Sunday, March 31, 2013

LDN Therapy and IBD


Low Dose Naltrexone


Naltrexone approved as a treatment of opioid (including heroin) and other chemical (including alcohol) dependence due to its ability to bind opioid receptors and prevent the opioids from binding to them.  It has been shown to be more effective for alcohol dependence treatment than opioid, but is approved for both uses.  It has also been used for general addiction and personality disorder treatments.  Side effects include GI-distress, and high dose Naltrexone has been controversially linked to liver damage.(1)

Low-Dose Naltrexone, or LDN, has a dosage below that which causes liver damage, and has a relatively safe profile.  It has been presented as a cure for everything from cancer to HIV infections to IBD, predicated on the valid (but simplified) concept that immune cells also have opioid receptors that can influence cell function.  In theory, LDN can act as an immunomodulator by effecting the behavior of these cells.(2)

Because they have a valid theory of action, LDN treatments deserve a look for autoimmune diseases.  Though the theory of action is incomplete (the effect on those immune cells with opioid receptors may nor may not end up helping with any given underlying condition), the treatment deserves to be considered in at least pilot studies for efficacy and safety.  Specifically for the treatment of IBD, there is one key pilot study that was performed in 2007.

The study in question enrolled 17 patients and was completely unblended (the doctors and the patients knew what they were getting in terms of medication).  There was no control group, and the subjects all took other medications concurrently.  One subject dropped out due to a flare, and two others stopped their regular meds, resulting in one having a flare.  They included the data from the patients as intent-to-treat, which is generally good and provides a conservative result.  In this case, though, the dropout of the most severe would have resulted in a substantial skew of the end median results reported (all but the worst were averaged…)  That said, the study did have a generally positive trend, with a lowering of CDAI scores (not really a great measure in open label studies) and lab numbers, especially C-Reactive Protein numbers (a much better and more promising indicator).(3)

The next study (I am ignoring the single person case report as having no statistical significance (4)) was on pediatric patients and looked at both safety and efficacy.  The study involved 12 children with moderate-to-severe Crohn’s disease, and was 8 weeks of single blind placebo controlled study and 8 weeks of open label study.  Each group in the initial study had 6 participants.  One patient (implied to be in the LDN group, but not directly stated) suffered a flare.  There was no clinical difference in C-Reactive Protein scores, and there was no statistically significant difference in CDAI scores.  There were minimal side effects identified in the study.(5)

The final (and best) study looked at 40 individuals (really 34 – 6 were excluded from the start) in a true double-blind fashion.  As with the previous 2 studies, the safety profile showed no large side effect issues with the LDN patients.  This study looked not only at CDAI and C-Reactive Protein scores, but also mucosal healing (the patients should be commended for subjecting themselves to 3 colonoscopies over 24 weeks!) 

On the good news front, there were statistically significant CDAI drops on the LDN-treated study.  Additionally, there were positive endoscopic results showing more mucosal healing in the LDN group.  This continued in the open label group after an additional 12 weeks.  On the negative side, the blood markers showed no improvement (this isn’t particularly troubling – most patients started with low CRP numbers).  One issue cropped up in the statistics – the worst patient (one who had a flare) was removed from the LDN group, and two additional patients who flared in the open label portion.  Given the small sample size, the removal of these patients could create fairly significant statistical changes.  Additionally, there were differences in concomitant medications between the 2 groups (more LDN patients on corticosteroids) and the LDN patients started with higher CDAI scores.  This is not a flaw in the study, just the type of anomaly that occurs in small trials.(6)

LDN treatment has some promise for treating IBD based on the preliminary studies, but the data is very, very preliminary at this point and the studies are not conclusive.  The responses shown justify further testing, but they indicate the LDN is not ready to be used to treat IBD at this point (the majority of studies at this pilot stage end up not panning out in the long run).  Dr. Novella at Science Based Medicine provides some valid words of caution for those touting LDN to loudly at this point:

Ironically, LDN promoters may in fact harm research into LDN by giving it a bad name. Researchers may be reluctant to hitch their careers, or funding agencies commit resources, to a treatment that has a dubious reputation. If the research is promising it will still get done, but if anything it is likely to be slowed by the efforts of the LDN promoters.

Bottom Line


·         Low Dose Naltrexone has some positive results and some mixed results in very preliminary early testing to treat IBD.  Larger scale clinical trials are in-progress.
·         Good evidence is not there at this point that LDN can be used to positively treat IBD.  More work is needed before that can be said.
·         If patients are interested in LDN, enroll in one of the clinical studies.  Otherwise, avoid the therapy until further testing is done.
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1.       Marrazzi, Mary Ann, Jill M. Wroblewski, Joseph Kinzie, and Elliot D. Luby. "HighDose Naltrexone and Liver Function Safety." The American Journal on Addictions 6, no. 1 (1997): 21-29.
2.       McCarthy, Lois, Michele Wetzel, Judith K. Sliker, Toby K. Eisenstein, and Thomas J. Rogers. "Opioids, opioid receptors, and the immune response." Drug and alcohol dependence 62, no. 2 (2001): 111-123.
3.       Smith, Jill P., Heather Stock, Sandra Bingaman, David Mauger, Moshe Rogosnitzky, and Ian S. Zagon. "Low-dose naltrexone therapy improves active Crohn's disease." The American journal of gastroenterology 102, no. 4 (2007): 820-828.
4.       Shannon, Angela, Naim Alkhouri, Shadi Mayacy, Barbara Kaplan, and Lori Mahajan. "Lowdose naltrexone for treatment of duodenal Crohn's disease in a pediatric patient." Inflammatory bowel diseases 16, no. 9 (2010): 1457-1457.
5.       Smith, Jill P., Douglas Field, Sandra I. Bingaman, Robert Evans, and David T. Mauger. "Safety and Tolerability of Low-dose Naltrexone Therapy in Children With Moderate to Severe Crohn's Disease: A Pilot Study." Journal of clinical gastroenterology (2012).
6.       Smith, Jill P., Sandra I. Bingaman, Francesca Ruggiero, David T. Mauger, Aparna Mukherjee, Christopher O. McGovern, and Ian S. Zagon. "Therapy with the opioid antagonist naltrexone promotes mucosal healing in active Crohn’s disease: a randomized placebo-controlled trial." Digestive diseases and sciences 56, no. 7 (2011): 2088-2097.
7.       http://www.sciencebasedmedicine.org/index.php/low-dose-naltrexone-bogus-or-cutting-edge-science/

Sunday, March 24, 2013

New Protocols for IBD Treatment


IBD Primary Therapy Treatment Protocol


The current trend in treating IBD is to take a more aggressive approach to early treatment.   The historical treatment regimen would generally consist of two parts:

1.        The use of corticosteroids such as prednisone in a fairly high dose to stop the immediate damage being caused by inflammation and induce remission.
2.       The use of fairly low side effect drugs with lower efficacy, such as the 5-ASA drugs.

The treatment approach would then follow a continuum from lower side effect/lower efficacy to higher side effect/higher efficacy.  A common progression a decade ago may have been as follows (depending on the location effected):
1.       Take Pentasa/Asacol (Mesalamine), 2 grams (.8 grams for Asacol) daily
2.       Take Pentasa/Asacol (Mesalamine), 4 grams (1.6 grams for Asacol) daily*
3.       Move on to sulfasalazine. 
4.       Add in metronidazole and/or ciprofloxacin**
5.       Move to Azathioprine, 6-mercaptopurine and methotrexate.
6.       Go to using Infliximab
7.       Perform moderate surgical interventions
8.       Go to long term corticosteroid use
9.       Perform extreme surgical intervention go to Total Parenteral Nutrition (1)

The approach protocol has changed greatly due to more evidence-based approaches in recent years.  First, there is a general recognition that corticosteroids greatly reduce inflammation but don’t necessarily impact the underlying disease activity (they treat and even stop the symptoms, but not the cause).  Second, there are targeted approaches to medicines based on the problem, and surgery is recommended more to address point issues (e.g. structuring) as opposed to general treatment.  As an example, fistulizing disease had a separate treatment regimen (generally surgically focused), that isn’t addressed above.  The abilities of drugs like Cipro/Flagyl and the TNF-alpha drugs to close fistulae (and have better long-term outcomes) has reduced the “surgery first” approach in most cases.  Third, there is a move toward using more aggressive (though with potentially larger side effects) treatments earlier. 

The primary reason for taking a more aggressive initial approach to treatment is bowel preservation.  Once damage progresses to the point of structuring, it cannot be reversed.  The original Step-up approach allowed early bowel damage in non-responsive patients.  Because of this and because of new evidence on the 5-ASA (mesalamine) drugs (and several other immunosuppressants) in Crohn’s being less effective than initially thought, and because of the introduction of the biologics (the anti-TNF-alpha drugs), new treatment regimens were proposed in the past 5 years.(2)

Based on the evidence from the past few years, the following are the current consensus guidelines for the treatment of the disease:
Mild Ileocaecal Crohn’s:
1.     Give Budesonide to induce remission
2.     Monitor in remission to determine if any maintenance therapy is needed.

Moderate/Severe ileocaecal Crohn’s:
1.     Give Budesonide (Prednisone if non-localized Crohn’s) coupled with an Anti-TNF-Alpha agent
a.       Choose the Anti-TNF-Alpha agent based on cost, availability, and lifestyle impact
2.     For maintenance, continue the Anti-TNF-Alpha agent
3.     Switch to another TNF-Alpha agent if ineffective (3,4)
4.     Targeted surgery as needed

There is some evidence that Azathioprine and 6-mercaptopurine can induce remission quicker with the anti-TNF-Alpha agents, but the work in this area is still sparse.  Given the risk profiles of these drugs, more research on joint therapy v. monotherapy is needed.  Methotrexate in combination with ant-TNF-Alpha agents has not shown efficacy over monotherapy and should be dropped from the regimen. (5)

For UC, 5-ASA (especially topical) has some efficacy in inducing and maintaining remission in mild-to-moderate disease.(6)  Additionally, there are topical hydrocortisone and budesonide therapies that are effective in achieving remission.  As such, the following are recommendations for UC:

Mild UC:
1.     5-ASA (preferably topical) and Budesonide/Hydrocortisone enema to induce remission
2.     5-ASA for maintenance

Moderate/Severe UC:
1.     5-ASA (preferably topical) and Budesonide/Hydrocortisone enema to induce remission
2.     Anti-TNF-alpha Agents
3.     Colectomy

As with Crohn’s, the effectiveness of Azathioprine and 6-mercaptopurine in the treatment are UC are still effective, but slow in inducing remission.  (7)

All of the above are general guidelines based on the current research and consensus treatment protocols.  There may be economic reasons to use different treatments, acute presentations requiring immediate interventions, lack of responsiveness or tolerance of treatments due to side effects, and other factors that may support a deviation from the above.  If your doctor does deviate, ask them why and to provide supporting, recent, high quality evidence (and, as always, do your own homework!)  In a similar vein, keep current with the latest research - bigger, better controlled studies can disprove earlier work, and new treatments are always appearing.

Bottom Line


·         The treatment protocols to induce remission and maintain it have changed dramatically over the past 10 years – if your GI doc hasn’t kept up, it’s time to change providers or educate your current one.
·         Earlier, more aggressive treatment with anti-TNF-alpha drugs is now the current gold standard approach for moderate-to-severe IBD.
·         Older drug regimens (like 5-ASA for Crohns and widespread systemic steroid use) are no longer standard regimens.


*The efficacy of 5-ASA drugs in continuing remission v. placebo will be the subject of a future post.
** Another future post will look at combinatorial therapies with antibiotics and where they are appropriate. 

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1.     Sandborn, W. J., and B. G. Feagan. "Mild to moderate Crohn's disease–defining the basis for a new treatment algorithm." Alimentary pharmacology & therapeutics 18, no. 3 (2003): 263-277.
2.     Panaccione, R., Paul Rutgeerts, W. J. Sandborn, B. Feagan, S. Schreiber, and S. Ghosh. "Review article: treatment algorithms to maximize remission and minimize corticosteroid dependence in patients with inflammatory bowel disease." Alimentary pharmacology & therapeutics 28, no. 6 (2008): 674-688.
3.     Danese, Silvio, JF. Colombel, Walter Reinisch, and P. J. Rutgeerts. "Review article: infliximab for Crohn’s disease treatment–shifting therapeutic strategies after 10 years of clinical experience." Alimentary pharmacology & therapeutics33, no. 8 (2011): 857-869.
4.     Feagan, Brian G., Marc Lemann, Ragnar Befrits, William Connell, Geert D'Haens, Subrata Ghosh, Pierre Michetti et al. "Recommendations for the treatment of Crohn's disease with tumor necrosis factor antagonists: An expert consensus report." Inflammatory bowel diseases (2012).
5.     Alfadhli, A. A. F., J. W. D. McDonald, and B. G. Feagan. "Methotrexate for induction of remission in refractory Crohn’s disease." Cochrane Database System Rev 4 (2004).
6.     Feagan, Brian G., and John K. MacDonald. "Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis." Cochrane Database Syst. Rev 10 (2012).
7.     Kornbluth, Asher, and David B. Sachar. "Ulcerative colitis practice guidelines in adults: American college of gastroenterology, practice parameters committee."The American journal of gastroenterology 105, no. 3 (2010): 501-523.

