Category Archives: inflammatory bowel disease

Second-Guessing Aggressive Medical Treatment in Pediatrics

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An excerpt of a review of a recent study (Inflamm Bowel Dis. 2014;20:291-300.) from Healio Gastro, http://bit.ly/1njexRZ.  This study was briefly referenced at the bottom of a previous blog post (UC SUCCESS | gutsandgrowth).

Mortality and malignancy, the most serious complications of pediatric inflammatory bowel disease, were relatively rare and linked most commonly with aggressive treatment rather than the condition itself, according to recent study data.

In a multinational retrospective study, researchers surveyed all pediatric gastroenterologists in 20 European countries and Israel on cancer and/or mortality among their pediatric patients with inflammatory bowel disease (PIBD) from 2006 to 2011.

Among 44 children diagnosed with IBD (median age at diagnosis, 10 years; 26 boys), 18 cases of cancer were identified and/or 31 patients died. Twelve cancer patients had Crohn’s disease, and 19 patients who died had ulcerative colitis (UC). The most common cancers were hematopoietic tumors (n=11). Mortality was attributed to infections (n=14) and other causes, including cancer (n=5), uncontrollable disease activity related to IBD (n=4) and procedural complications (n=3).

“Cancer and mortality in PIBD are rare, but cumulative rates are not insignificant,” the researchers wrote. “…. At least six lymphomas were likely treatment-associated by virtue of their phenotype.”

Researchers said that aggressive therapy with immunosuppressants and biologics has become common among PIBD patients because their disease is often more severe than that found in adults with IBD…

“Nine out of 19 patients with UC died because of an infectious complication. These fatalities may have been prevented by earlier surgical intervention when intensified medical treatment is ineffective.”

Bottomline: Making a colectomy decision is quite difficult when medical therapies may be effective.  Recent guidelines using PUCAI scores may assist physicians in identifying medical failures more quickly.

 

CCFA Conference Notes 2014 (part 2)

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Yesterday’s notes highlighted the most useful discussion at this year’s meeting regarding mucosal healing (MH) in inflammatory bowel disease.

Many points were intriguing but often at odds. For example, the speakers noted that symptoms and scoring systems like CDAI are unreliable in establishing remission.  It was noted that the FDA is mandating more objective measures (like endoscopic improvement) in future studies. Yet, the studies cited for their arguments often were derived from studies which did not use objective endpoints. Similarly, some of the arguments were based on small studies and yet experts often caution to use evidence-based medicine.

Bo Shen (Cleveland Clinic) “Surgerical Options in IBD”

  • 50-71% of CD patients require some type of surgery within 10 years of diagnosis
  • End-ileostomy may be a cure for some CD patients,  For UC, end-ileostomy 98% are cured.  2% develop enteritis.
  • Can use infliximab after surgery.  Immune system different after surgery and may work even
  • ‘Don’t operate until a CD patient develops a complication. But, don’t wait until further complications develop.’

Different type strictures –web-like strictures are suitable for dilatation, others are more difficult: spindle-like (longer) , ulcerated stricture, and anastomotic.

  • Classification: Gast Endosc 2013; 78: 8181-35.
  • Etiology: primary, secondary (anastomotic), benign, malignant
  • Short-long: Length (<4cm) if dilating
  • Degree: high-grade, low-grade
  • Number: single, multiple
  • Associated conditions: abscess, others

Determining resection margin –does not depends on absence of histologic activity (Ann Surg 1996; 224: 563-71).  Try to save as much bowel as possible, often based on how thick bowel is rather than histologic margins.

Save the gut –stricturoplasty.  1st surgery –usually is a resection rather than stricture plasty.  Heineke-Mikulicz (most common) <10 cm for short , Finney for strictures 10-20 cm, Michelassi >20 cm (sid-to-side isoperistaltic). (Dis Colon Rectum 2007) Stricturoplasty –best for mid small bowel, minimum inflammation, no fistula

Fistula –Hollow-organ to hollow-organ fistula –treat surgically. Whereas if fistula is perianal, start with medical treatment. Perianal fistulas often treated with seton; seton often kept in place for a long time (“forever if not bothering patient”).

