Three Studies Show the Benefit of Concomitant Therapy for Inflammatory Bowel Disease (Part 2)

Posted on November 7, 2017 by gutsandgrowth

Continued from yesterday…

The third study (HM Kansen et al. JPGN 2017; 65: 425-29) retrospectively (2009-2014) examined 162 children (with available data) with Crohn’s disease (CD) for the development of anti-infliximab antibody (ATI) while receiving either monotherapy or concomitant therapy. This was a collaborative study from the Kids with Crohn’s Colitis (KiCC) working group (Netherlands). In the majority of their patients (222 of 229), IFX was initiated as step-up therapy. Key findings:

15% developed ATIs
6 of 62 (10%) developed ATIs while receiving ongoing concomitant immunosuppression
11 of 81 (14%) developed ATIs after receiving early concomitant immunosuppression (median of 6.2 months of concomitant immunosuppression followed by IFX monotherapy) 10 of 11 who developed ATIs within the first 12 months, compared to 1 of 26 (4%) after 12 months.
8 of 19 (42%) developed ATIs on IFX monotherapy

In their discussion, the authors note concerns regarding the safety of thiopurines. However, they point out that “the benefit of combination therapy (reduction of ATI formation) relative to IFX monotherapy should outweigh the risk of serious infections and malignancies to achieve an optimal treatment strategy for paediatric CD.” The authors: “combination therapy for approximately 12 months from initiation of IFX, followed by IFX monotherapy, may be equally effective alternative to continuous combination therapy.”

Overall, the totality of the evidence favors combination therapy for most patients with CD. Yet, there is wide variation in clinical practice. As I was thinking about this, I came across a recent commentary: “The Power of Regret” (J Groopman, P Hartzband. NEJM 2017; 377: 1507-9). The authors note that “disappointment is an unavoidable aspect of making difficult choices…but disappointment is not associated with self-recrimination and thus differs notably from regret.” They indicate that “process regret” occurs when patients do not consider information about all available choices before making a decision. I wonder if many patients/families fear using concomitant therapy because they worry they will regret the decision if a complication occurs. Perhaps, working with all available information, some reluctant patients/families will feel better about their decision if the process for their decision was thorough, considering the risks/benefits of the treatment but also the risks/benefits of not choosing the treatment. .

My take: Overall, for most pediatric patients with CD, to date, concomitant therapy has been the most effective treatment. More prospective studies are needed to determine more conclusively the benefit and optimal duration/timing of combined therapy, particularly with the more frequent use of therapeutic drug monitoring. Also, as will be noted in future posts from annual meeting, thiopurine use is declining.

Related blog posts:

Three Studies Show Benefit of Concomitant Therapy for Inflammatory Bowel Disease (Part 1)

Posted on November 6, 2017 by gutsandgrowth

In the first study (J Cheng et al. Inflamm Bowel Dis 2017; 23: 1762-73), the authors retrospectively reviewed 148 children (113 with Crohn’s disease, 35 with ulcerative colitis). 90 patients received concomitant therapy (infliximab with either a thiopurine [n=67], methotrexate [n=23]) and 58 received infliximab monotherapy. Key findings:

Concomitant therapy >6 months significantly lowered the risk of secondary loss of response in Crohn’s disease (CD) (HR =0.39) compared to monotherapy. A similar trend was noted with ulcerative colitis (UC) but did not reach statistical significance.
Steroid-free remission rates at 1 year were 78% for CD patients with concomitant therapy compared with 54% on monotherapy
Among primary nonresponders, 67% of CD patients and 75% of UC patients were receiving IFX monotherapy.
No differences in adverse events were evident between patients receiving monotherapy compared with concomitant therapy. One patient (receiving azathioprine) developed a follicular lymphoma; this patient was well 10 years later.

The second study (Y Qui et al. Clin Gastroenterol Hepatol 2017; 15: 1359-72) was a systemic review of 35 studies that met the authors’ inclusion criteria. In total, 6790 patients with inflammatory bowel disease were enrolled in these studies. This study looked at multiple anit-TNF agents including infliximab, adalimumab, certolizumab, and golimumab. Key finding:

Antidrug antibodies were reduced by 51% in patients receiving concomitant therapy
Conclusion from authors: “concomitant use of immunomodulators should be considered in patients treated with anti-TNF treatment.”

Infliximab Infusions Without Premedication

Posted on November 5, 2017 by gutsandgrowth

Briefly noted:

A recent study (SQ Hutsell, M Wu, KT Park. JPGN 2017; 65: 430-31) examined two practice changes with regard to infliximab (IFX) infusions:

1-hour infusions
Omission of premedications

The authors reviewed ~900 IFX infusions; though, only 111 infusions were administered without premedications. These two changes resulted in a 51% decrease in infusion hours, despite a 9% increase in total number infusions. No increase in adverse reactions was identified.

