Sunday, September 29, 2013

IBD in the Age of Cholera

Historical Treatment of IBD:  The Early Years


Crohn’s disease and Ulcerative Colitis have a long history.  The first discovery of thickening of the terminal ileum was recorded in 1761 by Morganini.  Unfortunately, most of the earlier observation of ileocolonic inflammation was post-mortem, greatly limiting the treatment options.  Most early sufferers of inflammatory bowel disease were thought to have other more common conditions, such as consumption (now known as tuberculosis), cholera, or chronic dysentery.(1)  Treatment options were limited to hydration and herbal options that were region-specific.  An example of early treatment options for treating colitis (with apparently a “kitchen sink” approach) is mentioned in the 1872 book “The Complete Herbalist”:

A free lobelia emetic may be given at the outset, and the bowels evacuated by a purge; castor-oil with laudanum is the best for this purpose. After the purge, take twenty grains of quinine and one drachm of leptandrin, divide into six powders and take one every hour until all are taken. The tenesmus should be relieved by injecting into the rectum five or six ounces of starch water, containing about twenty drops of laudanum, as often as is necessary. Ipecacuanha is a superior remedy. Gelsemium may be given afterwards, and if required the fever should be controlled by veratrum. The patient should lie quietly in bed, and his diet should consist of grapes, baked apples, flour porridge, bread, rice, coffee, beef-tea and ripe fruit. The astringents are of course necessary, and for this purpose tannic and gallic acids kino, rhatany, opium, capsicum, cranesbill, etc., can be given. Tonics should be combined when the patient is weak, and if the debility is very great the alcoholic stimulants should be administered. I can with safety recommend my "Restorative Assimilant" as a sure cure for both acute and chronic dysentery, as well as for all bowel complaints. The Herbal Ointment should be rubbed externally on the whole abdomen to relieve the inflammtion. In the chronic form, the astringents, with such other remedies as may be indicated by the symptoms, are all that is necessary.

While dismissed today as mostly bunk, there is some science behind a few of the recommended treatments above:

Lobelia Emetic:  The subspecies of lobelia known as “Indian Tobacco” was used extensively to treat many conditions by the induction of vomiting.  Unfortunately, given the dehydration that comes with chronic colitis, this was more likely to kill a patient than to cure her.(2)

Castor Oil:  The turn-of-the-century cure all (the 20th century, that is), castor oil and its derivatives are still used as laxatives and as medicinal delivery additives.  Unfortunately, the laxative effect would only exacerbate dehydration, and potentially cause further mucosal damage.(3)

Laudanum:  Also known as opium, this one would have had an actual short term effect.  Opiates are well known for decreasing bowel motility, and can reduce the effects of diarrhea.  While opium itself isn’t frequently used anymore (given the side effects), other opiates are still commonly used (that Immodium in your cabinet qualifies) to treat short term diarrhea.  The direct injection into the rectum may have had a more immediate effect.(4)

Quinine.  Not specific to colitis, but more relevant for malaria treatment, quinine is one of the earliest known medicines still in common use (though there are more effective anti-malarials).  If the patient had recently come from the tropics, this may have helped the underlying malaria if present, but not necessarily done anything for underlying Crohn’s or Ulcerative Colitis.(5)

Leptandrin.  There is no specific definition of what leptandrin was – it included plants such as veronicastrum virginicum (leptandra).  There is no proven efficacy for leptandra, but it still continues to be touted by homeopaths and others and is a frequent component of non-proven hemorrhoidal compounds.(6)

Ipecacuanha.  Carapichea ipecacuanha is still used in medicine as a strong emetic.  Poison control centers will recommend using Syrup of Ipecac in specific ingestion cases because of its immediate and strong effects.  As with lobelia, inducing vomiting to treat a disease that causes dehydration is strongly contra-indicated today.(7)

Gelsemium.  Lost in the annals of history as a potential anti-malarial treatment, there isn’t much in modern literature proposing this as a treatment for IBD, but there is some current research showing efficacy in animal models as an anti-anxiety drug.  The potential calming effect may have been present in the earlier treatments, allowing the patient to be less stressed about their condition.(8) 

Veratrum.  A fairly toxic plant that was originally used to treat high blood pressure, veratrum has fallen out of favor in light of more effective drugs.  A derivative, however, is still used as a treatment for certain cancers – cyclopamine (named for the birth defect from ingestion of veratrum that can cause single-eyed offspring).(9)

Grapes, baked apples, flour porridge, bread, rice, coffee, beef-tea and ripe fruit.  There is some vestige of this treatment modality present in the current (though controversial in efficacy) BRAT diet.(10)  The concept of having fairly easy to tolerate foods with any type of stomach upset is easily understandable, (though how easily tolerated grapes are compared to other foods is questionable).

