Macrophage activation syndrome (MAS) is a potentially fatal

condition. It is a rare complication of several autoimmune

disorders, including systemic lupus erythematosus (SLE) and

systemic juvenile idiopathic arthritis (sJIA). The incidence of

MAS associated with SLE is about 0.9–4.6% [1]. MAS is a

multifarious disease, presenting with several signs and symptoms, including high fever, hepatomegaly, splenomegaly,

hemorrhagic manifestations (e.g., purpura), and dysfunction

of the central nervous system, like lethargy. Furthermore,

MAS is characterized by several alterations in laboratory tests,

including pancytopenia, hypofibrinogenemia, hypertriglyceridemia, and hyperferritinemia.

MAS is classified among the group of hemophagocytic

lymphohistiocytosis (HLH), which includes familial HLH

and secondary HLH. Secondary HLH is triggered by several causes, including infection, drugs, malignancy, and

rheumatic disorder [2].

We report a rare case of MAS that occurred as first

manifestation of SLE treated with high dose intravenous

methylprednisolone and oral cyclosporine

Didona, Dario

Feola, Aldo

Granata, Guido

Granata, Massimo

Stifano, Giuseppina

English

PubMed

Macrophage activation syndrome (MAS) is a potentially fatal
condition. It is a rare complication of several autoimmune
disorders, including systemic lupus erythematosus (SLE) and
systemic juvenile idiopathic arthritis (sJIA). The incidence of
MAS associated with SLE is about 0.9–4.6% [1]. MAS is a
multifarious disease, presenting with several signs and symptoms, including high fever, hepatomegaly, splenomegaly,
hemorrhagic manifestations (e.g., purpura), and dysfunction
of the central nervous system, like lethargy. Furthermore,
MAS is characterized by several alterations in laboratory tests,
including pancytopenia, hypofibrinogenemia, hypertriglyceridemia, and hyperferritinemia.
MAS is classified among the group of hemophagocytic
lymphohistiocytosis (HLH), which includes familial HLH
and secondary HLH. Secondary HLH is triggered by several causes, including infection, drugs, malignancy, and
rheumatic disorder [2].
We report a rare case of MAS that occurred as first
manifestation of SLE treated with high dose intravenous
methylprednisolone and oral cyclosporine

