Systemic JIA subset linked to IL-18 may be at increased risk for cytokine storm
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A subset of patients with systemic juvenile idiopathic arthritis with elevated interleukin-18 markers could face “increased risk” for macrophage activation syndrome, according to a speaker at the Basic and Clinical Immunology for the Busy Clinician symposium.
“The problem is that the whole area [of autoinflammatory syndromes] has been evolving over time,” R. John Looney, MD, Stephen I. Rosenfeld Professor of Allergy and Clinical Immunology at the University of Rochester, told attendees. “It started out with these very characteristic, periodic febrile illnesses, particularly Familial Mediterranean Fever, Hyper IgD Syndrome, TNF-receptor-associated Periodic Syndrome. These would have very characteristic episodic fevers of various durations — Familial Mediterranean Fever the shortest and TNF-receptor-associated Periodic Syndrome the longest — and skin rashes as well.”
Looney noted that it took several years to finally identify the genes behind these common autoinflammatory diseases — Familial Mediterranean Fever in 1997 and Hyper IgD Syndrome, TNF-receptor-associated Periodic Syndrome in 1999. However, after the Human Genome Project finished in 2003, identifying the genes driving inflammation became significantly easier.
“The Genomic Revolution made all the studies of genes much faster,” he said. “Very rapidly we got a whole number of monogenic autoinflammatory diseases. Now, the genes involved in inflammation are just becoming more and more prevalent in the literature.”
With respect to rheumatology, the most common presentation of autoinflammatory diseases comes in the form of systemic-onset JIA or Still’s disease.
Looney noted that “although it’s not a terribly common disease, it’s not unusual [with] this very characteristic clinical picture of patients spiking fevers, [salmon-colored] rash that may come and go very quickly, arthritis, serositis, tremendous inflammation in peripheral blood and often very high leukocyte counts.”
In their study published in the Journal of Experimental Medicine in 2005, Pascual and colleagues determined that IL-1 was a significant mediator of the inflammatory cascade that underlies systemic-onset JIA and that this cytokine represented a key therapeutic target in this disease.
“[This study] provided very solid evidence that Still’s disease and systemic onset juvenile idiopathic arthritis are a form of autoinflammatory disease,” Looney said.
However, rarely are answers so straightforward when working with autoinflammatory diseases, as Looney also noted “that there may be two different types of systemic JIA.”
In a 2013 study in Cytokine, Shimuzu and colleagues observed that two different groups of patients with systemic JIA, who exhibited differing IL-6- and IL-18-dominant levels, could be characterized by distinct clinical features.
“If you plot IL-18 levels vs. IL-6 levels, you come out with two different groupings, which seem to have a difference in production of these two cytokines,” Looney said. “That wouldn’t be particularly interesting except that if you look at the clinical characteristics of these two groups, the IL-6 dominant group had a lot more arthritis and the IL-18 had all of the macrophage activation syndrome.”
In discussing how to treat macrophage activation syndrome in systemic JIA, Looney noted that the “the literature is still young, and we probably have a lot to learn.”
Although inhibiting both IL-1 and IL-6 — “especially the anti-IL-6 receptor” — is very effective in patients with systemic JIA, patients on both of these treatments were still associated with macrophage activation “and it doesn’t seem to be much different than if they weren’t on those treatments, which is peculiar,” according to Looney.
“It’s also peculiar because these same inhibitors have been used to treat macrophage activation syndrome in systemic JIA, sometimes at much higher doses,” he said. “Maybe that explains some of the difference between maintenance therapy and therapy when you have cytokine storm, but I’m not sure that’s the whole picture.”
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Looney RJ. Autoinflammatory Syndromes and Cytokine Storm. Presented at Basic and Clinical Immunology for the Busy Clinician; Feb. 5-6, 2021. (virtual meeting).
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