IBD Update March 2019

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.

Related blog posts:

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 alInflamm 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)

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.

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

Joshua Tree National Park

 

 

Oral Antibiotics For Refractory Inflammatory Bowel Disease

A recent retrospective study (J Breton et al. Inflamm Bowel Dis 2019; https://doi.org/10.1093/ibd/izz006) currently available online in advance of publication is likely to influence current practice in children with refractory inflammatory bowel disease (IBD). Thanks to Ben Gold for sharing this reference.

Link to abstract: Efficacy of Combination Antibiotic Therapy for Refractory Pediatric Inflammatory Bowel Disease

Here are some of the details:

  • There were 63 patients who met inclusion criteria.
  • 27 (43%) with colonic (n=18) or ileocolonic (n=9) Crohn’s disease (CD)
  • 23 (36.5%) with ulcerative colitis
  • 13 (21% classified with IBD-U.
  • 34 (54%) were corticosteroid-refractory or dependent
  • 62/63 with previous or present loss of response or primary nonresponse to anti-tumor necrosis factor (anti-TNF) therapy
  • 48 (76.2%) were receiving anti-TNF therapy at time of antibiotic initiation
  • Of the 37 with available anti-TNF trough, 23 (62.%) were considered therapeutic  (IFX ≥5, or ADA ≥7.5)
  • Medical refractoriness “was defined by corticosteroid resistance, as shown by no or partial response to more than 7 days of hgih-dose corticosteroids (≥ 1 mg/kg/day prednisone equivalent) or primary nonresponse or loss of response to a biologic”

Antibiotic regimens: A=Amoxicillin, D =Doxycycline, M =Metronidazole, C= Ciprofloxacin, V= vancomycin. Antibiotic therapy was based on previous study which used ADM. A =50 mg/kg/day divided TID to max 500 mg/dose; D =4 mg/kg/day divided BID to max 100 mg/dose; M 15 mg/kg/day divided TID to max of 250 mg/dose. In children <8 yrs, C =20 mg/kg/day divided BID to max of 250 mg.  Vancomycin 125 mg/dose QID in <8 y and 250 mg/dose QID in ≥8 yo could be added as a 4th drug and Gentamicin cold be substituted in those with a drug allergy.

  • 45% ADM
  • 8% ADMV
  • 8% CMV
  • 8% AMV
  • 8% ACM
  • 6% ADV
  • 17% Other

Improvement with Regimen:

  • Median PUCAI dropped from 55 at baseline to 10 (P<0.0001) by 3 weeks ± 1 week after antibiotic initiation
  • 40 (63.5%) experienced a clinical response with a change in PUCAI of ≥20 points
  • 25 (39.7%) entered clinical remission, including 6 who achieved corticosteroid-free remission
  • Other markers of improvement: increased median hemoglobin (10.7–>11.6), Improved median CRP (1.1 –> 0), improved median ESR (38 –>21)
  • Use of doxycycline (OR 0.25) and high PUCAI ≥ 65 (OR 0.2) were both associated with a much lower odds of clinical remission

Outcomes:

  • Among the 25 entering clinical remission, 13 (65%) had successful rescue of current anti-TNF therapy, 6 were transitioned to another biologic (vedolizumab or ustekinumab)
  • No serious adverse drug-related toxicities were evident.  No cases of Clostridium difficile. One patient had a vaginal yeast infection

Implications:

  • The authors interpret their findings as indicating that antibiotics could serve as an effective rescue therapy in some and potentially rescue anti-TNF therapy in patients with refractory disease.
  • The discussion speculates that improvement is related to microbial modulation as dysbiosis “may play a causative role in perpetuating inflammation”
  • In those placed on antibiotics, the authors state that “clinical response should be assessed frequently and therapy discontinued if no improvement is documented within 1 week”

Safety and Antibiotic Choice:

  • While there were no safety signals evident in this study over 1 year, the long-term risks of using antibiotics is uncertain. For example, with ciprofloxacin, a fluoroquinolone, there is a well-recognized risk of permanent damage to tendons/joints (link to FDA update) and fluoroquniolones increase the risk of aortic tear/rupture.  Because aortic rupture is rare, this increased risk represents a very low absolute risk.
  • The authors indicate that doxycycline, used in 45%, had a much lower response rate.  This makes the choice of antibiotic regimen uncertain –none of the other regimens were used in more than 8%.
  • Given the retrospective nature, it is unclear whether some of the improvement could be related to additional time for the adjunctive/non-antibiotic treatments to work. Though, the authors found that the effect of antibiotics seemed to be independent of therapy optimization.

My take: This is an important study for children with limited treatment options in the setting of refractory disease and may act to salvage current anti-TNF treatment or facilitate a bridge to an alternative treatment.  Though, the optimal antibiotic regimen in this setting is unclear.

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.

Heart-shaped Cactus, Joshua Tree National Park

Joshua Tree National Park. This image selected since this article discusses a ‘bridge’ therapy,

 

Toronto Consensus for Perianal Fistulizing Crohn’s Disease

A recent consensus report (AH Steinhart, R Panaccione et al. Inflamm Bowel Dis 2019; 1-13) provides updated guidelines for the management of perianal fistulizing Crohn’s disease (CD).

As an aside, the article starts off with an extremely lengthy disclosure (of financial interests) –more than 30 lines of extremely small font!

The scope of the problem:

  • About 21% of CD patients have developed perianal fistulizing disease by 10 yrs and 26% after 20 years.
  • This complication leads to significant morbidity/reduced quality of life and about 70% require surgical treatment during long-term followup.