Archivio della ricerca- Università di Roma La Sapienza

Case ReportMacrophage Activation Syndrome as Onset ofSystemic Lupus Erythematosus: A Case Report anda Review of the LiteratureGuido Granata,1 Dario Didona,2 Giuseppina Stifano,1 Aldo Feola,1 and Massimo Granata11UOC Immunologia Clinica A, Dipartimento di Medicina Clinica, Policlinico Umberto I,Sapienza Universita` di Roma, 00185 Roma, Italy2I Divisione Dermatologica, Istituto Dermopatico dell’Immacolata IRCCS, 00167 Roma, ItalyCorrespondence should be addressed to Guido Granata; guido.granata@uniroma1.itReceived 20 March 2015; Accepted 23 April 2015Academic Editor: Kenneth C. KalunianCopyright © 2015 Guido Granata et al.This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Macrophage activation syndrome (MAS) is a potentially fatal condition. It belongs to the hemophagocytic lymphohistiocytosisgroup of diseases. In adults, MAS is rarely associated with systemic lupus erythematosus, but it also arises as complication ofseveral systemic autoimmune disorders, like ankylosing spondylitis, rheumatoid arthritis, and adult-onset Still’s disease. Severaltreatment options for MAS have been reported in the literature, including a therapeutic regimen of etoposide, dexamethasone, andcyclosporine. Here we report a case of 42-year-old woman in whomMAS occurred as onset of systemic lupus erythematosus.1. IntroductionMacrophage activation syndrome (MAS) is a potentially fatalcondition. It is a rare complication of several autoimmunedisorders, including systemic lupus erythematosus (SLE) andsystemic juvenile idiopathic arthritis (sJIA). The incidence ofMAS associated with SLE is about 0.9–4.6% [1]. MAS is amultifarious disease, presenting with several signs and symp-toms, including high fever, hepatomegaly, splenomegaly,hemorrhagic manifestations (e.g., purpura), and dysfunctionof the central nervous system, like lethargy. Furthermore,MAS is characterized by several alterations in laboratory tests,including pancytopenia, hypofibrinogenemia, hypertriglyc-eridemia, and hyperferritinemia.MAS is classified among the group of hemophagocyticlymphohistiocytosis (HLH), which includes familial HLHand secondary HLH. Secondary HLH is triggered by sev-eral causes, including infection, drugs, malignancy, andrheumatic disorder [2].We report a rare case of MAS that occurred as firstmanifestation of SLE treated with high dose intravenousmethylprednisolone and oral cyclosporine.2. Report of CaseA previously healthy 42-year-old Caucasian woman wasadmitted to our department presenting an 8-week historyof persistent fever up to 39∘C with shiver unresponsiveto antipyretics, dyspnea, weight loss, malaise, and lethargy.Her medical past history was unremarkable for rheumaticdiseases, severe infections, or immunodeficiency. Her familyhistory also was negative for rheumatic diseases.Our clinical examination showed lymphadenopathy inthe axillae, a widespread rash prominent on her lower legs,symmetric arthritis involving hands and wrists, and bilateralpulmonary basal crackles.We started instrumental and laboratory tests to ruleout the presence of autoimmune, infectious, or neoplasticdisease. Repeated blood and urine cultures and a thoroughinfection screen including a viral panel for herpes zoster,herpes simplex (HSV-1, HSV-2), Epstein-Barr virus (EBV),cytomegalovirus, hepatitis B and C, HIV, coxsackie, and par-vovirus B19 viruses were negative. The tuberculin sensitivitytest (PPD test) was negative.Hindawi Publishing CorporationCase Reports in MedicineVolume 2015, Article ID 294041, 4 pageshttp://dx.doi.org/10.1155/2015/2940412 Case Reports in MedicineLaboratory routine showed pancytopenia, hypergamma-globulinemia, hyperferritinemia (1700mg/dL), hypofibrino-genemia (100mg/dL), hypertriglyceridemia (300mg/dL),and raised levels of alanine aminotransferase (ALT), aspar-tate aminotransferase (AST), 𝛾-glutamyl transferase, lactatedehydrogenase, and serum creatinine. The levels of bloodurea nitrogen and total bilirubin were within reference range.We also repeated ESR every five days, founding a progressivereduction in levels, ranging from 120mm/h to 2mm/h.Immunological screening was positive for ANA(1 : 240 homogenous), anti-dsDNA (40UI/mL), anti-Sm(154.56UI/mL), and anti-RNP (154.21 UI/m). Serum C3and C4 complement factors were low, respectively, 0.43 g/L(range 0.65–1.65 g/L) and 0.07 g/L (range 0.16–0.6 g/L).We performed an abdominal ultrasound exam, foundinga moderate hepatosplenomegaly. Echocardiography revealeda diffuse pericardial effusion without valvular vegetations,oscillating intracardiac mass, abscess, or valvular regurgita-tion. Chest CT examination showed a right-basal parenchy-mal thickening, a bilateral pleural effusion, and multiplemediastinal and axillary lymphadenopathy. Bronchoalveolarlavage revealed neutrophils and bronchial cells smears withsquamousmetaplasia but excluded the presence of neoplasticcells. Total lymphocyte count and CD4+/CD8+ T lymphocyteratio on bronchoalveolar lavage ruled out sarcoidosis. Wealso performed an axillary lymph node biopsy, which wasnegative for malignant lymphoproliferative disorder, and abone marrow biopsy, which detected hemophagocytosis.Thepresence of pancytopenia, polyarthritis, pleural and pericar-dial effusion, and positive ANA, anti-dsDNA, and anti-Smsuggested a diagnosis of LES, according to the Systemic LupusInternational Collaborating Clinics (SLICC) classificationcriteria [3]. At the same