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Wednesday, November 30, 2011

Better Treatments for Rheumatoid Arthritis Not Too Far Off


Rheumatoid Arthritis (RA) is an inflammatory autoimmune disease that most often targets peripheral joints, frequently resulting in pain, swelling, and possible deterioration and destruction of cartilage and bone located at the joint. RA afflicts more than 1.3 million people in the United States alone, and the disease is most prevalent among women and the elderly. For over 60 years, RA has been widely treated non-selectively with glucocorticoids (GCs), such as methotrexate, a type of steroid hormone, because of their unrivaled, potent anti-inflammatory effects. Despite the successful anti-inflammatory effects that GCs have on the joints of afflicted patients (in fact, GCs are successful in just about every type of inflammatory ailment), it is a costly treatment, and there are numerous, severe side effects due to their non-selective nature, including immunodeficiency, high blood sugar, and increased skin fragility and bruising, among others. Consequently, there is currently a necessity for research into possible steroid therapies better targeted to healing RA with greater efficiency and fewer adverse side effects.
When RA is treated with GC steroid hormones, the hormone binds to a glucocorticoid receptor (GR) located in host cells (and expressed nearly universally in all vertebrate cells). Once being bound by a GC, the GR then translocates into the host cell nucleus where it can act as a transcription factor, subsequently altering gene expression and helping to dampen the host immune response and reduce inflammation at the site of RA. The GR may carry out this function via two different modes of action: it may dimerize, or split into two separate subunits, and then bind to the gene promoter of GC-regulated genes, or it may remain as a single unit and interact with other DNA-bound transcription factors, thereby altering gene expression to induce anti-inflammatory function.
While it is well understood that GCs induce potent anti-inflammatory effects, the specific cells targeted by GCs and their underlying mechanisms are poorly characterized. Just yesterday, a study was published in the Proceedings of the National Academy of Science by Baschant and colleagues that identifies a potential mechanism by which GCs actually carry out their anti-inflammatory function. The paper suggests that the GR in T cells, which are cells that contribute to the inflammatory state in joints, is critical for the suppression of inflammation by GCs, and that the dimerization of GRs is necessary for the GC’s anti-inflammatory effects. To achieve this, the authors utilized a mouse model in which they used an antigen-induced arthritis (AIA) to mimic the severe inflammation in joints that is characteristic of RA, and serves as a model to examine the mechanism by which GCs carry out their function.
The authors infected mice with AIA by injecting methylated BSA (mBSA) into their arteries in the right knee joint, leading to severe, acute AIA (1). Firstly they determined a means to treat AIA with GCs by treating mice with the GR agonist dexamethasone, a GC that triggers a response from the GR. This significantly reduced joint swelling and other symptoms compared with control-treated AIA mice, and mice with AIA exhibited symptoms resembling those found in human RA. Therefore, the authors determined a treatment with the GC dexamethasone that resembles the therapeutic effects of GCs in human RA, thus providing a model for which to investigate cells involved in human RA steroid therapy.
