Acute lupus hemophagocytic syndrome: report of a high fever, pancytopenia, hepatosplenomegaly,...
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2010 Revista Nefrologa. rgano Oficial de la Sociedad Espaola de Nefrologa
Correspondencia: Carlos BotelhoRua So Teotnio Lote 17, 1. D.3000 Coimbra. Portugal.firstname.lastname@example.org
Acute lupus hemophagocytic syndrome: report of a case C. Botelho1, F. Ferrer1, L. Francisco2, P. Maia1, T. Mendes1, A. Carreira1
1 Departments of Nephrology and 2 Hematology. Centro Hospitalar de Coimbra. Coimbra. Portugal
Hemofagocitosis asociada con el lupus: caso clnico
La hemofagocitosis es un cuadro clnico caracterizado por laactivacin de los macrfagos y histiocitos, con intensa activi-dad fagoctica en la mdula sea e otras localizaciones del sis-tema reticuloendotelial, lo que provoca la fagocitosis de loseritrocitos, leucocitos, plaquetas y sus precursores. Su presen-cia puede estar asociada con infecciones, neoplasias, enfer-medades autoinmunitarias, drogas y una variedad de otrascondiciones mdicas. En este caso clnico, presentamos a unamujer de 36 aos, previamente sana, que desarroll hemofa-gocitosis, al mismo tiempo que complet los criterios de diag-nstico de lupus eritematoso sistmico. La hemofagocitosisasociada con el lupus es una entidad rara, potencialmentemortal, de diagnstico diferencial complicado y, que requie-re una intervencin teraputica urgente. Hay muy pocos ca-sos comunicados en la literatura, y es necesaria una mejorcomprensin de los aspectos clnicos, causas, fisiopatologa,criterios de diagnstico y tratamiento de este sndrome.
Palabras clave: Hemofagocitosis. Lupus eritematoso sistmico.
Hemophagocytic Syndrome is a clinical conditioncharacterized by the activation of either macrophages orhistiocytes with a prominent hemophagocytosis feature inthe bone marrow and other reticuloendothelial systems. Itleads to the phagocytosis of erythrocytes, leukocytes,platelets and their precursors. The presence ofhemophagocytosis can be associated to infections,malignancies, autoimmune diseases, drugs and a varietyof other medical conditions. We report a case of apreviously healthy 36 year-old woman that developedhemophagocytosis at the same time that fulfilleddiagnostic criteria for systemic lupus erythematosus.Lupus related hemophagocytic syndrome is a rare andpotentially fatal entity. It offers significant differentialdiagnosis challenges and requires urgent therapeuticintervention. There are only few cases reported in theliterature. However, much is still needed in order to betterunderstand its causes, all the immunopathogenicmechanisms, as well as its clinical and therapeutic aspects.
Key words: Hemophagocytic sndrome. Systemic lupuserythematosus.
Hemophagocytic Syndrome (HS) is a clinicopathologic entitycharacterized by increased proliferation and activation ofbenign macrophages with hemophagocytosis throughout thereticuloendothelial system.1 HS may develop as a rare butpotentially fatal complication of several disorders includingmalignancies, drugs, infections and autoimmune disorders.
Patients usually present with an acute febrile illness,sometimes fulminant and lethal. Common manifestations
include high fever, pancytopenia, hepatosplenomegaly,weight loss, lymphadenopathy, abnormal liver function tests(LFTs), hyperferritinemia and high blood triglyceride levels2.Disseminated intravascular coagulation and central nervoussystem dysfunction often ensue, and less frequently thelungs and cardiac tissues are involved.
Although the pathogenic mechanisms still remain unknown,overproduction of pro-inflammatory cytokines, uncontrolledactivation of T cells and macrophages, associated withdecreased natural killer cell and cytotoxic cell functions, seemto be the hallmarks of the immunologic abnormalities in HS3-5.
HS has been reported in patients with various connectivetissue diseases, such as systemic juvenile idiopathic arthritis,
casos clnicos 5499_n_02 12/3/10 10:18 Pgina 247
C. Botelho et al. Acute lupus hemophagocytic syndrome
adult-onset Stills diseases, scleroderma, dermatomyositis,and systemic lupus erythematosus (SLE). HS developed inactive SLE patients without evidences of other underlyingcauses of HS, such as infections or malignancies, has beencalled acute lupus hemophagocytic syndrome (ALHS)6.The occurrence of ALHS was closely related with thepresence of high titers of antinuclear antibodies (ANA)and hypocomplementemia, indicating that the immunecomplex-mediated mechanisms might be responsible forthe pathogenesis of ALHS7.