time, the particular evolution of theESR in association with the evidence of hemophagocytosisin the bone marrow and the exclusion of infection led us tothemain diagnosis ofMAS, according to the hemophagocyticlymphohistiocytosis (HLH) criteria as follows [2].HLH criteria (at least 5 criteria should be met for MASdiagnosis)temperature ≥38.5∘C for 7 days at least,spleen enlargement,hypertriglyceridemia (>160mg/dL),hypofibrinogenemia (<150mg/dL),ferritin ≥500𝜇g/L,hepatitis,sIL-2 receptor >2400 IU/mL,decreased or absent NK cell activity,hemophagocytic cells in bone marrow, spleen, orlymph nodes,cytopenia in 2 ormore cell lines (hemoglobin<9 g/dL,platelets <100 000/𝜇L, or neutrophils <1000/𝜇L).We started high-dose intravenous methylprednisolone(1 g/day) for three days. Then the drug was switched tooral prednisolone 60mg and cyclosporine 3mg/kg daily.After the end of methylprednisolone therapy, the patient wasapyretic; subsequently skin rash disappeared. The laboratoryparameters returned to normal levels within 2 weeks. Thepatient was discharged from the hospital and is now underfollow-up at the outpatient clinic.3. DiscussionMAS belongs to the group of hemophagocytic lymphohistio-cytosis (HLH), which includes familial HLH and secondaryHLH. The association between HLH and autoimmune orautoinflammatory disease is formally called MAS [4]. MASis commonly associated with sJIA [4] but has also beenreported in Kawasaki disease, adult-onset Still’s disease,rheumatoid arthritis, Sjo¨gren’s syndrome, dermatomyositis,mixed connective tissue disease, systemic sclerosis, and SLE[5]. MAS associated with SLE is rare and the incidence isabout 0.9–4.6% [1]. To date, only 26 cases ofMAS only relatedto the onset of SLE are reported in the literature [5–8].Wefindother several cases of MAS due to SLE in the literature, butthese cases are related to SLE flare-up or complication [5, 9].The diagnosis of MAS is a challenge. Indeed, the clinicalfeatures of MAS-associated SLE and active SLE are verysimilar. In a recent paper it is reported that respiratorysymptoms, jaundice, and lymphadenopathy are present in75% of patients [10]. However, hyperferritinemia is reputedthe best parameter to discriminate between MAS-associatedSLE and active SLE with a sensitivity and specificity of almost100% [1]. Nevertheless, severe leukopenia leads the clinicianto evaluate the presence of MAS [11]. In our patient, thediagnosis of MAS-associated SLE was made according toHLH-2004 criteria (see HLH criteria) [2].To date, the pathogenesis of MAS is not totally known.It is considered an intensive systemic inflammatory reac-tion, caused by a massive dysregulation of macrophage–lymphocyte interactions, which provokes increases in thelevels of several cytokines, particularly TNF-𝛼, M-CSF recep-tors, interleukin- (IL-) 1, IL-6, and interferon gamma- (IFN-)𝛾 [12].Index of suspicion for MAS is higher when an infectionis ruled out or inflammation persists and does not respondto treatment of an underlying infection. In this case, it couldbe useful to start an immunomodulatory therapy even inthe face of infection. To date, several therapeutic optionsare available, including nonbiologic and biologic treatments.The cornerstone is represented by steroids. An intravenousmethylprednisolone pulse therapy (e.g., 30mg/kg for threeconsecutive days) followed by 2-3mg/kg per day is themost common schedule [2]. However, several drugs areused alone or in combination to reduce steroids. Parenteraladministration of cyclosporine A (CSA) (2–7mg/kg/day)is usually started if methylprednisolone lacks improvement[13]. In addition, CSA is used after the discharge of patientsto maintain MAS under control [1]. In patients unresponsiveto steroids and CSA, HLH-2004 treatment protocol could beuseful [5]. This protocol includes dexamethasone, CSA, andetoposide. However, the potential liver toxicity of etoposiderestricts the use of this therapeutic option. Recently, Coca etal. reported the use of antithymocyte globulin (ATG) as anCase Reports in Medicine 3alternative to etoposide [14], but infusion reactions to ATGare commonly described in the literature [15]. Although someauthors reported the development of HLH after adminis-tration of TNF-𝛼 antagonist [16, 17], infliximab could be auseful treatment in refractory cases of MAS [18]. Rituximab[19] and intravenous immunoglobulin (IVIG) [20] have beenemployedwith good results inMAS triggered by viruses, suchas EBV or cytomegalovirus. In the pediatric community, IL-1blockers had become almost standard of care for treatment ofMAS regardless of underlying autoimmune disorder [21–25],although the role of IL-1 in the pathogenesis of MAS is stillonly partially known. However, some authors reported somecases of MAS possibly triggered by anakinra [24, 25].Conflict of InterestsThe authors declare that there is no conflict of interestsregarding the publication of this paper.References[1] S. Vilaiyuk, N. Sirachainan, S. Wanitkun, K. Pirojsakul, and J.Vaewpanich, “Recurrent macrophage activation syndrome asthe primarymanifestation in systemic lupus erythematosus andthe benefit of serial ferritinmeasurements: a case-based review,”Clinical Rheumatology, vol. 32, no. 6, pp. 899–904, 2013.[2] J.-I. Henter, A. Horne, M. Arico´ et al., “HLH-2004: diagnosticand therapeutic guidelines for hemophagocytic lymphohistio-cytosis,” Pediatric Blood and Cancer, vol. 48, no. 2, pp. 124–131,2007.[3] M. Petri, A.