Macrophage activation syndrome (MAS) is a underrecognized and potentially life-threatening complication of rheumatic diseases characterized by fever, pancytopenia, liver insufficiency, coagulopathy, and neurologic symptoms1 and is thought to be caused by uncontrolled activation and proliferation of T lymphocytes and macrophages, leading to widespread hemophagocytosis and cytokine overproduction.2,3

A previously healthy 20-year-old female presented with daily fever in the last 2 weeks, fatigue, anorexia, weight loss, polyarthralgia of the hands and dry mouth. She denied symptoms suggestive of infection, night sweats or swelling of the lymph nodes. No family history for rheumatic disease. Physical examination revealed normal vital signs except high temperature (38.8°C), pallor of the skin, mild tenderness at proximal interphalangeal joints without swelling or deformities. Cardiopulmonary, abdominal and neurological examination was normal. Small red and painful patches were observed on her fingers. No axillary, cervical and inguinal adenopathy or peripheral edema were noticed. Laboratory workup showed pancytopenia (Hb 8.4g/dL, WBC 1630/μL, platelet 108,000/μL), normal ESR and CRP, normal renal function, mild hypoalbuminemia (36.1g/L), high AST and ALT (98 and 81U/L, respectively), high ferritin (5075ng/mL) and hypertriglyceridemia (357mg/dL). High lactate dehydrogenase (LDH 1095U/L), low haptoglobin (<8mg/dL), positive direct coombs test, absence of schistocytes on the peripheral blood smear and reticulocytopenia were also observed. Coagulation tests showed normal prothrombin and activated partial thromboplastin time and hypofibrinogenemia (150mg/dL). Urine analysis was normal. Blood cultures and serological tests for infectious diseases, namely for cytomegalovirus and epstein barr virus, were negative. Autoimmune workup showed positive ANA (1:1280, homogenous pattern), anti-dsDNA (>800IU/mL), anti-Sm, anti-SS-A and anti-nucleosome antibodies and low complement levels (C3 54mg/dL, C4 8mg/dL). CT of chest, abdomen and pelvis showed cervical, axillary and retroperitoneal lymphadenopathy, hepatosplenomegaly with no focal lesions. No signs of infection or malignancy. Biopsy of axillary node showed non-specific reactive lymphadenitis. Bone marrow aspiration and biopsy were performed but the sample was inappropriate. Soluble CD25 in serum was only collected after 10 days of therapy. Even though, the level remained high (1187U/mL, N 158–623).

New-onset of systemic lupus erythematosus (SLE) associated with MAS was diagnosed. MAS was diagnosed according to the HLH-2004 criteria and the H-score.4,5 The patient started hydroxychloroquine 400mg daily, intravenous methylprednisolone pulse (1g daily for 3 days), followed by 1mg/kg daily of oral prednisolone and cyclosporine 3mg/kg daily. Prophylaxis for Pneumocystis jiroveci, calcium and vitamin D supplementation were also started.

A significant clinical and laboratory improvement was noticed with resolution of fever and constitutional symptoms, improvement of pancytopenia, hyperferritinemia, hypertriglyceridemia and hypofibrinogenemia. The patient was discharged after 3 weeks, with steroid tapering. At one year follow-up, a sustained remission was observed. Steroid was stopped and hydroxychloroquine 400mg daily and cyclosporine 2.5mg/kg daily were maintained.

MAS is rarely associated with SLE and the incidence is 0.9–4.6%.1,6 The mainstay of treatment is steroids.1,7 Concomitant use of other agents, such as etoposide, cyclosporine, high-dose IV immunoglobulin and anakinra is useful in patients with severe, corticosteroid-resistant or refractory MAS.7 Cyclosporine is a cyclic polypeptide immunosuppressant that suppresses the production of IL-2, IFN-γ TNF-α, IL-1 and IL-6, and also inhibits T lymphocyte activation.8 This agent is effective for the induction and maintenance of remission in patients with MAS associated with rheumatic diseases, even in the cases of severe and corticosteroid-resistant disease.9

Early diagnosis is crucial since mortality remains high, even in patients undergoing treatment.10 Here, we present an unusual, severe and life-threatening onset manifestation of SLE, MAS. Remission of the disease was achieved with corticosteroids and ciclosporine, with no adverse events reported, which corroborate the effectiveness, and also the safety, of this therapy.

Fever with constitutional symptoms and cytopenia can be clues to MAS and the level of suspicion should be high, to guarantee an early diagnosis. Looking for secondary causes of MAS, such as rheumatic diseases, is essential to ensure an accurate diagnosis and to select the appropriate treatment. However, a genetic predisposition can also exist and be related to dysregulated inflammasome activity (e.g., NLRC4 gene), and especially in situations with a positive family history of MAS, this should be investigated.

The authors declare they have no conflict of interest.