I survived... so it's raffle time!

As promised, I have done my raffle today, December 4, 2012... two days after my race.  Each of my donors received one entry for every $13.10 he/she donated.

And the winners are:

• Grand prize (GPS watch): Paul Hess
• Second prize (Team Challenge Sweaty Band): Michael Greenman
• Third prize (Runners World Wrist Wallet): Deborah Janks

Congrats to my raffle winners!  I will send out your prizes this week.

As for the half marathon...

It went really well.  I had set a goal to run it in 2:00, and I came out with a time of 1:59:08.  Pretty awesome.  Running the Vegas strip at night with so many other Team Challenge participants was extremely motivating!

Vegas... it's finally here!

First things first.  There are a few generous donors, who I have yet to notice.  Thank you to your continued support, even beyond my fundraising goal.  Thanks to you, I have managed to raise just shy of $3,000 for The Crohn's & Colitis Foundation of America!!  Your generous contributions will help us find better treatments or cures for inflammatory bowel disease.

Donor honor roll (since 11.6):

• Doreen Ableman
• B. K. Holzem Enterprises
• Karen Teasdale

If you haven't yet, you can still donate through my page.  It would be great to actually exceed the $3,000 mark.

Race day tomorrow (12.2)!

I am in the fabulous city of Las Vegas, and the race is tomorrow starting at 4:30 pm (Pacific time)!!  It should be a good run for me because things have been much better lately (not being anemic makes a world of difference for running endurance, not surprisingly).  I am hoping to complete the run in about 2:00.  Wish me luck!  If you would like to check out the course, here is the map.  Pretty much the whole course is along the strip.  My race number is 10580, but it does not seem that I can be tracked for free.  Hopefully, the times will be freely available after the race though.

Team Challenge is Everywhere

Now there are going to be a lot of people participating in the marathon or 1/2 marathon tomorrow who are not part of the CCFA Team Challenge, but there quite a few Team Challenge participants as well.  I have heard that there are ~1,000 Team Challenge participants for this race, and everywhere I seem to look, I see someone sporting his/her Team Challenge gear.  It is very encouraging to know there are so many people working toward the same mission.

So for fun, I want to break down the participation in this race into some numbers/impact for the CCFA.  Fundraising minimums probably vary to some extent, depending on where people are coming from, but for this race, every Team Challenge participant should have had to raise at least $2,700 (because airfare is not included at this level).  So if I just estimate that each of those 1,000 runners/walkers raised the minimum, that is $2.7 million raised.  Since the CCFA is an "A" rated charity, and 82 cents of every dollar actually goes toward research and patient care, that is over $2.2 million toward improving the lives of patients with Crohn's or colitis!  And this is just a conservative estimate, since most people will have raised well more than the minimum amount.  Now, this is awesome because this is the kind of effort that it will take to combat these illnesses.

Also remember, the raffle drawing will take place after I get back on Tuesday (12.4)!

Team Challenge Fundraising Goal Reached!!

Thank you, thank you, thank you!!  Today, I finally hit my Team Challenge goal amount of $2,700 to support research for Crohn's disease and ulcerative colitis.  I sincerely appreciate all of the support, donations, and words of encouragement you have all given me throughout this process.

Donor honor roll 11.4 - 11.6 (as of this post):

• Darlene Balto
• Igor Efimov
• Michael Greenman
• Deborah Janks
• Russell Nedved
• Kim Slabik

I'd like to give special mention to my friend Michael Greenman, who put in his generous donation early this afternoon to put me one dollar over my goal!  I needed the support of all of my contributors to get to this point though.

If you haven't made your donation yet... your contribution is no less important!

You can still make a donation through my Team Challenge page.  Any additional donations will go right to The Crohn's & Colitis Foundation of America... just like all other donations made up to this point.  Until we have a cure for inflammatory bowel disease, your support is still enormously important and appreciated!

Team Challenge Progress To Date

It's getting so close...  < one month to the big race and ~ a week and a half left of formal fundraising!  Thanks to my outstanding supporters, I am extremely close to my goal of raising $2,700 for The Crohn's & Colitis Foundation of America.  I am nearly 85% of the way there, and you can track my progress on my donation page.

This past week's donor honor roll:

• Tom Diehl
• Steve & Lisa Holzem
• Shiv am Shah

Thanks so much for your generous donations!  You have helped change the future of Crohn's disease research and, ultimately, treatment!  I can't wait to run those 13.1 miles with your support behind me.

Training progress

I am back!  After the recovery, and slowly building back up my endurance, I have finally been able to get back to my training program as scheduled.  I completed my 9 mile long run last Sunday and was able to start some speed training this past week.  Also, there is more good news, which helps my running endurance... my hemoglobin levels came back up thanks to the iron infusions.  I actually have a hemoglobin of 11.3 mg/dL, which, while still lower than normal, is higher than it has been for me since February.

I still feel a bit nervous about the race, as it draws close.  Who knows what will happen, but the point is not to win (or even run fast)... the point is just to cross that finish line.  If I have to stop, I have to stop.  If I don't have to stop, great!  Whatever happens, I will finish those 13.1 miles.

My most recent science post

I encourage you to read my latest science post about an article that got recognition on NPR's Science Friday.  It is some of the more interesting Crohn's research that I have read, and I think it could be a new therapeutic strategy for GI diseases.

Crohn's Research on SciFri

Given that Crohn's disease research was mentioned earlier this afternoon on NPR's Science Friday, I thought I would track down the first article mentioned in the interview with Dr. Russell Cohen, Co-Director of the Inflammatory Bowel Disease Center at the University of Chicago.  This article was a study (sort of) involving the use of probiotics for Crohn's disease and colitis therapy, though not in a purely straightforward sense.  Given my previous focus on probitics, I wanted to continue to follow this field.  In a later post, I will also discuss the second article mentioned in today's interview... a Nature article on genes for Crohn's.

Crohn's disease research is getting some recognition... this is good!  Go here to listen to the SciFri interview.

Today's featured article:

Motta et al. 2012. Food-grade Bacteria Expressing Elafin Protect Against Inflammation and Restore Colon Homeostasis. Science Translational Medicine 4:158ra144.

The one-sentence synopsis

Basically, Motta and colleagues expressed the protein, Elafin, in lactic acid bacteria and found that this bacteria could then reduce intestinal inflammation when fed to mice with colitis.

Elafin... the protein that I couldn't figure out how to spell from the SciFri broadcast

Elafin is a protein that serves as a protease inhibitor... literally, an inhibitor of proteases... which basically means that Elafin is a molecule that prevents other proteins from getting degraded ("chewed up and digested", if you will) by enzymes called proteases.  Elafin exists normally in cells of the human intestinal mucosa (lining) and has been previously demonstrated to possess anti-inflammatory properties.  This research group found that Elafin levels were reduced in patients with inflammatory bowel disease (IBD), so they wanted to see if giving back more Elafin could be helpful to reduce intestinal damage or inflammation.