-M. Orbai, G. S. Alarco˜n et al., “Derivation andvalidation of the systemic lupus international collaboratingclinics classification criteria for systemic lupus erythematosus,”Arthritis & Rheumatism, vol. 64, no. 8, pp. 2677–2686, 2012.[4] J. L. Stephan, J. Zeller, P. Hubert, C. Herbelin, J. M. Dayer, andA. M. Prieur, “Macrophage activation syndrome and rheumaticdisease in childhood: a report of four new cases,” Clinical andExperimental Rheumatology, vol. 11, no. 4, pp. 451–456, 1993.[5] G. Carvalheiras, D. Anjo, T. Mendonc¸a, C. Vasconcelos, and F.Farinha, “Hemophagocytic syndrome as one of the main pri-mary manifestations in acute systemic lupus erythematosus—case report and literature review,” Lupus, vol. 19, no. 6, pp. 756–761, 2010.[6] M. Tochihara, M. Kasai, Y. Katsumata et al., “Erythematosusplaques with macrophage infiltration as an initial manifestationof macrophage activation syndrome in a patient with systemiclupus erythematosus,” Modern Rheumatology, vol. 18, pp. 1–2,2014.[7] J. Bakshi, S. Hassan, D. D’Cruz, and A. Chan, “Rituximab ther-apy in refractorymacrophage activation syndrome secondary tosystemic lupus erythematosus,” Lupus, vol. 22, no. 14, pp. 1544–1546, 2013.[8] C. A. Egu¨es Dubuc, M. Uriarte Ecenarro, C. Meneses Villalba,V. Aldasoro Ca´ceres, I. Hernando Rubio, and J. BelzuneguiOtano, “Hemophagocytic syndrome as the initial manifestationof systemic lupus erythematosus,” Reumatologia Clinica, vol. 10,no. 5, pp. 321–324, 2014.[9] A. T. Jime´nez, E. S. Vallejo,M. Z. Cruz, A. C. Cruz, and B. S. Jara,“Macrophage activation syndrome as the initial manifestationof severe juvenile onset systemic lupus erythematosus. Favor-able response to cyclophosphamide,” Reumatologı´a Cl´ınica, vol.10, no. 5, pp. 331–335, 2014.[10] X. Li, B.Qu, Y.Nie,G. Zhu,W. Li, and F.Mu, “Clinical features ofmacrophage activation syndrome in the adult northernChinesepopulation,” Lupus, vol. 23, no. 8, pp. 785–792, 2014.[11] A. Parodi, S. Davı`, A. B. Pringe et al., “Macrophage activationsyndrome in juvenile systemic lupus erythematosus: a multina-tional multicenter study of thirty-eight patients,” Arthritis andRheumatism, vol. 60, no. 11, pp. 3388–3399, 2009.[12] Y. Osugi, J. Hara, S. Tagawa et al., “Cytokine productionregulating Th1 and Th2 cytokines in hemophagocytic lympho-histiocytosis,” Blood, vol. 89, no. 11, pp. 4100–4103, 1997.[13] G. S. Schulert and A. A. Grom, “Macrophage activationsyndrome and cytokine-directed therapies,” Best Practice &ResearchClinical Rheumatology, vol. 28, no. 2, pp. 277–292, 2014.[14] A. Coca, K. W. Bundy, B. Marston, J. Huggins, and R. J. Looney,“Macrophage activation syndrome: serological markers andtreatment with anti-thymocyte globulin,” Clinical Immunology,vol. 132, no. 1, pp. 10–18, 2009.[15] A. K. Ali, “Pharmacovigilance analysis of serious adverseevents reported for biologic responsemodifiers used as prophy-laxis against transplant rejection: a real-world postmarketingexperience from the US FDA adverse event reporting sys-tem (FAERS),” International Journal of Organ TransplantationMedicine, vol. 4, no. 2, pp. 62–71, 2013.[16] A. Aouba, M. De Bandt, E. Aslangul, N. Atkhen, and B. Patri,“Haemophagocytic syndrome in a rheumatoid arthritis patienttreated with infliximab,” Rheumatology, vol. 42, no. 6, pp. 800–802, 2003.[17] A. V. Ramanan and R. Schneider, “Macrophage activation syn-drome following initiation of etanercept in a child with systemiconset juvenile rheumatoid arthritis,” Journal of Rheumatology,vol. 30, no. 2, pp. 401–403, 2003.[18] H. Ideguchi, S. Ohno, K. Takase et al., “Successful treatment ofrefractory lupus-associated haemophagocytic lymphohistiocy-tosis with infliximab,” Rheumatology, vol. 46, no. 10, pp. 1621–1622, 2007.[19] G. Bosman, S. M. C. Langemeijer, K. M. Hebeda, J. M. M.Raemaekers, P. Pickkers, and W. J. F. M. van der Velden, “Therole of rituximab in a case of EBV-related lymphoproliferativedisease presenting with haemophagocytosis,” Netherlands Jour-nal of Medicine, vol. 67, no. 8, pp. 364–365, 2009.[20] A. G. Tristano, L. Casanova-Escalona, A. Torres, and M. A.Rodr´ıguez, “Macrophage activation syndrome in a patient withsystemic onset rheumatoid arthritis: rescue with intravenousimmunoglobulin therapy,” Journal of Clinical Rheumatology,vol. 9, no. 4, pp. 253–258, 2003.[21] M. Durand, Y. Troyanov, P. Laflamme, and G. Gregoire,“Macrophage activation syndrome treated with anakinra,” TheJournal of Rheumatology, vol. 37, no. 4, pp. 879–880, 2010.[22] A. Kelly and A. V. Ramanan, “A case of macrophage activationsyndrome successfully treated with anakinra,” Nature ClinicalPractice Rheumatology, vol. 4, no. 11, pp. 615–620, 2008.[23] P. M. Miettunen, A. Narendran, A. Jayanthan, E. M. Behrens,and R. Q. Cron, “Successful treatment of severe paediatricrheumatic disease-associated macrophage activation syndromewith interleukin-1 inhibition following conventional immuno-suppressive therapy: case series with 12 patients,”Rheumatology,vol. 50, no. 2, pp. 417–419, 2011.4 Case Reports in Medicine[24] A. Zeft, R. Hollister, B. Lafleur et al., “Anakinra for systemicjuvenile arthritis: the rocky mountain experience,” Journal ofClinical Rheumatology, vol. 15, no. 4, pp. 161–164, 2009.[25] P. A. Nigrovic, M. Mannion, F. H. M. Prince et al., “Anakinraas first-line disease-modifying therapy in systemic juvenileidiopathic arthritis: report of forty-six patients from an inter-national multicenter series,” Arthritis and Rheumatism, vol. 63,no. 2, pp. 545–555, 2011.

