Category Archives: inflammatory bowel disease

IBD Update April 2019

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Briefly noted:

Link (from KT Park’s twitter feed): What New Treatments for Crohn’s disease and Ulcerative Colitis Are Being Developed?

R Wittig et al. JPGN 2019; 68: 244-50. This study from Germany, using health insurance data, identified an overall pediatric inflammatory bowel disease (IBD) incidence of 17.41 per 100,000 in 2012 compared to 13.65/100,000 in 2009.  This is one of the highest incidence rates reported and agrees with other data suggesting increasing rates of IBD in pediatric populations.

B Christensen et al. Clin Gastroenterol Hepatol 2019; 17: 486-93.  This study provides data from 20 patients (CD =9, UC =11) who were treated with a combination of a calcineurin inhibitor and vedolizumab.  The calcineurin inhibitor was used as a ‘bridge’ treatment until the slower acting vedolizumab could be effective. After 52 weeks of treatment, 33% of the CD patients and 45% of the UC patients were in steroid-free clinical remission.  Three serious adverse events associated with calcineurin treatment.

G Pellet et al. Clin Gastroenterol Hepatol 2019; 17: 494-501. Retrospective study of calcineurin inhibitor induction with vedolizumab in 39 patients with refractory ulcerative colitis (36 had failed anti-TNF Rx).  11 patients (28%) required colectomy. week 14 response and remission noted in 56% and 38% respectively. Four serious adverse events were observed.

N Nalagatla et al. Clin Gastroenterol Hepatol 2019; 17: 494-501. In a retrospective study of 213 patients with steroid refractory acute severe ulcerative colitis, the authors did not find lower rates of colectomy in patients who received an accelerated infliximab dosing.  However, they were unable to control for confounding by disease severity. Patients who received an intial dose of 10 mg/kg had a lower colectomy rate than patients who received an initial dose of 5 mg/kg. Colectomy rates for accelerated vs standard infliximab dosing –in-hospital: 9% vs 8% respectively, at 3 months: 20% vs 14% respectively, at 12 months: 28% vs 27% respectively.

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Shenandoah National Park

Getting the Most Out of Vedolizumab

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A recent cross-sectional study (B Al-Bawardy et al. Inflamm Bowel Dis 2019; 25: 580-6) correlated vedolizumab (VDZ) trough drug levels (VDT) and clinical outcomes in 171 patients (62% Crohn’s disease (CD), 31% ulcerative colitis (UC), and 7% indeterminate colitis (IC)).

Key findings:

  • Median VDT was 15.3 microgr/mL.
  • Median VDT was 17.3 microgr/mL for patients with normal CRP compared with 10.7 for patients with high CRP.  This differnece was noted significantly for CD (20.3 vs 10.4) but not for UC.
  • No relationship  between VDT and mucosal healing was noted.
  • Shorter dose intervals and lower BMO resulted in higher VTLs
  • Only 1 patient had detectable antibodies to VDZ

A second systematic review (L Peyrin-Biroulet et al. Clin Gastroenterol Hepatol 2019; 17: 838-46) analyzed data from 10 cohorts who had received vedolizumab.  Most had prior anti-TNF exposure. Key finding: the pooled incidence rates of loss of response were 47.9 per 100 person-years of follow up among patients with CD and 39.8 per 100 person-years of follow up among patinets with UC.  Dose intensification restored response to the drug in 53.8% of secondary non-responders.

My take: While VDZ dose intensification can restore response, the utility of therapeutic drug monitoring is unclear with VDZ therapy.

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CHOP QI: Anemia in IBD Pathway

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A recent article in Gastroenterology & Enoscopy News, “QI Pathway Improves Anemia Management in Pediatric IBD” (also presented at NASPGHAN 2018 -abstract 7, J Breton et al), discusses anemia and provides a link to CHOP QI Pathway for Anemia

This link contains useful information regarding treatment options and links to recommendations on management.  This algorithm suggests using intravenous iron for anemia in all IBD patients with active disease as well as using intravenous iron for those with moderate to severe anemia.  The rationale for parenteral iron in those with active disease is due to two factors:

  1. to overcome the block to intestinal iron absorption induced by hepcidin in the setting of inflammation (making oral iron less effective in active IBD regardless of disease location)
  2. due to data showing  that oral iron may aggravate intestinal inflammation by altering the gut microbiome and increasing intestinal permeability

My take: The CHOP initiative provides some clear cut recommendations.for anemia in IBD.  Parenteral iron is more efficacious in improving anemia; however, the effects of parenteral iron on the microbiome and other potential risks (eg. increased sepsis) are not clear. In my view, more information about outcomes and costs are needed to determine the optimal approach.

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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.

AGA Recommendations for Management of Functional Symptoms in Patients with Inflammatory Bowel Disease

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Full text: AGA Clinical Practice Update on Functional Gastrointestinal Symptoms in Patients With Inflammatory Bowel Disease: Expert Review (JF Columbel et al. Clin Gastroenterol Hepatol 2019; 17: 380-90).

My take: Overall, this article presents a concise review of a tricky problem and appropiriate management.  The algorithm, tables and figures are useful.

Best practice advice 1: A stepwise approach to rule-out ongoing inflammatory activity should be followed in IBD patients with persistent GI symptoms (measurement of fecal calprotectin, endoscopy with biopsy, cross-sectional imaging).

In the report, the authors note that endoscopy and cross-sectional imaging are not needed in all patients; mainly in patients with a suspected flare based on presentation, calprotectin, and blood work.

Best practice advice 2: In those patients with indeterminate fecal calprotectin levels and mild symptoms, clinicians may consider serial calprotectin monitoring to facilitate anticipatory management.

Best practice advice 3: Anatomic abnormalities or structural complications should be considered in patients with obstructive symptoms including abdominal distention, pain, nausea and vomiting, obstipation or constipation.

Best practice advice 4: Alternative pathophysiologic mechanisms should be considered and evaluated (small intestinal bacterial overgrowth, bile acid diarrhea, carbohydrate intolerance, chronic pancreatitis) based on predominant symptom patterns.

Best practice advice 5: A low FODMAP diet may be offered for management of functional GI symptoms in IBD with careful attention to nutritional adequacy.

Best practice advice 6: Psychological therapies (cognitive behavioural therapy, hypnotherapy, mindfulness therapy) should be considered in IBD patients with functional symptoms.

Best practice advice 7: Osmotic and stimulant laxative should be offered to IBD patients with chronic constipation.

Best practice advice 8: Hypomotility agents or bile-acid sequestrants may be used for chronic diarrhea in quiescent IBD.

Best practice advice 9: Antispasmodics, neuropathic-directed agents, and anti-depressants should be used for functional pain in IBD while use of opiates should be avoided.

Best practice advice 10: Probiotics may be considered for treatment of functional symptoms in IBD.

Best practice advice 11: Pelvic floor therapy should be offered to IBD patients with evidence of an underlying defecatory disorder.

Best practice advice 12: Until further evidence is available, fecal microbiota transplant should not be offered for treatment of functional GI symptoms in IBD.

Best practice advice 13: Physical exercise should be encourage in IBD patients with functional GI symptoms.

Best practice advice 14: Until further evidence is available, complementary and alternative therapies should not be routinely offered for functional symptoms in IBD.

Monticello

Origins of Hygiene Hypothesis

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A recent NY Times article explains the background of the ‘hygiene hypothesis’ and how it has held up remarkably well as a likely factor in the rising number of allergic and immune-mediated diseases.

Link: Your Environment is Cleaner. Your Immune System Has Never Been So Unprepared

An excerpt:

The British Journal of Homeopathy, volume 29, published in 1872, included a startlingly prescient observation: “Hay fever is said to be an aristocratic disease, and there can be no doubt that, if it is not almost wholly confined to the upper classes of society, it is rarely, if ever, met with but among the educated.”..

In November 1989, another highly influential paper was published on the subject of hay fever. The paper was short, less than two pages, in BMJ, titled “Hay Fever, Hygiene, and Household Size.”

