Washington D.C.—At a Sunday, Nov. 17, Pediatrics Great Debate session of ACR Convergence, speakers argued whether patients with systemic juvenile idiopathic arthritis (sJIA) should continue their interleukin (IL) 1/IL-6 biologics if lung disease is suspected.
Randy Q. Cron, MD, PhD
Randy Q. Cron, MD, PhD, the director of the Division of Pediatric Rheumatology at the University of Alabama at Birmingham, made the case for discontinuing IL-1 or IL-6 inhibitors if lung disease is present.
In contrast, Karen B. Onel, MD, professor of clinical pediatrics at Weill Cornell Medicine and the chief of Pediatric Rheumatology at the Hospital for Special Surgery, New York City, argued for continuing standard sJIA biologic therapies, at least in some patients.
Dr. Karen Onel
Evolution of Treatment Options in sJIA
Both speakers emphasized the devastating nature and intense morbidity of untreated or inadequately treated sJIA. Dr. Onel pointed out that drugs used to treat the condition in the 20th and early 21st century were largely ineffective, and many were quite toxic.
But the advent of IL-1 and IL-6 inhibitors dramatically improved the situation for patients with sJIA. “When anakinra came out, it was nothing short of miraculous,” shared Dr. Cron. The biologics targeting IL-1 (anakinra, canakinumab and rilonacept) and IL-6 (tocilizumab) were well tolerated and highly effective, and clinicians quickly adopted them.
Current ACR guidelines recommend IL-1 or IL-6 inhibitors as first-line agents for sJIA patients, in both those who have or don’t have concurrent macrophage activation syndrome (MAS). Other biologics such as TNF inhibitors or conventional synthetic disease-modifying anti-rheumatic drugs can be utilized in patients with residual arthritis on IL-1 or IL-6 inhibitors. Current ACR guidelines do not directly speak to the management of sJIA patients on IL-1 or IL-6 inhibitors who develop lung disease.1
Lung Disease in sJIA & Biologic Cessation
The lack of complete understanding about the etiology of sJIA-related lung disease is part of what makes management decisions challenging. We must question whether IL-1/IL-6 cessation is appropriate in sJIA patients who develop lung disease.
Before the advent of IL-1 and IL-6 inhibitors, lung disease related to sJIA was generally described as sequela, such as pleuritis or pleural effusion, although the literature reflected a few isolated case reports of other types of lung disease. However, in the years after the introduction of IL-1 and IL-6 inhibitors, studies have indicated increasing numbers of patients with sJIA-related lung disease, with lung diagnoses rarely reported previously, including pulmonary arterial hypertension, interstitial lung disease and pulmonary alveolar proteinosis. Although still considered rare, when it occurs the disease is often fatal.2,3
Dr. Cron emphasized the risk factors that researchers have uncovered for sJIA-related lung disease, urging some type of lung screening for these high-risk patients. These factors include severe sJIA presentation, young age of onset, trisomy 21 and certain allelic variants of the HLA-DRB1 gene.2-4
One theory is that sJIA-related lung disease may represent a kind of delayed hypersensitivity response to IL-1 or IL-6 blockers, a “drug reaction with eosinophilia and systemic symptoms” (DRESS) which can cause hematologic manifestations, rash and the involvement of various internal organs. The theory is that IL-1 and IL-6 antagonists might impact antigen presentation to CD4+ T cells in a manner that is influenced by inherited HLA variations, ultimately leading to a DRESS-type response.4,5
Cessation of IL-1/IL-6 in sJIA-Related Lung Disease
“If these [IL-1 and IL-6] drugs are causing this, we probably shouldn’t be continuing them [in sJIA patients with signs of lung disease],” contended Dr. Cron.
However, countervailing pathophysiological theories, such as the cytokine plasticity hypothesis, have also been proposed.5
Dr. Onel also pointed out that although many patients with sJIA-related lung disease have had exposure to IL-1 or IL-6 biologics, that is not the case for all. She also emphasized the fact that not everyone with such lung disease possesses the implicated alleles, and conversely, patients can have the allele and sJIA but never present with lung symptoms. Dr. Onel cited studies from parts of the world where biologics are less readily available, showing that some children with sJIA not on these drugs do develop lung disease.