Macrophage Activation Syndrome as Onset of Systemic Lupus Erythematosus: A Case Report and a Review of the Literature

Macrophage activation syndrome (MAS) is a potentially fatal condition. It belongs to the hemophagocytic lymphohistiocytosis group of diseases. In adults, MAS is rarely associated with systemic lupus erythematosus, but it also arises as complication of several systemic autoimmune disorders, like ankylosing spondylitis, rheumatoid arthritis, and adult-onset Still’s disease. Several treatment options for MAS have been reported in the literature, including a therapeutic regimen of etoposide, dexamethasone, and cyclosporine. Here we report a case of 42-year-old woman in whom MAS occurred as onset of systemic lupus erythematosus

Guido Granata

Dario Didona

Giuseppina Stifano

Aldo Feola

Massimo Granata

Directory of Open Access Journals

Case Reports in Medicine

Macrophage activation syndrome (MAS) is a potentially fatal condition. It belongs to the hemophagocytic lymphohistiocytosis group of diseases. In adults, MAS is rarely associated with systemic lupus erythematosus, but it also arises as complication of several systemic autoimmune disorders, like ankylosing spondylitis, rheumatoid arthritis, and adult-onset Still’s disease. Several treatment options for MAS have been reported in the literature, including a therapeutic regimen of etoposide, dexamethasone, and cyclosporine. Here we report a case of 42-year-old woman in whom MAS occurred as onset of systemic lupus erythematosus.</jats:p

