FDA Warning ‘Bombshell’ Caps Top JIA Developments for 2024

For juvenile idiopathic arthritis (JIA), 2024 was marked by both successes and heightened controversy.

There were new US Food and Drug Administration (FDA) warnings for DRESS (drug reaction with eosinophilia and systemic symptoms) in patients receiving interleukin (IL)-1 or IL-6 inhibitors, which have been widely regarded as a remarkable advancement for treating systemic JIA (sJIA). “Exciting” data were presented on emapalumab in the treatment of refractory macrophage activation syndrome (MAS) in patients with sJIA/Still disease. And the FDA approved three new drugs for JIA. 

“The FDA dropped a bombshell last year with its new DRESS warnings,” inflaming an already passionate and controversial topic in the field of pediatric rheumatology, Susan Shenoi, MBBS, MS, clinical director of the Pediatric Rheumatology Division at Seattle Children’s Hospital, Seattle, said at the Rheumatology Winter Clinical Symposium (RWCS) 2025.

The FDA’s warning came after reports over the past decade of unusual lung disease (LD) developing in a small percentage of children with sJIA who are treated with IL-1 and IL-6 inhibitors and two retrospective, case-control studies published in 2022 and 2024. “What’s scary is that the lung disease is highly fatal,” said Shenoi, with 60%-70% mortality.

In her review of new developments in JIA, Shenoi maintained, however, that the cause of this LD in sJIA (sJIA-LD) is unknown. “I worry that we’re all looking at different parts of the same elephant and coming to different conclusions,” she said.

“I want us to recognize that there is a new safety warning label and to recognize the context in which the new label was [applied] to these IL-1 and IL-6 inhibitors,” she said. (Provider letters have asked prescribers to inform patients of the risk and to consider stopping the biologics in the case of serious allergic reactions.)

“My plea is, we don’t know what is causing the lung disease, and once we label something as DRESS, it closes our mind to the possibility of it being something else. This clearly is an evolving story. We don’t know the ending yet.”

Details on DRESS and the sJIA-LD Controversy

Features of DRESS, Shenoi said, include onset 2-8 weeks after drug initiation; generalized maculopapular rash, typically without blisters; and presence of features like fever, lymphadenopathy, eosinophilia, and abnormal organ function.

In patients with sJIA-LD, CT scans show early peripheral fibrosis with subpleural sparing, and nonspecific diffuse ground glass opacity. A “crazy pavement” pattern may also be seen.

In the key study published in 2022, investigators collected a multicenter series of 66 patients with Still disease (mostly pediatric patients) and a probable DRESS reaction to IL-1 inhibitors (anakinra, canakinumab, and rilonacept) and the IL-6 inhibitor tocilizumab, based on the RegiSCAR scoring system for DRESS. They compared them with 65 patients with Still disease who were deemed drug tolerant during biologic treatment and retrospectively analyzed clinical features as well as human leukocyte antigen (HLA) alleles.

Significantly more patients in the DRESS group had eosinophilia (89% vs 2%), aspartate aminotransferase-alanine aminotransferase elevation (75% vs 6%), and MAS (64% vs 3%). The HLA-DRB1*15 haplotype was found in 75% of the cases vs only 18% of the control individuals.

The 2024 study, led by the same group of researchers, similarly sought to characterize DRESS in 89 patients vs 773 control individuals and to analyze the outcomes of stopping vs not stopping the IL-1/IL-6 inhibitors in those deemed to have DRESS. Pulmonary complications, the researchers found, resolved in 67% of the 39 patients who stopped the biologics and in none who continued, and survival was improved.

Among the study’s limitations, the authors wrote, is the use of a convenience sample and possible selection bias, as well as possible bias in the control cohort toward more mild disease.

At RWCS 2025, Shenoi urged rheumatologists to consider these limitations. The 2024 study “was another retrospective case-control study that was a convenience sample,” she said, adding that some of the 89 patients in the drug reaction cohort had “Still-like disease” and did not meet oft-used diagnostic criteria. “Context is everything.”

Among the factors in favor of DRESS as a cause of sJIA-LD are the temporal association of the disease with increasing use of IL-1 and IL-6 inhibitors, improved survival with continuation of biologics, and the association of sJIA-LD with HLA alleles.

But there are numerous reasons, Shenoi said, to doubt DRESS as causal for sJIA-LD at this point: For one, not all patients taking the biologics for sJIA develop LD, and not all patients with sJIA-LD have received the biologics. “These molecules are lifesaving and only started to be used in the 2000s or so, and sJIA lung disease has been reported in 1990 and in papers before that,” she said.

Moreover, “there are many papers showing increased eosinophils in Still disease, and reports showing success with treating through sJIA-LD with [the inhibitors],” she said. Also, “lung involvement in MAS is common and many patients with sJIA-LD have increased MAS episodes.”

IL-1 and IL-6 inhibitors have been used in other diseases without DRESS, she also noted, and “it’s hard to imagine a common pathway of DRESS with [these biologics] that are completely different chemical molecules.”

The HLA-DRB1*15 genotype should be regarded as a risk factor for sJIA-LD, but it is a common genotype and not all patients with sJIA who have the allele develop LD, just as almost 20% of those in the 2022 study’s DRESS cohort did not carry the risk allele.

