Category Archives: inflammatory bowel disease

IBD Update 2014 (part 2)

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5. Inflamm Bowel Dis 2013; 19: 2927-36.  This reference is another article that tries to help discuss the risks and benefits of biologic therapy for pediatric inflammatory bowel disease.  After reviewing the potential risks, the authors provide their “Option Grid” (Page 2932).  The authors state, “in summary, the adult literature supports the concept of the early use of combination therapy…the risks associated with anti-TNF therapy are really not significantly different as compared with thiopurine therapy and perhaps in some cases safer.  Therefore, we should be moving closer to the idea of using anti-TNF therapy early, with or without an immunomodulator.  In the sickest patients, combination therapy probably adds benefit, and then once in remission, consideration can be given for stopping one of the medications, more likely the thiopurine.

6. Gut 2013; 62: 689-94.  Risk of ischemic heart disease in patients with inflammatory bowel disease: a nationwide Danish cohort study.  From 1997 to 2009, the authors compared 28,833 IBD persons to >4.5 million persons without IBD who were matched for age, gender, socioeconomic status, and calendar year.  With a mean follow-up of 13 years, they identified a 59% higher incidence rate of ischemic heart disease in patients with IBD.  Long-term use of immunosuppressive medications, such as azathioprine and anti-tumor necrosis factor-alpha agents, was not associated with an increased risk of ischemic heart disease.

7.   Gastroenterol 2013; 145: 1459-63.  AGA Guideline for Use of Thiopurines, Methotrexate, and Ant-TNF-alpha Biologic Drugs for the Induction and Maintenance of Remission in Inflammatory Crohn’s Disease. This reference was previously noted in blog (with a link) AGA Guidelines for the Use of Thiopurines and Anti … – gutsandgrowt.  The print version does have a nice algorithm (pg 1463).  The accompanying technical review: Gastroenterol 2013; 145: 1464-78.

8. BMJ 2013;347:f6633. Free full-text BMJ article PDF. (Thanks to Mike Hart for this reference) From the abstract:  During 3 421 972 person years of follow-up, we documented 284 cases of Crohn’s disease and 363 cases of ulcerative colitis. The risk of Crohn’s disease was inversely associated with physical activity (P for trend 0.02). Compared with women in the lowest fifth of physical activity, the multivariate adjusted hazard ratio of Crohn’s disease among women in the highest fifth of physical activity was 0.64 (95% confidence interval 0.44 to 0.94). Active women with at least 27 metabolic equivalent task (MET) hours per week of physical activity had a 44% reduction (hazard ratio 0.56, 95% confidence interval 0.37 to 0.84) in risk of developing Crohn’s disease compared with sedentary women with ❤ MET h/wk. Physical activity was not associated with risk of ulcerative colitis (P for trend 0.46). The absolute risk of ulcerative colitis and Crohn’s disease among women in the highest fifth of physical activity was 8 and 6 events per 100 000 person years compared with 11 and 16 events per 100 000 person years among women in the lowest fifth of physical activity, respectively. Age, smoking, body mass index, and cohort did not significantly modify the association between physical activity and risk of ulcerative colitis or Crohn’s disease (all P for interaction >0.35). Conclusion In two large prospective cohorts of US women, physical activity was inversely associated with risk of Crohn’s disease but not of ulcerative colitis.

Comment: While physical activity may directly reduce the risk of Crohn’s disease, it could also be an epiphenomenon of another unmeasured variable (eg. dietary habits) that modifies this risk.

Related blog post:

Understanding IBD Therapy Risks -A Good Link | gutsandgrowth  Provides link to useful 6-minute internet video for families.

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.

Malignancy Risk with Thiopurines

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Based on a large retrospective, nationwide cohort study, it has been estimated that patients with ulcerative colitis have a 4-fold increase in the risk of lymphoma compared with patients who have not been treated with thiopurines (Gastroenterol 2013; 145: 1007-15).  While this study enrolled data from 36,891 patients followed for a median of 6.7 years, this study should not be interpreted in isolation.  The editorial (pages 927-30) provides some important context.

Besides the risk of lymphoma in patients treated with the thiopurines, the editorial briefly states the potential for life-threatening infections, primarily varicella and hemophagocytic lymphohistiocytosis which may complicate primary EBV infection.  The latter is much more common in younger patients.

With regard to malignancy, besides lymphoma, thiopurines also increase the frequency of nonmelanoma skin cancer.  Since these are not life-threatening, in many patients the risk of lymphoma is “the major limiting factor for the prolonged use of thiopurines.”  Furthermore, the risk of lymphoma may increase relative to treatment duration according to the above-referenced study. The editorial notes that there are three types of lymphoma to be considered:

  1. Posttransplant-like lymphoma associated with EBV seropositivity. Absolute risk in all IBD patients ~ 1 per 1000 patient-years.  All EBV-seropositive patients are at risk.
  2. Early post-mononucleosis lymphomas. Absolute risk in all IBD patients ~0.1 per 1000 patient-years; however, the risk in young men who are seronegative for EBV (<35 years) is ~3 per 1000 patient-years.
  3. Hepatosplenic T-cell lymphomas.  Absolute risk in all IBD in all IBD patients ~0.05 per 1000 patient-years; again, in young patients (mostly men) the risk is ~0.1 per 1000 patient-years.

The second and third types of lymphomas can be reduced by limiting thiopurines in young men.

Despite the risks posed by thiopurines, the overall benefit-risk balance needs to consider the fact that the risk of colorectal cancer “is markedly reduced in patients with long-standing extensive colitis exposed to thiopurines.”  Thus, the lowered risk of colorectal cancer “may outweigh the excess risk of lymphoma.”

Also, in considering thiopurines:

Inflamm Bowel Dis 2013; 19: 2801-08.  “Thiopurines are Associated with a Reduction in Surgical Re-resections in Patient’s with Crohn’s Disease.”  This study was a retrospective review of 567 patients of whom 237 (41.8%) developed a surgical recurrence after a median of 70 months.  Taking thiopurine was associated with a hazard ratio of 0.51.  Due to small numbers, the results with anti-TNF therapy was not conclusive, but “seems promising as well.”

Related blog posts:

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.

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: