‘What causes Rheumatoid arthritis?’- new insights

Rheumatoid Arthritis (RA) is an autoimmune disease. Simply speaking, one’s own body recognizes his/ her own joints as foreign & attacks them. This immune attack causes inflammation of the joints & the consequent arthritis. We have not been able to fully understand what really leads the body to consider its own joints as foreign (cause of the autoimmunity). It is considered as a result of multiple factors like genetic predisposition & environmental insults.
Easier said than done! We have not been able to scientifically show the combined effect of these factors & explain the mechanism of RA causation. The best explanation is the ‘soil & seed hypothesis’ wherein genetic predisposition provides the right soil & environmental factors the seed for RA causation.
Recent research has given us further insight into how these two factors actually lead to arthritis.

The genetic breakthroughs in RA:
Though RA is known to occur in families, it is not a genetically inherited disease like thalessemia, sickle cell disease. In these diseases there is a definite pattern of inheritance & one can actually calculate the risk of the disease in the child.
We now know about multiple genes that confer the risk of developing RA. In the 1980s, multiple gene sequences within the HLA-DRB1 gene were found to increase the risk of developing RA. These were named the shared epitope. Over the years, numerous such sequences (PADI4, CTLA4, PTPN22, CD40) have been found & shown to increase the risk of developing RA.
These risk sequences are strongly associated with anti CCP (cyclic citrullinated peptide) positive RA. In fact further research showed that these sequences actually contributed to development of ACPAs (anti citrullinated peptide antibodies), which in turn led to development of RA.
At the same time, genetic predisposition alone is not sufficient for development of RA. Various environmental influences trigger the arthritis process in the genetically susceptible individuals.

Does any environmental influence predispose to RA?
In the search for environmental triggers; viral infections, smoking, alcohol consumption, BMI, prior blood transfusion, hormonal factors, and coffee consumption have been studied for the risk of developing RA.
Smoking has been found to be the most important risk factor for developing RA. The risk of RA increases with the amount & duration of smoking. However, interestingly smoking was found to increase the risk of anti CCP positive RA (rather than the anti CCP negative) in individuals who carry the shared epitope.

What is anti CCP antibody?
Anti CCP antibody stands for anti-cyclic citrullinated peptide antibody.
It is an antibody with a high specificity for RA.

What is citrullination—
It is a process in which the amino acid arginine is replaced by citrulline in various proteins. The resultant proteins are called as citrullinated proteins. In animal studies, citrullination of body proteins like collagen & fibrinogen has been shown to trigger arthritis. Antibodies to body antigens modified by citrullination (Anti CCP antibodies) are present in about two-thirds of all RA patients but are rare (2%) in healthy individuals and relatively rare in other inflammatory conditions. These findings make citrullination very important in our understanding of the development of RA.

Gene–environment interaction
Individually, both smoking & the shared epitope sequence have been shown to increase the risk of RA. However, when combined they multiply the RA risk. There is a 21-fold increased relative risk of RA in smokers carrying 2 copies of the risk gene (shared epitope sequence) compared with nonsmokers without the risk gene. This implies a major genetic- environment interaction.

The new hypothesis—
Based on the above-mentioned studies, Lars Klareskog & colleagues came up with the following hypothesis to explain the causation of RA —
1. Long-term exposure to cigarette smoke, and probably also to other (still unknown) environmental stimuli, may induce mechanisms that accelerate citrullination of body antigens present in the lungs.
2. Individuals with the RA risk gene sequences may be genetically prone to develop antibodies to citrullinated proteins.
3. Activation of the immune response to citrullinated proteins occurs years before clinical onset of disease & is signaled by the presence of ACPAs even prior to development of frank RA.
4. Some further event (presently unknown) would cause citrullination of proteins in the joint synovium. In individuals with anti citrulline antibodies, this would trigger joint inflammation & the consequent arthritis.

The unanswered questions—
1. The hypothesis has no explanation for the causation of the anti CCP negative RA.
2. The genetic studies have been conducted mainly in the Caucasian population. The same findings may not be true globally.

This hypothesis, for the first time, tries to scientifically explain the interaction of the genetic & environmental factors in the causation of RA. With said research & the hypothesis, we are probably at the beginning of the era in which we would be able to solve the mysterious relationship between the various (genetic & environmental) causative factors of RA.


12 Responses to ‘What causes Rheumatoid arthritis?’- new insights

  1. chhaya says:

    Nice one!
    Really did not know about what goes on behind the scenes in RA!
    Thanx for the insight.


  2. Kelly says:

    One more for the “unanswered questions” list:

    * With Juvenile RA, there has been no opportunity for environmental factors to begin to work. What happens here? It can occur as young as 6 months.


  3. Adult as well as Juvenile RA (JIA) is caused by an interplay of genetics, environmental influences & the immunity. As you said, the environmental exposures are limited in juvenile arthritis & this also remains the main reason for our poor understanding of the same.

    Breastfeeding, childhood infections, vitamin D deficiency and maternal smoking have been shown to influence the risk of JIA. Being a childhood autoimmune disease it could also be a defect in the maturation of the immune system. However, we do not have sufficient scientific data in JIA as yet.

    In adult RA, this scientific evidence has reached a critical mass to put forth the said hypothesis.

    I’m sure with the scientific advances, we should have the answer in JIA soon.


  4. My Great Grandfather on my father’s side had severe, crippling arthritis (Rheumatism)and now I am the only person in my family with RA. It’s skipped two generations.

    I have tested negative for anti-CCP;ANA; and RF but I definitely have RA! I don’t meet any of the criteria you mention.

    I believe my RA was triggered by menopause; I also have secondary hypo-pituitarism that results in hypo-thyroidism and and hypo-cortisolism.

    My RA is under excellent control; my DAS28 is .6. After two years of Methotrexate and Planquil, I feel almost normal, but very weak.

    I don’t think that there is enough recognition of Seronegative patients–we suffer too.


    • Dear Jamilla,

      Yes, i fully agree. Seronegative RA is in no way less painful as compared to a seropositive RA.
      In fact, the rule of thumb is — ‘do not to underestimate any RA, be it seropositive or seronegative’.
      Both require agressive treatment & early control. In fact, seronegative patients tend to suffer more as they are not diagnosed early.
      I’m happy for you; your RA is well controlled.


  5. sadaj says:

    Keep up the amazing work!! I love how you wrote this. thanks!


  6. iorch says:


    Very interesting article. I have a question, which, so far, I have no reply to.

    You’re talking about the “presence” of the CCP antibodies. What does that mean? A concentration bigger than zero? Positive as per laboratory measurements and ranges?

    Does it mean that, a body producing just one of those antibodies, suppose that the inmune system is starting to fail? Healthy individuals are supposed to have zero concentrations of them?

    I’m asking this, because, I was tested for RA. I obtained 0.22 AntiCCP value, being positive any value bigger than 1.As per your description, I’m kind of worried..since there is presence of those in my blood.
    So far, I’ve been checked by two rheumatologists and I’ve been told I have no signs of RA. Blood is ok and no swelling, tenderness or stiffness.. but some kind of diffuse pain.


    • There are two types of tests.
      First, tests that give results along a continuous scale. Examples of such tests are hemoglobin, blood sugar levels. These tests provide useful information with whatever value they give.
      The other type of tests like anti CCP give results in terms of positive or negative.
      Now, how does one determine what level is positive? First of all, none of the tests is absolutely perfect. Each test will correctly identify those who really have the disease (true positives), wrongly identify (as positive) those who do not have the disease! (false positives), miss out on a few who have the disease (false negatives), & correctly identify those who do not have the disease (true negatives). If we want to increase the accuracy (i.e. increase the number of those correctly identified) one has to set the cutoff values. These values are based on conducting these tests in patients as well as normal individuals & further applying statistical tests.
      When you say your anti CCP result was 0.22, it is negative. It simply means that there are no anti CCP antibodies in the blood. Do not look at the numbers.

      If the joints are not swollen, tender; RA is less likely. Have you gone through the article in the series that deals with the causes of diffuse pain ? Vitamin D3/ b12 deficiency & hypothyroidism/ fibromyalgia remain important causes of diffuse pain.


  7. I have interpret a only one of the articles on your website at this very moment, and I really like your tastefulness of blogging. I added it to my favorites. Thanks.


  8. Ledapayhope says:

    Hello. This post was extremely interesting, particularly since I was searching for thoughts on this matter last Wednesday.


  9. mercante123 says:

    Hello and thank you for a most interesting overview. I have recently been recommended a citrulline supplement by a nutritionalist, however I am concerned because my mother was a chronic RA sufferer and I have psoriasis – so I guess this supplementation could be quite risky for me if citrulline intolerance is the precursor for RA?


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