The Future: Predicting Rheumatoid Arthritis Severity | Rheumatoid Arthritis Warrior

The Future: Predicting Rheumatoid Arthritis Severity

The future of RA testing…

Predicting Rheumatoid Arthritis is still impossible, but times are changing

Once upon a time, there was the Rheumatoid factor. Rheumatology could hope that the Rheumatoid factor (Rf) would be to Rheumatoid Arthritis what glucose measurement is to diabetes. But it was not so – neither for diagnosis nor for disease management. About a third of RA patients have negative Rheumatoid factor results. To my chagrin, there are still labs or rheumatologists who use the phrase “RA test” to refer to Rheumatoid factor.

But times are changing… slowly. The anti-CCP test which measures ACPA (anti-citrullinated protein/peptide antibodies) has gained in importance over the last decade is much more specific for RA (98% specificity for RA). However, many general practitioners still use an Rf or a sed rate to determine whether a rheumatology referral is warranted. The anti-CCP is said to have about 70% sensitivity for RA.

I was talking with my smart rheum doc several months ago about this problem. I asked, “I wonder how many other antibodies they will find and what they will know in a few years. The Rheumatoid factor was just the first one and the name still confuses people to think we have a definitive test.” Smart doc said, “Yes, and now they have found the MCV.” I remember reading an abstract that night which said the anti-MCV test may someday be used alternately with the anti-CCP. Scientists are doing tests to determine whether anti-MCV (anti-mutated citrullinated vimentin) better predicts Rheumatoid Arthritis diagnosis or disease severity or measures disease activity.

What we all "know" changes.

The future will come for predicting Rheumatoid Arthritis – eventually

Since finding anti-CCP and anti-MCV, researchers are looking for more antibodies against citrullinated proteins.  Look at a study published this summer examining the synovial fluid of rheumatoid arthritis patients for other antigens that are citrullinated. Some points I read with interest:

  • Besides the Rf, there are “immunoglobulins, complement factors, and other components” present in the immune complexes (IC) from the serum of RA patients. I knew it.
  • “Because of the pathogenic nature of IC in RA, it is important to identify the antigens in these complexes. After identification of these antigens, a better understanding of the immunological process in the affected joints can be achieved.”
  • Investigation of the immune complexes in synovial fluid could be even more informative than analyzing serum or plasma. This is a big one. What difference could this make to patients who have “normal” test results with blood serum?
  • They concluded: anti-CCP positive “RA patients are more susceptible to the perpetuation of inflammation and possibly have a more severe disease state.” The data indicates that citrullinated vimentin is an important antigen in the immune complex of RA patients. This “implies its importance in the pathology of RA.”

Edit: 11 am: In just a few short years, things tend to look very different: Perhaps we have found only the tip of the proverbial iceberg with RA antigens. Take the example of  the whole new science called epigenetics that has come about after the completion of the human genome project –  all we assumed about gene theory and DNA (A,T,C,& G) could be altered with this one new discovery of genes being turned on and off at different times or places in the body.

Recommended reading:

 

Kelly O'Neill Young

Kelly O'Neill (formerly Kelly Young) has worked over 10 years as an advocate helping patients to be better informed and have a greater voice in their healthcare. She is the author of the best-selling book Rheumatoid Arthritis Unmasked: 10 Dangers of Rheumatoid Disease. Kelly received national acknowledgement with the 2011 WebMD Health Hero award. She is the president of the Rheumatoid Patient Foundation. Through her writing and speaking, she builds a more accurate awareness of rheumatoid disease (RD) aka rheumatoid arthritis (RA) geared toward the public and medical community; creates ways to empower patients to advocate for improved diagnosis and treatment; and brings recognition and visibility to the RA patient journey. In addition to RA Warrior, she writes periodically for newsletters, magazines, and websites. There are over 60,000 connections of her highly interactive Facebook page. You can also connect with Kelly by on Twitter or YouTube, or LinkedIn. She created the hashtag: #rheum. Kelly is a mother of five, longtime home-schooler, NASA enthusiast, and NFL fan. She has lived over thirteen years with unrelenting RD. See also https:/rawarrior.com/kelly-young-press/

