Incidence of cancer in TNF-inhibitor treated patients with rheumatoid arthritis

In one of the articles from this week, we read about how various cytokines have key roles in the pathogenesis of rheumatoid arthritis (RA). I wanted to find out more about TNF inhibitors because they seem to have become a standard treatment for RA patients. I came across this article, which covers the potential role of these therapeutics in the development of certain cancers in patients who were treated with TNFα inhibitors. These are patients who were diagnosed with chronic immune-mediated diseases, including those with rheumatoid arthritis.
The researchers aimed to find a correlation (or lack thereof) between cancer risk and TNFα inhibition therapy. They conducted a Safety Assessment of Biological Therapeutics (SABER) study to comparatively analyze the safety of TNFα inhibitors to alternative treatment strategies. Recently, there have been many studies suggesting the malignancy of TNF inhibitors and the detrimental health risks they can induce in RA patients. This article covers a different stance in that the researchers conclude that short-term cancer risk is not increased in RA patients treated with TNFα inhibitors compared to other commonly used therapies for chronic inflammatory diseases.
Previous studies have produced divided conclusions, some stating that the incidence of cancer did indeed increase in TNFα-inhibitor treated RA patients and others arguing that no solid cancers were seen in among RA patients treated with these inhibitors. One thing these studies have in common is that they all focused on only TNFα inhibitors and compared the incidence of cancer in RA patients treated with TNFα inhibitors to those who were not treated. The article above brings something new to the table, suggesting that comparing other drugs to TNFα inhibitors will provide more information to physicians and clinicians about which treatments should be favored with RA patients. The researchers are not hypothesizing whether or not TNFα inhibitors directly increase the incidence of cancer in RA patients. They realize that this form of therapy could very well result in some health risks, but the greater goal was to find out if these inhibitors create more harm than their counterparts (similar drugs). And as seen in the findings, this was not the case.
With that said, is it fair to say that TNF inhibitors are causing an increased incidence of cancer in RA patients when alternative treatments are just as risky (if not riskier) but less effective? Would you be willing to possibly risk causing harm to other parts of your body in order relieve the agonizing pain from arthritis? Will we be able to find a treatment that will not make us choose between one illness and another, or is this unavoidable? 
Here is another recent article from a general interest news source on the newer RA drugs to stimulate your brain.

Unusual Arthritis remedies

Arthritis refers to about 120 different diseases that affect your joints and other soft tissues. Osteoarthritis, which is the most common form, affects about 21 million adults in the country! Unfortunately there is no cure for arthritis but they have found ways to “treat” it to prevent further damage. In class we heard about possible natural and medical cures so I decided to do a blog on some of the unusual treatments for arthritis people are trying.  One remedy I found that was funny an oil called Emu Oil. It is derived from Emu fat and has been used for centuries for its natural anti-inflammatory properties. It contains a sort of menthol that helps take your mind of the pain.  Another remedy are capsules called superior joints that are made from eggshell membranes. It contains chrondroitin, hyaluronic acid, collagen and other glycosamino-glycans and has been clinically proven to reduce joint pain without any side effects.  Some people felt an improvement within 10 days.  Another strange remedy is one called Rhus Tox. Which is made from the oil of the poison ivy plant. Usually you want to stay away from poison ivy but here they put it inside this homeopathic medicine. It is said to work by producing similar symptoms to arthritis and is given with the aim of counteracting discomfort. I’m sure arthritis is horrible to live with and these bizarre treatments might even help. I would probably consider some before turning to traditional medicine or surgery. How about you?

Arthritis

Since the topic for the next two weeks is arthritis I did some research on it and the different types. According to the Centers for Disease Control and Prevention (CDC), arthritis means joint inflammation, but in the public health world, the term is used to describe more than 100 rheumatic diseases that affect joints, the tissues which surround the joint and other connective tissue. Rheumatic conditions are usually characterized by pain and stiffness in and around one or more joints. Certain rheumatic conditions can also involve the immune system and various internal organs of the body.

The CDC lists childhood arthritis, fibromyalgia, general arthritis, gout, osteoarthritis, rheumatoid arthritis, and systemic lupus erythematosus as the most common forms of arthritis. Since osteoarthritis and rheumatoid arthritis are the two types that are talked about in the articles this week, I will go into some detail about them.

Osteoarthritis is also known as degenerative joint disease and is characterized by the degeneration of cartilage and its underlying bone within a joint as well as bony overgrowth. The breakdown of these tissues eventually leads to pain and joint stiffness. The joints most commonly affected are the knees, hips, and those in the hands and spine. Disease onset is gradual and usually begins after the age of 40. There is currently no cure for osteoarthritis.

Rheumatoid arthritis is a systemic autoimmune inflammatory disease which manifests itself in multiple joints of the body. The inflammatory process primarily affects the lining of the joints, but can also affect other organs. The inflamed synovium leads to erosions of the cartilage and bone and something joint deformity. This leads to pain, swelling, and redness. The cause of rheumatoid arthritis is believed to be from a faulty immune response. It can begin at any age and there is also no cure for this type of arthritis.

"Arthritis." Centers for Disease Control and Prevention, 01 Aug. 2011. Web. 24 Mar. 2013.

Fecal Transplant possible treatment for IBD

During our discussions of IBD these past weeks, the helminthic treatment kept reminding me of an equally gross treatment: fecal transplant. I mentioned it in class, but decided to do a bit more research on it and share it with you guys. Typically, fecal microbotia transplant (FMT) is used to treat Clostridium difficile, a bacteria that causes severe diarrhea and other intestinal issues, which occurs in people who are usually in and out of the hospital and have been on several antibiotics for an extended period of time. The antibiotics wipe out the "good bacteria" in their gut and the C. difficile bacteria takes over. FMT has proved to be very successful in treating and overcoming C. difficile, and patients agree that the relief from this devastating infection (which can sometimes lead to life-threatening issues) far outweighs the "gross factor" associated with the treatment which involves infusions of a donor's stool (sometimes a relative's) either through enema, colonoscope, or nasogastric tube.

During my research of FMT I came across some articles and blogs that mentioned FMT as a treatment for IBD. Most of the research is relatively new and inconclusive, however, one article, presented a few cases from research articles where recurrent FMT was successful in actually reversing IBD. According to researchers from the Center for Digestive Diseases in Australia, "FMT may act as an antagonist to etiological infective agent(s) and aid in re-establishing depleted bacterial species, thereby reversing IBD." The article describes the gruesome, painful symptoms that the IBD patients experience, similar to the article we read with the women with IBD/IBS testimonials.  I wonder if those women would consider FMT as a treatment.

Since this article is from 2011, I only hope more research is being done on FMT treating or even reversing IBD. I wonder which treatment would work better; helminthic or FMT, and which would patients choose? 

Article can be found here: http://www.sciencedaily.com/releases/2011/10/111031114945.htm

Helminths, the Hygiene Hypothesis, and Eating Worms.

The article, now from last week here, focuses on discussing the role of helminths in host immunological function as a possible treatment for IBD. The authors argue that helminths subdue their hosts immune systems in order to colonize, and by doing so revert the over active inflammatory response that leads to IBD.

Some of the worms looked at in this article have coevolved with their hosts for over 100,000,000 years to live symbiotically with them. As such, they have adopted factors and receptors nearly identical to the host, making them adept at evading immune defenses. They can even absorb tissue and cells from the host which help to conceal it.

An important finding in the demographics of IBD was that less developed countries had a lower incidence rate of IBD. There are even gradients in the US and Europe that support this evidence. For instance, early studies into IBD found the disease more common in the northern vs southern areas of the United States. In these areas with increased helminth infection rate, allergic disorders are decreased, asthma is reduced, and even multiple sclerosis is less frequent. The problem in developed countries is that the environment we grow up in is free of such helminths giving our immune system the possibility to over compensate.

Experiments referenced in the paper included clinical trials in humans as well as rats and mice. In humans it is a commonly held notion that the adaptive immune system, specifically Th1 cell activity exceeding Th2 activity, is overzealous in its production of inflammatory cytokines which in turn leads to IBD. To enforce this, some experimental evidence was provided. In Rats, Th1-type colitis was induced and then reverted by using the intestinal roundworm T. Spiralis. Also, in murine models induced with Th1-type colitis, a helminth modulating the pro-inflammatory products INF-gamma/IL20 p40 in the colon down regulated inflammation. Infection with a worm also showed a down regulation in the Th1 pathways of the gut by up regulating Th2 cytokines like IL4 and IL13.