Tannic Acid.  The use of tannic acid at the time would likely have been a misuse related to tea.  Teas contain tannin (not tannic acid), and are the subject of a full post.  Various tannates (e.g. albumin tannate) are anti-diarrheals and this would have had a possible positive effect.

Gallic Acid.  Similar to tannic acid (and also found in tea leaves), gallic acid is a long used astringent.  There is little evidence of efficacy in colitis, but there is some preliminary data that showed some efficacy in treating NSAID-induced gastropathy.(11)

Kino and Rhatany.  These are both herbs that contain tannin compounds – see tannic acid above.

Opium.  See laudanum above.

Capsicum.  Capsicum plants are part of the nightshade family and include many peppers.  The ingestion of associated capsaicin would have negative short term effects on any active colitis, but there is some preliminary evidence that there may be long term positive effects (http://evidencebasedibd.blogspot.com/2013/04/burn-baby-burn.html).

Cranesbill.  Also known as germaniums, cranesbill hasn’t had any evidence of efficacy in modern medicine.  They do make a very nice addition to any garden as a robust, flowering plant that is fairly hardy and comes in a multitude of colors.

Alcoholic Stimulants.  Alcohol use and any form of colitis is contraindicated.  A large enough dose may have taken the person’s mind off their colitis, but the dehydrating effects would not have been welcome.  As with tea, alcohol warrants its own posting.

Restorative Assimilant.  Unfortunately, this is too reminiscent of recent offerings.  The author touts his own cure-all for treating colitis, and like so many other cure-alls over the years this one didn’t pan out.  This should hopefully be a lesson for those viewing ads that claim to cure any disease, small or large, with one simple solution…

This historical view of treating colitis is interesting and informative.  While taking all of the items recommended by “The Complete Herbalist” is likely to end up with a person becoming much sicker than when they started, some of the components that had a basis in observational medicine, the predecessor (but not a replacement for) science-based medicine, produced derivatives with efficacy in treating some of the symptoms of IBD.  Additionally, the shotgun-based approach of all of the above drugs could cause untold interactions – a cautionary tale for modern medicine.  The next post will look at the advancements in treatment of inflammatory bowel disease in the following century, through the present day.

Bottom Line


·         Some of the treatments in the 1800s have modern derivatives that are still used to treat disease.
·         Though some of the cures had a basis in observational medicine, many were still based in tradition and superstition – something that evidence based medicine still fights.

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1.       Schofield, Philip F. "The Natural History and Treatment of Crohn's Disease: Hunterian Lecture delivered at the Royal College of Surgeons of England on 11th November 1964." Annals of the Royal College of Surgeons of England 36, no. 5 (1965): 258.
2.       Laffan, Robert J., and Herbert L. Borison. "Emetic action of nicotine and lobeline." Journal of Pharmacology and Experimental Therapeutics 121, no. 4 (1957): 468-476.
3.       Capasso, Francesco, Nicola Mascolo, Angelo A. Izzo, and Timothy S. Gaginella. "Dissociation of castor oilinduced diarrhoea and intestinal mucosal injury in rat: effect of NGnitroLarginine methyl ester." British journal of pharmacology 113, no. 4 (1994): 1127-1130.
4.       Machella, Thomas E. "The Medical Management of Chronic Idiopathic Ulcerative Colitis." Annals of the New York Academy of Sciences 58, no. 4 (1954): 499-502.
5.       Achan, Jane, Ambrose O. Talisuna, Annette Erhart, Adoke Yeka, James K. Tibenderana, Frederick N. Baliraine, Philip J. Rosenthal, and Umberto D’Alessandro. "Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria." Malar J 10, no. 144 (2011): 1475-2875.
6.       Boskowitz, George W. Extracts from lectures on therapeutics. Printed by courtesy of FA Greene, 1910.
7.       Magnani, Paolo, Anita Conforti, Elisabetta Zanolin, Marta Marzotto, and Paolo Bellavite. "Dose-effect study of Gelsemium sempervirens in high dilutions on anxiety-related responses in mice." Psychopharmacology 210, no. 4 (2010): 533-545.
8.       Magnani, Paolo, Anita Conforti, Elisabetta Zanolin, Marta Marzotto, and Paolo Bellavite. "Dose-effect study of Gelsemium sempervirens in high dilutions on anxiety-related responses in mice." Psychopharmacology 210, no. 4 (2010): 533-545.
9.       Taipale, Jussi, James K. Chen, Michael K. Cooper, Baolin Wang, Randall K. Mann, Ljiljana Milenkovic, Matthew P. Scott, and Philip A. Beachy. "Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine." Nature 406, no. 6799 (2000): 1005-1009.

10.   Duro, Debora, and Christopher Duggan. "The BRAT Diet for Acute Diarrhea in Children: Should It Be Used?." Practical Gastroenterology 31, no. 6 (2007): 60.

Sunday, September 22, 2013

Acupuncture and Inflammatory Bowel Disease

On Pins and Needles Looking for a Cure


Acupuncture is one of the favorite “traditional Chinese medicine” techniques put forth as alternative medicine for many conditions.  It involves placing needles at strategic locations called meridians, which assist in the alignment of qi within the body.  Similar treatments include acupressure (used to put strategic pressure at meridian locations) and moxibustion (burning a particular mixture of dried mugwort, in combination with acupressure or standalone).

Acupuncture is generally tested for efficacy by using sham acupuncture – utilizing real practitioners and processes, but the needles are either not placed at “meridians” or penetrating needles aren’t used.  Unlike drug trials, there is a greater possibility in bias given the protocols.  First, individuals that are used to having acupuncture applied may question new locations or sensations.  Second, the study can’t be blinded from those providing the therapy (they know if they are performing real or sham acupuncture). This requires more stringent controls elsewhere in the study design to compensate.  Studies looking at acupuncture in IBD have been performed on at least two occasions, and other studies are currently planned.(1)  While there are two other studies published in the Journal of Traditional Chinese Medicine, a lack of adherence to acceptable research protocols and standards precludes their results from being validated.(2)

In a 2006 study looking at acupuncture as a treatment for ulcerative colitis (in conjunction with moxibustion), Joos et al treated 29 randomly assigned patients for 5 weeks (with follow-up for 16 weeks) with either real acupuncture or sham acupuncture (through non-meridian points).  The study primarily looked at the colitis activity index, finding that “the CAI decreased from 8.0 (+-/3.7) to 4.2 (+-/2.4) points and in the control group from 6.5 (+-/3.4) to 4.8 (+-/3.9) points”.  Given the initial differences in CAI starting points (likely an artifact of a small sample size), both showed equal drops in CAI.  The authors draw a conclusion that is used by many in alternative medicine and is the antithesis of evidence based medicine, specifically “Both traditional and sham acupuncture seem to offer an additional therapeutic benefit in patients with mild to moderately active UC.”  Unfortunately, all this study did was to confirm the presence of the placebo effect in acupuncture.  The same conclusion would have held for any control group exhibiting the placebo effect and is not proof of efficacy.(3)

The second study frequently cited was similarly performed by Joos et al, but focusing on Crohn’s disease.  The study looked at 51 patients over 4 weeks, with a twelve week follow-up.  The study looked at blood markers as well as the CDAI scores for an acupuncture group and a control group.  Similar to  the UC study, there was a CDAI drop in both groups, finding that in the treatment group “the CDAI decreased from 250 ± 51 to 163 ± 56 points as compared with a mean decrease from 220 ± 42 to 181 ± 46 points in the control group”.  The study further found a drop in α1-acid glycoprotein concentration in the treatment group but not the control group.  The authors concluded that “Apart from a marked placebo effect, traditional acupuncture offers an additional therapeutic benefit in patients with mild to moderately active CD.”(4)  

Although they note the placebo effect, their conclusion on the finding of an additional therapeutic benefit is way overdrawn.  The CDAI measure suffers from the same issues as in the UC study.  The alpha-1 AGP numbers appear promising, but suffer from a few problems.  First, when multiple blood measures are used, the p-value needs to be adjusted to consider any of the values having a positive outcome, not just a single measure, which was not done.  Second, alpha-1 AGP has been shown to be a poor marker for Crohn’s activity, though the research largely post-dates the author’s work (but the work is still cited as evidence of efficacy by others).(5)

A systemic review of gastrointestinal diseases and acupuncture in 2007 looked at the two studies above as well as the two poorly controlled studies from China that were noted.  The systemic review, based on the two studies above, reached an even more far-reaching set of conclusions.  Specifically:

With regard to inflammatory bowel diseases, the study results of Joos et al[20,21] show a statistically and clinically relevant improvement of disease activity pointing to some specific effects of acupuncture. Subgroup analyses in both studies revealed that higher activity grades and disease duration of less than 5 years seem to predict the efficacy of acupuncture therapy. Psychoneuroimmunologic pathways influenced by acupuncture may be an explanation for the presumed acupuncture effects in Crohn and Colitis patients. This needs to be evaluated in further clinical and experimental studies

The conclusion is baffling, until you look at the author list (a conflict of interest statement would have been nice).  Unfortunately, the data do not support the conclusions drawn.(6)

The two trials that studied the use of acupuncture to treat IBD showed nothing conclusive beyond the placebo effect.  Because acupuncture has no sound biological basis for action and there are no large scale trials showing its efficacy, there is no reason to recommend it for IBD treatment at this time.  Fortunately, if proper sterilization techniques are used, it is relatively benign, tongue in cheek references to spontaneous human combustion aside. (7)

Bottom Line


·         Acupuncture has been proposed as a treatment option for both Crohns and Ulcerative Colitis.
·         There is currently no evidence that acupuncture has efficacy in treating IBD beyond the placebo effect.
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2.       Wu, Meng, Jingqing Hu, and Biaoyan Liu. "The Reporting Quality Assessment of Complex Interventions’ Articles in Traditional Chinese Medicine." Evidence-Based Complementary and Alternative Medicine 2013 (2013).
3.       Joos, Stefanie, Nicole Wildau, Ralf Kohnen, Joachim Szecsenyi, Detlef Schuppan, Stefan N. Willich, Eckhart G. Hahn, and Benno Brinkhaus. "Acupuncture and moxibustion in the treatment of ulcerative colitis: a randomized controlled study." Scandinavian journal of gastroenterology 41, no. 9 (2006): 1056-1063.
4.       Joos, Stefanie, Benno Brinkhaus, Christa Maluche, Nathalie Maupai, Ralf Kohnen, Nils Kraehmer, Eckhart G. Hahn, and Detlef Schuppan. "Acupuncture and moxibustion in the treatment of active Crohn’s disease: a randomized controlled study." Digestion 69, no. 3 (2004): 131-139.
5.       Chambers, R. E., P. Stross, R. E. Barry, and J. T. Whicher. "Serum amyloid A protein compared with Creactive protein, alpha 1antichymotrypsin and alpha 1acid glycoprotein as a monitor of inflammatory bowel disease." European journal of clinical investigation 17, no. 5 (1987): 460-467.
6.       Schneider, Antonius, Konrad Streitberger, and Stefanie Joos. "Acupuncture treatment in gastrointestinal diseases: A systematic review." World Journal of Gastroenterology 13, no. 25 (2007): 3417.

Sunday, September 15, 2013

IBD, Ginger Ale, and Coke

Soda and Nausea in Inflammatory Bowel Disease


Many of us remember getting sick as a child and being given soda for an upset stomach.  The soda was generally either ginger ale (the ginger was the theoretical active ingredient) or Coke (the syrup had alleged anti-emetic value).  Preparation varied based on tradition – sometimes it was allowed to go flat, sometimes it was room temperature, sometimes it was only the alleged active ingredient that was given (raw ginger or cola syrup).  Sometimes alternatives were used – 7-Up instead of Ginger Ale.  Despite the anecdotal reports and tradition (which can certainly have a pronounced placebo effect on nausea), what does the evidence tell us?
Those with IBD tend to suffer from nausea for lots of reasons – post-surgical nausea, flare-based nausea, or nausea from certain medications.  Most of the anti-nausea studies don’t specifically address IBD, but they do look at nausea related to chemotherapy, post-surgical status, or other drug-induced nausea.  These studies are not all robust, but they may provide some insight for IBD patients looking to treat nausea with a traditional remedy.

