Print version ISSN 0482-5004
Rev. Bras. Reumatol. vol.52 no.5 São Paulo Sept./Oct. 2012
Marco Antonio Cuellar ArnezI; Mario Newton Leitão de AzevedoII; Blanca Elena Rios Gomes BicaIII
IPostgraduate in Rheumatology, Universidade Federal do Rio de Janeiro - UFRJ; Master's degree candidate in Internal Medicine, Rheumatology Service, UFRJ
IIPhD in Internal Medicine, UFRJ; Associate Professor in Rheumatology, Faculdade de Medicina, UFRJ
IIIAdjunct Professor in Rheumatology, Faculdade de Medicina, UFRJ; Head of the Rheumatology Service, Hospital Universitário Clementino Fraga Filho - HUCFF-UFRJ
The macrophagic syndrome or reactive haemophagocytic syndrome (RHS) is a complication resulting from systemic inflammatory diseases and may also be related to malign neoplasias, immunodeficiencies and to a variety of infections caused by virus, bacteria, and fungus. It is characterized by an excessive activation of macrophages and histiocytes along with intense hemophagocytosis in bone marrow and reticulum-endothelial system, causing the phagocytosis of erythrocytes, leukocytes, platelets, and their precursors. The clinical manifestations are fever, hepatosplenomegaly, lymphadenomegalies, neurological involvement, variable degrees of cytopenias, hyperferritinemia, liver disorders, intravascular coagulation, and multiple organs failure. We report a rare case of recurrent RHS complication in a systemic lupus erythematosus male patient after two years. Although extremely rare it has evolved with an improvement after a pulse methilprednisolone and cyclophosphamide therapy.
Keywords: reactive macrophage syndrome, hemophagocytic lymphohistiocytosis, systemic lupus erythematosus.
The reactive haemophagocytic syndrome (RHS), well-known as hemophagocytic lymphohistiocytosis, is a potentially lethal, rare, clinical, and pathological condition characterized by a massive production of proinflammatory cytokines, which causes clinical manifestations and frequently results in multiple organs failure. The clinical picture presents fever, hepatosplenomegaly, pancytopenia, limphadenopathy, neurological involvement, and comsumption coagulopathy.1,2 It can be associated with systemic infections, immunodeficiencies, lymphoproliferative, and autoimmune diseases. Among the inflammatory diseases the juvenile idiopathic arthritis with systemic onset is the most frequently described disorder.3-5 Its clinical presentation in juvenile systemic lupus erythematosus (SLE)6 and in juvenile dermatomyositis7 is sporadic.
We report a case involving a patient diagnosed with SLE who presented with two RHS episodes. The clinical picture was controlled with the recognition of complication and appropriate treatment based on corticotherapy, pulses of cyclophosphamide (CPM) and cyclosporine.
A 49-year-old male patient presented with polyarthralgia, weight loss of 15 kg in a year, evening fever, night sudoresis, positive antinuclear factor, pointed pattern (1:200), anti-RNP antibodies (1:500), positive anti-Ro and anti-Sm antibodies, polyclonal hypergammaglobulinemia, hemolytic anemia, and 1 g/24 hours proteinuria. He was diagnosed with SLE and treated using pulse therapy associated with methylprednisolone (three pulses) and CPM (12 monthly pulses), followed by prednisone and azathioprine, obtaining a controlled disease.
Four years later the patient returned reporting daily fever (39ºC-40ºC) for a month, generalized weakness, dorsalgia, sudoresis, and discrete weight loss, when he was readmitted to hospital for better investigation. The routine laboratory examinations showed increased levels of transaminases, leukopenia, thrombocytopenia, positive direct Coombs, elevated erythrocyte sedimentation rate, hyperferritinemia, in addition to a 1240-mg proteinuria level in 24-hour specimen of urine along with negative blood culture and urine culture (Table 1).
