Tag Archives: Ulcerative colitis

Family Resource for IBD

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In cooperation with ImproveCareNow, EmpoweredByKids.com, which was started by a group of parents, developed ‘The Book of Hope.’ This book “contains stories of hope and inspiration from parents and patients of Inflammatory Bowel Disease.  These are encouraging stories to let families know someone else has been there too and you are not alone.”

You can download a copy of the IBD Book of Hope here.

I read through the downloaded version.  In my view, the general theme was of perseverance.  Given some of the difficulties shared in the book, this book might be best when someone is hospitalized and/or very sick rather than at the onset of diagnosis.

What do you think?

Additional family resource:

Free Self Management Handbook endorsed by ImproveCareNow:

https://improvecarenow.org/patients/self-management-handbook

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Predicting Remission in Pediatric Ulcerative Colitis

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Trying to offer realistic information to families on the long-term success of infliximab (Remicade) for pediatric ulcerative colitis has been difficult due to a limited amount of data.  In addition, many studies have a number of limitations which can make it difficult to extrapolate to a less-selected population (According to the study which you would never qualify for …).

A recent post hoc analysis (Clin Gastroenterol Hepatol 2013; 11: 1460-65) from 51 children (age 6-17 years) provides some insight into this issue.  The authors used data collected prospectively during the T72 clinical trial (Clin Gastroenterol Hepatol; 10: 391-99 -reviewed in blog post: Infliximab for children with Ulcerative Colitis | gutsandgrowth).

Results:

  • Week 8 PUCAI scores best predicted which patients would be in steroid-free remission after 1 year of treatment: 9 of 17 (53%) with scores <10 points were in sustained remission compare with 4 of 20 (25%) with scores ≥10.
  • Week 8 PUCAI outperformed mucosal healing in predicting remission.

Key points:

  • PUCAI may have outperformed mucosal healing because the latter can lag behind clinical response.  Furthermore, mucosal healing is more subjective with less interobserver reliability.
  • In patients with known inflammatory bowel disease, endoscopic assessment remains important in several situations: condition or reason for symptoms is in question (eg. exclude irritable bowel symptoms or medication-induced symptoms), acute severe colitis not responding to 3-day treatment with intravenous steroids to exclude superinfection, and to assess mucosa before major treatment changes “such as when starting or stopping biologics and before referral for colectomy.”

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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.

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.

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Fecal Transplants -NY Times Opinion Piece

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The following link (thanks to Kayla Lewis) to a recent NY Times article provides a first hand anecdotal account of fecal microbiota transplant for an adult patient with ulcerative colitis and discusses the use of FMT for Clostridium difficile infections.

http://opinionator.blogs.nytimes.com/2013/07/06/why-i-donated-my-stool/?ref=health

Bottom-line: Expect more questions about this emerging treatment.

Also, a quick way to keep up on NY Times -follow the twitter feed: @nytimesHealth

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Microparticles and Pediatric IBD

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Before reading a recent publication (JPGN 2013; 56: 401-07), I was not aware of microparticles; microparticles may play an important role in the development of venous thromboembolism (VTE).  Pediatric patients with inflammatory bowel disease (IBD) have a higher relative risk of VTE compared to their peers than individuals >60 years of age, though the absolute risk is low.  Much of the pathophysiology underlying the increased VTE risk remain uncertain.

Microparticles have been called “platelet dust” and are microvesicles that are released from the plasma membrane of many cells (leukocytes, red blood cells, endothelial cells, and platelets).

This study examined plasma samples from 33 pediatric patients with Crohn disease (CD), 20 pediatric patients with ulcerative colitis (UC), and 60 healthy controls. Subsequently, microparticles’ procoagulant activity was measured.  The CD and UC patients were consecutively enrolled from the outpatient clinic.  Only 3 patients in each IBD group was receiving a biologic therapy (infliximab). The disease activity and extent were compared with measures of procoagulant activity.

Several assays were undertaken to assess microparticles and thrombin generation. Key findings:

  • Increased procoagulant function of microparticles was identified in all CD patients (active and quiescent) and in UC patients with active disease.
  • A positive correlation was found between disease activity scores and procoagulant activity.

The authors note that elevated microparticles “may play a role in inflammation.” Inflammation and coagulation likely influence each other.  The authors note that VTE risk is greatest during flares but is still increased in patients in remission compared with controls.

The authors do not discuss the relationship of mucosal healing to microparticles or VTE. However, given that clinical remission is not defined currently based on mucosal healing, it would be of interest to know the status of these microparticles and the risk of VTE with mucosal healing. Perhaps the “quiescent” CD patients have ongoing disease contributing to their increased risk of VTE and increased procoagulation function of microparticles.

Related blog entry:

VTE with IBD | gutsandgrowth

**According to previous expert consensus guidelines, “routine heparin prophylaxis cannot be justified in children until better evidence is available to suggest that the benefit outweigh the risks”  (Turner D, et al. Am J Gastroenterol 2011; 106: 574-88).

FMT -not quite the new Laser

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I distinctly remember one of my high school teachers saying that if you asked someone if they were willing to have a serious operation like a brain lobe removal, that most would be unwilling unless there was no other choice.  However, if you told them that you were going to do it with a laser, people would want to get it done right away.  Such was the mesmerizing appeal of the word “laser.”

Fecal microbiota transfer (FMT) certainly does not sound as enticing as a laser treatment. Nevertheless, the authors of a recent report state that “we received interest from patients all over the world to participate.”  That being said, this recent report reintroduces the concept of FMT for ulcerative colitis (UC) (JPGN 2013; 56: 597-601).

In the introduction, the authors note that probiotics, in particular VSL#3, have shown usefulness in the treatment of UC and have noted previous sporadic reports of FMT for inflammatory bowel disease.  This led to their pilot study of 10 subjects (7 to 21 years); this was a single-center, uncontrolled study.  Due to financial constraints, there was no correlation with fecal microbial profiling, histologic/colonoscopic activity, or stool inflammatory markers.

The authors extensively describe their protocol of FMT (240 mL [in four aliquots] daily for five days) including donor exclusion criteria and donor screening.  Participants did not receive any bowel preparation prior to FMT.  The majority of participants had pancolitis;  only one patient had disease limited to proctitis. One of the ten patients could not retain FMT enemas.

Results:

  • Short-term improvement was noted with 7 of 9 (78%) achieving a clinical response within one week and 3 of 9 (33%) achieving a clinical remission.
  • The authors note that 6 of 9 (67%) maintained a clinical response at 1 month.  Although if one examines the study’s figure 2, this graphically demonstrates a fairly meager response in about half of these patients based on their PUCAI score.
  • The authors do not overstate their interpretation of their results.  “This unique biologic is potentially efficacious.”
  • Adverse effects appeared to be mild and self-limiting.

Ultimately if FMT proves efficacious for inflammatory bowel disease, feces with the right microbial mix would be quite valuable.  For now, this study indicates that further research is needed in this area.

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Simponi (Golimumab) Approved for Ulcerative Colitis

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The U.S. Food and Drug Administration on 5/15/13 approved a new use for Simponi (golimumab) injection to treat adults with moderate to severe ulcerative colitis.

Here’s the link:

FDA approves Simponi to treat ulcerative colitis

From the link:

The U.S. Food and Drug Administration today approved a new use for Simponi (golimumab) injection to treat adults with moderate to severe ulcerative colitis.

Simponi works by blocking tumor necrosis factor (TNF), which plays an important role in causing abnormal inflammatory and immune responses. Previously approved to treat rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis (arthritis affecting the joints in the spine and the pelvis), Simponi is now approved to treat adults with moderate to severe ulcerative colitis that is resistant (refractory) to prior treatment or requires continuous steroid therapy.

Ulcerative colitis is a chronic disease that affects about 620,000 Americans. It causes inflammation and ulcers in the inner lining of the large intestine and is one of two main forms of chronic inflammatory bowel disease. The inflammation can lead to abdominal discomfort, gastrointestinal bleeding, production of pus and diarrhea.

