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Natural killer cell dysfunctionA common pathway in systemic-onset juvenile rheumatoid arthritis macrophage activation syndrome and hemophagocytic lymphohistiocytosis.

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Vol. 50, No. 3, March 2004, pp 689–698
DOI 10.1002/art.20198
© 2004, American College of Rheumatology
Natural Killer Cell Dysfunction
A Common Pathway in Systemic-Onset Juvenile Rheumatoid Arthritis,
Macrophage Activation Syndrome, and Hemophagocytic Lymphohistiocytosis?
Alexei A. Grom
tions secondary to mutations in the gene encoding
perforin (PRF1). Interestingly, similar immunologic abnormalities have also been documented in patients with
MAS (15,16). Furthermore, increasing evidence suggests
that low NK cell function associated with abnormal
levels of perforin expression may be a feature that
distinguishes patients with systemic JRA from those with
other clinical forms of JRA (17,18). If confirmed, these
observations not only will lead to an explanation for the
increased incidence of MAS in systemic-onset JRA but
also will provide clues for further mechanistic studies of
this syndrome. The purpose of this review is to summarize the current understanding of the pathophysiology of
MAS as well as its relationship to other hemophagocytic
One of the most intriguing features of systemiconset juvenile rheumatoid arthritis (JRA) is its association with macrophage activation syndrome (MAS), a
life-threatening complication caused by excessive activation and proliferation of T cells and macrophages (1–
14). Such activation leads to an overwhelming systemic
inflammatory reaction. The pathognomonic features of
this syndrome are observed in bone marrow aspirates:
numerous well-differentiated macrophages actively
phagocytosing hematopoietic elements. Such cells may
infiltrate almost any organ in the body and may account
for many of the systemic features of this syndrome,
including cytopenias and coagulopathy.
MAS is a daunting clinical challenge. In fact, it
has been a major source of mortality in pediatric rheumatology. It is becoming increasingly clear, however,
that the understanding of the pathophysiology of MAS
not only may define better treatment and improve the
outcome, but also may provide important clues to the
discovery of new pathways involved in the downregulation of cellular immune responses in humans.
MAS has strong clinical similarities with familial
hemophagocytic lymphohistiocytosis (HLH). In familial
HLH, the uncontrolled proliferation of T cells and
macrophages has been recently associated with decreased natural killer (NK) cell and cytotoxic cell func-
In the early 1980s, several reports described
patients with systemic-onset JRA in whom a severe
coagulopathy resembling disseminated intravascular coagulation (DIC) developed. Such coagulopathy was often associated with mental status changes, hepatosplenomegaly, increased serum levels of liver enzymes,
and a sharp fall in blood cell counts and the erythrocyte
sedimentation rate (ESR) (2–4). In 1985, Hadchouel et
al (5) linked these symptoms to massive proliferation of
activated non-neoplastic macrophagic histiocytes with
prominent hemophagocytic activity. The term “macrophage activation syndrome” was eventually introduced
in 1993 by Stephan et al, in a followup report originating
from the same center (6). Over the following years,
several more reports from various countries described a
number of patients with very similar symptoms (7–12).
Although MAS has also been observed in a small
number of patients with polyarticular JRA (13,14) and
Supported by NIH grant PO1-AR-048929 and Children’s
Hospital Research Foundation of Cincinnati.
Alexei A. Grom, MD: Cincinnati Children’s Hospital Medical
Center, Cincinnati, Ohio.
Address correspondence and reprint requests to Alexei A.
Grom, MD, Assistant Professor of Pediatrics, Cincinnati Children’s
Hospital Medical Center, Division of Rheumatology ML 4010, 3333
Burnet Avenue, Cincinnati, OH 45215. E-mail:
Submitted for publication July 29, 2003; accepted in revised
form November 20, 2003.
Table 1.
Clinical characteristics of HLH and MAS*
Age at onset
Family history
Viral trigger
Persistent fever
Hemorrhagic skin rash
CNS abnormalities
Elevated SGOT, SGPT levels
Prolonged PT, PTT
Hemophagocytosis in bone marrow
⬍12 months
Often positive
Very frequent
Very frequent
Very frequent
Very frequent
Very frequent
Usually negative
Very frequent
Very frequent
Very frequent
Very frequent
Very frequent
Very frequent
Very frequent
Very frequent
Very frequent
Very frequent
Very frequent
Very frequent
Very frequent
* HLH ⫽ hemophagocytic lymphohistiocytosis; MAS ⫽ macrophage activation syndrome; CNS ⫽ central
nervous system; SGOT ⫽ serum glutamate oxaloacetate transaminase; SGPT ⫽ serum glutamate pyruvate
transaminase; PT ⫽ prothrombin time; PTT ⫽ partial thromboplastin time.
