In acquired cases of macrophage activation syndrome (MAS), the clinical course is usually rapidly progressive with multi-system organ failure often occurring within weeks of the initial diagnosis of the syndrome. This syndrome is caused by dysregulated macrophage-lymphocyte interaction, which leads to uncontrolled proliferation of macrophages and CD8
+ T-cells with up-regulated release of monokines, mainly of the interleukin-1 family (interleukin-1α and 1β and interleukin-18), whereas levels of T-cell–derived cytokines, such as interferon-γ, are much less increased [
12]. Recently, cell-type specific characteristics of ‘immature antigen presenting cells (APC)’ from patients with MAS have been described. It is known that tumours (especially fibroblasts) can express M-CSF, which could influence the development of immature phagocytic APCs [
13]. In our patient, fulminant MAS was present for approximately 3 weeks until the initiation of therapy. The standard definition of HLH requires the presence of at least five of nine clinical criteria. Our patient fulfilled seven of these criteria (Table
2). Additionally, we could find an extramedullary manifestation of MAS, namely a proliferative (Ki-67-positive) histiocytic cell infiltrate in both elbows of the patient. Typically in the acute phase of the cytokine storm, lymphohistiocytic infiltrates can be found in the spleen, lymph nodes and bone marrow [
5]. A CD1a staining of the cubital veins remained negative, thus making the diagnosis of Langerhans-cell histiocytosis unlikely. In the absence of a clinically apparent malignancy, in addition to MAS, the differential diagnosis for fever with splenomegaly, liver failure and bilaterally enlarged lymph nodes includes premalignant, inflammatory, infectious, genetic and toxic causes. All of these could be ruled out on the basis of the history and laboratory studies. Acute EBV and CMV infections are associated with fever, pharyngitis, lymphadenopathy and fatigue and would likely have been self-limited. The differential diagnosis of sarcoidosis was mainly ruled out because no granulomas could be found in any of the biopsies. Furthermore, the bone marrow did not show any premalignant, infiltrative or infectious processes.
Several treatment options have been reported in the literature for MAS. A treatment protocol from the Histiocyte Society recommends a therapeutic regimen of etoposide, dexamethasone and cyclosporine [
14]. In other cases, high-dose steroids, cyclosporine, antihuman thymocyte globulin (ATG), intravenous immune globulin (IVIG), plasma exchange and allogeneic bone marrow transplantation have been described. Recently, treatment with an IL-1 beta receptor antagonist (anakinra) was successful in several cases of severe paediatric rheumatic disease-associated MAS [
15,
16]. It can be speculated that other immunomodulatory therapies (alemtuzumab, infliximab, daclizumab, selective IL-1 and IL-6 antagonists) might influence the course of the disease beneficially, but clinical trials remain almost impossible due to the rare occurrence of the disease.
In summary, we describe the first patient with macrophage activation syndrome (MAS) and a history of an inflammatory myofibroblastic tumour, which could be controlled by immunosuppressive therapy including steroids and cyclosporine.