“Simponi is an important new treatment option for patients with moderate to severe ulcerative colitis,” said Andrew E. Mulberg, M.D., deputy director of the Division of Gastroenterology and Inborn Errors Products in the FDA’s Center for Drug Evaluation and Research. “It is critical that patients suffering from the serious and painful symptoms of ulcerative colitis have additional treatment options since patients experience the effects of the disease and respond to treatments differently.”

The safety and effectiveness of Simponi for ulcerative colitis were established in two clinical studies. Evaluations of patients included measures of stool frequency, rectal bleeding, endoscopic findings and a physician’s overall assessment.

In the first study, 513 patients with moderate to severe ulcerative colitis who could not tolerate or failed to respond to other therapies were randomly assigned to receive Simponi or a placebo. Results showed that a greater proportion of Simponi-treated patients achieved clinical response, clinical remission and, as seen during endoscopy, had improved appearance of the colon after six weeks compared with the placebo group.

In the second study, 310 patients with moderate to severe ulcerative colitis who were responders to Simponi were randomly assigned to receive Simponi or placebo. A greater proportion of Simponi-treated patients maintained clinical response through week 54 and had clinical remission at both weeks 30 and 54.  

The most common side effects in patients treated with Simponi are upper respiratory infection and redness at the site of injection. Patients treated with Simponi are at increased risk of developing serious infections, invasive fungal infections, reactivation of Hepatitis B infection, lymphoma, heart failure, nervous system disorders and allergic reactions.

Global increases in IBD incidence

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Two more studies have shown increasing incidence of pediatric inflammatory bowel disease.

First in Victoria, Australia (mostly Melbourne) (Inflamm Bowel Dis 2013; 19: 1-6).

Over a 60-year span (1950-2009), a retrospective review was undertaken of ulcerative colitis (UC) pediatric patients. In total, 342 children were diagnosed with UC. Key finding: The number of reported cases increased by 11-fold during the study period with a marked increase since 1990 (0.15 –>1.61/100,000).  In addition, recently diagnosed children have had more extensive disease.

Next in Spain (Inflamm Bowel Dis 2013; 19: 73-80).

This retrospective study from hospitals’ databases looked at the incidence between 1996-2009 in the pediatric population (<18 years).  A total of 2107 patients were identified: 1165 with Crohn’s disease, 788 ulcerative colitis, and 154 IBD unclassified. Median age at diagnosis was 12.3 years.  Key finding: in the last 14 years, pediatric IBD incidence has almost tripled (0.9 –>2.8/100,000).

Both of these studies have limitations related to large retrospective reviews in terms of potential problems with capturing all of the patients and the potential for misdiagnosis.  However, the trend is clear.  In addition, these studies show incidence rates comparable to several other Western studies.  The increasing incidence of IBD ‘argue for a common environmental factor in their pathogenesis.’  While interest has focused on microbial factors, the basis for this increased incidence currently remains elusive.

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Budesonide for Ulcerative Colitis

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Budesonide (Uceris) has been formulated with the MMX delivery technology and now has been FDA approved for mild to moderate ulcerative colitis in adults.  The potential advantage of budesonide compared with conventional corticosteroids is for targeting anti-inflammatory activity to the colon with less systemic side effects.  The potential downside includes the high cost.  According to one website (see below), the average wholesale cost is just below $1500 per month.  In addition, only a minority of individuals responded to budesonide in published studies:

Induction of Remission in Studies 1 and 2 (reference below)

Treatment Group

Study 1 n/N (%)

Study 2 n/N (%)

UCERIS 9 mg

22/123 (17.9)

19/109 (17.4)

UCERIS 6 mg

16/121 (13.2)

9/109 (8.3)

Reference Arm*

15/124 (12.1)

13/103 (12.6)

Placebo

9/121 (7.4)

4/89 (4.5)

Treatment Difference between UCERIS 9 mg and Placebo (95% CI)†

10.4% (2.2%, 18.7%)

12.9% (4.6%, 21.3%)

Data for budesonide for pediatric patients with ulcerative colitis is not available.