Macrophage Activation Syndrome Treatment & Management

Updated: Nov 21, 2018
  • Author: Angelo Ravelli, MD; Chief Editor: Lawrence K Jung, MD  more...
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Treatment

Medical Care

The treatment of macrophage activation syndrome (MAS) is traditionally based on the parenteral administration of high doses of corticosteroids. However, some fatalities have been reported, even among patients treated with massive doses of corticosteroids. [2, 4, 17] The administration of high-dose intravenous immunoglobulins, cyclophosphamide, plasma exchange, and etoposide has provided conflicting results.

The use of cyclosporin A (CyA) was considered based on its proven benefit in the management of familial hemophagocytic lymphohistiocytosis (FHLH). CyA was found to be effective in severe or corticosteroid-resistant macrophage activation syndrome. [21, 44, 45] In some patients, this drug exerted a “switch-off” effect on the disease process, leading to quick disappearance of fever and improvement of laboratory abnormalities within 12-24 hours. [21] Because of the distinctive efficacy of CyA, some authors have proposed using this drug as the first-line treatment for macrophage activation syndrome occurring in childhood systemic inflammatory disorders. [21, 44]

Increased production of tumor necrosis factor (TNF) in the acute phase of macrophage activation syndrome has suggested the use of TNF-α inhibitors as potential therapeutic agents. However, although Prahalad et al reported the efficacy of etanercept in a boy who developed macrophage activation syndrome, [46] other investigators have observed the onset of macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis (SJIA) who were treated with etanercept. [46, 47] Similarly, Lurati et al reported the onset of macrophage activation syndrome in a patient with systemic juvenile idiopathic arthritis during treatment with the recombinant interleukin (IL)-1 receptor–antagonist anakinra. [48] Macrophage activation syndrome has also been reported in a patient with adult-onset Still disease who was receiving anakinra. [49]

Although the association between macrophage activation syndrome onset and treatment with etanercept or anakinra may be coincidental and not causal, the above-mentioned observations suggest that inhibition of tumor necrosis factor (TNF) or IL-1 does not prevent macrophage activation syndrome. Moreover, although macrophage activation syndrome–like symptoms are almost completely prevented by elimination of CD8+ T cells or by neutralization of INF-λ in perforin-deficient mice, the animal model of hemophagocytic lymphohistiocytosis (HLH), inhibition of IL-1 or TNF provides only mild alleviation of the symptoms.

Despite these observations, several cases of SJIA-associated macrophage activation syndrome dramatically benefiting from anakinra after inadequate response to corticosteroids and cyclosporin have now been reported. [50, 51, 52, 53, 54, 55] For those severely ill children, IL-1 blockade has been remarkably effective in a relative brief time frame.

Other forms of HLH not associated with rheumatic diseases usually require more aggressive treatment: for instance, children younger than 1 year in whom FHLH is suspected and all patients with severe signs and symptoms are candidates for combination therapy with dexamethasone, cyclosporin A, and etoposide. Etoposide has been shown to improve prognosis for Epstein-Barr virus (EBV)–related HLH; its effectiveness may be explained by inhibition of synthesis of EBV nuclear antigen. Whether HLH therapeutic protocols are suitable for use in children with macrophage activation syndrome associated with rheumatic diseases is unclear.

Despite aggressive treatment, long-term disease-free survival in patients with FHLH can be reached only after stem cell transplantation. [56]

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Consultations

Multiple subspecialists are often needed to manage a patient with macrophage activation syndrome and may include rheumatologist, hematologist/oncologist, infectious disease specialist, intensivist, and others.

A study looked for insights into the heterogeneity of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA) through the analysis of a large patient sample collected in a multinational survey. The study found that patients seen in North America were given biologics more frequently. Patients entered by pediatric hemato-oncologists were treated more commonly with biologics and etoposide, whereas patients seen by pediatric rheumatologists more frequently received cyclosporine. The study underscores the need to establish uniform therapeutic protocols. [57]

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