The substance of the article are summarized in Table 4 and Figure 1. The recommendations all are considered to be based on either low quality of evidence or very low quality of evidence:

  • In those with active fistulizing disease, the authors recommend imaging (EUS or MRI)
  • In those with evidence of complicated fistulizing disease, “we suggest surgical consultation.”
  • In those with active fistulizing CD, “we suggest the use of antibiotic therapy for initial management.”
  • In those with active fistulizing CD, “we recommend the use of anti-TNF therapy” for induction and maintenance.
  • In those with active fistulizing CD, “when starting anti-TNF therapy, we suggest it be combined with thiopurine or methotrexate over monotherapy to optimize pharmacokinetic parameters.”
  • In those with active fistulizing CD, surgical management is recommended in those when there is an inadequate response to medical management.

Some additional pointers:

  • Early surgical consultation is recommended in setting of suspected clinical abscess (eg. pain, fever, leukocytosis).
  • The authors’ algorithm suggests that if early surgical intervention is not required, then patients should first receive antibiotics for initial symptom control, followed by imaging, and, if uncomplicated fistulizing disease on imaging, followed by anti-TNF therapy (with either MTX or thiopurine).  If complicated fistulizing disease, then surgical intervention may be needed prior to institution of anti-TNF therapy.
  • “The rate of fistula healing was 43% with medical therapy alone and 53% with combination surgical and medical therapy” based on a systematic review of 8 cohort studies.

My take: This article helps simplify/streamline the approach to this troubling complication.

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.

 

Shoshone, California

Can Therapeutic Drug Monitoring with Monotherapy Achieve Similar Results as Combination Therapy for IBD?

A recent retrospective study (S Lega et al. Inflamm Bowel Dis 2019; 25: 134-41) suggests that proactive therapeutic drug monitoring (pTDM) with infliximab (IFX) helps achieve similar outcomes as combination therapy (with immunomodulator) in patients with inflammatory bowel disease.

Before reviewing the key findings, it is important to emphasize a few crucial limitations/methods:

  • The study enrolled 83 patients; only 16 received were in the monotherapy pTDM group.
  • This was a retrospective study
  • The authors utilized TDM at week 10.  If the IFX level was <20 mcg/mL, the dose and frequency of infliximab were both adjusted. If the level was between 20 & 25, either the frequency was adjusted or no adjustment, and if the level was >25, then no adjustment in dosing was performed.

Key findings:

  • The frequency of infliximab discontinuation with mono therapy in those with pTDM was lower than in those with ‘standard of care’ TDM (P=0.04) but did not differ from patients receiving combination therapy
  • Overall 9 of the 83 patients (11%) discontinued IFX during the 1-year study

In the discussion, the authors suggest that week 14 TDM may be suboptimal as this is the first time patients have an 8-week interval.

My take: The jury is out with regard to whether pTDM can negate the need for combination therapy  –a prospective trial is needed; however, the idea of getting TDM a bit earlier is intriguing, particularly as it has been shown that a high percentage of pediatric patients are receiving an insufficient dose of infliximab (Is Standard Infliximab Dose Tool Low in Pediatrics?)

Key words: 10 weeks, therapeutic drug monitoring, infliximab, trough

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.

View from Artist’s Drive, Death Valley

Management of Acute Severe Colitis

A recent review (KG Whatley, MJ Rosen. Inflamm Bowel Dis 2019; 25: 56-66) succinctly summarizes the contemporary medical management of acute severe ulcerative colitis (ASUC).

Figure 1 provides a useful initial checklist which includes the following:

  • PUCAI score
  • Labs/Imaging: CBC/d, CMP, CRP/ESR, Stool studies (culture/C diff), AXR
  • Pre-salvage labs: TB screen, Hep B serology, VZV serology if needing anit-TNF, TPMT if contemplating thiopurine, lipids if contemplating calcineurin inhibitor
  • Endoscopy: Consider Flex Sig (unsedated) with tissue for CMV PCR if not responding to 3 days of IV steroids
  • Thromboembolism prophylaxis: Low molecular weight heparin (adults, & high-risk pediatric patients), pneumatic compression (low-risk pediatric)
  • Nutrition plan
  • Corticosteroids: methylprednisolone 1-15. mg/kg (to max of 40-60 mg daily)

Each of these recommendations is discussed. For the flex sig recommendation, the authors note that a “full colonoscopy is not recommended due to risk of perforation.” With regard to CMV, the authors acknowledge the low quality of evidence to support antiviral treatment of CMV in this setting.  In addition, the authors suggest PCP prophylaxis in those who receive triple immunosuppression or in those receiving calcineurin inhibitors.

Figure 2 provides a handy algorithm for infliximab salvage therapy in the setting of ASUC:

  • If salvage therapy with infliximab is indicated (day 3-5 of IV steroids), the authors recommend 10 mg/kg dosing.  If there is no response after 3-5 days, repeat dosing is recommended.  If there is no response after an additional 3-5 days, colectomy is recommended.
  • If there is a response to infliximab, the algorithm recommends outpatient management. At time of the 3rd dose (week 5-6), the authors obtain an IFX level.  In those with a level <15, then dosing at 4 week maintenance is recommended; whereas in those 15 and above, every 8 week maintenance is recommended.

The authors discuss some potential emerging treatments. Recommendations from the authors with regard to surgery:

  • Most patients are best served with a subtotal colectomy/end ileostomy in preparation for future ileal pouch anal anastomosis
  • “Surgery should not be delayed to enhance nutrition or taper steroids.”

My take: This article summarizes current approaches with emphasis on not waiting a long time for salvage therapies and using early therapeutic drug monitoring to assist in dosing frequency.

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.

Death Valley