Category Archives: inflammatory bowel disease

IBD References 10/13

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Recent useful references:

Inflamm Bowel Dis 2013; 19: 2490-2500.  “Endemic Fungal Infections in Inflammatory Bowel Disease Associated with Anti-TNF Antibody Therapy”

  • Reviews histoplasmosis, blastomycosis, & coccidioidomycosis. Provides endemic maps (which are available at CDC website), diagnostic tips, and treatment recommendations.  Of these three infections, blastomycosis is endemic in Northern Georgia.
  • Histoplasmosis can be diagnosed with urinary antigen, Blastomycosis is most commonly diagnosed with sputum cultures or bronchial washings for cytology, and coccidioidomycosis can be identified with serology (Coccidioides immittis)
  • Generally a good idea to get a chest radiograph in patients with respiratory symptoms, fever, chills, myalgias, and headaches.
  • CDC Fact Sheet – Centers for Disease Control and Prevention  Map for several endemic fungal diseases, including histoplasmosis and blastomycosis.
  • CDC Features – Valley Fever: Awareness is Key Map for endemic coccidiomycosis.

Inflamm Bowel Dis 2013; 19: 2457-2463. “Efficacy and Safety of Natalizumab in Crohn’s Disease Patients Treated at 6 Boston Academic Hospitals”

  • 44 of 64 with adequate evaluation had either a partial or complete clinical response.  In this select group of complicated patients, about one-third had clinical improvement for more than a year.
  • No cases of PML noted in this cohort.

Inflamm Bowel Dis 2013; 19: 2433-2439. “Serum IL-17A in Newly Diagnosed Treatment-Naive Patients with Ulcerative Colitis Reflects Clinical Disease Severity and Predicts the Course of Disease”

  • Mucosal mRNA expression of IL-17A was 99.8 times higher in ulcerative colitis patients compared to controls.
  • Serum IL-17A correlated with clinical disease severity and was a marker for disease course over the following 3 years.

Inflamm Bowel Dis 2013; 19: 2440-2443. “Assessment of the Relationship Between Quality of Sleep and Disease Activity in Inflammatory Bowel Disease Patients”

  • Data found an association between poor sleep quality and disease activity.  Furthermore, patients in clinical remission with abnormal sleep have a high likelihood of subclinical disease activity (another question for the EPIC smartform?).

Inflamm Bowel Dis 2013; 19: 2423-2432. “Nationwide Temporal Trends in Incidence of Hospitalization and Surgical Intestinal Resection in Pediatric Inflammatory Bowel Diseases in the United States from 1997-2009”

  • Annual percent increase (API) of 2.1% noted in incidence of intestinal resection for Crohn’s disease.  Stable colectomy rate for ulcerative colitis during this period.
  • Annual incidence of hospitalization was 5.7 per 100,000 for Crohn’s and 3.5 per 100,000 for ulcerative colitis; there was a significant increases during study period: 3.8% API for Crohn’s and 4.5% for ulcerative colitis.

Crohn’s Research: Going to Pot

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A recent pilot study using Cannabis for Crohn’s disease is certain to attract a lot of attention (Clin Gastroenterol Hepatol 2013; 11: 1276-80).  The side effects are definitely less frightening than many of the accepted treatments.

Background: Cannabis has a long record of medicinal uses; it contains more than 60 different compounds, though Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are thought to be the most active.  Cannabis has known antiinflammatory properties and has been shown to reduce colitis in a mouse model.

Study design/characteristics: 21 of 51 screened patients participated; these patients had active Crohn’s disease despite thiopurines in 20  or 21 and anti-tumor necrosis factor (TNF) therapy in 18.  These 21 patients were enrolled in a double-blind, placebo-controlled study.  The average age in the cannabis group was 46 years compared with 37 in the placebo group.  Both groups received cigarettes twice daily; the cannabis cigarettes had 115 mg of THC whereas the placebo group had cannabis flowers in which the THC had been extracted.  Though this was a double-blind study and efforts were made to mask the psychotropic effects by recruiting patients naive to cannabis, nevertheless, by the end of the study most of the patients knew whether they were in the active group or the placebo group.

