Tag Archives: Crohn’s disease

Should All Pediatric Patients with Crohn’s Disease Continue Combination Therapy?

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Among patients/families who are not in denial about their inflammatory bowel disease, especially Crohn’s disease, an important discussion is the use of combination therapy.  This has been discussed on this blog before (see some links below).  More data on this subject has been published and again favors the use of combination therapy (V Grossi, T Lerer, et al. Clin Gastroenterol Hepatol 2015; 13: 1748-56).

This study collected data from 2002-2014 on 502 children who participated in a prospective multicenter study. This data was derived from an observational registry rather than a randomized trial, but likely reflects real-world experience with regard to newly diagnosed patients. The authors excluded those with prior biologic therapy and prior resectional surgery.

KEY FINDINGS:

  • Children receiving combination immunomodulator (IM) treatment were more likely to have durable infliximab therapy at 1 year, 3 years, and 5 years.
  • Greater length of concomitant IMs was associated with better durability.
  • For patients who had IM > 6 months after starting infliximab (n=194), durability was 0.70 at 5 years compared with 0.55 for patients with IM <6 months (n=144), and 0.48 for those who did not receive IMs (n=135).
  • In boys, methotrexate appeared to be superior to thiopurines (P<.01): 0.98 at 5 yrs compared with 0.58.  However, there were 60 males receiving methotrexate.  In the study, only 21 females received methotrexate which limited any conclusions.

Among patients who stopped IFX, the reasons included loss of response (n=61, 43%), hypersensitivity reaction (n=41, 29%), elective (n=25, 18%), lost to f/u (n=5, 3%), and other causes (10, 7%).

The “right” dose of methotrexate as a combination agent remains unclear.  There was a wide range of dosing schedules in this study.  It is worth observing that the COMMIT study in adults found no significant difference in adults who received methotrexate in addition to infliximab compared with those receiving infliximab monotherapy.

Take-home message: In this large pediatric observational study, the use of immunomodulators increased the likely durability of infliximab.  Given prior conflicting data (particularly with regard to methotrexate), even more studies are needed to determine exactly how useful combination therapy is and when monotherapy will suffice.  From my viewpoint, I worry much more about loss of efficacy to infliximab than I worry about medication adverse effects.  As such, I will continue to inform families that combination therapy appears to improve infliximab durability.

Related blog posts:

Mount Washburn, Yellowstone

Mount Washburn, Yellowstone

1000th Tweet: GI Symptoms Preceding IBD Diagnosis

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Another milestone for this blog: since 2012, the blog has been publicized on twitter; this is the 1000th tweet. It is also 1314th blog post over nearly 4 years.

A recent study (H Singh et al. Clin Gastroenterol Hepatol 2015; 13: 1302-09) indicates that children with inflammatory bowel disease (IBD) were more likely to have gastrointestinal symptoms in each of the 4 years before the diagnosis of IBD than children without IBD.

In this study, the researchers identified all children with IBD from a population-based Manitoba database; Manitoba had a population of 1.27 million in 2012.  651 children were matched with 5950 controls without IBD.  The study’s Table 1 & 2 indicates that children with IBD had increased clinic visits prior to diagnosis:

  • 54-66 months prior: standardized rate ratio for number of ambulatory visits 1.15; & for ≥1 visit due to GI symptoms odds ratio 1.44
  • 42-54 months prior: standardized rate ratio for number of ambulatory visits  1.22; & for ≥1 visit due to GI symptoms odds ratio 2.05
  • 30-42 months prior: standardized rate ratiofor number of ambulatory visits 1.19; & for ≥1 visit due to GI symptoms odds ratio 2.16
  • 18-30 months prior: standardized rate ratio for number of ambulatory visits 1.23; & for ≥1 visit due to GI symptoms odds ratio 2.93
  • 6-18 months prior: standardized rate ratio for number of ambulatory visits  1.15; & for ≥1 visit due to GI symptoms odds ratio 5.23

There was not a clear trend in increased symptoms between those who developed Crohn’s disease compared with Ulcerative Colitis. In addition, the study noted a trend towards decreased colectomy and resective surgery in Crohn’s in the time period 2002-2010 compared with 1987-2001.  One limitation of this study is the few number of pediatric gastroenterologists in Manitoba (only 1 before 2003); the lack of pediatric gastroenterology availability could impact timely diagnosis.

My take: This data shows that GI symptoms still predate diagnosis in many children and indicate a potential for diagnosis delay. The authors note that noninvasive tools like stool calprotectin have not been widely adopted (at least in Manitoba) and could be helpful in reducing diagnostic delays.

