Sanjay Gupta is Wrong… about Stem Cell Therapy

Posted on January 14, 2014 by gutsandgrowth

According to a 3 min video (and article) publicized on twitter by Dr. Sanjay Gupta, Stem Cell therapy for Crohn disease is 97% effective. ow.ly/smrJM I sent him a tweet asking for data to support this figure but have not heard back. That being said, there are very few treatments that work in 97% of patients with any chronic disease.

The context of the video regards a model who has had 75 hospitalizations for Crohn disease and is unable to tolerate standard treatment. “Thus far, there is a 97 percent success rate with this procedure, but it’s not fully covered by insurance, so Jocelyn must find the money for the procedure, her travel, and the long recovery.”

To my knowledge, stem cell therapy, while promising, for Crohn disease remains an experimental treatment without any large studies proving its effectiveness.

An abstract at DDW last year (Stem Cell Transplantation Halts Crohn’s Disease – Medscape) reported that among the 22 patients in the stem cell treatment group (who were refractory to multiple other medications), 40% had mucosal healing and 58% had segmental healing. The presenting physician, Dr. Christopher Hawkey, noted ‘there were serious adverse events and many patients were not cured…. We need controlled trials showing a long-term risk/benefit ratio.’

Another study (Blood. 2010;116:6123-6132) with 24 patients, reported that “the percentage of clinical relapse-free survival defined as the percent free of restarting CD medical therapy after transplantation is 91% at 1 year, 63% at 2 years, 57% at 3 years, 39% at 4 years, and 19% at 5 years.”

Bottomline: I think the information in the video is not accurate. Inevitably, it will lead to a lot of ill-informed questions by families. When a respected physician posts this type of unsupported information, it has the potential to undermine not just his credibility but other physicians as well. Perhaps, Dr. Gupta will consider revising this information.

Related article:

Clin Gastroenterol Hepatol 2014; 12: 64-71: “A phase 2 study of allogeneic mesenchymal stromal cells for luminal Crohn’s disease refractory to biologic therapy.” Results: among the 15 patients (of 16) who completed the study, the mean CDAI score was reduced from 370 to 203. Twelve patients had a clinical response and eight had clinical remission. All patients received 4 weekly infusions of mesenchymal stromal cells. One patient had a stage 1 adenocarcinoma (colon) but the authors think that this was likely present prior to the infusions. Why this study is important? If shown effective in larger studies, mesenchymal stromal cells are much safer than allogeneic stem cells as donor to recipient matching is not needed nor chemotherapeutic marrow conditioning.

IBD Update 2014 (part 1)

Posted on January 2, 2014 by gutsandgrowth

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.

JAMA Thalidomide Study for Crohn’s Disease

Posted on December 29, 2013 by gutsandgrowth

The link (from KT Park’s twitter feed): media.jamanetwork.com/news-item/drug-improves-remission-crohn-disease-among-children-adolescents/ …

An except:

The study included 56 children and was conducted August 2008-September 2012 in 6 pediatric care centers in Italy. Children were randomized to thalidomide or placebo once daily for 8 weeks. The primary measured outcomes were a reduction in the Pediatric Crohn Disease Activity Index (PCDAI) score of ≥ 25 percent or ≥ 75 percent at weeks 4 and 8 (clinical remission). Nonresponders to placebo received thalidomide for an additional 8 weeks. All responders continued to receive thalidomide for an additional minimum 52 weeks.

The researchers found that clinical remission was achieved by more children treated with thalidomide (13/28 [46.4 percent] vs. 3/26 [11.5 percent]). Responses were not different at 4 weeks, but greater improvement was observed at 8 weeks in the thalidomide group. Of the nonresponders to placebo who began receiving thalidomide, 11 of 21 (52.4 percent) subsequently reached remission at week 8. Overall, 31 of 49 children treated with thalidomide (63.3 percent) achieved clinical remission, and 32 of 49 (65.3 percent) achieved 75 percent response.