Results:

  • Cannabis group had a 45% remission rate (5 of 11) with a CDAI of ≤150; the placebo group had a 10% remission rate.  This did not achieve statistical significance.
  • The response rate (CDAI drop of >100) was noted in 90% (10 of 11) of cannabis group compared with 40% in the placebo group.
  • The mean CDAI reduction was 177 in the study group compared with 66 in the placebo group (P= .005).
  • There were no significant laboratory changes (eg. Hgb, CRP, LFTs, kidney function).
  • No significant side effects were noted.  The study group reported less pain, improved appetite, and better satisfaction with their treatment.

In their discussion, the authors note that this is a small study.  They chose the smoking route with THC-rich cannabis to achieve higher blood levels, but note that oral dosing may be effective.  The 8-week duration of the study and lack of more objective markers of response precludes firm conclusions.

Take-home message: Cannabis should be studied further for its potential role in controlling inflammation.  This study’s timing will increase the broader interest in medical marijuana applications.

Related links:

Pediatric Consensus Statement: Perianal Crohn Disease

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A recent report provides a useful reference for the often difficult care of pediatric perianal Crohn disease (JPGN 2013; 57: 401-412).

The statement reviews the background, etiology, presentation and classification systems. Most helpful are Figures 2 & 3.

Figure 2 provides an algorithm for assessment and treatment of perianal fistula.

  1. History/Physical (including rectal exam for stricture) along with colonoscopy
  2. Next either exam under anesthesia (with or without endoscopic ultrasound) or MRI
  3. Main treatments:
  • consider antibiotics, anti-TNF, and immunomodulators
  • in some cases a noncutting seton or fistulotomy will be needed
  • consider advancement flap in rectovaginal fistulae

Figure 3 provides an algorithm for assessment and treatment of perianal abscess.

  1. History/Physical (including rectal exam for stricture) along with colonoscopy
  2. Next either exam under anesthesia (with or without endoscopic ultrasound) or MRI
  3. Main treatments:
  • Incision and drainage
  • Noncutting seton if perianal fistula
  • Antibiotics
  • Treatment of intestinal disease

After outlining these algorithms, the report details the treatments.  Almost all treatments that are effective or questionable for Crohn’s disease are discussed.  The report reiterates that ‘corticosteroids must be used with caution in treatment of perianal fistula; studies have shown worse fistula outcomes for steroid-treated patients.

With regard to noncutting setons, the authors note that they do not prevent treatment with biologic agents and help prevent abscess formation.  They “usually deteriorate and fall out on their own in about 1 year.”  Medical therapy often allows for seton removal.

Ostomy diversion can be helpful in patients with severe perianal disease; however, “the risk of the ostomy becoming permanent is significant.”

Rectal strictures are typically dilated with multiple sessions with general anesthesia.  The goal is at least 18 mm in younger patients and at least 24 mm in adolescents.

Related blog post:

Previous references:

  • -Clin Gastro & Hep 2010; 8: 13.  Another algorithm.  For simple fistula, Rx w abx & medical (thiopurine or Remicade).  If not better, fistulotomy, &/or Rx as complex fistula.  For complex fistula, seton placement, abx, anti-TNF.  If not better, consider tacrolimus or proctectomy.
  • -JPGN 2010; 50: 99.  Perianal dz in young children may be due to autoimmune neutropenia.
  • -Clin Gastro & Hep 2009; 7: 1037.  MRI study of choice for perianal fistulas.  Algorithm: If superficial fistula, Rx c fistulotomy & Abx If deeper, noncutting seton c Abx, 6-MP +/- infliximab; if not effective, try tacrolimus; if not effective, surgery
  • -Ann Intern Med 2001; 135: 906-918.
  • -IBD 2008; 14: 1236.  Anal skin tag description
  •  -JPGN 2005; 41: 667.  Discusses several cases of highly destructive perianal dz. -Gastro 2003; 125: 1503-1507, 1508-1530.  Technical review.
  • -Gastro 2003; 125: 291.  Bourne test to detect occult bladder fistula.  Following nondiagnostic barium enema, urine can be collected, centrifuged,  and xrayed to determine if there is  a connection.

