Fresh Insights into Red Flags for MAS in sJIA

Minoia F, Davì S, Horne AC, et al.  Clinical features, treatment and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis A multinational, multicenter study of 362 patients.Arthritis & Rheumatism (2014) Accepted Manuscript. doi: 10.1002/art.38802

The potentially deadly complication of macrophage activation syndrome (MAS) can emerge as prolonged high fever and soaring ferritin and liver enzymes shortly after or even concurrently with a diagnosis of systemic juvenile idiopathic arthritis (sJIA), a new international study shows.

In the multi-center retrospective analysis of records for 362 children with sJIA from 33 countries, the average age at sJIA onset was five years and the median disease duration was four months after onset of MAS.

In 22% of these children, MAS was diagnosed simultaneously with sJIA. They tended to be younger and to have more CNS involvement than others in the study.

MAS is an out-of-control immune response with rapid activation and expansion of T-cells and macrophages, leading to extreme cytokine overproduction and hemophagocytosis. It’s seen in 10% of sJIA cases, and may be present subclinically in three to four times as many.

Because the condition is potentially fatal (8% of this study cohort died of MAS), swift diagnosis and treatment are essential. However, while there are preliminary diagnostic criteria for MAS in sJIA, no single clinical or laboratory factor is sufficient to establish a definite diagnosis.

It is easy to mistake MAS for sJIA flares and sepsis-like syndromes that can  produce high fever.  It also resembles a cluster of disorders known as hemophagocytic lymphohistiocytosis (HLH). So these researchers tracked changes in laboratory values and assessed other clinical signs associated with MAS.

Among the study cohort, 96% of those with MAS presented with protracted high fever, 70% with an enlarged liver, and 90% had abnormal levels of ferritin, liver transaminases, platelets, lactate dehydrogenase, triglycerides, and D-dimer at MAS diagnosis.

The greatest change was in ferritin levels, which spiked by 556% from pre-MAS visits. The normal range for ferritin is 18-300 ng/ml. In children with MAS, median ferritin pre-diagnosis was 900; at diagnosis the median was above 8,000 ng/ml. Extreme hyperferritinemia, a feature of MAS, can itself be life-threatening.

The liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT) soared by 346% and 325%, respectively.

For more than half of the children, MAS arose during active disease or a flare. More than a third showed signs of an infectious trigger, most commonly Epstein-Barr virus (EBV).

Central nervous system (CNS) involvemen, reported in 35% of the group, ranged from seizures to lethargy, irritability, headache, and coma. Around 20% of the children had hemorrhages.

Most patients (78%) were treated by a pediatric rheumatologist. Almost all received corticosteroids, most often intravenously. Two-thirds were given cyclosporine. Around a third (n=82) required admission to intensive care, and 28 children died of the condition.

These outcomes in MAS underscore the importance of well-established diagnostic criteria and the need for new therapies “that target more precisely its pathogenetic pathways,” the researchers conclude.