36 thoughts on “The Future: Predicting Rheumatoid Arthritis Severity

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  • October 4, 2010 at 9:01 am
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    I love that you posted this now. I was at a 2nd rheum doc about a month ago, and got all the tests/xrays. My CCP was 250+ (reference of <20) but my RF was normal – what I understand to be sero negative? I don't know much about this stuff, but I know that I have a lot of pain that's not going away.
    I went back to my 1'st doc b/c I didn't like the new one, and I mentioned that my disability hearing was coming up. She recognized that I needed help – but she says only for 6 months, and then the cimzia (my new med) should start to have helped by then, and I can look "aggressively" for work. I've been trying meds for over 3 years now, with little to zero success, but for some reason, she thinks she can PREDICT that I'm going to be better within 6 months…well why didn't we do this medicine from the beginning then?????? I mean if it's predictable, she should have predicted this years ago!!! She also mentioned that she is a libertarian and doesn't believe in getting help from government, so I guess I'm just out of luck. She also mentioned that when I go back to work and lose my medicaid, I could just apply for help to the drug co's (I take a dozen different meds). I'm all for working if it's possible, but only when it is, not predicting that I'll be well enough. Unbelievable. It's back to the drawing board for finding a new doc for me.

    Reply
    • October 4, 2010 at 10:04 am
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      I hear you, Michael. There is not a lot of logic to using the term “sero-negative” with the off the chart CCP result. I don’t think all rheum docs do that. I know it was the orginal definition – but that was before we even had CCP, which is much more specific to RA. Also, the 250+ score does indicate severity in the minds of many & it’s particularly aggravating when they cling to a negative Rf in that case. Your own report of your pain/ disability should account for a good amount of your assessment. That’s not just my opinion – read this – click here. Anyway, if that’s her viewpoint, then you are right – you’ll probably have to find another opinion.
      We all know there is no way to predict response to RA treatment & it hurts my brain as I try to figure out what these docs are thinking when they try to convince you your RA is not so bad.

      Reply
      • October 4, 2010 at 10:49 am
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        Thanks, Kelly. Appreciate the link – the one you have on your post was really interesting also. I’m learning more and more about this stuff, and becoming a more empowered patient; I think I need to get those dr. notes and see what’s going through her mind – b/c it hurts my brain too. I just couldn’t believe she actually told me she was “libertarian”, like her politics should play a role in my care. I wish she would have mentioned this a long time ago. I think the worst part, is that she keeps insisting that we’ll have the RA “under control”, as if she has a crystal ball.

        Reply
        • October 4, 2010 at 11:11 am
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          You are right that politics should not play a part in this. If she has crystal ball powers, ask her to use them to make me well too. LOL.

          Reply
        • October 4, 2010 at 2:16 pm
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          Wow Michael, unbelievable! I would be so outta there, see me? I’m a dot. (That is fighter pilot talk, a dot in the sky, cause their gone so fast). My husband’s a retired pilot. This doc is just hoping it comes true so she can look like a hero or something, making fairy tales comes true. I do hope she’s right, for your sake.

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  • October 4, 2010 at 9:21 am
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    So very interesting Kelly, thank you for posting…All my tests other than ANA have come back normal with an occasionally elevated sed rate. The very fact that I am anti-ccp negative is the very reason my Rheumy will not treat with anything other than Plaquenil. I had come across an interesting article on something called Palindromic Rheumatism..it states…”The use of anti-malarial drugs (e.g. Plaquenil) in patients with palindromic rheumatism has been associated with decreased risk of developing rheumatoid arthritis or other connective tissue diseases, according to a study published in the January 2000 issue of the Journal of Rheumatology” http://arthritis.about.com/od/diseasesandconditions/a/palindromic.htm
    Isn’t that interesting ….the use of an RA DMARD causing a decreased risk of developing RA with those with PA (If there is such a thing)? Sometimes I wonder whether I was dx with sero negative RA in 1998 because he didn’t know what other name to give what was going on. He told me better to treat than not to treat…To treat or not to treat…that is what many Rheumy’s I think struggle with with patients like me. My dx of RA was on scant evidence…but as my original Rheumy said…if there is any chance that an RA process is going on I want to stamp out the fire…and if Plaquenil does not work we will keep going after it until we have success in making you feel better…and I will aggressively look for any signs of it getting worse or not responding. I heard once a podcast (I will look for it later online) that talks of Palidromic Rheumatism as really RA behaving like a car that can’t start. It is like RA trying to turn on but it doesn’t quite turn on all the way. Now isn’t that interesting? I do think that they WILL find more antibodies…and that RF and Anti-CCP antibodies are just the tip of the iceberg !!!

    Reply
    • October 4, 2010 at 10:13 am
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      Susan, I completely agree with your iceberg analogy.

      So are you thinking that you should have been diagnosed w/Palindromic Rheumatism (PR) instead of RA? How many days do your flares last? We do have some posts on PR here on the site – that’s the way my own RA was for decades. It comes and goes without obvious damage. But it is thought by some now to be just an earlier stage of RA – My GUESS is that something then happens to some patients to switch the RA on full blown. So, it sounds like I might agree with the podcast – I’ll look take a look at it later.

      Reply
    • October 4, 2010 at 10:16 am
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      Hmmm, wonder if you do the following also, if it will stop from progressing to full blown Ra:
      1- don’t smoke
      2- drink moderate amounts of alcohol
      3- take statins

      Also, depending on certain perameters taking a biologic in very early RA m-a-y also stop progression to worse disease. Though another study says there’s no difference between biologics, dmards and glucocortoids.

      Reply
  • October 4, 2010 at 9:34 am
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    Here is that podcast …describing Palindromic Rheumatism as RA trying to start but not quite…The reason I post this on this thread is this…There must be other anti-bodies involved in RA development… if all this is going on before a “definitive” (if you want to call it that) dx of RA.
    http://www.palindromicrheumatism.org/whatispr.shtml
    The podcast began right away after going onto the page…scroll down for controls.

    Reply
  • October 4, 2010 at 10:36 am
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    To answer your question…Yes and No…Personally I believe that Palidromic Rheumatism is RA….I believe it is the same process, like you describe….Just like I posted above…I believe, like the doc in the podcast, that PA is RA trying to start but not quite….I am not a doc…but it makes sense to me….So I say that I have RA…but clinically my current Rheumy is only going on what my old Rheumy dx me with and that is RA as well.
    The way my initial Rheumy explained it sounded more like RA that would not kick on. That is what made finding that podcast so impressive to me…that in 1998 my old rheumy was thinking that same thing…. I had some symptoms of PA and other symptoms that were more like RA….He explained to me that so many patients with “Atypical” (there is that word again LOL) symptoms of RA go on to develop full blown RA that he wanted to take it a step further and treat me as Sero Negative RA. I have had three separate flares since 1998. And I can see them as flare ups. The first fizzled out on its own with NSAIDS only..(only PCP treated) The last two required Plaquenil…I have responded beautifully both times…It takes two or three months but like clockwork both times it seemed to settle things right down…But this last time was far worse than the other two times…Sometimes my joints only swell up for a couple of days and then disappear other time my joints swell and they stay like that for quite awhile. Time will tell whether my PA/RA (or whatever…what’s in a name…LOL) will worsen or blow up to a greater degree… God only knows…meanwhile I will demand good Rheumy care…and I won’t be a good patient LOL

    Reply
    • October 4, 2010 at 10:44 am
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      Susan, you don’t mean psoriatic arthritis, right? Just clarifying for readers. I had always thought that palindromic flares last only a few days predictably – not that it would matter if you are taking plaq already. I’m glad you are on top of it w/ rheumy care.

      Reply
  • October 4, 2010 at 10:40 am
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    I have been sero negative throughout my 24 years with ra (I do have an SLE marker but no ra markers). I am so grateful that all those years ago my PCP and then my rheumatologist ignored the blood work and looked at the whole picture. Who knows how many additional antibodies will show up down the road.

    Reply
    • October 4, 2010 at 10:46 am
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      So true Mary. I know RA patients with horrible damage requiring surgeries or wheelchairs that have none of the current blood markers. Any doc who relies fully on current blood tests is not doing right – in just a few short years things look completely different.

      Reply
  • October 4, 2010 at 10:48 am
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    Oh Goodness….I did not mean to imply PA as being Psoriatic Arthritis…whoops…bad choice of initials… 🙁

    Reply
  • October 4, 2010 at 10:54 am
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    I meant PR or Palindromic Rheumatism…My hands are a mess today…sorry

    Reply
  • October 4, 2010 at 11:03 am
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    I ran across this article the other day using FDG PET imaging in RA (Assessment of Disease Activity in Rheumatoid Arthritis with 18F-FDG PET, Beckers, Journal of Nuclear Medicine June 2004). Basically they give you a microdose of glucose with radioactive fluorine attached to the molecule. The thought is that TNFa enhances glucose entry into the macrophages (both found in synovitis with RA) and that you can then image/measure the extent of synovitis. It’s a pretty cool idea, but I don’t see it really taking off. Never-the-less it does back up patient claims of pain and inflammation in the absence of overt outward signs.

    Reply
    • October 4, 2010 at 11:12 am
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      Very interesting. Why doesn’t it seem like it would be “really taking off”? Impractical?

      Reply
  • October 4, 2010 at 12:29 pm
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    Thanks for this post, Kelly. I’ve had RA for a year, am still seronegative(though we haven’t done the anti-CCP lately) and my most recent sed rate was 2. BUT, I’m in an incredible amount of pain, am swollen, and my “morning” stiffness exists for most of the day. I’ve been on Enbrel for almost 4 months and had about a 3 week stretch of less pain, but now I feel like I did before the Enbrel. I’m lucky to have a rheumy who has treated me by my symptoms, but I’m still frustrated by my lab results. Before staying home with my kids I was a Clinical Laboratory Scientist, and I feel like my science has failed me because I’m miserable, but my lab printouts make me look like the picture of health. I was just thinking this weekend that not only would identifying the other antibodies involved in RA make dx easier, but the creation of new treatments and possibly a cure, as well.

    Reply
    • October 4, 2010 at 1:48 pm
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      Hi Megan,
      It sounds like you have a good dr. The tests just are not there yet. Someday, you may have higher labs to match your symptoms and it will be small consolation trust me. I’m curious – in your former work, were you under the impression that the Rf was an “RA test” or that there were ways to diagnose rheumatoid diseases by lab results? Or was that something you ever thought about?

      Reply
  • October 4, 2010 at 12:44 pm
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    Probably the biggest obstacle would be access to a PET center. There aren’t that many of them.

    I think you also might have an issue of exposing patients to multiple scans to keep assessing disease activity. This stuff is radioactive after all. I don’t know anything about the safety of this stuff over repeated doses. It might be fine though since it is such a small microdose and it is gone pretty fast.

    Plus I think it has yet to prove that it is any better than what is already done. Asking a patient about their symptoms and believing what they say might be just as good.

    Reply
    • October 4, 2010 at 1:49 pm
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      Yes, I agree. Did you read that Pincus pdf I quoted to someone above? For some reason, there is resistance to using patient testimony, as I call it, but it is shown to be scientifically solid data.

      Reply
      • October 4, 2010 at 3:22 pm
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        Perhaps there is some resistance, but my doc showed me one time how he uses the questionaire that I fill out at the beginning of each visit and how he uses what I say to him and the nurse about my symptoms. So he doesn’t seem to have any resistance to using patient testimonial.

        Maybe if more patients would ask how their doc uses their information we might actually see that we are being listened to more so than we think.

        Reply
        • October 4, 2010 at 5:31 pm
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          What I suggest to patients is to read & maintain copies of doctor’s notes to be sure to be on the same page with the docs. There have been some truly shocking results to this practice.
          Anyway, it sounds like you have a good doc. I’ve never filled out a questionairre like that. I’ve never been asked the questions that are on it. At this point in my own treatment it’s a moot point since my doc is using the most aggressive path possible. I wrote a blog about the critical questions no rheum doc has ever asked me – click here. I do have lots of reports from other patients with similar scenerios.

