Tag Archives: Ulcerative colitis

What you might not know about anti-TNF monitoring…

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At a recent group dinner meeting, we had the opportunity to review therapeutic anti-TNF monitoring. In addition, we discussed emerging treatments for inflammatory bowel disease, like golimumab, tofacintinib and vedolizumab.

As noted in previous blog entries (see below), therapeutic anti-TNF monitoring can help adjust treatment.  Namely, if a patient loses response to therapy and has low trough levels of anti-TNF (Infliximab ❤ μg/mL, Adalimumab <8 μg/mL, or certolizumab <27.5 μg/mL) without antidrug antibodies (ADAs), then increasing the dose is likely to be effective.  However, if a patient has a therapeutic level and is not responding, changing to another agent and/or further investigation is worthwhile.

So, what information is new?

  • Only about 20% of patients who lose clinical response develop ADAs.  So, drug level, rather than ADAs, is most helpful.
  • For infliximab, adjusting dose 14 weeks into therapy to achieve a target trough level between 3-7 mcg/mL may be helpful.
  • Severe colitis patients may need higher initial doses (?as high as 20 mg/kg) due to potential for ‘antigen sink.’  This is due to notably higher clearance in the presence of low albumin, and high CRP.  Other factors that increase clearance include higher BMI and male gender.
  • About 1/2 of patients who receive higher doses due to severe disease may be able to deescalate dosage when improved. (?which half)
  • Currently, a reactive approach to checking levels is common in U.S. in part due to costs associated with checking trough levels and ADAs (as much as $2500).  That is, most commonly checking levels is undertaken in patients with suboptimal clinical response.  A proactive approach to achieve target levels may be shown to be helpful.
  • While studies have not shown higher adverse reactions with higher trough levels, there are a few clinical situations in which lower trough levels can be important.  In patients with psoriatic skin lesions and arthralgias, if trough levels are elevated, lowering the dose may be helpful.

Outstanding questions?

  • Should patients have drug levels checked when they are asymptomatic?
  • How does a practitioner account for variability among different laboratory assays?
  • What is the optimal target level for each anti-TNF agent? Is this different in Crohn disease compared with ulcerative colitis? Is the trough target level different in adults than children?
  • Is there a toxic level?
  • If a rapid test response were available, would checking drug levels be needed for hospitalized patients to assess anti-TNF rescue therapy?

Related blog links:

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

IBD Update 2014 (part 1)

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A number of recent articles that may be helpful for clinicians who help patients with inflammatory bowel disease.

1. Inflamm Bowel Dis 2013; 19: 2778-86.  “The Incidence and Predictors of Lupus-Like Reaction in Patients with IBD treated with Anti-TNF therapies.”  Key result: 20 of 289 (6.9%) developed lupus-like reactions (LLRs).  Female gender and IBD-unclassified were more prevalent in this group.  Clinical features included arthropathy (100%); fatigue and dermatitis were common.  All tested positive for ANA, 16 of 20 also had anti-dsDNA.  LLRs resolved with cessation of culprit agent and steroids.  Only one patient had recurrence who had switched to an alternative anti-TNF.

2. Inflamm Bowel Dis 2013; 19: 2753-62. This phase 3, randomized open-label multicenter study enrolled 60 children and provided data regarding infliximab pharmacokinetics in patients with moderate-to-severe ulcerative colitis.  The findings indicate that infliximab exposure-response is similar to adult patients.  At week 8, those with higher serum infliximab levels (≥41.1 mcg/mL) had higher efficacy (response 92.9%, remission 64.3%) compared with those with a lower levels <18.1 mcg/mL (response 53.9%, remission 30.8%).  Trough levels (at week 30) for q8 week-dosing was 1.9 mcg/mL compared with 0.8 mcg/mL for q12 week-dosing.

3. Inflamm Bowel Dis 2013; 19: 2744-52. A lot of pediatric IBD patients are colonized with Clostridium difficile.  In this prospective study of 85 outpatient IBD pediatric patients and 78 age-matched controls, asymptomatic C difficile carriage was noted in 17% of IBD patients compared with 3% of controls.  Use of proton pump inhibitors was associated with an increased carriage rate.

4. Inflamm Bowel Dis 2013; 19: 2937-48.  Excellent review article regarding fertility and pregnancy for women with IBD.  This review includes a discussion about the timing of pregnancy with regard to remission, effects of surgery and medications, acceptable radiology testing in pregnant patients, and issues regarding delivery.

Something New with FMT

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“Resentment is like drinking poison and then hoping it will kill your enemies.” –Nelson Mandela

A brief review on Fecal Microbiota Transplantation (FMT) (Gastroenterol 2013; 145: 946-53) made a few points that I was not familiar with and reiterated many other important aspects.

  • With regard to preparation of FMT, early data suggests that using water rather than saline may result in better resolution of Clostridium difficile infection (CDI)
  • Adequate volumes of FMT material are needed, with rates as high as 97% CDI resolution with infusions >500 mL
  • While preliminary data suggested higher CDI resolution with colonoscopy infusion, a recent randomized controlled trial indicated that duodenal infusion was as effective as colonoscopic administration
  • Short-term data indicate very low adverse effect rates
  • While the only accepted role for FMT outside of clinical trials is for CDI, the review examined the potential benefit for inflammatory bowel disease (IBD), irritable bowel syndrome, chronic fatigue syndrome, and metabolic/cardiovascular disorders.
  • With IBD, there are currently 6 registered trials testing FMT for patients with IBD.  Preliminary data have been more evident in small studies with ulcerative colitis.
  • The rationale for FMT in IBD is that IBD patients have reduced diversity and altered microbial flora.  “However, it is not clear whether these differences are a cause or a consequence of the development of IBD.”

Related blog posts:

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.

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.”

Related blog posts:

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.

Related blog posts:

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.

Related blog entries: