Is this the end of rheumatology as we know it?

Recently, an international research team led by Xavier Rodó published a fascinating study in PNAS suggesting that Kawasaki disease is caused by an agent transported by wind from farms in Northeast China.  This agent, possibly a fungal toxin, is responsible for triggering an exuberant immune response in children, causing the typical manifestation of the disease: fevers, rash, conjunctivitis, “strawberry tongue,” enlarged lymph nodes, and swelling of the extremities.  Untreated, Kawasaki disease can cause aneurysms of the coronary arteries, premature heart disease, and even death.

What I find so fascinating about this article is that it sheds light on the possible etiology of a rheumatic illness.  As rheumatologists, one of the biggest challenges we face is not knowing the causes of most of the diseases we treat (that’s our dirty little secret!).  Even though we use state-of-the-art medicines, our understanding of disease is still in the Dark Ages.

Fortunately, we’ve had some progress.  Rheumatic fever, for example, was found to be caused by Streptococcus, the same bug that causes Strep throat.  We learned that treating Strep throat with antibiotics prevents rheumatic fever, likely the reason why rheumatic fever is now extremely rare in the United States.

In the 1970′s, an epidemic of arthritis struck Connecticut, affecting many children.  Detailed research showed that it was due to a bacteria, Borrelia burgdorferi, carried by a tick.  To prevent disease, we advise people to use repellents and avoid tick-infested areas.  If they develop Lyme, we offer effective treatments with antibiotics.

We have also made progress in understanding of some types of vasculitis (diseases that cause inflammation of blood vessels).  Polyarteritis nodosa is often caused by hepatitis B virus, and cryoglobulinemic vasculitis is due to hepatitis C virus.  Cures for these types of vasculitides can be achieved by eradicating the virus.

Is it a coincidence that several diseases that we considered to be “rheumatic” are now known to be caused by bacterial, viral (and perhaps) fungal elements?  Not really, especially if we understand evolutionary medicine.  This often-overlooked field of study helps explain why humans, despite millions of years of evolution, are still vulnerable to disease.   Two common reasons include pathogens (which are able to evolve faster than we can), and the mismatch between our bodies and our new environment (likely responsible for the obesity epidemic).

Unfortunately, most rheumatology research is conducted without an awareness of evolution.  It seeks to find abnormalities of the immune system that cause disease, without first asking why any abnormality would exist in the first place.  It tries to identify genes that make people susceptible for a disease, without asking how deleterious genes could be passed down through generations.

Fortunately, the winds of change may be near.  Interest in P. gingivalis as a cause for rheumatoid arthritis continues to grow, and the role of the microbiome in the development of rheumatic diseases shows promise.  With a better understanding of why we get sick, we may uncover other environmental triggers responsible for the rest of the rheumatic diseases that we treat.

Gary Hoffman, a rheumatologist who studies vasculitis at the Cleveland Clinic, has said that understanding the cause of a disease is the “most crucial element.”  He writes: “How empowering that knowledge is, especially when the etiological agent persists and perpetuates the process.  In that setting, given adequate therapeutic interventions, we can even affect cures.”

Scientific progress is said to occur through “paradigm shifts,” or radical changes in our way of thinking, which abruptly transforms the field.  Will a fungal toxin mark this change for rheumatology?

Jonathan S. Hausmann is a rheumatology fellow who blogs at Autoinflammatory diseases.

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  • Arby

    I honestly hope it will change the course of medicine back to searching for etiologies instead of 10 minutes with a doctor to treat a symptom with a medication only to come back for more meds to deal with the side effects.

  • QQQ

    Tell that to big pharma and help find a cure that will rip through their profits! I’m sure them and the FDA won’t allow it!

  • ErnieG

    In answer to your question: Will the identification of a
    fungal toxin as a causative factor in Kawasaki disease mark a “paradigm
    shift” for rheumatology? The short answer is unlikely. We have postulated for years that the autoimmune and autoinflammatory rheumatic diseases are likely infectious in origin. In some cases they are recent or co-incident and therefore easy to identify, and in others they are likely distant and therefore hard to identify. Multiple labs have been able to “create” autoimmune diseases in mice that mimic human disease via infections. Identifying the fungal toxin is interesting
    and gives credence to the idea that infectious agents (in this case a fungal toxin) initiate rheumatic disease; whether that knowledge will help diagnose and treat Kawasaki is a different story. Medicine is not a pure science, and knowledge does not automatically translate into diagnosis or cure. For example, we have known for decades the exact problem with Sickle Cell Anemia- a one acid-base mutation in DNA leading to amino acid substation that has profound effects
    on deoxyhemoglobin structure. But we really don’t have effective therapy aimed at the root of the problem. So, will this identification of a toxin as a causative factor “change” rheumatology? Not
    really. In all deference to Dr. Hoffman, I do not believe that understanding the cause of disease it the most crucial; I believe that accurately diagnosing and treating are more important, and the most crucial thing is treating the human with the disease.