Average duration of clinical remission in the thalidomide group was 181 weeks vs. 6.3 weeks in the placebo group.

Related blog post:

When nothing else is working | gutsandgrowth

Fiber Intake and Crohn’s Disease

Posted on December 6, 2013 by gutsandgrowth

There are several lines of evidence that diet can contribute to the development and treatment of Crohn’s disease.

From a treatment standpoint, the most dramatic data has been with the effectiveness of enteral nutrition as a treatment option. In addition other environmental factors like being raised on a farm and use of antibiotics have been shown to alter the risk for Crohn’s disease; the former has been associated with a reduction in risk and the latter with an increased risk.

A new prospective study from 170,776 women followed over 26 years in the Nurses’ Health Study has identified up to a 40% reduction in the risk of Crohn’s disease among the highest fiber intake quintile (24 g/day) in comparison to the lowest intake quintile (12 g/day) (Gastroenterol 2013; 145: 970-77, editorial 925). Link to abstract: http://dx.doi.org/10.1053/j.gastro.2013.07.050 …

Specific findings:

Fruit intake was associated with greatest risk reduction. The median daily intake of fiber from fruit in the highest quintile was 6 g/day which is equivalent to 2 fruits (eg. banana or orange).
Vegetable intake was not associated with protection from Crohn’s disease.
The editorial notes that “reverse causation was addressed by evaluating cumulative exposure and including a 2-4 year lag period.”
However, the women in this study may not be representative and fiber intake could be an epiphenomenon. The women in the highest quintile were also less likely to smoke, use aspirin and have a body mass index <30 kg/m-squared.
Fiber intake did not significantly reduce the risk of ulcerative colitis

Bottomline: the “Institute of Medicine recommends that daily fiber consumption should be 14 g of fiber for every 1000 calories.” Thus, if one were to follow the guidelines by the IOM, all individuals would be consuming enough fiber to potentially reduce their risk of Crohn’s disease by 40%. Other fiber benefits include improve bowel habits, lowered cholesterol levels, weight loss, and lowered diabetes risk.

Family Resource for IBD

Posted on November 12, 2013 by gutsandgrowth

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

Related Blog Posts:

IBD References 10/13

Posted on October 28, 2013 by gutsandgrowth

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.

Top Lecture: Enteral Nutrition for Crohn’s Disease

Posted on October 17, 2013 by gutsandgrowth

In my opinion, the best lecture from this year’s postgraduate course was from Dr. Baldassano. Enteral nutrition in Crohn disease: Where should this be in our treatment algorithm? Robert N. Baldassano, MD (page 115)

Dr. Baldassono has personal experience with improving with enteral therapy after failing methotrexate/remicade. His conclusion:

Enteral Nutritional Therapy: Where should this be in our treatment algorithm?

Should be offered to all newly diagnosed Crohn’s patients who can tolerate Nutritional Therapy
Special groups (especially a good idea): Malnourished patients, Younger patients, Growth failure, History of Cancer, Family history of Lymphoma, Consider when failing other therapies

This conclusion is supported by his presentation.

Should we be immunosuppressing our Patients? Hypothesis: IBD arises from inappropriate handling of intestinal bacteria

Elements of Modern Lifestyle Lead to Changes in Gut Microbiota

Improved sanitation
Less crowded living conditions
Decline in parasites
Vaccinations
Increased antibiotic use
Caesarean section
Refrigeration
Food processing
Diet changes
Improved sanitation

Diet is associated with new onset IBD

High dietary intakes of total fats, PUFAs, omega‐6 and meat were associated with an increased risk of CD and UC
High fiber and fruit intakes were associated with decreased CD risk
High vegetable intake was associated with decreased UC risk. Reference: Hou JK et al. American Journal of Gastro 2011; 106:563-73
The Bacteroides enterotype highly associated with animal protein and saturated fats which suggests meat consumption as in a Western diet
The Prevotella enterotype, high values for carbohydrates and simple sugars, indicating association with a carbohydrate-based diet, more typical of agrarian societies. References: Wu G, et al. Science. 2011 Oct 7;334(6052):105‐8

Partial or Complete Enteral Nutrition?

50% vs 100% of total caloric needs for induction with elemental formula (PCDAI < 10 at 6 weeks)
50% of total caloric needs 15% remission
100% of total caloric needs 42% remission
Labs improved only in the 100% group
Weight gain similar in the 2 groups. References: Akobeng et al Clin Nutr 2007; Ludvigsson et al Acta Paediatr 2004;Johnson et al Gut 2006;Critch et al. JPGN: 2012

Pediatric Longitudinal Study of Semi‐Elemental Diet and Stool Microbiome (PLEASE)

Prospective cohort study of children with Crohn disease from Philadelphia (used Peptamen), Toronto (used Modulen) and Halifax (used Osmolite); (n=90)

Enteral therapy with defined formula diet (n=38) vs. anti‐TNFα therapy (n=52)
Similar drop in PCDAI and calprotectin in TNF group and diet group.

Other points:

Insurance generally will cover nasogastric feeds
Disease location –not clear that this matters with Crohn’s disease
The reason EN works may be not what you are giving the patient but what the patient is not getting
Bacterial populations in pediatric IBD subjects on semi‐elemental diet (16S rDNA sequencing) develop a rapid change in gut bacterial populations upon initiating diet.
Partial (50%) nutrition, as noted above, helped maintain remission compared to normal diet.

Nutrition Therapy: “European” Protocol

• Induction: Exclusive enteral nutrition with an elemental, semielemental,or polymeric formula

• Duration: 4 – 12 weeks

• Maintenance Therapy: (either)

– Nutritional therapy: Repeat 4 week cycle of exclusive enteral nutrition every 3– 4 months

– Medical therapy: 6‐MP/AZA/MTX after induction with nutritional therapy

CHOP EN Experience: What if >80% of calories is from Enteral Nutrition?

Methods: Semi‐elemental formula, 80%‐90% of patient’s caloric needs from formula, Nocturnal NG feeds (outpatient teaching program), Normal diet as tolerated during the day
Duration: 7 days per week for 8‐12 weeks (induction), 5 days per week (maintenance) Reference: Gupta et al. Inflamm Bowel Dis. 2013:1374-8.
Induction of remission: 65% (at 8 weeks)
Response: 87% (at 8 weeks)
Significant improvement in weight and linear growth
Protocol is well tolerated: no serious adverse events

Postgraduate Course Syllabus (posted with permission): PG Syllabus

Related blog posts:

Practical Advice on Enteral Nutrition | gutsandgrowth -includes link to 32 minute with family-oriented video on using enteral nutrition.
Rest easy with enteral nutrition | gutsandgrowth

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and specific medical management interventions should be confirmed by prescribing physician. Application of the information in a particular situation remains the professional responsibility of the practitioner.

Crohn’s Research: Going to Pot

Posted on October 7, 2013 by gutsandgrowth

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.

Thiopurines = Low Efficacy for Crohn’s

Posted on October 4, 2013 by gutsandgrowth

The enthusiasm for thiopurine therapy for Crohn’s disease (CD) had already dropped a lot before two pivotal articles were recently published that confirmed the modest efficacy:

Cosnes J, et al. Gastroenterol 2013; 145: 758-65
Panes J, et al. Gastroenterol 2013; 145: 766-74
Gastroenterol 2013; 145: 714-16 (editorial)

The Cosnes study (from the GETAID group) reports an open-label randomized trial in 147 adult patients with newly diagnosed CD (from 2005–>2010) and risk factors for disabling disease who were recruited from 24 French centers. Risk factors for disabling disease:

Age <40 years
Active perianal lesions
Corticosteroid use within 3 months of diagnosis

The characteristics and Paris classification are detailed in the paper’s Table 1. Patients were divided into early azathioprine or “conventional” treatment. Patient’s were followed for 3 years. Azathioprine was dosed at 2.5 mg/kg/day. The primary endpoint was the proportion of trimesters spent in corticosteroid-free and anti-tumor necrosis factor (TNF)-free remission.