Subsequently, Baschant and colleagues sought to identify precisely which cells are acted upon by GCs to trigger immune suppression of AIA. It is well known in the world of immunology that myeloid cells, including neutrophils and macrophages, are involved in the early clean-up and suppression of AIA. The authors examined inflammatory symptoms in AIA mice lacking the GR in these myeloid cells, and found that GCs were able to repress AIA just as well in these mice as in control mice, suggesting that the GR in myeloid cells is not essential for the anti-inflammatory effects of GCs in AIA. Next, since AIA is a T-cell dependant inflammatory disease, the authors examined the ability of GCs to suppress AIA symptoms in mice with non-functional GR in T cells, and found that inflammatory suppression was significantly impaired. Dexamethasone was unable to reduce swelling and production level of Il-17, a pro-inflammatory cytokine, in these cells, suggesting that T cells are the target for GC suppression of AIA symptoms.
Next, the authors sought to elucidate which mechanism T cell GRs use to induce their transcriptional alterations. Using mice with impaired GR dimerization, Baschant and colleagues examined inflammatory symptoms in relation to wild-type mice with functional T cell GRs, and found that GC steroid therapy failed to suppress inflammation in these mice, while GC therapy was successful in wild-type mice. Thus, they concluded that dimerized GR is required for anti-inflammatory effects of GCs in AIA, and these results held true for another analogous arthritis model, further solidifying their results.
Following this experiment, Baschant and colleagues investigated how, precisely, GCs regulate T cells in AIA. What they determined was that very few helper T cells, or CD4 T cells (which help B cells produce antibody in response to the presence of antigen) produced cytokines indicative of a TH1 immune response – which typically is inflammatory in nature – upon re-stimulation with mBSA. This indicated that antigen-induced TH1 response is diminished in WT mice but not the mice with impaired dimerizing function in GRs. A similar result was found for TH17 cells, which also are involved with the inflammatory response. The authors ultimately concluded that a reduction of both TH1 and TH17 cells probably contributes to the anti-inflammatory effects of GCs in AIA.
Lastly, with this knowledge, the authors examined to what extent the reduction of TH1 and TH17 cells contributes to the anti-inflammatory effects of GCs. The cytokine Il-17 was previously mentioned to have a pro-inflammatory response, and is produced by TH17 cells. Thus, the authors tested if this reduction in Il-17 is what is causing the anti-inflammatory effects of dexamethasone, and found that indeed mice deficient for Il-17 are resistant to dexamethasone treatment and exhibit AIA symptoms.
Moreover, the study wonderfully demonstrates that GR dimerization in T cells and the consequent reduction of IL-17 are critical for the anti-inflammatory effects of GCs in AIA. As this antigen-induced arthritis is analogous to human RA, this provides significant insight into the mechanisms that may underlie GC function in suppressing inflammation in patients, and will help focus future therapeutic endeavors, thereby hopefully avoiding the severe side effects of current non-focused GC treatments. These new drugs could potentially go to clinical trials in the not-too-distant future, propelling us one step closer to providing sufferers of rheumatoid arthritis with better means to cure their symptoms. The next step will be developing glucocorticoid treatments that specifically target T cell glucocorticoid receptors, while not having broad immunosuppressive implications.
Reference: Baschant, U., Frappart, L., Rauchhaus, U., Bruns, L., Reichardt, H. M., Kamradt, T., Bräuer, R., et al. (2011). Glucocorticoid therapy of antigen-induced arthritis depends on the dimerized glucocorticoid receptor in T cells. Proceedings of the National Academy of Sciences of the United States of America, 108(48), 19317-19322. doi:10.1073/pnas.1105857108
Other References:
(1) Irmler, I. M., Gajda, M., & Bräuer, R. (2007). Exacerbation of antigen-induced arthritis in IFN-gamma-deficient mice as a result of unrestricted IL-17 response. Journal of immunology (Baltimore, Md. : 1950), 179(9), 6228-36. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/17947698
Cronstein, B. N. (2005). Low-Dose Methotrexate : A Mainstay in the Treatment of Rheumatoid Arthritis. Pharmacological Reviews, 57(2), 163-172. doi:10.1124/pr.57.2.3.mittently

