New research suggests a link between a particular gene variation, as well as environmental factors like cigarette smoking, in the development of and the severity of rheumatoid arthritis.
Researchers from Michigan Medicine found that smokers who also have the human leukocyte antigen (HLA) gene variant have a higher likelihood of developing rheumatoid arthritis and are more likely to suffer from greater pain and swelling, as well as more severe bone destruction.
“We found a particular enzyme that acts as a channel, or pathway, in the cell for a conversation between the two culprits, so they work together to do greater damage,” Joseph Holoshitz, MD, professor of internal medicine and associate chief for research in the Division of Rheumatology at the University of Michigan School of Medicine, said in a statement. “Individually they are bad, but together, they’re worse.”
The researchers found that cigarette smoke was the top environmental factor in developing the disease, but other factors like living in close proximity to environmental pollutants also plays a role. For example, living in an urban area or near a highway may expose people to the chemical dioxin.
“One scenario is that air pollution from vehicles on highways produces dioxin or other pollutants,” Holoshitz said. “Dioxin is just one of many chemicals that similarly activate this pathway.”
Dioxin also has been shown to increase severity in an experimental model of another autoimmune disease, multiple sclerosis.
“We’ve shown in this study that the interaction between dioxin and the HLA gene variant activates events known to be associated with rheumatoid arthritis,” Holoshitz said. “And we’ve demonstrated quite convincingly that this facilitates bone destruction.”
Bone degeneration in rheumatoid arthritis is caused by hyperactivity of certain bone cells called osteoclasts, which absorb bone tissue.
“In our research with the combination of dioxin and the HLA gene variant, we saw that osteoclasts are overactive and overabundant, and that bone is destroyed because of it,” Holoshitz said.
Treatments for rheumatoid arthritis are generally focused on the inflammation associated with the disease. However, there is no treatment available that targets bone destruction at this time.
“Once we have better drugs that directly and specifically address bone destruction in this disease, we’ll have better treatment,” Holoshitz said. “As a separate project, we have a couple of early-stage drug candidates that block the HLA gene-activated pathway and are effective in preventing bone damage.
“These drugs almost completely inhibit experimental rheumatoid arthritis and bone damage in mice,” he added. “By understanding the mechanisms, we may be able to develop better inhibitors to prevent disease and identify therapeutic targets for new treatment strategies.”
The study was published in the Proceedings of the National Academy of the United States of America.
