Understanding Mechanisms of Systemic-Onset Juvenile Idiopathic Arthritis
Systemic-onset juvenile idiopathic arthritis is one of the most devastating rheumatic diseases in childhood. "At the beginning, it can be viewed as an exaggerated immune response probably triggered by infection," explains Alexei Grom, MD, of the Division of Rheumatology at Cincinnati Children's. Spiking fevers, rash, and enlarged lymph nodes, spleen and liver are characteristic manifestations of systemic inflammation that can also involve the heart, lungs and blood vessels.
"This systemic inflammation eventually settles in the joints, leading to irreversible joint damage by the end of the second year of the disease in about half of these children. Many children with systemic-onset juvenile idiopathic arthritis often have multiple joint involvement and require joint replacement early in life," Dr. Grom says.
Identifying 'Diagnostic Signature'
"Powerful new biologic and immunosuppressive drugs might prevent severe joint damage if used early enough, but clinicians can miss the window of opportunity," Dr. Grom says. In its early stages, systemic-onset juvenile idiopathic arthritis mimics many other diseases, making it difficult for pediatricians to make a definitive diagnosis.
Dr. Grom and his colleagues are using microarray gene expression profiling to analyze blood and synovial fluid samples in an attempt to identify an "early diagnostic signature" that would identify patients bound to develop severe joint damage. Finding such a marker and then developing a laboratory test that pediatricians could order as part of a diagnostic workup would allow clinicians to anticipate the course of the disease and ambush its relentless advance.
Finding Similarities
Macrophage activation syndrome (MAS) is a life-threatening complication of systemic-onset juvenile idiopathic arthritis. "Overactive macrophages phagocytose normal cells and release inflammatory cytokines," Dr. Grom explains. This in turn leads to the uncontrolled systemic inflammatory response that can be fatal. "MAS is a major cause of mortality," Dr. Grom says. Systemic-onset juvenile idiopathic arthritis accounts for 10 to 20 percent of juvenile arthritis cases, but about 66 percent of the deaths.
There are similarities in the MAS mechanism with those seen in septic shock syndrome and an autosomal recessive disease called familial hemophagocytic lymphohistiocytosis. Looking at similarities and degrees of divergence with these conditions could establish the mechanisms of the disease process and suggest how pediatricians and other physicians could effectively intervene.
Explaining Clinical Features
Many of the clinical features of systemic-onset juvenile idiopathic arthritis may be explained by an immune response involving interleukin-1 (IL-1) and interleukin-6 (IL-6). "Preliminary evidence suggests that therapy targeted against IL-1 and IL-6 might be useful," Dr. Grom says. In preclinical trials, a molecule called the "IL-1 Trap" was shown to block the effects of IL-1, decrease inflammation and impede cartilage erosion in the joint. To better understand the pathophysiologic basis for the effectiveness of this treatment in systemic juvenile rheumatoid arthritis (JRA), Dr. Grom will analyze samples from patients enrolled in the Phase I trial of the IL-1 Trap.
Dr. Grom's interest in pediatric rheumatology predates his affiliation with Cincinnati Children's. Originally from Riga, Latvia, in 1991 he was studying in St. Petersburg (then known as Leningrad), Russia (then part of the Soviet Union), when he accepted an offer to work here on rheumatology clinical trials. He completed a clinical residence and fellowship at Cincinnati Children's in 1995.
Dr. Grom is assistant professor of pediatrics in the Division of Rheumatology. His review on the role of natural killer cell dysfunction in systemic-onset juvenile rheumatoid arthritis, macrophage activation syndrome, and hemophagocytic lymphohistiocytosis was published in Arthritis and Rheumatism (50[3]:689-698, 2004 March).
