Enthusiasm for Vedolizumab

Posted on January 3, 2015 by gutsandgrowth

A recent GI & Hepatology News article quoted several leading IBD researchers stating that they consider Vedolizumab a first-line biologic therapy for ulcerative colitis. Here’s the link:

Vedolizumab for UC

Here’s an excerpt:

Dr. Feagan presented outcome results after 80 and 104 weeks of vedolizumab treatment of 278 patients with ulcerative colitis who had completed a full year of treatment during the GEMINI 1 trial [Phase 3, Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction and Maintenance of Clinical Response and Remission by Vedolizumab in Patients with Moderate to Severe Ulcerative Colitis] (N. Engl. J. Med. 2013;369:699-710). He reported that the percentage of patients in clinical remission grew from 66% after 52 weeks on treatment (the time of entry into the long-term phase of the study), to 77% after 80 weeks, which then dropped to 73% after 104 weeks. Patients with a clinical response increased from 78% after 52 weeks to 88% after 80 weeks, and then dropped to 83% after 104 weeks.

During weeks 53-104 on treatment the rates of adverse events, serious adverse events, serious infections, adverse events resulting in treatment discontinuation, enteric infections, and malignancies were all low and similar to the event rates seen among the patients randomized to placebo in the GEMINI 1 study.

The results suggest that with vedolizumab treatment of inflammatory bowel disease “once you achieve an effect it is long-lasting,” Dr. Rutgeerts said in an interview. But he cautioned that the long-lasting efficacy was achieved with treatment every 4 weeks. While this approach was safe, it would also be expensive in routine practice, he noted. “The safety looks good, but the cost would be very high.”

“A key concept of vedolizumab is that it builds efficacy over time,” commented Dr. Silvio Danese during a talk at the meeting. “Vedolizumab is not the fastest runner, but [treating inflammatory bowel disease] is a marathon, and the important thing is getting to the finish”

Bottomline: Head-to-head trials would be helpful to determine which biologic agent should be considered first-line.

Related blog posts:

Lack of Meaningful Improvement in Crohn’s Patients with Tofacitinib

Posted on December 19, 2014 by gutsandgrowth

As noted in a previous blog (see below for link), tofacitinib, an oral Janus Kinase Inhibitor has shown promise as an agent for ulcerative colitis. However, its results thus far for Crohn’s disease (CD) have been discouraging. Another study (Clin Gastroenterol Hepatol 2014; 12: 1485-93) reiterates that message.

In brief, 139 patients with moderate-to-severe active CD were randomly assigned to 3 dosage groups of tofacitinib (1-, 5-, and 15-mg) and compared with placebo. There were no significant differences in response or remission between tofacitinib and the placebo group, though there were reductions in both C-reactive protein and fecal calprotectin among patients given the 15-mg dose.

Related blog posts:

Four IBD Articles –Four Teaching Points

Posted on December 5, 2014 by gutsandgrowth

Inflamm Bowel Dis 2014; 20: 1891-1901
Inflamm Bowel Dis 2014; 20: 1996-2003
Inflamm Bowel Dis 2014; 20: 2013-21.
Inflamm Bowel Dis 2014; 20: 2056-66.

The first article is listed as a ‘basic science’ article. However, it has direct relevance to the clinical problem of anti-TNF-induced psoriasiform skin lesions. The article notes that this problem affects about 5% of patients treated with anti-TNF agents. The authors found that IL-36γ and IL-17C are increased in anti-TNF-induced psoriasiform skin lesions of patients with Crohn’s disease (n=13 patients). An important clinical point was that 7 of these patients with “severe anti-TNF induced skin lesions were successfully treated with the IL-12/IL-23 neutralizing antibody ustekinumab.” This was superior to topical steroids or topical tacrolimus.

The second article is a proof-in-principle type article showing that proactive measurements of infliximab (IFX) levels may improve outcomes. This retrospective observational study examined 48 patients who had proactive IFX levels. In 12 of 48, IFX dosing was escalated after the first proactive monitoring. In addition, over the study period, 15% of patients had their dosing lowered. In those with proactive monitoring, the probability of remaining on IFX was >80%. Those patients who achieved trough levels >5 mcg/mL had >90% probability of remaining on IFX therapy. The authors hypothesize that better IFX levels may reduce anti-infliximab levels.