    Two final points-
    I do not believe that most rheumatology research is done “without an awareness of evolution.” I am not even sure what that means, other
    than the failure to “ask why such a gene” would be passed along in the first place. As long as set of “disease” or fatal genes aren’t expressed before reproduction, there is no evolutionary pressure to “kill” that gene. The gene is passed along, diseasing or killing after reproduction.
    I also do not believe that the biggest challenge in rheumatology is “not knowing” the cause of a disease. In my practice, the biggest challenge in rheumatology is diagnosis and treatment– taking a set of symptoms often disparate and vague, examining the patient, interpreting both, using labs and imaging studies to support a diagnosis, and treating the patient.

    • Arby

      I have always used etiology to refer to the cause of a symptom, therefore an accurate etiology for signs and symptoms is an accurate diagnosis. Now I am confused. Why is an accurate diagnosis not based on an accurate etiology?

      • ErnieG

        Etiology simply means cause. The cause/etiology of a symptom or sign may be a disease; the etiology of a disease may be known or unknown. Whether a sign or a symptom is a disease, or whether is disease exists or not, does not necessarily depend on knowing the cause of a disease. The etiology/cause of a disease may or may not have a clinical impact on diagnosis and treatment or may or may not have an impact on how the disease is understood or defined.

        • Arby

          That was something to get my head around, but I think I understand it now. Thank you very much!

    • Ron Smith

      Hi, Ernie.

      “In all deference to Dr. Hoffman, I do not believe that understanding the cause of disease it the most crucial; I believe that accurately diagnosing and treating are more important, and the most crucial thing is treating the human with the disease.”

      I have to respectfully disagree with you in support for Drs. Hausmann and Hoffman.

      I would have to assume that one would have the skills to accurately diagnose and treat as a base part of of understanding the cause.

      Take for example, rheumatic fever. My Father’s brother died of rheumatic carditis in the 1930s. At that time sore throats were common and the role of strep was poorly understood.

      In my 31 years in Pediatrics, I’ve had one case of Rheumatic Fever. The young girl, about 12 or so, was the sister of a patient that I was seeing. After I finished examining her sister, mom turned turned to me and asked if I had any thoughts about this young girls slightly shaky left hand. The tremors were obvious to me, and after lab evaluation, I concluded she had neuropathy from Rheumatic Fever.

      The short of it was that I made the diagnosis because I understood the disease better than fellow physicians did in the 1930s. But what followed after the diagnosis was even more interesting.

      This young girl required daily penicillin (which soon changed to monthly Bicillin CR 900/300 injections). The tremors stopped. She took them for years. I hadn’t seen her in some time when she appeared in my office around age 18 for something else. She told me that she had tried stopping the injections altogether after taking them for many years. After three months without the penicillin, she restarted the injections, because the shaking returned. The shaking tremors stopped abruptly with the treatment.

      Understanding the disease was crucial. I knew that she would need the penicillin, but I had no understanding prior to this, that there is, or at least appeared to be, an ongoing relationship between her immune system and strep that apparently colonize or somehow is exposed to her body without actually infecting.

      There is clearly more to understanding the relationship of strep to rheumatic fever than just a simple ‘its the cause.’ Perhaps there are now cross reactions to other bacterial infections that caused the shaking and not strep itself.

      Nowhere have I found this experience of the neuropathy being held at bay by using an antibiotic perpetually. How else could you explain the relationship without understanding the link or links to bacterial agents? It is clear that this young girl will have to take penicillin the rest of her life, unless we uncover more understanding about this disease process.

      And that is the reason that I have to respectfully disagree with you.