Estes Park, Colorado

Estes Park, Colorado

Head-to-Head: Nutritional Therapy versus Biological Therapy in Pediatric Crohn’s Disease

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The best data to date: D Lee et al. Inflamm Bowel Dis 2015; 21: 1786-93. In this prospective study, the authors studied treatment initiation in children (N=90), comparing partial enteral nutrition (PEN, n=16), exclusive enteral nutrition (EEN, n=22), and anti-TNF therapy (n=52).

Results:

  • Clinical response, defined by PCDAI reduction ≤15 or final PCDAI ≤10, was achieved by 64% PEN, 88% EEN, and 84% anti-TNF.
  • Fecal calprotectin ≤250 noted in 14% PEN, 45% EEN, and 62% anti-TNF

Because of the discrepancy between EEN and PEN, the authors speculate that the “efficacy of EEN may be a consequence of elimination of table food rather than providing a uniquely therapeutic method of delivering nutrients.”  They note that “choice of formula has not impacted the efficacy of enteral nutrition.”

More extensive information on this subject: D Lee et al. Gastroenterol 2015; 148: 1087-1106.

Bottomline: Anti-TNF therapy was as effective or more effective than EEN. And, “for patients who prefer treatment with a nutrition-based therapy, EEN seems superior to PEN.”

Related blog posts:

Street Art, NYC

Street Art, NYC

Not Using and Stopping Therapy in IBD

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Two recent articles show that a lot of patients are not receiving much therapy in inflammatory bowel disease.

  • Moreno-Rincon E et al. Inflamm Bowel Dis 2015; 21: 1564-71.
  • Melesse DY et al. Inflamm Bowel Dis 2015; 21: 1615-22.

In the first article, a multicenter retrospective study of 102 patients, the authors examined the relapse rates of patients with ulcerative colitis who had withdrawal of thiopurines.  They defined “significant clinical relapse” (SCR) as “the occurrence of UC typical signs or symptoms requiring a rescue therapy such as oral or intravenous corticosteroids, biological therapy, immunosuppressant drugs, recapture with TP [thiopurine] or surgery.”

Key findings:

  • Overall SCR was 32.35%.
  • Predictors of relapse included pancolitis (HR 5.01) and duration of treatment with thiopurines (HR 0.15).

Among those without relapse, the mean duration of remission prior to withdrawal of thiopurines was 54 months compared with 34 months in those who relapsed. In figure 2, the authors note that the rate of relapse was 19.2% for those who received >48 months of thiopurine treatment compared with a 45% rate of relapse for those who received treatment for 13-47 months.  The authors note that several studies have shown higher relapse rates than reported in this cohort and that interruption of therapy is associated with a considerable risk of relapse.

Limitations: small retrospective study and the expectation that their SCR would capture the true relapse rate.

The second study, using a Manitoba database, shows a strikingly-high rate of nonuse of medical therapy. Between 1996-2012, 3902 patients with IBD were identified; 47% with Crohn’s disease (CD) and 53% with ulcerative colitis (UC).  While only 11.7% of IBD patients did not have medication dispensed in the first year after diagnosis, beyond this period, “roughly half of all patients with IBD have not used IBD-specific medications in the previous year.”  The authors are not certain how much nonuse is due to nonadherence or nonprescription. They note that there was higher nonuse in patients with CD, possibly due to use of surgical treatment.  However, they note that multiple medications have been shown to reduce postsurgical relapse in CD.

My take: There are a lot of patients off therapy, both due to withdrawal of therapy when doing well and others due to nonadherence or nonprescription.  With or without overt symptoms, these studies make one wonder whether undertreatment will lead to long-term complications or whether there could be a significant number of patients who are overtreated.  Either way, it remains quite difficult to predict which patients will do well off medical therapy.

Broadcasters Really Know the Key Points to Winning!

Broadcasters Really Know the Key Points to Winning!

Is It Right? Anti-TNF Therapy Does Not Fix IBD-Related Anemia

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A surprising study (Koutroubakis, IE et al. Inflamm Bowel Dis 2015; 21: 1587-93) of prospectively-collected data from 430 patients with inflammatory bowel disease (IBD) showed that the rate of anemia did not change after 1 year in patients treated with anti-tumor necrosis factor (anti-TNF) therapy and oral iron.

