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 Table of Contents  
Year : 2021  |  Volume : 5  |  Issue : 2  |  Page : 236-239

“What lies beneath” – macrophage activation syndrome unveiled systemic lupus erythematosus

Department of Dermatology, St. John's Medical College Hospital, Bengaluru, Karnataka, India

Date of Submission03-Jun-2020
Date of Decision04-Sep-2020
Date of Acceptance23-Nov-2020
Date of Web Publication26-Aug-2021

Correspondence Address:
J P Prathibha
Department, of Dermatology, St. John's Medical College, Bengaluru - 560 034, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CDR.CDR_87_20

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Macrophage activation syndrome (MAS) is a potentially fatal condition characterized by massive systemic inflammatory response in the setting of a myriad of systemic disorders such as autoimmune collagen vascular disease, infections, drug-induced, and malignancies. It falls under a group of disorders known as hemophagocytic lymphohistiocytosis of which familial and acquired types have been described. Here, we report a case of acquired MAS secondary to acute systemic lupus erythematosus (SLE). Early diagnosis and timely intervention resulted in a favorable outcome.

Keywords: Hemophagocytic lymphohistiocytosis, macrophage activation syndrome, systemic lupus erythematosus (SLE)

How to cite this article:
Prathibha J P, Pai V, Bhat P I. “What lies beneath” – macrophage activation syndrome unveiled systemic lupus erythematosus. Clin Dermatol Rev 2021;5:236-9

How to cite this URL:
Prathibha J P, Pai V, Bhat P I. “What lies beneath” – macrophage activation syndrome unveiled systemic lupus erythematosus. Clin Dermatol Rev [serial online] 2021 [cited 2022 May 23];5:236-9. Available from: https://www.cdriadvlkn.org/text.asp?2021/5/2/236/324580

  Introduction Top

Macrophage activation syndrome (MAS) is a rare, potentially life-threatening condition that occurs in the setting of several systemic conditions such as autoimmune diseases, infections, and malignancies. It belongs to the group of disorders known broadly as hemophagocytic lymphohistiocytosis (HLH). MAS has been described commonly with systemic juvenile idiopathic arthritis, but it may occur rarely with SLE and Kawasaki disease.[1],[2] MAS a multiorgan disorder typically characterized by prolonged high-grade fever, hepatosplenomegaly, neurological symptoms, coagulation abnormalities, pancytopenia, elevated liver enzymes, and hyperferritinemia. Bone marrow studies typically show benign macrophages exhibiting hemophagocytic activity.[3] The incidence of MAS in SLE is estimated to be 0.9%–4.6%, with a high mortality rate of 8%–22%.[4] To the best of our knowledge, very few cases of MAS with SLE have been reported[2] and we report a case of SLE presenting as MAS.

  Case Report Top

A 52-year-old male presented with a 15-day history of fever associated with skin lesions. On cutaneous examination, gross periorbital edema with hemorrhagic crusting on the forehead and lips was present. He also had erythematous and purpuric papules and plaques on the neck, anterior chest, upper back, and ear lobes. Oral mucosa had purpura and ulcers over the hard palate. Conjunctival congestion was seen [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d. On general physical examination, the patient was febrile (fever of 101°F) with tachycardia (pulse 102/min). Other systemic findings were normal.
Figure 1: (a) Purpuric plaques on the forehead, cheeks, hemorrhagic crusts on the lip, oral ulcers and periorbital edema, erythematous nodules on the chest and back. (b) Purpuric plaques on the forehead, cheeks, hemorrhagic crusts on the lip, oral ulcers and periorbital edema, erythematous nodules on chest and back. (c) Purpuric plaques on the forehead, cheeks, hemorrhagic crusts on the lip, oral ulcers and periorbital edema, erythematous nodules on chest and back. (d) Purpuric plaques on the forehead, cheeks, hemorrhagic crusts on the lip, oral ulcers and periorbital edema, erythematous nodules on the chest and back

