Macrophage activation syndrome( MAS) is a life threatening condition. It belongs to the hemophagocytic lymphohistiocytosis(HLH) group of diseases which includes familial HLH and secondary HLH. Secondary HLH is triggered by several causes that disrupts immune homeostasis. including infection, drugs, malignancy and rheumatic disorder. HLH is characterized by proliferation and activation of T lymphocytes and macrophages, which produces an excessive inflammatory response and hypersecretion of cytokines. Clinically, patients usually present with prolonged fever, pancytopenia, hepatosplenomaegaly, liver function abnormalities, coagulopathy and hyperferritinemia[13]. Systemic lupus erythematous is a systemic autoimmune disorder involving multiple visceral organs. In adults, MAS is rarely associated with systemic lupus erythematous. The incidence of MAS associated with SLE is about 0.9- 4.6% [4, 10]. Here we report a rare case of MAS that occurred as a first manifestation of SLE.
Case:
A previously healthy 42 year old Caucasian woman was admitted with a history of fever with rash since past two days. Patient reported that she was recently started on new medication lamotrigine and abilify for her bipolar disorder. She told that she started developing fever with rashes right after starting the new medications. Patient also had mild shortness of breath, cough and peripheral arthritis on presentation. Her past medical history was unremarkable for rheumatic disease, severe infections or immunodeficiency. Her family history was also negative for rheumatic disease. Vitals signs were normal except for temperature of 101.5 F On clinical examination, she had diffuse erythematous non itchy rashes over her face and chest. Since she complained of the rashes right after starting the new medication we treated her as an allergic reaction to new drug with Benadryl and solumedrol. She started spiking fever along with worsening of her rash despite being on steroids.
We started work up to rule out infectious, autoimmune or neoplastic disease. Blood culture, urinanalysis, Chest Xray was unremarkable. Viral panel for Epstein- Barr virus, cytomegalovirus, Hepatitis B and C, HIV and RPR test was unremarkable.
Laboratory results showed hyperferritinemia 13615 ng/ml, Reference range: 13-150 ng/ml, elevated lactate dehydrogenase 1767 U/L (122-214 U/L) . Immunological screening was positive for ANA, Anti Ds DNA 344 IU/ml( 0-99 IU/ml), anti Histone Ab 210 AU/ml( 0-99 AU/ml), serum C3 complement was 35 mg/dl ( 90-180 mg/dl), serum C4 was 9 mg/dl ( 10-140 mg/dl) .Chest CT showed axillary, cervical and supraclavicular lymphadenopathy. Since the patient had elevated ferritin and lymphadenopathy seen on CT, there was a concern of macrophage activation syndrome. Bone marrow biopsy showed increased number of macrophages showing hemophagocytosis suggestive of macrophage activation syndrome. Soluble IL-2 receptor was found to be high 3463 U/ ml ( 223-710 ) U/ml and and natural killer cell activity was low, CD 15/56 absolute NK cells 7 cells/microL( 78-470 cells/microL) .We also performed axillary lymph node biopsy which was negative for malignant lymph proliferative disorder and it showed some hemophagocytosis.
The presence of fever, joint pain, positive ANA, anti ds DNA, anti histone Ab, low complement suggested a diagnosis of systemic lupus erythematous according to Systemic lupus International Collaborating Clinics ( SLICC) classification criteria[11]. At the same time, presence of fever, elevated ferritin, low NK cell activity, elevated soluble IL-2 receptor and hemophagocytic cells in bone marrow and lymph node led us to the main diagnosis of MAS according to the hemophagocytic lymphohistiocytosis ( HLH) criteria[13]
We started her on high dose of intravenous methyprednisolone 120 mg/day for 3 days. Then the drug was switched to oral prednisone 60 mg daily and hydroxychloroquine 200 mg twice daily. After the end of methylprednisolone therapy, the patient’s fever went down, subsequently the skin rashes disappeared. The laboratory parameters, ferritin, LDH started down trending. The patient was discharged from the hospital and is now under follow up at the outpatient clinic.
Discussion:
The term ‘macrophage activation syndrome’ was used in a description of the disorder by Albert et al. [18] in 1992 and furthered by Stephan et al. [16]. This terminology remains prevalent in the rheumatology literature, whereas syndromes described in the hematology and infectious disease literature often describe a similar phenomenon as secondary HLH [19]. It is now recognized that MAS is a form of secondary HLH.
MAS is a form of hemophagocytic lymphohistiocytosis that occurs primarily in patients with juvenile idiopathic arthritis or other rheumatologic diasease. In 1991 Wong et al. [13] proposed a disease entity of acute lupus haemophagocytic syndrome, in which haemophagocytosis occurs in association with the SLE flare and the corticosteroid therapy was effective in those cases. To date, only 26 cases of MAS at the onset of SLE are reported in the literature[7]. We found other several cases of MAS due to SLE in the literature but these cases were related to SLE flare up. . The features of MAS-associated SLE and active SLE are quite similar, so it is difficult to differentiate between these two entities.