The authors state that these changes improve patient experience, shorten monitoring time, and reduce costs.

More on It’s Past Time to Split

Posted on November 4, 2017 by gutsandgrowth

In followup to this morning’s post, Pediatric Liver Transplantation: It’s Past Time to Split, one reader pointed out an abstract by Emily R. Perito et al.presented at this year’s AASLD which showed that pediatric deaths would decrease if more livers were split.

ABSTRACT #137

Increasing split liver transplantation in the U.S. could decrease pediatric deaths on the liver transplant waiting list

Emily R. Perito1,3, Garrett Roll2, Jennifer L. Dodge2,

Background: In the United Kingdom, defaulting to split liver transplantation (LT) with suitable deceased donor grafts has virtually eliminated pediatric waitlist (WL) mortality. In the US, only <2% of LTs are split, but 1 in 10 infants die on the WL.

Methods: Using UNOS STAR data, livers for potential split LT were identified from all transplanted, deceased-donor livers 2010-15 who fit strict criteria: age 18-40y, BMI<30, recovered in US after donor brain death, 0-1 vasopressors, a <155meq/L, AST/ALT<100IU/L, bilirubin<3mg/dL, <7d hospitalized, cardiac arrest≤30min, HBV/HCV neg, not CDC high-risk, steatosis≤10% if biopsied, not multi-organ transplant, and no bloodstream infection. Livers allocated to patients high-risk for split LT were also removed: status 1A or MELD/PELD≥40 at WL removal, re-transplant, in the ICU, BMI>34, or >300mi from donor hospital. Pediatric WL deaths included deaths and removals for too sick to transplant, never relisted.

Results: Of 35,461 livers transplanted 2010-15, 6.7% were potentially utilizable for split LT based on donor characteristics. Of these, 95% were transplanted whole (n=2,253). 50% went to recipients deemed possibly high-risk for split LT. This left 1,116 potential livers for split LT (FIGURE); 78% of their primary recipients were listed as willing to accept a segmental liver, and 97% to accept cold ischemia time≥6h (CIT, median 12h). Median donor risk index for this subset was 1.06 (max 1.67). During the same 5y, 261 children died after ≥3d on the WL (median 57d, IQR 15-161)—87% of all pediatric WL deaths. Of these, 56% were <2y of age, 26% 2-12y, 18% 13-18y. Median weight was 9.2kg (IQR 5.9-29.4kg). 36% died at centers that reported doing no pediatric split LTs (15%) or ≤1/year (22%).

Conclusions: Increased utilization of split LT could decrease US pediatric WL mortality—without decreasing LT access for adults. Barriers are significant, but changes to allocation policy, increasing centers with splitting experience, and splitting on normothermic perfusion could increase access and reduce WL mortality.

Jose Garza, Chelly Dykes, Elvis, and Jay Hochman at Cincinnati Children’s Reception

Pediatric Liver Transplantation: Past Time to Split

Posted on November 4, 2017 by gutsandgrowth

A recent study (EK Hsu et al. Gastroentorol 2017; 153: 988-95, editorial 888-89) exposes some deep flaws in organ transplantation in U.S.

The retrospective study examined children on the U.S liver transplant wait-list from 2007-14. This included 3852 pediatric candidates. Key findings:

Of 27,831 adults who underwent transplantation, 1667 (6%) received livers from pediatric donors (<18 years)
Of children who died or were delisted, the centers caring for 173 (55%) had received an offer of 1 or more livers that was subsequently transplanted into another pediatric recipient. The remaining 45% died or delisted with no offers. High-volume (>15 transplants per year) centers were more likely to accept an organ than a low-volume center (<5 transplants per year).
Only 29% of children received a split graft. When a splittable adult liver graft was allocated to an adult the chance of it being used as a split was 0.6%.

Background:

Children have much lower survival rate than adults on waiting list. Of adults who died or delisted, 85% receive at least one transplant offer; whereas, nearly half of all children never even receive an offer. Children who died/delisted had wait-time of 33 days compared with 92 days for adults who died/delisted.
Less than 10% of all liver transplant recipients are pediatric transplants. Per editorial, “a measure that improves pediatric access by 20% would only reduce adult access by 2%.”
There are more than 100 pediatric liver transplant centers in U.S. Certainly, this improves convenience; however, per editorial: “three-fourths are very low volume centers, performing <5 liver transplantations per year…Death on waiting list” occur 5 times more at low-volume transplantation centers.
In this study, only 29% of children received split livers; in comparison, in the UK, >80% receive either a split graft or living donor graft.

