JIA Remission Is Not a Return to Normal

Janis C. Kelly

September 27, 2013

Gene expression profiling has confirmed what many pediatric arthritis experts have long suspected: Treatment-induced juvenile idiopathic arthritis (JIA) remission is not the same as restoration of normal immune function. The data confirm that JIA is a disease of disordered gene regulation, not autoimmunity.

JIA remission does not represent a return to normal immune homeostasis but is a reordering of leukocyte gene transcription so that anti-inflammatory responses balance proinflammatory responses, Kaiyu Jiang, MD, from the Department of Pediatrics, Pediatric Rheumatology Research, University of Oklahoma Health Sciences Center, Oklahoma City, and the Department of Pediatrics, Rheumatology Research, SUNY Buffalo Clinical and Translational Research Center, Buffalo, New York, and colleagues report in an article published online August 30 in Arthritis Research & Therapy. The immune function reordering affected cells of both the innate and the adaptive immune systems was different with methotrexate (MTX) alone than with MTX plus etanercept and likely involved transcription factor hepatocyte nuclear factor 4 alpha (HNF4a), a steroid hormone receptor not previously identified in leukocytes.

New Data Shatter Old Model of JIA

"This is a real game-changer," pediatric arthritis expert Carol A. Wallace, MD, told Medscape Medical News. "We have suspected that kids with JIA don't really 'return to normal' and that chronic [medications] might be needed for very long periods of time, but no one had biologically demonstrated this before. This is huge. The 'teaching' had always been that with the proper treatment, the immune system would return to normal and there could be a long-lasting remission without medications."

These data show that is probably not the case, according to Dr. Wallace, professor of pediatrics and director, Division of Rheumatology, University of Washington and Seattle Children's Hospital, Seattle.

"This study explains a lot about remission that we didn't previously understand. Most especially, it explains why children continue to have disease flares even after they achieve remission on medication [CRM]," senior author James M. Jarvis, MD, told Medscape Medical News.

"We show that immunologic abnormalities persist, and that, although phenotypically normal, children in remission still have immunologic perturbations," continued Dr. Jarvis, who is clinical professor of pediatrics in the University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York. "The study also tells us something that we've suspected but haven't known for sure: remission achieved on MTX isn't exactly the same as remission achieved on a [tumor necrosis factor] inhibitor. Whether the differences in expression profiling are directly due to the medications or the underlying state of children who achieve remission only with etanercept remains to be understood."

The researchers compared gene expression profiles in 2 independent cohorts of patients with JIA in CRM and with profiles from healthy children. All patients had normal physical examinations, no morning stiffness, and normal complete blood counts and erythrocyte sedimentation rates, and all had maintained the inactive disease state for at least 6 months. Participants included 14 children who had achieved CRM with MTX alone, 14 children who achieved CRM only after addition of etanercept to MTX, and 15 healthy children.

The investigators used whole-genome microarrays to identify differentially expressed genes in RNA from peripheral blood mononuclear cells (PBMCs) and from granulocytes. They confirmed the gene expression profiling by quantitative, real-time polymerase chain reaction.

Test results were validated in a separate patient cohort of 8 children who achieved CRM with MTX alone, 8 who achieved CRM only after the addition of etanercept, and 8 healthy children.

Adding Etanercept Changed Neutrophil Gene Expression in JIA

Gene expression profiles in PBMC and in granulocytes from children with JIA in CRM differed from those in healthy children. PBMC gene expression profiles were similar in JIA remission achieved with either MTX or MTX plus etanercept, but neutrophil gene expression differed according to treatment.

"Gene expression in both PBMC and granulocytes remains abnormal when patients in remission are compared with healthy control children," the authors write. "Furthermore, while there are some overlapping points, remission achieved on MTX differs from remission achieved on MTX + [etanercept], especially in granulocytes, suggesting overlapping but not identical 'set points' for each of these remission states."

"We were not surprised by the neutrophil data," Dr. Jarvis told Medscape Medical News. "I suppose that people who are still stuck in the idea that JIA is an autoimmune disease will be surprised, even though the evidence that JIA is triggered by T-cell recognition of self peptides is very sparse. Under any circumstances, we are now working with a completely different model of JIA that views it from the standpoint of disordered gene regulation."

The analysis also showed that the steroid hormone receptor superfamily member HNF4a is at the center of several gene networks that distinguish healthy children from those with JIA. "Confocal microscopy revealed that HNF4a is present in both T lymphocytes and granulocytes, suggesting a previously unsuspected role for this transcription factor in regulating leukocyte function and therapeutic response in JIA," the authors note.

First Piece of the Roadmap Toward JIA Remission

"Our findings suggest that we can develop objective biomarkers to determine exactly when children have achieved remission. This would be very helpful in pediatric rheumatology clinical trials, for example. They also give us a piece of a roadmap toward remission. Eventually, we want to build a 'genomic map' that crisply defines, in relevant cells, how children progress from active, untreated disease to remission. By having this roadmap, we hope to design strategies to get to remission more quickly and efficiently," Dr. Jarvis said.

The study was supported by the National Institutes of Health, the Oklahoma Center for the Advancement of Science and Technology, and the Arthritis Foundation. The authors and Dr. Wallace have disclosed no relevant financial relationships.

Arthritis Res Ther. Published online August 30, 2013. Full text

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