Category Archives: inflammatory bowel disease

Infliximab -Low Response in Young Kids (7 years and younger) with IBD

Posted on by

 JPGN 2014; 59: 758-62. The full abstract for this reference follows but the message from this retrospective study of 33 children is clear –a much smaller percentage of the youngest children respond to infliximab compared to older children, adolescents and adults. In the discussion, the authors note that younger children may need higher dosing to maintain good infliximab levels or the disease pathogenesis may be much different (eg. underlying immunodeficiency and different gene mutations).

Here’s the abstract (from JPGN twitter feed):

Background: Infliximab (IFX) is efficacious for induction and maintenance of remission in pediatric patients with moderate-to-severe inflammatory bowel disease (IBD). It has, however, not been studied in patients 7 years old and younger. Our aim was to characterize efficacy and safety of IFX therapy in this cohort.

Methods: This was a retrospective study of patients with IBD ages 7 years and younger, treated with IFX between 1999 and 2011. Medical records were reviewed for age of diagnosis, disease phenotype, therapy, surgery, IFX infusion dates, dose, and intervals. Outcome measures included physician global assessment, corticosteroid requirement, and adverse events.

Results: Thirty-three children (ages 2.4–7 years) were included. Twenty patients had Crohn disease, 4 had ulcerative colitis, and 9 had indeterminate colitis. Maintenance of IFX therapy at 1, 2, and 3 years was 36%, 18%, and 12%, respectively. Patients of age 5 years and younger had the lowest rates of maintenance of therapy at 25% at year 1, and 10% at years 2 and 3 combined. Nine percent of all of the patients demonstrated response measured by the physician global assessment and were steroid free at 1 year. There were 8 infusion reactions. There were no malignancies, serious infections, or deaths.

Conclusions: IFX demonstrated a modest response rate and a low steroid-sparing effect in patients with IBD 7 years old and younger. Although this is a limited study, there appears to be a trend for decreased sustained efficacy with IFX in this age group, particularly in children 5 years old and younger, when compared with the previously published literature in older children.

IBD Update January 2015 (Part 2)

Posted on by

1. A retrospective study (Inflamm Bowel Dis 2014; 20: 2292-98) of 217 patients with inflammatory bowel disease(108 infliximab-treated, 109 adalimumab-treated) provides data which indicates that combination therapy (mainly with thiopurines) resulted in higher trough levels and lower antibodies to infliximab (ATI) than monotherapy in patients treated with infliximab (IFX).  This was not evident in the adalimumab (ADA)-treated patients. Overall, approximately 90% of study population had Crohn’s disease.

Key points from this study:

  • The majority of trough level/antidrug antibody levels were drawn due to loss of response.  This is a major limitation of this study.
  • Among IFX-treated patients, those with combination therapy had trough level of 7.5 mcg/mL compared with 4.6 mcg/mL.  In combination therapy patients, the incidence of ATIs was 5.7% compared with 29.8% in monotherapy patients.
  • According to this study, the dose of the immunomodulator (IM) did not significantly influence the infliximab trough level or antibody formation; that is, more than half of patients were receiving “suboptimal dosed IM” and their infliximab levels/ATIs were similar to those who were optimally-dosed.
  • Among those who were receiving combination therapy, the incidence of antibody formation was lower in IFX-treated patients who started IM concurrently with IFX compared with those in which IM was added subsequently.
  • There were many other limitations in this study, including the finding that 94% of monotherapy patients had received previous immunomodulator therapy.

Bottomline: This study suggests that combination therapy is beneficial for patients receiving infliximab (in agreement with the previous SONIC study) and may not be beneficial for patients receiving adalimumab; however, only a well-designed prospective study

2. Inflamm Bowel Dis 2014; 20: 2266-70.  This study with 749 patients from Sweden showed that a large number of inflammatory bowel disease patients did not receive with iron supplementation: “Only 46% of patients with anemia were treated with iron supplementation or blood transfusion.”  This study showed frequent persistence of anemia one year after diagnosis, especially in children. At time of diagnosis, 55% of children and 27% of adults had anemia and 28% and 16% at one year followup, respectively.

My take: Treatment of the underlying IBD, often helps anemia.  However, in some patients treating the anemia with iron may help improve symptoms as much or more than other aspects of treatment.

3. Inflamm Bowel Dis 2014; 20: 2433-49.  Reviews pain management approaches for patients with IBD. The article emphasizes how pain can be multifactoral and that opiod-induced hyperalgesia may worsen pain.