Sunday, March 17, 2013

Artificial Sweeteners and Crohns/Ulcerative Colitis

Aspartame, Sucralose, and Saccharin



Artificial sweeteners are one of the more controversial dietary topics.  They have been vilified as having causal relationships to everything from cancer to weight gain.  They have also been bandied about in relation to inflammatory bowel disease.  The speculation ranges from blaming artificial sweeteners for IBD due to their prevalence (and IBD’s prevalence) in more developed societies, to being patented as a treatment for IBD.  No, seriously – Coca-cola patented an artificial sweetener delivered mechanism for “treating” autoimmune disorders back in 2007.(1)  What does the evidence say about artificial sweeteners and IBD?

Artificial sweeteners are sugar substitutes made chemically (as opposed to being extracted from a plant source).  For the purposes of this entry, I will not include things like corn syrup, sorbitol, Stevia, or xylitol in the discussion as they are (relatively) direct extracts of plants, nor those that are banned in the US for good reason (like lead acetate – very sweet and low calorie, but the side effect of lead poisoning really ruins the experience).  There are two primary concerns surrounding IBD that are commonly voiced related artificial sweeteners – first, that they are related or exacerbate IBD.  Second, that they cause diarrhea or other gastrointestinal upset.

There are 3 primary artificial sweeteners in the US market – Aspartame (Nutrasweet, Equal), Saccharine (Sweet’N’Low) and relative newcomer Sucralose (Splenda).  They all add “sweetness” to products without the calories of sugar, and have varying properties related to heating/storage/etc as differentiators.  Unfortunately, they have recently been “linked” to IBD by a paper in the World Journal of Gastroenterology – “Etiology of inflammatory bowel disease: A unified hypothesis” by Qin, which has been reported in many news sources. (2)

In his article, Qin hypothesizes that “it is proposed here that saccharin and sucralose might be the key causative factors for IBD”, in addition to suggesting that Ulcerative Colitis and Crohns Disease are actually two manifestations of the same disease (I won’t cover that in this entry, but I will look at the causative nature of sucralose and saccharine in IBD).

The first step in analysis is the plausibility of the mechanism of action.  Qin provides the mechanism of action that is consistent with the current complexity model of IBD – namely that it is a combination of genetics and environmental factors.  One factor cited by Qin in his hypothesis is the increased intestinal permeability in not only IBD patients but relatives and spouses, who would share a common environmental factor.  This holds for Crohn’s Disease, but recent work on UC points toward no increased permeability for spouses (supporting a genetic factor for permeability and potential predisposition.)  The recent work is still on a small scale, but the research for increased permeability in co-habitating non-relatives in UC is sketchy at best. (3) 

The second part of the mechanism cited is the increased dietary intake of saccharine and sucralose causing a reduction in gut bacteria.  There is no valid evidence that sucralose reduces gut bacteria, even in rats.  The cited study (4) was discredited for major deficiencies shortly after publication.(5)  In general, the most current review shows that early animal models didn’t translate well to human studies, with no major biological impact based on normal consumption of artificial sweeteners, including saccharine and sucralose, in humans.(6)  An even larger trial on the metabolic effects of sucralose is currently underway: http://clinicaltrials.gov/ct2/show/NCT01200940, and includes effects on stomach emptying.
Because the mechanism for action is not supported by the current research, it would tend to disprove any correlation epidemiologically having a causative relationship (at least by the mechanism described).  That said, let’s look at a few contrarian epidemiological results:

·         The incidence rate in Alberta between 1977 and 1981 was one of the highest ever for Crohn’s, recorded at 10 in 100,000, with UC at 19.6 out of 100,000.  This was after saccharine was banned but before sucralose was introduced.(7)  No commensurate change was seen in the followup study a decade and a half later.
·         Crohn’s and UC have been either increasing or stable everywhere since 1980.  Sucralose was not introduced until the early 1990s (up to the mid-2005s for Europe), and took a while to increase in usage, which saccharine usage was overtaken by Aspartame in 1986/1987.(8,9)
·         One of the key markers in the consumption of artificial sweeteners was the removal of saccharine by Coke and Pepsi in 1984/1985.  Consumption was predominantly female at the time, yet no drop was seen in incidence after this action.  Additionally, the female to male ratio for UC is less than one, inconsistent with an expected dose-response (though it is greater than one for males)(10)