Crossref

Case ReportMacrophage Activation Syndrome as Onset ofSystemic Lupus Erythematosus: A Case Report anda Review of the LiteratureGuido Granata,1 Dario Didona,2 Giuseppina Stifano,1 Aldo Feola,1 and Massimo Granata11UOC Immunologia Clinica A, Dipartimento di Medicina Clinica, Policlinico Umberto I,Sapienza Universita` di Roma, 00185 Roma, Italy2I Divisione Dermatologica, Istituto Dermopatico dell’Immacolata IRCCS, 00167 Roma, ItalyCorrespondence should be addressed to Guido Granata; guido.granata@uniroma1.itReceived 20 March 2015; Accepted 23 April 2015Academic Editor: Kenneth C. KalunianCopyright © 2015 Guido Granata et al.This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Macrophage activation syndrome (MAS) is a potentially fatal condition. It belongs to the hemophagocytic lymphohistiocytosisgroup of diseases. In adults, MAS is rarely associated with systemic lupus erythematosus, but it also arises as complication ofseveral systemic autoimmune disorders, like ankylosing spondylitis, rheumatoid arthritis, and adult-onset Still’s disease. Severaltreatment options for MAS have been reported in the literature, including a therapeutic regimen of etoposide, dexamethasone, andcyclosporine. Here we report a case of 42-year-old woman in whomMAS occurred as onset of systemic lupus erythematosus.1. IntroductionMacrophage activation syndrome (MAS) is a potentially fatalcondition. It is a rare complication of several autoimmunedisorders, including systemic lupus erythematosus (SLE) andsystemic juvenile idiopathic arthritis (sJIA). The incidence ofMAS associated with SLE is about 0.9–4.6% [1]. MAS is amultifarious disease, presenting with several signs and symp-toms, including high fever, hepatomegaly, splenomegaly,hemorrhagic manifestations (e.g., purpura), and dysfunctionof the central nervous system, like lethargy. Furthermore,MAS is characterized by several alterations in laboratory tests,including pancytopenia, hypofibrinogenemia, hypertriglyc-eridemia, and hyperferritinemia.MAS is classified among the group of hemophagocyticlymphohistiocytosis (HLH), which includes familial HLHand secondary HLH. Secondary HLH is triggered by sev-eral causes, including infection, drugs, malignancy, andrheumatic disorder [2].We report a rare case of MAS that occurred as firstmanifestation of SLE treated with high dose intravenousmethylprednisolone and oral cyclosporine.2. Report of CaseA previously healthy 42-year-old Caucasian woman wasadmitted to our department presenting an 8-week historyof persistent fever up to 39∘C with shiver unresponsiveto antipyretics, dyspnea, weight loss, malaise, and lethargy.Her medical past history was unremarkable for rheumaticdiseases, severe infections, or immunodeficiency. Her familyhistory also was negative for rheumatic diseases.Our clinical examination showed lymphadenopathy inthe axillae, a widespread rash prominent on her lower legs,symmetric arthritis involving hands and wrists, and bilateralpulmonary basal crackles.We started instrumental and laboratory tests to ruleout the presence of autoimmune, infectious, or neoplasticdisease. Repeated blood and urine cultures and a thoroughinfection screen including a viral panel for herpes zoster,herpes simplex (HSV-1, HSV-2), Epstein-Barr virus (EBV),cytomegalovirus, hepatitis B and C, HIV, coxsackie, and par-vovirus B19 viruses were negative. The tuberculin sensitivitytest (PPD test) was negative.Hindawi Publishing CorporationCase Reports in MedicineVolume 2015, Article ID 294041, 4 pageshttp://dx.doi.org/10.1155/2015/2940412 Case Reports in MedicineLaboratory routine showed pancytopenia, hypergamma-globulinemia, hyperferritinemia (1700mg/dL), hypofibrino-genemia (100mg/dL), hypertriglyceridemia (300mg/dL),and raised levels of alanine aminotransferase (ALT), aspar-tate aminotransferase (AST), 𝛾-glutamyl transferase, lactatedehydrogenase, and serum creatinine. The levels of bloodurea nitrogen and total bilirubin were within reference range.We also repeated ESR every five days, founding a progressivereduction in levels, ranging from 120mm/h to 2mm/h.Immunological screening was positive for ANA(1 : 240 homogenous), anti-dsDNA (40UI/mL), anti-Sm(154.56UI/mL), and anti-RNP (154.21 UI/m). Serum C3and C4 complement factors were low, respectively, 0.43 g/L(range 0.65–1.65 g/L) and 0.07 g/L (range 0.16–0.6 g/L).We performed an abdominal ultrasound exam, foundinga moderate hepatosplenomegaly. Echocardiography revealeda diffuse pericardial effusion without valvular vegetations,oscillating intracardiac mass, abscess, or valvular regurgita-tion. Chest CT examination showed a right-basal parenchy-mal thickening, a bilateral pleural effusion, and multiplemediastinal and axillary lymphadenopathy. Bronchoalveolarlavage revealed neutrophils and bronchial cells smears withsquamousmetaplasia but excluded the presence of neoplasticcells. Total lymphocyte count and CD4+/CD8+ T lymphocyteratio on bronchoalveolar lavage ruled out sarcoidosis. Wealso performed an axillary lymph node biopsy, which wasnegative for malignant lymphoproliferative disorder, and abone marrow biopsy, which detected hemophagocytosis.Thepresence of pancytopenia, polyarthritis, pleural and pericar-dial effusion, and positive ANA, anti-dsDNA, and anti-Smsuggested a diagnosis of LES, according to the Systemic