The echocardiogram revealed grade I diastolic dysfunction with a mild increase in the volume of right heart cavities associated with a slight tricuspid incompetence and 37-mmHg pulmonary arterial pressure. It was detected hepatomegaly. The peripheral blood exam showed anisopoikilocytosis, tear shaped erythrocytes, acanthocytes, neutrophils presenting the Pelger-Huet anomaly, and a mild thrombocytopenia. The bone marrow aspiration procedure revealed erythroid hypoplasia, interrupted maturation with a discrete dyserythropoietic anemia, presence of histiocytes which have phagocytes absorbing erythroid and myeloid line cells, normal hypogranular myeloid cells, and megakaryocytes. The patient improved his clinical picture after being treated with methylprednisolone pulse therapy.
Two years later the patient returned with worsening of overall health status, presenting fever up to 40ºC and dyspnea to minimal efforts which started 18 days before his return. He was admitted to the hospital and the antibiotic therapy was introduced evolving with disorientation. The patient underwent cranial computed tomography which presented no changes. The cerebrospinal fluid (CSF) analysis showed 101 cell/m3, with 94% mononucleated cells, 100 mg/dL protein and 22 mg/dL glucose. The patient underwent therapy with acyclovir.
The patient presented an increase in hepatic enzymes, pancytopenia, moderate anemia and hyperferritinemia. CSF cultures were negative for fungi, acid-fast bacilli, bacteria, mycobacteria, and cytomegalovirus. The patient evolved to acute lung edema and to acute respiratory distress, being performed orotracheal intubation and mechanical ventilation. It was introduced the pulse of methylprednisolone therapy for three days with no significant improvement. Cyclosporine has been gradually introduced for controlling the clinical picture. The patient was discharged from hospital and treated with low doses of corticoids and cyclosporine.
We describe a rare case involving a patient with SLE who developed an episode of RHS with recurrence of this complication after two years. There are several triggering factors but the infectious processes are important starting elements for this complication.8,9
The clinical manifestations can be explained by overproduction of pro-inflammatory cytokines (interleukin 1, tumoral necrosis factor, gamma-interferon, among others), which are responsible for this severe complication.10-12
The diagnostic difficulty is due to the fact that disease activity shares common signs and symptoms, in addition to clinical pictures associated with infectious agents.13,14 According to many authors the presence hiperferritinemia is a highly suggestive sign of reactive macrophage disease and this factor associated with the bone marrow aspirate has defined RHS clinical features.15 The patient presented the diagnostic criteria for hemophagocytic syndrome proposed by the Histiocyte Society16 and by Imashuku,17 Tsuda,18 and Ishikura,8 characterized by the presence of fever, cytopenia, hyperferritinemia, an increase in lactate dehydrogenase, and prominent hemophagocytosis in bone marrow aspirate. Although the SLE in itself may trigger this severe complication,19 we can not exclude the possibility that an infectious clinical picture may have been the starting point in our patient's second episode, considering that the CSF clinical features were compatible with viral infection. The clinical features such as fever, pancitopenia, and hiperferritinemia have also suggested the possibility of recurrent RHS which improved after immunosupression, but with no confirmation due to lack of exams showing the clinical picture as peripheral blood studies and myelogram. In many cases is not possible to determine the triggering etiological factor of hemophagocytosis.
Good responses to the pulse methylprednisolone and cyclophosphamide therapies following the cyclosporine treatment have already been described in medical literature presenting satisfactory results in many case reports.8
The difficulty for excluding an associated infection delays the beginning of immunosuppressive therapy, which is critical for treatment and for this incident evolutionary process. Hemophagocytosis must be suspected in patients with systemic inflammatory diseases such as SLE and those patients who present with clinical and/or laboratorial manifestations suggestive of RHS.
