Macrophage activation syndrome (MAS) is a life-threatening complication of rheumatic disease that, for unknown reasons, occurs much more frequently in individuals with systemic juvenile idiopathic arthritis (SJIA) and in those with adult-onset Still disease. Macrophage activation syndrome is characterized by pancytopenia, liver insufficiency, coagulopathy, and neurologic symptoms and is thought to be caused by the activation and uncontrolled proliferation of T lymphocytes and well-differentiated macrophages, leading to widespread haemophagocytosis and cytokine overproduction.

The incidence of MAS is unknown as there is a wide spectrum of clinical manifestations, and episodes may remain unrecognized.

Recent findings in haemophagocytic lymphohistiocytosis, a disease that is clinically similar to MAS, highlight the possible pathogenetic role of a defective function of perforin, a protein involved in the cytolytic processes and control of lymphocyte proliferation.

Primary MAS is the most typical manifestation of rare autosomal-recessively inherited disorders due to several genetic defects involved in granule-mediated cytotoxicity, killing of infected cells and termination of immunologic responses. It has been shown that mutations of the perforin gene (PRF-1,10q21) can explain 20-40% of primary forms of MAS.

Secondary or acquired forms of MAS can break out at any time during the course of a primitive disease and occasionally it might be its presenting manifestation. In cases of acquired MAS no underlying immunologic deficiency can be identified. Acquired forms of MAS are most frequent in children with systemic onset-juvenile idiopathic arthritis: some authors suggest an association rate of 5-10%, and MAS is believed to contribute significantly to mortality rate in this category of juvenile idiopathic arthritis.

Both primary and acquired forms of MAS can be triggered by viral, bacterial, fungal infections, parasitic infestations or specific drug administrations.

Although the clinical features of MAS have been well documented, early diagnosis can be difficult. Measurement of the serum ferritin level may assist in the diagnosis and may be a useful indicator of disease activity, therapy response, and prognosis. The recognition that MAS belongs to the secondary or reactive haemophagocytic syndromes has led to the proposal to rename it according to the contemporary classification of histiocytic disorders.

The principle challenge for treating patients with HLH is making a timely diagnosis. It is also critical to search for and treat underlying triggers of HLH, and institute specific antimicrobial therapy.

Although HLH appears to be a disease of excessive immune activation, the ideal form of immune suppression/anti-inflammatory therapy remains unknown. Although somewhat responsive to corticosteroids and clearly responsive to etoposide or anti-T-cell serotherapy (ATG or alemtuzumab), HLH remains difficult to treat. Generally, HCT is recommended in the case of documented familial HLH, recurrent or progressive disease despite intensive therapy, and CNS involvement.