Introduction

Macrophage activation syndrome (MAS), also referred to as secondary hemophagocytic lymphohistiocytosis (HLH), is a rare life-threatening complication of rheumatologic diseases. It is observed most commonly in systemic juvenile idiopathic arthritis (sJIA) and its adult equivalent, adult-onset Still disease (AOSD) [1,2,3]. It is also encountered in other rheumatologic diseases, mainly systemic lupus erythematosus (SLE) and Kawasaki disease [4,5,6]. It is estimated that approximately 10% of children with sJIA develop overt MAS, but apparently up to 40% of cases have a milder, often subclinical form, of the syndrome [7, 8]. In adults, however, the syndrome is much less common. MAS is characterized by a dysfunctional immune response that leads to exaggerated expansion and activation of cytotoxic cells with hypersecretion of proinflammatory cytokines, which eventually result in hematologic alteration and organ damage [9,10,11,12,13]. The clinical presentation of MAS is usually acute and dramatic, with rapid development of multi-organ failure. Therefore, prompt recognition of this syndrome and immediate therapeutic intervention are imperative. Fever is the main clinical manifestation of MAS. Additional clinical findings are hepatosplenomegaly, generalized lymphadenopathy, central nervous system (CNS) dysfunction and hemorrhagic manifestations. Cardiac, pulmonary and renal involvement are seen in the most severe cases, usually resulting in a fatal outcome [14]. Typical laboratory features in MAS are pancytopenia, elevated liver enzymes, hypofibrinogenemia, hypertriglyceridemia, and markedly elevated ferritin levels [15]. Hemophagocytosis identified in the bone marrow or in other tissues of the reticuloendothelial system is a characteristic feature of MAS. However, hemophagocytosis is observed in approximately 60% of the patients only and, therefore, its absence does not exclude the diagnosis of MAS [16]. A couple of sets of diagnostic and classification criteria are used in order to identify MAS. The HLH-2004 criteria for MAS are widely used and are termed the revised diagnostic guidelines for HLH. They are established of either a molecular diagnosis consistent with HLH or fulfillment of five out of eight clinical and laboratory diagnostic criteria [11]. Since no controlled studies on the treatment of MAS are available, the management of this syndrome is mainly empiric and based on small case series, mainly consisting of children [17,18,19,20,21,22]. Data regarding the clinical characteristics, treatment and prognosis of MAS in adults are scarce. Therefore, we described in detail the clinical course, treatment and outcome of 7 cases of MAS complicating rheumatologic diseases in adults in our medical center and reviewed the literature for previous cases of adult patients with MAS.

Patients and methods

In order to identify and characterize adult MAS patients in our institution we performed a retrospective search for all patients with ferritin levels measured above 1000 ng/ml in the Chaim Sheba Medical Center between the years 2007 and 2017. Among these patients, we retrieved those diagnosed with MAS. In addition, using electronic medical records, we performed a search for ICD-9 codes of both MAS and hemophagocytic syndrome. Adult patients with autoimmune/rheumatologic diseases were listed in our cohort as presenting with MAS if they fulfilled a definite diagnosis of MAS according to the HLH-2004 criteria [11] or a probable diagnosis due to lack of all criteria needed yet with a very high level of clinical suspicion. Five of eight of the following criteria must be fulfilled for diagnosis of MAS: fever, splenomegaly, hypertriglyceridemia, bicytopenia, hemophagocytosis, low/absent NK-cell activity, hyperferritinemia and high soluble IL-2 receptor levels.

Detailed information regarding the clinical course of the disease was collected from the medical files and recorded. It included demographic findings, background diseases, clinical and laboratory presentation, treatment and outcome of all patients. The study was approved by the Sheba Medical Center review board (1/2017). All patients gave their informed consent to participate in the study. For the patients who deceased, consent for participation was given from the next to kin.

Literature review

The available literature in english was reviewed the literature for cases of MAS among adults. We searched the MEDLINE/PubMed and Scopus databases until 2018 for the following keywords: hemophagocytosis, macrophage activation syndrome, hemophagocytic syndrome, and secondary hemophagocytic lymphohistiocytosis. We excluded cases of pediatric population (age < 18 years), and cases not fulfilling criteria for MAS.

Statistical analysis

Data were analyzed using the Statistical Package for the Social Sciences (IBM SPSS statistics) software version 21.0. Continuous variables were expressed as medians and ranges. Categorical variables were expressed as frequencies (percentage).