      Warmest regards,

      Ron Smith, MD
      www (adot) ronsmithmd (adot) com

      • ErnieG

        I don’t think we disagree. Notice that Dr. Hoffman’s belief (as
        characterized by the Dr. Haussman) is that understanding the cause of a disease
        is the most crucial element, is modified by the statement that this is more so
        when the causative agent continues to perpetuate the process. This qualifier is
        important in my response to the OP. I think that it is not obvious, nor
        necessarily follow, that understanding the cause of a disease leads to treatment
        or cure for the disease, and is therefore not the most crucial element. I think
        the most important and the most crucial thing in medicine, is how the treatment
        and diagnosis of disease in humans affects our lives, and how that can be
        improved. Your example of strep throat, rheumatic fever, and neuropathy is
        interesting. While seems to prove Dr. Hoffman’s point, it does so only because
        the causative agent perpetuates it. There are any number of disease for which
        we understand molecular mechanism and causes, yet cannot do much to change the
        disease. There are any number of candidate treatments based on understanding of
        those causes, yet make the patient worse or fail as treatments. That is not to
        say that understanding the cause of a disease can’t lead to treatment or cure,
        but that it does not necessarily lead to one. There are also diseases for which
        the cause is not so important, because the treatment is easy. Finally, much of
        medicine is based on serendipity- smart men and women with scientific minds
        looking for one thing that end of finding something else.

        To go back to your example, the use of penicillin in your patient
        in some way proves a point- the disease is affecting her, the penicillin works,
        you can make an argument (though unproven) that there is chronic non GAS
        infection/colonization. The point is—the
        treatment of the patient is what is driving you, not necessarily the
        understanding. The lack of understanding of the molecular mechanisms in this
        case are not stopping you from treating her. The most crucial thing is that she
        is better. As you know, there are other ways antibiotics work other than
        antimicrobials effects.

        Francis Bacon, the philosopher wrote somewhere about “experiments
        of light” and “experiment of fruit,” which I take to described between knowledge
        that explained natural phenomenon and knowledge that led to something. I wish
        to make a subtle distinction in medicine, because, in the end it is a human
        art, not a natural science. It is not enough to know, but rather to do (and not

  • SteveCaley

    I endorse Ernie’s statement – I also do not believe that the biggest challenge in rheumatology is “not knowing” the cause of a disease. In my practice, the biggest challenge in rheumatology is diagnosis and treatment– taking a set of symptoms often disparate and vague, examining the patient, interpreting both, using labs and imaging studies to support a diagnosis, and treating the patient.
    I call Rheumatology a Right-Brain profession, and Cardiology a Left-Brain profession, to use a suspect meme from long ago. I am an Internist because I am joyfully bilobate.
    I diagnosed a patient of mine with MCTD, and made her feel better. It’s not a matter of percent stenosis of which diagonal, but very holistic, IMHO.

  • Kristy Sokoloski

    I found this article interesting on the one hand, but yet on the other I find it confusing as well when it comes to some parts. With that in mind I do have one question. What exactly is the Rheumatologist’s role when it comes to the diagnosis, and treatment management of osteoarthritis? The reason I ask this is because I have a situation going on with regard to my osteoarthritis where it’s going through one of its phases of getting worse and now the things that my rheumatologist has been using (including the medicine that he was using to treat the symptoms as necessary during the last 6 years and the most recent combination of medicines administered both in Feb and again on May 2nd) now does not work. And when my arthritis gets worse I don’t have just joint pain the way that everyone else does. When my arthritis acts up enough to let me know that it’s getting worse as it does every so many years I will feel pain in my left thigh muscle area and the nerves will also bother me enough to cause burning. I am very grateful to my Primary Care Physician for what he did in Jan with the medicine he put me on so that I wouldn’t feel this issue when I sleep at night. It’s been a big help to me. I will also be having a further conversation with my Pain Management doctor about other options she can provide me to get my arthritis back under control if that’s possible. But given what has been happening to me I am not sure exactly what the role of my rheumatologist is in relation to the way he deals with my arthritis. I have been seeing him since I was in my 20s. (Yes, I have been dealing with osteoarthritis as a diagnosis since my early 20s with symptoms starting at age 19. And yes, my arthritis presented the same way, meaning with the symptoms that lets me know my arthritis is getting worse every so many years. As for having symptoms of osteoarthritis at 19 that’s where I am zebra because that’s just the way my body worked when it came to this.)

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