          Reply
  • October 4, 2010 at 1:01 pm
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    I have to confess I always get squirrelly when talk of the blood markers comes up. I have low positive RF, normal everything else, minimal visible swelling, and patterns of pain that look like both RA and PA (psoriatic). I’ve had come-and-go joint pain for years including one episode that was diagnosed as parvovirus, but really might have been my first mega-flare. I’ve had a low positive RF and was being “monitored” for about three years before the pain and fatigue hit with a vengeance.

    One of the biggest things I wrestle with is not having more more “proof” besides the pain and fatigue that this disease is real. I mean, on one level, there’s no question. My life has been turned upside down. And I certainly don’t wish it to be worse with swelling and high inflammation markers. It just creates occasional waves of anxiety that they’ve gotten it all wrong and I’m taking these serious drugs and if they’re wrong then what the heck IS wrong with me. Some of this is just denial still kicking in. It’s only been a year since diagnosis.

    I’m lucky to have a doc who treats the patient not the lab results, and he assures me that I do indeed have RA, PA, or both. He treats it aggressively, and though I wish he would take more time with me sometimes, he trusts my self reports of pain and fatigue.

    Thanks to those who posted about being in a similar situation with minimal or no positives in their bloodwork. It helps to know I’m not the only one whose RA/PA didn’t get the memo.

    Reply
    • October 4, 2010 at 1:50 pm
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      😀 Yeah friend, I have RA that didn’t read the books either. LOL. Turns out some of the books are wrong anyway.

      Reply
  • October 4, 2010 at 1:08 pm
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    And now a question: do any of these markers predict responsiveness to treatment? I see there’s some theory that high markers predict disease severity, but does that mean general disease aggressiveness (if left untreated) or that it’s nonresponsive? (I’m guessing these studies aren’t letting people go untreated, but how do they account for the variable of differences in treatment courses?)

    With only a low positive RF, it still seems like my body quickly figures out how to “outsmart” the drugs (giving me relief that can be counted in weeks) and/or doesn’t respond at all. So far I’ve “failed” MTX and am on my way to failing Humira–though I prefer to say they’ve failed me. I guess my immune system is an over-acheiver.

    Reply
    • October 4, 2010 at 1:53 pm
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      There are hints about that. But for every study about prediction I read, I read another that says, “nope, not yet.” I know they are working on this. Also, I know people personally who have low Rf and have severe damage that occured quickly. Also, I know people with longstanding disease & much damage who have a fluctuating Rf. Also, my own Rf responds to Biologics, but my symptoms do not. So, we are just not there yet. I look forward to other answers you may get though.

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    • October 4, 2010 at 2:04 pm
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      Your labs sound like my labs. At first I just had loads of pain in the joints and not much swelling. Red, sore joints, but not swollen like a bad sprain.

      My rheumy told me that it was a good thing, in a way, what the labs were showing. He seemed to think that the more positive lab tests you have the more chance you have for having a more agressive form.

      Unfortunately I don’t think the typical RA lab tests have any predictive ability in your responsiveness to treatment. Honestly I don’t think they know definitively how some of the older DMARDs work. So how could you begin to design a test for prediciting effectiveness without more study. They know the mechanism of action for the newer biologics but I don’t think they have any accompanying diagnostics available.

      Reply
  • October 4, 2010 at 3:02 pm
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    Thanks Kelly, this is all very intriguing and thought provoking. I can’t wait for science to discover more!

    Once I was finally tested, I had an easy diagnoses with high positives on all markers. One thing I did notice for almost 2 years prior to diagnosis is a high platelet count on all my blood tests. It was in the range of 450-550,not remarkably high. One doctor noticed it and said we should watch this, but I didn’t see her again. I asked my GP about it it later noticing it continued to be high, he said it was nothing. I watched it go to normal after starting Methotrexate and Enbrel, so I did research online and found it to be connected to RA. Now I see on my last blood test it is in the high range again. I know why! Enbrel stopped working for me and I have been in a flare. This, and fever are good indicators of disease activity for me.

    Looking back at my original diagnosis labs, I notice C4 complement flagged as low, haven’t been able to find the significance of this, any thoughts Kelly or anyone else?

    Reply
  • October 4, 2010 at 6:39 pm
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    Never having been one who saw a dr on a regular basis, I really have no idea if I had any “markers” early on. I have had on and off my entire life weird and un-explainable joint issues….started as a young teen with horrid hip/knee/ankle pain (mostly knees tho) and went thru a battery of tests (this is in the mid-60’s so….) and nothing was “found” but the dr put me on asprin therapy and said I should “grow out of it” and I did after awhile…then have fought off neck issues, knee issues, etc off and on since…..until last fall when I knew something very serious was happening to me. Was the earlier stuff the PR stuff, who knows….my hopes is with the researchers working and finding new things, they can find things that will work better to help us in pain, can help pin-point someone who’s labs show nothing and of course the biggie TADA, maybe a cure! Now wouldn’t that be something huh? My labs were positive like crazy in the beginning of my diagnoses, after MTX have come back down, but I am one of those lucky ones whos dr goes by what I feel, not labs and swelling…I can be in EXTREME pain with no noticable signs…Thanks Kelly for keeping us up-to-date with all this info :announce:

    Reply
    • October 4, 2010 at 9:53 pm
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      Thanks Nancy. Love the megaphone! :heart: I appreciate your contributions so much.

      Reply
  • October 5, 2010 at 8:47 am
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    All of this is so comforting me. As a nurse, I have relied on lab results for years. I am sero neg. My sed rates are high and interestingly enough I have no idea what my CCP has been. I’ve been told by my first Rheumy that being neg means that even though I may have pain, the joint damage will most likely be minimal. He did not xrays and only treated with more anti inflammatories. Then, I was lucky enough to be sent to his partner. She xray’d my hands and feet. I had no erosions, thankfully, but I did have severe osteopenia. Am I wrong in thinking this is damage? She began aggresively treating at that point. I still find myself doubting if I really have RA, all because of a silly blood test. I know it is irrational. I think I have major denial issues. The nurse in me loves thinking that they will eventually find a test that lets me know definitively that I have RA. But the patient in me is just greatful for my Rheumy, Kelly and this site. You have saved my metal stability in so many ways!

    Reply
    • October 5, 2010 at 8:48 am
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      Ooops…. I meant MENTAL stability. I think my joints are a little too stiff for typing so early in the morning!

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  • October 7, 2010 at 11:13 am
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    Thanks, Kelly,
    for posting this article!

    Your post corrects a popular misunderstanding, it certainly does: There isn’t just one single laboratory test for rheumatoid arthritis – there are several serological tests used for diagnosing the disease. And today the most meaningful in fact are the ACPA tests, which are detecting the so called “anti-citrullinated protein antibodies”. You will find a quite good overview in ACPAs on the corresponding Wikipedia site: http://en.wikipedia.org/wiki/Anti-citrullinated_protein_antibody

    Kelly, you mentioned a research article on citrullinated vimentin (title: Citrullinated vimentin as an important antigen in immune complexes … http://arthritis-research.com/content/pdf/ar3070.pdf). That article has been completely unknown to me, but it clearly is relevant to my work. Thanks for pointing towards it!

    Indeed, citrullination of proteins in general seems to play an important role in RA pathology, even though citrullination is occurring physiologically. Citrullinated vimentin has been known to be an important antigen in rheumatoid arthritis for years now, and doing research on different types of citrullinated vimentin and its mutated form so called mutated citrullinated vimentin, or: MCV, is an important field of study in my company.

    The authors of the above mentioned research article hypothesize that citrullinated vimentin plays an important pathophysiological role in the persistence of RA – and, moreover, the presented data seem to corroborate their hypothesis. That sounds interesting, because understanding RA pathology eventually will be a big step forward to predicting rheumatoid arthritis severity.

    A terrific post, Kelly, keep up the good work!

    Best wishes
    Tobias Stolzenberg

    Reply
    • October 10, 2010 at 6:26 pm
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      Tobias, This comment was just found in the spam folder. I see it was 3 days old. I’m so glad I found it. Spam plugins are required since I get 100 of them per day. My apologies.

      Reply to post: That was my thought also. Each piece of the puzzle brings us improved odds at prediction, treatment, and one day maybe prevention and cure. Regarding the popular misunderstanding: Tragically, it is the case with many physicians. I believe that there will be a great impact on patients if we can educate doctors.

      Reply

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