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.