Results

We identified seven patients with MAS complicating rheumatologic diseases (five females and two males). The median age of diagnosis was 32 (range 26–57) years. The median follow-up was 30 months (range 6.95–36.5) months. The underlying rheumatologic disease was AOSD in three patients, sJIA in two patients, SLE in one patient, and systemic vasculitis in one patient. Four patients developed MAS concurrently with the clinical development of the rheumatologic disease (Table 1). The main clinical and laboratory features of the patients were fever, lymphadenopathy, splenomegaly, leukocytosis, elevated liver enzymes and bictyopenia/pancytopenia (Table 2). Median ferritin levels of the patients were 33,607 (range 1428–345,891) ng/ml. Median triglyceride levels were 325 (range 225–1726) mg/dl. Other laboratory characteristics are presented in Table 3. All the patients were treated with systemic corticosteroids. Five patients were treated with cyclosporine A (CSA), one patient was treated with anakinra, two patients were treated with tocilizumab, two patients were treated methotrexate (MTX), one patient was treated with anti-tumor necrosis factor (TNF)-α, one patient was treated with etoposide (VP-16) and one patient was treated with intravenous immune globulin (IVIG). Two patients deceased during the hospitalization. One of them had AOSD which presented initially 12 years before his admission and had an cyclic disease pattern. During his hospitalization, he received corticosteroid treatment and CSA with partial improvement, but developed several bouts of sepsis and eventually multi-organ failure. The other patient that deceased had a history of several months of leukocytoclastic vasculitis. She presented with a clinical picture compatible with systemic vasculitis. She was treated with corticosteroids with no response and developed multi-organ failure several days after her admission. Five patients survived and were in remission with a median follow-up time of 30 (range 6.95–36.5) months (Table 4).

Table 1 Baseline medical background and demographics of patients with macrophage activation syndrome
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Table 2 Clinical characteristics of patients with macrophage activation syndrome
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Table 3 Laboratory characteristics of patients with macrophage activation syndrome
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Table 4 Treatment and outcome of patients with macrophage activation syndrome
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Literature review

Our literature review identified 92 cases of MAS complicating rheumatologic diseases [3, 5, 17, 23,24,25,26,27,28,29,30,31,32,33,34]. The main underlying diseases were AOSD (79%) and SLE (16%). MAS developed concurrently with the underlying rheumatologic disease in 27% of the patients, and mortality rate was 33%. Most of the patients were treated with glucocorticoids (93%). The most common treatments were IVIG (28%) and CSA (15%) (Table 5).

Table 5 Underlying rheumatologic disease, treatment and outcome of patients with macrophage activation syndrome—study cohort and literature cohort
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Discussion