Elafin levels are reduced in IBD

Before they did anything with bacteria, Motta and colleagues actually studied the expression levels (i.e. amount) of Elafin in the gut.  To do this, they took colonic biopsy tissues from normal control individuals and IBD patients with Crohn's disease or ulcerative colitis.  When they compared the amount of Elafin between IBD patients and normal control individuals, they found the amount of Elafin to be greatly reduced in the colonic specimens from IBD patients.  With that, they also found that the activity of proteases was higher in the IBD patient colon specimens, presumably because there is not enough Elafin around to inhibit the proteases.

Tinkering with genes in bacteria

In order to get more Elafin into the gut, Motta and colleagues engineered (which is sort of just a fancy way to say that they tinkered with or changed) two different strains of food-grade (can be eaten) lactic acid bacteria.  The specific bacteria strains they used were Lactococcus lactis and Lactobacillus casei.  As for L. casei, I currently have some Greek yogurt in my fridge that contains this bug as one of its active cultures.  I don't think there is an L. lactis in any of my yogurt, but that's probably because (according to wikipedia) it is used for the production of buttermilk and cheese.  For their genetic engineering of these bacteria, they introduced the gene for Elafin protein.

Bacteria for the therapetic delivery of Elafin

To test whether bacterial delivery of Elafin could improve gut inflammation, Motta and colleagues used a mouse model of IBD, in which colitis was induced by a chemical.  The authors fed the engineered L. lactis and L. casei to the mice with colitis, and they found that the protease activity and inflammation could be dramatically reduced in the colon of these animals.  They compared this result with feeding the IBD mice normal (i.e. with no Elafin gene) L. lactis, and the normal L. lactis had no effect on the gut inflammation... meaning it is the Elafin here that is helping the inflammation, not just the bacteria itself.

So would this work for chronic disease or in an actual IBD patient?

Well, maybe.  To strengthen their above results, the investigators also tested their Elafin-engineered L. lactis in a mouse model of chronic colitis and found that inflammatory gut damage could be reduced in this model.  In addition, Motta and colleagues continued with studies of the effects of their engineered bacteria in human intestinal epithelial cell monolayers (human gut cells, but grown in a dish).  These cells in a dish were made to have "inflammation" by exposing them to TNF-alpha, the same inflammatory molecule that tends to be in too high of levels in Crohn's disease.  However, I have put "inflammation" in quotations here intentionally.  The GI inflammation in Crohn's disease is certainly not just due to TNF-alpha, but is largely due to damage from inflammatory cells, which would not be in the dish.  Regardless, the investigators did see improvements in some of the inflammatory markers in the TNF-alpha-exposed human cells in a dish.

Why this is cool research (btw "cool research" is not an oxymoron)

Gene therapy has been on the horizon for a while now, but has thus far been largely unsuccessful in humans.  The idea with gene therapy is to basically replace a missing or defective gene in a cell that needs it... e.g. replace the gene for the defective chloride transporter in cystic fibrosis.  For those of you that don't know, genes basically tell your cells how to make proteins (although this is not the only thing written in your DNA).  So when a gene is bad, the protein can be bad too... either missing all together or just dysfunctional.  However, if we could somehow put in the correct gene through gene therapy, then the cell could make the correct protein, potentially curing the disease.  One of the major problems with gene therapy (and why it has been unsuccessful or even, perhaps, dangerous) is because scientists haven't completely figured out a good way to deliver the correct genes into the cells that need them.

This is one situation in which it could actually be beneficial for treatment purposes that IBD impacts the intestinal tract.  Because the gut interfaces with the environment through whatever you eat or drink, scientists can essentially do gene therapy on the GI system without necessarily putting the genes directly into gut cells.  Instead, the scientists put the gene into bacteria (a much easier feat than putting them into a human), the bacteria make the protein, and we eat the bacteria with the protein... cool stuff.  Thus, a whole new field of therapeutics is potentially evolving with the bacteria we can eat.

So, you may or may not be wondering why we can't just eat the protein...  the simple reason is that it would get digested before it could ever reach the parts of the intestine where it could provide some benefit.  Some of the bacteria would be destroyed by the stomach too, but enough can sneak by to the lower intestine, where they will thrive and multiply.  Thus, the bacteria can make something that would otherwise be hard to get into the human body and could serve as therapeutic vessels.

Long-term data on a biologic for Crohn's

Testing a new blog format

So... I have been realizing that my goal to try and pick a Crohn's-related topic that seems interesting (to me), and then produce an unbiased review on that subject, may have been a bit overambitious.  Thus, I am going to try a new format for most of my blog posts.  I am going to start with an interesting article, and then base my post around that particular article (more journal club style... and way more manageable).  I hope that this will allow me to post more frequently and enable me to more thoroughly discuss the article theme.  I still plan to do larger "review" articles, but more intermittently, as time permits.

Today's featured article:

Seminerio et al. 2012. Infliximab for Crohn’s Disease: The First 500 Patients Followed up Through 2009. Digestive Diseases Science DOI 10.1007/s10620-012-2405-z.

Although I am not on… nor have I yet tried… infliximab (better known by its brand name of Remicade), I thought this would be a great article for the IBD community because there is finally some long-term data regarding the use of this biologic therapy for Crohn's patients.  We are now starting to get information about the durability of the clinical response to a biologic agent, as well as results about long-term side effects of biologic therapies.

Infliximab: the background

Infliximab is of the class of therapies called biologics (please see my previous post for a summary of Crohn’s therapies), and this particular drug is an antibody that targets the molecule TNF (short for tumor necrosis factor).  TNF is one of the nasty players mediating overaggressive immune responses… in Crohn’s disease and other autoimmune conditions.  Thus, the objective is for the infliximab antibodies to bind to the excess TNF, neutralize it, and inhibit its activity.

In 1998, infliximab became the first-approved biologic therapy for Crohn’s disease in the US.  It was initially approved only for short-term induction therapy in Crohn’s patients with moderate to severe disease, for whom other therapies had failed (Targan et al. 1997., Present et al. 1999.).  The FDA approval was extended to include long-term maintenance therapy in 2002 (Hanauer et al. 2002., Sands et al. 2004.)  Following the introduction of infliximab, a couple of other similar TNF-targeting medications were introduced, including adalimumab (Humira) and certolizumab pegol (Cimzia).  Once these biologic agents started to gain greater clinical use, more adverse effects of these medications were recognized... including tuberculosis, certain types of fungal infections, and, in rare cases, even lymphoma (Brown et al. 2002., Keane et al. 2001., Lee et al. 2002., Mackey et al. 2007.).  Thus, long-term evaluation of the risks and benefits of these medications has been needed... and now has finally been published.

Study patients, infliximab treatment regimen, & measurement of response

The investigators identified 512 Crohn's patients that were treated with infliximab between 1998 and 2002 and who were followed-up through 2009.  Of those patients, 496 gave consent to review of their medical records and were included in the study.  Patients initially received an infliximab dose of 5 mg/kg body weight by two-hour intravenous infusion and were given one to three doses within three weeks as induction therapy.  Some patients continued to receive maintenance therapy with infliximab, but the dosing regimens were variable depending on patient response and physician treatment strategies.  Of the initial patient population, 37% (182 patients) received maintenance therapy with infliximab at some point.