LupusInternational Collaborating Clinics (SLICC) classificationcriteria [3]. At the same time, the particular evolution of theESR in association with the evidence of hemophagocytosisin the bone marrow and the exclusion of infection led us tothemain diagnosis ofMAS, according to the hemophagocyticlymphohistiocytosis (HLH) criteria as follows [2].HLH criteria (at least 5 criteria should be met for MASdiagnosis)temperature ≥38.5∘C for 7 days at least,spleen enlargement,hypertriglyceridemia (>160mg/dL),hypofibrinogenemia (<150mg/dL),ferritin ≥500𝜇g/L,hepatitis,sIL-2 receptor >2400 IU/mL,decreased or absent NK cell activity,hemophagocytic cells in bone marrow, spleen, orlymph nodes,cytopenia in 2 ormore cell lines (hemoglobin<9 g/dL,platelets <100 000/𝜇L, or neutrophils <1000/𝜇L).We started high-dose intravenous methylprednisolone(1 g/day) for three days. Then the drug was switched tooral prednisolone 60mg and cyclosporine 3mg/kg daily.After the end of methylprednisolone therapy, the patient wasapyretic; subsequently skin rash disappeared. The laboratoryparameters returned to normal levels within 2 weeks. Thepatient was discharged from the hospital and is now underfollow-up at the outpatient clinic.3. DiscussionMAS belongs to the group of hemophagocytic lymphohistio-cytosis (HLH), which includes familial HLH and secondaryHLH. The association between HLH and autoimmune orautoinflammatory disease is formally called MAS [4]. MASis commonly associated with sJIA [4] but has also beenreported in Kawasaki disease, adult-onset Still’s disease,rheumatoid arthritis, Sjo¨gren’s syndrome, dermatomyositis,mixed connective tissue disease, systemic sclerosis, and SLE[5]. MAS associated with SLE is rare and the incidence isabout 0.9–4.6% [1]. To date, only 26 cases ofMAS only relatedto the onset of SLE are reported in the literature [5–8].Wefindother several cases of MAS due to SLE in the literature, butthese cases are related to SLE flare-up or complication [5, 9].The diagnosis of MAS is a challenge. Indeed, the clinicalfeatures of MAS-associated SLE and active SLE are verysimilar. In a recent paper it is reported that respiratorysymptoms, jaundice, and lymphadenopathy are present in75% of patients [10]. However, hyperferritinemia is reputedthe best parameter to discriminate between MAS-associatedSLE and active SLE with a sensitivity and specificity of almost100% [1]. Nevertheless, severe leukopenia leads the clinicianto evaluate the presence of MAS [11]. In our patient, thediagnosis of MAS-associated SLE was made according toHLH-2004 criteria (see HLH criteria) [2].To date, the pathogenesis of MAS is not totally known.It is considered an intensive systemic inflammatory reac-tion, caused by a massive dysregulation of macrophage–lymphocyte interactions, which provokes increases in thelevels of several cytokines, particularly TNF-𝛼, M-CSF recep-tors, interleukin- (IL-) 1, IL-6, and interferon gamma- (IFN-)𝛾 [12].Index of suspicion for MAS is higher when an infectionis ruled out or inflammation persists and does not respondto treatment of an underlying infection. In this case, it couldbe useful to start an immunomodulatory therapy even inthe face of infection. To date, several therapeutic optionsare available, including nonbiologic and biologic treatments.The cornerstone is represented by steroids. An intravenousmethylprednisolone pulse therapy (e.g., 30mg/kg for threeconsecutive days) followed by 2-3mg/kg per day is themost common schedule [2]. However, several drugs areused alone or in combination to reduce steroids. Parenteraladministration of cyclosporine A (CSA) (2–7mg/kg/day)is usually started if methylprednisolone lacks improvement[13]. In addition, CSA is used after the discharge of patientsto maintain MAS under control [1]. In patients unresponsiveto steroids and CSA, HLH-2004 treatment protocol could beuseful [5]. This protocol includes dexamethasone, CSA, andetoposide. However, the potential liver toxicity of etoposiderestricts the use of this therapeutic option. Recently, Coca etal. reported the use of antithymocyte globulin (ATG) as anCase Reports in Medicine 3alternative to etoposide [14], but infusion reactions to ATGare commonly described in the literature [15]. Although someauthors reported the development of HLH after adminis-tration of TNF-𝛼 antagonist [16, 17], infliximab could be auseful treatment in refractory cases of MAS [18]. Rituximab[19] and intravenous immunoglobulin (IVIG) [20] have beenemployedwith good results inMAS triggered by viruses, suchas EBV or cytomegalovirus. In the pediatric community, IL-1blockers had become almost standard of care for treatment ofMAS regardless of underlying autoimmune disorder [21–25],although the role of IL-1 in the pathogenesis of MAS is stillonly partially known. However, some authors reported somecases of MAS possibly triggered by anakinra [24, 25].Conflict of InterestsThe authors declare that there is no conflict of interestsregarding the publication of this paper.References[1] S. Vilaiyuk, N. Sirachainan, S. Wanitkun, K. Pirojsakul, and J.Vaewpanich, “Recurrent macrophage activation syndrome asthe primarymanifestation in systemic lupus erythematosus andthe benefit of serial ferritinmeasurements: a case-based review,”Clinical Rheumatology, vol. 32, no. 6, pp. 899–904, 2013.[2] J.