The third article examines carbohydrate intake in relation to the development of Crohn’s disease (CD) and ulcerative colitis (UC). The authors utilized the “EPIC” cohort (European Prospective Investigation into Cancer and Nutrition) (Public Health Nutr 2002; 5: 1113-24). among 401,326 enrollees at recruitment, the dietary intakes of carbohydrates were measured using validated food frequency questionnaires. In this cohort, 110 developed CD and 244 developed UC during followup. Key finding: there was no significant risk for IBD based on total carbohydrate intake. This study does not exclude the possibility that specific carbohydrates could have an etiological role.

The fourth article, a case-control study (2002-2011), examines risk factors for endoscopy-associated perforation and perforation-associated complications (PAC) in patients with and without IBD. n=217,334 lower endoscopies (with 9518 in IBD patients). Perforation rates: 18.91 per 10,000 and 2.50 per 10,000 for IBD and non-IBD endoscopy respectively. The use os systemic corticosteroids at the time of endoscopy was associated with a 13 times greater risk for PAC.

Related blog posts:

Anti-Tumor Necrosis Factor Therapies and Cochrane Reviews

Posted on December 4, 2014 by gutsandgrowth

A recent article (Inflamm Bowel Dis 2014; 20: 2132-41) reviews the best available evidence on anti-TNF therapies. This article emerged from a Cochrane collaboration session at Digestive Diseases Week (DDW) in 2013.

Key points:

“There is insufficient evidence to recommend ECI (early combined immunosuppression)) for every newly diagnosed patient, although it may be justifiable in some “high-risk” patients.”
With Crohn’s disease, combination of infliximab and azathioprine significantly improved remission, steroid-free remission, and mucosal healing rates compared with infliximab alone.
“A recent Cochrane review has shown that infliximab, adalimumab, and certolizumab are all effective…The choice of TNF-α antagonist depends on adherence, patient preference, mode of delivery, and cost.“
Elective switching of TNF-α antagonists: in patients who are doing well, elective switching “may be associated with loss of both tolerance and efficacy.” “Dose intensification or early treatment termination was observed in 47% of patients who switched to adalimumab after an ongoing response to scheduled maintenance infliximab therapy compared with 16% of patients who remained on infliximab maintenance therapy.” 28% of ADA patients discontinued therapy compared with 2% of IFX patients.
When to stop therapy: among patients in deep remission >6 months who stopped, relapse occurred in 43.9% over 1 year.
Patients who take thiopurines or biologics (IFX or ADA) have an increased risk of nonmelanoma skin cancer. Odds ratio, compared to controls, as high as 6.75 for combination therapy (>365 days).
Lymphoma: the Cochrane review “found no statistically significant difference in the incidence of lymphoma between biologics and control treatment…and data from the TREAT registry also demonstrated no apparent signal for TNF-α antagonist (i.e. infliximab)-related lymphoma or overall malignancy.”
There has been incremental risk of Non-Hodgkin’s lymphoma and hepatosplenic T-cell lymphoma with azathioprine (thiopurines).

Related blog posts:

New Normal for Ulcerative Colitis

Posted on December 3, 2014 by gutsandgrowth

A recent study (Clin Gastroenterol Hepatol 2014; 12: 1887-93) shows that patients with ulcerative colitis (UC) with subclinical activity, based on fecal calprotectin levels, improve with mesalamine escalation. DEAR, the acronym for this study, stands for Dose Escalation And Remission.

Methods: The researchers screened 119 patients with UC who were considered to be in remission based on the Simple Clinical Colitis Activity Index score. 52 patients who had calprotectin > 50 mcg/g and were receiving no more that 3 g/day of mesalamine were identified and switched to a mesalamine MMX 2.4 g/day dose for 6 weeks. Then the group was divided into an escalation group (4.8 g/day) or control group (continued with 2.4 g/day) for an additional 6 weeks.