There have been no significant clinical studies done evaluating Coke, cola syrup, or similar products to evaluate their efficacy in nausea treatment.  Additionally, there is no cause-of-action that would give a high prior probability to these treatments working.  Evaluations of the upper-GI following consumption of a carbonated cola beverage showed no significant physiological response.(1)  Interestingly, one of the few treatments to use Coke is to combat phytobezoars, a blockage due to intestinal accumulation of plant fiber (2).

What about ginger ale?  There are no specific studies looking at ginger ale, however there are multiple studies looking at ginger itself.  With regards to pregnancy, a double blind study looking at 1 gram of ginger v. placebo in treating nausea and vomiting in pregnancy showed a decline in both with the ginger group.(3)  A contemporaneous meta review showed that ginger had positive effects on nausea and vomiting in pregnancy, seasickness, and chemotherapy-induced nausea, but concluded that the studies to-date were small and not conclusive. (4)  A much larger study of 576 patients undergoing chemotherapy showed that ginger at .5 and 1g doses had a moderate positive effect, but surprisingly the effect reversed at 1.5g.  The lack of a dose-response is interesting and needs more explanation through further research.  Ginger itself is not known to have significant side effects at the doses tested. 

The current research leans toward ginger having a small but positive effect on mild-to-moderate nausea when taken in moderation.  That said, many commercial ginger ales have “ginger flavoring” that has no real ginger, and the ones that have real ginger are fairly quiet about the amount included.  Additionally, chewing ginger root may exceed the .5 to 1g doses that appear to have a positive effect unless carefully doled out.  If you are experiencing mild to moderate nausea with your Crohn’s or Ulcerative Colitis, a small dose of ginger may help and isn’t likely to cause any harm, but don’t expect your ginger ale to provide it (unless you make it yourself) -- there is no evidence that commercial ginger ale provides any benefit.

Nausea that leads to vomiting is another story.  Repeated vomiting, especially when combined with diarrhea and fever, can lead to fluid loss.  For those with fluid loss, soda products are not a great choice – they don’t address potential electrolyte imbalances.  Especially in younger children, fluid loss can be a life threatening condition and replacing the water and the electrolytes through products like Pedialyte (or home-made variants containing the right sugar-salt-water balance, supplemented with potassium) is a better choice. 

Bottom Line


·         There is no evidence that Coke or cola syrup help with nausea. 
·         Small amounts of ginger (1g) have shown a preliminary, positive effect on mild to moderate nausea and vomiting.
·         Many commercial ginger ales have little or no ginger in them, and no evidence that ginger ale itself helps with nausea and vomiting beyond the comfort factor.
·         As long as you don’t have significant fluid loss, drink whatever provides you comfort.  If you do have fluid loss, stick with liquids that help electrolyte balance and get help if it becomes extreme.

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1.       Cuomo, Rosario, Maria Flavia Savarese, Giovanni Sarnelli, Giovanna Vollono, Alba Rocco, Pietro Coccoli, Carla Cirillo, Lorenzo Asciore, Gerardo Nardone, and Maxime Buyckx. "Sweetened carbonated drinks do not alter upper digestive tract physiology in healthy subjects." Neurogastroenterology & Motility20, no. 7 (2008): 780-789.
2.       Ladas, Spiros D., Konstantinos Triantafyllou, Charalabos Tzathas, Pericles Tassios, Theodore Rokkas, and Sotirios A. Raptis. "Gastric phytobezoars may be treated by nasogastric Coca-Cola lavage." European journal of gastroenterology & hepatology 14, no. 7 (2002): 801-803.
3.       Vutyavanich, Teraporn, Theerajana Kraisarin, and Rung-aroon Ruangsri. "Ginger for nausea and vomiting in pregnancy: randomized, double-masked, placebo-controlled trial." Obstetrics & Gynecology 97, no. 4 (2001): 577-582.
4.       Ernst, E., and M. H. Pittler. "Efficacy of ginger for nausea and vomiting: a systematic review of randomized clinical trials." British journal of anaesthesia84, no. 3 (2000): 367-371.

