Gum Infections May Cause Rheumatoid Arthritis, Johns Hopkins Research Says

Gum Infections May Cause Rheumatoid Arthritis, Johns Hopkins Research Says

By Staff

Researchers from Johns Hopkins say they have evidence that bacteria that causes gum infections triggers an autoimmune response like that of those who have rheumatoid arthritis (RA).

Researchers say in a press release that the common denominator they identified in periodontal disease (gum disease) and in many people with RA is Aggregatibacter actinomycetemcomitans. An infection with A. actinomycetemcomitans appears to induce the production of citrullinated proteins, which are implicated in activating the immune system and driving the cascade of events leading to RA.

Their research was published in the journal Science Translational Medicine.

“This is like putting together the last few pieces of a complicated jigsaw puzzle that has been worked on for many years,” says Felipe Andrade, M.D., Ph.D., the senior study investigator and associate professor of Medicine at the Johns Hopkins University School of Medicine.

“This research may be the closest we’ve come to uncovering the root cause of RA,” adds first author Maximilian F. Konig, M.D., a former Johns Hopkins University School of Medicine fellow now at Massachusetts General Hospital.

Medical investigators have observed a clinical association between periodontal disease and RA since the early 1900s, and over time, researchers have suspected that both diseases may be triggered by a common factor. In the last decade, studies have focused on a bacterium known as Porphyromonas gingivalis, found in patients with gum disease. However, while major efforts are currently ongoing to demonstrate that this bacterium causes RA by inducing citrullinated proteins, all attempts by this research team have failed to corroborate such a link, says Andrade. But his team has persisted on finding alternative bacterial drivers, he says, because of intriguing links between periodontal disease and RA.

For this study, the investigative team with expertise in periodontal microbiology, periodontal disease and RA began to search for a common denominator that may link both diseases. Initial clues came from the study’s analysis of periodontal samples, where they found that a similar process that had previously been observed in the joints of patients with RA was occurring in the gums of patients with periodontal disease. This common denominator is called hypercitrullination.

Andrade explains that citrullination happens naturally in everyone as a way to regulate the function of proteins. But in people with RA, this process becomes overactive, resulting in the abnormal accumulation of citrullinated proteins. This drives the production of antibodies against these proteins that create inflammation and attack a person’s own tissues, the hallmark of RA.

Among different bacteria associated with periodontal disease, the research team found that A. actinomycetemcomitans was the only pathogen able to induce hypercitrullination in neutrophils, an immune white blood cell highly enriched with the peptidylarginine deiminase (PAD) enzymes required for citrullination. Neutrophils are the most abundant inflammatory cells found in the joints and the gums of patients with RA and periodontal disease, say the researchers. These cells have been studied for many years as the major source of hypercitrullination in RA.

  1. actinomycetemcomitans initiates hypercitrullination through the bacterial secretion of a toxin, leukotoxin A (LtxA), as a self-defense strategy to kill host immune cells. The toxin creates holes on the surface of neutrophils, allowing a flux of high amounts of calcium into the cell where concentrations are normally kept low. Since the PAD enzymes are activated with calcium, the abrupt exposure to high amounts of calcium overactivates these enzymes, generating hypercitrullination.

The researchers previously found that a similar type of pore-forming protein that was produced to kill pathogens by host immune cells was driving hypercitrullination in the joints of patients with RA. These findings point to a common mechanism that is poking holes on cells, which may be relevant to the initiation of RA and also when the disease is being established, says Andrade.

As part of its study, the team developed a test using the bacterium and LtxA to detect antibodies against A. actinomycetemcomitans in blood. Using 196 samples from a large study of patients with RA, the researchers found that almost half of the patients — 92 out of 196 — had evidence of infection by A. actinomycetemcomitans. These data were similar to patients, with periodontal disease with approximately 60 percent positivity, but quite different in healthy controls, who only had 11 percent of people positive for A. actinomycetemcomitans. More strikingly, exposure to A. actinomycetemcomitans was a major determinant in the production of antibodies to citrullinated proteins in patients with genetic susceptibility to RA.

Konig cautioned that more than 50 percent of the study participants who had RA had no evidence of infection with A. actinomycetemcomitans, which, he says, may indicate that other bacteria in the gut, lung or elsewhere could be using a similar mechanism to induce hypercitrullination.

Andrade further cautions that his team’s study only looked at patients at a single point in time with established RA, and that to prove cause and effect of A. actinomycetemcomitans and RA, more research will be needed to track the potential role of the bacteria in the onset and evolution of the disease, which can span decades. “If we know more about the evolution of both combined, perhaps we could prevent rather than just intervene.”

An estimated 1.5 million people nationwide live with rheumatoid arthritis, according to the Centers for Disease Control and Prevention. Current treatments with steroids, immunotherapy drugs and physical therapy help some by reducing or slowing the crippling and painful joint deformities, but not in all patients. The exploration of alternative treatment options is necessary.

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Authored by: Staff

There are 7 comments for this article
  1. Geraldine Radovanovich at 8:54 pm

    This is good news that finally someone is doing this research again. My husband has had RA since January this year. He responded to Prednisone and Methotrexate until August when he developed a sudden Serious Bacteriaemia from a urinary infection related to an enlarged prostate. He was immediately started on IV Cefipime 2 gms a day and the methotrexate was discontinued. From day one the RA symptoms disappeared. He was discharged from the hospital on a further ten day course of Levofloxicin. He remained RA symptom free for approx a month but the symptoms gradually returned after 6 weeks. The Rheumatologist would not continue the antibiotic treatment protocol but also did not give him any other option. Soon after we started him back on the Prednisone and after 3 months of no other treatment he has started on Sulfasalazine and after a visit to an infectious disease DR started on Minocycline. It is a slow process. He continues to take other supplements including Probiotics and has just started Hyuralonic Acid supplements also. We believe that this disease was a result of residual infections persisting in areas of the body that are difficult to treat. That includes gum ( or under dental crowns) I had requested the Rheumatologist to continue the antibiotic shortly after he finished the Levofloxacin but that was not an option because that is not their protocol. The Minocycline is only taken on alternate days. Some local clinics that do treat RA with the antibiotic protocol are inundated and charge exhorbitant prices which is unethical when the actual drugs do not cost that much. I am grateful that this research has been published.

  2. Jean Price at 9:49 am

    Kristine…thanks for being concerned enough to hold this up, it’s appreciated and also important for others to know. With Orencia, one of the potential side effects, as it depresses your immune system, is contracting a fatal infection. So becoming resistant to antibiotics is a Catch 22 for me, because it could have the same outcome as the biological therapy. And others who might use antibiotics as an adjunct therapy for treating RA pain or are contemplating this, definitely need to discuss this with the doctor. On the whole, I have been a remarkably healthy “sick person”…not catching colds or having infections from traumas or even post operatively. In fact, while on Orencia, I laid open my lower leg to the tune of 25 stitches, and also had a kidney totally occluded for five months without getting any infection. So, in discussing this with my doctor and weighing quality of life issues, I felt this was worth the risk and he was willing to bless my choice…at least to try it with the least possible dosing that produced results. I am so sorry you have such a resistance to antibiotics. That is a major life issue!! And most likely you must be very careful to live as germ free as possible, with this ax hanging over your head now. I applaud your diligence in setting up the information to get in touch with Mayo before any therapy is initiated! (Worthy of a tattoo, I’d think! Ha ha!). Thanks again for holding up this major red flag, Kristine! It’s always important to revisit this along the way, too…and your comment just further reinforced this for me. Being a nurse doesn’t always mean we think clearly where we ourselves are concerned! Or even follow our best advice! So again. I appreciate your caring way of offering help…it speaks to your kindness and your concern for others…even while you have your own issues to deal with! Bless you!

  3. MichaelL at 4:50 pm

    Hardtimes, The same people that retired me ten years early for trying to treat chronic and acute pain patients compassionately, write the rules. Don’t want to practice cutting edge medicine out in Podunk! They will finish you!

  4. Kristine Anderson at 10:18 am

    It’s great to hear that antibiotic treatment helps you, but BIG WARNING SIGN! I know you are a nurse and are aware of the overuse of antibiotics and that they are still being prescribed way, way too much. I am actually completely antibiotic resistant (and have developed allergies to some) from being prescribed them for sinus infections in the 1980s for years, also prophylactically in winters. Do be careful. I cannot even use an OTC cream from the drug store. If I am in a life-threatening condition and need antibiotics, it is written in all my records that the Mayo Clinic Infectious Diseases department is to be phoned immediately. The last one I had was a 30-day in-house course of Ertapenum at Mayo and got my fourth case of C-Diff from that. Please think about this very carefully, Jean. I’d hate to see you end up like me.

