A history of cigarette smoking is linked to the development of rheumatoid arthritis (RA) and specific immune responses to proteins within the body. However, a team of researchers from the Johns Hopkins Division of Rheumatology studying patients seen at Arthritis Center, found that smoking was not the driving force behind the generation of antibodies that bind to an enzyme called PAD4. This suggests that environmental factors other than smoking are responsible for the generation of these antibodies in patients with RA. Since patients with antibodies to PAD4 have the most severe joint and lung disease, understanding the environmental risk factors that lead to their development could lead to strategies to prevent their generation in the future.
Why was this study done?
A combination of genetic and environmental factors is thought to be responsible for the development RA. In particular, a history of cigarette smoking has been most strongly linked to the development of this inflammatory joint disease, as well as resulting immune responses to citrullinated proteins. These immune responses are detected in the clinic by the anti-CCP assay. Citrullinated proteins are generated by an enzyme called PAD4, and some patients with RA also make antibodies to the PAD4 enzyme . However, it was unknown if smoking was responsible for the development of antibodies to this important enzyme. This study was done to understand if a history of cigarette smoking was linked to the development of antibodies to PAD4 in patients with RA.
How was this study done?
The research team studied 274 people with RA seen at the Johns Hopkins Arthritis Center who agreed to participate in this study. Study participants had routine clinical exams, completed a questionnaire that collected information about their smoking history, and donated blood for PAD4 antibody testing. These data were then analyzed by the research team to identify factors, including smoking history, that may be linked to the development of PAD4 antibodies in patients with RA.
What were the major findings?
In this group of patients, PAD4 antibodies were found more commonly individuals who had RA for a long period time, an average of 15.5 years. These individuals were also more likely to have specific genetic features called the “HLA shared epitope”, test positive for anti-CCP antibodies, and have evidence of more joint damage on X-ray. When the participants were asked about their smoking history, researchers found that a history of ever smoking was not linked to the development of PAD4 antibodies. In fact, current smokers were less likely to develop PAD4 antibodies than people who did not actively smoke at the time of the study.
What is the impact of this work?
Although smoking is linked to several severe health problems, including the development of RA, it does not appear to be the driving factor for the development of PAD4 antibodies in patients with RA. It is important to understand why people develop RA and generate specific immune responses to self proteins, like PAD4. If smoking is not the responsible driving factor, it is important to explore other environmental triggers that might lead to the development of these antibodies found in patients with the most severe RA. Other possible culprits include infections, including infections of the gums, which have recently been linked to RA development. Identifying modifiable environmental triggers of RA and resulting immune responses could lead to preventative strategies to one day stop their development.
This research was supported by:
Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program under Award No. W81XWH-15-1-0159, and the Camille Julia Morgan Arthritis Research and Education Fund.
Link to original research article:
Smoking is not linked to the development of anti-peptidylarginine deiminase 4 autoantibodies in rheumatoid arthritis
Laura C. Cappelli†, Maximilian F. Konig†, Allan C. Gelber, Clifton O. BinghamIII and Erika Darrah †Contributed equally.
Arthritis Research & Therapy201820:59