The author looked at the prevalence of hay fever among 17,414 children born in March 1958. Of 16 variables the scientist explored, he described as “most striking” an association between the likelihood that a child would get hay fever allergy and the number of his or her siblings.

It was an inverse relationship, meaning the more siblings the child had, the less likely it was that he or she would get the allergy…The paper hypothesized that “allergic diseases were prevented by infection in early childhood, transmitted by unhygienic contact with older siblings, or acquired prenatally from a mother infected by contact with her older children…

[To avoid disease] we started washing our hands and took care to avoid certain foods that experience showed could be dangerous or deadly…Particularly in the wealthier areas of the world, we purified our water, and developed plumbing and waste treatment plants; we isolated and killed bacteria and other germs…

What does the immune system do when it’s not properly trained?

It can overreact. It becomes aggrieved by things like dust mites or pollen. It develops what we called allergies, chronic immune system attacks — inflammation — in a way that is counterproductive, irritating, even dangerous.

The percentage of children in the United States with a food allergy rose 50 percent between 1997–1999 and 2009–2011, according to the Centers for Disease Control and Prevention…

There are related trends in inflammatory bowel disease, lupus, rheumatic conditions and, in particular, celiac disease. The last results from the immune’s system overreacting to gluten..

And even doctors have been wrong….They have vastly overprescribed antibiotics. These may be a huge boon to an immune system faced with an otherwise deadly infection. But when used without good reason, the drugs can wipe out healthy microbes in our gut.

My take: With the increasing frequency of many diseases, there has to be environmental influences since our population genetic makeup does not change rapidly. Thus factors like infections, microbiome and exposure to antibiotics are likely important in the changing epidemiology.

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AGA Guidelines on the Management of Mild-to-Moderate Ulcerative Colitis

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A recent AGA Clinical Practice Guideline on the Management of Mild-to-Moderate Ulcerative Colitis was published along with patient guide (pg 766-67), a brief summary (pg 768) (“spotlight”) and technical review.

  • CW Ko et al. Gastroenterol 2019; 156: 748-64.
  • S Singh, JD Feuerstein et al. Gastroenterol 2019; 156: 769-808.

Summary of Recommendations for the medical management of mild-to-moderate ulcerative colitis: (available from AGA Website, my comments in blue & I bolded some of the recommendations):

1.    Use either standard dose mesalamine (2-3 grams/day) or diazo-bonded 5-ASA [Balsalazide or Olsalazine] rather than low dose mesalamine, sulfasalazine or no treatment in patients with extensive mild-moderate UC. (Strong recommendation, moderate quality evidence) [The article notes several potential exceptions for sulfasalazine: doing well on current treatment, prominent arthritic symptoms, or cost]

2.    In patients with extensive or left-sided mild-moderate UC, add rectal mesalamine to oral 5-ASA. (Conditional recommendation, moderate quality evidence)

3.    In patients with mild–moderate UC with suboptimal response to standard-dose mesalamine or diazo-bonded 5-ASA or with moderate disease activity, use high-dose mesalamine (>3 g/d) with rectal mesalamine. (Conditional recommendation, moderate-quality evidence [induction of remission], low-quality evidence [maintenance of remission])

4.    In patients with mild–moderate UC being treated with oral mesalamine, use once-daily dosing rather than multiple times per day dosing. (Conditional recommendation, moderate quality evidence) [In the commentary, the authors note that 4 RCTs have shown no differences when using equivalent dose once a day compared to divided dose and that once a day promotes adherence]

5.    In patients with mild–moderate UC, use standard-dose oral mesalamine or diazo-bonded 5-ASA, rather than budesonide MMX or controlled ileal-release budesonide for induction of remission. (Conditional recommendation, low quality of evidence)

6.    In patients with mild–moderate ulcerative proctosigmoiditis or proctitis, use mesalamine enemas (or suppositories) rather than oral mesalamine. (Conditional recommendation, very-low-quality evidence) [In commentary, the authors note that oral mesalamine can be given based on patient preference, but that for distal disease there is likely a higher response with topical therapy]

7.    In patients with mild–moderate ulcerative proctosigmoiditis who choose rectal therapy over oral therapy, use mesalamine enemas rather than rectal corticosteroids.(Conditional recommendation, moderate-quality evidence)