Abscess—avoid surgical drainage if possible.  Delineate anatomy and consider elective surgery later.  If less than 3 cm, could aspirate and not leave in drain. If >3 cm, start with interventional radiology

Post-op management –Ruttgerts score.  Rescope 6 months post-op to determine if needs more aggressive treatment.

UC Surgery: issues: preoperative biologics, 2- or 3-stage operations, what type of pouch

  • There may be increased risk with biologics (studies have not shown this consistently) –depends on type of surgery.  If very sick, use 3-stage rather than 2-stage operation.  Don’t do pouch at time of 1st operation if very sick DCR 2013; 56: 1243-52).
  • J-pouch now standard.  Kock pouch –catheterize pouch/no ostomy.  S-pouch –problemswith mechanical obstruction.
  • Even with mucosectomy (vs. stapler/no mucosectomy)–can still develop cuffitis and malignancy.  Mucosectomy may increase risk of incontinence.

Edward Loftus (Mayo Clinic) “Optimizing Biologic Therapy: Maximizing Benefit and Minimizing Risk”

Is azathioprine an effective drug? Should we be using biologics sooner?

Key points:

  • ACT1 and ACT2 were pivotal studies for infliximab approval for UC.  1/3rd chance of going into full remission, 1/3rd chance of response, 1/3rd chance of not responding.  Infliximab lowers risk of colectomy.  Favorable studies of other anti-TNFs as well: adalimumab (Gastroenterol 2012; 142: 257-65) and golimumab (Gastroenterol 2014; 46: 85-95 & 96-109). No head-to-head anti-TNF trials.
  • Crohn disease:  5-ASA products don’t work for Crohn disease.  Reviewed pivotal trials of anti-TNF agents (infliximab, adalimumab, certolizumab)-30% in remission.
  • Natalizumab (anti-alpha 4 integrin) for refractory disease was discussed (NEJM 2005; 353: 1912-25).  Takes longer to work then anti-TNFs but maintenance data look good. PML risk: 395 cases among 118,100 patients treated as of August 2013.  Lots of paperwork and physicians have to be certified.  If you are JC virus serology is negative, “your risk is about 1 in one million in the next year. If you are positive, about a 1% risk in the following year.”
  • Azathioprine (AZA) not very effective (Gastroenterol 2013; 145: 766-74 & 758-65).  Prospective double-blind Spanish study (n=131) –no statitistical benefit.  2nd reference is French study. N=132. No significant difference at 36 months in patients with added AZA.  In U.S., most “thought leaders” going straight to anti-TNFs.
  • Combination therapy works best in adults (SONIC study for Crohn disease, UC Success for UC).  UC Success only studied 16 weeks, no maintenance therapy trial.  However, methotrexate (MTX) with anti-TNFs combination has not been proven to be effective (Gastroenterol 2014; 146: 681-8).  Reason this was a negative study, per lead author, may have been related to steroid use.

Other pointers:

  • Don’t rely on symptoms alone.  Symptoms/CDAI do not correlate with CDEIS (endoscopic improvement).  FDA mandating all future trials have an endoscopic endpoint and not rely on use of CDAI alone. Other factors cause symptoms including IBS, infections, and bacterial overgrowth. Take-home point: Need to look (endoscopy) if someone is not doing well.
  • In the SONIC trial –if there was inflammation on endoscopy, there was an impressive 30% delta in response to treatment (with combination therapy compared with AZA monotherapy). Whereas if you have no lesions, combination therapy no more effective than either monotherapy agent.  Patients whose complaints are due to irritable bowel rather than inflammation do not respond well to treatment.
  • OLD paradigm –treat based on symptoms.  NEW paradigm–treat based on biologic/radiographic markers or endoscopic findings.  “Treat to target” has been approach used by Dr. Sandborn. Target mucosal healing and then assess mucosal healing every 6 months until target achieved, then less frequently.  Yet mucosal healing cannot be achieved in many/most patients.
  • Therapeutic drug monitoring.  For example, 6-TGN >235 associated with better response to AZA (OR 5.0)
  • Pharmacokinetics of anti-TNFs: lower clearance if concomitant use of immunomodulators, increased clearance if high CRP, higher BMI
  • New drugs: Ustekinumab –three phase 3 trials underway.  Should be available in about 2 yrs for Crohn disease. Vedolizumab –under FDA review (NEJM 2013; 369: 699-710).  Infusion (similar to remicade frequency). Blocks lymphocyte homing in the gut. UC data much more robust than with CD, but probably will be approved for both.  Rate of adverse events were low. Etrolizumab—similar to Vedolizumab, but SC administered. Currently, this drug is in phase 2 studies.

Eva Szigethy (Pittsburgh Pediatrics) “Psychological evaluation and assessment in IBD”

Key points:

  • Anxiety/depression ~25-40% of pediatric IBD.  Occurs in both active and inactive disease.
  • IBD effects on brain: inflammation, drugs (steroids, biologics)–both have direct effects on brain.
  • 15% of kids and 25% of adults are having thoughts of death on screening tools. Pain is frequent trigger for suicidal thoughts.
  • Simple depression screen: Mood, Energy, Sleep, Suicide/Self-esteem, Anhedonia (lack of pleaure), Guilt, Eating (change in appetite)
  • We should not ignore adjustment disorders.  We may be able to prevent a full-blown psychiatric disorder.  Each time we let problems like anxiety or depression go untreated, this can leave long-term changes in brain.
  • Anxiety screen: Tense, Tired, Recurrent worries/fear, Restless, Avoidance, Poor sleep/nightmares, Poor concentration
  • Important to look at patient perspective of their disease: identity (what they see as their symptoms), cause/etiology, timeline (how long the patient believes that the illness will last), consequences, cure/control.
  • Catastrophizing –more persistent pain and increased visceral hyperalgesia.  Abnormal brain activation. Poor coping drives development of depression and anxiety.
  • With adult IBD, 20% of patients consume up to 80% of medical costs.  Chronic pain and depression are key factors (Binion et al 2010).
  • Management of anxiety/depression: Cognitive Behavioral therapy –changing behaviors and thinking, problem-solving. ACT –activities, calm (relaxation, guided imagery, hypnosis), think positive (cognitive reframing). Antidepressants: TCA, SSRI, SNRI.  SSRI/SNRI –few side effects or drug interactions.  Overdose risk is highest with TCA (but typically using low doses of these agents).  No pediatric studies in IBD and only small studies in adults. If inactive IBD, SSRI often 1st line. If active IBD, Bupropion often used as 1st line.
  • For anxiety, most likely use SSRI if comorbid anxiety
  • For pain, most likely use SNRI  or low dose TCA
  • Opiates are problematic due to psychological/physical dependence, increased mortality/infection risk, narcotic bowel
  • Sleep –don’t go to bed if not tired, aim for consistency, if not asleep in 20 minutes, then do something else.  1st line pharmacology: consider antihistamines or melatonin.

Sachin Kunde (Michigan State University, Helen DeVos Children’s Hospital) “FMT for IBD”

Key points:

  • Microbial diversity altered in IBD –can we modulate dysbiosis to treat IBD?
  • Issues with cause and effect.  Is dysbiosis due to IBD or causing IBD.
  • FMT –“the ultimate probiotic.” Application of FMT.  For recurrent C difficile, cure rate nearly 90% –?better with lower GI route. For any indication besides C difficile infection (CDI), can only be given through clinical trials (FDA IND).  Currently 9 ongoing trials for IBD (1 pediatric, 3 in U.S).