MAS is due to excessive inflammation and tissue destruction due to abnormal immune activation and excessive inflammation. Excessive inflammation is thought to be caused by a lack of normal down regulation of activated macrophages, Histiocytes and lymphocytes. Normal function of histiocytes, a major population of cells within the innate immune system include phagocytosis, antigen presentation and activation of adaptive immune system through contact and cytokine signaling. Macrophages become activated and secrete excess amount of cytokines causing severe tissue destruction. Also the function of natural killer cells to eliminate macrophages is lost. Natural killer cells play a major role in maintaining a healthy threshold of immune responsiveness to noxious stimuli and are critical to prevention and control of autoimmune conditions. These cells modulate the initial responses of antigen presenting cells to incoming pathogens, thus attenuating the subsequent activation of antigen specific T cells. NK cells also play a role in selecting activated T cells and histiocytes in later stages of antigen driven activation contributing to the natural contraction of the immune response. The lost of NK cell function results in excessive macrophage activity and elevated levels of interferon gamma and other cytokines. However if the NK function is within normal limits, it should not preclude the diagnosis of HLH[12]. Hemophagocytosis refers to the engulfment of host blood cells by macrophages. It is mediated through CD163 heme-scavenging receptor[24 ]. Proliferation of CD163+ hemophagocytic macrophages in marrow and lymphoid tissues is a central feature of hemophagocytic disorder. It is characterized by the presence of red blood cells, platelets or white blood cells within the cytoplasm of macrophages. It can be seen on biopsies of immune tissues( lymph nodes, spleen, liver) or bone marrow. Although it can be a marker of excess macrophage activation and supports the diagnosis of HLH, hemophagocytosis alone is not pathognomonic of diagnosis of HLH. Infiltration of bone marrow by active macrophages along with global clinical evaluation may distinguish HLH from other causes of hemophagocytosis.
The diagnostic criteria of HLH be based upon the following criteria:
Proposed HLH diagnostic criteria, 2004.[13]
1.Molecular diagnosis of hemophagocytic lymphohistiocytosis (HLH) or X-linked lymphoproliferative syndrome (XLP).
Or
Five of the 8 criteria listed below are fulfilled:
1. Fever ≥ 38.5°C
2. Splenomegaly
3. Cytopenias (affecting at least 2 of 3 lineages in the peripheral blood) Hemoglobin < 9 g/dL (in infants < 4 weeks: hemoglobin < 10 g/dL), Platelets < 100 × 103/mL Neutrophils < 1 × 103/mL
4. Hypertriglyceridemia (fasting, > 265 mg/dL) and/or hypofibrinogenemia (< 150 mg/dL) 5. Hemophagocytosis in bone marrow, spleen, lymph nodes, or liver
6. Low or absent NK-cell activity
7. Ferritin > 500 ng/mL‡
8. Elevated sCD25 (α-chain of sIL-2 receptor)§
Studies of cytokine level in blood have indicated persistently elevated circulating level of multiple proinflammatory cytokines during symptomatic disease. It is currently believed that hypercytokinemia and hyperchemokinemia generated by uncontrolled activation of histiocytes and T cells underlies the progressive organ dysfunction that eventually leads to death in affected patients. These symptoms include fever, hyperlipidemia, endothelial activation/coagulopathy, hepatitis, Central nervous system vasculitis, inflammatory lung disease with acute respiratory distress syndrome and bone marrow hyperplasia or aplasia. Parodi et al. [20] mentioned that the strongest indicator to separate MAS from active SLE was hyperferritinemia, but they did not report whether ferritin level can be a predictor of disease severity or prognosis of the disease. Emmenegger et al. [21] showed that the absolute values did not strictly reflect the clinical severity from a comparison among individuals, but serial ferritin measurements in a single patient reliably reflected disease activity at least during the initial phase of MAS. Ferritin level above 10000 mg/L is specific and sensitive for HLH. In patients without a significant medical history and new onset of febrile illness with highly elevated ferritin, the diagnosis of HLH should be evaluated.[14]. Diagnostic confirmation through the demonstration of macrophage hemophagocytosis in the bone marrow may not be necessary in the presence of the typical clinical and laboratory features of the syndrome.[20]
Index of MAS should be high when an infection is ruled out or inflammation persists and does not respond to treatment of underlying condition. There are several therapeutic options available including biologic and non biologic agents. Effective initial therapy of HLH consists of combination of proapoptotic chemotherapy and immunosuppressive drugs targeting hyperactive T cells and histiocytes. The mainstay of treatment is steroids. An intravenous methyprednisolone pulse therapy ( 30 mg/kg for three consecutive days) followed by 2-3 mg/kg/day is the most preferable. Several other drugs can be used in combination to reduce the dose of steroids. Hydoxychloroquine in combination with oral steroids is known to control the disease. Therapies that target activated macrophages/histiocytes( etoposide, steroids, high dose IVIG) and activated T cells( steroids, cyclosporine A, antithymocyte globulin) are known to suppress HLH. The need to treat coexisting infections, potential triggers of HLH is obvious. The importance of timely diagnosis and treatment is evidenced by the >90% fatality rate in patients prior to treatment strategies with immune modulating drugs [22].
Conclusion:
Although rare MAS can be the initial presentation of SLE. It is not easy to differentiate hemophagocytic syndromes occurring secondary to infection from those occurring due to a rheumatological cause like SLE. Cytopenia are common manifestations of both HLH and SLE and the existence of HLH may lead to a delay on diagnosis of SLE .It is essential that this distinction is made with timely immunological testing because HLH due to SLE responds rapidly to steroids and immunosuppressants.[23] A good prognosis can be obtained with early diagnosis and prompt administration of steroids.