8.    In patients with mild–moderate ulcerative proctitis who choose rectal therapy over oral therapy, use mesalamine suppositories. (Strong recommendation, moderate-quality evidence)

9.    In patients with mild–moderate ulcerative proctosigmoiditis or proctitis being treated with rectal therapy who are intolerant of or refractory to mesalamine suppositories, use rectal corticosteroid therapy rather than no therapy for induction of remission. (Conditional recommendation, low-quality evidence)

10.    In patients with mild–moderate UC refractory to optimized oral and rectal 5-ASA, regardless of disease extent, add either oral prednisone or budesonide MMX. (Conditional recommendation, low-quality evidence)

11.    In patients with mild–moderate UC , AGA makes no recommendation for use of probiotics. (No recommendation, knowledge gap)

12.    In patients with mild–moderate UC despite 5-ASA therapy, AGA makes no recommendation for use of curcumin. (No recommendation, knowledge gap)

13.    In patients with mild–moderate UC without Clostridium difficile infection, AGA recommends fecal microbiota transplantation be performed only in the context of a clinical trial. (No recommendation for treatment of ulcerative colitis, knowledge gap)

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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

Joshua Tree National Park, Hike to Warren Peak

A Role for Thiopurine Therapy

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In high school, the usual advice on multiple choice questions was to avoid picking “always” and “never” on multiple choice questions.

A recent commentary (KH de Boer et al.”Thiopurine Therapy in Inflammatory Bowel Diseases: Making New Friends Should Not Mean Losing Old Ones”Gastroenterol 2019; 156: 11-4) makes the point that “never” is probably the wrong answer with regard to thiopurine usage.

Key points:

  • “Thiopurine therapy has proven its value in maintenance of remission, decreased need for surgery, lowered colorectal cancer risk, less phenotypic disease progression, and synergistic effects when used with infliximab therapy, including increased biologic drug levels and less antibody formation.”
  • “Notwithstanding the extensive experience by many physicians, the clinical use of conventional immunosuppressive therapies has been questioned in recent years.”
  • “In this issue of Gastroenterology, Hanauer et al share their expert opinion on the evolving use of thiopurines and methotrexate in daily practice. In their literature review, the importance of assessing the risks (infections and cancer risk) and benefits (maintenance of remission) of thiopurine therapy is highlighted”
  • Lymphoma risk: “The recent nationwide cohort study based on French National Health Insurance databases is illustrative. Including 189,289 patients, it was demonstrated that both thiopurine (adjusted hazard ratio of 2.6) and anti-TNF monotherapy (adjusted hazard ratio of 2.4) were associated with a similar small but statistically significant increased risk of lymphoma. Furthermore, combination therapy of thiopurine and anti-TNF was associated with a higher chance of developing a lymphoma (adjusted hazard ratio of 6.1).”
  • “The individual absolute risk remains low, especially in patients without additional risk factors such as a young age in male patients and negative Epstein-Barr virus serology.”

The author’s conclusion: “The thiopurines are not perfect regarding both efficacy and toxicity, but in recent years they may have been portrayed in a worse light than they deserved. No doubt, the thiopurines will be surpassed eventually by newer safe and economical (oral) therapies, but it is too early to discard these old friends.”

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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.

Monticello

 

IBD Update March 2019

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Briefly noted:

W El-Matary et al. Inflamm Bowel Dis 2019; 25: 150-5. This retrospective study of 667 children with Crohn’s disease who were prospectively enrolled in an inception study found that 85 (12.7%) had fistulizing perianal disease. The mean infliximab (pre-fourth dose) was 12.7 mcg/mL in responders compared with 5.4 mcg/mL in the active disease group.  My take: Higher trough levels are desirable in those with fistulizing disease.

LJT Smits et al. Inflamm Bowel Dis 2019; 25: 172-9. In a  prospective cohort with 83 patients with IBD (57 with Crohn’s disease) with at least 2 years of followup, 66% of IBD patients continued CT-P13 after switching from Remicade; two patients developed anti-drug antibodies.  The absolute numbers suggest no adverse impact of a single switch to the biosimilar product.