FMT in IBD: Studies:

  1. -Anderson et al.  Aliment Phar Ther 2012: 13/18 without CDI had some resolution of IBD symptoms.
  2. -Kunde et al JPGN 2013: n=10. PUCAI decrease by 15 indicated response found in 78% (7/9) at 1 week, and 67% (6/9) at 1 month, 3 (33%) went into remission.
  3. -Kump et al IBD 2013: n=6. FMT for UC was not effective.  Transient improvement in 2/6 patients, 1/6 improved on Mayo sub score.

Bottomline for FMT & IBD: More questions than answers: efficacy, route of administration, # of infusions needed, fresh vs. frozen, adverse effects, best donor, etc.

For today’s post today and yesterday’s post, I may have made some transcription errors and these notes were not reviewed with the speakers.  Also, due to brevity, some useful information was not included.  Thus, the disclaimer with these posts is particularly important.

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.

Related blog posts:

CCFA Conference Notes 2014 (part 1)

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Each year our local CCFA chapter holds a one day seminar with separate lectures for health care providers and families.  Overall, it is a good opportunity to hear ‘cutting edge’ material.  I did not pick up as much at this year’s seminar as in previous years, but will highlight what I thought was most important.

Key points:

  1. Symptoms are not accurate at determining effectiveness of IBD therapy.
  2. More frequent use of objective markers are needed to optimize treatment.  Mucosal healing is starting to be a target in clinical practice, but limited by number of medications available.
  3. Stricture classification and operative techniques were reviewed.
  4. IBD frequently results in psychological problems: anxiety, depression, pain, sleep. 15% of kids and 25% of adults are having thoughts of death on screening tool intake.
  5. Fecal microbiota transplantation (FMT) –not enough data to recommend for IBD.  Clinical trials ongoing.

Debate: What should be the End Points in Therapy? 

  • Tanvi Dhere (Emory): Goal: clinical symptoms
  • Cary Sauer (Emory Pediatrics): Goal: mucosal healing and normal bloodwork

In my opinion, this was the most thought-provoking and best presentation

Mucosal healing (MH) consensus definition –normal mucosa after previously abnormal with complete absence of ulceration, macroscopic and histologic signs of inflammation.  In practice MH = absence of ulcerations.

Reasons why mucosal healing as a target is problematic:

  • Problems with MH –not validated.  No long-term data utilizing endoscopic scoring indices of MH.
  • MH relies on a binomial endpoint –Yes or no, but there may be intermediate endpoints.
  • How likely is MH (different definitions in these studies)?  SONIC –MH in 43.9% of combination Rx (30.1% in those with infliximab monotherapy); EXTEND (Adalimumab) 27% and 24.2% 12/52 weeks; MUSIC (certolizumab at 10/54 weeks) 11.5% and 18.9%.

In practice, Mayo Score 0-1 both considered to have MH.

MayoScore Visual

Images above online at www.nature.com

In small study, MH at 1 year were not associated with improved outcomes at 5 years.  Risks of MH: more procedures, more costs of treatment, and potential for more complications.

Dr. Sauer’s reply.  Three simple questions –why should I try to target MH, is it possible, what is needed to get this done?

  1. If the goal were only an asymptomatic patient – why do screening colonoscopy in the general population, much less in IBD?
  2. In IBD, long-term evolution of IBD (Cosnes J et al. Inflamm Bowel Dis. 2002 Jul;8(4):244-50) is toward structuring and penetrating disease. CD Evolution This needs to be modified if possible.

Why MH? Improved symptoms, better quality of life, less likely to develop colon cancer, and it is an objective measure of treatment response.

  • In MH patients, less steroids and fewer flares over 2 year period.
  • MH healing patients have sustained clinical benefit over 96 months.
  • With MH, there is a decreased colectomy in UC.  In one study, there was a lower  colectomy rate at 8 years if colonic CD (62% vs 8%), decreased steroids in CD, decreased hospitalizations, & decreased fistulae.

Is MH possible in clinical practice?  The accuracy of CDAI to detect endoscopic healing is low in patients with CD. (Bouguen G et al Clin Gastrohep 2014).  More frequent adjustments in medical therapy –could lead to MH in up to 80% over 80 week study period.  Same story in UC (Bouguen G et al IBD 2014).

What do I need to do to obtain MH? Endoscopy (or MRE), maximize medications (checking levels), change medications, and most important –set a target. “Adjusting infliximab dose alone could lead to MH in up to 60%.”

When to assess for MH?  Consider endoscopy at 6 months into treatment if symptoms and at 12 months if in clinical remission.

Other viewpoints on MH from panel:

Dr. Loftus –“I think of this like oncology.” He agreed with using the best evaluating tool 6 months into treatment.  Cross-sectional imaging is often more helpful, but may need more than one tool.

Dr. Long—“Are we going to check every 6 months?” No.  She stated that she does not do this and tries to avoid repeated endoscopic procedures if this will not change treatment.  Goal is to make sure patient is headed in right direction, often after starting therapy.  Dr. Long stated that stool biomarkers most useful for colonic disease.

Dr. Dhere—documenting MH is important for deescalating treatment.

Millie Long  “Quality of Care in IBD”

  • 75% of Crohn disease patients will need surgery, 10% in 1st year
  • “One way to gauge quality of care is to examine the degree of consistency in care”
  • High variability in care in IBD (Aliment Pham Ther 2007; 26: 1005-18)
  • “Over half of institutions with worst quality have mortality in normal range.” Outcomes may not occur until several years after treatment, thus more useful to measure process measures

PQRS IBD Quality Measures in Adults: 10 Measures

  • #1 Establishing/documenting IBD type, anatomic location, and activity
  • #2 Preventive care: corticosteroid sparing.  Steroids associated with mortality (OR 2.1 in TREAT registry)
  • #3 Preventive care:  Preventing bone loss.  Limiting steroid use.  Recommend weight-bearing exercise, Quit Smoking, Measure DEXA, added Calicum/Vit D/Bisphosphonates
  • #4: Vaccination –pneumococcal vaccine.  Avoid live virus vaccines
  • #5 Vaccination –influenza vaccine, zoster vaccine
  • #6 Testing for latent TB prior to anti-TNF
  • #7 Testing for hepatitis B virus
  • #8 Testing for C diff with patients hospitalized with IBD
  • #9 VTE prophylaxis in adult IBD patients.  Risk assessment on admission to hospital is recommended.  IBD patients have 1.5-3.5-fold higher risk of VTE àwhich can increase mortality risk
  • #10 Screening for tobacco.  Tobacco use after surgery increases recurrence by 2.5-fold.  It also increases risk for reoperation.

Last year’s notes:

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.

More on Gut Microbiome and Crohn Disease

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Earlier this week on NPR there was a story summarizing the altered microbiome in Crohn disease and a related recent paper; here’s the link: Mix Of Gut Microbes May Play Role In Crohn’s Disease.  Other media outlets covered the story too:

The graphical abstract (Cell Host & Microbe, Volume 15, Issue 3, 382-392, 12 March 2014) is noted below:

Graphical Abstract

The link to the full study is listed below if you want to see the source article.  The amount of data that is presented is impressive but easy to follow with the figures:

Full link to article (from Kipp Ellsworth twitter feed): http://goo.gl/603Rbz 

Related blog posts:

Calprotectin: Part of diagnostic algorithm for IBD?

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Full text available at this link from Jeremy Adler: cghjournal.org/article/S1542-3565(13)01044-6/abstract#.Ut5vnV5z8Cw.twitter …

This article describes the use of fecal calprotectin (FC) levels as a screen for inflammatory bowel disease.  The false-negative rate for this assay is related to pre-test probability of having IBD.  Thus, in patients with a low probability of IBD, a normal calprotectin may allow avoidance of endoscopic evaluation and may be “particularly cost-effective when baseline clinical suspicion for IBD is low to moderate…the low FC cutoff value of 50 μg/g would substantially reduce the likelihood of false-negative FC, minimizing delayed diagnosis of true IBD.” In those with persistent symptoms, the article’s algorithm recommends proceeding with endoscopic evaluation.

Excerpt from abstract:

Conclusions

Screening adults and children to measure fecal levels of calprotectin is effective and cost-effective in identifying those with IBD on a per-case basis when the pre-test probability is ≤75% for adults and ≤65% for children. The utility of the test is greater for adults than children. Increasing the FC cutoff level to ≥50 μg/g increases diagnostic accuracy without substantially increasing total cost.

Related blog posts:

UC SUCCESS

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The results of the “UC SUCCESS” trial show that combination therapy with infliximab and azathioprine is more effective than either medication as monotherapy in ulcerative colitis (UC) (Gastroenterol 2014; 146: 392-400). This study findings are similar to the SONIC trial in Crohn’s disease (CD).

Study Design: randomized, double-blind trial with evaluation at 16 weeks with a total of 239 patients.  In patients assigned to infliximab (IFX) alone, they were given daily oral placebo pills. In patients with azathioprine monotherapy (AZA), dosed at 2.5 mg/kg/day, they also received placebo infusions.  Patients had moderate to severe UC as defined by Mayo scores at baseline and had not responded adequately to a course of corticosteroids.  All patients were naive to tumor necrosis factor α antagonists (anti-TNFα).  Mean age was approximately 40 years.

Results:

  • IFX/AZA had a 39.7% corticosteroid-free remission at week 16 compared with 22.1% with IFX monotherapy and 23.8% with AZA monotherapy.
  • Mucosal healing at week 16 was evident in 62.8% of combination group compared with 54.6% IFX monotherapy and 36.8% with AZA monotherapy.
  • Serious adverse events were noted more frequently in the AZA monotherapy group, though this did not reach statistical significance.
  • A subset of patients had antibodies to infliximab (ATIs) measured.  ATI-positivity was more common with IFX monotherapy (19%, 7 of 37) than for IFX/AZA combination (3%, 1 of 31)

While this study indicates that for moderate to severe UC combination therapy with IFX/AZA was superior in this age group, there were several limitations.  Given the slow onset of action of azathioprine, more patients may have responded to this therapy if longer treatment duration was studied.

Take-home message: Combination therapy for UC, like CD, is more effective.  In this small study population, the adverse events were not increased. In the pediatric population, particularly males, the concern for malignancy in patients (especially males) treated with combination therapy may limit the frequency of combination therapy.

Related blog posts:

Other recent IBD articles of interest:

Inflamm Bowel Dis 2014; 20: 291-300. “Malignancy and Mortality in Pediatric Patients with Inflammatory Bowel Disease”  This article presented the results of a survey of 20 European countries and Israel.  Key finding: 18 cases of cancer and 31 deaths in 44 children. 5 of the deaths were due to cancer; the most common cause of mortality was infectious (n=14).  In this cohort, all HSTCL or EBV-positive lymphomas were treated with thiopurine monotherapy.

Inflamm Bowel Dis 2014; 20: 196-212.  “Opportunistic Infections Due to Inflammatory Bowel Disease Therapy”  This review article covers a broad range of pathogens and includes recommendations for prophylaxis and treatment (Table 3).  In addition the authors  provide suggestions for checking for several infections prior to treatment and vaccinations.

Superiority of Anti-TNF Therapy in Children

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This study’s conclusion comes as no surprise:

“In children newly diagnosed with comparably severe CD, early monotherapy with anti-TNFα produced better overall clinical and growth outcomes at 1 year than early monotherapy with an immunomodulator. Further data will be required to best identify children most likely to benefit from early treatment with anti-TNFα therapy.”