Another fascinating property of these worms is the ability to influence immune cell function by modifying cell receptors. An example of this is H. polygyrus and mucosal T cells. This worm induces the production of TLR4 receptors in the mucosal T cell membrane which, upon activation, cause the cell to secrete modulating factors, TGF-B and IL10, that help control a Th1 response instead producing pro-inflammatory molecules.

Although this article provided great information into the advancing field of helminth treatment, it was sorely lacking figures. Some of the pathways and interactions explained in the article would have been much easier to understand if a relevant figure would have been made available. The two provided are unsatisfactory and contribute nothing to the content of the paper.

Some of the questions I had

1) Is down regulating our immune response safe when we are constantly dealing with other types of infection? A TB study I looked at found results indicating helminth infection increased the susceptibility to TB.

2) If helminth infection decreases vaccine efficacy, wouldn’t this be a problem in developing countries where vaccines to diseases like polio are very important?

3) Would you rather be on immunosuppressants or helminth therapy?

Freewheel training on intestinal lymphocyte expression of inflammatory cytokines and apoptotic proteins

Prior epidemiologic studies have suggested that long-term physical activity protects against the onset of IBD. With this in mind, the chosen article primarily focuses on long-term voluntary exercise on the expression of pro- and anti-inflammatory cytokines in mice. Moreover, side objectives of the study included analysis of intestinal lymphocyte (IL) expression of apoptotic proteins and inflammatory cytokines following a brief session of high intensity exercise.
Figure 1 on pg. 1108 provides a great schematic representation of the experiment layout.

As the authors predicted, the mice that regularly exercised expressed lower pro-inflammatory cytokine levels (TNF-a & caspase 7) and higher anti-inflammatory cytokine levels (IL-6 & IL-10) than the sedentary mice. In addition, it was found that an acute session of intense activity caused increases in pro-inflammatory cytokines and pro-apoptotic protein (caspase 3).
The results suggest that long-term physical activity can provide an 'anti-inflammatory effect' by promoting higher levels of “good” anti-inflammatory cytokines. In contrast, acute sessions of intense exercise promoted a temporary state of inflammation and destruction that eventually returned to basal levels.
My analysis of the article suggests that regular light intensity sessions of exercise such as walking is the best intervention for all individuals regardless of their health. This is because less vigorous sessions of activity provide an 'anti-inflammatory effect' on the body in addition to other health benefits without taxing the CNS and promoting inflammation. I do believe high intensity bouts of exercise are beneficial to overall health; however, I see it as a 'trigger' to those suffering from IBD. This is because IBD results from a chronic state of inflammation and intense exercise would contribute further to the imbalance of pro-inflammatory cytokines.

Do others believe high intensity bouts of exercise should be avoided by IBD patients too?

The article discussed can be found at: http://www.sciencedirect.com/science/article/pii/S0889159110001054

Adiponectin and its Presence in Crohn's Disease

In this research article, the researchers show this interesting correlation with our adipose tissue (energy storage system) and our immune system.  Naturally, we would never think that fat has anything to do with immune responses, but clearly seen here in this research, we see some beneficial anti-inflammatory occurrences. 

Crohn's disease is known to affect any part of the GI tract, and in this study, they mainly examined the area around the small intestine, the mesenteric adipose tissue.  Looking at the adipocytes in this area, they concentrated on one of the bioactive molecules that were secreted--adiponectin.  Adiponectin has been shown to have a ton of biological effects, but more importantly, it has anti-inflammatory properties in endothelial cells and macrophages.

They looked at patients with Crohn's Disease (CD), ulcerative colitis (UC), and then for the control, patients who have had surgical resection due to colon cancer.  With their samples from the patients, they imaged for adipocytes, immunohistologically stained for CD3, CD20 and CD68 (proteins seen on T cells), determined adiponectin and IL-6 concentrations, looked at short term adiponectin release, and looked at mRNA levels for adiponectin.

Overall, the observation was that adiponectin was prevalent in the mesenteric adipose tissue.  The adipocytes were smaller, there was evidence of T cell presence in these areas, and adiponectin concentration, release, and mRNA levels were higher in the hypertrophied areas of Crohn's disease patients.   Logically so, CRP levels and IL-6 (proinflammtory markers) both had an inverse relationship with the level of adiponectin.

One of the interesting things for me was that, in patients with UC, their adiponectin levels were the lowest, even lower than the controls.  My thought process for this was based on the location of where they took the samples.  UC usually manifests itself in the colon (large intestine) areas while a majority of the CD patients were afflicted in the ileal areas of their small intestine.  The mesentery is also what holds up the parts of the small intestine to the back wall of the abdomen.  As a result, the samples they got might have just been farther from the large intestine, and with less inflammation from UC.

Looking to Th17 for explanations in UC and CD

     For quite a while the focus in IBD has revolved around Th1 and Th2 cell interactions. These cells have been widely implicated as being out of balance, and one of the prime examples of immuno-dysregulation causing the harmful disease IBD. Examples of this are abundant in previous papers regarding this topic, but this week we will be taking a look at another player, the Th17 cell. The paper being discussed is this article published in 2010, where the authors delve into the effector cytokines, genes involved in differentiation, and recruitment of Th17 cells.

     Please refer to the paper to see which interleukin’s and proteins are involved in each category (located in the abstract) as I explain their findings. This study aimed to clarify the involvement of Th17 in UC, CD, and most importantly control groups. In order to quantify these concentrations and asses involvement with each scenario, mRNA levels of each cytokine, differentiation, or migration factor were evaluated by analyzing biopsies of inflamed or healthy areas. PCR was used to amplify these findings.

     The results of the collected mRNA discussed on page two under the effector cytokines section had a couple of interesting results. IL17A and IL22 were found to be highly expressed in all affected participants, except in ileal CD where IL17A was weakly expressed, compared to the control. This finding suggests that both IL17A and IL22 are very important in the pathogenesis of IBD if they are so conserved. I believe more testing needs to be conducted to discover what secretes each of these interleukins and how they work, considering current research appears to be lacking on specifics. Another interesting finding was that patients with UC located in the colon had higher levels of IL17A and IL21 than patients with CD in the colon. IL21 is responsible for activated NK and CTL cells, which I find curious. Why the need to activate CTL cells, which deal with predominately viral problems, in a bacterial area? This does, however, give support to the growing notion that CD and UC are indeed separate diseases aside from affected locations.

     In terms of the recruitment genes, CCR6 and CCL20, there were also peculiar findings. It is important to understand that CCR6 is a receptor for the CCL20 molecule as may be obvious the ‘R’ and ‘L’ present in the respective abbreviations denoting receptor and ligand. CCR6 is attached to dendritic cells along with a number of lymphocytes, including Th17 cells, but needs more research.  CCL20 is expressed by inflamed tissues, including intestinal epithelia, and directs Th17 cells to the site of inflammation. However, lower levels of CCR6 and CCL20 in ileal samples suggest less Th17 involvement in this area. Why would there be a greater need for Th17 in the colon? Unfortunately this area needs more research to discern the reason for this behavior.

     A few words of caution are raised in this article pertaining to data collection. The first is that 42% of the affected patients were taking anti-inflammatory medication at the time of sample collection. This gives rise to the possibility of skewed cytokine expression, but the data was still significant enough to be considered reliable information. The other concern was in regards to using mRNA as a means to determine immunological function instead of actual cytokine concentration but again, contributed to significant findings.

     An area of puzzlement in this paper was in its discussion of the RORC gene. The paper refers to it as a master transcription factor with specific isoforms for activated T cells, but I was having a lot of difficulty in researching RORC’s function. If anyone is able to find information on this it would be appreciated.

     Overall this paper came to the conclusion that Th17 is indeed highly involved in IBD, but the areas being affected, be it UC or CD, offer variable expression. With these results it should be worth considering different therapies or treatments should be pursued based on the location and type of disease that has manifested. In my opinion, more work needs to be put into discovering exact secretion and function of IL17A, IL22, and CCR6 to help narrow down the root cause of IBD.