Key findings:

26.9% of the escalation group and 3.8% of the control group achieved a calprotectin <50 mcg/g.
52.6% of the escalation group and 15.8% of the control group achieved a calprotectin <100 mcg/g.
76.9% of the escalation group and 16.7% of the control group achieved a calprotectin <200 mcg/g.

This study shows that higher doses of mesalamine were more effective in improving the calprotectin biomarker; however, the exact target value for calprotectin is not entirely clear. This study is in agreement with several others which have suggested a dose-response relationship with mesalamine therapy. This study suggests that a “quiescent” ulcerative colitis by scoring indices may overestimate the extent of colitis control. However, the associated editorial (pg 1894) cautions that “the current data are not sufficient to warrant the use of mesalamine dose escalation in patients with UC in clinical remission who have an increased FC (fecal calprotectin) concentration greater than 50 mcg/kg.”

Also noted: Clin Gastroenterol Hepatol 2014; 12: 1865-70. Prospective study of 59 patients with UC with clinical and endoscopic remission. 18 (30.5%) had histologic inflammation which correlated with elevated fecal calprotectin: median 278 mcg/g compared with 68 mcg/g for those without histologic inflammation.

Take-away message: If histologic inflammation is important, then fecal calprotectin can help identify this in patients otherwise considered to be in remission.

Related blog posts:

Methotrexate Abstract: Subcutaneous vs. Oral Administration

Posted on December 2, 2014 by gutsandgrowth

A recent abstract (Link: Gut doi:10.1136/gutjnl-2014-307964) indicates that there may be some advantages with subcutaneous methotrexate compared with oral administration, especially at the onset of treatment.

Here’s the abstract (thanks to KT Park for sharing this abstract on his twitter feed):

Efficacy of oral methotrexate in paediatric Crohn’s disease: a multicentre propensity score study

Background Oral methotrexate (MTX) administration avoids weekly injections, reduces costs and may improve quality of life of patients with Crohn’s disease (CD), especially children. Routes of administration have never been systematically compared in CD. We aimed to compare effectiveness and safety of orally (PO) versus subcutaneously (SC) administered MTX in paediatric CD.

Methods 226 children with CD treated with oral or subcutaneous MTX were included in a multicentre, retrospective 1-year cohort study (62% boys, mean age 13.8±2.8 years, 88% previous thiopurines). 38 (17%) were initially commenced on oral, 98 (43%) started subcutaneous and switched to oral and 90 (40%) were treated with subcutaneous only. Matching and ‘doubly robust’ weighted regression models were based on the propensity score method, controlling for confounding-by-indication bias. 11/23 pretreatment variables were different between the groups, but the propensity score modelling successfully balanced the treatment groups.

Results 76 children (34%) had sustained steroid-free remission with a difference that did not reach significance between the PO and the SC groups (weighted OR=1.72 (95% CI 0.5 to 5.9); p=0.52). There were no differences in need for treatment escalation (p=0.24), elevated liver enzymes (p=0.59) or nausea (p=0.85). Height velocity was lower in the PO group (p=0.006) and time to remission was delayed in the PO group (p=0.036; Fleming (0, 1) test).

Conclusions In this largest paediatric CD cohort to date, SC administered MTX was superior to PO, but only in some of the outcomes and with a modest effect size. Therefore, it may be reasonable to consider switching children in complete remission treated with subcutaneous MTX to the oral route with close monitoring of inflammatory markers and growth.

Related blog posts:

NASPGHAN Notes –Last Word for this Year

Posted on November 13, 2014 by gutsandgrowth

This blog entry has abbreviated/summarized several presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

IBD Treatment: Targets for the Modern Age –Eric Benchimol (Children’s Hospital of Eastern Ontario)

Goal: Review mucosal healing and best targets to measure to predict prognosis

Treat-to-target:

Regular assessment of disease activity using objective outcome measures.
Adjust treatment if not accomplishing goal.
Proven helpful in rheumatoid arthritis, hypertension, diabetes, and hypercholesterolemia.

