IL-1, IL-6 inhibitors trigger eosinophilia, systemic symptoms in Still's disease subset
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A subset of patients with Still’s disease develop drug reactions with eosinophilia and systemic symptoms to interleukin-1 and IL-6 inhibitors, with strong associations among those with common HLA-DRB1*15 haplotypes, according to data.
“Subsequent to a change in treatment of Still’s disease, a new high fatality parenchymal lung disease has occurred in some patients,” Vivian E. Saper, MD, of Stanford University, told Healio Rheumatology.
“Along with my colleagues, particularly Drs. Mellins, Hollenbach, and Ombrello, we report that recently introduced medications inhibiting IL-1 or IL-6, typically very effective in treating this condition in most patients, in a subset of patients, are each implicated in a severe delayed drug reaction, which can include the lung disease,” she added. “Moreover, 80% of patients studied who suffered this severe delayed drug reaction had a particular HLA allele.”
To analyze the clinical features of drug reactions with eosinophilia and systemic symptoms (DRESS) in patients with Still’s disease, and to examine HLA alleles as potential inherited risk factors for DRESS with these medications, Saper and colleagues conducted a case/control study. The researchers recruited 66 patients with Still’s disease and features of DRESS in reaction to anakinra (Kineret, Sobi), canakinumab (Ilaris, Novartis), rilonacept (Arcalyst, Regeneron) and/or tocilizumab (Actemra, Genentech), and 65 patients with Still’s disease who were tolerant of the same drugs, from a total of 37 centers in the United States, Canada and Australia.
In addition, the researchers examined data from 550 additional patients with Still’s disease from the International Childhood Arthritis Genetics Consortium (INCHARGE) sJIA database, and ancestry-matched them to 3,279 individuals in the INCHARGE healthy control population, to compare for HLA allele frequencies. HLA associations were also compared between the patients with and without drug reactions, as well as among 19 others with Kawasaki disease from a phase ½a trial of anakinra.
According to the researchers, who published their findings in the Annals of the Rheumatic Diseases, DRESS features in patients with Still’s disease included eosinophilia in 89% of cases, AST-ALT elevation in 75%, and non-evanescent rash in 95% cases, 88% of which involved the face. Macrophage activation syndrome (MAS) occurred during treatment in 64% of DRESS cases in patients with Still’s disease, compared with 3% among drug-tolerant patients with the disease (P = 1.2x10–14).
In addition, Saper and colleagues noted “striking enrichment” for HLA-DRB1*15 haplotypes in DRESS cases among patients with Still’s disease, compared with INCHARGE controls with Still’s disease (P = 7.5x10–13) as well as self-identified, ancestry-matched controls with the disease (P = 6.3x10–10). Among the Kawasaki disease cohort, DRB1*15:01 was present only in those with suspected anakinra reactions.
“Pre-determination of HLA and careful consideration of this adverse reaction can alert the clinician to consider an alternate treatment approach,” Saper said. “Data presented show if any of eosinophilia, macrophage activation syndrome, a non-evanescent rash unusual for Still’s or elevated liver enzymes occur during drug treatment, a severe delayed drug reaction may be present.
“Drug reaction features can be asynchronous and discontinuous allowing this type of drug reaction to hide in plain sight,” she added. “Although this has been uncovered within Still’s, adverse reactions to these inhibitors of IL-1 and IL-6 may be hiding in other conditions where these medications are used as treatment.”
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