† Based on refs. 24 and 59.
‡ Based on refs. 13, 14, and 27.
those with some other rheumatic diseases (14,19,20), it is
seen most commonly in patients with the systemic form
of JRA.
Because excessive activation and proliferation of
tissue macrophages, or histiocytes, exhibiting hemophagocytic activity (often triggered by infections) is a
pathognomonic feature of MAS, the term reactive hemophagocytic lymphohistiocytosis (HLH) has been preferred by some authors to classify this condition
(14,21,22). This term suggests that MAS may belong to
a group of histiocytic disorders collectively known as
HLH. HLH is a more general term that describes a
spectrum of disease processes characterized by accumulations of histologically benign well-differentiated mononuclear cells with a macrophage phenotype (23,24).
Because such macrophages represent a subset of histiocytes that are distinct from Langerhans’ cells, this entity
should be distinguished from Langerhans’ cell histiocytosis as well as from other dendritic cell disorders.
In the contemporary classification of histiocytic
disorders, HLH is further subdivided into primary, or
familial, HLH and secondary, or reactive, HLH. Clinically, however, these disorders may be difficult to distinguish from each other. Familial HLH is a constellation
of rare autosomal recessive immune disorders. The
clinical symptoms of familial HLH usually become evident within the first 2 months of life, although initial
presentation as late as 22 years of age has been reported
as well (25). Secondary HLH tends to occur in older
children and more often is associated with an identifiable infectious episode, most notably Epstein-Barr virus
(EBV) or cytomegalovirus (CMV) infection. The group
of secondary hemophagocytic disorders also includes
malignancy-associated HLH.
Similar to the clinical course of MAS, the clinical
course of the most typical form of HLH is characterized
by persistent fever and hepatosplenomegaly. Neurologic
symptoms can complicate and sometimes dominate the
clinical course. Hemorrhagic rash and lymphadenopathy
are observed less frequently. Laboratory findings such as
cytopenias (particularly thrombocytopenia), elevated
liver enzyme levels, hypertriglyceridemia, and hypofibrinogenemia also overlap with MAS. Finally, as in MAS,
hemophagocytosis in bone marrow is a hallmark of HLH
(Table 1). Despite all of these clinical similarities, the
exact relationship between MAS and HLH is not understood.
Diagnosis and epidemiology of MAS
Epidemiologic studies of MAS have been complicated by the lack of well-defined diagnostic criteria. In
most cases reported in the literature, the diagnosis of
MAS was initially suspected based on the development
of cytopenias and coagulopathy and then was confirmed
at biopsy by the demonstration of hemophagocytosis.
However, many clinicians believe that MAS may simply
represent a severe end of the spectrum of such abnor-
malities. Indeed, some degree of coagulopathy, a major
clinical feature of MAS, may be present in the majority
of patients with systemic-onset JRA (4,26), a view that
was reinforced by a recent report by Ravelli (27). In
this review, clinical and laboratory manifestations of
JRA-associated cases of MAS reported in the literature were compared with those in patients with active
systemic-onset JRA. As a result, threshold values for
certain measures of coagulopathy and inflammatory
activity have been proposed for use as possible diagnostic criteria. The variables with the highest sensitivity and specificity were serum levels of ferritin
(⬎10,000 mg/ml), triglycerides (⬎160 mg/dl), and fibrinogen (⬍250 mg/dl).
Despite the lack of diagnostic criteria, due to
increasing awareness of MAS this syndrome is being
recognized more and more frequently. According to
one report originating from a tertiary level pediatric
rheumatology unit, 7 of 103 patients in whom systemiconset JRA was diagnosed between 1980 and 2000 developed MAS at some point during the course of their
illness (13). In another retrospective review of patients
with reactive HLH, the authors noted that more than
one-third of the patients fulfilled the criteria for
systemic-onset JRA or adult-onset Still’s disease, thus
prompting them to question the distinct nature of the 2
conditions (28).