Patients' response to therapy was assessed by looking at overall symptomatic resolution during the treatment period... e.g. decreasing diarrhea (reduction in frequency > 90%), relief of abdominal pain or cramping, fistula healing, etc.  More rigorous quantitative measures, such as the Crohn's Disease Activity Index (CDAI), were not used because this was a retrospective study*, and CDAI measures were not routinely taken at doctors' visits.

Short- and long-term response to therapy

The majority of patients demonstrated at least some response to infliximab induction therapy... with 20% having a partial response (response lasting < 3 weeks) and 61% having a complete response.  The rest of the patients in the study either had no response (13%) or were considered lost to follow-up (5%).

As for the long-term data, what seems to be the good news is that 97 (20%) of the patients were still using infliximab at the final evaluation point (presumably because they were still having clinical benefit and not experiencing significant adverse effects) and another 64 (13%) had discontinued the medication because they had achieved remission of the disease.  Thus, even after > 10 years of follow-up after initial infliximab treatment, a sizable proportion of patients had continued benefit.  Not unexpectedly, the majority of patients (57%) did need dose escalation or shortening of the interval between infusions at some point during the follow-up.  The dose escalation/interval change over time did also parallel the discontinuation of the drug over time... indicating that there is loss of response to infliximab in the long term.

The less-good (but not entirely surprising) news is that a relatively high proportion (39%) of patients experienced at least one adverse event during the follow-up period, and the longer the follow-up, the more likely these events were to occur.  Now, adverse events could either be minor or major, and included all infections, malignancy, hypersensitivity reactions, autoimmune reactions, and death.  The most prevalent adverse events seemed to be infusion or hypersensitivity reactions (17% of patients), a single abscess (10% of patients), or minor bacterial infections (14% of patients).  Pre-cancerous lesions (dysplasia) occurred in 17 patients (3%), and cancer developed in 26 patients (5%).  Although the cancer incidence is increased from the general population, it is hard to say that this is due to infliximab therapy... there could be referral bias in the patient population or an increased risk of cancer due to Crohn's disease.

Concluding thoughts

 
Infliximab therapy seems to be a good long-term option for a proportion of Crohn's patients, but could potentially cause serious complications in others if used for many years.  Although, major adverse events that are clearly caused by infliximab therapy are relatively rare, even after 10-year follow-up, they do indicate the need for watchful evaluation in patients on this drug.

Currently, we don't have any research to suggest for which patients infliximab (or any other therapy for that matter) will work wonders or for which other patients it will cause problems.  This is a major issue that needs to be addressed by more research.  For example, in my own care, I feel that we are just throwing random drugs at the disease to see what sticks.  If we had more individualized data to suggest what drugs to use for which patients, treatment strategies for Crohn's disease could be less haphazard than they are now.  We do have some good medications now (although we do still need more), but they are not applied optimally... leading to waste and poor outcomes.

*Terminology explanation:

Retrospective study: This is a type of study design in which the investigators look back at events that have already taken place.  While not the most rigorous type of study, because there often isn't good control data to match the treatment group, this type of study does allow potentially useful information to be extracted from existing records.  Also, these type of studies can usually be done more quickly than a prospective (watching individuals going forward) study.  In the case of this particular article, a similar prospective study would have taken greater than 10 years to complete, from inception to end.

Bibliography:

Brown et al. 2002. Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the food and drug administration. Arthritis & Rheumatism 46:3151–3158.

Hanauer et al. 2002. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 359:1541–1549.

Keane et al. 2001. Tuberculosis associated with infliximab, a tumor necrosis factor alpha- neutralizing agent. New England Journal of Medicine 345:1098–1104.

Lee et al. 2002. Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept. Arthritis & Rheumatism 46:2565–2570.

Mackey et al. 2007. Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease. Journal of Pediatric Gastroenterology & Nutrition 44:265–267.

Sands et al. 2004. Infliximab main- tenance therapy for fistulizing Crohn’s disease. New England Journal of Medicine 350:876–885. 

Team Challenge Recommitment!

First of all, I would like thank my recent donors.  I very much appreciate your generous support of my cause to raise money for more Crohn's research!!  With one month left to fundraise, I am about 80% of the way to my goal.  Check out the status bar on my donation page.

Donor honor roll (weeks 9.29 to 10.13):

• David and Nancy Rae Holzem
• Patrick and Stepanie Holzem

Raffle reminder

Just want to remind you that I am offering raffle entries in exchange for donations... and the grand prize is a GPS watch!  Please check out my donation page for more details!

Recommitment

The Crohn's & Colitis Foundation Team Challenge has a recommitment stage... basically ~midway through the fundraising and training they allow you to affirm that you will reach your goal amount and complete the race (or, alternatively, drop out).  Thus, I recommitted this past Monday (10.15).  Thanks to the support I have received up to this point, I feel confident that I will raise $2,700 by November 14th and run 13.1 miles on December 2nd.

Team Challenge Training & Surgical Recovery

So I would like to just let everyone know that I am recovering well from the surgery I had 10.3, and this surgery actually had nothing to do with my Crohn's.  On the contrary, this procedure was actually postponed multiple times because of health issues related to Crohn's... so, in a sense, it's actually good news that I was able to go through with it.  The surgery was a jaw surgery and was quite invasive, so I have taken the necessary time off of training for recovery.

The surgery itself went as well as could have hoped, given my circumstances.  My surgical team and GI care were well coordinated, and everyone was on board to ensure the best possible outcome...  so I thank everyone who was involved in my care (without naming names) for their diligence.  I also appreciate the care and assistance that I received from my husband and parents (who traveled from WI to help out).  Certainly, this made the recovery go more smoothly.  It was also good to finally have gotten the procedure out of the way, so that it won't impede any of the clinical decision making for my Crohn's treatment (more on this in a future post on clinical trials).

As for training, I am back to (slow) jogging at this point, but I have been able to complete 6 miles at a time, as long as I don't push it.  There are two issues that I am dealing with... one is obviously that my face is not completely healed yet, and the other is that I actually lost a good amount of blood during the surgery (on top of my usual, anemic Crohn's state).  My latest Hgb was 8.5 mg/dL, with a Hct of 25%, so I need those numbers to come back up before I start running harder.  Thankfully, I am getting some IV iron infusions to help boost my iron stores, since the oral iron supplement that I have been taking didn't seem to be doing the job.

Team Challenge Progress: Week of 9.23 to 9.29

Thank you to my amazing donors for the past week!  You have helped me get even closer to my fundraising goal.  I am now up to 70%... check out my fundraising status bar on my donation page!  Together, we will help support more research through The Crohn's & Colitis Foundation.

This past week's donor honor roll:

• Cody Locke
• Matt Sakumoto

Team Challenge/Crohn's Progress

Running has actually been going reasonably well, despite the Crohn's flare and my knee issues.  I was actually able to complete my 10-K race this Sunday (I ran on my treadmill during the Green Bay Packer game... which always gets me fired up).  I completed the run in with a time of 53:35, which is an 8:38 pace.  I am pretty happy with this, given that I had to slow up once for my knee pain, but otherwise, I do feel like incorporating some speed/race work has been making me faster.