MAS complicating rheumatologic diseases is observed mainly in children, occurring in up to 40% of patients with sJIA [7, 8]. This syndrome is much less common in adults, where it occurs mainly among patients with AOSD [1,2,3]. In light of the rarity of MAS in adults, no randomized control studies assessing the management of this syndrome exist. Data regarding the clinical course, management and outcome of patients with MAS are limited. In our study, we identified seven adult patients with MAS over a period of 11 years, confirming the low prevalence of this syndrome. In our study, the underlying rheumatologic disease was AOSD in three patients, sJIA in two patients, SLE in one patient and systemic vasculitis in one patient. In most previous case series and case reports of patients with MAS, AOSD was the underlying rheumatologic disease [3, 5, 17, 23,24,25,26,27,28,29,30,31,32,33,34]. However, MAS has been observed in other rheumatologic diseases in adults, including SLE, rheumatoid arthritis (RA) and inflammatory myositis [5, 31,32,33]. The prevalence of MAS in AOSD patients in previous studies ranged from 3.2 to 19.3%. The presence of lymphadenopathy, abdominal pain, markedly elevated ferritin levels and high systemic score values were associated with MAS occurrence in AOSD patients [3, 17, 26, 27, 30]. In our study four of seven patients developed MAS concurrently with the diagnosis of the rheumatologic disease. This finding is in line with findings in previous studies, which demonstrated a high rate of concurrent appearance of MAS and the underlying rheumatologic disease, particularly AOSD [3, 17, 26, 27, 30]. These findings underscore the diagnostic challenge of MAS, as it may mimic a wide range of infectious, malignant and inflammatory diseases. Prompt diagnosis of MAS is particularly challenging when it presents concurrently with the underlying rheumatologic disease. In our study, five patients underwent bone marrow biopsy, and in none of these cases was hemophagocytosis observed. Previous studies have demonstrated a rate of 43–94% of hemophagocytisis among adult MAS patients, the great majority of whom consisted of patients with AOSD [3, 7, 26, 27, 30]. The difference between the findings in our study and previous studies may be explained by the fact that in our cohort only three patients had AOSD, which is the main rheumatologic disease associated with MAS. The rate of hemophagocytosis in MAS secondary to other rheumatologic disease is not well established, since the rarity of this syndrome in adults without AOSD. In addition, it is possible that some of the patients had hemophagocytosis in other hematopoietic tissues, namely the liver and lymph nodes, which were not examined in most of our patients. It should be noted that the diagnosis of MAS is based on a combination of clinical and laboratory criteria [11]. Since MAS is often a rapidly progressive life-threating disease, fulfillment of these diagnostic criteria is not always required to initiate treatment. Specifically, treatment of MAS should not be delayed awaiting results of bone marrow results or specialized immunologic tests. The clinical and laboratory features of MAS are nonspecific. Elevated ferritin is one of the diagnostic criteria for MAS. In our study, mean ferritin level was 73,725 ng/ml. This value is compatible with previous studies in which patients with MAS demonstrated very high levels of ferritin [3, 5, 17, 23,24,25,26,27,28,29,30,31,32,33,34]. Extremely elevated ferritin is considered a hallmark for MAS. A previous study be Schaffner et al. evaluated the spectrum of diagnoses associated with ferritin levels > 2000 ng/ml among hospitalized adults. They found that as a group, HLA/MAS patients had the highest mean and median ferritin values. However, elevated ferritin was a highly nonspecific marker for the diagnosis of MAS [35]. Therefore, markedly elevated ferritin levels should be interpreted in the appropriate clinical context, taking into account other clinical conditions besides MAS. No controlled studies regarding the treatment for MAS are available. Therefore, the management of this syndrome is mainly empiric and based on relatively small case series. In our study, all the patients were treated with high-dose steroids. Glucocorticoid is used in nearly all patients with MAS, in accordance with previous studies [3, 5, 17, 23,24,25,26,27,28,29,30,31,32,33,34]. Combining CSA and glucocorticoids is considered the mainstay of treatment for MAS complicating sJIA. However, adult patients with MAS were treated with CSA in 15% of the cases in previous cohorts [3, 5, 17, 23,24,25,26,27,28,29,30,31,32,33,34]. In our study, five of seven (71%) of the patients were treated with CSA. Anakinra, an IL-1 inhibitor, is often administrated in MAS patients refractory to treatment with corticosteroids and CSA. Previous studies have shown favorable results with anakinra. In Lenert’s group, all seven patients with AOSD and MAS were treated with anakinra with 100% survival during follow-up [17]. Loh et al. described a patient with MAS secondary to AOSD witch was refractory to standard immunosuppression that responded dramatically to anakinra [28]. In our study, only one patient received anakinra, and he did not survive. Based on published experience, it seems than anakinra has a favorable effect on MAS. However, more information is needed to determine the exact role of anakinra in the management of MAS. Anti IL-6 treatment through the monoclonal antibody tocilizumab has proved efficacious in treating AOSD [36, 37]. In our study, two patients, both with AOSD, were treated with tocilizumab with a favorable result. Previous experience with tocilizumab in MAS is limited to several case reports [25, 29] showing favorable results. However, in one of these cases MAS was attributed to initiation of anti IL-6 therapy [29]. Therefore, the role of anti IL-6 for the treatment of MAS is yet unknown. VP-16 if part of the protocol developed for treating familial HLH [11]. However, since this treatment carries a high risk of mortality, it may not be appropriate for patients with MAS. In our study, one patient was treated with VP-16. In previous reports, we identified only one patient only who was treated with VP-16. Whether less toxic doses of VP-16 may be beneficial for the management of MAS is unclear. In our cohort, one patient was treated IVIG in conjunction with CSA and VP-16 with a favorable outcome. The role of IVIG in the management of MAS is limited. Wohlfarth et al. reported a series of eight critically ill adults with MAS that were treated with anakinra in combination with IVIG and corticosteroids. This treatment regimen resulted in a hospital survival rate of 50% despite a vast degree of organ dysfunction and the need for aggressive intensive care unit (ICU) treatment. However, only one of these cases was secondary to a rheumatologic disease [34]. Accordingly, IVIG may be considered in critically ill patients with MAS as salvage therapy in refractory cases. Our study has several limitations. First, this is a retrospective case series. Since MAS in adults is quite rare, conducting randomized controlled studies is difficult. Previous studies comprise case reports and small case series. Another limitation is the small sample size. However, this limitation applies to most other reports of MAS in adults. The cases we presented hereby may aid clinicians in the diagnostic work-up and management of this life-threatening, relatively rare syndrome.

In conclusion, we presented in detail seven cases of adults with MAS complicating rheumatologic diseases. Our cohort and previous cohorts demostrate that MAS often presents concurrently with the underlying rheumatologic disease and is associated with a high mortality rate. Prompt diagnosis and treatment of this life-threatening syndrome are essential. Further large prospective studies are needed to determine the optimal management of MAS.