Background

Macrophage activation syndrome (MAS) is a life-threatening condition characterized by cytopenia, high fever, liver insufficiency, and coagulopathy. Excessive activation and proliferation of T lymphocytes and macrophages or histiocytes lead to extensive hemophagocytosis in the bone marrow and a cytokine storm [1]. MAS, also known as an autoimmune-associated hemophagocytic syndrome (AAHS), is considered as a type of secondary hemophagocytic lymphohistiocytosis (sHLH) in patients with autoimmune or autoinflammatory disorders [2]. It accounts for 7.0–15.3% of sHLH [3, 4]. As a complication of systemic lupus erythematosus (SLE) in adults, it is relatively uncommon. The occurrence of MAS in SLE has been reported to range from 0.9% to 4.6% [5].

Because MAS and SLE share clinical and laboratory features, which include fever, cytopenia, and splenomegaly, distinguishing MAS from SLE flare has been challenging. Following multiple-organ failure, if MAS is left untreated or even undetected, the mortality rates can rise to 11% and 42% in pediatric and adult patients, respectively [6, 7].

Several treatment options for MAS in SLE have recently been proposed: high-dose corticosteroid treatment including pulse methylprednisolone (mPSL) is the suggested initial treatment of choice in MAS, and second-line agents include cyclosporine, azathioprine, tacrolimus, etoposide, thalidomide, or anakinra [8, 9]

Here, we are reporting a case of SLE flare complicated with MAS in a middle-aged female, who was successfully treated with dexamethasone sodium phosphate (DSP), intravenous immunoglobulin therapy (IVIG), and oral cyclosporine after a poor response to mPSL. We hypothesized that DSP could be a successful alternative treatment for MAS patients in whom the response to pulse mPSL was inadequate to manage their illness.

Case description

A 33-year-old Egyptian female with a 4-week history of fever, abdominal pain, malaise, and progressive fatigue was referred for hospital admission after being discovered to have pancytopenia. She had a 5-year history of SLE and antiphospholipid syndrome (APS) featuring arthritis, oral ulcers, leukopenia, positive antinuclear antibodies (ANA), Anti-double stranded DNA (Anti-dsDNA), recurrent venous thromboembolism (VTE), miscarriages, and antiphospholipid antibodies, confirming the diagnosis of SLE (ACR 5/11 and SLICC 5/13) with APS [10, 11]. She had no previous history of skin rash, For the previous 8 months, she had been taking hydroxychloroquine (400 mg/day), prednisolone (7.5 mg/day), and warfarin (5 mg/day). Upon admission, she was febrile with a maximum temperature of 38.6 °C, pulse was 107 beats per minute, and she had otherwise normal vital signs. She had a height of 175 cm and weighed 80 kg. Physical examination revealed an enlarged liver of 3 cm and a spleen of 4 cm palpable below the costal margin, while examination of the respiratory system, nervous system, and precordium was normal. Laboratory studies showed pancytopenia, reticulocytosis, hyponatremia, liver dysfunction, and proteinuria. Further workup showed that she had marked elevated d-dimer, ferritin, lactate dehydrogenase (LDH), and triglycerides, prolonged activated partial thromboplastin time (aPTT), decreased complement levels (C3), and elevated erythrocyte sedimentation rate (ESR), with positive direct antiglobulin (Coombs) test. A 24-hour urine protein test demonstrated proteinuria in the subnephrotic range (0.54 g/24 hours). Abdominal ultrasonography confirmed hepatosplenomegaly, while chest X-ray and echocardiography were normal. The SLE Disease Activity Index (SLEDAI) score was 11, indicating a moderate flare.

Our differential diagnosis was taken into consideration: MAS, SLE flare-up, viral infection, sepsis, leukemia, and lymphoma. The diagnosis, however, was difficult in part owing to strong similarities between MAS, SLE flare, and sepsis. Repeated blood, urine cultures, and viral panels for SARS-CoV-2, hepatitis B and C viruses, Epstein–Barr virus, herpes simplex virus, coxsackievirus, cytomegalovirus, human immunodeficiency virus, and parvovirus B19 were all shown to be negative. Renal biopsy was considered. However, due to the patient’s severe thrombocytopenia, it was postponed.

Based on the laboratory and clinical findings in accordance with the HLH diagnostic criteria, a diagnosis of MAS secondary to SLE flare was made. Intravenous methylprednisolone (mPSL) 1 g/day for 3 days followed by oral prednisone 60 mg daily and IVIG 2 g/kg over 5 days was started. Subsequently, oral cyclosporine 300 mg daily was started. The fever, abdominal pain, malaise, and fatigue were partially resolved while her counts were a little improved 7 days after starting treatment. Hence, we decided to switch from oral prednisolone to intravenous DSP 9 mg/day. Within 4 days, the platelet, white blood cell (WBC) counts, hemoglobin, inflammatory indices, LDH, and ferritin levels all eventually returned to normal (Table 1).