The epidemiological data is not supportive of the hypothesis, and further research would not likely be a valuable course to pursue without a stronger mechanism for action or better dose-response epidemiological data.  Qin, hypothesis was interesting (and his papers though provoking), and keeping an open dialog is valuable, but the work isn’t supported by the research.  If this isn’t a basis for avoiding artificial sweeteners, what about potential GI side effects?

Artificial sweeteners have many unproven rumors that about related to their use.  Saccharine was the subject of a major controversy based on research showing increased cancer rates in rat studies in the mid-1970s (and the subject of controversies in the early part of the century largely due to industrial battles).  Later studies showed that the rat models did not translate to humans, and there were no deleterious side effects on human consumption, with the National Cancer Institute concluding “Human epidemiology studies (studies of patterns, causes, and control of diseases in groups of people) have shown no consistent evidence that saccharin is associated with bladder cancer incidence”.(11)  Because of this, saccharine and other artificial sweeteners have been the subject of many conspiracy theory mechanisms of effect, but there is no evidence of any of the three major sweeteners having a causal relationship with cancer.

The other place that artificial sweeteners get a bad rap is from the products of digestion they produce.  The general digestive impacts of the three most common artificial sweeteners would be based on their breakdown in the GI tract, which is well understood:
·         Aspartame.  Breaks down into constituent amino acids aspartate and phenylalanine, as well as methanol.  Individuals with phenylketonuria (the inability to metabolize phenylalanine) may have issues with aspartame, but there are no other concerns.  A comprehensive review in 2002 found “When all the research on aspartame, including evaluations in both the premarketing and postmarketing periods, is examined as a whole, it is clear that aspartame is safe, and there are no unresolved questions regarding its safety under conditions of intended use.” (12)
·         Saccharine.  Saccharine is absorbed in the intestines without being broken down into constituent components (hence the lack of associated calories).  The absorbed saccharine is excreted in urine, and does not accumulate in tissues over time.(13)
·         Sucralose.  Sucralose is made from sucrose with chlorine atoms substituted for three hydroxyl groups.  Rumor-mongering makes reference to the toxicity of chlorine, but sucralose isn’t actually broken down by the body and is released (in feces and urine) intact.(14)
The final issue with the major sweeteners is confusion with the sugar alcohols, like sorbitol and mannitol.  Most sugar alcohols are strong laxatives (mannitol was used as a medical laxative), and have numerous GI impacts ranging from diarrhea to bloating.  As little as 5g of sorbitol can cause symptoms, with most individuals showing distress after 20g of consumption (a stick of gum has approximately 1.5g).  While there are products that have both a sugar alcohol and another artificial sweetener (for example, many sugar free gum products and ice creams have sucralose and sorbitol), the GI upset has been shown to be caused by the sugar alcohol when isolated.(15,16) 

Bottom Line


·         There is no evidence that the artificial sweeteners (sucralose, aspartame, saccharine) are linked to causing IBD or exacerbating it.
·         None of the major sweeteners (sucralose, aspartame, saccharine)  have ever shown in a controlled study to have negative GI side effects (IBD-related or otherwise). 