Also, because of my continued anemia (have been hanging around in the ~10 mg/dL range for the past year and a half), I finally asked my gastroenterologist to run another iron study.  That came back showing that my iron stores are quite low... I have a ferritin level of 7 ng/mL (ferritin is a protein in the body that stores and releases iron in a controlled fashion, and the normal range for females is something like 15-200 ng/mL).  Thus, oral iron supplementation has not been sufficient to boost my stores, so my GI doc has ordered some intravenous iron infusions for me.  Hopefully these infusions will help my body make some more red blood cells, which would improve my running (and general well being).

I haven't had any clear response to the methotrexate yet, but it is still early.  Supposedly, it will take about 3-6 weeks to show symptomatic improvement.  Hope it kicks in soon!

Healing or just feeling better?

When I finally go into histologic remission, I will throw a party... that day will be worth celebrating.  So what do I mean by histologic remission?  I mean that I would like to have biopsy-confirmed results showing my gut has been healed by the motley collection of pills and injections that I find myself currently taking for Crohn's.  There are several types of medications that are prescribed to treat Crohn's disease (therapy options range from corticosteriods to so-called "antimetabolites"* to new biologic therapies*... and even antibiotics*), and they range in their efficacy and mechanisms of action.

In my personal experience thus far, I haven't found the right medication(s) to significantly impact the colonoscopic or pathologic results in my gut, but there has been one medication in particular that has improved my more quality-of-life-type symptoms (e.g. fevers and malaise)... prednisone.  At this point, I have heard a few gastroenterologists say that cortiosteroids (prednisone is one particular example of this class of medications) make Crohn's patients feel better, but don't actually get them better.  What this means is that while steroids are good at suppressing systemic (whole body) inflammation, they are potentially less good at actually healing the mucosa (lining) of the gut.  So even though the quality of life of a Crohn's patient on corticosteroids might be significantly improved, if that same patient were to get several gut biopsies, there might still be extensive evidence of active disease.

Pathologic features of Crohn's

In order to make a diagnosis of Crohn's disease, usually some kind of endoscopic examination will need to be done.  This can be in the form of a colonoscopy or upper endoscopy, and often both.  During that exam, if the gross pathology (evidence of the disease that can be seen with the naked eye or, in this case, camera) is suggestive of inflammation, the gastroenterologist can take a few biopsy specimens for further analysis under a microscope.  A gut with Crohn's disease will have some key features if examined under magnification... the microscopic architectural features will be disorganized and high levels of certain inflammatory cells will be present (Geboes and Dalle. 2002).  The inflammatory features on biopsy can sometimes be telltale for Crohn's (this situation will often include "granulomatous" inflammation), but in many cases the inflammatory process in the bowel can be non-specific and, thus, not itself diagnostic.

So, the ultimate goal for a Crohn's patient would be to achieve remission of the disease from an endoscopic and histologic standpoint... although symptomatic remission is what is most commonly achieved and, in a sense, is most important.  If a repeat colonoscopy is done when symptoms are under control, confirmation of gut healing by pathologic examination would be the best way to show that disease activity is absent or very low... and that the medications have done their job.

Prednisone & the power to heal?

Published studies seem to show poor colonic mucosal healing with corticosteroid use in patients with Crohn's disease (Landi et al. 1992., Oliason et al. 1990.).  Landi and colleagues gave high-dose prednisolone (the dose was 1 mg/kg/day, and prednisolone is an active corticosteroid that is essentially what prednisone gets converted into inside your body) to 147 patients with acute attacks of colonic or ileocolonic Crohn's disease.  After 5 weeks, they found that 136 of these patients had achieved clinical remission, but 96 still had lesions on endoscopy.  The study by Oliason and colleages was much smaller, having only 8 patients with ileal Crohn's disease... thus, I will consider these results as more of a case study than a controlled trial.  With 20-30 mg/kg/day doses of prednisolone for 6-9 weeks, the patients had significant improvement in activity indices, but essentially no improvement in ileal inflammation.  However, there was one study that showed rectal biopsy normalization in patients taking a combination of prednisolone and sulphasalazine; although the results with prednisolone on its own were less striking (Schmitz-Moorman et al. 1988.).  This study suggested there was a good relationship between Crohn's Disease Activity Index score and histologic improvement in their subjects.  Taken together, it seems that symptomatic relief with corticosteroid medications is much greater than the impact that steroids have on gut pathology.

Prednisone: commentary on the benefits and risks

My husband and I actually got into a heated debate about this topic, so I am going to try to summarize both of our viewpoints on this subject (while hopefully not completely botching his opinion).  I want to leave my commentary for this post open to different viewpoints on this subject.

First the setup to the debate: While short courses of corticosteroids can be fine, long-term corticosteroid use is considered relatively dangerous.  These drugs have a whole host fairly common, and fairly unpleasant, side effects, including weight gain, insomnia, bone loss, muscle loss, diabetes, and on and on.  I currently have a bit of a moon face from the several months of prednisone.

My opinion: Given all of the side effects, my opinion is that there must be some perceived health benefit of corticosteroids, beyond their ability to improve the quality of life for Crohn's patients, in order for them to be so widely prescribed for therapy.  This benefit need not be a real benefit of actually suppressing the overactive, damaging inflammation in the gut, but could just be a perceived benefit by  clinicians... i.e. because it is a known powerful immunosuppressive, it should, theoretically, impact the course of Crohn's disease.  My point is not to say that quality of life issues aren't important or shouldn't be treated... very much the contrary.  I know better than most how difficult it is to just go about normal life when running a fever or to the bathroom 10x per day.  My argument is simply that corticosteroid should be used sparingly if they do not impact the course of the inflammatory bowel disease.  The risks seem to outweigh the benefits of just making me "feel good".

I would analogize the situation to the use of opioid medications for pain.  My perception (which may or may not be true) is that physicians have a bias toward underusing opiates to relieve pain. Clearly, this is because there are certainly dangerous side effects of these medications.  But in addition, I think that the fact that opioids just relieve pain... and don't do anything to fix the underlying problem... is another reason why they may be cautiously prescribed.  Here there is a clear dissociation: a drug that can improve quality of life in a patient with chronic pain, but doesn't do anything to treat the underlying pain mechanism.  In my opinion, the cost-benefit calculus is shifted toward greater cost in this situation, where the benefit is one that only impacts quality of life for a risky medication.

Opiates are actually a great category of drug to talk about because an interesting counterpoint to the use of opiates for pain, is the use of opiates for diarrhea.  The notable medication here is loperamide (i.e. Imodium), which is the same type of medication as an opiate used to treat pain... with the important caveat that it doesn't cross the blood-brain barrier (thus, no pain relief or risk of addiction).  Similarly to opiates for pain, loperamide treats the symptoms of diarrhea, without healing the underlying cause of the diarrhea.  However, in this situation, the medication (generally) carries minimal risk of adverse effects, so it is used quite widely.  The cost-benefit analysis is heavily weighted toward the benefit of symptom relief, even if it will not impact the course of the illness.

