Mystery of Childhood Arthritis Yielding to Improved Treatments

David Glass, MD, recalls a time not long ago when the diagnosis of childhood arthritis meant anything but a normal childhood.

As their immune systems attacked their knees, hips and other joints, children often lost the ability to walk. These days, however, children with juvenile idiopathic arthritis (JIA) rarely need wheelchairs. In fact, those attending Camp Wekandu – an annual summer camp co-sponsored by Cincinnati Children’s – enjoy horseback riding, swimming, even zipping along rope courses.

“We haven’t ordered a wheelchair in years,” says Glass, a longtime arthritis researcher and associate director of the Cincinnati Children’s Research Foundation.

Indeed, treatments for JIA have come a long way. Thanks to more precise diagnoses, and powerful treatments and wider use of physical therapy, the vast majority of kids with arthritis maintain full mobility well into adulthood.

Childhood arthritis is the No. 1 cause of acquired disability in children and the sixth most common childhood disease, according to the Childhood Arthritis & Rheumatology Research Alliance (CARRA).

Yet the disease remains far from fully understood. Outcomes range from complete recovery to persistently active disease, joint destruction and disability. Determining which children need long-term therapy and which do not remains difficult.

There is progress, however. New lines of research are revealing new gene associations, potential biomarkers for diagnostic testing and fresh targets for improved treatment.

The Division of Rheumatology at Cincinnati Children’s is involved in large-scale international efforts to identify more of the genes associated with juvenile arthritis, to find biomarkers for more sophisticated diagnostic tests, to evaluate new medications and to study the quality of arthritis care.

As the mystery of JIA unfolds, investigators see great potential for improved clinical care. 

Searching the genome

Experts suspect that 30 to 50 genes may be involved in the seven clinical subtypes of JIA.

Most of those genes remain unidentified.

“Advancing genetic discovery in JIA is important to the understanding of autoimmune disease in general,” says Susan Thompson, PhD, a biologist at Cincinnati Children’s.

Thompson, Glass and other colleagues at Cincinnati Children’s are working with 10 other medical centers to run more biological samples from JIA patients through genome-wide analysis.

Some gene candidates are well known. Scientists have known since the early 1990s about links between arthritis and genes within the HLA region, a part of chromosome 6 that plays a vital role in
immune system function.

“It’s what makes up the rest that has taken a long time to uncover,” Glass says. “It has to do with the fact that there are multiple genes with small effects, which was unexpected.”

Information about these small-effect genes is beginning to flow.

Last fall, Thompson was the lead author among 20 investigators who reported details on seven single-nucleotide polymorphisms (SNPs) newly associated with JIA. The findings appeared in the November 2010 edition of Arthritis & Rheumatism.

“We have made great progress, but we are not there yet,” Thompson says. “To date, we have about 10 strong findings and have completed a genome-wide association study on our first cohort of about 800 JIA patients. We will have a second cohort of more than 1,000 completed in spring of 2011.”

Thompson is focusing specifically on two genes – JMJD1C and PTPN2 – both of which are not only risk factors for disease but may also help explain why some JIA patients respond poorly to methotrexate, a commonly prescribed treatment.

“JMJD1C is interesting because it belongs to a family of genes involved in histone demethylation, which relates to turning genes on and off in development and maybe also during normal cellular processes. Not much is known about this gene, but it is an attractive candidate to study because of its potential regulatory role,” Thompson says.  “Meanwhile, PTPN2 is associated with many other autoimmune diseases including adult arthritis and Crohn’s disease and has a role in cytokine signaling.”

The challenge in genetics is figuring out the relationship between a DNA polymorphism and biological change in the patient. “These two genes offer that potential,” Thompson says.

Developing biomarkers

As more genes are identified, delving into gene expression signatures could eventually identify biomarkers for tests to assess and predict the severity of JIA.

The earlier people are treated, the more effective the treatment will be, Glass says. Doing that, however, requires identifying biomarkers that can determine what kind of drug is most likely to be successful on a given patient.

Cincinnati Children’s is using an NIH grant to pursue biomarker development for JIA. Improved testing could help physicians determine which patients will need more aggressive treatment and which ones can safely discontinue certain treatments, thus reducing risks of long-term side effects.

Advancing new therapies

Methotrexate – a form of cancer chemotherapy – emerged in the 1980s as a breakthrough treatment for arthritis. But the drug does not work for everyone and it leaves children with weakened immune systems. In the past decade, newer biologics have added to the success, primarily by blocking TNF-alpha, a substance known to harm tissue.

More medications are moving through the pipeline, says Daniel Lovell, MD, MPH. Lovell is chairman of the Pediatric Rheumatology Collaborative Study Group, a research network based in Cincinnati that includes more than 85 medical centers.

The group is working on 11 advanced stage clinical trials – eight phase III and three phase IV studies – of agents that show high promise of improving treatment of JIA. Two closely watched efforts include studies of tocilizumab, an interleukin-6 blocker and canakinumab, an interleukin-1 blocker.

Rethinking systemic JIA

Scientists also are taking a closer look at systemic onset JIA, an unusual subtype of the disease. While other types of JIA focus on which and how many joints are affected by arthritis, systemic JIA includes symptoms that have little to do with the joints, such as sudden high fevers and rashes.

Alexei Grom, MD, is leading research at Cincinnati Children’s that focuses on systemic onset JIA and an associated condition known as Macrophage Activation Syndrome (MAS).

Grom’s studies explore how natural killer (NK) cells function in these conditions. Recent observations suggest MAS patients have profoundly depressed NK function. A large subgroup of systemic JIA patients also experience similar abnormalities, which may make their bodies less able to control inflammation.

More findings to come

Cincinnati Children’s has applied to renew an NIH Program Project grant to continue investigating gene expression profiles in JIA. The first cycle of the grant led to 26 published findings. Even more significant findings are on the horizon.

“It’s a story of continuing gene and gene expression research,” Glass says. “It’s an incomplete story. But a vast amount of progress has been made understanding the molecular basis of JIA, and from that, people will introduce new treatments.”