Based on our own experience and review of the
literature, MAS occurs with equal frequency in boys and
girls. There appears to be no racial predilection, and
MAS may occur in children of almost any age. The
youngest MAS patient reported to date was 12 months
old (2). Although in most patients this syndrome develops sometime during the course of their primary rheumatic disease, the occurrence of MAS at the time of the
initial presentation of a rheumatic illness has been
described as well (2,12). The vast majority of patients
have an active primary rheumatic disease prior to the
development of MAS. One report, however, described a
patient whose polyarticular JRA was not active at the
time of MAS presentation (7).
Although it is now evident that development of
MAS can be precipitated by virtually any infectious
agent (bacterial, fungal, and even parasitic) (20), viral
illnesses, particularly EBV and infections caused by
other members of the herpesvirus family, appear to be
most commonly described (7,13–15). In several reports,
the triggering of MAS coincided with modifications in
drug therapy, most notably administration of gold preparations (5,6,29), methotrexate (30,31), sulfasalazine
(32), and tumor necrosis factor (TNF)–blocking agents
(33). These associations, however, should be interpreted
cautiously, because many of the described patients had
very active underlying rheumatic disease, and MAS
might have been developing when therapy with the drugs
was started. In most patients, triggering events are not
Clinical features
The clinical findings in MAS are dramatic (14).
Typically, patients with a chronic rheumatic condition
become acutely ill with persistent fever, mental status
changes, lymphadenopathy, hepatosplenomegaly, liver
dysfunction, easy bruising, and mucosal bleeding. These
clinical signs and symptoms are associated with a precipitous fall in the levels of at least 2 of 3 blood cell lines
(leukocytes, erythrocytes, and platelets). A decline in the
platelet count is usually an early finding. Because bone
marrow aspiration typically reveals significant hypercellularity and normal megakaryocytes, such cytopenias do
not seem to be secondary to inadequate production of
cells. Increased destruction of the cells by phagocytosis
and consumption at the inflammatory sites are more
likely explanations.
A precipitous fall in the ESR is another characteristic laboratory feature, which probably reflects the
degree of hypofibrinogenemia secondary to fibrinogen
consumption (27) and liver dysfunction (6,9). In fact,
liver involvement is common in MAS. Significant hepatomegaly is frequently present. Mild jaundice develops
in some patients. Liver function tests often reveal high
serum transaminase activity and mildly elevated levels of
serum bilirubin. Moderate hypoalbuminemia has been
reported as well (2). Serum ammonia levels are typically
normal or only mildly elevated.
Encephalopathy is another frequently reported
clinical feature of MAS. Mental status changes, seizures,
and coma are the most common manifestations of
central nervous system (CNS) disease (5,6). Cerebrospinal fluid pleocytosis with mildly elevated protein levels
has been noted in some studies (5). Significant deterioration in renal function has been noted in several series
(6,13) and in one study was associated with particularly
high mortality (13). Pulmonary infiltrates have been
mentioned in several reports (7,9), but the extent to
which they can be attributed to MAS is not clear.
Additional laboratory findings in MAS include
highly elevated serum levels of triglycerides and ferritin.
The elevation of ferritin is particularly marked (⬎10,000
ng/ml in most patients) (27) and appears to parallel the
degree of macrophage activation (34).
A hemorrhagic syndrome resembling DIC is the
most striking abnormality in MAS (2–14). Hemorrhagic
skin rashes (from mild petechiae to extensive ecchymotic
lesions), epistaxis, hematemesis secondary to upper gastrointestinal bleeding, and rectal bleeding are the most
commonly observed clinical features caused by coagulation abnormalities in MAS (2–6). Further laboratory
evaluation reveals prolonged prothrombin and partial
thromboplastin times, marked hypofibrinogenemia, and
moderate deficiency of vitamin K–dependent clotting
factors. A decrease in factor V levels is usually mild.
Fibrin degradation products may be present as well.
In early reports, the coagulation abnormalities
observed in this syndrome were interpreted by several
authors as “consumption coagulopathy” triggered by the
vasculopathic component of the disease (2). Indeed,
“low level DIC,” possibly reflecting endothelial cell
damage, may be a part of active systemic JRA (26).
