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CASE REPORT
Year : 2020  |  Volume : 18  |  Issue : 1  |  Page : 52-54

Systemic lupus erythematosus presenting as macrophage activation syndrome in an adult male


1 Department of Internal Medicine and Rheumatology, VPS Lakeshore Hospital, Kochi, Kerala, India
2 Department of Pathology, VPS Lakeshore Hospital, Kochi, Kerala, India
3 Department of Family Medicine, VPS Lakeshore Hospital, Kochi, Kerala, India

Date of Submission22-Oct-2019
Date of Decision06-Nov-2019
Date of Acceptance19-Dec-2019
Date of Web Publication03-Feb-2020

Correspondence Address:
Dr. Muhammed Jasim Abdul Jalal
Department of Internal Medicine and Rheumatology, VPS Lakeshore Hospital, NH-47 Byepass, Maradu, Nettoor PO, Kochi - 682 040, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cmi.cmi_50_19

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  Abstract 

Macrophage activation syndrome (MAS) is a rare, life-threatening, hyperinflammatory state where there is a combination of fever with cytopenias, high ferritin, high aspartate transaminase, and high triglyceride levels. In adults, MAS infrequently occurs as a complication of systemic lupus erythematosus (SLE). SLE presenting as MAS is extremely rare in adults. We report a patient with MAS who presented with fever, rash, and high ferritin level (>2000).

Keywords: Hemophagocytic lymphohistiocytosis, macrophage activation syndrome, systemic lupus erythematosus


How to cite this article:
Abdul Jalal MJ, Mohammad Iqbal K M, Mahadevan P, Neethu S. Systemic lupus erythematosus presenting as macrophage activation syndrome in an adult male. Curr Med Issues 2020;18:52-4

How to cite this URL:
Abdul Jalal MJ, Mohammad Iqbal K M, Mahadevan P, Neethu S. Systemic lupus erythematosus presenting as macrophage activation syndrome in an adult male. Curr Med Issues [serial online] 2020 [cited 2020 Feb 24];18:52-4. Available from: http://www.cmijournal.org/text.asp?2020/18/1/52/277525




  Introduction Top


Macrophage activation syndrome (MAS) is an uncommon, critical, secondary hemophagocytic lymphohistiocytosis triggered by rheumatic diseases. It may present as an initial manifestation or in the course of the autoimmune process.[1] MAS has been reported with systemic lupus erythematosus (SLE), Still's disease, juvenile idiopathic arthritis, Kawasaki disease, etc., The incidence of MAS in SLE patients is estimated to be 0.9%–4.6%,[2] with a mortality rate of 8%–22%.[1] We report a case of MAS as a complication of adult SLE.


  Case Report Top


A 21-year-old male manual laborer presented with fever and foul-smelling painful left ear discharge of 3-week duration. The tubo-tympanic type of active left ear chronic suppurative otitis media was accompanied by intermittent high-grade fever with rigor and chills not responding to empirical antibiotics.

He lost around 10 kg weight within 1 month and was not able to eat well due to loss of appetite. He denied dysuria, cough, chest pain, loose stools, breathlessness, joint pains, recurrent urinary tract infections, oral ulcer, genital ulcers, or rashes.

Initial investigations done 3 weeks back showed pancytopenia (hemoglobin (Hb) – 8.3g/dl, Total leucocyte count – 2600/μL, and platelet – 1.04 lakhs/μL), raised erythrocyte sedimentation rate (ESR) (135 mm/h), and increased ferritin (>2000 ng/ml).

On examination, he was febrile (101.8°F) with tachycardia (116/min) and blood pressure 100/67 mmHg. He was thin built and poorly nourished but conscious and oriented. There was mild pallor without any conjunctival congestion or icterus.

Left axilla showed 2 cm × 2 cm, nontender, firm single lymph node. There were no signs of deep-vein thrombosis, rashes, psoriatic skin lesions, dystrophy, or discoloration of nails or hair changes. The left ear showed foul-smelling, yellowish discharge. Heart rate was regular. All peripheral pulses were palpable and saturation was well maintained (99%) in room air.

Systemic examinations were within normal limits. Fundus showed engorged veins with erythematous background. There were borderline features of synovitis in the right knee. Disseminated intravascular coagulation (DIC) was suspected and further investigated.