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A Tinsley et al. Inflamm Bowel Dis 2019; 25: 369-76. This study documents the increased risk of influenza and increased influenza complications among IBD patients based on a database cohort of 140,480 patients (with and without IBD). The risk of hospitalization was 5.4% in patients with IBD compared with 1.85% in non-IBD patients.

Related blog post: Almost Everybody Needs Flu Shot -IBD Patients at Higher Risk

YY Xu et al. Inflamm Bowel Dis 2019; 25: 261-9. This meta-analysis included 18 nonrandomized controlled trial studies with 1407 patients who received preoperative infliximab and 4589 patients.  The authors showed that preoperative infliximab was not associated with any statistically significant differences for the 2 groups for any complications, reoperation, readmission or mortality.

CN Bernstein et al. Inflamm Bowel Dis 2019; 25: 360-8. This study, using population-based administrative health data (Manitoba) found increased burden of psychiatric disorders in IBD: compared with controls the incidence rate ratio for depression was 1.58, for anxiety 1.39, for bipolar disorder 1.82, and for schizophrenia 1.64.

Related blog post: #NASPGHAN17 Psychosocial Problems in Adolescents with IBD

View from Ryan Mountain, Joshua Tree National Park

Pushing the Boundaries on Dietary Therapy for Crohn’s Disease (CD-TREAT)

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A recent study (available online in advance of publication) (V Svolos et al. Gastroenterology https://doi.org/10.1053/j.gastro.2018.12.002) examines the feasibility and science of modifying a diet to mimic exclusive enteral nutrition.

Full text accepted manuscript (from ScienceDirect/Gastroenterology website): Treatment of Active Crohn’s Disease With an Ordinary Food-based Diet That Replicates Exclusive Enteral Nutrition (PDF 135 pages)

Background: The authors note that exclusive enteral nutrition (EEN) is the only established dietary treatment for Crohn’s disease.

This complicated study had three main parts:

  1. Examining the effects of their CD-TREAT diet compared to EEN in 25 healthy adults in a randomized control trial
  2. Animal experiments (rat model) to explore the anti-inflammatory effect of CD-TREAT
  3. Pilot open-label study of 5 children with CD-TREAT diet (8-weeks)

In the first part of this study, the authors modeled a diet based on the components of the formula modulen. This diet continued to exclude gluten, lactose, and alcohol and tried matching other components (macronutrients, vitamins, minerals, fiber).  In place of maltodextrin (the commonest carbohydrate in EEN feeds), the authors substituted foods high in starch and low in fiber.  Also, the authors decreased carbohydrates in CD-TREAT (particularly complex carbohydrates) in favor of protein.  This diet was given to 25 healthy adults.

Key findings:

  • CD-TREAT induced similar effects to EEN on fecal microbiome, composition,metabolome, mean total sulfide, pH, and short-chain fatty acids (SCFA)

In the second part of this study, in the rat model, CD-TREAT and EEN produced similar changes in bacterial load, short-chain fatty acids, microbiome, and in ileitis severity.

In the third part of the study with 5 children, after 8 weeks —Key findings:

  • 4 (80%) had a clinical response
  • 3 (60%) entered a clinical remission with concurrent reductions in calprotectin (mean decrease of 918 +/- 555 mg/kg)

The CD-TREAT diet appears to affect the taxon abundance of many species of the microbiome in a manner similar to EEN therapy.  The authors noted that CD-TREAT also changed the abundance of genera belonging to Actinobacteria, Bacteroides, and Firmicutes.

Unlike EEN, the CD-TREAT diet is subject to more variable individual intakes; it is not identical in all individuals.

My take: The mechanism of action of EEN therapy remains poorly understood.  The CD-TREAT diet, which is far more diverse than EEN, appears to replicate many of the effects of EEN: “the microbial composition, fecal pH, SCFA, total sulfide, fecal bacterial load and fecal metabolome significantly changed in the same direction for both diets.” A larger clinical study is needed to confirm the effectiveness of the CD=TREAT diet.

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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

Joshua Tree National Park