Category Archives: Uncategorized

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

MD Job Dissatisfaction –Million $ Mistake?

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A recent report indicates a high level of job dissatisfaction among physicians, leading some to conclude that it could be a million dollar mistake: http://www.cbsnews.com/news/1-million-mistake-becoming-a-doctor … (from Eric Benchimol’s twitter feed)

Here’s an excerpt:

If you are brilliant, ambitious and gifted in science, you may consider becoming a doctor. If so, think twice. According to a new survey by personal finance site NerdWallet, most doctors are dissatisfied with the job, and less than half would choose a career in medicine if they were able to do it all over again….

Worse, the cost of becoming a doctor has soared, with higher education expenses leaving the average newly minted physician with $166,750 in medical school debt, while average salaries are declining. Nearly one-third of doctors — 28 percent – saw a cut in pay last year, according to NerdWallet’s research….

To be sure, pay is still high, with of six-figure positions in the country, according to government data. But it also takes between 11 and 14 years of higher education to become a physician. That means the typical doctor doesn’t earn a full-time salary until 10 years after the typical college graduate starts making money. 

That lost decade of work costs a cool half-million dollars, if you assume this individual could have earned just $50,000 annually, and the typical medical school candidate is smart and successful enough to earn considerably more.  Add in the time and cost it takes to pay off medical school debt and a dissatisfied physician may well consider pursuing medicine a $1 million mistake.

Take-home message: Financial considerations are probably the wrong reasons to to pursue a career in medicine.

Related blog posts:

In PURSUIT of Better Treatment for Ulcerative Colitis

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Patient education materials:

#1  Ulcerative Colitis For Dummies | UC Patient Resource This link connects to a free educational book promoted by Salix pharmaceuticals.  In order to receive a free download, you have to register and include your email.  I have not read this book but other similar books (eg. Colonoscopy for Dummies) by Salix have been well-written.

#2 This link, ow.ly/sPX95, is to the ImproveCareNow visit planner website.  It poses of ~ 8 questions and a text box  for “my list of things I’m concerned about and questions that I have.”  Families that use this planner may help themselves achieve more comprehensive care.

Anyone who follows this blog knows that I really enjoy a good study acronym.  The Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment (PURSUIT) is responsible for two papers in the most recent Gastroenterology issue:

  • Gastroenterol 2014; 146: 85-95
  • Gastroenterol 2014; 146: 96-109

PURSUIT is composed of >200 sites from around the world.  The first study was a combined phase 2 and phase 3 study. It enrolled 1064 adults with moderate to severe ulcerative colitis (UC) who were randomly assigned to either placebo, 200/100 mg or 400/200 mg of SC golimumab at 0 and 2 weeks.  All patients were naive to previous anti-TNF therapies. The average duration of disease was 6 years among the participants. The primary endpoint of the phase 3 part of this study was the clinical response at 6 weeks.  Clinical response was at least a 30% improvement and a ≥3-point improvement in the Mayo score. At baseline, the average Mayo score was 8.

  • The golimumab groups had response rates of 51.8% and 55.0% respectively compared to 29.7% for placebo.
  • Approximately 18% of patients achieved a clinical remission with treatment compared with 6% of placebo patients.
  • Approximately 10% had healed mucosa compared with ~4% in the placebo group.
  • Adverse events: Rates of serious infection were 1.8% for the active treatment group compared with 0.5% for placebo-treated patients.  In the 400/200 mg dosing group, there was 1 death attributed to peritonitis and sepsis after multiple procedures for ischiorectal abscess repair.  In addition, a single case of demyelination was noted in this group.

The second study, a phase 3 double-blind trial, evaluated the efficacy of maintenance treatment of 50 mg or 100 mg SC every 4 weeks in those with a successful induction (n=464).  This study took place at 251 centers between 2007-2011. At 54 weeks, the actively-treated gourds had maintained a clinical response, using the Mayo score, in 47.1% and 50.6% respectively compared to 31.4% for placebo.  Antibodies to golimumab developed in 2.9%, two-thirds of these antibodies were neutralizing.  Antibody formation was lower in those receiving concomitant immunomodulators. 4 cases of tuberculosis were noted from endemic regions despite previous screening.  Overall, infections occurred in 28% of those treated with placebo compared with 39% of those treated with golimumab.

During the course of the study, three deaths were reported, all in the 100 mg golimumab maintenance group.  The causes were malnutrition/sepsis, cardiac failure/thrombosis, and disseminated tuberculosis (patient was receiving isoniazid). After the study, another 6 deaths were reported, including two in the placebo group.  Three malignancies were reported through week 54 in patients receiving golimumab maintenance, two of these presented in the induction period while receiving placebo rectal cancer and thyroid cancer) and one (lung adenocarcinoma) occurred in a patient with a 40-year smoking history who received golimumab for induction and maintenance.

Taken together, about 25% of patients randomized to and maintained on golimumab achieved a clinical response lasting >1 year; similarly, about 17% had clinical remission at 1 year.

In the commentary (page 13-15), Stephen Hanauer notes that better response was noted with higher serum levels and there remains “a strong possibility that optimal dosing was not achieved.”  He and the authors comment on the observation that less-severe patients had a better response, indicating that  “greater disease severity may be correlated with more rapid clearance.”

