Since this study relied on administrative data, there are several limitations.  Billing codes may not reflect the procedures accurately.  For example, ICD-9 codes for laparascopic sleeve gastrectomy were not available until 2011.  Nevertheless, this study provides some insight into the trends with bariatric procedures in adolescents.

Related blog link:

Six year outcomes with bariatric surgery | gutsandgrowth

Closer to Star Trek Medicine

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In Star Trek, Dr. Leonard McCoy used a medical tricorder to effortlessly diagnose a lot of conditions (Tricorder – Wikipedia, the free encyclopedia, Medical tricorder – Wikipedia, the free encyclopedia).  While many of the newest diagnostic tests are not as portable, they share a feature of being able to diagnose a wide range of conditions quickly.  These tests include imaging studies like MRI and CT, genetic microarrays, and now PCR panels to diagnose a broad array of respiratory and gastrointestinal ailments.

One of the newest is the “xTAG GPP.”  With one stool sample, this Gastrointestinal Pathogen Panel (GPP) can detect at least 11 common bacteria, viral, and parasitic pathogens in about five hours.  Thus, all patients with identifiable gastroenteritis illnesses can be diagnosed more quickly.  The test relies on a “multiplex nucleic acid test.”

FDA News Release Jan 15, 2013  (Press Announcements > FDA permits marketing of first test that can …):

“Infectious gastroenteritis is an inflammation of the stomach and intestines caused by certain viruses, bacteria, or parasites. Common symptoms include vomiting and diarrhea, which can be more severe in infants, the elderly, and people with suppressed immune systems. Gastroenteritis can be spread easily through person-to-person contact and contaminated food, water, and surfaces. 
 
The Centers for Disease Control and Prevention reports that between 1999 and 2007 gastroenteritis-associated deaths in the United States increased from nearly 7,000 to more than 17,000 per year. Norovirus and Clostridium difficile accounted for two-thirds of the deaths. 
 
The xTAG Gastrointestinal Pathogen Panel (GPP), a multiplexed nucleic acid test, detects the following causes of gastroenteritis:
 
Bacteria
  • Campylobacter
  • Clostridium difficile (C. difficile) toxin A/B
  • Escherichia coli (E. coli) O157
  • Enterotoxigenic Escherichia coli (ETEC) LT/ST
  • Salmonella
  • Shigella
  • Shiga‐like Toxin producing E. coli (STEC) stx 1/stx 2
 
Virus
  • Norovirus
  • Rotavirus A
 
Parasite
  • Cryptosporidium
  • Giardia
 
“Tests such as the XTag GPP that can detect viruses, bacteria, and parasites from one sample at the same time can help clinicians more quickly identify and treat what’s causing gastroenteritis,” said Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostics and Radiology at the FDA’s Center for Devices and Radiological Health. “The test could also allow clinicians and public health professionals to more quickly identify and investigate the source of potential gastroenteritis outbreaks.”
The manufacturer demonstrated the performance of the xTAG GPP by collecting samples from 1,407 patients with suspected infectious gastroenteritis and comparing the xTAG GPP results to individual tests that are known to separately and reliably detect the 11 viruses, bacteria, or parasites associated with the xTAG GPP. The manufacturer also ran the test on 203 samples from patients with previously confirmed infectious gastroenteritis, and 313 additional specimens from pediatric patients with suspected infectious gastroenteritis. Results were comparable to the individual tests. Due to the risk of false positives, all positive results from the xTAG GPP need to be confirmed by additional testing (blog entry underlined for emphasis, not in original FDA release).
 
Luminex, Inc., of Austin, Texas, manufactures the xTAG.”
According to manufacter’s website, the test also detects Yersinia, Entamoeba histolytica, and adenovirus.  It reports sensitivity of of >94% for almost all pathogens (except Salmonella which was 84%) and specificity of >94% for all of the pathogens.

Is functional pain more common in children with Celiac disease?

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A recent study adds information to the title question but does not resolve it (J Pediatr 2013; 162: 505-09).

The authors note that they expected to find a higher prevalence of abdominal pain and abdominal pain/functional gastrointestinal disorders among children with diagnosis of celiac disease.  They note that functional disorders have been more common after acute gastroenteritis and cow’s milk hypersensitivity of infancy presumably due to preceding inflammation.  Persistent low-grade intestinal inflammation and immune activation have been proposed as precipitating susceptibility to functional abdominal pain.

In this small retrospective study, a statistically significant difference in functional GI disorders was not observed.  Enrolled families were contacted by telephone at least 6 months after the diagnosis of Celiac disease.  They completed a telephone questionnaire and a separate Rome III questionnaire.

Celiac cases (n=49):  abdominal pain (24.5%), functional abdominal pain (4.8%), IBS (6.1%), dyspepsia (4.8%), abdominal migraine (4.8%), nonspecific abdominal pain (6.1%)

Control cases (n=48): abdominal pain (14.6%), functional abdominal pain (6.3%), IBS (2.1%), nonspecific abdominal pain (6.1%)

Given the question that the authors were trying to answer, this study was unlikely to be helpful.  Problems with the study:

  • The biggest problem is the small number of patients.
  • Cross-sectional design
  • Reliance of recall symptoms
  • Lack of information on dietary adherence
  • Collection of information from only parents contributed

Bottomline: While screening for celiac disease is common in patients with possible functional abdominal pain, treatment with a gluten-free diet may not resolve these symptoms. Functional abdominal pain is at least as common in children with celiac disease as in the general population.

Related blog post:

Early antibiotic use and the development of inflammatory bowel disease

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Another study adds weight to the idea that early antibiotic use may increase the risk of developing inflammatory bowel disease (IBD) (J Pediatr 2013; 162: 510-4).

Using a nested case-control design, the authors matched 2377 controls to 294 children with IBD in a population-based database from Manitoba, Canada.  Specifically, the authors looked at the frequency of otitis media diagnosis and the likelihood of subsequent IBD.  By age 5 years, 89% of IBD cases had at least one diagnosis of otitis media, compared with 82% of the controls.  Despite the high frequency in both groups, the authors determined that individuals with a diagnosis of otitis media before age 5 years were 2.8-fold more likely to be an IBD case.

Some of the strengths of this study included the fact that it was a population-based analysis dating back to 1984 and likely captured almost all pediatric IBD cases (<19 years).  Nearly all physicians in Manitoba submit billing claims to a single publicly funded source.  Due to the nature of administrative data, this eliminates recall bias.

However, administrative data have several limitations as well.  Other confounding conditions may have been present and not identified; this could include family history and autoimmune diseases.

The authors “suspect” that the linkage between otitis media and IBD relates to the usage of antibiotics and subsequent alterations of the intestinal microflora.  Otitis media may serve as a “sensitive proxy measure” of antibiotic use.  Also, as boys are more frequently treated for otitis media, this may relate to the generally higher incidence of pediatric IBD in males.

For anyone interested in the association between antibiotic exposure and IBD, this study is useful and provides a number of references as well.

Related blog entries:

Does negative testing reassure patients?

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Probably not according to a recent study (JAMA Intern Med, published online Feb 25, 2013, d0i:10.1001/jamainternmed.2013.2762).

Citation: A Rolfe, C Burton. JAMA Intern Med. 2013;173(6):407-416. Open access! Reassurance After Diagnostic Testing With a Low Pretest Probability of Serious Disease

In this study, the authors systematically reviewed the literature and, after screening 9742 studies, identified 14 randomized controlled trials (n=3828 patients) which met inclusion criteria, including the following:

  • Randomized control trial
  • Adult participants with symptoms indicating a low probability of serious disease

Studies were excluded if they were not published in a peer-reviewed journal or if they were undertaken in a tertiary care setting.  Eight trials involved diagnostic testing for dyspepsia (mainly endoscopy), three involved radiography for back pain, and the other three included testing for chest pain, headache and palpitations.  Long-term follow-up varied from 4 to 18 months.

Key Findings:

  • Patients’ illness concern (odds ratio 0.87 in three trials) and anxiety (standardized mean difference 0.06 [-0.16 to 0.28] in two trials) were not reduced in the short or long term.
  • No overall long-term effect on symptom persistence was noted (odds ratio 0.99)

Limitations:

  • The authors examined only reassurance for patients, not for physicians.
  • Participants were not blinded
  • Overall, small number of study participants

In the discussion, the authors note that observational studies “suggest that illness concerns reappear within hours of receiving a normal (negative) test  result.”

For pediatric gastroenterologists, the conclusions from this article add another wrinkle when deciding how much workup is indicated for conditions like recurrent abdominal pain.  Previous data indicate that maternal anxiety is the most consistent predictor of outcome for recurrent abdominal pain (Acta Paediatr 2007; 96: 697-701); this study does not address whether patient proxies are reassured by negative testing.  And, other studies have shown that patients rate their care higher after diagnostic testing (Don’t miss the gorilla! | gutsandgrowth).

As a fellow, I was told: “Don’t just do something, stand there” from Bill Balistreri; he also recommended avoiding the mentality of “Scope first, think second.” While this current study suggests that there is a lack of long-term benefit when testing is done primarily for reassurance, convincing families that their child does not need testing is often difficult.

Update for Peutz-Jegher Syndrome

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A recent case series provides some useful insight into this rare condition (JPGN 2013; 56: 191-95).  Peutz-Jegher syndrome (JPS) has an incidence between 1 in 8500 to 1 in 120,000.  It is caused by a germline mutation in the STK11 gene.  It is associated with a serine threonine kinase that functions as a tumor suppressor.

14 children were identified through a medical records review at the Children’s Hospital Colorado between 2000-2011.  Inclusion required 2 or more of the following criteria:

  • 2 or more characteristic hamartomatous polyps of the small intestine
  • typical mucocutaneous pigmentation
  • positive family history (absent in about 25% of cases historically)

Results: Median age at first clinical evaluation was 4.5 years.  Intussusception was noted 7 times in 5 children (ages 5 to 16 years). Surgical reduction was required in 5 of the events. Polyps were found in the stomach/duodenum in 5 (36%), small bowel in 7 (50%), and colon in 3 (21%). Sertoli cell tumors was identified in 2 of the 10 boys at ages 8 years and 11 years.

Based on their experience, the authors suggest the following:

  • Initial screening start at age 4-5 years of age.  They recommend capsule endoscopy, upper endoscopy, and colonoscopy (CE/EGD/colon) as initial screen.  Then, they suggest repeating every 1-2 years until no polyps and then every 2-3 years.
  • In boys, they recommend breast exams for gynecomastia and testicular exams annually to screen for Sertoli cell tumor.  In girls, monitoring for precocious puberty and if present, then further evaluation for Sertoli cell tumor.

Given the small size of their cohort and the likelihood that asymptomatic children may not have been seen, it is too early to know if the approach recommended by the authors is justified.  Will earlier screening result in any long-term benefit &/or reduce complications related to JPS?