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DENVER — New analyses of results from the first-line options for systemic juvenile idiopathic arthritis (sJIA) treatment (FROST) study revealed insights into long-term outcomes of treatment with either an interleukin (IL)-1 or IL-6 inhibitor, the impact of concurrent glucocorticoid use, and what factors may help to predict response to IL-1 inhibitors, researchers reported at CARRA 2025: Childhood Arthritis and Rheumatology Research Alliance Annual Scientific Meeting in early April.

The FROST study was a prospective, observational real-world comparative effectiveness study involving 73 pediatric patients with new-onset sJIA between 2016 and 2019. The four CARRA consensus treatment plans (CTPs) being compared were glucocorticoids, methotrexate, an IL-1 inhibitor, and an IL-6 inhibitor. Patients kept a home diary on rash, fever, pain, and the use of glucocorticoids every 2 days for 2 weeks and then weekly for 3 months. The researchers collected clinical data and patient-reported outcomes data during study visits at baseline, 2 weeks, 1 month, 3 months, and then every 3 months for 2 years.

The initial findings revealed that 86% of patients had opted for biologic therapy, and 57% of patients had clinically inactive disease at 9 months without using glucocorticoids. Since the study’s conclusion, researchers have analyzed the data in follow-up studies, including the three presented at CARRA this year.

Effects of Glucocorticoids on Patient Outcomes

One of these studies found that the use of glucocorticoids in new-onset sJIA did not appear to make a difference to patient-reported outcomes in those also taking an IL-1 or IL-6 inhibitor, according to a poster by Karen E. James, MD, a pediatric rheumatologist at the University of Utah School of Medicine and Primary Children’s Medical Center, Salt Lake City, Utah, and colleagues.

Among 63 patients with new-onset sJIA who had been untreated prior to enrollment in the study but then opted to start an IL-1 or IL-6 inhibitor, about half (51%) received glucocorticoids in the first month. (Prior to enrollment, glucocorticoid use for < 14 days was allowed.) There was no significant difference between those receiving glucocorticoids and those not receiving them in terms of the patients’ age, sex, race, days since diagnosis and symptom onset, physician and patient global score, number of active joints, lab values, 10-joint clinical Juvenile Arthritis Disease Activity Score (cJADAS-10), or various clinical characteristics.

All the participants reported experiencing a rash and fever, but there was no significant difference in pain score or fever between those taking glucocorticoids and those not taking them during weeks 5-12. Over the first year, patients reported a modest, nonsignificant decline in fatigue and pain interference and a modest, nonsignificant increase in mobility. Upper extremity function initially improved and then declined almost to baseline levels but was also nonsignificant.

Given the lack of significant differences between the groups in patient-reported outcome improvements and in fever from weeks 5-12, the researchers concluded that “in combination with biologics, early glucocorticoid use may not have a significant effect on sJIA patients’ experience of their disease.” 

Although steroids were a mainstay of initial treatment for sJIA in the past, the availability of newer biological therapies means physicians now “try to avoid using them unless needed for severe disease or complications, such as macrophage activation syndrome,” Grant Schulert, MD, PhD, an associate professor of pediatrics in rheumatology at Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, told Medscape Medical News.

“These results are reassuring that patients who do need steroids at diagnosis seem to do well long-term,” said Schulert, who was involved in the third FROST study described below but not involved in this one. “However, this study didn’t address more long-term steroid use. We know that chronic corticosteroid use can lead to significant long-term complications and side effects, so this will be an important area of future study in FROST.” 

Long-Term Outcomes of FROST Participants

In a separate poster, Timothy Hahn, MD, an assistant professor of pediatrics and rheumatology at Penn State Children’s Hospital, Hershey, Pennsylvania, and colleagues reported on 2- and 3-year outcomes for patients who continued with follow-up visits every 6 months past the initial study.

Of the 73 initially enrolled patients, 41 had complete data at the 2-year visit and 32 at the 3-year visit. The most common CTP remained use of an IL-1 or IL-6 inhibitor, reported by 87.8% of patients at the 2-year and 96.9% of patients at the 3-year visits. The primary outcome of clinically inactive disease without current use of glucocorticoids included 58.5% of patients at 2 years and 65.6% of patients at 3 years.

For secondary outcomes, clinically inactive disease regardless of current steroid use occurred in 61% at 2 years and 67.7% at 3 years, cJADAS-10 score ≤ 2.5 with no fever and no current steroid use occurred in 81.6% at 2 years and 80% at 3 years, cJADAS-10 ≤ 2.5 independent of current steroid use occurred in 85.4% at 2 years and 82.1% at 3 years. At both 2- and 3-year time points, about 9% of patients were taking glucocorticoids. Overall, 87.6% of 32 patients had achieved clinically inactive disease at any point during the 3-year follow-up.