Other investigators, however, proposed that severe liver
dysfunction induced by macrophages infiltrating the
liver parenchyma is more relevant to the pathogenesis of
coagulation abnormalities (6,9). Indeed, liver disease
may result in a complex coagulopathy caused by decreased synthesis of clotting factors, such as fibrinogen.
The liver also produces inhibitors of coagulation such as
antithrombin III, protein C, and protein S, and is the
clearance site for activated coagulation factors and
fibrinolytic enzymes. Thus, patients with severe liver
dysfunction are predisposed to DIC and may develop
systemic pathologic fibrinolysis. For these reasons, coagulation defects in advanced liver disease are often
difficult to distinguish from those in DIC.
Prahalad et al (12) described a patient with MAS
in whom severe acute hemorrhagic diathesis developed
in the absence of significant liver dysfunction. The
vasculopathic component in the hemorrhagic skin lesions was not prominent. The authors suggested that the
coagulopathy in that patient might have been related to
the procoagulant activity of the activated macrophages.
Indeed, in an inflammatory response, activated macrophages can be induced to produce the hemostatic tissue
factor. In turn, the tissue factor expressed in macrophages and on TNF␣-stimulated endothelial cells has
been shown to be central to the pathogenesis of DIC in
both experimental and clinical conditions (35). A strong
correlation between serum levels of soluble TNF receptors and prolongation of the partial prothrombin time in
patients with systemic-onset JRA (36) suggests that
increased TNF␣ activity observed in MAS (6,10,37)
further contributes to the development of the coagulation abnormalities.
Tissue histopathology
The most common histopathologic finding in
patients with MAS is tissue infiltration with T lymphocytes and cytologically benign yet actively phagocytic
macrophages (Figure 1). Although demonstration of
macrophages phagocytosing hematopoietic elements in
the bone marrow or lymph nodes is virtually diagnostic,
negative results may be reported due to sampling difficulties or timing of the procedure (13). The macrophages may also be found in various organs and may
account for many of the systemic features of this syndrome. Postmortem evaluation of one patient with MAS
revealed extensive macrophagic infiltration of the heart,
adrenal glands, liver, pancreas, and meninges (20). In
addition to revealing sinusoidal and periportal infiltration with macrophages, histologic evaluation of the liver
often reveals severe diffuse fatty changes (5). The development of fatty changes in the liver may be related to
the metabolic effects of TNF␣. TNF␣ has been shown to
stimulate hepatic lipogenesis and to inhibit synthesis of
lipoprotein lipase, an enzyme needed to release fatty
acids from circulating lipoproteins so that they can be
used by the tissues. The same mechanism also appears to
be responsible for the high serum levels of triglycerides
seen in MAS patients.
Two recent reports described patients with
systemic-onset JRA/MAS who also had necrotizing histiocytic lymphadenopathy consistent with Kikuchi’s disease (15,38). Given the rarity of both conditions, this
association may not be random. The most common
cutaneous manifestations of MAS are panniculitis and
purpura (12,39). Most biopsy specimens show edema
and hemorrhage associated with a mononuclear cell
infiltrate and numerous macrophages occasionally showing hemophagocytosis. Schuval et al described 2 patients
with histiocytic cytophagic panniculitis associated with
systemic manifestations such as fever and hepatosplenomegaly (40). At some point during the course of their
disease, acute pancytopenias developed in both patients
and responded to cyclosporin A. Although these patients
did not have apparent coagulation abnormalities, activation of macrophages did play a role in the pathogenesis
of their diseases, suggesting that there may be a signifi-
Figure 1. Bone marrow aspirate specimens revealing activated macrophages (hematoxylin and eosin–stained; original magnification ⫻ 1,000). A,
Myelocyte within activated macrophage. In addition, there are multiple adherent red blood cell and myeloid precursors. B, Activated macrophage
engulfing a neutrophilic band form. C, Neutrophilic band forms and metamyelocyte within an activated macrophage. Nuclei of band forms appear
condensed. D, Activated macrophage with hemosiderin deposits and a degenerating phagocytosed nucleated cell. Reproduced, with permission, from
ref. 12.
cant overlap between the pathogenic mechanisms involved in MAS and histiocytic cytophagic panniculitis.
