OKLAHOMA CITY, Oklahoma—Gene expression profiling of children whose polyarticular juvenile idiopathic arthritis (JIA) is in remission confirms that clinical criteria for remission and active disease reflect underlying biology. But the study also shows that JIA in clinical remission without medication is not really quiet.1

"We are eventually going to have to discard the 'autoimmune’ model of JIA, at least polyarticular JIA, and look at new, non-linear models of pathogenesis."—James N. Jarvis, MD
“Remission, as reflected at the molecular level, is clearly not a return to a normal immune/inflammatory state. Rather, the gene expression profiles suggest that remission is a state of homeostasis in which anti-inflammatory (e.g. TGFβ-driven) mechanisms balance the dysregulatory elements that lead to chronic inflammation,” the researchers wrote.

The study by Nicholas Knowlton, MS, James N. Jarvis, MD, and colleagues in the Department of Pediatric Rheumatology at Oklahoma University Health Services Center in Oklahoma City, discovered:
  • a set of 10 genes whose expression levels accurately differentiate JIA is active disease, clinical remission off medication, or clinical remission with medication from a normal control
  • major differences between JIA patients in remission off medication and those in remission with medication
  • complete remission with medication is achieved by suppression of IL-6, IL-4- and INFγ.-regulated networks
  • in complete remission with medication, there is more persistent activity in proinflammatory networks than in treatment-free complete remission
  • even in unmedicated CR, the gene expression profile of peripheral blood monocytes does not normalize.

“Remission in polyarticular JIA is not a return to "normal." It is a homeostatic state in which proinflammatory networks are counter-balanced by anti-inflammatory networks,” Dr. Jarvis told MSKreport.com.

Time to dump the “autoimmune” model of JIA?

Dr. Jarvis said that nothing in the gene networks resembles inappropriate recognition of a ‘self’ antigen by a T cell. “We are eventually going to have to discard the 'autoimmune’ model of JIA, at least polyarticular JIA, and look at new, non-linear models of pathogenesis,” he said.

The researchers conclude, “These findings reveal that remission is not a return to normalcy but, rather, a physiologic state in which proinflammatory elements are countered or kept in check.” They suggest that this finding helps explain why disease recurrences or flares are so common when medications are tapered or discontinued in JIA patients with apparently well-controlled disease.

“The most surprising thing for me was the fact that even children in remission have a very different gene expression profile from healthy controls,” Dr. Jarvis said. “But pediatric rheumatologists have all had the experience of having a child appear in their office with recurrence of their disease symptoms months or years after coming off medication. Our data explain why this is so. If, as it seems, remission is a homeostatic state, then factors that perturb that balance might very well be expected to result in disease recurrence.”

JIA gene expression: Translating research into practice

Dr. Jarvis explained that carefully defining phenotype is critical before one can interpret array data. “In this case, the 'phenotypes’ are the disease state categories, that we developed by our colleague and co-author, Dr. Carol Wallace in Chicago,” Dr. Jarvis said. “Pediatric rheumatologists used to be criticized, no, worse, patronized, by some adult rheumatology investigators because of the ‘descriptive’ nature of their research. However, because of this research, we have good cohorts of well-characterized children with arthritis to which we can apply across-the-genome technologies to understand the disease better.”

The Oklahoma researchers' long-term goal is to develop an array-based assay that will allow clinicians to know which patients can safely come off medication. “New data from my laboratory suggest that such an assay will be feasible and practical,” Dr. Jarvis said.

Reference

1. Knowlton N, Jiang K, Frank MB, et al. The meaning of clinical remission in polyarticular juvenile idiopathic arthritis. Gene expression profiling in peripheral blood mononuclear cells identifies distinct disease states. Arthritis Rheum. 2009;60:892-900.