Among the 29 adverse events reported in 19 participants, 15 were serious, including two infections that required hospitalization. The most common adverse events were sJIA flare and macrophage activation syndrome. The overall rate of adverse events was 12.7 per 100 patient-years and, for serious adverse events, 6.6 per 100 patient-years. No patients developed sJIA lung disease, but one participant died from acute liver failure 2.6 years after enrolling.

These findings suggest overall that most children with sJIA have “excellent long-term outcomes with our current treatment approaches,” Schulert said.

Substantial limitations of the study, however, included the small population and the attrition, with 43.8% of the original cohort remaining at the 3-year visit. Its small size means “we can’t draw firm conclusions regarding more uncommon safety issues,” Schulert added. “In particular, it will be important to understand better those who had poor clinical responses, adverse events, or were lost to follow-up,” he said. Regardless, the results offer “some of the best ‘real-world’ data on long-term outcomes of systemic JIA across North America,” he said.

Clinical Parameters of IL-1 Inhibitor Responders

In the third study presented at CARRA, Michael G. Matt, MD, MS, a pediatric rheumatology fellow at Cincinnati Children’s Hospital Medical Center, presented findings on clinical parameters and protein biomarkers that were associated with response status to an IL-1 inhibitor.

Previous research has shown that taking more time to start an IL-1 inhibitor is linked to greater risk of not responding and that high baseline neutrophil counts are strongly associated with clinically inactive disease at 1 year, Matt told attendees. Previous research has also shown that an elevated IL-18/CXCL9 ratio at baseline is seen in responders to the IL-1 beta inhibitor canakinumab.

The researchers divided participants who received IL-1 inhibitors into responders and nonresponders based on the Wallace and colleagues criteria for clinically inactive disease at 6 months. Clinically inactive disease required no active joints, no fever or rash, normal erythrocyte sedimentation rate and C-reactive protein, and no morning joint stiffness lasting more than 15 minutes. Patients requiring steroids or who switched to an IL-6 inhibitor were classified as nonresponders.

Among 30 patients who received IL-1 inhibitors and had available biosamples, there were 17 responders and 13 nonresponders. The researchers found no difference in the baseline joint count and days from symptom onset to therapy initiation between responders and nonresponders. However, nonresponders had significantly higher baseline physical global disease activity scores, lower baseline neutrophil counts, and more persistent arthritis at 1 month.

Although IL-18 and CXCL9 levels were higher in nonresponders at baseline, the difference was not significant, and the IL-18/CXCL9 ratio was statistically similar in responders and nonresponders.

The fact that IL-19 levels and the IL-18/CXCL9 ratio were not elevated in responders differed from previous findings, Matt noted. “Our results may differ from other published data on IL-1 inhibitor response due to different platforms, use of real-world data, and the specific inclusion and exclusion criteria for the FROST study,” he said.

Meanwhile, nonresponders had significantly higher CD25 baseline levels and lower CCL25 baseline levels. At 6 months of treatment, responders had significant reductions in multiple inflammatory cytokines, Matt told attendees, including IL-18, interferon gamma, CD25, GDF-15, IL-23, and CD163. But in nonresponders, only IL-18 and IL12-p70 were significantly decreased at 6 months.

Matt said the next steps will be to use these clinical parameters, cytokine data, genetic and genomic predictors, and gene transcription analysis to build a statistical prediction model of IL-1 inhibitor nonresponse.

“This study addresses a really important question in pediatric rheumatology and is a step closer towards precision medicine for patients with systemic juvenile idiopathic arthritis,” Lauren Henderson, MD, MMSc, a pediatric rheumatologist at Boston Children’s Hospital and an associate professor of pediatrics at Harvard Medical School, Boston, told Medscape Medical News.

“It would be wonderful if we had a biomarker or a blood test that could tell us which patients are less likely to respond to traditional therapies so we could start a different medication for them right away. This would help patients to do better faster,” said Henderson, also the chair of CARRA’s Translational Research and Technology Committee. “More studies will need to be done to confirm these findings, but it is an excellent start.”

The FROST study was funded by CARRA and Genentech. The authors for all three studies reported no disclosures. Schulert reported consulting fees from Novartis and Sobi, and Henderson reported consulting for Sobi, serving on a grant review panel for Pfizer, and receiving an investigator-led research grant from BMS.

Tara Haelle is a science/health journalist based in Dallas.