My husband's opinion: I think he basically puts more weight on the improvement of quality-of-life-type symptoms, and, thus, his analysis of the costs versus benefits of prednisone (having seen my personal short-term response to it) is more favorable toward the benefits.  Even if there is no mucosal healing that occurs, because it eliminates fevers and improves general wellbeing, short-term use is fine (don't know the tipping point when short term ends and long term begins though).  Btw, he also thinks that opiates are under prescribed to treat pain... with which I do agree.

*The (very) basic run-down of Crohn's drugs (other than corticosteroids):

Antibiotics: Probably most everyone has been at least one, if not several, of these for various bacterial infections, so I don't need to be too detailed... but these medications either slow down the growth of or kill bacteria.  In Crohn's, antibiotics such as flagyl or ciprofloxacin are sometimes prescribed with the idea that if you change the bacterial balance in the colon, it could help slow the inflammatory response.

Antimetabolites: Generally speaking, antimetabolites are medications that inhibit the use of a chemical in normal metabolism.  For Crohn's disease, these medications include azathoprine, 6-mercaptopurine, and methotrexate and are drugs that impact the production of lymphocytes (white blood cells) in the bone marrow... the idea being if you have less lymphocytes around, they can't do as much damage to the GI tract.

Biologic therapies: These medications are the newer frontier of therapy for Crohn's disease.  Biologics are components that are synthesized by biologic processes instead of a chemical ones, but this descriptor really says nothing about what the drugs do.  Most of the current biologic therapies used for Crohn's are designed to bind to and inhibit TNF-alpha, a molecule that seems to be a be a bad actor in overaggressive inflammation.  Trials for different kinds of biologic therapies are currently underway though.

Bibliography:

Geboes and Dalle. 2002. Influence of treatment on morphological features of mucosal inflammation. Gut 50(Suppl III):iii37-iii42.

Landi et al. 1992. Endoscopic monitoring of Crohn's disease treatment: a prospective, randomized clinical trial. The Groupe d'Etudes Therapeutiques des Affections Inflammatoires Digestives. Gastroenterology 102:1647-1653.

Oliason et al. 1990. Glucocorticoid treatment in ileal Crohn's disease: relief of symptoms but not of endoscopically viewed inflammation. Gut 31:325-328.

Schmitz-Moorman et al. 1988. Relationships between drug regime and histology of rectal mucosa in CD. Pathology - Research and Practice 183:30–34. 

Team Challenge Progress: Week of 9.16 to 9.22

Thank you to my supporters during the past week... now several weeks into the Team Challenge program, things are still going strong!  Because of your generous donations, I am very close to the $2,000 fundraising mark for The Crohn's & Colitis Foundation of America.  Check out my status bar on my donation page.  Can't wait to run those 13.1 miles for you all!

This week's donor honor roll:

• Jenny Enright
• Marge Holzem
• Marv Holzem
• Alexandra Lingle
• B. K. Holzem Enterprises

Training/Crohn's progress:

I have started my training program this past week (see my last post for the whole schedule), and while I did not adhere to things perfectly, I have started working on my speed and endurance.  I did do some fartlek work and did my tempo, speed-building run mid-week.  As expected, going back up on prednisone has helped quench some of the pain in my right knee... making running more comfortable in that respect.

With regard to the Crohn's, my GI system has not really improved since this "flare" got going.  It is pretty frustrating to know that things were sort of in control a couple of weeks ago, and then they just sporadically snapped back out of hand.  So now, my gastroenterologist and I have reached the point in my treatment where it its time to test my response to a medication that we have been avoiding up to this point... methotrexate.  For those of you who don't know, methotrexate is an immunosuppressant drug that tends not to be first-line therapy for Crohn's in women of child-bearing years.  Methotrexate is a pregnancy category X medication, which means that this drug should not be used during pregnancy because it is a known teratogen (i.e. can cause developmental defects for the fetus).  Taking this drug does not prohibit me from ever getting pregnant... this drug would just need to be stopped before that can happen.  Am I worried about taking this medication?  Sure, I would have rather avoided it.  But research shows that having active Crohn's during pregnancy is one of the worst things for the developing fetus, so it's not like I could get pregnant until this disease gets under control anyway.  I need to be well first, and then worry other things in life later.  I will always keep running no matter what is going on (I do slow up if I need to)... running through it all keeps me feeling in control of something!

Team Challenge Progress: Weeks of 9.2 to 9.15

The training plan

So, I have made a regimen to get myself ready for the 13.1-mile haul.  My goals, in order of importance, for this Vegas race will be to 1) just finish... maybe with an at least slightly better time than I had for my first half marathon... 2) run the whole race, and 3) get a decent time.  I'm not exactly aiming to win the race... but I am hoping to survive better than my first half marathon attempt (an experience which I have recounted on my donation page).  At least I know what issues I am up against this time, which should help.

I made a training plan for myself from this week on out to race day.  It is somewhat based off of Hal Higdon's intermediate half marathon training program, but it does have several adjustments based on life events scheduled between now and December 2... and some alterations based on my personal exercise preferences.  Given that I have been running consistently for a couple of years now, I have incorporated some shorter speed work into the plan.  It would be nice to actually get a little bit faster, but it is only goal priority #3.

Here is the whole schedule:

So you may be wondering about the meaning of some of my training terms, so I will explain.

Crosstrain: Some kind of cardiovascular exercise that is not running... in order to mix up the training routine and to help prevent injuries.  Examples would be elliptical training, swimming, kickboxing, etc.

Fartlek: In addition to being a funny word to say, fartlek basically means "speed play" in Swedish.  It is  a type of workout that mixes continuous and interval training to stress both the aerobic and anaerobic (i.e. with and without oxygen) systems.  I will basically do several shorter runs (on the order of 400 meters) that are a mixture of sprints and easy runs.

Kickboxing: Basically my preference for crosstraining.  These are cardiovascular workouts that incorporate kicking and punching moves based off of the martial arts Muay Thai kickboxing and Karate, as well as some Western-style boxing.  I go to a gym in St. Louis called The Boxing Gym.

Pace: These runs are supposed to be done at the pace at which I intend to run the half marathon... I guess somewhere around a 9-minute mile.

Tempo: This is a continuous run with a speed buildup in the middle.  For this kind of run, I will start easy for the first 1/3, buildup to about a 10-K pace in the middle 1/3, and then return to an easy pace toward the end.

Strength: Maybe this is obvious, but I mean strength training... or weight bearing exercise.  I probably will do some push-ups, free-weights, and maybe some additional weight machine work at the gym.