The first line therapy for the treatment of HS associated withautoimmune diseases includes high-dose corticosteroids andimmunosuppressives, such as cyclophosphamide andcyclosporine8. High-dose intravenous immunoglobulin,9
anticancer drugs and TNF- inhibitor (etanercept) havebeen used in the refractory cases10.
We report a case of SLE with an unusual presentation.The patient presented with acute febrile illness along withprogressive pancytopenia. Concomitant polyarthritis,myositis, nephritis, high titer of antinuclear factor and positivetest for anti-DNA antibody, made her fit the diagnostic criteriaof SLE. No definitive evidence of associated infections wasconfirmed by the bacteriologic, serologic and viral studies.ALHS was diagnosed and the patient was treated with high-dose steroids and cyclophosphamide with an excellentoutcome.
The case is intriguing because ALHS is a rare and life-threatening entity, challenging in differential diagnosis thatrequires urgent therapeutic intervention. Making a systematicreview of the Medline database, we found only a few casesreported in the literature.
Possible pathogenetic mechanisms and currently appliedtherapeutic modalities are also briefly reviewed.
A 36-year-old, caucasian woman, with no previous seriousillnesses, was admitted to our hospital because of continuousfever lasting for 4 weeks and thrombocytopenia. She had nofamily history of HS, and had been well until 2 monthsbefore admission, when she began increased muscleweakness, fever, weight loss, photosensitivity and symmetricpolyarthritis involving the small joints of the hands andwrists.
On clinical examination, she appeared unwell, was febrileat 39 C, with a marked photosensitive rash on her faceand an extensive confluent psoriasiform rash on bothshoulder areas. A vasculitic rash most prominent on thetips of the fingers with periungual erythema and alopeciawas present. The patient also had multiple painful oral
lesions with necrotizing ulceration on the buccal mucosa,upper palate, and lips. No evidence of lymphadenopathywas observed and the rest of the examination wasunremarkable.
Laboratory evaluation on admission revealed normochromicnormocytic anemia (hematocrit 24.5%, haemoglobin 8,1g/dL, red blood cell count 2,9 x 1012/L), leukopenia (whitecell count 2,92 x 103/L with normal differential) and lowplatelet count (PLT 21 x 103/L). Biochemistry wasabnormal for aspartate transaminase 84 U/L (normal range,15-46 U/L), alanine transaminase 200 U/L (normal range,10-66 U/L), gGT 144 U/L (normal range 12-58 U/L),lactic dehydrogenase 1,182 U/L (normal range 313-618U/L) and albumin 21 g/L (normal range 35-50 g/L). Ureaand creatinine were normal.
Erythrocyte sedimentation rate (ESR) was markedly elevatedat 115 mm/ 1sth (normal range
C. Botelho et al. Acute lupus hemophagocytic syndrome
Histological examination at light microscopy showedsclerosis in 6 of the 9 glomeruli, modest mesangialproliferation, tubular atrophy and diffuse interstitial fibrosis(figure 2).
Immunofluorescence staining of 6 glomeruli revealedmesangial deposits of IgM and C3 (figure 3). The diagnosisof Focal Proliferative Lupus Nephritis (class III WHO) wasestablished.
No causative disorder for HS could be detected other thanactive SLE. The diagnosis of acute lupus hemophagocyticsyndrome was established.
The patient was treated with high-dose corticosteroid therapywith intravenous administration of methylprednisolone,1 g/day for 3 days followed by 1 mg/Kg/day p.o. Because ofa partial response, five days after the initiation of thetherapeutic scheme, 1 g of intravenous cyclophosphamidewas added to her treatment.
As the consequence of these treatments the patient improvedclinically, the cytopenias reversed concomitantly with thesuppression of hemophagocytic histiocytes, and theinflammatory indices, LFTs, and ferritin levels all graduallyreturned to normal. Two weeks later she was discharged ingood condition on a tapered dose of oral steroids.
Hematologic involvement in SLE is a very commonfinding, but usually only one or 2 cell lines are affected.Pancytopenia occurs in fewer than 10% of patients and, inthe absence of offending medication (ie, azathioprine,cyclophosphamide, and so on), is usually the result ofperipheral destruction6,11.
In our patient, all laboratory findings pointed to centralmarrow suppression. The extremely high ferritin, withnormal CRP could not be explained by any other factor(ie, infection) than HS, because our patient also did nothave evidence of malignancy or hemochromatosis. Liverdysfunction and excessively high ferritin fit well in HS andare caused by high levels of circulating cytokine (IL-1, IL-6,interferon-gamma [INF-gamma], TNF )12.
HS is a rare entity characterized by the proliferation ofnonneoplastic cells of the histiocyte lineage that phagocytosethe hematopoietic cells. It is usually aggressive, the outcomevaries, and some cases are lethal2,6.
HS can be associated with infection, malignancies,autoimmune diseases, drugs and immunosuppression. Theinf