Clinical and Experimental Rheumatology 2002; 20: 121-123. EDITORIAL Is activation In 1985, Hadchouel, Prieur and Griselli where (5). In this essay I suggest that described a syndrome characterized by MAS be placed in terms of nosology syndrome a new entity? h e m at o l ogi c, n e u ro l ogic and hep at i c and classification where it belongs Ð abnormalities in association with sys- n a m e ly, among the histiocytic disor- B.H. Athreya temic onset JRA (1). Although such an ders. This should facilitate better com- association was known and individual munication between different special- Balu H. Athreya, MD, Division of Rheuma- case reports had been written by others, ties, and help in the development of tology, Alfred I. duPont Hospital for Chil- these authors recognized the similari- uniform diagnostic criteria and, hope- dren, Wilmington, Deleware, and Professor ties of this syndrome to Familial Hemo- fully, uniform treatment strategies. of Pediatrics, Thomas Jefferson University, p h ago cytic Syndrome and Chediak- The term “ h i s t i o cy t e s ” i n cludes two Jefferson Medical College, Philadelphia Higashi syndrome in which macropha- groups of immune cells Ð the - Pennsylvania, USA. ges play an important role.Therefore presenting dendritic cells and the anti- Please address correspondence to: the authors suggested the term Macro- ge n - p rocessing macro p h ages. Condi- Balu H. Athreya, MD, Pediatric Rheuma- tology, Alfred I. duPont Hospital for Chil- phage Activation Syndrome (2). This tions characterized by the proliferation dren, 1600 Rockland Road, P.O. Box 269, name is now well-entrenched in pedi- and accumulation of and Wilmington, Deleware 19899, USA. atric rheumatology (3, 4). dendritic cells are grouped under the Received on February 5, 2002; accepted The same name, Macrophage Activa- cl a s s i fi c ation of . At the on February 11, 2002. tion Syndrome (MAS), is pre s e n t ly initiative of Giulio D’Angio, MD, an applied by rheumatologists to the other I n t e rn ational Society wa s © Copyright CLINICAL AND EXPERIMEN- reactive forms of hemophagocytic syn- formed in 1985. The Writing Group of TAL RHEUMATOLOGY 2002. drome, which could suggest that this this society recommended a classifica- represents a unique, hitherto unknown tion of disorders associated with histio- syndrome. Consequently, specialists in cytosis as follows: Class I - Langerhans other fields (such as infectious diseases cell histiocytosis; Class II - Non-Lan- and hematology) who are very familiar gerhans cell histiocytosis and Class III with the syndrome are often unaware of - (6). Subse- the rheumatology literature on this sub- quently this classification was modified ject. For example, a recent review of ( Table I) and these conditions we re secondary hemophagocytic lymphohis- d ivided into the subgroups dendri t i c tiocytic syndromes in a monograph on c e l l - re l ated disord e rs , m a c ro p h age - histiocytic disorders published in 1998 related disorders, and malignant disor- did not mention the word MAS any- ders of (7).

Table I. Classification of histiocytic disorders (7).

Disorders of varied biological behaviour -related disorders histiocytosis Secondary dendritic cellprocesses and related disorders Solitary histiocytomas of various dendritic cell phenotypes

Macrophage-related disorders Hemophagocytic syndromes Primary hemophagocytic lymphohistiocytosis Secondary hemophagocytic syndromes Infection-related Malignancy-related Other Roasi-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) Solitary with macrophage phenotype Others including multicentric and generalized eruptive histiocytoma

Malignant Disorders related malignant disorders Leukemia Extramedullary monocyte tumor or sarcoma ( monocyte counterpart of granulocytic sarcoma) Dendritic cell-related (localized or disseminated) Specific phenotype; follicular dendritic cell, interdigitating dendritic cell etc. Macrophage related histiocytic sarcoma (localized or generalized)