Training & Crohn's progress:

I am sad to say that the past couple of weeks have been frustrating... weaning off of the steroids didn't quite work, and I started to flare.  I finally feel like I understand what a Crohn's "flare" is.  Basically I started to have fevers early last week, without clear additional symptoms, but then had worsening GI issues later in the week.  My interpretation of the flare is basically that the immune system starts getting overactive, but the damage resulting from that activity takes a few more days to develop.  Needless to say, this hasn't made training easy.  In addition, I have continued to have a bit of right knee pain.  I am pretty convinced that my knee just has some irritation and inflammation, and nothing more serious (I had my husband perform a bit of a physical exam from our med school training... and he couldn't provoke any pain), but I don't want to overdo my workouts on a painful joint.  So lately I have been mixing running and crosstraining... just doing what I can based on the degree of pain.  I am still managing to workout 5-6 days/week, but I think I will only log about 20 miles of running for this week.

Getting back to the Crohn's flare issue though, my doctor has told me to go back up on the steroids (prednisone) to the previous dosage that was working for me (20 mg/day, which thankfully is still a relatively low therapeutic dose).  As a bonus, the side benefit of the steroids will likely be some suppression of the inflammation in my knee joint as well.  My GI doc has also added the antibiotics flagyl and ciprofloxacin, so I will probably do a post in the near future about the scientific evidence on the use of antibiotics for Crohn's therapy.  These drugs are all on top of a background of Crohn's maintenance therapy with Humira + azathioprine.  So, yes, if you were counting, I am currently taking five medications for the same illness.  It seems pretty clear to me that the available therapies for Crohn's disease treatment are inadequate if a patient needs five different drugs simultaneously.  Also, while I do need to take these medicines to alleviate the damage of my immune system on my intestines (and body... it's also important to remember that systemic inflammation is bad for your whole system), a couple of the drugs I am taking have dangerous side effects, and should not be used for long periods of time.  Thus, we need more effective and specific medications to treat Crohn's... we need more research!

NSAIDs & Crohn's: Part I

The setup

On the day of my diagnosis, the gastroenterologist I was seeing at the time told me that I should totally avoid nonsteroidal anti-inflammatory drugs* (NSAIDs).  She mentioned that this class of medications was not safe for Crohn's patients because they could cause the disease to flare.  Acetominophen (which you probably know as the active ingredient in Tylenol), though, was considered a safe alternative therapy for general aches and pains.  I imagine many Crohn's patients were given similar recommendations by their GI physicians at or around the time of diagnosis.

In many regards, it seems plausible that NSAIDs could cause trouble for Crohn's patients.  NSAIDs definitely cause other GI problems, including stomach ulcers and colitis (remember colitis is the general term for colonic inflammation... but it can be inflammation due to anything, not necessarily inflammatory bowel disease), and there is a clear mechanism by which NSAIDs act to screw up the GI mucosal barrier (i.e. the protective lining of the GI tract).  But what gives... just because a doctor says its true doesn't make it true... the scientific data need to support the claim.  Thus, I have set out to investigate the research on NSAID use and Crohn's disease.  And this week I am in luck (or maybe not), because there are a plethora of publications on this topic... so much so that I might have to make this a two-post series.  I want to ensure that I look at enough published science so as to not be biased in my presentation.

An aside... evidence-based living

In my blog post from a week ago, I brought up the concept of evidence-based medicine (EBM) as the ultimate standard for clincal practice.  In this post I am going to mention another concept that I made up based off of EBM... evidence-based living (EBL)... basically, trying to make personal decisions for my own health based on strong scientific research.

Now, this is somewhat of an impossible goal... to live one's life in accordance with scientific evidence.  Everyone has their biases and quirks (including and especially me), and there is simply too much scientific literature out there to keep track of it all.  But, if I know that the scientific data support or refute some sort of behavior, I try my best not to ignore those results.  For example, I don't take a multivitamin anymore, because studies have generally shown either no benefit, or in some cases, even detrimental effects of their use (Dolara et al. 2012).  Also, new evidence from the Women's Health Initiative* that calcium supplementation may do more harm than good has prompted me to stop taking so much Viactiv (Jackson et al. 2011)... but these data are from older individuals and other published results disagree with this study.  A Swiss clinical trial actually showed that the risk of fractures was reduced in healthy individuals with calcium supplementation (Bischoff-Ferrari et al. 2008).  This latter study, and the maintained hope for the potential benefits of vitamin D (and the fact that the caramel flavor is actually quite tasty... not the chocolate, which tastes like chalk), have kept me taking the occasional Viactiv chew.  (An important note... I would like to be clear that these studies for multivitamin and calcium supplementation are specifically for supplementation on top of a normal diet.  Clearly, vitamins and minerals are important when consumed in foods as part of a healthy diet.  The major question with these research trials is whether or not there is added benefit to taking vitamins and minerals as pure-ish compounds in amounts above what is in the normal diet).  So, getting back to NSAIDs, my EBL intention is to make my personal decision about NSAID use based on the scientific evidence on the matter.

So how did this whole story about NSAIDs and Crohn's get started anyway?

Some of the first possible links between NSAID use and Crohn's exacerbations came in the form of case studies* stating that four individuals taking NSAID had their IBD flare up (Kaufmann and Taubin. 1987.).  In addition to only being putative associations, in my opinion, several of the first supposed cases of NSAID use and Crohn's exacerbations are pretty weak.  One patient had a diagnosis of Crohn's and was supposedly in remission for three years, when on one fateful day he was given the NSAID indomethacin for sciatica.  Twenty-four hours later he developed bloody diarrhea, and then had a flexible sigmoidoscopy that revealed 60 cm of uniform colitis.  Really, indomethacin was the cause of this guy's exacerbation?  With 60 cm of uniform inflammation, isn't it more likely that he had active Crohn's disease that had been going for a long time?  It seems possible to me that he maybe had some increased GI bleeding due to the indomethacin (NSAIDs are also well-known inhibitors of blood clotting... this is why "baby" aspirin is prescribed for the prevention of cardiovascular disease), but it seems unlikely that this single dose of medication played any role in his significant inflammation.  Thus, I would generally say interpret case "studies" with a grain of salt; they shouldn't result in significant shifts in clinical practice recommendations, but may point out the need for controlled studies on the subject.

For what it's worth, there were a couple other case reports from the 1980s suggesting an association between exacerbations of ulcerative colitis (the other major form of IBD) and NSAIDs (Rampton et al. 1981., Rampton et al. 1983.)... neither of the others discuss Crohn's disease.  Just want to mention that this sort of questionable association from my previous paragraph wasn't the only case report mention linking NSAIDs and IBD.

The other side of the NSAID coin (or pill)

Given that NSAIDs are part anti-inflammatory, it also seems conceivable that they could be beneficial in Crohn's disease.  Crohn's disease is over-activation of the immune system (see my previous blog post for a more detailed explanation on the mechanisms of Crohn's), and if NSAIDs could suppress this inflammation, then they could inhibit disease activity.  Unfortunately, the immune system is not quite so straightforward--there are many arms of it, and inhibiting one side could shift the balance too much toward the other, etc.  Also, NSAIDs have a lot of effects other than just being anti-inflammatory.  But, the potential benefit for NSAIDs in IBD was at least considered in some earlier publications (Campieri et al. 1980., Rask-Madsen et al. 1990.).  In the end, though, NSAIDs don't work as Crohn's treatment and are not indicated for IBD therapy.