Investigations revealed anemia (Hb – 8.6g/dl), leukopenia (total white blood cell – 1260/ μL), platelet count of 1.4 lakhs/ μL with raised ESR (100mm/h), elevated Creactive protein (CRP), deranged renal function (creatinine – 1.5mg/dl), and liver function (aspartate aminotransferase/alanine aminotransferase [AST/ALT] – 238units/L/170units/L; albumin 2.6g/dl). Urine microscopy showed albumin++ along with granular cast. His total ironbinding capacity was elevated (194 μg/dl). Swab culture from left ear discharge yielded Acinetobacter. He was started on cefoperazone-sulbactum, teicoplanin, imipenem, and fluconazole according to the ear swab culture report. He became afebrile after the onset of antibiotic coverage.

Other infective causes such as  Brucella More Details, Epstein–Barr virus, Cytomegalovirus, scrub typhus, leptospirosis, and dengue were ruled out. Negative blood culture and normal echocardiography were against infective endocarditis.

Malaria and tuberculosis were ruled out by negative peripheral smear and negative Mantoux, respectively. HIV, hepatitis C virus, and HBsAg were all nonreactive. Noninfectious inflammatory diseases were the second concerns, especially SLE. Elevated 24h urine protein (1881mg/day) along with positive antinuclear antibody (ANA) (5.6 – cutoff >1), strongly positive dsDNA (6.1 – cutoff >1), and low complement levels C3 (0.27 g/L – cutoff 0.8–1.6 g/L) and C4 (0.07 g/L – cutoff 0.16–0.48 g/L) in the background of deranged lung function test, respiratory function test, and cytopenia favored SLE. Further evaluation showed positive direct Coombs test, 0.3% reticulocyte count with highly elevated lactate dehydrogenase (LDH), and negative P-antineutrophil cytoplasmic antibody (ANCA) and C-ANCA. High serum ferritin (>2000 ng/ml), high LDH (1226 U/L), and high triglyceride (253 mg/dL) with features of DIC (fibrinogen – 146mg/dl, fibrin degradation product – 800mg/L) and cytopenia suggested MAS. Our patient fulfilled four immunological criteria (positive ANA, positive anti-dsDNA, positive direct Coomb's test, and low complements) and one clinical criterion (leukopenia) from the Systemic Lupus Collaborating Clinics criteria for SLE. Even though the patient was treated as SLE with MAS, neoplasms were also ruled out due to persistent pancytopenia and decreased response to steroids.

He was pulsed with 500-mg methyl prednisolone for 3 consecutive days after bone marrow biopsy in view of pancytopenia. Peripheral smear was negative for abnormal cells. Positron emission tomography scan done for the same showed an infective etiology and suggested left axillary lymph node biopsy. Bone marrow results showed trilineage hemopoieis with suppressed myeloid series. [Figure 1] shows phagocytosed erythrocytes. He was started on hydroxychloroquine as the treatment for SLE because other drugs such as methotrexate, azathioprine, and mycophenolate mofetil were not suitable in view of pancytopenia and deranged liver and renal functions. His nutrition was maintained most of the time with nasogastric tube feeding.
Figure 1: Bone marrow biopsy showing phagocytosed erythrocytes

Click here to view


Urine output was measured regularly for reassuring good renal function and maintained in a positive balance. Oral steroids were not considered due to decreased food intake, persistent nausea, and intermittent vomiting.

Lymph node biopsy and renal biopsy were planned but withheld due to fluctuating thrombocytopenia.

His condition improved, and counts were showing improvement during the later phase of hospital stay. He was discharged with hydroxychloroquine and low-dose oral steroids in a hemodynamically stable ambulant condition with advice to follow-up. Our plan was to start him on steroid-sparing agents during follow-up once his liver and renal functions became normal. However, the patient did not turn up and is currently following up in a local hospital due to financial constraints.


  Discussion Top


MAS is characterized by fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, and hemophagocytosis.[3] Pathogenesis in MAS involves severe systemic inflammatory reaction caused by a massive dysregulation of macrophage–lymphocyte interactions (increased tumor necrosis factor-alpha, M-colony stimulating factor receptors, interleukin [IL] IL-1 and IL-6, and interferon-alpha).[3] Activation of macrophages and abnormal clearance leads to hemophagocytosis causing pancytopenia.

The clinical features of MAS-associated SLE and active SLE are very similar. This makes the diagnosis of MAS challenging. However, hyperferritinemia is the best parameter to discriminate between MAS-associated SLE and active SLE with a sensitivity and specificity of almost 100%.[3] Treatment includes high-dose glucocorticosteroids and second-line therapy based on cyclosporine, intravenous immunoglobulins, etoposide, and recently biologicals in nonresponders.