121 EDITORIAL Macrophage activation syndrome: a new entity? / B.H. Athreya

Table II. Diagnostic guidelines for hemophagocytic lymphohistocytosis (HLH). the initial manifestation, thus masking the features of the primary malignancy. Clinical criteria Treatment depends on the type of ma- *Fever lignancy involved (5). *Splenomegaly R h e u m atic disease-associated hemo- Laboratory criteria p h ago cytic syndrome has been seen *Cytopenias (affecting ³ 2 of 3 lineages in the peripheral blood): most often with systemic onset JRA. Hemoglobin (<90 g/L) This is the entity that has been named Platelets (<100 x 109/L) Neutrophils (<1.0 x 109/L) MAS. I have observed this syndrome in *Hypertriglyceridemia and/or hypofibrinogenemia (fasting triglycerides ³ 2.0 mmol/L or ³ 3SD of the association with SLE as well and as the normal value for age, fibrinogen £ 1.5 g/L or £ 3 SD) initial pre s e n t ation of systemic JRA. St e ro i d s , cycl o s p o r ine (13) and more re- Histopathologic criteria *Hemophagocytosis in or or lymph nodes. No evidence of malignancy cently anti-TNF agents (14), have been used with success in the treatment of *All criteria required for the diagnosis of HLH. In addition, the diagnosis of FHL is justified by a this syndrome. positive family history, and parental consanguinity is suggestive. Signs and symptoms in the reactive or Comments: se c o n d a r y for m of hemophagoc ytic lym - 1. If hemophagocytic activity is not proven at the time of presentation, a further search for hemo- p h o h i s t i o cytosis (IAHS, MAHS and phagocytic activity is encouraged. If the bone marrow specimen is not conclusive, material maybe RAHS) are almost identical to those obtained from other organs,especially the lymph nodes or spleen (fine needle aspiration ). seen in the familial variety. High fever, Serial marrow aspirates over time may also be helpful. 2. The following findings may provide strong supportive evidence for the diagnosis: (a) Spinal fluid clouding of the consciousness and sei- pleocytosis (mononuclear cells); (b) histologic picture in the resembling chronic persistent zures may be dramatic.There is gener- hepatitis (biopsy); (c) low natural killer cell activity. a l i zed ly m p h a d e n o p at hy and hep at o- 3. Other abnormal clinical and laboratory findings consistent with the diagnosis are as follows:cere- s p l e n o m ega ly. Th e re may be a ra s h bromeningeal symptoms; enlargement; jaundice; edema; skin rash; hepatic enzyme abnormalities; hyperferritinemia; hypoproteinemia; hyponatremia; spinal fluid protein ¹ ; VLDL which is different from the rash of JRA ¹ ; HDL ; circulating soluble IL-2 receptor ¹ . or petechiae and purpura due to throm- bocytopenia. There may also be fea- Reproduced with permission from Hematol Oncol Clin North Am 1998; 12: 425. tures of mild DIC. There is definitely th ro m b o c ytopenia. Howeve r, the pre- Our interest is in the macrophage-relat- a s s o c i ated hemophago cytic syndro m e sence of should alert the ed disorders. As can be seen in Table I, (IAHS or VAHS) during the first attack. clinician, particularly in systemic JRA. hemophagocytic syndromes form one Mortality is very high, with a median A b n o rmal liver function studies of the subsets in this group. Among the survival of 2 months from the time of include elevated aminotransferase and secondary hemophagocytic syndromes diagnosis. Recently a defect in the gene bilirubin levels and a prolonged pro- (also called re a c t ive hemophago cy t i c for perforin has been found in some t h rombin time. The most dra m at i c s y n d ro m e s ) , the infe c t i o n - a s s o c i at e d patients with this syndrome (10). Earli- clues are a fall in the sedimentation rate (IAHS) and malignancy - a s s o c i at e d er tre atments using cort i c o s t e ro i d s , in the face of a worsening clinical situ- (MAHS) forms are well known. The cyclosporine and ATG resulted in pro- ation and the very high levels of fer- h e m o p h ago cytic syndrome associat e d longed remissions, but allogenic bone ritin. CSF pleocytosis may be seen. In with rheumatic disord e rs belongs to marrow transplantation may lead to a one infant we were able to demonstrate this subset and should be referred to as cure (11). in the CSF. Serum sodi- such Ð viz. rheumatic disease associat- Infection-associated (IAHP) hemopha- um may be low and some of the CNS ed hemophagocytic syndrome (RAHS). goc ytic syndrome (histiocytosis) is seen changes may be related to the metabol- The current terminology of MAS gives in all age groups and has been reported ic changes. The bone marrow or lymph the impression that it is a unique syn- m a i n ly in association with herp e s , node will show the accumu l ation of drome with different characteristics. adeno and Epstein-Barr viruses. It has non-malignant histiocytes engulfi n g The clinical, laboratory and pathologi- also been reported in association with most often the red cells but sometimes cal fe at u res of the pri m a ry va ri e t y, bacteria, rickettsia, parasites and fungi also WBC and platelets (pac-man syn- called Familial Hemophagocytic Lym- (5,12). In children it occurs most com- drome). phohistiocytosis (FHL, FHLH), and of monly before the age of 3 years. The These features are the same in all three the secondary varieties are almost iden- m o rtality is high without t re at m e n t . varieties. Therefore, what we in rheu- tical. FHLH is an autosomal recessive Trea tment app ro a c hes inclu d e IV gam- matology call MAS should be placed condition which can be fatal (8, 9). The maglobulin and etoposide. under the major cat ego ry of Macro- presentation is most often during the M a l i g n a n cy - re l ated hemophago cy t i c phage-Related Disorders and be listed first year of life. It can be precipitated ly m p h o h i s t i o cytic syndrome (MAHS) under Secondary or Reactive Hemo- by an infection and therefore may be may be seen during the treatment of phagocytic Syndromes. This would be diagnosed as the secondary infection- one of the malignancies or can occur as helpful for the following reasons:

122 Macrophage activation syndrome: a new entity? / B.H. Athreya EDITORIAL

1. It would provide a common termi n o l - 561. 9. HENTER J-I, ARICO M, ELINDER G, I M A- ogy for all the subspecialists (hema- 2. STEPHAN JL, ZELLER J, H U B E RT PH, H ER- SHUKA S,JANKA G:Familial Hemophagocyt- BELIN C, DAYER JM, PRIEUR A-M: Macro- ic Lymphohistiocytosis: Primary Hemopha- t o l ogi s t s , n e u ro l ogi s t s , ga s t ro e n t e r- p h age activation syndrome and rheumat i c gocytic Lymphohistiocytosis. Hematol Oncol o l ogi s t s , i n fectious disease ex p e rt s diseases in childhood: A report of four new Clin North Am 1998; 12 : 417-33. and rheumat o l ogists) who may be cases. Clin Exp Rheumatol 1993; 11: 451-6. 10. STEPP SE, D U F O U R C Q - L AGELOUSE R , LE called on to care for these children. 3. GROM AA, PASSO M: Macrophage activation DEIST F et al.: Perforin gene defects in Famil- syndrome in Juvenile Rheumatoid Arthritis. J ial Hemophago cytic Ly m p h o h i s t i o cy t o s i s . 2. We can start using the criteria devel- Pediatr 1996; 129: 630-2. Science 1999; 286: 1957-9. oped by the Histiocyte Society 4. RAVELLI A, CARIA MC, BURATTI S, MALAT- 11. BOLME P, HENTER J-I, WINIARSKI J ELIN- (Table II), modifying these criteria TIA C, TEMPORINI F, M A RTINI A : M e t h o- DER G, LJUNGMAN P, LONNERHOLM G, instead of creating new ones. trexate as a possible trigger of macrophage RINGDEN O: Allogeneic bone marrow trans- a c t ivation syndrome in systemic juve n i l e plantation in hemophagocytic lymphohistio- 3. The recognition of gene (s) involved i d i o p athic art h ritis. J Rheumatol 2001; 28: cytosis in Sweden. Bone Marrow Transplant in the familial variety may be of help 865-7. 1995; 15: 331- 5. in looking for related genes in the 5. JANKA G, IMASHUKA S, ELINDER G, 12. REINER A P, S P I VAK JL: H e m o p h ago cy t i c SCHNEIDER M, HENTER J-I: I n fection and lymphohistiocytosis: A report of 23 new pa- reactive types of lymphohistiocytic Malignancy associated Hemophagocytic Syn- tients and rev i ew of literat u re. M e d i c i n e hemophagocytosis. dromes: Secondary hemophagocytic lympho- 1988; 67: 369-88. 4. This in turn may help in the develop- histiocytosis. Hematol Oncol Clin North Am 13. MOUY R,STEPHAN J-L,PILLET P, HADDAD E, ment of better treatment strategies to 1998; 12: 435-44. HUBERT P, PRIEUR AM: Efficacy of cyclo- 6. WRITING GROUP OFTHE HISTIOCYTE SOCI- s p o rine A in the tre atment of macro p h age treat this potentially fatal syndrome. E T Y: H i s t i o cytosis syndromes in ch i l d re n . activation syndrome in juvenile rheumatoid It is interesting to note that the origina- Lancet 1987; 1: 208. arthritis: Report of five cases. J Pediatr 1996; tors of the term MAS seem to agree 7. FAVARA BE, FELLER AC , PAULI M et al. : 129: 750-4. with this idea, as shown in the title of C o n t e m p o ra ry cl a s s i fi c ation of histiocy t i c 14. PRAHLAD S, BOVE KE,DICKENS D, LOVELL disorders. The WHO Committee on Histio- DJ, GROM AA: Etanercept in the treatment of an article published in November 2001 cytic/Reticulum Cell Proliferations. Reclassi- macrophage activation syndrome J Rheuma - (15). fication Working Group of the Histiocytic So- tol 2001; 28: 2120-4. ciety. Med Pediatr Oncol 1997; 29: 157-66. 15. STEPHAN JL, KONE-PAUT I, GALAMBRUN C, References 8. ARICO M, JANKA G, F I S C H E R A et al. : MOUY R, BADER-MEUNIER B, PRIEUR AM: 1. HADCHOUEL M, PRIEUR A-M, GRISCELLI C: H e m o p h ago cytic ly m p h o h i s t i o cy t o s i s : R e- R e a c t ive Hemophago cytosis Syndrome in Acute hemorrhagic, hepatic, and neurological port of 122 children from the International children with inflammatory disorders. A ret- manifestations in JRA: Possible relationship registry. FHL Study Group of the Histiocyte rospective study of 24 patients. Rheumatol - to drugs and infections. J Pediatr 1985; 106: Society. Leukemia 1996; 10: 197-203. ogy (Oxford) 2001; 40: 1285-92.

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