 

Practical Advice on Enteral Nutrition

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In a previous post (NASPGHAN: Enteral Nutrition for Crohn’s Remission | gutsandgrowth), this blog provided a link to NASPGHAN information on enteral nutrition. Having reviewed this information further, I wanted to post some more information about one of the references which offers a terrific professional-quality 32 minute video (from IWK Health Centre in Canada).  This You-tube video on tube feeds provides interviews mostly from kids/family members along with some input by physicians and nutritionists; it is a fabulous resource for families weighing the option of tube feeds.  Around minute 23, a teen walks through the process of NG placement including advice on taping.  Around minute 31, a number of written tips are given like cleaning tubing with vinegar (& then rinsing with water).  According to the website there were only 275 views when I had clicked on this.  If that is accurate, it is a real shame.

Here’s the link:

Crohn’s Survival Guide: The Real Deal on Tube Feeds – YouTube

Other information from the NASPGHAN handout (which offers CME) in the link above:

  • Duration of enteral nutrition to induce remission: 8-12 weeks.  Enteral nutrition can induce remission in about 80% and is similar in effectiveness as corticosteroids.
  • Caloric needs: typically 120% of recommended daily allowance
  • Other foods? usually allowed water or clears like sodas, soup broth, and popsicles.  In some studies, up to 10% of energy intake as various other foods have been allowed; however, this creates a lot of difficulty monitoring.
  • Maintenance strategies: partial enteral nutrition (nighttime feeds only) can reduce recurrence.  More typical approaches included maintenance medication for long-term treatment, or enteral therapy in combination with maintenance medical therapy.  Alternatively, maintenance treatment can be instituted with cycles of 1 month exclusive enteral nutrition every few months.
  • What type of formula for NG tube? most commonly polymeric formulas
  • Refeeding syndrome: in children with severe malnutrition institution of tube feedings should be instituted more slowly over several days with electrolyte monitoring.

Anti-TNF therapy for IBD

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In the same issue as the vedolizumab phase 3 studies, there is a succinct review of tumor necrosis antagonist therapy (anti-TNF) therapy for IBD (NEJM 2103; 369: 754-62).

Useful points about IBD:

  • Prevalence of ulcerative colitis (UC) and Crohn’s disease (CD) in North America: 780,000 and 630,00 respectively
  • In first 10 years of CD, cumulative rate of surgery is 40-55%.
  • In first 20 years of UC, rate of colectomy is ~15%.
  • “Recent meta-analysis do not indicate that this drug (mesalamine) has any clinically relevant efficacy in patients with” Crohn’s disease.

Anti-TNF agents:

  • Agents for IBD include infliximab, adalimumab, certolizumab pegol, and golimumab.
  • No head-to-head comparisons have been studied, though the “clinical trials suggest similar efficacy among the available drugs.”
  • Newest approved anti-TNF is golimumab which is administered subcutaneously at a dose of 200 mg at week 0, followed by 100 mg at week 2 and then 100 mg every 4 weeks.
  • A “considerable number of patients with Crohn’s disease (10-40%, depending on selection criteria) do not have a clinically relevant response to currently available TNF inhibitors (primary treatment failure) and among patients with ulcerative colitis, this proportion may be as high as 50%.”
  • “In addition, only about one third to one half of patients with Crohn’s disease have a complete remission, and about two thirds of patients do not have a response that is sustained during 12 months of continuous treatment (secondary treatment failure).”  Many of these patients will respond to dose escalation.
  • The “annual projected cost of each biologic agent for a 70-kg patient with inflammatory bowel disease is approximately $19,000 in the first year and $15,000 in subsequent years.”  These figures exclude the costs associated with administration and dose escalation.