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On investigations, the patient was found to have severe pancytopenia, hypertriglyceridemia, elevated liver enzymes, and hyperferritinemia. Complement levels (C3 and C4) were low. These findings were suggestive of a systemic inflammatory process and hence workup for collagen vascular disease was initiated. Antinuclear antibody was positive with speckled pattern. Immunoline showed positivity for Anti-Sm antigen. Hence, the diagnosis of systemic lupus erythematosus was confirmed. The laboratory parameters are listed in [Table 1].
Table 1: Patient's blood report

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Bone marrow aspiration showed cellular marrow with erythroid maturation along with hemophagocytosis [Figure 2]c.
Figure 2: (a) Skin biopsy H and E, ×10 showing features suggestive of lupus erythematosus. (b) Special ×10 AB-PAS showing abundant interstitial Mucin. (c) H and E, ×100 oil immersion: bone marrow showing features suggestive of hemophagocytosis

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Histopathological examination of skin lesion showed epidermal findings of necrotic keratinocytes, basal cell vacuolation, and focal thinning of the basement membrane. Dermis showed perivascular inflammatory infiltrate of lymphocytes and plasma cells with nuclear debris and abundant interstitial mucin. The above was consistent with lupus erythematosus [Figure 2]a and [Figure 2]b. Serological investigations further confirmed the diagnosis of SLE.

With the bone marrow showing features of hemophagocytosis in the setting of systemic lupus erythematosus, a final diagnosis of HLH secondary to SLE was confirmed. HLH associated with autoimmune disease is formally called as MAS.[5]

The patient was started on methylprednisolone pulse along with cyclosporine 5 mg/kg/day. After 7 days of treatment, his condition improved remarkably with a decrease in periorbital edema, improvement of skin lesions, and normalization of blood parameters. During the subsequent weeks, skin lesions had resolved with complete recovery of blood count.

We present this rare case of acquired HLH secondary to SLE. Early diagnosis and prompt therapy resulted in a favorable outcome.

  Discussion Top

MAS is a potentially fatal, hyperinflammatory condition caused by highly stimulated but ineffective immune response which leads to activation and expansion of T-cells and macrophages. This results in the massive and unregulated secretion of pro-inflammatory cytokines such as Interferon-γ, Tumor necrosis factorα, interleukins (IL) such as IL-1, IL6, IL10, IL12, IL18, and macrophage colony-stimulating factor.[3] The incidence is estimated to be approximately 1.2 cases per million individuals per year. MAS belong to the group of disorders called HLH which can be classified according to the underlying etiology into primary (Genetic) and secondary (Acquired). Primary/Familial HLH is seen in the pediatric population with genetic abnormalities of cytotoxic function of NK cells and T-cells and may or may not be associated with immunodeficiency syndromes. Secondary/acquired HLH is seen in adults in association with infections such as Epstein–Barr virus/Avian flu, malignancies, post medication, rheumatological disorders, and metabolic diseases.[6]

MAS presents clinically as unremitting fever, generalized lymphadenopathy, hepatosplenomegaly, and hemorrhagic manifestations resembling disseminated intravascular coagulation. Neurological involvement can present as seizures and coma. Laboratory findings often show pancytopenia, elevated liver enzymes, abnormal coagulation profile with hyperfibrinogenemia, hypertriglyceridemia, and inflammatory markers such as hyperferritinemia.[5] Bone marrow examination characteristically shows numerous well-differentiated macrophages actively phagocytosing hemopoietic cells and this finding is confirmatory of MAS. Validated criteria for the diagnosis of HLH have been established by the International Histiocyte Society [Table 2]. MAS' diagnosis is challenging, especially in the setting of SLE, who commonly have cytopenias independent of MAS.[7]
Table 2: Diagnosis of hemophagocytic lymphohistiocytosis established if one of either 1 or 2 below is fulfilled

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Our patient fulfilled five of the eight criteria which is been highlighted in table above, hence the HLH diagnosis established.