5.       Ryan, Julie L., Charles E. Heckler, Joseph A. Roscoe, Shaker R. Dakhil, Jeffrey Kirshner, Patrick J. Flynn, Jane T. Hickok, and Gary R. Morrow. "Ginger (Zingiber officinale) reduces acute chemotherapy-induced nausea: a URCC CCOP study of 576 patients." Supportive Care in Cancer 20, no. 7 (2012): 1479-1489.

Sunday, September 8, 2013

Fecal Calprotectin as an IBD Diagnostic Tool

Monitoring IBD and Fecal Calprotectin


One of the less used tests for gauging the status of inflammatory bowel disease is fecal calprotectin.  Most have never heard of it – its less commonly used than C-Reactive Protein and other testing, and it’s not cited as frequently as lifestyle scores like CDAI.  What is fecal calprotectin and what can it tell us about IBD?

Calprotectin is a protein strongly correlated with intestinal inflammation.  It is measured through fecal testing at a standard lab.  Because it only involves proving a stool sample (and waiting up to 2 weeks), the testing is non-invasive. Additionally, it is a marker of inflammation and is not elevated in those with irritable bowel syndrome.(1) 

The first area of interest in the fecal calprotectin test is for use in diagnosing IBD.  While the test alone cannot provide the location and complications related to IBD, it can help in rule out IBD without resorting to colonoscopy or other more invasive measures.  In a 2010 meta-analysis, Van Rheenen et al looked at individuals showing symptoms of IBD and found that the sensitivity was .93 and the specificity was .96 in adults, with lower values for teenagers and children.  This means, in practical terms, that 7% of adults with IBD will not register on the initial testing and will not be diagnosed, and 4% of those diagnosed will not have IBD.  Because the next step in screening for those with a positive fecal calprotectin is a more invasive procedure (colonoscopy, endoscopy, small bowel study, etc.), the 4% can be largely ignored in the analysis (without the test they would have undergone the invasive testing anyway).  That leaves 7% that are undiagnosed by the testing but actually have IBD.  That is, in general, a reasonable tradeoff.  The 7% that are undiagnosed are likely to be watched for followup, and an invasive procedure performed several months later if symptoms do not abate (or another fecal calprotectin test performed – the study did not look at the impact of successive testing).

The second area of interest is in monitoring the activity of Crohn’s and Ulcerative Colitis.  Smaller, earlier studies showed a strong correlation between fecal calprotectin score and the likelihood of relapse in Ulcerative Colitis (but not Crohn’s).(3)  Further review showed that it was predictive in certain types f Crohn’s disease, namely ileocolonic and colonic, but not upper GI-centric Cronhn’s.(4)  While not predictive of relapse in Crohn’s it was found to be strongly correlated to the Simple Endoscopic Score, better than CRP, the CDAI, and other testing.  A 2010 analysis found that:

The SES-CD correlated closest with calprotectin (Spearman's rank correlation coefficient r=0.75), followed by CRP (r=0.53), blood leukocytes (r=0.42), and the CDAI (r=0.38)

Additionally, the testing found a response curve where the fecal calprotectin level corresponded with the severity of the disease (mild, moderate, or severe).(5)
Fecal calprotectin isn’t the only game in town – other markers, such as fecal lactoferrin, show promise as well (though with cost and stability issues).  Additionally, further biomarkers for differentiating Crohn’s and Ulcerative Colitis are being investigated, and may result in fewer invasive procedures for diagnosis and monitoring.  The fecal calprotectin testing is inexpensive (though not all insurance may yet cover it), and it is fairly new for doctors, but the evidence shows that it should be used more frequently at all stages of IBD analysis.

Bottom Line


·         Fecal calprotectin is a better measure for predicting IBD than traditional test like C-Reactive Protein tests.
·         Fecal calprotectin is correlated strongly with the level of disease activity, and can be used as part of monitoring.
·         The evidence shows that fecal calprotectin testing should be incorporated into both initial diagnostic and ongoing monitoring testing regimes.