Areas of uncertainty according to the authors:

  • “The value of concomitant treatment with immunosuppressive agents and TNF inhibitors has been debated intensely.”  Combination therapy results in superior efficacy and lower rates of antibodies to anti-TNF agents.  However, “the benefit of combined treatment for more than 12 months is uncertain.”
  • “There are no data to confirm that it (top-down treatment) is actually superior to conventional step-up therapy in terms of disease progression”

Related blog links:

Coming Soon to a Pharmacy Near You (part 1)…

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Vedolizumab!

Two articles indicate that Vedolizumab will be an important agent for treating Ulcerative Colitis (UC).  The first article, NEJM 2013; 369: 699-710, describes two integrated studies (GEMINI 1 studies) in the use of this agent for induction and then for maintenance therapy of UC.

Background: Vedolizumab is a gut-selective blocker of lymphocyte trafficking (see previous post: Vedolizumab -another new IBD treatment | gutsandgrowth).  It is similar to natalizumab which was approved in 2008 for Crohn’s disease.  In phase 3 trials, natalizumab was demonstrated a response in 48% of patients with moderate-to-severe disease, but its large-scale use has been precluded by the potential for reactivation of the John Cunningham (JC) virus and progressive multifocal leukoencephalopathy (PML).

Study design: this study was a phase 3, randomized, double-blind, placebo-controlled study conducted at 211 medical centers in 34 countries from 2008-2012.  At baseline some of the assessments included blood tests, stool for enteric pathogens, chest radiography, stool calprotectin, QuantiFERON-TB Gold assay and sigmoidoscopy.  Intravenous vedolizumab was administered at a dose of 300 mg or placebo at days 1 and 15 during induction; also patients were stratified for glucocorticosteroids, use of immunosuppressives and prior use of TNF antagonists.  In total, 746 patients received vedolizumab and 149 received placebo.

Some of the baseline patient characteristics:

  • Mean age: 40.3 yrs
  • Median prednisone dose: 20 mg
  • Average fecal calprotectin: 899 mcg/gr.
  • Site of disease: 37% pancolitis, 13% rectum/sigmoid only, 37.9% left-sided disease, 12.2% disease proximal to splenic flexure.
  • Prior anti-TNF therapy: 48.2%

Results:

  • Induction: at week 6, 47.1% of vedolizumab and 25.5% of placebo-treated patients had a clinical response
  • Maintenance: at week 52, of patients randomly assigned to continue receiving vedolizumab, 44.8% every 4 weeks, 41.8% every 8 weeks were in clinical remission compared with 15.9% receiving placebo
  • Glucocorticoid-free remission at 52 weeks in 45.2% of patients receiving vedolizumab every 4 weeks, 31.4% receiving every 8 week treatment, and 13.9% of placebo-treated patients.
  • Figure 1 details important changes in Partial Mayo score, IBDQ score, Fecal calprotectin, and prednisone dose changes.  With regard to fecal calprotectin, at week 6 the median calprotectin level had dropped approximately 70%.  Smaller decreases were noted in patients continuing vedolizumab at week 52.
  • Safety: “no important differences” according to the authors between vedolizumab and placebo.  Specifically, there were no cases of PML; however, routine JC virus testing was not performed in this study.  Infusion reactions were seen in three cases (two with detectable antibody). a mild increase in nasopharyngitis was noted.
  • Cancer: 1.1% of placebo-treated patients developed a malignancy (1 colon cancer, 1 transitional-cell carcinoma, 1 squamous-cell carcinomas of skin) and 0.2% of vedolizumab (1 colon cancer)
  • Drug levels: mean vedolizumab concentrations at every 4 week dosing: 38.3 mcg/mL and at every 8 week dosing: 11.2 mcg/mL
  • Antibodies: 3.7% had samples that were positive for anti-vedolizumab antibodies at any time.  1% developed persistent antibody positivity.

Bottom-line: This large study shows that vedolizumab is effective in a large number of patients with UC, many who were refractory to other treatments, including anti-TNF agents.

