Juvenile idiopathic arthritis (JIA) has long been considered a group of autoimmune diseases. However, some pediatric rheumatology researchers are beginning to rethink this long-held belief. One view, according toRandy Cron, MD, director of the Division of Pediatric Rheumatology at the University of Alabama at Birmingham School of Medicine, is that at least one form of JIA, systemic JIA (sJIA), is autoinflammatory rather than autoimmune. “It is kind of a technical distinction, but it is different,” he says. Still, other researchers are exploring whether other subtypes are neither autoimmune nor autoinflammatory, but are caused by something else. These debates could affect the way the diseases are treated now and in the future.
Autoimmune vs. Autoinflammatory JIA
A healthy immune system easily distinguishes between the body’s tissues and foreign invaders. Autoimmune diseases result from an error in the part of the immune system known as the acquired or adaptive immune system. This complex subsystem, which develops throughout life, fights foreign substances that invade the body by recognizing invaders and producing proteins called antibodies to fight them. By remembering invaders, it can fight them quickly if they return. White blood cells called lymphocytes are key to the acquired immune system.
The other arm of the immune system is the innate system, a simpler but broader subsystem, which is present at birth. This subsystem uses white blood cells called monocytes and neutrophils to rid the body of harmful substances.The innate immune system has been implicated in autoinflammatory diseases characterized by episodes of intense inflammation resulting in symptoms such as fever, rash or joint swelling. When there is an error in the innate immune system, this inflammation occurs for unknown reasons.
“I think that definitely everyone agrees that that systemic JIA is autoinflammatory,” says Carol Wallace, MD, professor of pediatric rheumatology at the University Of Washington School Of Medicine in Seattle.
“The thought to define it as such was a gradual process based on an increasing understanding of mechanisms of autoinflammatory diseases and the mechanisms of inflammation in SJIA,” says Daniel Lovell, MD, at Cincinnati Children's Hospital Medical Center.
However, there are some researchers who think SJIA may be a combination of an autoinflammatory and an autoimmune disease.Peter A. Nigrovic, MD, director of the Center for Adults with Pediatric Rheumatic Illness at Brigham and Women’s Hospital in Boston and an assistant professor at Harvard Medical School, says SJIA may begin as an autoinflammatory condition, causing fever and other systemic symptoms. When those symptoms begin to fade and arthritis appears, SJIA behaves more like an autoimmune disorder.
The Role of Faulty Genes
One researcher, James M. Jarvis, MD, clinical professor of pediatrics at the University at Buffalo School of Medicine and Biomedical Sciences, in Buffalo, N.Y., is taking the debate a step further by contending that that no type of JIA is autoimmune in origin.
Dr. Jarvis’ research suggests that JIA – specifically the polyarticular and oligoarticular subtypes – results from dysregulation of the more than 80 genes that control the actions of white blood cells. This gene dysregulation puts the body in a chronic state of low-level inflammation.
The impairment in gene regulation may be caused by a combination of genetic factors and epigenetic changes – changes that cause genes to turn off and on without changing their DNA blueprint. Epigenetic processes are natural and essential for many organism functions. In many cases these changes are normal and benign, but in some cases, they can create havoc in body systems, Dr. Jarvis says.
Dr. Jarvis and his research team have been studying the role of gene dysregulation in JIA for about 10 years. “We first stumbled into this idea in our earliest studies of gene regulation in JIA,” he says. “Computer models of gene expression suggest that there was a loss of cohesion in the patterns of gene expression in JIA white blood cells.”
When he began his research there was a large amount of published work, showing how the genome – an organism’s complete set of DNA, including all of its genes – regulates the process of coordination, he says. “As I read the research in model organisms and spent more time talking with genome scientists from all over the world, it seemed more and more plausible to hypothesize that there would be human disease that emerge because of loss of this genome-wide coordination.”
Dr. Jarvis acknowledges that the view he is espousing is not one that has been generally embraced by pediatric rheumatologists, but that the more he learns about genomes the more plausible his view appears to be.
Whether the impairment in gene regulation might also be responsible for systemic JIA, Dr. Jarvis can’t say. “[Systemic JIA] looks so different from other forms of JIA, at least in the acute setting,” he says. “I tend to agree with the accepted idea that this subtype is an ‘autoinflammtory’ disease.”
Dr. Wallace, who is not part of Dr. Jarvis’ research team, believes the thinking that JIA is not an autoimmune disease may change as research reveals more about the disease. But, she adds that for about 5 percent of children with JIA – those with a positive rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) antibodies – the disease is autoimmune in nature and the antibodies are associated with more severe disease.
Pathway to New JA Treatments
Dr. Jarvis says that looking at JIA as something other than an autoimmune disease will open doors for new, more effective treatments. Changing views about the disease are already leading to changes in the ways the different forms are treated. For example, interleukin-1 (IL-1) blockers are proving to be effective for treating systemic JIA, but not the other JIA forms, while some effective treatments for other forms of JIA, such as methotrexate and tumor necrosis factor (TNF) blockers, have been found to have little benefit for systemic JIA.
He believes that further understanding of the disease will lead to new treatments that regulate the genes at the root of inflammation, rather than just suppressing the immune system.