MAUI, HAWAII (FRONTLINE MEDICAL NEWS) The use of new classification criteria for macrophage activation syndrome specific to systemic juvenile idiopathic arthritis will help to avoid missing patients with the criteria that hematologists have used to diagnose the condition, which they call hemophagocytic lymphohistiocytosis, according to Dr. Anne M. Stevens, a pediatric rheumatologist at the University of Washington, Seattle.

“The problem is, if we try to use the HLH [hemophagocytic lymphohistiocytosis] criteria, we’re going to miss a lot of patients with systemic juvenile idiopathic arthritis–related macrophage activation syndrome, so we’re not going to treat them aggressively and many of them will die,” she said at the 2016 Rheumatology Winter Clinical Symposium.

Indeed, roughly one-third of patients with macrophage activation syndrome (MAS) arising as a complication of systemic juvenile idiopathic arthritis (SJIA) don’t meet the HLH diagnostic criteria. And the mortality of untreated MAS is up to 28%, Dr. Stevens noted.

MAS isn’t a new entity. It has become a more frequent topic of discussion lately because the pathogenesis of this cytokine storm is better understood, and biologic agents addressing the underlying disease mechanisms are in clinical trials. But MAS was first described nearly 40 years ago at a pediatric rheumatology conference in Park City, Utah.

Recently, an international consensus panel convened as a collaboration between the European League Against Rheumatism, the American College of Rheumatology, and the Paediatric Rheumatology International Trials Organisation has developed a new set of classification criteria for MAS complicating SJIA ( Arthritis Rheumatol. 2016 Mar;68[3]:566-76 ).

In a validation study, the criteria had a sensitivity of 73% and a specificity of 99% for the diagnosis.

Under the 2016 criteria, a patient with known or suspected SJIA is classified as having MAS if he or she is febrile, has a serum ferritin level in excess of 684 ng/mL, and meets any two of the following four criteria: a platelet count of 181 x 109/L or less, triglycerides greater than 156 mg/dL, a serum aspartate aminotransferase level in excess of 48 U/L, or a fibrinogen level of 360 mg/dL or lower.

The specific cutoff threshold values for these laboratory measures are mainly of interest for research purposes in assuring appropriate patient enrollment in clinical trials. Practically speaking, it’s time to suspect MAS – a true medical emergency – in a child with SJIA whose fever has become persistent all day every day, rather than the quotidian fever that spikes in the evening characteristic of SJIA, along with hemodynamic instability, altered mental status, a rash, organomegaly, relative or progressive cytopenias, a very high ferritin level, and/or a relatively low or falling erythrocyte sedimentation rate.

A child with MAS superimposed on SJIA will look septic, according to Dr. Stevens. And if the ESR was 75 mm/hr yesterday and has “improved” to 45 mm/hr today, yet the child looks sicker or the other blood parameters are falling, that’s not an encouraging sign.

A very high serum ferritin level in patients with SJIA-related MAS is a red flag for increased mortality risk, as demonstrated in a study by physicians at Seattle Children’s Hospital. They retrospectively looked at 171 patients with a serum ferritin of 1,000 ng/dL and showed that the mortality risk climbed in parallel with the peak ferritin level. Children with a peak serum ferritin greater than 3,000 ng/mL had a 4.3-fold increased risk of mortality and a 2.5-fold greater risk of ICU admission than did those with a ferritin level of 1,000-3,000 ng/mL ( Pediatr Crit Care Med. 2011 Nov;12[6]:e233-6 ).

Based upon these data, Dr. Stevens said she considers a serum ferritin of 1,000 ng/mL or more worthy of immediate attention.

The current standard of care in treating SJIA-related MAS is high-dose pulsed methylprednisolone at 30 mg up to 1 g/kg and IV cyclosporine at 5 mg/kg per day divided into two doses.

“There are good data to show that this will turn around half of affected kids,” according to the pediatric rheumatologist.

Second-line therapy targets interleukin-1: either IV anakinra (Kineret) at 2 mg/kg per day titrated up to 10 mg/kg, or canakinumab (Ilaris) at 4 mg/kg titrated up to 12.5 mg/kg every 4 weeks.

However, the current thinking is that what tips patients with SJIA into MAS is high levels of free interleukin-18. For that reason, several different anti–IL-18 agents are now under study, including tadekinig alfa, an IL-18 binding protein, and rituximab (Rituxan) for patients with Epstein-Barr virus–related MAS.

Dr. Stevens reported having no relevant financial conflicts.


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