The patient also met Parodi et al. criteria for diagnosis of MAS in SLE. The need for separate set of criteria to diagnoses MAS in SLE, was felt because the cytopenias could be a result of SLE disease activity itself, independent of MAS, hence Parodi et al. suggested separate set of diagnostic criteria for MAS in the setting of SLE patients[8] [Table 3].
Table 3: Diagnostic criteria for macrophage activation syndrome: Parodi's preliminary diagnostic guidelines for macrophage activation syndrome as a complication of juvenile systemic lupus erythematous

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Hence, our patient fulfilled both HLH and MAS criteria in SLE.

The diagnosis of MAS requires the simultaneous presence of at least one clinical criterion and at least two laboratory criteria. In our case, two of the clinical criteria and five of the laboratory criteria and histopathological criteria were met.

[Table 3] is copied from Parodi et al.[8]

Differentiate MAS from active rheumatic diseases discussed by Alkoht et al., who proposed that decrease in platelets, derangement of liver enzymes, and hypoalbuminemia points toward early diagnosis MAS in contrast to active rheumatic disease.[4]

Fardet et al. suggested a scoring system for diagnosing reactive hemophagocytic syndrome in adults called HScore. The HScore is the first validated score devoted to the diagnosis of reactive hemophagocytic syndrome. This scoring system is freely available online (http://saintantoine.aphp.fr/score/). HScore helps clinicians in diagnosing hemophagocytic syndrome in routine clinical practice.[9]

When we applied to our patient HScore of 243 was achieved which made the probability of HLH 99.076%.

After ruling out infections and malignancy patient was started on methylprednisolone pulse and cyclosporine-A, the patient had significant improvement of skin lesions [Figure 3], blood counts, and he is under regular follow-up. Although rare, MAS can be an initial presentation of SLE. The diagnosis of MAS in the setting of SLE is challenging. Moreover, awareness of its existence is important to manage this potentially fatal condition. MAS should be considered in all patients who present with unexplained fever, severe cytopenias, hypertriglyceridemia, and hyperferritinemia. Rarity of this disease prompted us to present this case.
Figure 3: (a) Post treatment skin lesions healed with post inflammatory hyperpigmentation. (b) Post treatment skin lesions healed with post inflammatory hyperpigmentation

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Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed

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Conflicts of interest

There are no conflicts of interest.

  References Top

Bracaglia C, Prencipe G, De Benedetti F. Macrophage activation syndrome: Different mechanisms leading to a one clinical syndrome. Pediatr Rheumatol Online J 2017;15:5.  Back to cited text no. 1
Rahal AK, Fernandez J, Dakhil C. Undiagnosed systemic lupus erythematosus presenting as hemophagocytic lymphohistiocytosis. Case Rep Rheumatol 2015;2015:748713.  Back to cited text no. 2
Minoia F, Davì S, Horne A, Demirkaya E, Bovis F, Li C, et al. Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: A multinational, multicenter study of 362 patients. Arthritis Rheumatol 2014;66:3160-9.  Back to cited text no. 3
Alkoht A, Hanafi I, Khalil B. Macrophage activation syndrome: A report of two cases and a literature review. Case Rep Rheumatol 2017;2017:5304180.  Back to cited text no. 4
Janka G. Hemophagocytic lymphohistiocytosis: When the immune system runs amok. Klin Padiatr 2009;221:278-85.  Back to cited text no. 5
Yeap ST, Sheen JM, Kuo HC, Hwang KP, Yang KD, Yu HR. Macrophage activation syndrome as initial presentation of systemic lupus erythematosus. Pediatr Neonatol 2008;49:39-42.  Back to cited text no. 6
Grom AA, Mellins ED. Macrophage activation syndrome: Advances towards understanding pathogenesis. Curr Opin Rheumatol 2010;22:561-6.  Back to cited text no. 7
Parodi A, Davì S, Pringe AB, Pistorio A, Ruperto N, Magni-Manzoni S, et al. Macrophage activation syndrome in juvenile systemic lupus erythematosus: A multinational multicenter study of thirty-eight patients. Arthritis Rheum 2009;60:3388-99.  Back to cited text no. 8
Fardet L, Galicier L, Lambotte O, Marzac C, Aumont C, Chahwan D, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol 2014;66:2613-20.  Back to cited text no. 9


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3]


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