130 comments:

  1. Thank you for this informative and concise post! It seems like you really put a lot of effort, and I can appreciate that.

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  2. So interesting! And, a truly great use of italics

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  3. Glad to see that better treatment is in sight! Very informative, nice work.

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  4. This may be the most intriguing write-up of RA I have seen in my entire lifetime. It captivated me,keeping me glued to the page. I was spell-bound, lusting for the next word. Concise, yet full of knowledge. Perfectly articulated in such a manner that it inspired a true passion. Amazing job Neil.

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  5. I had no idea that RA affected so many people across the nation/world! Because so many people are affected, it really is wonderful that this new research is coming to light. Having relatives who are plagued by RA, I hope that this will lead to new treatment options available for patients who may not respond favorably to previous methods. Thank you for bringing this spark of hope into view!

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  6. Neil, my hope is that one day the government can implement a more lax drug regulation policy that will allow experiment results such as these to be put to better use in a more efficient manner. With an ever-aging population such as the one we have in the US, it is critical (and potentially revenue generating) that we put new drugs out on the market in order to sustain the health of our elders. With more drugs on the market, perhaps the price of drugs will decrease because of an increase in consumer choices which would help to stimulate our failing economy.

    It is incredible that scientists such as these are able to conjure up these experimental methods in order to demonstrate a molecule's specific affect on mammalian cells. Although I do feel bad for the mice at times, i believe that it is researchers such as these that continue in the betterment of health and well being in our society.

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  7. I'm a Colgate Alum who is currently doing research on RA, and I'm glad that the professors back at the 'gate are continuing to produce students with such skills.

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  8. Neil, excellent work. I am forwarding this to my dear old grandmother who is suffering from RA.

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  9. Very thorough work, indeed. It's great to see students really passionate about important issues and sharing that passion with others. I hope more people follow your example, Neil.

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  10. Wonderful work Neil! I know so much more about RA now. This is an interesting and thought provoking post. You are a gentleman and a scholar.

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  11. This was a great post. Both my mom and grandma are affected by RA, so I'm glad you were able to give it the attention it deserves. Great work, very well written

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  12. Knowing very little about this affliction other than the crippling effects of RA I had seen in a commercial for Orencia I was very intrigued to learn more about the condition. I am so glad to see that people like you are committed to learning more about it; you are an asset tot he pursuit of a better future in medicine. Your work and clear dedication should give hope to anyone who suffers from RA.

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  13. This is brilliant work, it truly deepens my understanding RA, and might even inspire me to become a doctor.

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  14. Smart stuff Neil, interesting and informative. I did some T-Cell targeting tests for couple weeks at UCONN Medical Health center and it looks like things are really coming along on the glucocorticoid treatment front.

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  15. Great stuff Neil, I now know more about RA than I ever have, which I suppose will be important in the future because my family has a history of RA...

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  16. I was unaware of the problems of treating RA with GCs. Very interesting stuff and very well written.

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  17. Smart stuff. I thought at first this was written by a professor, excellent work, undergrad neil krulewitz. So glad you used the Cronstien article, some real gems in there as far as treatment. Keep up the good work syb.

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  18. wow, i gotta show this to my aunt. i always knew she had RA but never really knew what that was, but i know that it is really starting to impact her day to day life. she's pretty stubborn and hasnt really listened to much advice, but maybe reading something like this if i send it to her will do some good.
    Keep up the good work!

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  19. Neil, this is truly intriguing. I have several family members with RA; I plan to pass along your excellent work.

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  20. What a baller. This guy clearly knows his stuff. I've never learned more about RA in one place. Well done.

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  21. I agree with the above comment. Truly Neil has outdone himself yet again. What a champ.

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  22. How long did this research take? Did you enjoy the process? I am considering a similar task and topic for an upcoming project? Thank you good sir

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  23. Frankly I am not at all impressed wit this effort. Perhaps you should have looked into deeper questions--this is merely a grade school look at RA. I would expect higher level work out of a college student. Better luck next time.

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  24. I found this to be deeply informing. I like it! Thumbs up and great work Neil! Articles like this one are what make me so damn proud to be an American! God Bless America!

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  25. With RA being such a prevalent problem around the world. I'm surprised that there has not been more attention toward it nationwide. Does anyone else agree? Is there no one else?

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  26. My grandma has this; it's awful!

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  27. I absolutely agree. It's a serious problem, and should be treated as such. Clearly, it has not been given the attention it deserves yet, and I'm glad that people such as Neil here are interested in trying to make it more widely recognized.