Old targets:

“Clinical remission”
“Feeling better”
Indices: PCDAI, CDAI, Harvey-Bradshaw
Problem: Active disease is not well-predicted by symptoms or laboratory markers
2^nd Problem: Active symptoms not always due to active IBD (could be due to functional complaints)
PUCAI score in ulcerative colitis does reflect ulcerative colitis severity fairly well

New Targets

High correlation with outcomes
Cost-effective
Available

Is mucosal healing achievable? If you were scoped and adjustments made in therapy, then much higher rate (HR >4) of remission. Bougen, Clin Gastroenterol Hepatol 12: 978. Endoscopy may be best way to assess mucosal healing. Since it is invasive, efforts have been made to identify surrogate markers.

Treat-to-Target Algorithm

Surrogate Markers

Ultrasound –can be useful but operator-dependent
MRE had 83% accuracy for endoscopic remission: Gastroenterol 2014; 146: 374.
Calprotectin not as accurate in children? Am J Gastroenterol 2014; 109: 637. Sensitivity high 97%, specificity for remission 68%
CRP –if elevated, higher risk of complications or surgery. However, sensitivity is much lower for disease activity than calprotectin/imaging studies for active disease
Drug levels. Therapeutic IFX trough levels (and adalimumab) are highly predictive of mucosal healing.

Bottomline (my interpretation): Resolution of clinical symptoms and improvement in bloodwork is not good enough. When/timing to assess with sensitive surrogate markers is still uncertain. In many patients, endoscopy is needed to assure adequate improvement; however, in others, a followup imaging study (eg. MRE) or sensitive stool assays may be the best approach.

A related story (from AGA’s Today in Medicine email feed & pointed out to me by Ben Gold) indicates that estimation of clinical symptoms is not accurate:

Survey Suggests Severity Of IBD Is Underestimated By Gastroenterologists.

MedPage Today (10/31, Walsh, 186K) reports that survey results presented at a medical conference indicate that “the severity of inflammatory bowel disease is significantly underestimated by gastroenterologists.” Researchers found that “a total of 55% and 67% of physicians who participated in a web-based survey rated cases of Crohn’s disease and ulcerative colitis as being mild when they were actually moderate.” Meanwhile, “for case studies that represented severe disease, 76% and 81% of the physicians gave ratings of either moderate or mild for Crohn’s disease and ulcerative colitis, respectively.”

Related blog posts:

Risk Stratification in Pediatric IBD: Are we there yet? Jeffrey Hyams (Connecticut Children’s

Initially, Dr. Hyams described the exploding head syndrome; many attendees might have thought they had this due to information/”big data” overload, but this syndrome is a sleep disorder/parasomnia event. Here’s a link to the image from his talk. Then, Dr. Hyams reviewed data on risk stratification:

Mutations: Some genetic mutations are associated with disease severity
Still needed: specific pediatric data
Microbiome: Some profiles associated as prognostic factors in pediatric RISK study
Early anti-TNF associated with improved outcomes (using propensity analysis) Gastroenterol 2014; 146: 383.

Bottomline: Not there yet with risk stratification. Many factors environmental, genetic susceptibility, immune response, and treatment need to be sorted out with “big data.”

Key Clinical Questions for your practice at this time:

Does this patient have known risk factors for doing poorly?
Am I using current therapies properly?
What is the risk of undertreated disease? This needs to be considered with discussion of safety of IBD meds.

Cross Examination of Cross-Sectional Imaging in IBD –Sudha Anupindi (Radiology/CHOP)

For the most part, barium studies discouraged (eg. UGI/SBFT) by speaker; radiation ~1 mSv.
CT (conventional) widely available and easy –if needed urgently/middle of night.

Initial presentation: imaging of choice

MR enterography –no radiation, better contrast resolution, best for perianal disease, able to evaluated peristalsis. Two limitations: cost, interpretation
CT enterography –fewer motion artifacts (0.6 seconds), lower cost, increased availability, better spatial resolution radiation reduced with current technology at most Children’s hospitals: 1-2 mSv

Abdominal ultrasound holds promise as alternative imaging with lower cost.

