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The interleukin (IL)-1 receptor antagonist anakinra (Kineret) showed promise in critically ill children who develop the often-lethal condition known as secondary hemophagocytic lymphohistiocytosis (sHLH)/macrophage activation syndrome (MAS), a retrospective single-center study found.
However, the benefits in this analysis, which included 44 patients, were seen only among those whose underlying disease was autoimmune or rheumatic, according to Randy Q. Cron, MD, PhD, and colleagues from the University of Alabama at Birmingham School of Medicine.
For instance, there were no deaths among the 13 patients with systemic juvenile idiopathic arthritis (sJIA), whereas all three patients with an underlying hematologic malignancy (leukemia) died, giving survival rates of 100% vs 0% (P=0.006), the investigators reported online in Arthritis & Rheumatology.
The disorder referred to as sHLH is characterized by a "cytokine storm" with release of many proinflammatory cytokines including IL-1, IL-6, IL-12, and IL-18, as well as interferon gamma and tumor necrosis factor. Disease features include unremitting high fever, hepatosplenomegaly, central nervous system manifestations, and thrombocytopenia.
When associated with rheumatic diseases such as sJIA, the condition has generally been referred to as MAS, and both sHLH and MAS have been linked with mutations in the lymphocyte cytolytic pathway genes. Infections, most often with herpes viruses, have been implicated as triggers.
Anakinra has shown success in various conditions, including sJIA and sJIA-related MAS, but a potential role in non-sJIA sHLH has been less clear.
Therefore, to evaluate the efficacy and safety of this agent in patients with sHLH/MAS and a wide range of underlying diseases, Cron's group conducted a chart review of patients treated with anakinra at their center from 2008 to 2016.
The majority of the 44 patients were female, and their mean age was 10.3.
Other than sJIA and leukemia, the underlying diseases were systemic lupus erythematosus in five patients, mixed connective tissue disease in three, gastroparesis in three, uveitis with spondyloarthritis in two, and other autoimmune conditions such as Sjogren's disease, vasculitis, or Crohn's disease in five, and unknown in 10. Infections were identified in six patients without an identified underlying disorder and in 13 of those with diagnosed underlying diseases.
Almost all patients had fevers, 30% had hepatomegaly, and 34% had splenomegaly. Leukopenia was present in 55%, anemia in 68%, and thrombocytopenia in 71%.
In the 35 patients who underwent bone marrow biopsy, hemophagocytosis was identified in 40%.
Genetic testing for HLH-associated genes was performed for 38 patients, with heterozygous mutations detected in 34%. The mutation was an amino acid substitution or splice variant in UNC13D in six patients, one of whom died. In addition, five patients had one or more mutations in STXBP2, four of whom died.
Analysis of the baseline characteristics found that mortality was significantly increased among those with thrombocytopenia, with platelet counts below 100,000/µL (100% vs 59%, P=0.008) and those with an STXBP2 mutation (80% vs 20%, P=0.012).
Thrombocytopenia at any time during the hospital stay was also associated with worse mortality. "Thus, thrombocytopenia in the setting of an inflammatory state that often leads to thrombocytosis is a poor prognostic finding," Cron and colleagues observed.
The overall mortality was 27%, and median hospital stay was 15 days. Causes of death included shock in five patients and multi-organ system failure in six. Six patients also had systemic infections, with five having positive cultures for fungi.
Among the 12 patients who died, 11 were on concurrent immunosuppressives including corticosteroids.
"Not surprisingly," the investigators said, starting anakinra early (by day 5) was associated with lower mortality.
An additional outcome that was associated with improved survival was a decrease in the serum ferritin level within 15 days of hospitalization, which was seen in 85% of those who survived compared with only 35% of those who died (P=0.0202). Starting anakinra within 5 days of diagnosis also was associated with a 90% decline in ferritin level compared with a 54% decrease when anakinra was started later.
Regarding the genetic mutations, the authors wrote, "STXBP2 is important for apical trafficking in epithelial cells as it is necessary for fusion of vesicles with the plasma membrane, and lack of STXBP2 function results in villous atrophy and intestinal atresia critical for gut barrier protection." This mutation therefore may place patients at risk for enteropathy and sepsis, the team suggested.
"Based on these results, we recommend the use of anakinra as a safe and promising treatment for non-malignancy-related sHLH/MAS patients, especially when given early in the disease course," Cron and co-authors concluded.
Limitations of the study, the team noted, were the retrospective design and lack of treatment controls.
The researchers added that a randomized, placebo-controlled study of anakinra for pediatric and adult sHLH/MAS is currently underway.
The authors reported financial relationships with SOBI (Swedish Orphan Biovitrum).