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  28. Very well written. I have a few relatives with RA and this article has been very enlightening

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  29. sweet work bro - really got a lot out of this article!

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  30. wow seems like you really know your stuff. Now i understand how far off a cure for rheumathoid arthritis. You truly are a titan in your field Neil!!

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  31. great article man!

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  32. You turned "RA" into "play" with that article neil! But enough kidding hands down not only best article i've ever read, but arguably the best piece of writing ever compiled by a squirrel or other small mammal. Truly Breathtaking.

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  33. Wow great job man this is really concise!

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  34. Agreed with the above commenter! (the one who said great job...not the small mammal reference ahha)

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  35. If only earlier generations had the same information you have now made available. lives could have been improved exponentially!

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  36. This changed my perspective on the crazy world we live in

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  37. I was completely unaware of the widespread effects of this affliction....congratulations on opening a door to a potential cure for so many!

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  38. Neil we have yet to meet, but I feel like we would have a great conversation about RA. Let's get dinner sometime, Jug afterwards?

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  39. 70% of those affected by RA are women...I hope that the findings from this article can help save these females and thus further propagate the human race!

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  40. with such a bleak future ahead for humanity (the potential of Lower Manhattan being completely underwater in 50 years due to global warming) this really helps me in my prayers for a better future!

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  41. In response to the above comment, if everyone painted the roofs of their houses white, instead of the requisite black, that would be the equivalent of taking 11 million cars off the road! As important as RA research is, I think there are better things for people to be spending their research budgets on, i.e. ways to save the planet...

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  42. With all due respect, sir or madam, I think it is completely at the discretion of the researcher as to what they spend their money on...If RA is what is important to this person, as it is to so many people, then I am thrilled that they are using their passion to better humanity!

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  43. Fantastic point. It truly is an amazing world we live in where people can use their passions to bolster the fitness of mankind.

    Great work, Neil!

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  44. Neil that was some deep stuff

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  45. great article, mccoy approves.

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  46. Good to know! Quite interesting

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  48. "RA"... sounds more like "bad day".

    - am i right?

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  49. Very informative, thank you!

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  50. RA is for GDIs right?

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  51. What's golden? This article. This research makes it rain 3's all day-- ballin' H.A.M. Keeps it real Krulewitz is what they call him, Teflon Don of italics.

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  53. what to say about this article? simply that it is the single most influential piece of writing to exist since the discovery of the rosetta stone.

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  54. neil krulewitz... more like spitting truthewitz

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  58. Three Words: No Bel Prize

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  62. I bin had, bin had, bin had RA

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  63. is there any correlation between RA and low chill to pull ratios?

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  67. But why male models?

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  68. Neil what are your thoughts on modernity's role in reshaping the social and political landscape in post-colonial Tunisia?

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  69. People, let's keep the commentary topic to RA research! Does anyone have any interesting ideas of how to generate a more specific treatment that targets T cell glucocorticoid receptors?

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  70. in response to neil's question perhaps we could use atom colliders? or possibly reboot the main frame?

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  71. wow, i typed up a whole response neil but when i tried to post i was somehow rerouted into friendster. sorry

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  72. I feel that targeting glucocorticoid receptors would negatively impact the regulation of transcription within the cell. GC receptors are vital to combinatorial regulation of gene expression within the cell. Modification of these receptors could result in the knockout of certain genes.

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  73. WTF, why do I keep ending up in friendster

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  74. I'm pretty sure I have whatever disease this is... doctor anyone?

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  77. Dr. Gregory House, star of FOX's hit medical drama, House, would have figured this RA out already.

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  78. Tigers *love* pepper. They hate cinnamon.