The editorial points out that splittable livers that are allocated to adults are virtually never split; this is either due to inconvenience or lack of expertise. A small increase in liver splitting would dramatically lower the pediatric mortality wait list. There is no incentive in the current system to split a liver/save a child’s life.

My take: The data from this study points out glaring problems in pediatric liver transplantation.

Children are dying due to lack of prioritization. Pediatric livers are going to adults.
There is practically no splitting when liver organs are allocated to an adult. Incentives to increase organ splitting would save many children from dying waiting for an organ.
Large volume pediatric centers are much more likely to accept a liver offer for patients waiting at their centers. There is an increased wait-list mortality at very low volume centers, perhaps due to lack of expertise and passing up viable organs. Do hepatologists/surgeons at these centers explain this risk to families at their centers?

Related blog posts:

#NASPGHAN17 GI Care For Kids Experience with Vedolizumab

Image

>99% Accuracy in Non-Biopsy Diagnosis of Celiac Disease

Posted on November 3, 2017 by gutsandgrowth

Another large study (KJ Werkstetter et al. Gastroenterol 2017; 153: 924-35) shows a high accuracy of diagnosing celiac disease (CD) without a biopsy when very high celiac titers are identified in symptomatic patients. A previous study (n=898) this year also showed similar findings: The Non-Biopsy Diagnosis of Pediatric Celiac Disease

The current study (2001-2014) identified 743 consecutive pediatric patients with positive celiac serology (TTG-IgA). Key findings:

If TTG-IgA was higher than 10-fold the upper limit of normal and a separate sample tested positive for endomysial antibodies, then non-biopsy approach had a positive predictive value >99.6%. The authors utilized a variety of TTG-IgA assays.
The authors noted that HLA-DQ2/DQ8 typing did not improve the accuracy of CD diagnosis. “Negative results for HLA-DQ2/DQ8 in patients with TGA or EMA positivity are most likely false negative …or due to very rare risk-allele combinations not recognized by the test systems.”
“At least 50% of affected children in clinical practice will benefit from this nonbiopsy approach, which reduces burden and risks of endoscopy and anesthesia” and is more cost-effective.

The authors’ conclusion: “allowing omission of biopsies enables a correct diagnosis of CD in symptomatic children if TTG-IgA exceed 10xULN and positive EMA-IgA confirms celiac disease autoimmunity in a second blood sample. If one of these criteria is not fulfilled, biopsy should be performed to confirm the diagnosis.”

My take: This study provides convincing data that CD diagnosis does NOT require an intestinal biopsy under specific conditions.

Related blog posts:

The MH Score: Separating primary Hemophagocytic Lymphohistiocytosis from Macrophage Activation Syndrome

Posted on November 2, 2017 by gutsandgrowth

“Sincerity is the key to success. Once you can fake that, you’ve got it made.”

–Groucho Marx

The above quote is not particularly related to this blog post –but I like it.

A recent study (F Minoia et al. J Pediatr 2017; 189: 72-8) provides data supporting a scoring system which helps distinguish primary hemophagocytic lymphohistiocytosis (HLH) from macrophage activation syndrome (MAS).

Background: “By convention, secondary HLH seen in rheumatic disorders is termed macrophage activation syndrome…occurs most commonly in systemic juvenile idiopathic arthritis (sJIA).” Both HLH and MAS are life-threatening, though HLH tends to be more severe. The treatment for the two disorders is much different.

HLH typically develops in the first year of life, though some remain asymptomatic until later. Identification of pathologic mutations (primary HLH is not a single disease) is considered the gold standard, but this “takes weeks to complete and is not available in many resource-limited areas.”

In this study, the authors reviewed clinical features from 362 patients with MAS and 258 patients with HLH to develop a scoring system that more readily distinguished these conditions.The data from 80% of the patients was used to construct the scoring system and then this was validated with the remaining 20%. MH Score:

Age of onset, years: 0 points if >1.6 yr, 37 points if ≤1.6 yr
Neutrophil count, x 10 to the 9th/L: 0 points if >1.4, 37 points if ≤1.4
Fibrinogen, mg/dL: 0 points if >131, 15 points if ≤131
Splenomegaly: 0 points if no, 12 points if yes
Platelet count, x 10 to the 9th/L: 0 points if >78, 11 points if ≤78
Hemoglobin, g/dL: 0 points if >8.3, 11 points if ≤8.3

The age of onset and severe neutropenia are weighted the most heavily as they most heavily influence the odds ratio of having HLH; with multivariate analysis (Table 3), age of onset ≤1.6 yrs had an OR of 40.3, and neutrophil count ≤1.4 had an OR of 39.3. All of the other parameters had OR between 2.9 and 4.4. Hepatomegaly favored HLH as well but was not independently associated with the diagnosis.

