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.
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.