What “Treat-to-Target” Could Look Like in Crohn’s Management

Posted on June 30, 2015 by gutsandgrowth

A recent study (treat to target full text -Bouguen G et al. Clin Gastroenterol Hepatol 2015; 13: 1042-50) proposes a “new paradigm for the management of Crohn’s disease.” The concept of treating-to-target has been discussed in several previous blogs:

The concern with the traditional management has been ongoing damage to the bowel in many patients and lack of optimizing long-term outcomes. The authors in the report make the following points:

Only 10% of Crohn’s disease (CD) patients experience prolonged remission of symptoms
Even asymptomatic patients often have evidence of active inflammation on endoscopy
The majority of patients will require surgery
Two big obstacles: delay in initiation of highly effective therapy (eg. combined biologic/immunosuppressant) and underestimation of disease activity due to poor correlation of symptoms to actual disease activity

While the fact that the majority of patients are at risk, some populations are at increased risk including the following:

those who smoke cigarettes
patients younger than 40 years at diagnosis
stricturing or penetrating disease
need for surgery
inability to wean corticosteroids
deep ulcerations on endoscopy

However, the authors note that “the lack of adequate data in this area of research makes risk stratification very difficult in clinical practice.” The authors review several studies:

ACCENT-I
Step-Up Top-Down trial
IBSEN population-based cohort study
SONIC
The Leuven cohort study
EXTEND trial

The data from these studies is used to base their argument of pursuing mucosal healing/more aggressive treatment, though they acknowledge that one risk is potentially subjecting some patients to overtreatment. The review indicates that mucosal healing (MH) is defined endoscopically as “the disappearance of ulceration” and that endoscopy is the tool for testing for MH for the near-term, but that other markers including MRE and surrogate biomarkers may be useful alternatives.

The authors’ Table 1 list their proposed recommendations for CD, modeled after similar recommendations for Rheumatoid Arthritis. The Four Key points:

The physician and patient need to agree on the treatment target strategy
The primary target for treatment of CD should be absence of endoscopic ulceration
The use of both clinical symptoms and objective measures of inflammation (endoscopic or imaging) is required in routine clinical practice to guide treatment decisions
Until the desired treatment target is reached, MH should be assessed every 6 months until the disappearance of ulceration and every 1-2 years thereafter. Drug therapy should be adjusted accordingly.

Limitations on this strategy:

Cost of assessment–both endoscopy and MRE are expensive
Cost of therapies
While MH can be achieved in a higher percentage of patients, there are some patients who will not respond to any of the currently available therapies
Risk of therapies. Some patients will develop adverse effects from the available therapies which will limit their therapeutic options.
This proposed strategy has very limited data in clinical practice

Take-home message from the authors: The “natural history” is not likely to improve unless the overall, symptom-based, therapeutic strategy for CD is changed.

Atlanta Zoo, Wreathed Hornbill

Money Matters in Pediatric Inflammatory Bowel Disease

Posted on June 26, 2015 by gutsandgrowth

A very pragmatic article (Sin AT et al. Inflamm Bowel Dis 2015; 21: 1368-77) describes the out-of-pocket cost burden in pediatric inflammatory bowel disease (IBD). For anyone who lives on planet earth, how much a procedure or treatment costs weighs very heavily on many decisions. This is particularly relevant in pediatric IBD.

In a cross-sectional cohort analysis, the researches collected data with surveys from 150 parents of children with IBD (67 Crohn’s disease, 83 Ulcerative colitis). The median patient age was 14 years.

Findings:

Annually, out-of-pocket expenses were >$5000 in 5.3%, >$1000 in 28.6%, and >%500 in 63.6%.
Increased expenditures were derived from the following: emergency department visits with 36% having had an ED visit in past year, procedures/testing with 20% who spent >$2000, and from treatments (medications/diet). 10.7% reported missing medications due to cost.
“Families with household incomes between $50,000-100,000 had a statistically-significant probability (80.6%) of higher annual OOP costs than families with lower income…or higher income.”
Not surprisingly, patients with IBD “who have relapsing or uncontrolled IBD states are particularly at risk to require acute care services, which represent high OOP costs for families.”
The authors also describe missed workdays and lost wages as another financial burden.