Basic Science Year in Review –#NASPGHAN 2014

Posted on November 6, 2014 by gutsandgrowth

John Barnard –Basic Science Year in Review

“Emerging Trends and Provocative Findings in Basic Science”

This blog entry has abbreviated/summarized this terrific presentation. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well. To minimize these issues, I have placed a link to most of Dr. Barnard’s slides which he shared:

2014 John Barnard Slides

“Big Data” –big increase in “big data” cited in pubmed over past year.

Good read on this subject: Foreign Affairs: The Rise of Big Data Kenneth Cukier

Scientific fraud –more attention to this issue this past year. Two papers in Nature were retracted. One researcher committed suicide and one arrested. Scientific fraud undermines important messages & ruins credibility of other important advances.

CRISPR-Cas9: Gene editing. CRISPRs –“RNA guides” Cas9: “molecular scissors” (endonucleases)

“Genome editing has never been easier.” Examples:

Cell Stem Cell 2013: 13: 653-58. “Functional repair of CFTR by CRISPR-Cas9”
Also, genome editing has been used in mouse model of tyrosinemia.

Liver regeneration in zebrafish. Implication: Liver cells will be regenerated in humans. Gastroenterol 2014; 146: 789.

Microbiome Big Data:

J Clin Invest 2014; 124: 3617. This was a very important and complex study. The slides explaining this study start at slide 35.
Pediatric Crohn disease exhibit specific ileal transcriptome and microbiome signature.
RISK study (CCFA). Treatment-naïve, 28 sites.
1281 ileal host genes in ileocolonic Crohn’s, 1055 in Colonic Crohn’s had ileal host genes =82% similar, 232 host genes in ulcerative colitis –18% similar to ileocolonic Crohn’s.
Tissue microbiomes are where changes are noted; changes are not evident in luminal microbiome.
Antibiotics worsen dysbiosis.
Microbiome at diagnosis strongly correlates with Crohn’s disease.

Microbiome –affects the entire body:

J Clin Invest 2014; 124: 3391. Incorporation of microbes with genetically-engineered E coli can prevent obesity in mice

Recommended Reading by Dr. Barnard: “Missing Microbes” How the overuse of antibiotics is fueling our modern plagues. Martin Blaser

“Genetic Testing and the Future of Pediatric Gastroenterology”

Posted on October 23, 2014 by gutsandgrowth

Last night, a symposium on “Genetic Testing and the Future of Pediatric Gastroenterology” sponsored by Children’s Healthcare of Atlanta took place. The speakers included Dr. Ben Gold from our pediatric GI group (GI Care for Kids), Dr. Saul Karpen and Dr. Subra Kugasthasan (Emory), and Dr. Robert Heuckeroth (CHOP).

This blog entry has abbreviated/summarized the presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well. All of the speakers had terrific presentations.

GI Genetic Testing –Subra Kugathasan

Reasons for genetic testing:

Predicting prognosis: predicting stricturing/fibrosis in Crohn’s, predicting cancer in ulcerative colitis; BRCA1 in breast cancer
Choosing the right medicine: pharmcogenomics
Precision medicine: prevention of disease, slowing progression of disease.

Examples in current medicine:

Recurrent pancreatitis –novel mutations identified in SPINK1. Also now hereditary pancreatitis may be due to mutations in CPA1, GGT1, CLDN2, MMP1, MTHFR in addition to CTRC, SPINK1, CFTR, and PRSS1.
Inflammatory bowel disease (IBD):IL10 Receptor mutation , TTC7A –>VEO IBD; IPEX gene (can worsen with immunosuppression). Panel testing now available for 40 genes –4 of 22 patients identified with IBD. Identifying cause of VEO IBD may lead to treatment: bone marrow transplantation.
IBD: CLIA/CAP certified Emory Genetics panel ~50 genes (genetics.emory.edu/egl/tests/view.php?testid=4420). Dr. Kugathasan indicated that this testing is likely to be a better 1st step then exome testing. Yield with exome sequencing (in highly selected populations) about 25% at this time but likely to increase. If negative, can proceed with whole exome sequence. Numerous problems with exome sequencing; for example, exome sequencing may identify genes of unknown significance and identifying genetic problems unrelated to clinical issue.

