The platelet count is still within the laboratory reference range. But yesterday it was much higher. Ferritin is rising, liver tests are worsening, and the patient with Still’s disease looks increasingly ill. Waiting for every result to cross a diagnostic threshold may miss the trajectory that matters.
Macrophage activation syndrome (MAS), within the spectrum of secondary hemophagocytic lymphohistiocytosis (HLH), is a time-sensitive syndrome of systemic hyperinflammation and organ dysfunction. In an unstable patient, recognition, investigation, and treatment must proceed together.
Compare with the patient’s baseline
Active Still’s disease can produce leukocytosis, thrombocytosis, and high fibrinogen. A fall from those elevated values can therefore be concerning before an absolute cytopenia or low fibrinogen appears. Interpret ferritin, blood counts, transaminases, triglycerides, coagulation studies, and fibrinogen serially alongside the examination.
A falling ESR is not necessarily reassurance when fibrinogen is falling and the patient is deteriorating. Persistent fever, altered mental status, bleeding, hepatitis, or evolving organ dysfunction should accelerate assessment. IL-6-directed therapy can modify fever and acute-phase responses, making reliance on a single CRP value especially hazardous.
Use criteria to support judgment
The 2016 MAS classification criteria were developed for systemic JIA. HLH-2004 criteria and the HScore serve different populations and purposes. They can organize evidence, but none should become a requirement to delay action in a rapidly evolving clinical syndrome.
Hemophagocytosis is neither required at the first assessment nor specific when present. A high ferritin concentration is an important clue, not a diagnosis by itself. Consider the whole pattern and the pace of change.
Look for triggers while controlling inflammation
Infection, malignancy, and rheumatic disease may trigger or coexist with HLH/MAS. Finding one contributor does not necessarily exclude another. The EULAR/ACR points to consider emphasize early recognition, investigation for contributing conditions, intervention, and repeated monitoring in parallel.
Coordinate rheumatology, hematology, infectious diseases, and critical care according to the presentation. Obtain appropriate microbiologic and diagnostic samples promptly when feasible, while avoiding unsafe delays in a patient whose organ function is worsening. Treatment of an infection and treatment of hyperinflammation may both be necessary.
Match treatment to the syndrome and its severity
High-dose glucocorticoids remain an important component of Still’s-associated MAS treatment. Anakinra, ciclosporin, and other therapies may be selected by experienced teams according to response, severity, and the underlying process. Management of malignancy-associated HLH or genetic HLH may require a different strategy. This is not a setting for a one-size-fits-all drug sequence.
A current treatment update: US labeling now includes emapalumab for adults and children with HLH/MAS associated with known or suspected Still’s disease when glucocorticoids are inadequate or not tolerated, or when MAS recurs. This is a specific indication, not approval for every form of secondary HLH. The March 2026 prescribing information details infection screening, prophylaxis considerations, surveillance, and infusion risks; specialist teams should use the full label.
Reassess rather than declaring victory from one result
Improvement should be assessed across clinical status, organ function, and serial laboratory findings. A falling ferritin with worsening oxygenation or coagulation is not sufficient reassurance. If the course is atypical or response is inadequate, revisit triggers and competing diagnoses.
Selected patients with severe, recurrent, early-onset, or otherwise suggestive disease may benefit from genetic evaluation. A variant of uncertain significance, or a single variant in a recessive HLH-associated gene, does not by itself establish a genetic diagnosis. Expert interpretation is essential.
The practical priority is to recognize a dangerous change early and mobilize a coordinated response. Criteria can help describe the syndrome; they should not obscure a deteriorating patient.
Keep reading
Sources and further reading
- EULAR/ACR points to consider for early suspected HLH/MAS (2023)
- 2016 classification criteria for MAS complicating systemic JIA
- EULAR/PReS Still’s disease recommendations (2024)
- FDA: Gamifant (emapalumab) prescribing information, revised March 2026
Adapted from Jonathan S. Hausmann’s presentation, “The Management of Still’s and Macrophage Activation Syndrome,” with references and terminology updated for this article. Individual patient cases and slide images have not been reproduced.
This article provides general education, not a diagnosis or an individual treatment plan. Discuss personal medical decisions with your care team.