Take-home message: This study helps quantitate the out-of-pocket expenses and financial burden that families face when they have a child with IBD. In some patients, improved control of IBD will lower these expenses by decreasing costs from emergency department visits, office visits, and hospitalizations.

Cumberland Island

PCDAI -Not Good Enough

Posted on June 25, 2015 by gutsandgrowth

Two articles reinforce the view that the pediatric Crohn’s Disease activity index (PCDAI) is not good enough to rely on for research and for clinical practice.

Sun H et al. JPGN 2015; 60: 729-36
Vubin G, Peter L. Inflamm Bowel Dis 2015; 21: 1386-91

The first article is a review of the PCDAI and its derivatives (abbreviated, short, modified, and weighted) as well as the Harvey-Bradshaw Index (HBI). Key points:

There was an “absence of evidence demonstrating correlation with clinically relevant inflammation.”
“Available evidence indicates that CDAI, HBI, and 5 versions of PCDAI lack adequate measurement properties for use as a primary endpoint for phase 3 trials.”
“Endoscopic or radiology-based mucosal and histological examination may need to be considered as 1 outcome measurement.”

The second article describes a prospective cohort of 24 newly diagnosed children (<16 years). The authors found the following:

At diagnosis, PCDAI had poor correlation with endoscopic disease activity (SES-CD)
After induction: 11/24 had inactive disease based on SES-CD; however, PCDAI had poor correlation. Many children with active disease (SES-CD ≥3) had normalization of PCDAI as well as CRP.
Fecal calprotectin had better correlation.

Take-home point: These articles add to the growing literature regarding the lack of reliability of clinical activity indices.

Related blog posts:

Cumberland Island

Soiling Stinks!

Posted on June 24, 2015 by gutsandgrowth

The initial title of this post was too boring: “Documenting the Detrimental Effects of Fecal Incontinence on Quality of Life”

In perhaps one of the least surprising conclusions, the authors of a recent study (Kovacic K, et al. J Pediatr 2015; 166: 1482-7) have shown that “fecal incontinence significantly decreases quality of life compared with functional constipation alone in children.” This multicenter prospective study surveyed families of 410 children (2-18 years).

Despite the obvious findings, I still think that the burden of fecal incontinence is underestimated by families and practitioners. Here is an excerpt from this article’s discussion:

“Fecal incontinence impairs general functioning for children and their families…[it] is an insidious burden with substantial economic impact and adverse effects on quality of life…this effect increases as children approach adolescence…The devastating effect of fecal incontinence on quality of life and social functioning make it imperative that health professionals address defecation disorders proactively. When aggressive and appropriate medical therapies are unable to provide a satisfactory outcome, then a multidisciplinary approach or a surgical option (e.g. cecostomy tube for antegrade enema) may be justified.”

Bottomline: Soiling stinks! We need to keep working on this problem even if aggressive interventions are needed.

Related blog posts:

Not Letting Go of a Log -Can Lead to Problems

Watch Vitamin Levels in Shwachman-Diamond Syndrome

Posted on June 21, 2015 by gutsandgrowth

According to a recent small retrospective study in Pancreas (May 2015 – Volume 44 – Issue 4 – p 590–595) with 21 children, there were high rates of vitamin deficiencies (particularly vitamin A) and selenium deficiency.

Nutritional Status in Children with Schwachman-Diamond Syndrome

From abstract:

Results: Twenty patients (95%) had pancreatic insufficiency receiving PERT, 10 (47%) had a combined vitamin and trace element deficiency, 6 (29%) had an isolated vitamin deficiency, and 4 (19%) had an isolated trace element deficiency. Vitamins A and E deficiency occurred in 16 (76%) and 4 (19%) of 21, respectively. Low serum selenium was found in 10 (47%), zinc deficiency in 7 (33%), and copper deficiency in 5 (24%). Eleven patients (52%) were on multivitamin supplementation, and 2 (10%) on zinc and selenium supplements. No statistical differences were found between repeated measurements for all micronutrients.

Conclusions: More than 50% of the children had vitamin A and selenium deficiencies despite adequate supplementation of PERT and supplements. Micronutrients should be routinely measured in SDS patients to prevent significant complications.

10 Years of Anxiety and Upper Endoscopy Correlation

Posted on June 19, 2015 by gutsandgrowth

A recent 10-year Swedish study (Aro P, et al. Gastroenterol 2015; 148: 928-37) provided further evidence of a link between anxiety, but not depression, and functional dyspepsia (FD).

This study took a group of 1000 individuals who had been randomly selected to undergo upper endoscopy, the Abdominal Symptom Questionnaire, and the Hospital Anxiety and Depression Scale Questionnaire (1998-2001). Among the 887, who completed the initial portion of the study, 703 subjects were available for followup study in 2010.

FD was defined in this study based on the Rome III definition: weekly bothersome postprandial fullness or early satiety; epigastric pain or burning without organic findings on endoscopy. FD was further divided into postprandial distress syndrome which consisted of postprandial fullness or early satiety or epigastric pain syndrome.

Key findings:

At baseline, 15.6% of subjects had FD. At followup, 13.3% had FD including 48 new cases.
Anxiety at baseline was associated with new-onset FD at the followup evaluation with an odds ratio of 7.6.
Anxiety was also associated with postprandial distress syndrome at baseline with an odds ratio of 4.83.

Take-home point: Anxiety often precedes functional dyspepsia. This association was not evident with depression.

Related blog posts:

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.

Zoo Atlanta

Cancers Complicating Inflammatory Bowel Disease

Posted on June 18, 2015 by gutsandgrowth

In several prior posts, the issue of cancer and inflammatory bowel disease (IBD) has been discussed. In my view, even the word “cancer” is so scary that it can make people make bad choices (related: Facts, “Misfearing” and Women’s Health | gutsandgrowth). An up-to-date succinct summary (Laurent Beaugerie, M.D., Ph.D., and Steven H. Itzkowitz, M.D. N Engl J Med 2015; 372:1441-1452) provides a fairly good overview of “Cancers Complicating Inflammatory Bowel Disease.”

Key points:

“Smokers are overrepresented among the patients with Crohn’s disease…results in an excess rate of smoking related cancers.” (Smoking also is associated with more aggressive Crohn’s)
Colorectal cancers risk factors (Table 1), specific to IBD, include coexisting primary sclerosing cholangitis (PSC), and increasing duration & extent of colonic IBD.
A “progressive decrease in the excess risk of colorectal cancer in patients with IBD has been noted over time.” This may be due to better control of inflammation, surveillance, and colectomy. Still, the risk of colorectal cancer in patients with IBD is 1.5 to 2 times greater than the general population risk.
Small-bowel adenocarcinoma –risk is 20-30 times that of the general population, typically arises more than 8 years after diagnosis. Absolute risk in those with disease more than 8 years is estimated at “0.5 per 1000 patient-years.”
Intestinal lymphomas –absolute risk is about 0.1 per 1000 patient-years.
Cholangiocarcinoma (CCA)–absolute risk is approximately “0.08 per 1000 patient-years.” CCA is mainly evident in patients with PSC who have a risk ~160 times the general population and lifelong risk of 5-10%.
Non-Hodgkin’s lymphoma –“whether TNF-alpha antagonists promote lymphomas by themselves in patients with IBD is difficult to assess…” A recent study found no excess risk in patients receiving TNF-alpha antagonists after adjustments for cotreatments.
Skin Cancers –nonmelanoma skin cancer, though not life-threatening, occur more often in those with current thiopurine usage.
HPV-Related Cervical Cancer –“it is still unclear whether the risk of HPV-related cervical cancer is intrinsically increased in woman with IBD or independently worsened by exposure to an immunosuppressant.”
Thiopurines: “after adjustment for confounders, current use of thiopurines for IBD has been shown to be associated with an overall relative risk of cancer of 1.3 to 1.7.”
TNF-alpha antagonists: “There is no overall excess risk of cancer in patients treated with TNF-alpha antagonists for IBD.” However, more long-term data are needed.

Recommendations:

Figure 2 provides recommendations for colorectal cancer surveillance based on the American Gastroenterological Association (AGA), British Society of Gastroenterology (BSG) and European Crohn’s and Colitis Organisation (ECCO) recommendations. Typically, 8-10 years after diagnosis of colitis, starting surveillance (with chromoendoscopy if available) is recommended. In patients with Crohn’s disease, “the excess risk appears when more than 30 to 50% of the colonic surface is ever involved.” However, with PSC, the excess risk of colorectal cancer is significant at the time of diagnosis.
For cholangiocarcinoma screening in those with PSC, “most experts recommend noninvasive annual imaging of the biliary tract (MRCP or ultrasound) and serum CA 19-9.”
For HPV, vaccination is recommended and regular Papanicolaou tests

Take-home message: Some cancers are increased in association with IBD. However, the medications, particularly immunosuppressants, may reduce the incidence of inflammation-related cancers…or promote immunosuppression-related cancers.

Complex Family of CFTR-Associated Disorders

Posted on June 17, 2015 by gutsandgrowth

While most clinicians are familiar with cystic fibrosis (CF), much fewer are familiar with a group of disorders related to the cystic fibrosis transmembrane conductance regulator (CFTR) that do not meet the criteria for cystic fibrosis. A summary of these disorders is provided in a recent editorial (Levy H, Farrell PM. J Pediatrics 2015; 166: 1337-40). In addition, the editorial provides insight into a related study: Groves T et al.. J Pediatrics 2015; 166: 1469-74.

The editorialists note that new disorders have been created due to newborn screening and due to the use of CF mutation analysis. New disorders:

CRMS -CFTR-related metabolic syndrome. CRMS describes infants with elevated immunoreactive trypsinogen and inconclusive sweat testing and DNA results. Inconclusive sweat testing includes sweat tests 30-59 mmol/L if age <6 months or 40-59 mmol/L if >6 months on at least 2 occasions. DNA testing is inconclusive if there are fewer than 2 CF disease-related mutations identified. DNA testing is also considered inconclusive if there are 2 CFTR mutations but sweat testing is normal.
CFTR-RD -CFTR related disease. CFTR-RD describes symptomatic individuals beyond infancy who have sweat testing <60 mmol/L and up to 2 CFTR mutations, at least one of which is not clearly categorized as a CF-causing mutation. Thus, these individuals do not fulfill criteria for CF but could have congenital bilateral absence of vas deferens, acute recurrent or chronic pancreatitis, or disseminated bronchiectasis.
Delayed CF -Delayed CF describes patients eventually diagnosed with CF who had initially intermediate sweat chloride values. Over time, their condition evolves to fulfill the criteria for CF. In the retrospective study by Groves et al, 14 of 29 (48%) evolved to a diagnosis of CF. These patients with delayed CF had less pancreatic insufficiency (OR 0.06), milder obstructive lung disease, less colonization with Pseudomonas aeruginosa (OR 0.04), and overall disease severity as measured by Shwachman scores at 2 years.
Nutritional outcomes were improved at 2 years in this Delayed CF cohort in comparison to 28 matched patients diagnosed with CF in the newborn period, but did not persist to later ages.

The editorial notes that nearly 20% of patients with CF are being enrolled in the CF foundation patient registry without sweat chloride testing results. They do not favor this approach because the diagnosis of CF requires proof of CFTR dysfunction, not simply CF DNA mutations.

Take-home message: Patients who do not meet the criteria for CF but who have intermediate sweat testing or abnormal CF DNA mutations need to be followed. Some will fulfill the criteria with time and others may develop other clinical problems even without having CF.

Understanding the Reasons for Abnormal Liver Enzymes in Pediatric Inflammatory Bowel Disease

Posted on June 16, 2015 by gutsandgrowth

A recent large single center study (Pusateri AJ et al. JPGN 2015; 60: 592-97) provides some very practical information regarding elevated liver enzymes in the setting of inflammatory bowel disease (IBD). Because there are some serious liver diseases associated with IBD and due to the potential for liver toxicity from many of the medications, bumps in liver enzymes need to be carefully considered.

This retrospective study with 514 patients indicates that 77% of these elevations are transient. Table 1 lists the definitions (chronicity, severity) and patterns that were analyzed. Transient elevations were broken down into brief (<30 days), prolonged <180 days, chronic >180 days and either intermittent or continuously abnormal. The three types were the following:

Hepatic: elevated ALT and/or AST; normal alkaline phosphatase (AP), GGT, and direct bilirubin (DB)
Cholestatic: elevated AP, GGT, and/or DB; normal ALT and AST
Mixed

Severity or degree was classified as follows:

1 –peak liver enzyme 0-1 x ULN
2 –peak liver enzyme >1-2 x ULN
3 –peak liver enzyme >2-4 x ULN
4 –peak liver enzyme >4 x ULN

Key findings:

219 of 514 patients had 1 or more episode of abnormal liver enzymes; five patients with preexisting liver disease were excluded from the analysis.
Of 214 patients (152 with Crohn’s disease [CD], 62 with Ulcerative colitis [UC]) with abnormalities, 69% had a hepatitic pattern, 8% had a cholestatic pattern, and 23% had a mixed pattern. There was no association between the pattern and the final diagnosis (eg. idiopathic vs defined etiology)
Only 128 had adequate data to assess chronicity. In this group, 77% had transient elevations (CD 75%, UC 80%)
87% of elevations were considered idiopathic. 65% of patients with idiopathic elevation had levels < 2 times ULN.
Among patients with levels <2 times ULN, 95.3% had an idiopathic etiology.
Among patients with levels >4 times ULN, 63% had a benign idiopathic etiology
Figure 1 provides a pie chart of diagnoses. Among the 12.6% with a specific etiology for elevated liver tests, drug toxicity was the most common reason: 51.9% were considered due to 6-MP therapy, 3.7% due to methotrexate, 3.7% due to acetaminophen.
Other identified causes among the 12.6% with a defined etiology included NAFLD in 11.1%, infections (CMV,EBV, Histoplasmosis) in 14.8%, cholelithiasis in 3.7%, autoimmune hepatitis in 3.7%, primary sclerosing cholangitis/overlap in 3.7%, and vascular malformation in 3.7%.

As with any retrospective study, there are a number of limitations, especially underdiagnosis given a lack of uniform approach to evaluation. That being said, all patients had a minimum follow-up of at least nine months and most patients with prolonged liver enzyme elevation would have been examined closely.

Bottomline: This study provides reassurance that liver enzyme elevations are common in children with IBD, occurring in >40% of patients over 3 years at this center; most often these elevations are benign and transient.

Related blog posts:

Trending on Twitter: Good Advice Regarding Dr. Oz

Posted on June 15, 2015 by gutsandgrowth

Since many followers of this blog are not using twitter, I am retweeting (via this blog) Eric Benchimol’s retweet regarding Dr. Oz:

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gutsandgrowth

Pediatric Gastroenterology

Category Archives: Pediatric Gastroenterology Intestinal Disorder