CCFA Conference Notes 2016 (part 5) -Emerging Therapies

Posted on April 30, 2016 by gutsandgrowth

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

PF-00547,659

S1P Modulators:

Fingolimod

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.

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

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

Ustekinumab

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

FMT. Further studies are needed

CCFA Conference Notes 2016 (part 3) -Malignancy and IBD

Posted on April 28, 2016 by gutsandgrowth

This blog entry has abbreviated/summarized this terrific presentation; most of the material has been covered in this blog in prior entries 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.

3^rd Lecture: Prevention and management of malignancy in IBD –Dr. Thomas Ullman

Malignancy risk (colorectal cancer [CRC]) is present with prolonged ulcerative colitis, though more recent studies have shown lower risk than in the past –not much higher than the general population.

CRC surveillance–colonoscopy monitoring after 8-10 years. Typically colonoscopy every other year for most patients, every year in higher risk patients (eg. PSC).

Unclear if chemoprevention is effective (5-ASA, thiopurines, others).
Chromoendoscopy “has not been consensus on its use in our field (yet).” It is time consuming and expensive and unclear if it will improve outcome.

Does medical therapy for IBD predispose to developing cancer?

Thiopurines increase the risk of malignancy. (Pasternak et al) though the risk returns to near baseline when stopped according to study below.

No overall increased risk with anti-TNF agents with RCTs (may not follow patients long enough) but also not seen in Danish registry either (JAMA study)

No increased risk of malignancy in this study with Anti-TNFs

Lymphoma risks: age, immunodeficiency, EBV
EBV negative are at risk for HLH with thiopurines
HTSCL ~200, >90% men and >90% <35 years. NOT EBV-related. Has not been identified in anti-TNF monotherapy.

Skin cancer –main concern is in non-melanoma skin cancer (possibly melanoma too). Skin cancer increase has not been noted with methotrexate. Prevention: Skin care, and annual dermatology visits.
Cervical cancer—likely increased risk in IBD, probably due to thiopurine exposure and reduced immune surveillance. Prevention: HPV vaccination, Pap testing.
Urinary Tract cancers –especially in those >65 years with thiopurine exposure

CCFA Conference Notes 2016 (part 2) -Pediatric Lecture

Posted on April 27, 2016 by gutsandgrowth

2^nd Lecture: What is Next in Treatments for Pediatric Patients? –Dr. Michael Rosen

I really enjoyed meeting Dr. Rosen. He is super-friendly and knowledgeable.

Combination therapy. Grossi V et al showed improvement in infliximab durability with concomitant therapy.

Now starting COMBINE trial (ImproveCareNow)–randomized to low dose MTX or placebo in combination with anti-TNF agent.

Therapeutic drug monitoring in pediatrics. Is this an alternative to combination therapy? Rationale (see slide): lower antibody formation if trough levels maintained. IFX level >5.5 associated with persistent remission (Singh et al 2014). Children are growing and they may need more adjustments. In Cincy, checking levels at week 14 after initiation and then every 6-12 months.

Acute Severe Ulcerative Colitis. High rates of dose escalation in this population. Some of this is due to more rapid clearance of anti-TNF –leaking in gut and other mechanisms as well. Week 8 level of 40 associated with clinical response. Thus, this population may benefit from 10 mg/kg at start (in those with albumin <3) and may need more frequent dosing, especially early into treatment (?0, 2, 6, 10). ARCH study to look into this further

Vedolizumab. Conrad MA 2015. About 1/3^rd of these refractory patients in this abstract responded.

Ustekinumab . IL-12 & IL-23 blockage. No studies in pediatrics. Case report reviewed of good response in a refractory case.

Enteral therapy. Specific carbohydrate diet experience. These diets have some published data, most retrospective studies. Our group (Cohen SA et al) did perform a small prospective study. Sigall-Boneh R et al showed improvement with partial enteral nutrition.

Very early-onset of IBD. IL-10 receptor deficiency was a key early discovery and can be treated with stem cell transplant. STAT3 mutation case reviewed which was managed with tocilizumab. More targeted therapy expected based on specific mutations.

CCFA Conference Notes (Part 1): Preemptive Therapeutic Drug Monitoring Not That Helpful

Posted on April 26, 2016 by gutsandgrowth

Optimizing Therapeutic Drug Monitoring –Dr. Hans Herfarth

Trough levels have been recognized to correlate with remission rates. Good data from SONIC (2010) for infliximab. Ultra2 trial (2013) showed similar data for adalimumab.

Low albumin predicts higher rates of failure, possibly due to loss of infliximab in stool.

Reviewed algorithm for loss of response to infliximab based on trough levels. If low infliximab and no antibodies, increase dosing of infliximab has high likelihood of clinical response.
If high infliximab and not responding, evaluate for other reasons including irritable bowel, and strictures.

Scenarios that create confusion with therapeutic drug monitoring:

If clinically-well patient has antibodies and adequate drug level, could observe or possibly add immunosuppressive agent. ~3% of patients have simultaneous ATI and IFX detection.
If clinically-well with low infliximab level, could increase dose or observe.

In TAXIT study, however, lowering dose (panel B above) to get in target range was associated with a lower rate of response. No clear difference between clinically-based changes compared with proactive monitoring. Proactive adaption of trough levels may help prevent relapse in ~10% but not shown to alter long-term outcomes

TAILORIX study looked at tailoring dose at week 14. ‘Week 14 adaption did not make a significant difference at 1 year.’ Limitation: 122 patients.

Hard to see Group C (clinically-based group) in this slide

Drug monitoring has become popular but its importance as a preemptive measure is unclear. Dr. Herfarth’s practice is to monitor when loss of response but not to monitor if doing well. His view: if someone is doing well, therapeutic drug monitoring can be confusing. It is not proven that optimizing drug levels will improve long-term outcomes. (In children, especially due to growth, drug monitoring may be more important.)

One other recommendation from Dr. Herfarth: he recommends combination therapy in his patients are started on a 2^nd anti-TNFs.

Don’t Touch That Cute Turtle

Posted on April 25, 2016 by gutsandgrowth

The risk of Salmonella from turtles is well-known. A recent report (Walters MS et al. Pediatrics 2016; 137: 1-9) with data from 2011-2013 highlights the ongoing risk with reports of 8 multi-state outbreaks of Salmonella and pet turtles were the key risk factor.

Children <5 years and Hispanics were disproportionately affected.
88% of the turtles were considered small (< 4 inches)

Here’s an excerpt from the abstract:

RESULTS: We identified 8 outbreaks totaling 473 cases from 41 states, Washington DC, and Puerto Rico with illness onsets during May 2011–September 2013. The median patient age was 4 years (range: 1 month–94 years); 45% percent were Hispanic; and 28% were hospitalized. In the week preceding illness, 68% (187 of 273) of case-patients reported turtle exposure; among these, 88% (124 of 141) described small turtles. Outbreak strains were isolated from turtle habitats linked to human illnesses in seven outbreaks. Traceback investigations identified 2 Louisiana turtle farms as the source of small turtles linked to 1 outbreak; 1 outbreak strain was isolated from turtle pond water from 1 turtle farm.

My take: Turtles make lousy pets. Salmonella infection can be fatal in some and in others leave lasting problems.

Related posts:

Eric Carle artwork at High Museum

Guidelines for Traveler’s Diarrhea in Adults

Posted on April 22, 2016 by gutsandgrowth

Full text: Guidelines on Traveler’s diarrhea in Adults from ACG

Some of the recommendations:

-use of oral rehydration if severe diarrhea (especially elderly). “Most individuals with acute diarrhea…can keep up with fluids and salt by consumption of water, juices, sports drinks, soups, and saltine crackers
-against use of probiotics for acute diarrhea except in cases of post antibiotic-associated diarrhea
-for use of bismuth subsalicylates to slow stool passage
-for use of adjunctive loperamide in patients receiving antibiotics for traveler’s diarrhea (to increase chance for cure)
-for antibiotics in traveler’s diarrhea “where the likelihood of bacterial pathogens is high enough to justify the potential side effects of antibiotics”
-against antibiotics for community-acquired diarrhea

Table 4 outlines antibiotic selection.

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Don’t Let the Chief of Staff Review This Constipation Study

Posted on April 21, 2016 by gutsandgrowth

A useful study from Cincinnati (D Klaus et al. J Pediatr 2016; 171: 183-8) provides data on the high prevalence of constipation in Duchenne Muscular Dystrophy. (DMD) Though, the authors acknowledge that rectal examination was “deferred unless clinically indicated.” I’m fairly certain that the former chief of staff, if asked for input, would have stated that the only two reasons for not doing this part of the exam was “either no rectum or no finger.”

In this prospective cross-sectional study, the authors relied on the Questionnaire on Pediatric Gastrointestinal Symptoms based on Rome-III criteria (QPGS-RIII) to identify constipation. Based on this questionnaire, 46.7% (56 of 120) of patients with DMD were diagnosed with functional constipation.

Traditional features of constipation like bowel movement infrequency of <3/week and hard stools were present in only 16% and 17% respectively.
Other features that identified constipation included straining with defecation in 35.1%, painful defecation (27.8%), and clogging toilet (22.6%)
The Bristol Stool scale had a low sensitivity for detecting constipation (only 18%) but had a high specificity of 95% if type 1 or 2.
Constipation did not increase with age or functional status which makes the concern that this is primarily related to an ineffective bear-down (Valsalva) less likely

My take: Constipation in children with DMD is underreported and often overlooked. It needs to be considered more carefully at routine visits.

Related posts:

Vik Muniz Art at High Museum

When you look closely at the horse’s nose, you can see that this art was completed with toy soldiers

Anti-TNF therapy and Pregnancy -More Data

Posted on April 8, 2016 by gutsandgrowth

G Broms et al (Clin Gastroenterol Hepatol 2016; 14: 234-41) provide more data on the ‘low risk of birth defects for infants whose mothers are treated with anti-tumor necrosis factor agents during pregnancy.”

From a Danish/Swedish cohort of 1,272,424 live births (2004-2012), the authors found the following (in comparison to healthy infants):

Birth defects were increased in chronic inflammatory bowel disease: 4.8% vs. 4.2%
43 (6.3%) of the infants born to women with IBD who received anti-TNF therapy (683) had birth defects. The OR for any defect was 1.32 (CI 0.93-1.82). The types of defects were generally similar, including VSD, ASD, hypospadias, and hydronephrosis

Limitations:

In infants of mothers with chronic diseases, it is possible that more careful screening identified some less apparent defects.
Study did not examine rates of stillborn or abortions

My take: Overall there is a slightly but not significantly increased risk in birth defects based on the use of anti-TNF therapy. Stopping anti-TNF therapy is likely to be more detrimental.

Briefly noted: P Wils et al. Clin Gastroenterol Hepatol 2016; 14: 242-50. This retrospective study of 122 patients showed that 65% had a clinical benefit within 3 months of receiving ustekinumab for Crohn’s disease refractory to anti-TNF therapy. Concomitant immunosuppressant therapy was associated with an increased likelihood of benefit (OR 5.43)

Related blog posts:

Goldilocks and Gluten

Posted on April 5, 2016 by gutsandgrowth

A recent study (CA Aronsson et al. Clin Gastroenterol Hepatol 2016; 14: 403-09, editorial 410-12) suggests that how much gluten is given may be another important factor rather than looking at the timing with regard to the development of celiac disease (CD).

In this 1-to-3 nested case-control study with 146 cases of CD and 436 controls, the authors indicate that a larger intake of gluten than controls increased the likelihood of celiac disease. Specifically, children receiving large amounts of gluten (>5 g/day) during their first 24 months had a 2.6-fold increased risk of CD compared to those who consumed lower quantities.

The associated editorial notes that the total amount of gluten intake was only marginally increased in CD cases versus all control patients (OR 1.05) and that the association was decreased when individuals with first-degree relatives with CD were excluded. In addition, this high consumption increased the risk after the first 2 years of life, rather than during this period of high consumption.

Does this make sense? Not to me. These findings need to be replicated in other studies to determine if gluten exposure is like Goldilocks: too little, too much –>just right.

My take: For now, I think sticking with the timing of gluten exposure (recommended at 4-6 months) rather than the quantity is worthwhile.

Related blog posts:

Eosinophilic Esophagitis: the Limits of “Clinical Remission”

Posted on March 31, 2016 by gutsandgrowth

Among patients with eosinophilic esophagitis (EoE), two issues are particularly vexing for families:

The recommendation to use endoscopy to assess response to treatment.
Using proton pump inhibitor (PPI) therapy as first line treatment when other therapies have higher response rates

To some extent, these issues are intertwined because PPI therapy works in less than half of patients and to determine this conclusively, an endoscopy is needed. Clearly, a reliable noninvasive biomarker would be quite helpful.

In the meantime, another study (CE Kuehni et al. Gastroenterol 2016; 150: 581-90, editorial 547-48) has shown that “clinical remission” has modest accuracy in detecting endoscopic and histologic remission in EoE.

This prospective observational study, performed between 2011-14, recruited 269 consecutive adults in Switzerland and U.S.. 67% male median age 39 years.

Key finding:

Of 111 who were in clinical remission (41.3%), only 79 (72%) and 75 (68%) were in endoscopic and histologic (<20 eos/mm2 which corresponds to <5 eos/median hpf) remission respectively.

My take (borrowed): “Physicians cannot rely on lack of symptoms to make assumptions about lack of biologic disease activity in adult EoE patients.”

Related blog posts:

Gibbs Gardens

gutsandgrowth

Pediatric Gastroenterology

Category Archives: Pediatric Gastroenterology Intestinal Disorder

CCFA Conference Notes 2016 (part 5) -Emerging Therapies

CCFA Conference Notes 2016 (part 3) -Malignancy and IBD

CCFA Conference Notes 2016 (part 2) -Pediatric Lecture

CCFA Conference Notes (Part 1): Preemptive Therapeutic Drug Monitoring Not That Helpful

Don’t Touch That Cute Turtle

Guidelines for Traveler’s Diarrhea in Adults

Don’t Let the Chief of Staff Review This Constipation Study

Anti-TNF therapy and Pregnancy -More Data

Goldilocks and Gluten

Eosinophilic Esophagitis: the Limits of “Clinical Remission”