How to use this scoring system:

In this cohort, the MH score ranged from 0 to 123. The median value was 97 for HLH and 12 for MAS.
A cutoff of ≥60 yielded a sensitivity of 91% and specificity of 93% for the diagnosis of HLH. Higher values increased the probability of HLH further.

Most laboratory studies were more abnormal with HLH; however, both ferritin elevation and LDH elevation were more pronounced with MAS. Median ferritin was 5353 with MAS and 2910 with HLH. Median LDH was 1230 with MAS compared with 696 with HLH.

This study validated the MH score for distinguishing HLH from MAS associated with sJIA; this can allow early introduction of aggressive treatment and appropriate genetic/immunologic evaluation. The applicability of the MH score for distinguishing HLH from other conditions is unclear. Further prospective evaluation of the MH score is needed.

My take: This is a very helpful study and is likely to influence diagnostic workup and management of these sick patients. Due to the liver and spleen abnormalities, pediatric gastroenterologists need to be able to recognize both HLH and MAS.

Related blog post:

What’s with $1040 -is a fine of $40 more going to make a difference?

Breastfeeding: Protection from Inflammatory Bowel Disease

Posted on November 1, 2017 by gutsandgrowth

Xu L, et al. Systematic review with meta-analysis: breastfeeding and the risk of Crohn’s disease and ulcerative colitis. Aliment Pharmacol Ther. 2017;46:780-789.

https://doi.org/10.1111/apt.14291Thanks to Mike Hart for this reference.

From abstract:

Results

A total of 35 studies were included in the final analysis, comprising 7536 individuals with CD, 7353 with UC and 330 222 controls. Ever being breastfed was associated with a lower risk of CD (OR 0.71, 95% CI 0.59-0.85) and UC (OR 0.78, 95% CI 0.67-0.91). While this inverse association was observed in all ethnicity groups, the magnitude of protection was significantly greater among Asians (OR 0.31, 95% CI 0.20-0.48) compared to Caucasians (OR 0.78, 95% CI 0.66-0.93; P = .0001) in CD. Breastfeeding duration showed a dose-dependent association, with strongest decrease in risk when breastfed for at least 12 months for CD (OR 0.20, 95% CI 0.08-0.50) and UC (OR 0.21, 95% CI 0.10-0.43) as compared to 3 or 6 months.

From associated editorial by David Rakel:

This meta-analysis of 35 studies shows that there is a dose–response protective effect of the duration of breastfeeding on inflammatory bowel disease. The association shows as much as an 80% reduction in risk for both Crohn’s disease and ulcerative colitis for breastfeeding more than 12 months.

Breast Feeding Graph

Inflammatory bowel disease arises from a complex set of interactions related to genetic susceptibility, environmental exposures, and a dysregulated immune response to dysbiotic intestinal microbiota, according to the study authors. These data will give us one more reason to encourage breastfeeding, ideally for a year or more.

Assessing Neonatal Jaundice with Smartphone App

Posted on October 31, 2017 by gutsandgrowth

A recent study (Taylor JA, et al. Pediatrics 2017; 140 (3) e20170312) reports on the effectiveness of a smartphone app, BiliCam, to detect total serum bilirubin (TSB) in a diverse sample of newborns < 7 days old. Thanks to Ben Gold for this reference.

BiliCam uses a calibration card which is placed on the infant’s sternum to standardize the color (and jaundice) reading in the photo; the image goes via the internet to a server for analysis.

Key findings:

Estimated bilirubin levels using BiliCam were compared with TSB levels in 530 newborns which included 20.8% African American,, 26.3% Hispanic and 21.2% Asian American
The overall correlation was 0.91 were similar among all ethnic groups with correlations ranging from 0.88 to 0.92
The sensitivity of Bilicam was 84.6% is for identifying infants with a TSB in the high-risk zone of the Bhutani nomogram. The sensitivity was 100% for identifying TSB > 17 mg/dL. Specificities were 75.1% adn 76.4% respectively.

For more commentary on this article: AAP Journals Blog: Bilirubin phone apps –our future calls!

My take: This article indicates that a digital image with Smartphone app analysis is much more accurate in detecting jaundice that a visual assessment.