Active SLE can have elevated ESR, but CRP is usually in the low normal range. In a febrile lupus patient, CRP elevation favors bacterial infection or polyserositis.[4] Our patient did not show any evidence of an infectious process complicating SLE; therefore, we suspected MAS with regard to high serum ferritin (>2000ng/ml), high LDH (1226U/L), high triglyceride (253mg/dl) with features of DIC (fibrinogen – 146mg/dl, fibrin degradation product – 800mg/L), and pancytopenia. Our patient presented with elevated aminotransferase levels. AST was 238 U/L and ALT was 170 U/L. Albumin of 2.6 g/dL (below 3 g/dl) was also noted to be a strong predictor, further reinforcing the diagnosis of MAS.

The HLH [Hemophagocytic lymphohistiocytosis] criteria for the diagnosis of MAS include:

  1. Temperature ≥38.5°C for 7 days at least
  2. Spleen enlargement
  3. Hypertriglyceridemia (>160 mg/dL)
  4. Hypofibrinogenemia (<150 mg/dL)
  5. Ferritin ≥500 μg/L
  6. Hepatitis
  7. sIL-2 receptor >2400 IU/mL
  8. Decreased or absent natural killer cell activity
  9. Hemophagocytic cells in bone marrow, spleen, or lymph nodes
  10. Cytopenia in two or more cell lines (Hb <9 g/dL, platelets <100 000/μL, or neutrophils <1000/μL).


At least five of the above criteria should be met for the diagnosis of MAS. Majority of the patients with MAS are found to have good response with corticosteroids and hence, a trial of high-dose corticosteroids remains the initial treatment for this condition.[5]

Cytotoxic therapy with cyclophosphamide;[5] immunomodulators such as mycophenolate and hydroxychloroquine sulfate; antimetabolites such as azathioprine; and biologicals such as rituximab play a role in the treatment of MAS.[5] Splenectomy is considered in MAS patients nonresponsive to medical therapy.[5] Higher risk of relapse in MAS patients makes close follow-up important. The natural clinical course of MAS patients can be aggressive, with a sudden progression to renal failure, shock, sepsis, and death.[6]


  Conclusion Top


SLE presenting as MAS is not common. Our literature review showed around 27 case reports of MAS at the onset of SLE, mostly in children.[7] Usually, MAS is related to SLE flare-up or complication. The features of MAS associated with SLE and active SLE are quite similar, so it is difficult to differentiate between these two conditions. A high index of suspicion is required for the identification of MAS.

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.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Sen ES, Clarke SL, Ramanan AV. Macrophage activation syndrome. Indian J Pediatr 2016;83:248-53.  Back to cited text no. 1
    
2.
Granata G, Didona D, Stifano G, Feola A, Granata M. Macrophage activation syndrome as onset of systemic lupus erythematosus: A case report and a review of the literature. Case Rep Med 2015;2015:294041.  Back to cited text no. 2
    
3.
Carvalheiras G, Anjo D, Mendonça T, Vasconcelos C, Farinha F. Hemophagocytic syndrome as one of the main primary manifestations in acute systemic lupus erythematosus – Case report and literature review. Lupus 2010;19:756-61.  Back to cited text no. 3
    
4.
Tripathy R, Panda AK, Das BK. Serum ferritin level correlates with SLEDAI scores and renal involvement in SLE. Lupus 2015;24:82-9.  Back to cited text no. 4
    
5.
Szulawski R, Kourlas PJ, Antonchak M. Macrophage Activation Syndrome (MAS) in a recently released prisoner with Systemic Lupus Erythematosus (SLE). Am J Case Rep 2018;19:734-8.  Back to cited text no. 5
    
6.
Beyan E, Beyan C, Demirezer A, Ertuǧrul E, Uzuner A. The relationship between serum ferritin levels and disease activity in systemic lupus erythematosus. Scand J Rheumatol 2003;32:225-8.  Back to cited text no. 6
    
7.
Poudel P, Swe T, Rayancha S. A Rare Case of Macrophage Activation Syndrome Presenting as theFirst Manifestation of Systemic Lupus Erythematosus. J Investig Med High Impact Case Rep 2018;6:2324709618812196. doi: 10.1177/2324709618812196.  Back to cited text no. 7
    


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