Related blog posts:

Injection Flu Vaccine Safe for Patients with IBD

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A recent article from Pediatrics, published online May 6, 2013
(doi: 10.1542/peds.2012-3567), confirms that influenza vaccination (injection/inactivated vaccine) is safe in patients with inflammatory bowel disease:

“Safety and Utilization of Influenza Immunization in Children With Inflammatory Bowel Disease”  Eric I. Benchimol, Steven Hawken, Jeffrey C. Kwong, and Kumanan Wilson

Abstract:

OBJECTIVE: Influenza immunization is recommended for children with IBD, however safety concerns may limit uptake. This study assessed whether immunization was associated with adverse events in IBD patients using a population-based database of children with IBD.

METHODS: All children <19 years diagnosed with IBD in Ontario, Canada between 1999–2009 were identified using health administrative data, and matched to non-IBD controls. Self-controlled case series (SCCS) analyses determined health services event rates (outpatient visits, hospitalizations and emergency visits) in any 2-week risk period to 180 days post-immunization compared to a no-risk control period. Relative incidence (RI) was calculated for overall and IBD-related events and rates were compared between IBD cases and controls using relative incidence ratios (RIR).

RESULTS: 4916 IBD patients were matched to 21,686 controls. IBD patients were more likely to have received immunization than controls (25.3% vs. 13.2%, P < .001). No increased event rates existed in IBD cases during risk periods (pooled RI 0.95, 95% CI 0.84–1.07), including hospitalizations and emergency visits. There was a slightly higher event rate in IBD cases versus controls for days 3–14 (RIR 1.60, 95% CI 1.05–2.44, P = .03). IBD-related visit rates were lower in risk periods compared to control period (pooled RI 0.81, 95% CI 0.68–0.96).

CONCLUSIONS: There was no increase in health services use in the post-vaccine risk period in IBD patients, and there was evidence for a protective effect of influenza immunization against IBD-related health services use. Influenza immunization is safe in children with IBD and should be encouraged to improve poor coverage rates.

Understanding IBD Therapy Risks -A Good Link

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This link was posted on the GI Bulletin Board.  It is a 6 minute internet video overview of the treatments for IBD -it would be a useful resource for most families:

http://www.youandibd.com/en/understanding-ibd/understanding-the-risks-and-benefits-of-ibd-therapies.html

Some related blog posts:

TNF Antagonists and Psoriasis

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Using data from the adverse event reporting system (AERS) from the FDA, the authors of a recent report identified a large number of psoriasis rashes which developed among patients receiving tumor necrosis factor α (TNF) antagonists (Inflamm Bowel Dis 2013; 19: 1164-72).

From more than 13 million AERS reports (2004-2011), a total of 5432 reports of psoriasis were noted: 1789 for infliximab, 3475 for adalimumab, and 168 for certolizumab compared with 88 for a control group which consisted of the following medications: propranolol, melamine, and lithium. While the absolute number for certolizumab is lower, the relative risk is similar to infliximab when adjusted for frequency of usage.

The AERS database relies on voluntary reporting and there are numerous reporting biases.  Given that AERS captures only a fraction of all true adverse events, the authors extrapolate that more 15,000 psoriasisiform adverse events occur each.  They note that these reactions typically occur in individuals without a personal or family history of psoriasis.  The onset is variable, but typically occurs 9-11 months after initiating therapy.

Additional references:

  • -IBD 2011; 17: 2512.  n=50.  Skin reactions with adalimumab.  62% of pts develop skin reactions: eczema, acne-like dermatitis, psoriasis-like (6 of 50).  Adalimumab d/c’d in 22%.
  • -JPGN 2010; 52: 230. 6 of 73 pts (8%) developed IFX-induced psoriasis -managed with topical Rx.
  • -Clin Gastro & Hep 2010; 8: xxiv. Image of psoriaform rash assoc with infliximab
  • -Aliment pharmacol Ther 2009; 29: 921-27. Review of psoriaform rash assoc with infliximab. Majority improved when TNF stopped.  Options: Rx w steroids for 3 days around Rx or add MTX.
  • -NEJM 2009; 361: 496. Review of psoriasis.

Unrelated link:

For those of you who do not have teenage sons, perhaps you are not familiar with Jimmy Kimmel’s:  This Week in Unnecessary Censorship – YouTube