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1.       Costa, F., M. G. Mumolo, M. al Bellini, M. R. Romano, L. Ceccarelli, P. Arpe, C. Sterpi, S. Marchi, and G. Maltinti. "Role of faecal calprotectin as non-invasive marker of intestinal inflammation." Digestive and liver disease 35, no. 9 (2003): 642-647.
2.       Van Rheenen, Patrick F., Els Van de Vijver, and Vaclav Fidler. "Faecal calprotectin for screening of patients with suspected inflammatory bowel disease: diagnostic meta-analysis." BMJ: British Medical Journal 341 (2010).
3.       Costa, F., M. G. Mumolo, L. Ceccarelli, M. Bellini, M. R. Romano, C. Sterpi, A. Ricchiuti, S. Marchi, and M. Bottai. "Calprotectin is a stronger predictive marker of relapse in ulcerative colitis than in Crohn’s disease." Gut 54, no. 3 (2005): 364-368.
4.       Mao, Ren, Yinglian Xiao, Xiang Gao, Baili Chen, Yao He, Li Yang, Pinjin Hu, and Minhu Chen. "Fecal calprotectin in predicting relapse of inflammatory bowel diseases: A metaanalysis of prospective studies." Inflammatory Bowel Diseases 18, no. 10 (2012): 1894-1899.

5.       Schoepfer, Alain M., Christoph Beglinger, Alex Straumann, Michael Trummler, Stephan R. Vavricka, Lukas E. Bruegger, and Frank Seibold. "Fecal calprotectin correlates more closely with the Simple Endoscopic Score for Crohn's disease (SES-CD) than CRP, blood leukocytes, and the CDAI." The American journal of gastroenterology 105, no. 1 (2009): 162-169.

Sunday, September 1, 2013

Warning Signs in IBD Studies

Protocol and Interpretation Issues and IBD Trials (Scientific Cooking Part 2)


The last post dealt with some of the statistical issues that can be associated with IBD clinical trials.  There are not only statistical issues, however, that can occur – protocol errors can produce misleading results, study design can be poor, and the analysis of the results can be taken to the extreme.  As with the statistical anomalies, these flaws can be either intentional or inadvertent.  Sometimes the error is not with the protocol itself, but with drawing inappropriately broad or unjustified conclusions from a study.  This post looks at a few common things you can use to evaluate research studies.

Small Sample Size


Though this is also a statistical problem, small sample size studies are always suspect.  Generally, smaller sample size studies are used to do a pilot proof-of-concept that a particular treatment can be effective.  Unfortunately, they are not good at doing even that.  Let’s assume a new drug cures 20% of the IBD population, and has no effect on the remaining 80%.  If we do a study in 5 individuals, there is a 1 in 3 chance that none of them get better (which would be a false positive).  Flipping it around, if 1 in 5 people enter spontaneous remission in a 1 year period, taking any drug would result in a 2 in 3 chance that at least one study participant shows improvement.  Any study that states that there is an improvement that cannot be shown to be statistically significant is really saying that the data is too poor to draw any conclusions.*

No Control Group


Double blind studies, but definition, have a control group.  Frequently, purveyors of less than rigorous science will do a study without a control group.  This is sometimes used to tease out environmental factors in retrospective studies, but has no place in prospective studies.**  In any prospective study, however, all it provides is a way for the researchers to claim results that are unbalanced.  If there is no control, researchers can cite any individuals in the study that improve as being attributed to the treatment they are proposing.  In reality, with a large enough group, some individuals will enter remission from a flare with no treatment at all.  Others will have clinical improvement on their CDAI or other testing, many times as a small peak in an otherwise downward trend (why we all have “good days and bad days”).  A large cohort with infrequent testing is likely to turn up some number of individuals who show a positive movement – without a control group, there is no way to know if that improvement is due to the drug, is due to external factors, or is the same improvement that could be expected from a group of individuals with no treatment at all.

The Wrong Control Group


Just like having no control group, having the wrong control group may unfairly bias the view of a new treatment.  In the United States, one of the things that the Food and Drug Administration looks at when evaluating a new therapy is the efficacy compared to existing therapies.  Generally, a new drug will only be approved if:

·         It shows a higher degree of efficacy than existing treatments or;
·         It has lesser efficacy (but still clinically significant) but greatly reduced side effects or;
·         It treats a segment of the population for which the extant treatments do not cover (a particular genetic subset of individuals, a particular age group, pregnant mothers, etc.)
·         The efficacy would is the same as existing treatments, but other factors (like cost and availability) make it advantageous to the public.