Who/When to test?

Very early onset disease (<10 years), atypical presentation, perhaps treatment-refractory.

Take-home point: “All GI diseases have genetic testing in future.” Testing for highly selected patients for gene defects can be accomplished with gene panel and if negative, whole exome testing.

Related blog posts:

Liver: Cholestatic & Metabolic Diseases of Infants and Children —Saul Karpen

Potential areas for genetic testing:

Neonatal cholestasis: PFIC, Metaboic, Biliary Atresia
NAFLD
Transplant

“Why bother…they all get transplanted anyway…” According to Dr. Karpen, this view needs to be reconsidered.

Neonatal cholestasis:

(Front Pediatr 2014; 2: 65) 41% with biliary atresia, 13% idiopathic, and a lot of others. N=82. Other etiologies: Genetic disorders; Biliary disease (eg. Caroli), transporter defects (PFICs/BRICs), Metabolic (Niemann-Pick C, tyrosinemia, HFI, Peroxisomal, GSDs, Peroxisomal, Mitochondrial, A1AT). Thus, panels to identify these disorders can be very helpful.
Emory Cholestasis 56+ Gene Panel. Testing is cheaper than endoscopy

PFIC: Progressive Familial Intrahepatic Cholestasis

PFIC1: ATP8B1 (Byler) –besides cholestasis, patients often with diarrhea, hearing loss, very itchy; can have cirrhosis at 2 years of life
PFIC2: ABCB11 (BSEP deficiency) –can have cirrhosis at 6 mo, prone to HCC (as early as 13 mo), very itchy
PFIC3 (high GGT) ABCB4 –can have cirrhosis at 5 mo, can cause problems at later ages as well (eg. intrahepatic cholestasis of pregnancy, gallstones); increase risk for HCC/cholangiocarcinoma.
Identifying PFIC (could mimic PSC) and BRIC (Benign Recurrent Intrahepatic Cholestasis)–is helpful in following patients for specific management when symptoms recur and to screen for complications (eg. HCC).

Biliary Atresia:

No clear genetics in most
Laterality defects in 5-10% -asplenia/polysplenia, cardiac defects
GPC1 gene is a susceptibility gene in zebrafish
ADD3 gene identified in Han Chinese OR 2.38 –may be a susceptibility gene. (30% of cases, 17% of controls)

NAFLD: Associated with increased mortality compared with matched controls. Patients develop thicker atherosclerotic plaques. PNPLA3 gene identified as a susceptibility gene for NAFLD and is highly prevalent in Hispanic populations. Similarly, PNPLA3 has been associated with NASH in Italian populations. If you have this genotype, this increases risk of liver fat in the face of increased sugar consumption.

Transplant medicine: Deoxyguanosine Kinase Deficiency (DGUOK) –rapid sequencing for this gene pretransplant –If positive, should not be transplanted. These individuals have systemic disease that cannot be cured with liver transplantation.

Who/When for genetic testing?: DGUOK in liver failure patients, and in infants without diagnosis after liver biopsy/exclusion of A1AT

Take-home message: Genetic testing has a role in pediatric liver disease and it is affordable.

Related blog posts:

GI –Single Microbes to the Microbiome and GI Disease —Ben Gold

Described why changes in our environment can trigger development of disease due to changes in microbiome (eg. immigrants/children with IBD in developed countries at much higher rate than at developing countries)
Discussed Helicobacter pylori –‘how a single microbe which may have been good turned bad’
Described pathogenesis. What you get exposed to early on may lead to an exaggerated response by T-cells/immune system. Healthy microbiota is critical to train the immune system via GALT to protect host and decrease the chances for immune overexpression.