NSAIDs and Crohn's incidence

There are a few studies that have looked at the relationship between NSAID use and the development of inflammatory bowel disease (IBD).  One cohort study* showed that there was a small (and I mean small) increase in the incidence (number of new cases in the population) of Crohn's disease and ulcerative colitis in women who were frequent NSAID users (Ananthakrishnan et al. 2012.)...  fyi, the authors of this study defined frequent use as greater than 15 days per month.  Now, this does not prove any sort of causal link between NSAID use and IBD.  To borrow an analogy from Stephen Dubner, author of Freakonomics, just because a lot of people carry umbrellas on a rainy day does not mean umbrellas caused it to rain.  Similarly, high NSAID use does not necessarily cause IBD.  An alternative explanation might be that women with IBD experience more pain from their disease, and, therefore, take more NSAIDs.  Also, this study showed no association between low NSAID use and IBD.

To be continued...

Due to the depth of this topic, it does seem deserving of more attention and justice than I can humanly summarize in a single blog post.  Thus, next week I will continue this subject with the scientific data on NSAIDs and Crohn's flares and on the potential differences between COX-1 and COX-2 inhibitors (and any other important NSAID-related matters I find in the meantime).  I will also weigh in on my own EBL decision about the use of NSAIDs.  So please check back next weekend for more!

Bibliography:

Ananthakrishnan et al. (2012) Asprin, nonsteroidal anti-inflammatory drug use, and risk for Crohn's disease ulcerative colitis: a cohort study. Annals of Internal Medicine 156:350-359.

Bischoff-Ferrari et al. (2008) Effect of calcium supplementation on fracture risk: a double-blind randomized controlled trial. American Journal of Clinical Nutrition 87:1945-51.

Bjamason et al. (1988) Clinicopathological features of nonsteroidal antiinflammatory drug-induced small intestinal strictures. Gastroenterology 94:1070-1074.

Dolara et al. (2012) Antioxidant vitamins and mineral supplementation, life span expansion and cancer incidence: a critical commentary. European Journal of Nutrition Jun 9 [Epub ahead of print].

Jackson et al. (2011) Calcium plus vitamin D supplementation has limited effects on femoral geometric strength in older postmenopausal women: the Women's Health Initiative. Calcified Tissue International 88:198-208.

Kauffman et al. (1987) Nonsteroidal anti-inflammatory drugs activate quiescent inflammatory bowel disease. Annals of Internal Medicine 107:513-516.

Rampton et al. (1981) Relapse of ulcerative proctocolitis during treatment with NSAID. Postgraduate Medical Journal 57:297-299.

Rampton et al. (1983) Analgesic ingestion and other factors preceding relapse in ulcerative colitis. Gut 24: 187-189.

*Some more specific terminology explanations:

Case study: The more preferable term to refer to a case study might actually be "case report" because "study" is sort of a misnomer, at least in terms of how these reports are used in the biomedical literature, in my opinion.  Case reports are basically descriptive or explanatory articles (i.e. published papers) on a single or small group of patients that have an interesting/unusual/rare medical issue.  They enable physicians to share patient cases that might have greater relevance or may establish a potential interesting disease association (e.g. NSAIDs and Crohn's)... but this putative association will need to be investigated in larger, controlled studies.

Cohort study: This is a particular type of research study in which a large group of people without a particular disease are followed over time to see if they develop the disease.  Then, basically, the researchers go back to see what kind of risk factors (e.g. smoking, dietary habits, etc.) might be present in those individuals who developed the disease of interest.  These studies are purely correlational... they do not prove that the risk factor caused the disease.

Nonsteroidal anti-inflammatory drugs (NSAIDs): This is a class of medications that provide analgesic (pain relieving), anti-pyretic (fever reducing), and, at high doses, anti-inflammatory effects.  Many of these medicines are available over the counter, and, chances are, most of you have taken them at some point in your lives.  Common examples are aspirin, ibuprofen, and naproxen.  The "NS" or "nonsteroidal" part of NSAIDs distinguishes these drugs from the steroid class of anti-inflammatory medications... steroids being a common class of anti-inflammatory drugs prescribed for a host of autoimmune diseases, including Crohn's disease.  NSAIDs are the most prescribed of the anti-rheumatic drugs (i.e. drugs prescribed for arthritis), which suggests that they are very efficacious as anti-inflammatory analgesics (Takeuchi et al. 2006.).

Women's Health Initiative (WHI): The WHI is a program started by the NIH (see previous post for information about the NIH) in order to investigate the major health problems in older women.  Some of the major WHI study topics include cardiovascular disease, osteoporosis, and cancer.

Team Challenge Progress: Week of 8.26 to 9.1

Happy Labor Day weekend and a big thank you to all of my Team Challenge donors from this past week!  With your help, we will make an impact on the future of Crohn's disease research and awareness.  I am > 60% of the way to reaching my fundraising goal.  Please check out my progress bar on my donation page.

This week's donor honor roll (in order by surname):

• Eva Glasser
• John Glasser
• Anne Klemens
• Chrissy Klemens
• Lee Klemens
• Florence Kozak
• Barb Peasall
• Jennifer Swenson
• David Van Essen
• Isabel Van Essen
• Ned Zeljkovich

There were several extremely generous donations this week, so thank you all for your support!  I would give a special word of appreciation to Lee & Anne Klemens, David & Isabel Van Essen, and Eva & John Glasser for being my top donors of the week!

Training Progress

I took things a bit easier this week because I've had a couple knee aches.  But I still managed to log 29 miles for the week.  I will probably take the holiday weekend as an opportunity to rest up a bit, but it is time for me to put my half marathon training schedule together.  Expect to see that posted next week!

Symptom wise, things have continued to be stable for the past week, so I am feeling pretty good about my current treatment regimen.  Things seem like they are finally falling into place.

Do I really need that test?

Medical testing for diagnosis and disease monitoring become sort of a routine part of a Crohn's patient's life.  These tests run the gamut from less-invasive blood and stool tests and diagnostic imaging to invasive colonoscopies.  I am particularly interested in the research on appropriate clinical testing for Crohn's activity, for both the personal reason of balking every time my gastroenterologist recommends another colonoscopy, and because I think the "right" amount of testing is an extremely complicated issue for any doctor and patient to work out.  The reasons for this are muti-fold... sometimes the incentives for testing are not in the right place, the tort* culture of medicine in the US makes it so that missing a diagnosis or complication is a major concern for physicians, and personal anecdotes and experience heavily influence human decisions (and doctors are not immune to this fact).  This is not to say that physicians just order tests all willy-nilly.  Most doctors are well aware of the costs associated with over testing... both the indirect costs of inflating health care expenditures and the direct costs to the patient of potentially identifying "incidentalomas" (An incidentaloma is essentially a made-up term to describe some test finding that would have never caused any problems for the patient, but because it is discovered by a clinical test, it necessitates even more testing and evaluation... e.g., a benign mass that is identified by MR imaging.).  Also, despite the fact that evidence-based medicine* is the ideal for practice, every patient situation is unique, and controlled research studies cannot possibly address every scenario, which sometimes makes it hard for the clinician to make decisions solely on research conclusions.