-I. Henter, A. Horne, M. Arico´ et al., “HLH-2004: diagnosticand therapeutic guidelines for hemophagocytic lymphohistio-cytosis,” Pediatric Blood and Cancer, vol. 48, no. 2, pp. 124–131,2007.[3] M. Petri, A.-M. Orbai, G. S. Alarco˜n et al., “Derivation andvalidation of the systemic lupus international collaboratingclinics classification criteria for systemic lupus erythematosus,”Arthritis & Rheumatism, vol. 64, no. 8, pp. 2677–2686, 2012.[4] J. L. Stephan, J. Zeller, P. Hubert, C. Herbelin, J. M. Dayer, andA. M. Prieur, “Macrophage activation syndrome and rheumaticdisease in childhood: a report of four new cases,” Clinical andExperimental Rheumatology, vol. 11, no. 4, pp. 451–456, 1993.[5] G. Carvalheiras, D. Anjo, T. 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Grom, “Macrophage activationsyndrome and cytokine-directed therapies,” Best Practice &ResearchClinical Rheumatology, vol. 28, no. 2, pp. 277–292, 2014.[14] A. Coca, K. W. Bundy, B. Marston, J. Huggins, and R. J. Looney,“Macrophage activation syndrome: serological markers andtreatment with anti-thymocyte globulin,” Clinical Immunology,vol. 132, no. 1, pp. 10–18, 2009.[15] A. K. Ali, “Pharmacovigilance analysis of serious adverseevents reported for biologic responsemodifiers used as prophy-laxis against transplant rejection: a real-world postmarketingexperience from the US FDA adverse event reporting sys-tem (FAERS),” International Journal of Organ TransplantationMedicine, vol. 4, no. 2, pp. 62–71, 2013.[16] A. Aouba, M. De Bandt, E. Aslangul, N. Atkhen, and B. Patri,“Haemophagocytic syndrome in a rheumatoid arthritis patienttreated with infliximab,” Rheumatology, vol. 42, no. 6, pp. 800–802, 2003.[17] A. V. Ramanan and R. Schneider, “Macrophage activation syn-drome following initiation of etanercept in a child with systemiconset juvenile rheumatoid arthritis,” Journal of Rheumatology,vol. 30, no. 2, pp. 401–403, 2003.[18] H. Ideguchi, S. Ohno, K. Takase et al., “Successful treatment ofrefractory lupus-associated haemophagocytic lymphohistiocy-tosis with infliximab,” Rheumatology, vol. 46, no. 10, pp. 1621–1622, 2007.[19] G. Bosman, S. M. C. Langemeijer, K. M. Hebeda, J. M. M.Raemaekers, P. Pickkers, and W. J. F. M. van der Velden, “Therole of rituximab in a case of EBV-related lymphoproliferativedisease presenting with haemophagocytosis,” Netherlands Jour-nal of Medicine, vol. 67, no. 8, pp. 364–365, 2009.[20] A. G. Tristano, L. Casanova-Escalona, A. Torres, and M. A.Rodr´ıguez, “Macrophage activation syndrome in a patient withsystemic onset rheumatoid arthritis: rescue with intravenousimmunoglobulin therapy,” Journal of Clinical Rheumatology,vol. 9, no. 4, pp. 253–258, 2003.[21] M. Durand, Y. Troyanov, P. Laflamme, and G. Gregoire,“Macrophage activation syndrome treated with anakinra,” TheJournal of Rheumatology, vol. 37, no. 4, pp. 879–880, 2010.[22] A. Kelly and A. V. Ramanan, “A case of macrophage activationsyndrome successfully treated with anakinra,” Nature ClinicalPractice Rheumatology, vol. 4, no. 11, pp. 615–620, 2008.[23] P. M. Miettunen, A. Narendran, A. Jayanthan, E. M. Behrens,and R. Q. Cron, “Successful treatment of severe paediatricrheumatic disease-associated macrophage activation syndromewith interleukin-1 inhibition following conventional immuno-suppressive therapy: case series with 12 patients,”Rheumatology,vol. 50, no. 2, pp. 417–419, 2011.4 Case Reports in Medicine[24] A. Zeft, R. Hollister, B. Lafleur et al., “Anakinra for systemicjuvenile arthritis: the rocky mountain experience,” Journal ofClinical Rheumatology, vol. 15, no. 4, pp. 161–164, 2009.[25] P. A. Nigrovic, M. Mannion, F. H. M. Prince et al., “Anakinraas first-line disease-modifying therapy in systemic juvenileidiopathic arthritis: report of forty-six patients from an inter-national multicenter series,” Arthritis and Rheumatism, vol. 63,no. 2, pp. 545–555, 2011.Submit your manuscripts athttp://www.hindawi.comStem CellsInternationalHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014MEDIATORSINFLAMMATIONofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Behavioural NeurologyEndocrinologyInternational Journal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Disease MarkersHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014BioMed Research InternationalOncologyJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Oxidative Medicine and Cellular LongevityHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014PPAR ResearchThe Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Journal ofObesityJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014 Computational and  Mathematical Methods in MedicineOphthalmologyJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Diabetes ResearchJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Research and TreatmentAIDSHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Gastroenterology Research and PracticeHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Parkinson’s DiseaseEvidence-Based Complementary and Alternative MedicineVolume 2014Hindawi Publishing Corporationhttp://www.hindawi.com

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Macrophage Activation Syndrome as Onset of Systemic Lupus Erythematosus: A Case Report and a Review of the Literature

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