1. Ravelli A. Macrophage activation syndrome. Curr Opin Rheumatol 2002;14(5):548-52. [ Links ]
2. Romanou V, Hatzinikolaou P, Mavragani KI, Meletis J, Vaiopoulos G. Lupus erythematosus complicated by hemophagocytic syndrome. J Clin Rheumatol 2006;12(6):301-3. [ Links ]
3. Sawhney S, Woo P, Murray KJ. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch Dis Child 2001;85(5):421-6. [ Links ]
4. Grom AA. Natural killer cell dysfunction: a common pathway in systemic-onset juvenile rheumatoid arthritis, macrophage activation syndrome, and hemophagocytic lymphohistiocytosis? Arthritis Rheum 2004;50(3):689-98. [ Links ]
5. Avcin T, Tse SM, Schneider R, Ngan B, Silverman ED. Macrophage activation syndrome as the presenting manifestation of rheumatic diseases in childhood. J Pediatr 2006;148(5):683-6. [ Links ]
6. Javier RM, Sibilia J, Offner C, Albert A, Kuntz JL. Macrophage activation in lupus. Rev Rheum Ed Fr 1993;60(11):831-5. [ Links ]
7. Kobayashi I, Yamada M, Kawamura N, Kobayashi R, Okano M, Kobayashi K. Platelet-specific hemophagocytosis in a patient with juvenile dermatomyositis. Acta Paediatr 2000;89(5):617-9. [ Links ]
8. Kumakura S, Ishikura H, Kondo M, Murakawa Y, Masuda J, Kobayashi S. Autoimmune-associated hemophagocytic syndrome. Mod Rheumatol 2004;14(3):205-15. [ Links ]
9. Janka GE. Hemophagocytic syndromes. Blood Rev 2007;21(5):245-53. [ Links ]
10. Silva CA, Silva CH, Robazzi TC, Lotito AP, Mendroni Junior A, Jacob CM et al. Síndrome de ativação macrofágica associada com artrite idiopática juvenil sistêmica. J Pediatr (Rio J) 2004;80(6):517-22. [ Links ]
11. Rosa DJ, Nogueira CM, Bonfante HL, Machado LG, Rodrigues DO, Fernandes GC et al. Síndrome de ativação macrofágica após o uso de Leflunomida em paciente com doença de Still do adulto. Relato de caso. Rev Bras Reumatol 2007;47(3):219-22. [ Links ]
12. Behrens EM. Macrophage activation syndrome in rheumatic disease: what is the role of the antigen presenting cell? Autoimmun Rev 2008;7(4):305-8. [ Links ]
13. Tanaka Y, Seo R, Nagai Y, Mori M, Togami K, Fujita H et al. Systemic lupus erythematosus complicated by cytomegalovirusinduced hemophagocytic syndrome and pneumonia. Nihon Rinsho Meneki Gakkai Kaishi 2008;31(1):71-5. [ Links ]
14. Arceci RJ. When T cells and macrophages do not talk: the hemophagocytic syndromes. Curr Opin Hematol 2008;15(4):359-67. [ Links ]
15. Favara BE, Feller AC, Pauli M, Jaffe ES, Weiss LM, Arico M et al. Contemporary classification of histiocytic disorders. The WHO Committee On Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society. Med Pediatric Oncol 1997;29(3):157-66. [ Links ]
16. Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemofaphagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol 1991;18(1):29-33. [ Links ]
17. Imashuku S. Differential diagnosis of hemophagocytic syndrome: underlying disorders and selection of de most effective treatment. Int J Hematol 1997;66(2):135-51. [ Links ]
18. Tsuda H. Hemophagocytic syndrome (HPS) in children and adults. Int J Hematol 1997;65(3):215-26. [ Links ]
19. Papo T, André MH, Amoura Z, Lortholary O, Tribout B, Guillevin L et al. The spectrum of reactive hemophagocytic syndrome in systemic lupus erythematosus. J Rheumatol 1999;26(4):927-30. [ Links ]
Correspondence to: Received on 04/14/2011 Rheumatology Service, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro - HUCFF-UFRJ.
Marco Antonio Cuellar Arnez
Hospital Universitário Clementino Fraga Filho. Universidade Federal do Rio de Janeiro
Av. Prof. Rodolpho Paulo Rocco, 255 - Cidade Universitária - Ilha do Fundão
Rio de Janeiro, RJ, Brazil. CEP: 21941-913
Approved on 06/27/2012
The authors declare no conflicts of interest.
Received on 04/14/2011
Rheumatology Service, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro - HUCFF-UFRJ.