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  79. we could use microscopes to get to the bottom of this

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  80. I think we can find a more effective treatment for RAs by going directly to their source, residential life. It is my understanding that RAs are the inflammatory nuisances living in and around first and second year dormitories, who opt for punitive measures against underage students in order to limit their consumption of alcohol. Many have suggested that we should get rid of RAs altogether rather than simply try to curtail their power - I happen to agree. Rather than treating T cell glucocorticoid receptors, we should just get rid of residential life completely.

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  81. James while John had had had had had had had had had had had a better effect on the teacher.

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  82. I have learned much about RA from your article. Thank you for enlightening my feeble mind. I look forward to reading more of your work in the future.

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  85. How did you get into this? im premed and have been trolling the fields of science for something interesting to research undergrad, and this is really good stuff!

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  86. I appreciate the lightheartedness of this comment section, but the truth is that RA is a serious condition, and these new treatments need to be available as soon as possible. While thorough testing is obviously important, what is more important is helping the people afflicted with this terrible condition, and doctors really need to push for these treatments to hit the shelves as soon as possible.

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  87. I could not agree more. I know several people who suffer from RA, and it is nothing to laugh at. These people are in serious pain, and plenty of my colleagues have friends and loved ones who need these new treatments right away. Neil, I commend you for bringing justice to this issue, as it is one that was in sore need of being addressed.

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  88. He's absolutely right.

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  89. I agree with the above post. Neil put in a tremendous amount of research into RA so that we can be educated on a disease that affects over one million people. Some of these comments are funny, but I think Neil would appreciate more RA-related feedback after putting his heart and soul into this blog post.

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  90. Great article Neil! My grandma has been suffering from RA in both of her hands for many years now and this was quite informative!

    Also, I heard this guy McCoy wrote a decent article. Everyone should check it out.

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  91. Can someone please provide a distinction between RA and a RA? I don't get it

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  92. Neil, what activities/sports/everyday tasks are affected if one has RA?

    Great work by the way, see you in class tomorrow

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  93. First off, well done Neil. I was surprised by how many comments your post had, but after reading your post, it makes sense. Extremely informative. To answer the gentleman/lady who posted above me, RA stands for Rheumatoid Arthritis. On the other hand, a RA is an old wooden ship that was sailed during the Civil War Era.

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  94. Is RA fatal? Or is this a rumor?

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  95. Things not on my Christmas List: Rheumatoid Arthritis

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  96. Wow great job Neil! Not only a well written essay but its quite evident that tons of hard work was put into researching RA. Please keep up the fantastic work!

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  98. Neil, interesting read. I really didn't know much about RA until reading this article. As a novice to science and technical terminology, some of it was a bit above me, but I learned important facts nonetheless. Thank you!

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  99. What parts of the body does RA most frequently affect?

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  100. What part of the body does RA most severely affect?

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  102. What is youngest documented age someone has been diagnosed with RA?

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  103. What is youngest documented age someone has been diagnosed with RA?

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  104. Very informative!I had no idea you could take steroids to treat RA. I'm an athlete and think I've been misdiagnosed and actually have RA (because my knees hurt occasionally) Do you know if these steroids would show up in a urine test?

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  105. very informative! my grandfather has RA

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  106. i just shed a tear after reading this amazing article Mr. Krulewitz you are a gentleman and a scholar

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  107. its good to see there are even better treatments coming in the future

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  108. I couldn't sleep last night, I was too hot and bothered with Neil's take on RA. Literally life changing

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  109. I would expect nothing less than the greatness that was this article out of Mr. Colgate 2009

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  110. I bet neil would look great in a trucker hat

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  111. glucocorticoids out for the boys

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  112. I hear whirl butter-substitute is an effective treatment as well. What are your thoughts?

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  114. Neil, great job on the article. I can't get over how bright you are! You make us so proud every day that goes by.

    Love,

    Mom and Dad

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  115. so basically RA is like diabeetus?

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  117. Dr. Krulewitz,

    Does this affect one's ability to make sandwiches?

    Your concerned friend,

    McCoy

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  120. Niel, what are your thoughts on the healing powers of The Almighty?

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