Results:

67% of azathioprine group achieved the primary endpoint compared with 56% in the conventional group. The difference in achieving the primary endpoint was not statistically significant between the two groups. Also, 41 (61%) of the conventional group were placed on azathioprine (mean time 11 months after enrollment).
The azathioprine group patients were more likely to not have perianal surgery (96%) compared with the conventional group patients (82%).
Adverse events included pancreatitis in 7 (10%) of azathioprine group compared with 1 (1%) of conventional group. Elevated liver function tests were noted in 3 (4%) compared with 1 (1%) respectively. No cases of neutropenia were noted in early azathioprine group.

The latter finding is interesting especially as the authors did not check thiopurine methyltransferase (TPMT) assays in a systematic manner.

Panes et al (for the AZTEC study group) performed a prospective double-blind trial of adult patients with a recent CD diagnosis (<8 weeks). This study enrolled 131 patients from 31 centers in Spain. 68 received azathioprine (2.5 mg/kg/day) and 63 received placebo.

Results:

After 76 weeks of treatment, 30 (44.1%) azathioprine patients and 23 (36.5%) placebo-treated patients were in sustained corticosteroid-free remission (P= .48).
Relapse rates were lower in azathioprine group compared with placebo: 11.8% vs 30.2%.
Serious adverse effects were more frequent in the azathioprine group compared with placebo: 20.6% vs. 11.1% (P= .16). In the azathioprine group, 7 (10%) developed pancreatitis, 16 (24%) developed leukopenia, 9 (13%) developed anemia, and 9 (13%) developed abnormal liver function tests. Infections were more common in the placebo-treated group (24%) compared with 12% in the azathioprine group

The accompanying editorial should be mandatory reading for all health care providers who help manage inflammatory bowel disease (IBD) patients. The editorial traces how thiopurines (azathioprine and 6-mercaptopurine) became an accepted cornerstone of IBD treatment. In adults, after initial disappointing results from Summers et al (Gastroenterol 1979; 77: 847-69), efficacy was demonstrated in a seminal study by Present et al (NEJM 1980; 302: 981-87). However, the authors note that a recent Cochrane review reported that “thiopurines are not effective for induction of remission, but are effective for maintenance of remission.”

The editorial notes that a high degree of efficacy was demonstrated from a small but influential pediatric study of 55 patients. After a high remission rate (89%) for all patients, this study showed that among those in remission, “1 patient (4%) in the 6MP group had a relapse within 180 days of achieving remission, compared with 7 patients (28%) in the placebo group.”

The editorial draws the following conclusions from the current studies:

“The remaining indications for primary therapy with thiopurines are maintenance of steroid-induced remission/steroid sparing in patients with CD that is not newly diagnosed, and prevention of postoperative recurrence.”
“The strongest indication for thiopurines may be as part of combination therapy.”
“If TNF antagonists had a similar low cost as generic thiopurines, there would likely be little debate regarding an evolution toward treatment of CD with TNF antagonists, either as monotherapy or ideally as combination therapy. Currently, the annual costs of TNF antagonists is 10-20 times that of thiopurines.”
Because of the difference in cost.., “the use of thiopurines in CD is likely to persist, despite the shrinking number of indications, the modest effect size, and the suboptimal safety profile.”

Related blog posts:

Practical Advice on Enteral Nutrition

Posted on September 18, 2013 by gutsandgrowth

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.

gutsandgrowth

Pediatric Gastroenterology

Tag Archives: Crohn’s disease