Continuous infusions of anakinra effectively halts the overactivation of immune and inflammatory responses in adults with a type of secondary hemophagocytic lymphohistiocytosis (HLH) called macrophage activation syndrome (MAS), according to a small study.
These findings support the use of anakinra as an effective therapy for MAS in adulthood, and may help to optimize treatment guidelines for this difficult-to-treat patient population.
The data also suggest that intravenous anakinra may be considered as an approach to manage exacerbated inflammatory responses following COVID-19 infection — a response mainly associated with severe cases.
The study, “Continuous Intravenous Anakinra Infusion to Calm the Cytokine Storm in Macrophage Activation Syndrome,” was published in the journal ACR Open Rheumatology.
HLH is a rare, life-threatening disease caused by an immune system gone awry, where immune cells produce high levels of inflammatory molecules called cytokines — an event known as a “cytokine storm” — that lead to organ failure.
The disease can be inherited through genetic mutations (primary HLH) or triggered by a number of illness-related events (secondary HLH). MAS is a type of secondary HLH associated with an autoimmune or autoinflammatory disease, being most commonly linked to systemic juvenile idiopathic arthritis (sJIA), lupus, and adult-onset Still’s disease.
MAS is characterized by sustained fever, higher-than-normal levels of ferritin — a potential prognostic biomarker for adult secondary HLH — low counts of platelets and red and white blood cells, coagulation problems, and liver dysfunction.
Anakinra, sold as Kineret by Sobi, is an immunosuppressive therapy that works by blocking a cytokine called interleukin-1, thereby reducing inflammation and immune responses. The therapy is approved to treat some autoimmune and autoinflammatory diseases, including rheumatoid arthritis.
While increasing evidence suggests that anakinra can also ease symptoms and improve the survival in people with sJIA and lupus, data on its effects in secondary HLH patients remain limited.
A recent study showed that the therapy is effective in treating children with secondary HLH associated with rheumatic disease, but few studies have reported the use of anakinra in MAS, especially in adults.
A team of researchers have now reported the cases of five adults (four women and one man) with MAS who received anakinra after failing to respond to initial therapy at Regions Hospital, in Saint Paul, Minnesota.
The team retrospectively analyzed the demographic, clinical, and laboratory data of these patients.
The mean age of the patients at diagnosis was 44 years (range 38–64), and four of them had an underlying autoimmune disease — two had lupus, one had adult-onset Still’s disease, and one had undifferentiated connective tissue disease. The remaining patient had no history of autoimmune disease and further analyses did not identify any cancer or infection (two known causes of secondary HLH).
All patients failed to respond to initial immunotherapy, including methylprednisolone, cyclosporine, tocilizumab, intravenous immunoglobulin, and cyclophosphamide.
After their initial therapies proved ineffective, anakinra was given intravenously to three patients and subcutaneously (under-the-skin) to two patients. Due to the worsening of their condition, all patients were given continuous intravenous infusions with rapid dose escalation up to 2,400 mg/day — the dose given in cases of kidney failure.
Data showed that the levels of ferritin and proteins associated with liver damage decreased within the first 48 hours after starting anakinra in four out of five patients, leading to subsequent clinical responses.
Three of these patients continued treatment with anakinra or Ilaris (canakinumab), with no signs of disease relapse to date. The other patient later developed sepsis (organ injury or damage in response to a body-wide infection) and died.
One woman never responded to treatment and died from multi-organ failure and septic shock (a life-threatening condition caused by uncontrolled sepsis).
All patients developed kidney damage and three showed low levels of more than one type of blood cell; it was unclear whether these events were caused by MAS or the high dose of anakinra, the researchers noted.
Three patients developed bacterial infections during their clinical course, two of which were associated with their death (sepsis). The team hypothesized that the development of these infections may be linked to longer periods under high doses of anakinra.
Overall, the team concluded that “continuous intravenous anakinra in a rapidly escalating dose regimen in a [group] of adult MAS patients with unregulated immune activation was successful at reversing cytokine storm when other modalities had failed.”
The team stated that personalized therapeutic approaches to people with MAS and other types of secondary HLH are necessary, and that continuous infusion of anakinra may be an effective therapy for adults with MAS.
“This method for treating cytokine storm should be considered in the current COVID-19 pandemic in the subgroup of patients with severe disease that have a cytokine storm presentation,” the researchers added.