Macrophage activation syndrome (MAS) is a life-threatening hyper-inflammatory syndrome characterised by excessive activation and proliferation of T lymphocytes and macrophages and a consequent massive production of cytokines, or ‘cytokine storm’. MAS is considered a secondary or acquired form of haemophagocytic lymphohistiocytosis (HLH) and is usually associated with infection (systemic Epstein-Barr virus or cytomegalovirus infections or tuberculosis), malignancy, or rheumatic diseases like systemic lupus erythematosus (SLE).

SLE-MAS can occur both in adult and childhood-onset,^{1 2} at the time of diagnosis of SLE and frequently relapses in adults. There are no validated diagnostic or classification criteria for HLH/MAS in adults. HLH-2004 criteria developed for children are often used but are not sensitive enough to allow early diagnosis. These criteria include fever, splenomegaly, cytopenia affecting at least two lineages (hemoglobin <10 g/dL, platelets <100,000/mm³, neutrophils <1000/mm³), hypertriglyceridaemia (fasting >265 mg/dL) and/or hypofibrinogenemia (<150 mg/dL), haemophagocytosis, hyperferritinemia (N: 500 mg/dL), impaired natural killer cell function and elevated soluble CD25. According to those, the diagnosis of HLH requires the presence of five out of eight criteria. Other biological features of MAS include significant increases of the levels of AST, LDH, CRP, and PCT

In SLE, MAS can mimic a flare of the underlying disease because both entities share some common features, such as fever, lymphadenopathy, and splenomegaly and blood cytopenias. This overlap in clinical presentations can hinder the recognition of incipient MAS and delay the selection of the most appropriate therapeutic approach. Additionally, a differential diagnosis between MAS, infections, and adverse effects of medications should also be considered in SLE. MAS can lead to a multiple organ dysfunction syndrome requiring hospitalization in Intensive Care Unit. Therapeutic regimen is based on high-dose steroids (IV methylprednisolone pulses) often associated with IV cyclophosphamide or etoposide.^{3 4} Other therapies have included ciclosporin, methotrexate, tacrolimus, intravenous immunoglobulin and biologics (rituximab, tocilizumab and anti-interferon gamma) in a very limited number of patients.

Learning objectives

• Diagnose MAS in SLE

• Make differential diagnosis between SLE flare and MAS

• Treat SLE–associated MAS

References

1. Borgia RE, Gerstein M, Levy DM, et al. Features, Treatment, and Outcomes of Macrophage Activation Syndrome in Childhood-Onset Systemic Lupus Erythematosus. Arthritis & Rheumatology 2018;70(4):616–24.

2. Gavand P-E, Serio I, Arnaud L, et al. Clinical spectrum and therapeutic management of systemic lupus erythematosus-associated macrophage activation syndrome: A study of 103 episodes in 89 adult patients. Autoimmunity Reviews 2017;16(7):743–49.

3. Grom AA, Horne A, De Benedetti F. Macrophage activation syndrome in the era of biologic therapy. Nature Reviews Rheumatology 2016;12(5):259–68.

4. La Rosée P, Horne A, Hines M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood 2019;133(23):2465–77.