Because of the FDA’s scrutiny, new treatments are generally tested against a comparable, existing treatment.  They may still have a small effect when tested against a group of untreated individuals, but it may be orders of magnitude less than current regimes or have greater side effects.  If only tested against an untreated control group, the new treatment may look very promising, but in reality be a much lesser option than the current options. 

Cherry Picking Evidence


This is generally done in retrospective studies where an individual starts out with a premise that XYZ causes Ulcerative Colitis or Crohn’s Disease.  They then look back through epidemiological data and cherry pick specific instances where the data matches their assertion, discarding those places where it doesn’t. 
Another place this crops up is with individuals looking to cite the efficacy of a particular treatment.  This is especially troubling when researchers look at a large number of studies and, instead of looking at the commonality in the higher quality ones, pick the worst controlled studies that show what they are looking for.  This is very common practice for purveyors of pseudoscience – though 100 studies might show that their method is ineffective, they highlight the single, biased study that has never been able to be replicated but shows the results they were hoping for.

Mistaking Causation v. Correlation


Another flaw of epidemiological studies is mistaking correlation for causation.  If a researcher chooses enough variables, eventually there will be a statistical correlation between two pairs (the birthday paradox makes this more likely than it would appear at first glance).  Just because two trends are correlated, however, doesn’t mean there is a causal relationship.  Unfortunately, we are all quick to ascribe causation.  Read any IBD message board and search for threads that start as “XYZ caused my Ulcerative Colitis”.  You’ll find everything from sugar to antibiotics to mercury to MSG blamed.  In many of the cases, the individuals are recalling an event that they have associated proximally with the onset of their diagnosis – “I had just been given doxycycline for an infection, and a week later my stomach started hurting”.  This is a poor application of logic, and researchers are not immune to this way of thinking.  Two variables, A and B that are strongly, correlated could mean:

·         A causes B
·         B causes A
·         A and B are both caused by an unknown variable, C

A simple example of correlation not being equal to causation would be looking at diarrhea. Individuals with IBD have a strong correlation between the diagnosis of their disease and diarrhea.  That does not mean that diarrhea causes IBD, but that same logic is applied to epidemiological data. 

An example frequently cited with IBD is the correlation between a Western diet with Crohn’s disease is high, but that does not mean that a Western diet causes Crohn’s (there are also counter examples where the correlation does not hold).  People with Crohn’s might be attracted to a Western diet unknowingly.  Western diets may be eaten by individuals with better access to diagnostics.  Environmental factors associated with Western diets may affect Crohn’s.  Individuals who do not eat a Western diet may have higher infant mortality in those who would later develop Crohn’s.  Teasing out causation in non-trivial, and implying that the correlation is causative is disingenuous.

Applicability of Animal Models


This tends to be a result of the media vice researchers, but is related to how researchers present their findings.  A preliminary study in rats may show mucosal healing due to the ingestion of some new wonder drug.  Even more tenuous, cells removed from the intestines may show changes when a new drug is introduced to them.  Inevitably, the headlines read “Cure for Ulcerative Colitis in the Works”. 

In reality, most treatments that show some efficacy in animals never matriculate as feasible options for humans.  The reasons are numerous, ranging from differences in animal anatomy (even with our closest analogues) to bioavailability to toxicity (to quote XKCD, a handgun kills cancer in a petri dish also).(1)


All of the above are just a few of the ways that good researchers can go off track.  There are a myriad of other things that can go wrong in research, and viewing any new press release with a critical eye will help the interested reader spot poor assumptions, statistical misuse, or outright fraud.

Bottom Line


·         Even honest researchers can fall victim to their desire to have a successful treatment by creating poor studies that show what they expect, then overstating the results. 

* One place that small samples are sometimes used effectively is not for efficacy trials but for toxicity trials.  An investigational new drug is given to healthy individuals in a small sample (at first) to see if there are side effects.  The sample size is increased with later rounds of testing so that the negative effect (if present) impacts the fewest individuals.
** The possible exception is with end-stage terminal patients, where withholding a drug that will likely cure them may be considered unethical. 
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1.       http://xkcd.com/1217/