Dr. Onel also explored sJIA complicated by MAS, a form of secondary hemophagocytic lymphohistiocytosis (HLH) which can cause cytokine storm and sometimes organ failure. Lung involvement is common in patients with HLH, whether from an autoimmune disease like sJIA or another indication like cancer or infection, and lung involvement is more common in patients with sJIA who have MAS than in those who do not.6
With respect to the underlying physiology of lung disease in sJIA, Dr. Onel countered, “Is it DRESS? Is it immune plasticity? I would argue that we really have no idea. We have to think about the clinical decisions that we make and decide whether they’re based on a kind of gestalt or whether they’re based on fact.”
Dr. Onel also emphasized the deficiencies of other treatment options, should physicians opt to remove IL-1 or IL-6 blockers in their patients who develop lung involvement. For example, she noted that although some clinicians might move to JAK inhibitors in such a setting, she has reservations related to the lack of studies in this application, and she has concerns about potential side effects documented in adults, such as cardiovascular events and cancer. “What are the alternatives?” she asked. “Do we really want to go back to the old days? I would say that there’s no turning back.”
Dr. Onel also noted anecdotally that she has never seen a patient with sJIA-related lung disease who had their sJIA truly well controlled before they developed lung symptoms. She added, “If someone is doing well on a biologic, I would say stopping treatment is a real problem.”
To counter, Dr. Cron underscored a recently published article which may help convince some people of the value of treatment cessation. The group retrospectively evaluated outcomes after physicians opted to stop or not stop an IL-1 or IL-6 inhibitor after an sJIA patient had an apparent DRESS response (the large majority of whom also had lung involvement).7
“It’s not a randomized trial, but it is data: If you develop lung disease in the setting of systemic JIA and you stop the offending agent—either the IL-1 or IL-6 inhibitor—you markedly improve survival,” said Dr. Cron. However, a single study of this nature cannot be definitive; although the two groups by chance ended up fairly balanced for risk factors, potential issues such as confounding by indication may still be at play.
In the end, the evidence may not yet definitively tip one way or the other, hence the need for a debate. After the talk, a poll revealed that audience members were evenly divided about cessation of IL-1/IL-6 inhibitors in this setting.
“We have to be cautious in both directions,” said Dr. Onel. “Like many questions in rheumatology, the answer is probably, ‘It depends.'”
Ruth Jessen Hickman, MD, a graduate of the Indiana University School of Medicine, is a medical and science writer in Bloomington, Ind.
References
- Onel KB, Horton DB, Lovell DJ, et al. 2021 American College of Rheumatology guideline for the treatment of juvenile idiopathic arthritis: Therapeutic approaches for oligoarthritis, temporomandibular joint arthritis, and systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2022;74(4):521–537.
- Saper VE, Chen G, Deutsch GH, et al. Emergent high fatality lung disease in systemic juvenile arthritis. Ann Rheum Dis. 2019;78(12):1722–1731.
- Schulert GS, Yasin S, Carey B, et al. Systemic juvenile idiopathic arthritis-associated lung disease: Characterization and risk factors. Arthritis Rheumatol. 2019;71(11):1943–1954. doi:10.1002/art.41073
- Saper VE, Ombrello MJ, Tremoulet AH, et al. Severe delayed hypersensitivity reactions to IL-1 and IL-6 inhibitors link to common HLA-DRB1*15 alleles. Ann Rheum Dis. 2022;81(3):406–415.
- Binstadt BA, Nigrovic PA. The conundrum of lung disease and drug hypersensitivity-like reactions in systemic juvenile idiopathic arthritis. Arthritis Rheumatol. 2022;74(7):1122–1131.
- Seguin A, Galicier L, Boutboul D, Lemiale V, Azoulay E. Pulmonary involvement in patients with hemophagocytic lymphohistiocytosis. Chest. 2016;149(5):1294–1301.
- Saper VE, Tian L, Verstegen RHJ, et al. Interleukin (IL)-1/IL-6-inhibitor-associated drug reaction with eosinophilia and systemic symptoms (DReSS) in systemic inflammatory illnesses. J Allergy Clin Immunol Pract. 2024;12(11):2996-3013.e7.