Table 1 Laboratory data upon admission, discharge, and 6 weeks after discharge
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Afterward, following the late acceptance of her husband, a bone marrow biopsy was performed 7 days after starting the treatment with mPSL, which showed focal evidence of hemophagocytosis (Fig. 1). The patient was discharged without symptoms, with monthly follow-up of complete blood count, LDH, ferritin, 24-hour urine protein, anti-dsDNA antibody, and complement levels. Oral prednisone was gradually tapered to 20 mg daily, and oral cyclosporine of 300 mg daily was continued. One year after treatment, the patient remains symptom-free without any potential adverse effects of the adherent medications, and the patient-reported outcome shows patient satisfaction.

Fig. 1
figure 1

Bone marrow biopsy showing focal evidence of hemophagocytosis (arrow)

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Discussion

HLH is a rare hematologic condition that can be divided into two types: familial (primary) and acquired (secondary) HLH. sHLH is seen in a heterogeneous group of diseases including infections, malignancies, hematological disorders, and autoimmune diseases [12]. sHLH related to rheumatic diseases has been referred to as MAS since it was first reported as a complication of sJIA in 1985 by Hadchouel et al. [13]. The clinical characteristics of MAS-associated SLE and active SLE are very similar, making MAS diagnosis difficult. With a sensitivity and specificity of about 100%, hyperferritinemia is considered as the chief significant parameter for distinguishing between both [14].

The 2004 proposed diagnostic criteria for HLH (Table 2) serve as a useful diagnostic tool [15]. The HScore (Table 3) may be applied to determine the probability of getting sHLH in adult patients [16].

Table 2 Diagnostic criteria of HLH—2004
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Table 3 HScore
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In secondary HLH, and MAS in patients with SLE in particular, there is no consensus treatment guideline for management. High-dose glucocorticoids, followed by second-line therapies such as cyclosporine, cyclophosphamide, anakinra, etoposide, and IVIG for severe or refractory cases, and plasma exchange in patients with life-threatening MAS were reported [17].

Corticosteroids inhibit the inflammatory function of macrophages through glucocorticoid receptors. Since the glucocorticoid receptors are located in the cytoplasm, effective delivery of corticosteroids into the cytoplasm can enhance their therapeutic effect on macrophages. Liposome-bound dexamethasone is effectively used by macrophages through phagocytosis. As a result, a large amount of DSP remains in the cytoplasm [18]. The reticuloendothelial system and some inflammatory cells, including macrophages, utilize DSP, a liposome-incorporated dexamethasone, which is much more efficient than free corticosteroids. Therefore, DSP has stronger anti-inflammatory activity [19].

Our case was presented with unremitting fever, progressive pancytopenia, hepatosplenomegaly, hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, and hyponatremia, with the diagnosis of SLE flare-associated MAS being made as she met the diagnostic criteria for HLH-2004 (5/8) prior to bone marrow examination. Our patient additionally had an HScore of 271, suggesting a greater than 99% probability of having sHLH/MAS [16].

Our patient was initially treated with intravenous mPSL pulse therapy, which was followed by a course of oral prednisolone, IVIG therapy, and oral cyclosporin, with the goal of treating MAS and inducting remission of SLE activity. However, after 7 days of treatment, the response to these drugs was not sufficient to manage their diseases. Subsequently, within 4 days after switching from prednisolone to intravenous DSP, the platelet, WBC counts, inflammatory markers, LDH, and ferritin levels dramatically returned to normal. To our knowledge, this is the first case report describing the successful use of DSP in a refractory case of MAS in adult SLE. The use of DSP has been driven by lessons observed in refractory cases of pediatrics MAS, considering the HLH-2004 dexamethasone, cyclosporine, and etoposide treatment regimen [20]. Furthermore, in two reports, dexamethasone palmitate (DP), a liposome-incorporated form of dexamethasone, was effective in a pediatric case of MAS associated with s-JIA, juvenile SLE (jSLE), and Kawasaki disease that was resistant to pulse methylprednisolone [21, 22]. From these findings, we hypothesized that DSP directly activated macrophages that could produce more effective anti-inflammation compared with other corticosteroids.

This study has some limitations. Because it is not based on systematic studies, it lacks the potential to generalize.

Conclusion

MAS should be included in the differential diagnosis of SLE patients with persistent fever and pancytopenia. Physicians ought to have a high level of suspicion for diagnosing MAS in the setting of relevant clinical symptoms and signs. Early and proper treatment is crucial to prevent the high mortality rate. Rather than renal abnormalities, anti-dsDNA antibody high titer, and complement levels, hyperferritinemia and hypertriglyceridemia are regarded as the most important parameters for differentiating between MAS and SLE flare.

Our case demonstrates that DSP can be a successful alternative treatment for MAS patients in whom the response to pulse mPSL was inadequate to manage their illness, proving to be remarkably effective in a relatively short time frame. In the future, larger trials are required to determine the value and exact mechanism of DSP in MAS patients.