The data was derived from 2010-2012 and included 324 patients with Crohn’s disease (51.6% females) with a median age of 41 years.  Anemia was defined as hemoglobin (Hb) <13 g/dL in men and <12 g/dL in women.  Patients with Hb <10 g/dL were considered to have severe anemia. Key findings:

  • Prevalence of anemia in IBD patients treated with anti-TNF was 38.1% at baseline and then 36.6% at 1 year.
  • Severe anemia was identified in 10% at baseline and 9.9% at 1 year.
  • A hematopoietic response with a Hb ≥2 g/dL was observed in 33.6% (n=45 of 134 anemic patients) and 14 (40%) of those with severe anemia.
  • There were 45 new anemic patients at 1 year; 64.4% were nonresponders to anti-TNF treatment.
  • Using multivariate logistic regression analysis, the author noted that use of immunomodulators was associated with an odds ratio of 2.56 of improvement in hemoglobin levels.

The authors state that anemia is the most common extra intestinal manifestation of IBD and remains underappreciated.  Anemia in IBD correlates with the extent of intestinal disease and activity.

Bottomline: “Use of anti-TNF therapy had only a modest effect on patients’ Hb level.”

From related post: IBD Update January 2015 (Part 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.

Related blog post: Microcytic Anemia Review | gutsandgrowth

Sandy Springs, Georgia

Sandy Springs, Georgia

 

How High Can You Go with Adalimumab?

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A recent study (Inflamm Bowel Dis 2015; 21: 1047-53) explored the “Efficacy and Safety of Adalimumab 80 mg Weekly in Luminal Crohn’s Disease.”

Methods: Between 2011-2012, 42 adults with active Crohn’s disease, defined by CDAI > 150 and an objective marker of inflammation, had a dose escalation of adalimumab to 80 mg weekly in prospective multi center study.

  • Objective markers could include CRP >0.5 mg/dL, fecal calprotectin >300 mcg/g, radiologic evidence or endoscopic evidence
  • Only 4 patients were receiving concomitant immunomodulators (& none were started)
  • There were no reports of adalimumab drug levels

Findings: At 14 weeks, 33.3% achieved a clinical remission (CDAI <150) and 23 (54.8%) had a clinical response.  These patients had associated improvements in CRP.  The authors do not report on serious adverse events; all AEs “were consistent with previous experience with this drug.”

Take-home point: The authors do not recommend this approach in routine clinical practice at this time.  However, it would seem that some patients with low adalimumab trough levels (and no anti-drug antibodies) may benefit from high doses of adalimumab

Briefly noted:

Fumery M, et al. JPGN 2015; 60: 744-48.  This retrospective study identified 27 children who received adalimumab (ADA) after infliximab failure.  Though ADA was well-tolerated, 8 (30%) had primary nonresponse to ADA and an additional 5 (26%) had ADA failure by 1 year.

Huang EY, et al. Inflamm Bowel Dis 2015; 21: 963-72.  “Exposure to dexamethasone in mice led to substantial shifts in gut microbiota over a 4-week period.” Take-home point: Corticosteroids may have both direct and indirect impacts on the microbiome as one mechanism of influencing disease response

Related blog posts:

Zoo Atlanta

Zoo Atlanta

Stopping Infliximab –What Happens Next?

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A recent retrospective single-center study (Papmichael K et al. Clin Gastroenterol Hepatol 2015; 13: 1103-10) of 100 patients with Crohn’s disease examined what happens to patients who discontinued infliximab therapy upon clinical remission.  The study used a medical database in Belgium.  The authors defined sustained clinical remission (SCR) as “maintenance of disease remission, without escalation in medical therapy or CD-related surgeries, until the end of the follow-up period, which was a median period of approximately 10 years.” 84 patients continued on immunomodulator therapy.

Key findings:

  • 52 (52%) had SCR.
  • Complete mucosal healing, lower infliximab trough concentrations, and serum positivity for vascular cell adhesion molecule-1 were factors associated with SCR.

Limitations: SCR was based on physician global assessment which may underestimate relapse rates and endoscopic data at the time of infliximab discontinuation was available in only a small subgroup.

Bottomline: In this small study, half of the patients did well clinically for a long time after stopping infliximab (most remained on immunomodulator therapy).  However, given the insidious nature of Crohn’s disease, careful monitoring before and after stopping infliximab is worthwhile.  In addition, other studies have demonstrated higher relapse rates.

Related blog posts:

 

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

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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:

  1. The physician and patient need to agree on the treatment target strategy
  2. The primary target for treatment of CD should be absence of endoscopic ulceration
  3. The use of both clinical symptoms and objective measures of inflammation (endoscopic or imaging) is required in routine clinical practice to guide treatment decisions
  4. 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

Atlanta Zoo, Wreathed Hornbill

 

 

Money Matters in Pediatric Inflammatory Bowel Disease

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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

Cumberland Island

Working on Transition Readiness

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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

Zoo Atlanta