Bottomline: These studies demonstrate that golimumab is an effective treatment for UC with a similar risk of adverse reactions as other anti-TNF agents.  The published studies are complicated and take some time to analyze.

Plus more references:

Gastroenterol 2014; 146: 110-18. “Adalimumab therapy is associated with reduced risk of hospitalization in patients with ulcerative colitis.” Data for this studies was derived from ULTRA1 and ULTRA2 trials with 963 patients.  Risk for hospitalization, whether due to UC or all-causes, was reduced between 40-50% compared to placebo within the first 8 weeks of adalimumab administration.

Clin Gastroenterol Hepatol 2013; 11: 1538-49.  Excellent review on pouchitis. Figure 5 (pg 1545) provides a nice treatment algorithm.  Initial approach is antibiotics (metronidazole or ciprofloxacin); in those responsive, either prn therapy or chronic treatment.  In those not responsive, look for pathogens (eg. CMV and C difficile) or determine it is immune-mediated (PSC-associated, IgG4-associated, or autoimmune).  The immune-mediated may respond to 5-ASA/budesonide or immunomodulators.

Clin Gastroenterol Hepatol 2013; 11: 1601-08. This case-control study with 141 UC controls and 59 patients who developed colorectal neoplasia found that increased inflammation was associated with colorectal neoplasia.  Use of immune modulators reduced the risk of colorectal neoplasia.

Related blog post:

Simponi (Golimumab) Approved for Ulcerative Colitis | gutsandgrowth

Pre-PEG UGIs -Low Yield If No Major Malformations or Cystic Fibrosis

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From JPGN online and NASPGHAN twitter feed, bit.ly/19q99Y8 :

Journal of Pediatric Gastroenterology & Nutrition:
doi: 10.1097/MPG.0000000000000282

Abstract: “We studied the utility of a preoperative upper gastrointestinal series in children with and without major congenital anomalies undergoing gastrostomy tube (G-tube) placement. Of 1163 children evaluated, 743 had major anomalies and a total of 39 episodes of malrotation were found. All of the children with malrotation either had major congenital anomalies or cystic fibrosis. Our study suggests that an upper gastrointestinal series may be unnecessary prior to G-tube placement in children without other congenital anomalies or cystic fibrosis.”

Comment: while I agree with the conclusions of the abstract, it is worth noting that upper gastrointestinal series will pick up other abnormalities as well, including duodenal stenosis (which I have seen picked up on two separate occasions).

Consensus Guidelines on FMT

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Recent links from AGA for FMT (fecal microbiota transplantation) for Clostridium difficile –excellent resource:

Also, summary of recent abstracts from ACG regarding FMT for C difficile, IBS, and IBD: http://t.co/7LFnDYq5V5

Some previous blog posts on this topic:

Micronutrient Monitoring in Intestinal Failure

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J Pediatr 2013; 163: 1692-6.  This retrospective study of prospectively collected data from 178 children provides data with regard to micronutrient deficiency among intestinal failure patients transitioning to enteral feeds. Figures 1 and 2 along with Table 2 provide the prevalence of micronutrient deficiency while receiving supplemental parenteral nutrition (PN) and while on full enteral nutrition (FEN).  Iron deficiency was most common in both situations with prevalence of 84% and 61% respectively. With the exception of folate (0%), all of the vitamins and micronutrients had fairly high rates of deficiency.  While on FEN,  deficiencies were  the following:

  • Vitamin A        19%
  • Vitamin B12    6.5%
  • Vitamin D        30%
  • Vitamin E          6%
  • Copper            8%
  • Iron                61%
  • Selenium         4%
  • Zinc               23%

The study does not indicate that the deficiency values were adjusted based on CRP values.  Instead, “low serum levels were used to define deficiencies.”  This is likely to lead to numerous errors.  Nevertheless, it is clear that these deficiencies are common.  Another finding of the study was that normal anthropometrics did not reduce the frequency of these deficiencies.  In their patient population, 57 of 136 (42%) with sufficient height and weight data had a height-for-age z-scores of <-2 by the time of FEN; where as 52 of 139 patients (37%) had weight-for-age z-scores of <-2.

A recent post on The Pediatric Nutritionist blog provides a suggested approach to the monitoring of vitamins and micronutrients based on the need for parenteral nutrition and on the need to consider inflammatory markers in the interpretation of these lab values: The Importance of Nutrition Lab Monitoring Protocols Featuring …

Bottomline: Vitamin and micronutrient deficiencies are common among intestinal failure patients.  In addition, a large percentage of these kids are not large at all.

Related blog post:

What happens to micronutrient levels in the hospital setting …

22Q on Video

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A couple recent youtube videos on 22Q deletion provide helpful information:

1. An Introduction to 22q112 Deletion Syndrome – YouTube –~20 minute video which provides an overview of the various problems and presentations of patients with 22Q deletion.

2. http://www.youtube.com/watch?v=34YhIYhNrdo -~ 5 minute video from the Netherlands conveys the message that kids with 22Q wanted to be treated like everyone else.

Related blog post:

Immunoglobulin deficiencies with DiGeorge Syndrome …  This post lists a number of references and resources related to 22Q (aka. DiGeorge Syndrome or Velocardiac Facial Syndrome).

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.

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