Here’s the reference:

Gastroenterology Volume 146, Issue 2 , Pages 383-391, February 2014

Here’s a link to the full text article:  Increased Effectiveness of Early Therapy with Anti-Tumor Necrosis Factor-α Versus an Immunomodulator in Children with Crohn’s Disease

Methods: “From 2008 through 2012 at 28 pediatric gastroenterology centers in North America. Patients were managed by physician dictate. From 552 children (median age, 11.8 y; 61% male; 63% with pediatric CD activity index scores >30; and median C-reactive protein level 5.6-fold the upper limit of normal), we used propensity score methodology to identify 68 triads of patients matched for baseline characteristics who were treated with early anti-TNFα therapy, early immunomodulator, or no early immunotherapy.”

Another reference/link from same issue:

Accuracy of Magnetic Resonance Enterography in Assessing Response to Therapy and Mucosal Healing in Patients with Crohn’s Disease

Does Sun Exposure Lower the Risk of Crohn Disease?

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An intriguing recent study suggests that individuals who spend more time outside are less likely to develop Crohn disease (CD) (Inflamm Bowel Dis 2014; 20: 75-81).

In this prospective cohort study from France, 123 cases of inflammatory bowel disease (45 CD, 71 ulcerative colitis, and 7 indeterminant colitis)  developed among the 91,870 women in the study.  The study period had a mean followup of 13.1 years and followed women between 40 and 65 years. The authors estimated residential sun exposure by utilizing a database (derived from satellite collection) containing the mean daily ultraviolet radiation dose for each French county.

Key findings:

  • Higher levels of sun exposure were associated with a decreased risk of Crohn disease with a Hazard Ratio (HR) of 0.49.
  • Sun exposure did not affect the likelihood of developing UC (HR 1.21).
  • In women with information about dietary vitamin D intake, higher sun exposure had a HR of 0.29 for developing CD.  That being said, the authors note a low dietary vitamin D intake in their population.

Despite the large cohort, this study has a number of limitations. The absolute number of IBD patients can lead to a Type 1 error (false-positive conclusion).  In addition, the age of the study population and the lack of data regarding individual sun exposure limit the conclusions as well.  Besides these factors, there may be confounders such as changes in diet and soil exposure which are not accounted for.

At the same time, there have been other studies which have shown a latitude effect.  As with this study, those living in sunny areas had a lower incidence of CD.

Bottomline: This study suggests that additional sun exposure is associated with a lower risk of developing Crohn disease.  Whether this lower risk is directly through better vitamin D levels or simply an epiphenomenon is unclear.

Other recent unrelated studies:

Gut 2013; 62: 1122-30.  A randomized phase 1 study of etrolizumab (rhuMAb β-7) in moderate to severe ulcerative colitis.  Etrolizumab is an adhesion cell molecular blocker.

Inflamm Bowel Dis 2014; 20: 21-35.  Meta-analysis of 23 randomized controlled trials of probiotics for UC, Pouchitis, and CD.  Probiotics, in particular VSL#3, increased UC remission rates and helped maintain remission in patients with pouchitis.

Inflamm Bowel Dis 2014; 20: 213-27. Review article of cutaneous manifestations of inflammatory bowel disease.  Good pictures of multiple problems including metastatic Crohn disease, erythema nodosum, pyoderma gangrenosum, Sweet’s syndrome, aseptic abscess syndrome, and epidermolysis bullosa acquisita.

Inflamm Bowel Dis 2013; 19: 1753-63.  Review on hair loss associated with inflammatory bowel disease. Remember telogen effluvium?

Related posts:

For those who read from the top to the very bottom, here’s a tangential question: Do you know what a “sun dog” is?   Sun dog – Wikipedia, the free encyclopedia

Sanjay Gupta is Wrong… about Stem Cell Therapy

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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 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.