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1.       Prakash, Indra, and Grant E. DuBois. "High-Potency Sweetener Composition for Treatment and/or Prevention of Autoimmune Disorders and Compositions Sweetened Therewith." U.S. Patent Application 11/556,118.
2.       Qin, Xiaofa. "Etiology of inflammatory bowel disease: A unified hypothesis."World Journal of Gastroenterology: WJG 18.15 (2012): 1708.
3.       Büning, Carsten, et al. "Increased small intestinal permeability in ulcerative colitis: Rather genetic than environmental and a risk factor for extensive disease?." Inflammatory Bowel Diseases (2012).
4.       Abou-Donia, Mohamed B., et al. "Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome p-450 in male rats." Journal of Toxicology and Environmental Health, Part A 71.21 (2008): 1415-1429.
5.       Brusick, David, et al. "Expert Panel report on a study of Splenda in male rats."Regulatory Toxicology and Pharmacology 55.1 (2009): 6-12.
6.       Brown, Rebecca J., and Kristina I. Rother. "Non-nutritive sweeteners and their role in the gastrointestinal tract." Journal of Clinical Endocrinology & Metabolism 97.8 (2012): 2597-2605.
7.       Pinchbeck, B. R., J. Kirdeikis, and A. B. Thomson. "Inflammatory bowel disease in northern Alberta. An epidemiologic study." Journal of clinical gastroenterology 10.5 (1988): 505.
8.       Molodecky, Natalie A., et al. "Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review."Gastroenterology (2011).
10.   Russel, Maurice GVM, and Reinhold W. Stockbrügger. "Epidemiology of inflammatory bowel disease: an update." Scandinavian journal of gastroenterology 31.5 (1996): 417-427.
11.   http://www.cancer.gov/cancertopics/factsheet/Risk/artificial-sweeteners
12.   Butchko, Harriett H., et al. "Aspartame: review of safety." Regulatory Toxicology and Pharmacology 35.2 (2002): S1-S93.
13.   Renwick, A. G. "The fate of intense sweeteners in the body." Food chemistry16.3 (1985): 281-301.
14.   Molinary, S. V., and M. E. Quinlan. "8 Sucralose." Sweeteners and Sugar Alternatives in Food Technology (2008): 130.
15.   Meihoff, Walter E., and Fred Kern Jr. "Bile salt malabsorption in regional ileitis, ileal resection, and mannitol-induced diarrhea." Journal of Clinical Investigation47.2 (1968): 261.
16.   Hyams, Jeffrey S. "Sorbitol intolerance: an unappreciated cause of functional gastrointestinal complaints." Gastroenterology 84.1 (1983): 30.

Sunday, March 10, 2013

Worms and IBD


Hemlinth Therapy


One of the more radical therapies being investigated as a treatment for IBD is worm therapy.  When most developed nations think of worms, the earthworm comes to mind.  In developing nations, worms evoke a different picture – endemic parasites that are present in undercooked food, contaminated water, and soil that can be transmitted by ingestion, through mosquito bites, or during sexual intercourse.  These worms, belonging to the family of helminths, are parasites that live off the largess of their host – in this case the human body.  They include hookworms, roundworms, pinworms, and tapeworms (amongst others). 

Helminths are the cause of many diseases, the most prevalent being the compromise of the immune system and malnutrition due to a hookworm, roundworm, or whipworm infection in the intestines.  Anemia, nausea, malabsorption, and intestinal blockages are all common side effects of helminthes infection.   Intestinal worms generate an immune response when they lay eggs, and they release toxins as a byproduct of their own digestive process, causing further systemic disturbance.(1)  Given their negative impact on intestinal functioning, why are the proposed as a treatment for IBD?

One of the postulated mechanisms of inflammation in IBD is the Th1 response goes out of control.  Th1, a cytokine producing helper T-cell, is believed to be the cause of autoimmune responses and is a generator of inflammation in the body.*  The corresponding Th2 cytokine producer modulates the Th1 response, reducing inflammation.  Both exist in relative homeostatis in a normal functioning human body.  Crohn’s disease is believed to be a Th1-mediated disease and Ulcerative Colitis a Th2-mediated disease, with some evidence of associated causality.(2)

Hemolinth parasite infection rates have been shown to be inversely proportional to allergy rates in many locations.  The inverse mapping applies to IBD infection rates as well.  Places in Asia and Africa with high infestation rates also show the lowest IBD infection rates.  There is additional support from studies involving children who grew up in high parasite areas then moved to low parasite areas having a lower incidence of IBD.  There are many other factors co-incident with poor sanitation and hemolinth infection, and there have been no studies that have conclusively isolated hemolinth infection and IBD prevention.  Though there is some correlation, there is no evidence of a causal relationship, though one has been postulated. 

Specifically related to immune response in an allergic sense, the chronic infection with hemolinth parasites has been shown to regulate Immunoglobulin E (IgE) response.(3,4)  IgE has been shown to assist in perpetuating a Th2 response.  Because Crohns is believed to be Th1 mediated disease and the Th1 response is inactivated by the presence of Th2, there is a theoretical basis that parasite infection may have a positive modulatory effect on the disease.  This is a simplistic explanation, but the actual relationship between the cytokines is significantly more complex and not completely understood.