A note to keep in mind...

For the record, it was difficult to find research the topic of testing indications during Crohn's management.  I found many articles on standard-of-care* guidelines for Crohn's treatments, but as for recommendations and indications for testing, there was shockingly little.  From the standpoint of controlling health care costs, this is fairly problematic... many doctors could be ordering unnecessary tests and driving up costs, simply because there's limited to no data to show that those tests are unnecessary... the research just isn't there.  That being said, I will review what publications I could find on the matter, and I will continue to follow the literature on this issue for updates.

Testing at the time of diagnosis

The diagnosis of Crohn's disease usually relies on the results from a number of different tests... including endoscopy, biopsy, blood, and diagnostic imaging results (Mowat et al. 2011).  The key finding for Crohn's diagnosis is generally a specific pattern of inflammation on endoscopy and biopsy, which distinguish it from other forms of inflammatory bowel disease ("skip lesions" and "granulomatous" inflammation... I will discuss these in detail in future posts), and the rest of the test results support the clinical picture, establish a baseline for disease activity at the time of diagnosis, and determine whether any complications are present.

Other situations when testing is (absolutely) necessary

I qualify "absolutely" because I struggle with saying that anything is ever definitive or true in all cases, but there are other situations in which testing definitely meets criteria for being the standard of care for Crohn's management.  When there is a dramatic change in Crohn's symptoms that is suggestive of an acute complication... for example, a sudden uptick in pain or blood loss or a striking decrease in frequency of bowel movements (BMs)... diagnostic testing, which will depend on the symptoms, is warranted.  As an aside, using the term BM always makes me think of one of Tina Fey's hilarious quotes from 30 Rock: "Boy, is anybody else BMing like a rock star?".  I think Crohn's patients should use this phrase gratuitously whenever their GI symptoms are in check.

Screening and surveillance colonoscopies are also recommended for patients following diagnosis, due to the increased risk of colon cancer in patients with Crohn's.  Friedman and colleagues followed 259 patients with Crohn's colitis for nearly 17 years, and found that 7% of these individuals had pre-cancerous or cancerous lesions on colonoscopy at some point over the evaluation period (Friedman et al. 2008).  In another study from Sweden, Crohn's patients were found to be at 2.5x increased risk of colon cancer compared with the general population, and that risk increased to 5.6x if the disease involvement was restricted to the colon (Ekbom et al. 1990).

The Crohn's & Colitis Foundation of America recommendations for colonoscopic cancer surveillance are as follows (Farraye et al. 2010):

• Patients with Crohn's disease with major colonic involvement (at least 1/3 of the colon) should have a screening colonoscopy at 8-10 years after disease onset (from start of symptoms... not diagnosis).
• The details of the second recommendation are somewhat complicated and confusing... but basically, if there are no pre-cancerous or cancerous lesions detected on the aforementioned screening colonoscopy, then surveillance colonoscopies should be done every 1-2 years.

Following up for therapeutic response

As for testing to monitor response to therapy, I thought I'd seek answers from clinical trial end points... i.e. what measures do clinical trials use to evaluate the efficacy of therapy?  Many trials use activity scores, such as the Crohn's Disease Activity Index* (CDAI) or Inflammatory Bowel Disease Questionnaire* (IBDQ), in order to measure patients' symptoms before and after therapy (Colombel et al. 2007., Feagan et al. 2008.).  These trials measured response as a decrease in the CDAI (by greater than or equal to 70 points) or as remission by CDAI (score less than or equal to 150).  C-reactive protein (CRP... see my previous post for a more detailed explanation on this blood marker) were also measured from patients in these trials, but this test was not used as an end point to evaluate drug response.  Currently, there isn't a clear precedent for using more invasive testing for monitoring response to therapy, but recommendations for endoscopic disease monitoring are contested (Rameshshanker and Arebi. 2012).

Concluding thoughts

While the gastoenterologist is going to be the expert, and, thus, the most informed person when it comes to making decisions about clinical testing, it is perfectly valid as a patient to have a discussion with your GI doc about his/her reasons for ordering that test and if it's absolutely necessary.  Generally, the litmus test for whether or not a clinical test is needed is based on the question, "Will the results of this test change the patient managment?".  If the answer is "no", then the test shouldn't be done, but if it is "yes" or "potentially", the test is often warranted.  But there are situations in which even this litmus test breaks down... what if a similar answer can be provided by a less-invasive test or just by watchful symptom evaluation over time?  Often things are not clear cut, and the patient and clinician should reach a mutually agreed upon decision for management.

Bibliography:

Colombel et al. (2007) Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology 132:52-65.

Ekbom et al. (1990) Increased risk of large-bowel cancer in Crohn's disease with colonic involvement. Lancet 336:357-359.

Farraye et al. (2010) AGA technical review on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology 138:746-774.

Feagan et al. (2008) Treatment of active Crohn's disease with MLN0002, a humanized antibody to the alpha4beta7 integrin. Clinical Gastroenterology and Hepatology 6:1370-1377.

Friedman et al. (2008) Screening and surveillance colonoscopy in chronic crohn's colitis: results of a surveillance program spanning 25 years. Clinical Gastroenterology and Hepatology 6:993-998.

Mowat et al. (2011) Guidelines for the management of inflammatory bowel disease in adults. Gut 60:571-607.

Rameshshanker and Arebi. (2012) Endoscopy in inflammatory bowel disease when and why. World Journal of Gastrointestinal Endoscopy 4:201-211.

*Some more thorough terminology explanations:

Crohn's Disease Activity Index (CDAI): The CDAI is essentially a way to more-or-less objectively rate the activity of Crohn's disease and is used as a tool for research investigations.  Most clinical trials to evaluate Crohn's therapies will use the CDAI to determine efficacy.  Several symptomatic factors are included into the CDAI computation, including number of stools per day, presence of complications, and general well-being.

Evidence-based medicine: The application of evidence obtained from scientific investigations to clinical decision making.  The goal of evidence-based medicine is to allow a clinician to make decisions about a particular testing or treatment strategy based on controlled studies in large populations instead of purely on personal experience, which can often be biased.  Evidence from controlled investigations can more accurately inform practice about the benefits and harms of a particular clinical strategy, and leads to may recommendations for standard-of-care (see below) practice.

Inflammatory Bowel Disease Questionnaire (IBDQ): This is a questionnaire for IBD activity that incorporates questions to assess the impact that the disease has on quality-of-life factors, such as social and emotional effects.  IBDQ scores generally correlate well with CDAI scores.

Standard of care: A medical treatment guideline that specifies the appropriate testing or treatment based on scientific evidence and the consensus of medical professionals.

Tort: Tort law is a type of jurisdiction that deals with situations in which one person's actions have unfairly caused another individual to suffer loss or harm... so that the harmed individual can recover his/her loss.  Applied to the health care field, tort law generally comes into play in the form of medical malpractice (where a doctor's negligence has caused a patient harm, and the patient or patient's family aims to recoup the costs of that harm).  Claims for medical malpractice must establish all four elements of the tort of negligence in order to be successful.