Sorry for the length, but I wanted to make up for a lack of discussion time in class.

‘‘I Know This Is Bad for Me, But.. .’’
A Qualitative Investigation of Women With Irritable Bowel Syndrome(IBS) and Inflammatory Bowel Disease(IBD): Part II
a link to the article

This week I will be summarizing a qualitative analysis the various detrimental behaviors of women with IBD and IBS. It is first important to note that while IBD and IBS have very similar symptoms they are different conditions. Patients with IBD experience alterations to their digestive tracts while those with IBS do not. This is important because the alterations that occur can increase a person's chances of developing colorectal cancer.

With this understanding this study examined the possibly detrimental behaviors of eight women from Ontario, Canada. The study included the analysis of a background questionnaire, a 14 day food diary, and semi-structured interview for each subject. The goal of the paper was to look into how women with IBS or IBD deal with the condition, specifically looking at possibly detrimental behaviors that they engaged in.

 Each of the women involved expressed the feeling that they were controlled by their digestive tract. In order to deal with this the women often engaged in food restriction or the use of medication in order to decrease the likelihood that would experience symptoms. One interesting finding was that many of the women would take medication preemptively in order to be able to eat one of their trigger foods. The participant expressed their wanting to be "normal" and not have IBS of IBD. This is both an interesting and logical feeling for these women. Of course they would want to be able to eat or drink whatever they want and not have to worry about experiencing symptoms which are often times embarrassing and extremely uncomfortable.

From this article the diagnosis of IBS or IBD is portrayed as life changing. The process is frustrating and those with these conditions are often not compliant with treatment for various reasons. The question is how can the health care providers make dealing with this disease easier?

Inflammatory Bowel Disease (IBD)

Crohn's Disease and Ulcerative Colitis...What are they?

Both of them are forms of IBD and happen to be idiopathic (unknown cause), with speculations lying in genetics and environmental factors.  According to a review article by Baumgart and Carding, lots of research has pointed in genetics being a major contributing factor, with Ashkenazi Jews having an 8 times increased risk compared to other ethnic groups.  Genetics only point at this trend but does not specifically answer why this trend exists.  More than a dozen mutated regions on our chromosomes have pointed to IBD, and with the variation, everybody is affected by IBD differently.  One gene that this review paper talks about in particular is the CARD15 (NOD2) gene.  This gene codes for the NOD2 protein, a intracellular pattern-recognition receptor.  With a mutation, it results "in a disturbance in the normal immunological unresponsiveness of the mucosal immune system to components of the commensal intestinal microbiota."  In short, the NOD2 recognizes the good things in our intestines as bad, and creates an inflammatory response. 

In the United States alone, the risk is higher for white and African-American individuals.  Most of IBD also has a higher occurence in more developed countries.  Epidemiological differences are seen in people of the same ethnicities, living in different locations. Researchers have looked into things we can change in order to alleviate the symptoms of IBD.  Lifestyle changes like breastfeeding, dietary consumption, and smoking have been hypothesized to help. 

What I find most interesting is the fact that environmental factors even has any effect at all on this disease.  Is it our lifestyle that causes these mutations, and if so, there seems to be some simple life altering choices we can make that would diminish the effects of IBD.

Innate and Adaptive Immunity in Inflammatory Bowel Disease

In the next few weeks our class will be discussing inflammatory bowel disease (IBD). IBD is actually a group of diseases characterized as the chronic inflammation of a the bowel, which leads to pain and some very unpleasant problems. Some of the most common are Ulcerative colitis and crohn disease. Essentially the cause of IBD is a dysregualtion of the immune system in the gastrointestinal tract which causes intestinal inflammation.
The paper proposes the cross-regulation or interaction between the innate and adaptive immune systems. The first proposed mechanism the review proposes is that there is a mutation in a particular receptor of the intestinal tract called NOD2 which is part of the innate immune system and serves to detect components of bacterial cell walls. In addition patients with the NOD2 mutation did not have macrophages which suppressed the secretion of pro-inflammatory molecules called cytokines and thus experienced inflammation.  Patients with IBD who have a mutation in the NOD2 receptor show a decrease in the expression of anti-microbial proteins which causes an increase in the number of bacteria which can cross the intestinal lining. This is the link to the adaptive immune system's involvement in IBD. Due to the defect in the innate immune system of the intestine more bacteria than usual are able to cross the intestinal lining and activate T-cells which in turn secrete pro-inflammatory cytokines to fight of the invading bacteria, and increasing inflammation of the intestine. In addition cells from the innate immune system can also secrete these cytokines and activate an adaptive immune response and increase inflammation.
Some studies have been done to study which cytokines are involved in IBD and further if blocking them is an effective treatment of IBD.
link to the paper: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3158392/

The Friendly Bug... Can worms in our stomach help boost our immune system? Yes or yuck...

First, I’ll give a brief overview of what inflammatory bowel disease (IBD) actually is.  Then I will address this rather bizarre and yet fascinating research being done on whipworms and their immunological benefits.  Essentially, IBD is an autoimmune disease, or more specifically, a type II immunopathology.  This occurs when antibodies are directed against a specific target tissue or cell within the person’s own body.  Sufferers of IBD have uncontrollable inflammation within the intestinal tract, which leads to a multitude of “unpleasant” problems.  Although the actual cause of IBD is still being worked out, the mechanism by which it happens is actually quite simple.  Basically, the individual’s own body attacks various components within the digestive system, causing inflammation and collateral damage.

Anyway, back to whipworms…

This article discusses the broader potential cures that whipworms may have to offer.  Aside from Crohn’s disease and ulcerative colitis, which are the major types of inflammatory bowel disease, research is being done on how it can benefit those with multiple sclerosis, rheumatoid arthritis, and even autism.  The underlying theory behind this whole whipworm fascination is that humans nowadays are too clean, which has resulted in a lackluster immune system (how ironic).  Because we are not exposed to as many microorganisms as our predecessor were, our immune system isn’t nearly as robust.  You can almost consider our ancestors to be “naturally” immunized.  This is the basis for the whipworm therapy.  By introducing ourselves to a safe microorganism, we can potentially “rebalance” our immune system.  Whipworms from pigs were chosen because they do not infect humans and cannot reproduce inside of humans, while still stimulating an immunological response (which is good).  These worms will later die and either be absorbed or “pooped” out.

In addition to stimulating a desired immune response, I have a question to stimulate some discussion.  Would you consider this form of therapy in the future if it proves to be effective?  Why or why not?  I wonder how it would taste…

For the article, go to

http://online.wsj.com/article/SB10001424052970204795304577220993641557460.html?mod=googlenews_wsj

Smoking, Nicotine and IBD: How Does Cigarette Smoking Affect IBD?

For the next 2 weeks, our class will be discussing Inflammatory Bowel Disease (IBD). This week will revolve around media and review articles, and the paper I will be analyzing is "Smoking, Nicotine and Inflammatory Bowel Disease." 

The article can be found at: http://ibdcrohns.about.com/cs/ibdfaqs/a/smokingguts.htm

Before discussing the paper, it would be helpful to have a quick refresher on IBD. 

• IBD involves chronic inflammation of all or part of the gastrointestinal tract. 
• Etiology is unknown; however, IBD is thought to involve genetic, immunologic, and environmental factors.
• The most common inflammatory bowel diseases are Ulcerative Colitis and Crohn's disease.
• IBD is a chronic illness and there is currently no medical cure.

This paper primarily discusses smoking and its affects on Ulcerative Colitis (UC). Prior research has strongly indicated that non and ex-smokers are at an increased risk for developing UC, and a decreased risk of developing Crohn's disease. This indicates that smoking may actually be beneficial for delaying the onset of UC. 

The author expands on this idea and explains that nicotine, a naturally occurring substance in tobacco, protects individuals against UC. According to a research article cited in the original paper, the exact protective mechanism(s) from nicotine are unknown; however, it is proposed that changes in intestinal motility, permeability, and colonic mucous are involved. Further studies involving nicotine were noted, but the protective effects against UC were accompanied with several negative symptoms.

Nonetheless, the risks of smoking far outweigh any possible benefit to a decreased risk of UC. Until the protective mechanism(s) of nicotine on UC are understood, it will be hard for pharmaceutical companies to formulate safe and effective medical interventions.

Outside research article:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014383/