Key points:

100 trillion bacteria that live in our GI tract. 10x number of human cells in our body and 100x as many genes as there are in the human genome. Partnership between humans and their microbiome developed over thousands of years.
Vaginal delivery is NOT sterile. Are there consequences to C-section? Food allergy for infant –OR 2.5 if Mom with food allergy delivers vaginally vs OR 7.8 if Mom has food allergy and delivers via C-section. Also, some data indicates increased risk of EoE if born via C-section. From DAY 1, microbiome can be influence by environmental factors.
Influencing microbiome happens mainly during first three years of life.

Why the microbiome is so important/more pointers:

Since 1950, there has been a huge decline in infectious diseases like measles, mumps, hepatitis A, tuberculosis, etc
Coincident with these decreases there has been increased multiple sclerosis, Crohn’s disease, asthma, food allergy, autoimmune diseases
Sanitized food supply, decrease in naturally fermented foods, urban lifestyle, antibiotics, C-section all lead to lower microbial exposure and altered intestinal microbiota. This in turn may lead to an inadequate immune response.
Elie Metchnikoff 1845-1916: suggested ingested bacteria could be healthy. Probiotics/prebiotics are not a new idea!
Obese patients had very high levels of Firmicutes and low Bacteroidetes.
Fecal microbial transplantation (FMT)–reseeding GI microbiome. FMT may be beneficial to many diseases and is being studied.

Helicobacter pylori -evidence of H pylori as far back as 60,000 years ago and has evolved with humans. H pylori may have helped provided a positive immune response in children and adults.

Bottomline: Human genetic diseases may be heavily influenced by the 300 trillion bacteria and their genes; these bacteria are susceptible to environmental disease.

Related blog posts:

Genetic Basis of Motility —Robert Heuckeroth

Basic machinery controlling motility described –enteric neurons, muscles, pacemaker cells.
Very little clinical overlap between modern genetic testing and applicable motility disorders: achalasia, gastroparesis, pseudoobstruction, Hirschsprung’s or irritable bowel
Focused testing for suspected diagnosis is being displaced by broader testing in serious disease, especially since more extensive genetic testing may be more cost-effective. When to do exome sequencing?

Hirschsprung’s disease:

1:5000 children.
100X higher risk in Down Syndrome.
Prenatal testing not helpful at this time. There may be >360 genes that increase risk (variable degree of risk) of Hirschsprung’s disease; hence prenatal testing not that helpful at this time.
30 associated genetic syndromes with Hirschsprung’s, >12 known gene defects. Hirschsprung’s disease: 25% with RET haploinsufficiency. RET haploinsufficiency –increases risk of Hirschsprung’s disease >2500-fold risk.
Gene environment interactions can increase risk of developing Hirschsprung’s disease –if vitamin A deficient, mice with increased risk.
RET gene –>too little RET increases risk of Hirschsprung’s
RET gene –>too much RET increases risk of MEN2B, MEN2A. Though 7.5% of MEN2A have Hirschsprung’s –works out to be 1 in 100 kids with Hirschsprung’s have MEN2A mutations. ??test for this??

Pseudoobstruction genetic basis– a number of genes identified, including ACTG2 (smooth muscle actin gene). If you understand etiology, this may lead to prevention and treatment.

Take-home message: Currently biggest problem with genetic testing, especially with motility disorders, is identifying genetic defect of unknown significance. Thus, testing needs to be done as part of research studies.

Related blog posts:

Anti-TNF Therapies: Safe in Pregnancy

Posted on October 20, 2014 by gutsandgrowth

According a review (Inflamm Bowel Dis 2014; 20: 1862-69) of 5 studies with 1216 patients, “the use of anti-TNFα therapy does not seem to increase the risk of unfavorable pregnancy outcomes among women with IBD, although the optimal timing of therapy through pregnancy and the postpartum period was not assessed.”

Other important points:

“Current recommendations suggest that anti-TNFα therapies be continued during the first 2 trimesters of pregnancy.” Withholding of infliximab and adalimumab during the third trimester is due to concerns of increased drug levels in infants.
Live virus vaccination should “be avoided for the first 6 months in children who had exposure to anti-TNFα therapies in utero.”

Related blog posts: