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

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:

Venous Thromboembolism: A Good Question for Pediatric Collaboration

Posted on June 15, 2015 by gutsandgrowth

Two recent clinical review articles (see below) indicate that most adults with inflammatory bowel disease (IBD) admitted to the hospital would benefit from venous thromboembolism (VTE) prophylaxis. Since children with IBD have a lower risk of VTE, it is unclear whether more efforts at VTE prophylaxis are needed in the pediatric population. Previous studies have shown that in those IBD patients less than 20 years, the incidence rate was 8.9 per 10,000 person years. In contrast, in those IBD patients older than 60, the incidence rate was 54.6 per 10,000 person years (VTE with IBD | gutsandgrowth).

Inflammatory Bowel Dis 2015; 21: 1195-1203.
Inflammatory Bowel Dis 2015; 21: 1204-1213.

In the first article, the authors review common risk factors and disease-specific risk factors. They state the following:

Because hospitalization puts the patient at greater risk for TE compared with an outpatient setting, all hospitalized patients should receive anticoagulant therapy in the absence of severe bleeding, even if the patients are in remission.

The second review describes epidemiological data, pathophysiology, and VTE prevention. They also state the following:

Currently, the most effective strategy for preventing VTE in hospitalized patients with IBD with active disease is prophylactic anticoagulation. In fact, all of the current guidelines for the management of patients with IBD suggest the use of anticoagulants to prevent VTE.

The authors note that the rates of thromboprophylaxis are “still unacceptably low.”

Bottomline: In adults with active IBD, VTE prophylaxis is recommended. In the pediatric population due to the lower incidence of VTE, more study is needed –perhaps another project for ImproveCareNow.

Briefly noted:

Cochrane Review of Vedolizumab for Ulcerative Colitis. Inflammatory Bowel Dis 2015; 21: 1151-59. Based on four studies (n=606 patients) with low risk of bias, pooled analysis showed that vedolizumab was superior to placebo for induction of remission (RR=0.86), clinical response (RR=0.82), endoscopic remission (RR=0.82) and for achieving remission at 52 weeks in week 6 responders (RR=2.73). No statistically significant difference was observed in the incidence of adverse events between vedolizumab and placebo.

Zoo Atlanta

Working on Transition Readiness

Posted on June 11, 2015 by gutsandgrowth

A recent study (Gray WN, et al. Inflamm Bowel Dis 2015; 21: 1125-31) examines preparedness of patients with inflammatory bowel disease (IBD) on the verge of transitioning to adult gastroenterologists from pediatric gastroenterologists.

Using a population of 195 patients (16-25 years), the authors used the Transition Readiness Assessment Questionnaire (TRAQ). Scoring system:

5= Yes, I always do this when I need to
4= Yes, I have started doing this
3= No, but I am learning to do this
2= No, but I want to learn
1= No, I do not know how

Specific Readiness Skills & Mean Scores (more complete data listed in Table 3):

Taking medicines correctly and on own 4.66
Arranging for ride to medical appointment 4.39
Managing money and budgeting 3.69
Calling doctor about unusual change in health 3.64
Reordering and getting refills on time 3.60
Calling doctor’s office to schedule an appointment 3.09
Getting financial help with school or work 2.92
Knowing what health insurance covers 2.60
Applying for health insurance if coverage lost 2.44

Key finding: “Only 5.6% older adolescents/young adults …met our institutional benchmark.”

To help with transition readiness the authors recommend the CDHNF/NASPGHAN Transition Checklist for parents and starting on transition issues between 12-15 years of age. Transition checklist available here: Transitioning a Patient With IBD From Pediatric to Adult Care –this is a simple 2-page handout!

Conclusion: Most patients need more work on transition readiness. If patients are not prepared, it is more likely that this will lead to medical setbacks.

Briefly noted:

“Exercise Decreases Risk of Future Active Disease in Patients with Inflammatory Bowel Disease in Remission” Inflammatory Bowel Dis 2015; 21: 1063-71. This prospective study used the CCFA’s Partners’ internet-based cohort. 227 of 1308 (17.4%) Crohn’s disease (CD) patients and 135 of 549 (24.6%) Ulcerative colitis/indeterminate colitis (UC/IC) patients developed active disease after 6 months. Key finding: Higher exercise level was associated with decreased risk of active disease for CD (adjusted relative risk 0.72) and UC/IC (adjusted relative risk 0.78). Take-home point: While there are several limitations to this study, it does seem likely that regular physical exercise is a good idea (not just in patients with IBD). In this population, subjective markers of disease activity (sCDAI and SCCAI) improved in those who exercised more.

Zoo Atlanta

Increasing Inflammatory Bowel Disease Among U.S. Patients From India

Posted on June 8, 2015 by gutsandgrowth

An interesting epidemiology study (Malhotra R, et al. Clin Gastroenterol Hepatol 2015; 13: 683-89) shows a high prevalence of inflammatory bowel disease among U.S. residents with Indian Ancestry.

Using a national pathology database on 1,027,977 subjects who had ileocolonic biopsies from 2008-2013, the authors identified 30,812 patients who were diagnosed with inflammatory bowel disease (IBD): 20,308 with ulcerative colitis (UC), 7706 with Crohn’s disease (CD), and 2798 with indeterminate colitis (IC).

Key findings:

Among patients with Indian ancestry, the overall prevalence of IBD was 9.1% (n=197 compared with 1960 controls) compared with 4.3% for those of Jewish ethnicity, 2.4% for hispanic ethnicity, and 1.4% for East Asian ethnicity. The adjusted odds ratio for patients with Indian ancestry was 2.5.
In addition, UC was predominant, accounting for 153 of the 197 cases; 26 were diagnosed with CD and 18 were IC. IBD and UC were highest in subjects with roots in Gujarat.

Take-home point (from authors): “Considering the reported relatively low prevalence of IBD in India, these findings suggest that genetic factors may interact with new environmental conditions to trigger the expression of disease.”

Related blog post: Emigration -One Way to Acquire IBD

Briefly Noted:

Rungoe C, et al. “Inflammatory Bowel Disease and Cervical Neoplasia: A Population-Based Nationwide Cohort Study” Clin Gastroenterol Hepatol 2015; 13: 693-700. Using a Dutch national cohort with more than 27,000 patients, the authors showed a “2-way association between IBD, notably CD, and neoplastic lesions of the uterine cervix.” Overall the risk was mildly increased; for CD, the incidence rate ratio of cervical cancer was 1.53 (CI 1.04-2.27).

Reinisch W, et al. “Factors Associated with Poor Outcomes in Adults with Newly Diagnosed Ulcerative Colitis” Clin Gastroenterol Hepatol 2015; 13: 635-42. The tables in this article summarize clinical characteristics, biologic markers, and treatment factors associated with poor outcomes. For clinical factors, younger age at diagnosis and age >65 years increase the risk for more severe disease. For biomarkers, increased CRP, ESR, and cal protection were associated with higher risk of progressing to colectomy. For treatment factors, not surprisingly, failing to respond to therapy and absence of mucosal healing were associated with higher risk of progressing to colectomy.

Chattahoochee River National Recreation Area

Toronto Consensus: Practice Guidelines for Nonhospitalized Ulcerative Colitis

Posted on June 3, 2015 by gutsandgrowth

A group of 23 experts followed a rigorous process over a 1-year period to assess the quality of evidence and develop consensus statements regarding the medical management of ulcerative colitis (UC) in adults (Bressler B, Marshall JK et al. Gastroenterol 2015; 148: 1035-58, editorial 877-80).

The need for updated guidelines has emerged due to practice variation related in part to a wider availability of treatments and diagnostic tools. It is recognized that early institution of effective therapy is associated with the best outcomes. In addition, due to the chronic nature of ulcerative colitis and the potential for reduced durability of biologic agents, careful decision-making can improve response.

Table 4 in the article summarizes the recommendations. I will list a few:

1. Thiopurines:

“In patients with UC, we recommend against the use of thiopurine monotherapy to induce complete remission.”
In selected patients, “we suggest thiopurine monotherapy as an option to maintain complete corticosteroid-free remission.”

2. Anti-TNF therapy:

“In patients with UC who fail to respond to thiopurines or corticosteroids, we recommend anti-TNF therapy to induce complete corticosteroid-free remission.”
“When starting anti-TNF therapy, we recommend it be combined with a thiopurine or methotrexate rather than used as monotherapy to induce complete remission.”
For UC patients with suboptimal response or for those who lose response to anti-TNF therapy, “we recommend dose intensification.” Dose optimization should be informed by therapeutic drug monitoring.

3. Vedolizumab

Vedolizumab is recommended with primary anti-TNF failure (rather than switching to an alternative anti-TNF), whereas either a 2nd anti-TNF or vedolizumab is recommended with secondary anti-TNF failure based on therapeutic drug monitoring.

4. Fecal microbial transplant (FMT)

“We recommend against FMT…outside the setting of a clinical trial.”

5. 5-ASA and Corticosteroids

Rectal 5-ASA is recommended at 1 g daily for mild-to-moderate ulcerative proctitis. 5-ASA enemas are recommended for mild-to-moderate left-sided ulcerative colitis.
In patients with moderate-to-severe UC, corticosteroids are recommended as 1st line therapy for induction of remission but not for maintaining remission. In addition, corticosteroids are recommended as 2nd-line agents for inducing remission in those with mild-to-moderate disease who do not respond to 5-ASA products.

With all of the treatments, the authors recommend followup to assure response to therapy; this followup ranges from within 2 weeks for steroids, to 4-8 weeks with 5-ASA products, to 8-14 weeks for biologic agents.

Overall, the emphasis of this consensus statement is on maximizing the response to biologic agents. By optimizing dosing and using combination therapy, the treatment guidelines aim to lower rates of antidrug antibody formation. This in turn should improve results and is in agreement with data from both the SONIC study and the UC-SUCCESS study.

The editorial comments that methotrexate “may be an attractive option for young male patients;” however, “the absence of data on risk of malignancy with methotrexate in IBD may reflect lower frequency of use for this indication.”

While these guidelines will be useful, there are many unanswered questions (discussed in editorial).

In patients on combination therapy, what is the optimal dose of the immunomodulator?
When or Should the immunomodulator be withdrawn?
For secondary failure, should a 2nd anti-TNF be used prior to vedolizumab?
How should these guidelines be tailored for the pediatric population (or the elderly)?
What is the optimal monitoring for UC patients with regard to biomarkers and endoscopy?
What is the appropriate role of therapeutic drug monitoring?

Bottomline: These guidelines are likely to promote the use of more combination therapy and help define the current role of vedolizumab.

Related blog posts:

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.

How to Incorporate Budesonide Foam into UC Treatment Algorithm

Posted on June 1, 2015 by gutsandgrowth

A recent study (Sandborn WJ, et al. Gastroenterol 2015; 148: 740-50, editorial 701-4) shows that budesonide foam can be helpful for patients with ulcerative proctitis and ulcerative proctosigmoiditis.

Design: Two identical randomized, double-blind, placebo-controlled trials examined the use of budesonide foam in 546 patients with mild to moderate ulcerative proctitis or ulcerative proctosigmoiditis. Patients had at least 5 cm of involved mucosa but no more than 40 cm. Dosing: 2 mg/25 mL twice daily for 2 weeks, then once daily for 4 weeks. The primary endpoint of remission was defined as an endoscopy subscore of ≤1, rectal bleeding subscore of 0, and improvement or no change from baseline in stool frequency subscore of the Mayo score. It is noted that about 90% of patients had moderate Mayo endoscopy subscore at baseline.

Key findings:

Combining the results of the studies, 41.2% achieved the primary end point of remission at the end of 6 weeks, compared with 24.0% of placebo patients.
There were 10 patients (3.7%) with low morning cortisol (compared with 0.7% of placebo-treated patients) and 14% who had abnormal ACTH testing at 6 weeks (compared with 4% of placebo-treated patients), though there no reported signs/symptoms of adrenal suppression present.

The associated editorial suggests that budesonide could be implemented in patients who did not respond to 5-ASA topical therapy (suppository for proctitis and enema for proctosigmoiditis). In addition, the editorial questions whether a single night-time administration may be more effective by maximizing adherence.

Bottomline: Budesonide foam was superior to placebo in this study and may eliminate the need for systemic steroid use. As the editorial suggests, 5-ASA topical therapy likely should be considered as first-line treatment.

Related blog post: Budesonide for Ulcerative Colitis

IBD Shorts -Skin, Adalimumab Kinetics

Posted on May 23, 2015 by gutsandgrowth

From the IMAgINE study with 192 pediatric patients (Sharma S et al. Inflamm Bowel Dis 2015; 21: 783-92), the authors determined levels for adalimumab, that at week 52, were associated with remission and response. A cutoff level of 3.6 mcg/mL had a sensitivity of 32.7% and specificity of 88.6% for predicting remission; the same cutoff had a sensitivity of 46.2% and specificity of 83% for predicting a response. Overall, the authors noted dose proportionality with patients who received higher (or more frequent) doses with higher serum levels.

“Concomitant Use of Azathioprine/6-Mercaptopurine Decreases the Risk of Anti-TNF-Induced Skin Lesions” (Soh JS et al. Inflamm Bowel Dis 2015; 21: 832-9). Among a cohort of 500 Korean patients, the incidence of psoriaform and eczematiform lesions was 6.2%. Concomitant use of a thiopurine was associated with a hazard ratio of 0.452 (lower risk) for developing these adverse skin reactions.

gutsandgrowth

Pediatric Gastroenterology

Category Archives: inflammatory bowel disease