Related blog posts:

 

Bryce Canyon

Bryce Canyon

 

IBD Update January 2015 (Part 1)

Posted on by

1. From the recent Advances in IBD Conference, Healio Gastroenterology reports on Dr. Baldassano’s update on PLEASE study which examined enteral nutrition in comparison to anti-TNF therapy.  Here’s the link: Enteral Nutrition Outcomes (Thanks to Kipp Ellsworth for this reference)

Here’s an excerpt:

Citing the findings from the Pediatric Longitudinal Study of Semi-Elemental Diet and Stool Microbiome (PLEASE), Baldassano demonstrated that greater mucosal healing was achieved in CD patients on exclusive enteral nutrition compared with partial enteral nutrition therapy. In this prospective cohort study, 38 children received enteral therapy with defined formula diet and 52 controls received anti-TNF-alpha therapy. The enteral nutrition group was further stratified to evaluate mucosal healing on a more restrictive diet; one subgroup received 80% to 90% of total caloric needs from enteral therapy, of which 14% achieved induction of remission at 8 weeks, the other subgroup received 90% to 100% of total caloric needs from enteral therapy, of which 45% achieved remission, and 62% of controls achieved remission.

2. NEJM 2014; 371: 2418-27. This is a case report of a 9-year-old with Crohn’s Disease and pulmonary nodules.  This report serves as a useful review.

3. Standardized use of fecal calprotectin (here’s the link -from KT Park’s Twitter feed):

Fecal calprotectin -use for identifying IBD and for identifying relapse risk

4. Inflamm Bowel Dis 2014; 20: 2247-59. Study examined factors associated with infliximab clearance.  Higher clearance noted with low albumin, high body weight, and the presence of antibodies to infliximab (ATI).  The authors note that higher concentrations with dose escalation are more likely when the dose interval was shortened than by increasing the administered dose.

5. Inflamm Bowel Dis 2014; 20: 2260-65. “Natural History of Perianal Crohn’s Disease After Fecal Diversion.”  Despite greater use of biologics, only 15 of 49 patients reestablished intestinal continuity between 2000-2011.  In this group of 15, only 5 remained reconnected and 3 of these 5 patients had procedures to control sepsis.  The likelihood of sustained intestinal continuity remains low in patients who have required a diverting procedure.

Related blog posts:

Sandy Springs, Georgia

Sandy Springs, Georgia

IBD Incidence Increasing: 30 Years of Data from Manitoba

Posted on by

A recent study (JPGN 2014; 59: 763-66) shows a steady trend of increased incidence of IBD in Manitoba. This figure is available online:

 

Increasing IBD Incidence in Children

Increasing IBD Incidence in Children from JPGNonline

Abstract:

Objectives: The aim of this study was to describe the incidence and prevalence of inflammatory bowel disease (IBD) in children <17 years of age in 30 years from 1978 to 2007.

Methods: From January 1, 1978, to December 31, 2007, the sex- and age-adjusted annual incidence and prevalence of pediatric IBD per 100,000 population were calculated based on the pediatric IBD database of the only pediatric tertiary center in the province. The annual health statistics records for the Province of Manitoba were used to calculate population estimates for the participants. To ensure validity of data, the University of Manitoba IBD Epidemiology Database was analyzed for patients <17 years of age from 1989 to 2000.

Results: The sex- and age-adjusted incidence of pediatric Crohn disease has increased from 1.2/100,000 in 1978 to 4.68/100,000 in 2007 (P < 0.001). For ulcerative colitis, the incidence has increased from 0.47/100,000 in 1978 to 1.64/100,000 in 2007 (P < 0.001). During the same time period, the prevalence of Crohn disease has increased from 3.1 to 18.9/100,000 (P < 0.001) and from 0.7 to 12.7/100,000 for ulcerative colitis (P < 0.001). During the last 5 years of the study the average annual incidence of IBD in urban patients was 8.69/100,000 as compared with 4.75/100,000 for rural patients (P < 0.001).

Conclusions: The incidence and prevalence of pediatric IBD are increasing. The majority of patients were residents of urban Manitoba, confirming the important role of environmental factors in the etiopathogenesis of IBD.

Unrelated: As a bonus for those who made it to the bottom of this post : there’s a new Bristol Stool App for iPhones.  Here’s the link: http://www.bristol-stool-scale.com (from John Pohl’s twitter feed)

 

Enthusiasm for Vedolizumab

Posted on by

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:

Screen shot 2015-01-01 at 2.41.27 PM

Lack of Meaningful Improvement in Crohn’s Patients with Tofacitinib

Posted on by

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 by
  1. Inflamm Bowel Dis 2014; 20: 1891-1901
  2. Inflamm Bowel Dis 2014; 20: 1996-2003
  3. Inflamm Bowel Dis 2014; 20: 2013-21.
  4. 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 by

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:

Other articles briefly noted:

Inflamm Bowel Dis 2014; 20: 2142-50. “Approach and management of patients with chronic hepatitis B and hepatitis C during the course of inflammatory bowel disease.”

Inflamm Bowel Dis 2014; 20: 2151-56.  Use of cyclosporin and tacrolimus in inflammatory bowel disease.  Checking hepatitis B surface antigen, surface antibody, and core antibody are recommended at the time of diagnosis of IBD. Algorithm for managing hepatitis B serology is given in Figure 1.

New Normal for Ulcerative Colitis

Posted on by

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 by

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: