Sunday, December 29, 2013

Pictures of the Gut

Capsule Endoscopy and IBD

Wireless capsule endoscopy, first introduced in 2000, provided a new method for imaging of the small bowel.  A patient with suspected IBD (generally Crohn’s disease), could swallow a “pill” after an overnight fast.  The pill contained a camera, a wireless transmission circuit, and a power source that lasted up to 8 hours.  The patient was required to wear a belt that would receive the signals from the pill, and then transmit them to a computer for image review.(1)  Since its inception, wireless capsule endoscopy (WCE) has undergone extensive testing and improvements in both protocol and technology.  How does it compare to other imaging techniques, is it contraindicated for anyone, and when should it be used?

First, WCE is now an accepted diagnostic tool – most insurance companies will pay for its use in the diagnosis of suspected Crohn’s disease, small bowel cancer, or suspected bleeding lesions in the small bowel.  It is widely available from practitioners, and is a relatively painless procedure.  The newer technology available provides high resolution imagery and up to 24 hours of battery life.  After swallowing the pill, the patient waits until it progresses through their system and then the pill itself is excreted and flushed.

The primary benefit of WCE is the imaging of the small intestine, specifically the middle portions.  A colonoscopy allows for the viewing of part of the terminal ileum (the end of the small intestine), and an upper endoscopy will allow for the viewing of the stomach and the beginning of the duodenum, but standard scopes don’t image the majority of the small intestine.  There are more invasive procedures, including single-and-double balloon endoscopy (balloons are used to allow the scope to travel up or down, depending on the insertion point, through the majority of the small intestine) and intraoperative enteroscopy (where a small incision in the bowel is made and a scope is inserted by a surgeon), but these are generally reserved as secondary options.  Traditionally, the primary imaging option has been an upper GI series with a small bowel follow-through, where the patient swallows radioactive barium (yummy!) and has their small bowel imaged as the barium coats it on its way through the intestines.  How does WCE compare to the traditional first line approach?

In a 2009 meta-analysis, the various studies comparing WCE to traditional imaging were reviewed.  The initial comparisons looked at suspected Crohn’s disease patients.  Compared to computed tomography enterography  (CT scans-based small bowel imagery using contrast), WCE won out with 68 vs. 21% yields.  Similarly, colonoscopy (including ileoscopy) found a higher yield for WCE (47 vs. 25% ).  Similar results were found in existing Crohn’s patients with computed tomography. (2)

What about magnetic resonance imaging and WCE?  The results are mostly comparable – the sensitivity and specificity of both approaches was very similar overall, though the number of studies performed (and the number of individuals in each study) were limited.(3,4,5)  One item of disagreement comes up, though, in a meta-analysis looking at CT v. MRI based approaches – that analysis found CT to be mostly equivalent to MRI (with the downside of additional radiation), which is inconsistent with MRI performing better and WCE.  More WCE work needs to be done on larger patient populations to confirm the results.(6)
For a second-line approach, WCE was again favorable when compared to single insertion double balloon endoscopy (inserted from the mouth or the anus), but not as good when measured against double balloon endoscopy.(7)  The risks and impact of double balloon endoscopy are higher, however, than other approaches and it is primarily a secondary option.

If WCE is comparable to existing small bowel studies, why isn't it used more often?  First, WCE is a newer technique, and not all facilities will have the ability to offer it as a diagnostic tool.  Second, there is the possibility of retention of the capsule, requiring medical or surgical intervention.  In suspected Crohn’s disease patients, a meta-analysis found a 2.6% retention rate, likely due to structuring.(8)  For existing Crohn’s disease patients, another study found 13% capsule retention due to structuring.  This risk can be reduced by giving a patency pill (a similar sized pill that dissolves over time) prior to the capsule endoscopy.(9)  Most retentions can be resolved without surgery, and there has even been an argument that retention itself is a valuable diagnostic tool.(10)  Third, reviewing the 50,000+ images from WCE can be time consuming, generally up to an hour and a half for the gastroenterologist.  Software is getting more advanced to assist with this task.  Fourth, the gastroenterologist cannot control pill transit time – some sections of the small bowel may have fewer images due to rapid movement.  This makes pinpointing the exact location of problem areas difficult.  Finally, any findings requiring surgical intervention (e.g. a biopsy or polyp removal) require a secondary procedure be performed.

For those with ulcerative colitis of Crohn’s colitis, WCE is not likely to be as helpful.  The preparation regimen (generally the worst part of the procedure) is similar for both.(11)  The value in colonoscopy, however, for UC and Crohn’s colitis patients is the biopsy and potential immediate removal of polyps and other colonic lesions.  While WCE may be helpful for general cancer screening, it is not at present a good substitute for routine colonoscopies.

Given all of the above data, where does the evidence show WCE can be best utilized?  First, it is best utilized for suspected or known small bowel disease and a colonoscopy is superior for known lower-GI disease.   Second, it is currently a toss-up whether or not an MRI-based small bowel study or WCE review is the best option for suspected Crohn’s disease.*  Because of this, the cost, availability, and experience of your gastroenterologist are likely to be the deciding factor.  If WCE is used, a patency pill check should be performed first. 

For existing Crohn’s patients, WCE can also be used as a first line monitoring tool.  If a patency pill test is successful, it is again a toss-up between WCE and MRI-based approaches. 

WCE technologies are improving, and pill size decreasing, every year.  As the size of the pill decreases and the image quality and software review capabilities improve, WCE is likely to be used more frequently as a first line diagnostic tool.

Bottom Line


·         Wireless Capsule Endoscopy is an accurate, effective first line tool for diagnosing suspected small bowel Crohn’s disease with comparable or better results than traditional imaging.
·         For individuals with suspected structuring, a patency pill should be given first to check for potential pill retention.
·         Wireless Capsule Endoscopy is not currently as useful for Crohn’s colitis or UC patients.

*CT approaches, while having equivalent diagnostic value, expose patients to additional radiation.  They are more readily available, however, and less expensive in most cases.  These are all factors to consider with your physician.
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1.       Iddan, Gavriel, Gavriel Meron, Arkady Glukhovsky, and Paul Swain. "Wireless capsule endoscopy." Nature 405 (2000): 417.
2.       Dionisio, Paula M., Suryakanth R. Gurudu, Jonathan A. Leighton, Grigoris I. Leontiadis, David E. Fleischer, Amy K. Hara, Russell I. Heigh, Arthur D. Shiff, and Virender K. Sharma. "Capsule endoscopy has a significantly higher diagnostic yield in patients with suspected and established small-bowel Crohn's disease: a meta-analysis." The American journal of gastroenterology (2009).
3.       Horsthuis, Karin, Shandra Bipat, Pieter CF Stokkers, and Jaap Stoker. "Magnetic resonance imaging for evaluation of disease activity in Crohn’s disease: a systematic review." European radiology 19, no. 6 (2009): 1450-1460.
4.       Jensen, Michael Dam, Torben Nathan, Søren Rafael Rafaelsen, and Jens Kjeldsen. "Diagnostic accuracy of capsule endoscopy for small bowel Crohn's disease is superior to that of MR enterography or CT enterography." Clinical Gastroenterology and Hepatology 9, no. 2 (2011): 124-129.
5.       Kovanlikaya, Arzu, Elizabeth Watson, Jessica Hayward, Debra Beneck, Robbyn Sockolow, Aliza Solomon, Paul Christos, and Paula W. Brill. "Magnetic resonance enterography and wireless capsule endoscopy in the evaluation of patients with inflammatory bowel disease." Clinical imaging 37, no. 1 (2013): 77-82.
6.       Panes, Julian, Rosa Bouzas, M. Chaparro, V. GarcíaSánchez, J. P. Gisbert, Blanca Martínez de Guereñu, Juan Luis Mendoza et al. "Systematic review: the use of ultrasonography, computed tomography and magnetic resonance imaging for the diagnosis, assessment of activity and abdominal complications of Crohn’s disease." Alimentary pharmacology & therapeutics 34, no. 2 (2011): 125-145.
7.       Chen, Xiang, Zhi-Hua Ran, and Jin-Lu Tong. "A meta-analysis of the yield of capsule endoscopy compared to double-balloon enteroscopy in patients with small bowel diseases." World Journal of Gastroenterology 13, no. 32 (2007): 4372.
8.       Liao, Zhuan, Rui Gao, Can Xu, and Zhao-Shen Li. "Indications and detection, completion, and retention rates of small-bowel capsule endoscopy: a systematic review." Gastrointestinal endoscopy 71, no. 2 (2010): 280-286.
9.       Cheifetz, Adam S., Asher A. Kornbluth, Peter Legnani, Ira Schmelkin, Alphonso Brown, Simon Lichtiger, and Blair S. Lewis. "The risk of retention of the capsule endoscope in patients with known or suspected Crohn's disease."The American journal of gastroenterology 101, no. 10 (2006): 2218-2222.
10.   Maunoury, Vincent, Gwenola VernierMassouille, and JeanFrederic Colombel. "Value in capsule retention in Crohn's disease." Inflammatory Bowel Diseases17, no. 8 (2011): E84-E85.

11.   Drew, K., S. Hardcastle, A. J. Lobo, D. S. Sanders, R. Sidhu, and M. McAlindon. "PTU-222 A comparison of patient tolerance of bowel preparation regimens used for conventional colonoscopy, small bowel and colon capsule endoscopy." Gut 61, no. Suppl 2 (2012): A276-A276.

Sunday, December 22, 2013

5-ASA Drugs and Inflammatory Bowel Disease

Mesalamine and IBD


Mesalamine (or mesalazine), also known as 5-aminosalicylic acid, has been a staple of the treatment for Crohn’s disease and Ulcerative Colitis for decades.  Sold as Canasa, Rowasa, and Pentasa under various formulations and delivery mechanisms, it has been known to have very low side effects, and was a traditional first-line favorite treatment.  What does the evidence tell us about its actual efficacy, though?

With mesalamine, the evidence for efficacy in Crohn’s disease and Ulcerative Colitis must be viewed separately.  Introduced in the 1970’s when it was discovered to be the active component of sulphasalazine,(1) it was touted as a low-risk treatment for inducing and maintaining remission in Crohn’s disease.  Initial clinical trials (many not using a placebo control) looked positive, and the drug was prescribed widely as a core treatment for the disease. In the late 1990’s and early 2000’s, larger, better controlled trials were performed when absorption of the drug and its impact on full thickness diseases like Crohn’s was questioned. 

When through meta-analyses were performed based on the larger studies, they found that there was no statistically significant difference between the mesalamine drugs and placebo in either inducing or maintaining remission.  A 2011 Cochrane summary concluded that “Mesalazine and mesalamine formulations are not effective for inducing remission in active Crohn's disease...Aminosalicylates are safe for patients with Crohn's disease. Side effects are generally mild in nature and typically include nausea, vomiting, diarrhea, abdominal pain and dyspepsia (upset stomach or indigestion). [T]he existing data show little benefit for mesalamine.”(2)  Similarly, another review in the American Journal of Gastroenterology found that there was “no definite benefit of mesalamine over placebo”, despite a benefit over sulfasalazine over placebo. (3)

The story is a bit different for UC patients.  Mesalamine can be delivered to the colon either through some form of controlled release pill or through enemas and suppositories.   When compared to placebo in maintaining remission, the mesalamine was more effective, with a relative risk of 0.65.  Similarly, in inducing remission the relative risk was 0.79 when compared to placebo.  These results come in a 2011 meta-analysis of the strongest clinical trials, showing that mesalamine has efficacy against UC (astute readers will note this was the same team that found no efficacy in Crohn’s using the same methodology).(4) 

Because of the different delivery mechanisms, there have been additional studies with UC to determine the efficacy of different formulations.  A review looking at sustained release pills, delayed release pills, and pro-drug variants all taken orally found no efficacy difference.(5)  Further review showed that once daily dosing orally had the same efficacy as 2-3 times a day dosing.(6)  Finally, a review looking at the efficacy of oral v. suppository/enema (topical) delivery found that both were effective, but that combined oral/topical and just topical were both superior to oral in inducing and maintaining remission.(7)

The mesalamine story is a great learning lesson for evidence-based medicine.  Based on the efficacy of sulfasalazine, these drugs should have worked in Crohn's disease, and were enthusiastically prescribed due to the low side effect factor.  Unfortunately, they were increasingly shown to be ineffective, but the evidence won out.  The medical establishment eventually came around, and they are now not part of general treatment protocols for Crohn's (with the possible exception of terminal ileum-only disease).  On the other hand, they performed as projected for UC and are now a low-risk, staple treatment for the disease.

Bottom Line


·         Although still being prescribed, the evidence does not show that 5-ASA drugs are effective treatments for Crohn’s Disease.
·         Both oral and topical 5-ASA drugs are effective at treating Ulcerative Colitis.  Once-a-day oral is as effective as multi-dosing oral.
·         Suppository and enema-based delivery are more effective either alone or combined with oral than just oral dosing.
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1.       Khan, A. K., Juan Piris, and S. C. Truelove. "An experiment to determine the active therapeutic moiety of sulphasalazine." The Lancet 310, no. 8044 (1977): 892-895.
2.       Lim, W. C., and S. Hanauer. "Aminosalicylates for treatment of active Crohn's disease." (2011).
3.       Ford, Alexander C., Sunanda V. Kane, Khurram J. Khan, Jean-Paul Achkar, Nicholas J. Talley, John K. Marshall, and Paul Moayyedi. "Efficacy of 5-aminosalicylates in Crohn's disease: systematic review and meta-analysis."The American journal of gastroenterology 106, no. 4 (2011): 617-629.
4.       Ford, Alexander C., Jean-Paul Achkar, Khurram J. Khan, Sunanda V. Kane, Nicholas J. Talley, John K. Marshall, and Paul Moayyedi. "Efficacy of 5-aminosalicylates in ulcerative colitis: systematic review and meta-analysis."The American journal of gastroenterology 106, no. 4 (2011): 601-616.
5.       Feagan, Brian G., Nilesh Chande, and John K. MacDonald. "Are There Any Differences in the Efficacy and Safety of Different Formulations of Oral 5-ASA Used for Induction and Maintenance of Remission in Ulcerative Colitis? Evidence from Cochrane Reviews." Inflammatory bowel diseases (2013).
6.       Feagan, Brian G., and John K. MacDonald. "Once daily oral mesalamine compared to conventional dosing for induction and maintenance of remission in ulcerative colitis: A systematic review and metaanalysis." Inflammatory Bowel Diseases 18, no. 9 (2012): 1785-1794.
7.       Ford, Alexander C., Khurram J. Khan, Jean-Paul Achkar, and Paul Moayyedi. "Efficacy of oral vs. topical, or combined oral and topical 5-aminosalicylates, in ulcerative colitis: systematic review and meta-analysis." The American journal of gastroenterology 107, no. 2 (2011): 167-176.




Sunday, December 15, 2013

Stopping Remicade - Can You Restart or Switch To Another Biological?

Infliximab Antibodies


Human anti-chimeric antibodies (HACA) are the generated when the body launches an immune response to biologicals.  They can occur when a patient takes infliximab, adalimumab, or other drugs and the body treats the medication as if it were a foreign invader.  What happens when the body launches an immune response to the very medicine that is meant to counteract an autoimmune problem?  Also, there is a persistent myth that stopping a biological “causes antibody formation” and that you can’t restart it.  Is there evidence to support this?

An increased HACA level has been shown to be related to a decreased efficacy with biologicals.  In 2010, a study focusing on HACA levels in IBD patients and its association with both disease activity and likelihood of improving conditions with an increased dosage of infliximab was done.  The study found a few interesting things:

·         When HACA levels were low and the body was showing a low level of infliximab upon testing:
o   Increasing the dose of infliximab helped in 86% of the cases whereas changing to another anti-TNF agent only helped in 33% of the cases.
·         When HACA levels were high, however:
o   Increasing the dose of infliximab helped in 17% of the cases, whereas changing to another anti-TNF agent helped in 92% of the cases.(1)

A smaller study looking at switches to adalimumab by infliximab intolerant patients showed that the prior intolerance had little impact on the efficacy of the new treatment(2), and this was borne out during the trials to use adalimumab for ulcerative colitis as well(3).  Similar results were found for switching to etanercept in RA patients(4,5).  Overall, studies have shown between 12% and 87% of patients on one of the three major anti-TNF-alpha agents generate antibodies in response to the drugs.(6)

One of the frequent questions that comes up is regarding the stopping and starting of anti-TNF-alpha drugs.  A search for the effects of this produced no large studies showing any dangers in doing so, however there are other reasons not to do so.  First, the overall relapse rate for Crohn’s patients taking infliximab for a year was 50% within the first year of stopping.  There were potential genetic predictors as to who may be at higher risk, but more research needs to be performed in this area.  Second, 88% of those who went back on infliximab had a positive response.(7)  Similar studies have shown slightly lower responses than the initial treatment, but with a still very-high efficacy.(8)

While the first study noted was only of 155 patients, it suggests a bifurcated course of action when a patient isn’t responding to a first-line anti-TNF-alpha agent.  If the patient has a high level of antibodies and a low blood level of the drug, then switching to another agent may be the best course.  Similarly, Alternatively, if the patient has a low level of antibodies and a low blood level, increasing the dosage may be the best initial course of action.

Similarly, there is no well researched evidence found of direct harm in stopping and starting an anti-TNF-alpha drug currently in the published literature.  There is a clinical reason to not stop – the likelihood of relapse goes way up.  Switching to another anti-TNF-alpha drug is a possibility in either case.

Bottom Line


·         If you want to stop taking a biological, you are at a higher risk for relapse, though you can  restart the biological and it will begin working again in most cases.
·         If you have a negative immune reaction to a biological, switching to another is likely to be effective.
·         If infliximab is not working for you, have your HACA level and blood levels of the drug tested.  If you have low blood levels of both, increase your dosage.  If you have a high HACA level, consider a switch to another biological.

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1.       Afif, Waqqas, Edward V. Loftus, William A. Faubion, Sunanda V. Kane, David H. Bruining, Karen A. Hanson, and William J. Sandborn. "Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease." The American journal of gastroenterology 105, no. 5 (2010): 1133-1139.
2.       Sandborn, William J., Stephen Hanauer, Edward V. Loftus, William J. Tremaine, Sunanda Kane, Russell Cohen, Karen Hanson, Therese Johnson, Debra Schmitt, and Resa Jeche. "An open-label study of the human anti-TNF monoclonal antibody adalimumab in subjects with prior loss of response or intolerance to infliximab for Crohn's disease." The American journal of gastroenterology 99, no. 10 (2004): 1984-1989.
3.       Afif, Waqqas, Jonathan A. Leighton, Stephen B. Hanauer, Edward V. Loftus, William A. Faubion, Darrell S. Pardi, William J. Tremaine et al. "Openlabel study of adalimumab in patients with ulcerative colitis including those with prior loss of response or intolerance to infliximab." Inflammatory bowel diseases 15, no. 9 (2009): 1302-1307.
4.       Haraoui, Boulos. "Differentiating the efficacy of the tumor necrosis factor inhibitors." In Seminars in arthritis and rheumatism, vol. 34, no. 5, pp. 7-11. WB Saunders, 2005.
5.       Haraoui, Boulos, Edward C. Keystone, J. Carter Thorne, Janet E. Pope, Isaac Chen, Charles G. Asare, and Jonathan A. Leff. "Clinical outcomes of patients with rheumatoid arthritis after switching from infliximab to etanercept." The Journal of rheumatology 31, no. 12 (2004): 2356-2359.
6.       Aikawa, Nádia Emi, Jozélio Freire de Carvalho, Clovis Artur Almeida Silva, and Eloísa Bonfá. "Immunogenicity of anti-TNF-α agents in autoimmune diseases."Clinical reviews in allergy & immunology 38, no. 2-3 (2010): 82-89.
7.       Louis, Edouard, Jean–Yves Mary, Gwenola Vernier–Massouille, Jean–Charles Grimaud, Yoram Bouhnik, David Laharie, Jean–Louis Dupas et al. "Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped." Gastroenterology142, no. 1 (2012): 63-70.
Buch, M. H., H. Marzo-Ortega, S. J. Bingham, and P. Emery. "Long-term treatment of rheumatoid arthritis with tumour necrosis factor α blockade: outcome of ceasing and restarting biologicals." Rheumatology 43, no. 2 (2

Sunday, December 8, 2013

Money and IBD

Costs of Care

The cost of continuous healthcare for those with inflammatory bowel disease is a frequent concern for patients, but also for insurance companies and public health systems.  Cost of treatment is a factor in many diagnostic and treatment decisions – do we do an MRI or is a less expensive x-ray the best option?  What treatment approach do we start with – less expensive prednisone or more expensive anti-TNF-alpha drugs?  

The cost equation is complex – if everyone with abdominal pain was subjected to a small bowel series/MRI, colonoscopy, and extensive bloodwork, everyone’s insurance premiums would go through the roof and no one would be able to afford medical care (and generate numerous false positives, unnecessarily worrying many individuals).  On the other hand, early diagnosis may reduce the lifetime costs of care.  Finding the balance between the most effective treatment and cost effective diagnostics requires understanding the true costs associated with IBD. 

Costs are very difficult to calculate in many cases.  The incremental cost of conducting an MRI is similar to that of a small bowel follow-through.  That said, the cost of purchasing and maintaining an MRI unit is significantly higher, and that cost must be amortized across the patients or the imaging center could not afford to implement it.  Similarly, if the lesser cost diagnostic tools are used but more tests are required, the costs could even out or even exceed those of using the pricier test first.  On the ongoing case side, if a particular drug is more effective, it may mean fewer tests and procedures, saving money in the long run over lesser cost drugs.  How do we untangle this mess?  Fortunately, epidemiologists and others have done extensive work in determining the cost of ulcerative colitis and Crohn’s on a continuing basis.

One of the general concerns regarding the anti-TNF-alpha drugs is their cost.  With generic versions at least 5 years away, they can represent some of the highest costs for an IBD patient.  How much do they cost?  A provider analysis showed the following average annual costs for the three main drugs for continuing care (after remission or a stable state has been achieved) in US dollars:

·         $15,836 etanercept (Enbrel)
·         $19,457 adalimumab (Humira)
·         $25,748 infliximab (Remicade) (1)

Another study in the UK looked at costs as well, and noted that infliximab is weight-dependent for the dosage and has a higher variable cost.  The mean costs were calculated as follows:

·         £6,294 Infliximab
·         £5,720 adalimumab(2)

After reviewing the spread of the costs in the patients reviewed, the infliximab and adalimumab ended up having negligible cost difference.  The differences between the two countries may be due to an increased cost of infusion facilities in the United States or different cost structures for the drugs based on the UK’s collective purchasing.  Either way, those without insurance (and not on a cost assistance program, which most of the pharma companies have available), are looking at approximately $20,000 per year in drug costs alone.

Most of the larger cost studies on overall costs of the diseases were done prior to the biologicals achieving the level of usage they currently have.  A 1995 study looked at the annual cost of treating a patient with Crohn’s disease and found the following costs:

·         Individuals Requiring Hospitalization - $37,135 ($55,261 in 2013 dollars)
·         Individuals Requiring Steroids and Immunosuppressants - $10,033 ($14,930 in 2013 dollars)
·         Other Individuals - $6,277 ($9,341 in 2013 dollars)

The overall mean cost came out to be $12,417.(3)

A 2008 study (after the introduction of anti-TNF-alpha therapies) found the following costs per person each year:

·         Mean annual costs for Crohn’s Disease - $8,265
·         Mean annual costs for Ulcerative Colitis - $5,066

The breakdown of the costs was as follows:

·         Surgery – 12.4%
·         Hospitalization (non-surgical) – 19%
·         Medications – 35.3%
·         Outpatient Services – 33.3%(4)

Overall, the cost to treat IBD has come down in both absolute and relative dollars – likely due to the improved detection and medical treatment reducing the surgical and hospital-stay related costs, even though the medication costs are higher (the 5-ASA drugs standard at the time were extremely inexpensive but much less effective than the biologicals, and the 6-MP treatments and AZA treatments had lower costs as well).

Bottom Line


·         The bulk of the costs in IBD has shifted from surgeries in 1995 to medications in 2008.
·         While expensive, the biologicals have reduced overall IBD treatment costs.
·         Biological costs are not likely to drop much until 2018, when Remicade comes off-patent.
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1.       Bonafede, Machaon MK, Shravanthi R. Gandra, Crystal Watson, Nicole Princic, and Kathleen M. Fox. "Cost per treated patient for etanercept, adalimumab, and infliximab across adult indications: a claims analysis." Advances in therapy 29, no. 3 (2012): 234-248.
2.       Lamb, C. A., M. Price, M. Robinson, M. C. Gunn, N. P. Thompson, and J. C. Mansfield. "A real life retrospective analysis of drug expenditure reveals no significant cost difference between infliximab and adalimumab in the treatment of adult crohn's disease." Gut 60, no. Suppl 1 (2011): A251-A252.
3.       Feagan, Brian G., Mary Glenn Vreeland, Leanne R. Larson, and Mohan V. Bala. "Annual cost of care for Crohn's disease: a payor perspective." The American journal of gastroenterology 95, no. 8 (2000): 1955-1960.

4.       Kappelman, Michael D., Sheryl L. Rifas–Shiman, Carol Q. Porter, Daniel A. Ollendorf, Robert S. Sandler, Joseph A. Galanko, and Jonathan A. Finkelstein. "Direct health care costs of Crohn's disease and ulcerative colitis in US children and adults." Gastroenterology 135, no. 6 (2008): 1907-1913.

Sunday, December 1, 2013

IBD Research Update - Fall

Research Update on Crohn's and Ulcerative Colitis


This has been an active season for both Crohn’s Disease and Ulcerative Colitis research.  Several papers looking at both biologicals and traditional treatments (Methotrexate) were published, and some new research on those with IBD and celiac disease was done.  While there are many other interesting publications this quarter, these are a good cross-sampling of the good work being done to help those with IBD by medical researchers around the globe.

Antibody Development


Researchers found that antibodies to Infliximab usually develop within the first 12 months of treatment if they are going to develop at all (90% of patients who developed them did so in that period).  They also found that a loss of responsiveness to treatment may lag antibody development by several months.  On the other hand, they found that immunomodulator therapy combined with infliximab maintained the drug’s effectiveness for a longer period in those who developed antibodies.

The research is important for both treatment choice and monitoring.  It may make sense to monitor for antibody development for the first year and then stop monitoring unless other systems appear (or decrease the frequency).  Additionally, if an individual develops antibodies, adding an immunomodulator to the regime becomes another option that may be better than switching to another anti-TNF-alpha drug in some cases.(1)

Anti-TNF-alpha Drugs and the Immune System


One of the frequent issues with Anti-TNF-alpha drugs is their impact on the immune system.  There have been multiple studies that have shown rates of opportunistic infection appear to be higher with those on the biologicals.  In a recent meta-analysis, the authors looked at opportunistic infections with those suffering from IBD and taking anti-TNF-alpha drugs v. placebo, including infections like herpes simplex, mycobacterium tuberculosis, and herpes zoster.

Overall, the rate of opportunistic infection rate of IBD patients on the biologicals was double that of those on placebo.  While that sounds drastic, it is a measure of relative risk.  If the overall risk of a given infection is still low, than doubling that risk may still be a low number.  (2)

Celiac Disease


Celiac disease has recently received a lot of attention in the press in relation to gluten.  While those suffering from celiac disease can’t tolerate gluten, the evidence doesn’t support a gluten-free diet for anyone else, including those with IBD.  That said, there are individuals that have both IBD and celiac disease and suffer from their double whammy.  Is there any difference in IBD presentation when an individual has both?

In new research, those with celiac disease and ulcerative colitis were found to be more likely to have pancolitis with an odds ratio of 3.3, and were more likely to use immunomodulators.  Otherwise, there did not appear to be any greater impact to the IBD in patients with Crohn’s disease or in other aspects of ulcerative colitis.  Finally, those with IBD were not at a higher risk for developing celiac disease, though those with celiac disease were at a higher risk for being diagnosed with IBD.(3)

Ulcerative Colitis and Methotrexate


Methotrexate has been a long-used second tier treatment for both Crohn’s and Ulcerative Colitis.  The cost factors and availability make it more attractive than biologicals, but only if the other side of the cost-benefit equation is valid.  Specifically for UC, there have been few prospective studies of the drug as an option for those who are resistant to or intolerant of thiopurines (e.g. 6-MP, AZA, 6-TG).

In a small-scale prospective study, researchers found methotrexate to not be effective in treating UC following thiopurine treatment failure, concluding “The efficacy of MTX in UC patients in this study was poor with a low clinical response rate (22%) and high colectomy rate (44%)”.  The results were not promising, but the study itself was too small to be considered conclusive.(4)

Bottom Line


·         If patients on Remicade fail to develop antibodies in the first 12 months, the likelihood of doing so goes down dramatically.
·         Anti-TNF-alpha drugs (the biologicals) double the risk for opportunistic infection in IBD patients.
·         Celiac disease isn’t more likely if you have IBD, but if you have UC and celiac disease there is an increase pancolitis risk.
·         Methotrexate, at least preliminarily, does not appear to be effective in treating UC, though bigger studies are needed for a definitive answer.
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1.       Ungar, Bella, Yehuda Chowers, Miri Yavzori, Orit Picard, Ella Fudim, Ofir Har-Noy, Uri Kopylov, Rami Eliakim, and Shomron Ben-Horin. "The temporal evolution of antidrug antibodies in patients with inflammatory bowel disease treated with infliximab." Gut (2013): gutjnl-2013.
2.       Ford, Alexander C., and Laurent Peyrin-Biroulet. "Opportunistic Infections With Anti-Tumor Necrosis Factor-α Therapy in Inflammatory Bowel Disease: Meta-Analysis of Randomized Controlled Trials." The American journal of gastroenterology (2013).
3.       Oxford, Emily C., Deanna D. Nguyen, Jenny Sauk, Joshua R. Korzenik, Vijay Yajnik, Sonia Friedman, and Ashwin N. Ananthakrishnan. "Impact of Coexistent Celiac Disease on Phenotype and Natural History of Inflammatory Bowel Diseases." The American journal of gastroenterology (2013).

4.       Basuroy, R., H. E. Johnson, T. Hollingworth, S. A. Weaver, and S. D. McLaughlin. "PTH-093 Efficacy of Methotrexate in Ulcerative Colitis: A District General Hospital Experience." Gut 62, no. Suppl 1 (2013): A249-A249.

Sunday, November 24, 2013

IBD and Travel

 Travelling with Crohn's Disease and Ulcerative Colitis


Tis the season … to travel.  Many of us will be travelling in November and December to visit friends and relations, or to take some long-needed vacation hours before they go away at the end of the year.  Travelling with IBD is different than travelling for others without the disease.  There are many sites good travel tips for those with IBD, ranging from getting extra meds to obtaining records from your doctor to finding restrooms.  Here are a few good links:

My own travel tip is to make use of hotel bathrooms.  They tend to be clean, readily accessible off the lobby, open 24 hours, and open to anyone who stops (its hard to know who is a guest and who isn’t).  But this site is above evidence-based IBD.  Are there increased risks for those with Crohn’s and Ulcerative Colitis?  How about hard numbers?  Fortunately, there has been some research into just these questions.

First off, travel has a bigger impact on individuals with IBD.  In a study of Crohn’s patients in remission, they found that 20.5% ended up with diarrhea while traveling, compared with 1.3% of healthy controls. Approximately 6% ended up in a flare post-travel. (1)  A second, larger study found a similar increase in risk with all IBD patients (both Crohn’s and UC), though not as extreme, finding that illness occurred in 15.1% of trips made by patients with IBD compared with 10.9% for controls.  This study differentiated travel in the developing world, and found that travel to high risk locations had equal risk for those with IBD, but travel to more industrialized areas put those with IBD at higher risk due to the underlying illness (and not local conditions).(2)

The second area that travel can have an impact is vaccinations – specifically international travel.  Those with IBD taking steroids, immunomodulators, or anti-TNF-alpha drugs are considered immunocompromised.  They should be vaccinated using any inactivated (dead virus) vaccines but not live virus vaccines prior to travel.(3)  There are two reasons that are given for avoiding live virus vaccines – 1) the efficacy may not be as great, 2) there may be a negative systematic response.  The first risk exists with any vaccine – the second only with live virus vaccines (Yellow Fever vaccine being the most often cited for travel reasons).  Despite the guidance provided, there is minimal evidence that rates of systemic infection are higher for those on anti-TNF-alpha drugs – this area requires further research, but avoidance of areas with endemic disease and the required vaccinations is the safer route until it occurs.

A final area of interest and the subject of recent research is high altitude travel (both in a plane and at higher altitude locations).  It is known that hypoxia can increase inflammation, and higher altitude environments can induce hypoxia in those not acclimated.  A research study out of Switzerland found an almost doubled risk of flare in IBD patients within four weeks of high altitude adventures (though pressurized, airplane cabin pressures are generally equivalent to an 8,000 foot altitude at their lowest pressure).  While avoiding air travel isn’t practical, individuals should be aware of the increased risk possible based on the preliminary data from this study.(4)  This may be the partial cause of the increased diarrhea and exacerbated illness risks noted above.

Whatever your travel plans, I wish everyone a fun an healthy holiday season.

Bottom Line


·         Those with IBD may have increased risk of diarrhea with travel.
·         Prolonged air travel or high-altitude vacation destinations may induce flares.
·         Live virus vaccines should be avoided, but more research needs to be done to confirm this.
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1.       Ellul, Pierre, Valerie Anne Fenech, Christine Azzopardi, Lara Callus, Nicholas Delicata, Jeffrey Muscat, Neville Azzopardi, and Mario Vassallo. "Diarrhoeal episodes in travellers suffering from IBD." Frontline Gastroenterology 4, no. 2 (2013): 120-124.
2.       Ben–Horin, Shomron, Yoram Bujanover, Shulamit Goldstein, Moshe Nadler, Alon Lang, Uri Kopylov, Lior Katz, Adi Lahat, Eli Schwartz, and Benjamin Avidan. "Travel-associated health risks for patients with inflammatory bowel disease." Clinical Gastroenterology and Hepatology 10, no. 2 (2012): 160-165.
3.       Wasan, Sharmeel K., Jennifer A. Coukos, and Francis A. Farraye. "Vaccinating the inflammatory bowel disease patient: deficiencies in gastroenterologists knowledge." Inflammatory Bowel Diseases 17, no. 12 (2011): 2536-2540.
4.       Vavricka, Stephan R., Gerhard Rogler, Sandra Maetzler, Benjamin Misselwitz, Ekaterina Safroneeva, Pascal Frei, Christine N. Manser et al. "High altitude journeys and flights are associated with an increased risk of flares in inflammatory bowel disease patients." Journal of Crohn's and Colitis (2013).

Sunday, November 17, 2013

Backdoor to your Soul

Eyes and IBD

One of the lesser known extraintestinal impacts of Crohn’s Disease and Ulcerative Colitis is on the eyes.  Because of the potential impact on vision, those with IBD should make sure they see an eye doctor for a regular exam (annually) to baseline and then monitor their vision.  In addition to the diseases themselves, certain drugs used to treat IBD have a negative impact on vision long-term.  Understanding the risks can assist in early detection of problems and intelligent choices in medication.
Overall ocular inflammation is much higher in IBD than in the general population.  The estimated rate of occurrence is currently between 4% and 12% of IBD sufferers that develop ocular manifestations.(1)  The two primary categories of inflammation not related to drugs are uveitis and scleritis.  A small study showed a much higher incidence of both occurring with colonic involved disease than with isolated small bowel disease, finding that “Patients with colitis or ileocolitis were more likely to suffer from ocular inflammation (23.9%, 17 of 71), than patients with small bowel involvement alone (2.8%, 1 of 36) (P = 0.013)”. (2)
Amongst the extraintestinal manifestations of IBD, iritis and uveitis are the most common, with 2.2% of women and 1.1% of men experiencing the issues.  They are most common in ulcerative colitis sufferers, with a rate of occurrence of 3.8% in women with UC.  These are actual IBD manifestations, as opposed to co-morbid diseases like asthma.  Uveitis is an often painful inflammation of the uvea, or middle structures of the eye.  Iritis is really anterior uveitis – the iris is part of the uvea – but is sometimes tracked separately.  Uveitis can result in blurry vision, light sensitivity, and redness in the eye.  Use of entanercept (Enbrel) was associated with an largely increased chance of uveitis occurring (beyond that of IBD in general), whereas infliximab (Remicade) and adalimumab (Humira) showed no increase in uveitis.(3,4)
Episcleritis and scleritis are an inflammation of the outer, white area of the eye.  Episcleritis is less severe in general, and both are treatable.  Though occurring at a higher rate in IBD, one of the primary treatments for both is the use of Infliximab, which has been shown to have a positive anti-inflammatory effect on the conditions.(5)
One of the biggest concerns for eyes and IBD comes not from the disease but from its treatment.  Prednisone use has been shown to greatly increase the risk of developing glaucoma through an increased Intraocular Pressure (IOP).  Specifically, a portion of the population is genetically susceptible to increased IOP through the use of steroids, potentially as high as one third.  The increased IOP causes nerve damage, and can eventually lead to blindness.(6)
The eyes are an often overlooked area for IBD to manifest itself.  Anyone with Crohn’s, especially Crohn’s Colitis, or with Ulcerative Colitis should get annual eye exams from a licensed optometrist or ophthalmologist.  Additionally, because an increased IOP can have rapid and irreversible impact, any eye issues should be treated as a medical emergency and evaluated immediately by a physician.

Bottom Line

·         Eye issues affect approximately 10% of those with IBD, and up to 20% of those with colon involvement.
·         All of eye issues can progress to glaucoma and potentially blindness.  Any eye problems that manifest should be treated as a medical emergency.
·         Yearly visits to your optometrist or ophthalmologist should be considered a regular part of your preventative care regimen. 
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1.       Manganelli, C., S. Turco, and E. Balestrazzi. "Ophthalmological aspects of IBD." Eur Rev Med Pharmacol Sci 13, no. Suppl 1 (2009): 11-13.
2.       Salmon, J. F., J. P. Wright, and A. D. Murray. "Ocular inflammation in Crohn's disease." Ophthalmology 98, no. 4 (1991): 480-484.
3.       Bernstein, Charles N., James F. Blanchard, Patricia Rawsthorne, and Nancy Yu. "The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study." The American journal of gastroenterology 96, no. 4 (2001): 1116-1122.
4.       Lim, Lyndell L., Frederick W. Fraunfelder, and James T. Rosenbaum. "Do tumor necrosis factor inhibitors cause uveitis? A registrybased study." Arthritis & Rheumatism 56, no. 10 (2007): 3248-3252.
5.       Mintz, Roni, Edward R. Feller, Robert L. Bahr, and Samir A. Shah. "Ocular manifestations of inflammatory bowel disease." Inflammatory bowel diseases10, no. 2 (2004): 135-139.

6.       Tripathi, Ramesh C., Sunil K. Parapuram, Brenda J. Tripathi, Yong Zhong, and K. V. Chalam. "Corticosteroids and glaucoma risk." Drugs & aging 15, no. 6 (1999): 439-450.

Sunday, November 10, 2013

Libations and IBD

Alcohol, Crohn's, and Ulcerative Colitis

Alcohol, more specifically ethyl alcohol (or ethanol), is a result of sugar fermentation.  Humans are believed to have consumed alcohol since prehistoric times.  Primarily a central nervous system depressant, alcohol has several sought-after psychoactive properties which have led to its recreational consumption in beverages and inclusion in recipes.  More specifically, small amounts of alcohol are found to produce short term euphoric effects, including increased self confidence and more relaxed social interactions.  In cooking, alcohol’s ability to evaporate quickly and act as a solvent for flavors that are not water-soluble are valuable assets, and the flair added to “flaming” dishes makes for dramatic presentation.