Hemolinth studies have occurred (and are still occurring) in humans for treating IBD.  The initial animal studies showed promise, but I will focus here on the human studies.  Some of the most promising studies involve Trichuris suis, or pig worm.  The initial work by Weinstock had three Crohns patients consume Trichuris suis eggs (or ova).  All three had objective improvements in their disease with no side effects.  Smaller follow-on studies showed similar results, as did studies involving UC patients (the mechanism for action on UC is less clear if the Th2 modulation model holds).(5,6)  Though the IBD treatments showed no major side effects, the largest study of T. Suis ingestion for allergic rhinitis did show significant side effects in the form of moderate to severe gastrointestinal issues lasting up to two weeks during the early ingestion stages, with continuing adverse reactions in a subclinical form for the mid-term use (long term data is not yet available).  While there is some speculation, there is no good data available right now on why there was a major discrepancy between the trials.(7)

The trials related to the use of T. Suis to treat IBD is promising, but not yet convincing for a few reasons:
1.        The sample sizes to-data have been small.  This is not unusual in pilot studies, it just shows the need for additional work.
2.       The majority of work has been done by the same group of researchers.  It would be beneficial to see repeatable results confirmed by other research teams to avoid potential issues with protocols or results reporting that may not be readily apparent. 
3.       There are known side effects of parasitic worm infection ranging from GI problems to malabsorption to increased susceptibility to bacterial infection.  The studies using T. Suis have conflicting information on adverse events and this needs to be resolved.
4.       While there was a clinical improvement in the trials against placebo, the treatment would still need to be compared to the current best treatment options in terms of both efficacy and side effects.  The efficacy cannot be adequately benchmarked given the small sample size of the previous trials.
5.       As with all similar treatments, if there is a secretion or other chemical action caused by T. Suis that leads to the postulated modulation, isolation of that mechanism and a more controlled implementation of just the active chemical action would be the most advantageous.

Hemolinth therapy shows promise for IBD, and the current recommendation would be to do larger, longer term trials in comparison to current gold standard treatment.  Given the potential for side effects, individuals not enrolled in trials should be taking a wait-and-see approach.

Bottom Line


·         T. Suis showed efficacy in reducing symptoms (objective and subjecting) v. placebo in pilot trials.
·         Adverse event activity associated with T. Suis has conflicting reports.  The potential for serious adverse effects exists, and needs to be quantified.
·         The evidence does not yet support implementation of T. Suis therapy for IBD patients outside of a clinical trial setting.

* Amongst other things, Th1 is responsible for the production of TNF-alpha. The biological treatments for IBD are thought to operate on this mechanism to interrupt the inflammatory response chain.

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1.       World Health Organization. "Prevention and control of intestinal parasitic infections." Report of a WHO Expert Committee. Ginebra: WHO (1987).
2.       Bouma, Gerd, and Warren Strober. "The immunological and genetic basis of inflammatory bowel disease." Nature Reviews Immunology 3.7 (2003): 521-533.
3.       Yazdanbakhsh, Maria, Anita van den Biggelaar, and Rick M. Maizels. "Th2 responses without atopy: immunoregulation in chronic helminth infections and reduced allergic disease." Trends in immunology 22.7 (2001): 372-377.
4.       Bashir, Mohamed Elfatih H., et al. "An enteric helminth infection protects against an allergic response to dietary antigen." The Journal of Immunology169.6 (2002): 3284-3292.
5.       Hunter, M. M., and D. M. McKay. "Helminths as therapeutic agents for inflammatory bowel disease." Alimentary pharmacology & therapeutics 19.2 (2004): 167-177.
6.       Summers, Robert W., et al. "Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease." The American journal of gastroenterology 98.9 (2003): 2034-2041.
7.       Bager, Peter, et al. "Symptoms after ingestion of pig whipworm Trichuris suis eggs in a randomized placebo-controlled double-blind clinical trial." PloS one6.8 (2011): e22346.

Sunday, March 3, 2013

Enemas and IBD, Number 2


Medical Enemas


Last week’s post covered controversial enema claims and unproven treatments.  There are, however, several uses for enemas that are supported by evidence-based medicine.  Enemas can be used in procedural preparation, as part of a post-operative regime, and as a medical delivery mechanism.  Their use is more frequent in distal Crohn’s disease effecting the large intestine and rectum and in left-sided Ulcerative Colitis and Ulcerative Proctitis, due to the fact that enemas generally only effect those locations in the GI tract.  A few of the evidence supported medical uses are covered below.

Drug Delivery


Drug delivery directly to the colon is done for three primary reasons – to decrease systemic absorption of specific drugs, to increase bioavailability of targeted drugs, and to provide direct application of drugs to effected areas. 

Many drugs used to treat IBD have a negative systemic impact.  Chief among these are corticosteroids, which can cause high blood pressure, eye problems, osteoporosis, unusual fat deposition, and increased risk of infection.  Because of this, targeted delivery of these drugs through the use of an enema reduces overall systemic absorption.  Both budesonide and prednisone, two key anti-inflammatory drugs used in IBD treatment, have been successfully delivered via enema.  The enemas can be liquid or foam-based, and have been shown to have fewer systemic side effects than oral use of the same drugs. (1,2)

A corollary to the systemic side effects is related to bioavailability.  There digestive system is complex, and everything from saliva to the inhospitable pH from stomach acids to pancreatic enzymes can degrade or render inert medicines.  Drug companies spend almost as much time engineering how to get a drug to the area of the body where it will be absorbed (and even better, time released) as they do in the basic research for the drug.  While injections are possible with certain drugs, others can be absorbed through the intestinal mucosal layer by being inserted into the other end – bypassing the digestive process.

The final reason is the direct delivery of drugs to the affected area.  Just like a topical treatment on the skin, direct delivery allows for a high dose of drugs to be brought to bear on the area of concern itself.  Drugs like mesalamine (Canasa ™) and hydrocortisone (Cortenema™) can be delivered directly to inflamed areas through enemas.(3)

Procedural Uses


For a lower-GI series, a barium enema is delivered through a tube into the rectum prior to taking X-rays of the large intestines.  The lower GI series allows for detailed imaging and review of the large intestine, and is an alternative mechanism to the colonoscopy.  The lower-GI barium series has generally been shown to be a less effective diagnostic technique than colonoscopy in most cases, and has fallen out of general favor as a primary diagnostic tool and is used only in very specific circumstances (e.g. severe stenosis).(4)

For preparation of the large intestine before a sigmoidoscopy, enemas are often used.  A single over-the-counter enema has been shown to be effective in cleaning out the lower parts of the GI tract for the procedure (and was more effective than suppositories).  Some rectal surgeries and prostate procedures use enemas as well for prep.(5)

Other preparatory uses have fallen out of favor.  For example, enemas were previously recommended for those having endourological surgery.  The theory was that the enema would prevent future urinary tract infections and other complications due to fecal contamination.  For the most part, there was no clinical difference between patients preparing with the enemas and those who did not in post-operative infection rates. (6)

Finally, enemas have been put forth as a delivery mechanism for fecal transplant operations.  The data on their effectiveness as a delivery mechanism is preliminary, but early studies show promise for getting the transplanted bacteria delivered to the distal small intestine.(7)

Bottom Line


·         Enemas have multiple medical uses in treating IBD, with new uses appearing and others being removed from common use.

1.       Danielsson, Å., et al. "A steroid enema, budesonide, lacking systemic effects for the treatment of distal ulcerative colitis or proctitis." Scandinavian journal of gastroenterology 27.1 (1992): 9-12.
2.       McIntyre, P. B., et al. "Therapeutic benefits from a poorly absorbed prednisolone enema in distal colitis." Gut 26.8 (1985): 822-824.
3.       Chourasia, M. K., and S. K. Jain. "Pharmaceutical approaches to colon targeted drug delivery systems." J Pharm Pharm Sci 6.1 (2003): 33-66.
4.       Rockey, D. C., et al. "Analysis of air contrast barium enema, computed tomographic colonography, and colonoscopy: prospective comparison." The Lancet 365.9456 (2005): 305-311.
5.       Underwood, D., et al. "A prospective randomized single blind trial of Fleet phosphate enema versus glycerin suppositories as preparation for flexible sigmoidoscopy." Irish journal of medical science 179.1 (2010): 113-118.
6.       Utrera, N. Miranda, et al. "An analysis of the value of bowel preparation for preventing postoperative complications in endoscopic surgery." actas urol esp34.3 (2010): 278-281.
7.       Silverman, Michael S., Ian Davis, and Dylan R. Pillai. "Success of Self-Administered Home Fecal Transplantation for Chronic Clostridium difficile Infection." Clinical Gastroenterology and Hepatology 8.5 (2010): 471-473.