Currently, Shenoi said, management varies, and some pediatric rheumatologists are discontinuing the biologics when patients develop LD in sJIA, whereas others “are opting to treat through with the IL-1 and IL-6 inhibitors even after the onset of sJIA-lung disease.”

At this point, she advised, “what’s key is to be aware of the high-risk population [those with risk factors for development of Still-LD], and to really carefully monitor them for lung disease development using periodic chest CTs and other tests,” she said.

Identified risk factors for sJIA-LD are young age at sJIA onset (< 5 years), trisomy 21, and higher serum IL-18. Identified risk factors for Still-LD in adults are lymphadenopathy and myalgia, high white blood cell counts, smoking, and frequent recurrence of Still disease. In both children and adults, the risk increases with prior episodes of MAS and a history of adverse reactions to IL-1 or IL-6 inhibitors, she said.

Alternate hypotheses for what may be happening in sJIA-LD include “that it’s a bad form of MAS because there’s so much IL-18 and so much interferon gamma activation in this disease,” Shenoi said. “And there’s a camp that believes the ‘cytokine plasticity hypothesis’ — the idea that inhibiting some cytokines allows others to become more active.”

Asked during the discussion period about possible reactivation of a latent virus, Shenoi said that Pneumocystis jirovecii pneumonia reactivation was initially suspected, but widespread use of Bactrim “didn’t make any difference.” Now, “there are theories about other viruses,” she said. “It’s being studied…it’s on people’s radar.”

Emapalumab in Refractory MAS

MAS in sJIA/Still disease is typically treated with pulse methylprednisolone, additional glucocorticoids, and high-dose anakinra, along with other agents such as cyclosporine as needed for first-line treatment. But what can be done when patients have an inadequate response?

Evidence is building that emapalumab — an anti–interferon gamma antibody currently approved for refractory primary hemophagocytic lymphohistiocytosis — can be effective in refractory sJIA-related MAS, Shenoi said.

A pooled analysis of data from two open-label, single-arm interventional studies has shown that emapalumab neutralized interferon gamma in all patients as assessed by CXCL9, and rapidly controlled MAS in over 80% of the 39 patients studied. The analysis, presented as a late-breaking abstract at the American College of Rheumatology 2024 Annual Meeting by Alexei Grom, MD, of Cincinnati Children’s Hospital Medical Center, included the 14 participants of the phase 2 EMERALD trial, whose findings were published in 2023.

All patients in the analysis had an inadequate response to high-dose glucocorticoids and other standard treatment prior to enrollment. Patients were allowed concurrent steroids and cyclosporine, “and what’s fascinating is that in an amendment to the protocol, they were even allowed concurrent anakinra” if it had been started at least 3 days prior, Shenoi said, sharing key parts of the abstract. Patients received acyclovir prophylaxis, and CXCL9 levels were used “to monitor how many more doses to give,” she said.

A “complete response” as defined by investigator assessment and normalization of seven MAS-related laboratory parameters (the primary outcome) was achieved in 54% of patients. In a post hoc analysis that excluded lactate dehydrogenase — the criterion most commonly not met — complete response increased to 69%.

Over 80% achieved an “overall response,” defined as complete or partial response, by week 8. The median time to first overall response was 2.3 weeks, “which is great,” and overall survival was 95%, Shenoi said, noting that significant glucocorticoid dose reduction was achieved as well.

Emapalumab was “fairly well tolerated,” she said, with six serious adverse drug reactions reported in four patients, none of which led to discontinuation. Patients had a median age of 12 years (range, 0.9-64).

New FDA Approvals for JIA

In 2024, three drugs gained new indications for JIA, and a host of biosimilars with pediatric indications were approved:

• Upadacitinib (a Janus kinase inhibitor) for polyarticular JIA and psoriatic JIA in children aged ≥ 2 years who have failed or become intolerant to at least one tumor necrosis factor (TNF) inhibitor
• Sarilumab (an IL-6 receptor inhibitor) for patients weighing ≥ 63 kg
• Certolizumab pegol (a TNF inhibitor) for polyarticular JIA in patients aged 2-17 years
• Six ustekinumab biosimilars (Steqeyma [ustekinumab-stba], Yesintek [ustekinumab-kfce], Imuldosa [ustekinumab-srlf], Otulfi [ustekinumab-aauz], Pyzchiva [ustekinumab-ttwe], and Selarsdi [ustekinumab-aekn]), giving a total of seven now approved
• One adalimumab biosimilar (Simlandi [adalimumab-ryvk]), making a total of nine now approved
• One biosimilar of tocilizumab (Tyenne [tocilizumab-aazg]), making a total of three now approved, including one approved in January 2025 (Avtozma [tocilizumab-anoh])

These approvals, combined with four other drugs approved for JIA during 2020-2023 (tofacitinib, golimumab, secukinumab, and ustekinumab), represent an “exponential rise” over the prior two decades — one that “was not random,” Shenoi said, but a result at least in part of advocacy by the pediatric rheumatology community.

“The FDA now agrees that for diseases that are similar or the same [in pediatric patients as in adults], you don’t need to do full-blown RCTs [randomized controlled trials], you can [collect] pharmacokinetic data and use extrapolation to get these medications approved for kids faster,” she said. 

Shenoi disclosed as a consultant for Pfizer and Sobi and served in the past as a consultant for AbbVie, Amgen, and Cabaletta Bio.