  5. Fallingon Hardtimes at 4:35 pm

    An estimated 1.5 million folks across the USA “live”? with rheumatoid arthritis according to the Center for Disease Control and Prevention. Steroids,immunotherapy drugs, and phsical therapy help……some, but not in all patients. This statement comes from our CDC. ALL patients need different degrees of treatment for chronic pain even if the patient does not have a malignant cancer. It is great to know that gum infections can cause rheumatoid arthritis. Good to know. Brush your teeth, floss, and see your dentist. Not all people can afford to even “see” a dentist. What happens when struck with a disabling disease that causes uncontrollable pain? Untreatable pain? No surgery can be done. Physical therapy, steroids, infusions, injections, or pain management stimulators don’t help. Obviously Americans just aren’t tough enough, right. No, pain IS treatable. Maybe not curable in a great deal of conditions, but definitely treatable. IF you can get the medication, whicn has become impossible. Who writes the rules? Oh yeah, I remember.

  6. Krissy at 3:52 pm

    I wonder how we can get more info. My mom had Juv. RA from Rheumatic Fever. I have Seronegative RA from Histoplasmosis, but I don’t even know which type of Sero I have because I was treated so badly by rheumatologists when I was young, I refused to go back to one. I was treated by our wonderful family Irish doctor (RIP, Patrick) and so was my mom, with gold, naprosyn (now Aleve or naproxen but then an Rx) and aspirin, among other remedies for many years. Anyone who has any insight, I would love to hear what you have to say.

  7. Jean Price at 12:27 pm

    Some research has been done over the years about the role of antiotics in helping RA pain and also back pain. Antibiotics are thought to reduce inflammation and the idea has been that there MAY be an underlying bacterial component to the disease. Perhaps this study will open the door further…for more research and finding a treatment of the cause…rather than just treating the many symptoms!

    Some years ago, prior to an involved dental procedure, I started prophylactic amoxicillin 500mg at bedtime and a repeat dose in the morning…only to have the procedure cancelled by the dentist for reasons of his scheduling!! So, I didn’t take any further doses. In a couple of days, I started realizing how MUCH better over all I felt since the day after I had taken that last dose….less pain, more stamina, even more energy and more drive! This lasted for about seven CONSECUTIVE days, which seemed nothing short of a miracle!! And just to see if I could repeat the experience, I took another two DOSES, exactly as I had before! Like magic, the day following the morning dose was better…and I continued to feel much better for another week. Then of course, I was back to my “usual” pain and struggles to function, which actually seemed worse than ever! (Yet this most likely was just the result from getting an almost two week reprieve from severe pain down to low moderate!) And just to note….i do have RA and also degenerative disk disease, along with multiple ruptured and fissured disks over the last couple of decades.

    So talked with my rheumatologist about this, and he said there WAS some evidence antibiotics COULD help those with RA, usuallly minocycline or doxycycline were the antibiotics of choice for treatment…given long term in low doses. After trying the first of these antibiotic for a couple of months…. with no results at all… I decided it must have been a fluke, and I just wasn’t a person this routine would help, and my doctor agreed. Yet over the years, I’ve always felt better when I have been on regular to high doses of antibiotics..not just for the condition treated…but ALSO my symptoms of pain and fatigue and lack of stamina were significantly improved.

    So last month, I decided to revisit this subject with my pain clinic doctor and also with my rheumatologist. My pain clinic doctor agreed this was possible, and I should do some more research and take it up with my rheumatologist again. I found there are quite a lot of articles on this, and one research study in Europe linked a bacteria with back pain from disk issues! They had used hefty doses of amoxicillin for 100 days! And thankfully, my rheumatologist was open to putting the Orencia on hold…and being “creative” to see if we could find a dose range of the amoxicillin, (which has seemed to alsways helo the most), and a treatment schedule that would really help me! (Starting out slowly and evaluating at one month to begin with.) He even ran some blood work, including the Vectra test, which is a blood test measuring ten different proteins, (their ranges were established only from those with RA), and then uses an algorithm to come up with a score representing the DISEASE ACTIVITY LEVEL. My past score, even while on monthly Orencia infusions, still runs above the moderate range, into the severe. We are hoping this treatment plan for me will reduce this and have me functioning better!

    I’m sure we will have to increase the dosing of amoxicillin from my current three times a week, yet starting out low will give me the chance to find the least amount to give the highest benefits. Seeing this article today, I feel more hopeful that I will find some significant relief from perhaps both the RA and the degenerative disk diseases!! Yet whatever the outcome, it just feels good to be working toward feeling better instead of just being in a holding pattern!! I think it’s worth a try for, myself definitely…and perhaps also for others with disk issues and/or RA if their doctors are willing to listen!