Alcohol use, like many other substances, has both positive and negative effects on those with IBD.  In general, the effects of moderate consumption of alcohol have been shown to have minimal negative and potential positive health effects.  The amount that is considered “moderate” varies per person and is a factor of gender, genetics, and size.  For an average woman, one-to-one and a half servings a day are considered moderate, whereas a large man may have two or two and a half servings at the moderate consumption level.  While most individuals with Crohn’s and Ulcerative Colitis are told to avoid alcohol, and they will self-report digestive problems after consumption, the number of individuals with IBD that drink is similar to the population at large.(1)

As a primary positive factor, a lower risk of coronary artery disease has been correlated with regular, small amounts of alcohol consumption.  With respect to IBD, moderate consumption has been shown to be correlated with lower C-Reactive Protein levels, one of the key markers associated with inflammation in the disease.(2)  Though there is a correlation, there is no direct evidence that there is a positive impact on intestinal inflammation, just systemic markers of inflammation (there is no negative impact shown either).  There is little evidence that minimum to moderate amounts of alcohol have any long-term negative effects on IBD outcomes.  In fact, consumption of smaller amounts of alcohol has been shown to have a protective effect against developing Ulcerative Colitis (odds ratio = .57).(3)

While moderate consumption has been shown to have minimal impact, higher consumption levels, both acute and chronic, have serious negative consequences.  The well-known acute impacts of consumption that are non-GI specific include impaired judgment, vomiting, slowing of cardiac function, and an altered level of consciousness (to include coma and death at the highest levels).  The effects of high level chronic consumption are additionally severe – including liver disease, coronary disease, and dependency-related issues.

While light-to-moderate consumption may show no evidence of impact on disease progression, moderate-to-heavy consumption has been shown to have an impact.  Ulcerative Colitis sufferers are more like have a relapse (Odds Ratio = 2.7) if they are in the top third of the IBD population in alcohol consumption v. the bottom third. (4) Additionally, because of intestinal permeability issues associated with IBD, there is a potential higher likelihood for co-morbid cirrhosis of the liver to develop in those who consume heavy amounts of alcohol. (5)

Despite the general rules, there are some specific circumstances where alcohol consumption is contraindicated for those with IBD.  Originally, metronidazole (Flagyl) was reported to have a deadly disulfiram-like reaction when alcohol was consumed while taking the drug.  The original reports have largely been dismissed at this point, though the possibility of multi-drug interactions still exist.(6,7)  Immunomodulators like methotrexate have an increased risk of liver damage, and alcohol consumption can increase this risk.  Additionally, drugs like Zantac and Tagamet can increase absorption leading to a higher blood alcohol level. (8)

Alcohol is not only in the things we drink – it can be in everything from cough medicines to mouth wash.  Alcohol is frequently used in cooking also – there is an unfounded assumption that alcohol burns off quickly (because of a quicker evaporation than water) .  The real story is more complicated – the smaller the pot, the less evaporates.  Additionally, the lower the temperature the less evaporates.  A table from the USDA (below) shows the evaporation for everything from flambé to simmering at various cooking times (uncovered).

Technique
Percentage Alcohol
Remaining
Alcohol, overnight evaporation
70
Alcohol added to hot liquid
85
Flambé
75
Alcohol 15 minutes cooking
40
Alcohol 30 minutes cooking
35
Alcohol 1 hour cooking
25
Alcohol 1.5 hours cooking
20
Alcohol 2 hours cooking
10
Alcohol 2.5 hours cooking
5


Bottom Line


·         Light consumption of alcohol is likely to have no negative effect on Crohn’s and Ulcerative Colitis progression
·         Heavy consumption of alcohol can have a serious impact on IBD and general health
·         If you are on medications, multi-drug interactions can be exacerbated by alcohol.  Talk to your doctor and ask them to show you the research on your particular meds!
·         Alcohol can and does appear in non-drink form in cough syrups, mouthwash, and many dishes in restaurants.  Cooking does not generally remove much of the alcohol content.

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1.       Swanson, Garth R., Shahriar Sedghi, Ashkan Farhadi, and Ali Keshavarzian. "Pattern of alcohol consumption and its effect on gastrointestinal symptoms in inflammatory bowel disease." Alcohol 44, no. 3 (2010): 223-228.
2.       Albert, Michelle A., Robert J. Glynn, and Paul M. Ridker. "Alcohol consumption and plasma concentration of C-reactive protein." Circulation 107, no. 3 (2003): 443-447.
3.       Nakarnura, Yosikazu, and Darwin R. Labarthe. "A case-control study of ulcerative colitis with relation to smoking habits and alcohol consumption in Japan." American journal of epidemiology 140, no. 10 (1994): 902-911.
4.       Jowett, S. L., C. J. Seal, M. S. Pearce, E. Phillips, W. Gregory, J. R. Barton, and M. R. Welfare. "Influence of dietary factors on the clinical course of ulcerative colitis: a prospective cohort study." Gut 53, no. 10 (2004): 1479-1484.
5.       Keshavarzian, A., E. W. Holmes, M. Patel, F. Iber, J. Z. Fields, and S. Pethkar. "Leaky gut in alcoholic cirrhosis: a possible mechanism for alcohol-induced liver damage." The American journal of gastroenterology 94, no. 1 (1999): 200-207.
6.       Williams, Caroline S., and Kevin R. Woodcock. "Do ethanol and metronidazole interact to produce a disulfiram-like reaction?." The Annals of pharmacotherapy34, no. 2 (2000): 255-257.
7.       Visapaa, J. P., Jyrki S. Tillonen, Pertti S. Kaihovaara, and Mikko P. Salaspuro. "Lack of disulfiram-like reaction with metronidazole and ethanol." The Annals of pharmacotherapy 36, no. 6 (2002): 971-974.