An overwhelming activation of cytotoxic T cells and well-differentiated macrophages leading to systemic overload of inflammatory mediators characterizes the so-called
macrophage activation syndrome (MAS); this potentially life-threatening clinical entity may derive from several genetic defects involved in granule-mediated cytotoxicity but has been largely observed in patients with
juvenile idiopathic arthritis, many rheumatologic diseases,
infections, and
malignancies. The occurrence of MAS in the natural history or as the revealing clue of monogenic autoinflammatory disorders (
AIDs), rare conditions caused by disrupted innate immunity pathways with overblown release of proinflammatory
cytokines, has been only reported in few isolated patients with
cryopyrin-associated periodic syndrome,
mevalonate kinase deficiency,
familial Mediterranean fever, and
tumor necrosis factor receptor-associated periodic syndrome since 2001. All these patients displayed various clinical, laboratory, and histopathologic features of MAS and have often required
intensive care support. Only one patient has died due to MAS. Defective cytotoxic cell function was documented in a minority of patients.
Corticosteroids were the first-line treatment, but
anakinra was clinically effective in three refractory cases. Even if MAS and
AIDs share multiple clinical features as well as heterogeneous pathogenetic scenes and a potential response to anti-interleukin-1 targeted
therapies, MAS requires a prompt specific recognition in the course of
AIDs due to its profound severity and high mortality rate.