Immunologic abnormalities in familial HLH
The pathogenic mechanisms involved in the development of MAS are not known. However, immunologic studies of the clinically similar entity familial HLH
suggest that there is an underlying abnormality in immunoregulation that contributes to the lack of control of
an exaggerated immune response (24,41). The clinical
findings during the acute phase of HLH can be explained largely as a consequence of the prolonged
production of cytokines and chemokines presumably
originating from activated macrophages and T cells. An
excess of circulating interleukin-1␤ (IL-1␤), TNF␣, IL-6,
and interferon-␥ (IFN␥) is likely to contribute to the
early and persistent findings of fever, hyperlipidemia,
and endothelial activation responsible in part for coagulopathy, as well as later sequelae including hepatic
triaditis, CNS vasculitis and demyelination, and bone
marrow hyperplasia. Hemophagocytosis, the pathognomonic feature of the syndrome, is a hallmark of
cytokine-driven excess activation of macrophages (24).
The most consistent immunologic abnormality
reported in these patients has been impairment of
cytotoxic functions. Thus, it has been demonstrated that
most patients with familial HLH have normal numbers
of B lymphocytes and normal serum immunoglobulin
levels (42). The majority of these patients have surprisingly normal absolute lymphocyte counts and normal
distribution of mature T cell subsets. In contrast, NK cell
function is markedly decreased or absent in virtually all
patients. Cytotoxic activity of CD8⫹ cells is also defective (42,43). In ⬃40% of patients with familial HLH,
these abnormalities have been associated with mutations
in the gene encoding perforin, a protein that mediates
cytotoxic activity of NK cells and T cells (44). Patients
with familial HLH usually have normal numbers of NK
cells but either very low or absent perforin expression in
all cytotoxic cell types, including NK cells. Therefore,
the cytolytic activity of such cells is impaired.
Patients with virus-associated HLH also have
very low or absent cytolytic NK cell activity. However, in
contrast to familial HLH, this phenomenon appears to
be related to profoundly decreased numbers of NK cells
rather then impaired perforin expression. In fact, perforin expression in both CD8⫹ and CD56⫹ cytotoxic
cells is often mildly increased (45). It appears that NK
cell function may completely recover in some of these
patients after the resolution of the acute phase of the
syndrome (Kogawa K: personal communication).
Interestingly, NK cells are also affected in the
Chédiak-Higashi syndrome, another disease associated
with the development of lymphohistiocytic expansion
and hemophagocytosis. In this disease, absolute numbers of NK cells in peripheral blood are normal, but the
cells are characterized by the presence of abnormal
granules containing perforin in the cytoplasm. The genetic defect in this condition appears to be a mutation in
the gene encoding one of the cytoskeletal proteins,
leading to impaired ability to mobilize perforin (46). As
a result, the cytolytic activity of NK cells and cytotoxic
CD8⫹ cells is greatly diminished (47).
Two other genetic conditions associated with
hemophagocytic lymphohistiocytosis are Griscelli syn-
drome and X-linked lymphoproliferative disease. In
Griscelli syndrome, hemophagocytic complications are
related to the deficiency of Rab27A, a cytoplasmic
protein involved in cytotoxic granule release (48), while
X-linked lymphoproliferative disease is caused by a
mutation in an adaptor protein, SH2DIA, that has been
implicated in the regulation of T cell activation and NK
cell effector function (49,50). In both syndromes, cytotoxic functions are greatly impaired (50).
Perforin expression and NK cell function in systemiconset JRA and MAS
Strong clinical similarities between HLH and
MAS prompted several groups of investigators to examine perforin expression and NK cell function in patients
with systemic-onset JRA and MAS. One recent study
demonstrated reduced perforin expression in NK cells
and in 2 subsets of cytotoxic CD8⫹ T lymphocytes
(CD45RA⫺,CD28⫺ and CD45RA⫹,CD28⫺) in patients with active systemic JRA compared with other
forms of JRA and healthy controls (16). Interestingly, in
4 patients perforin expression returned to normal levels
after autologous hematopoietic stem cell transplantation. This observation suggests that low perforin expression is likely to be induced by certain cytokines or
chemokines that are abundant in active systemic JRA.
Based on similarities with familial HLH, the authors also
suggested that reduced perforin expression might be
responsible for the increased incidence of MAS in
systemic-onset JRA (16).
Another study focused on the assessment of NK
cell function and perforin expression in 7 patients with
MAS presenting as a complication of systemic-onset
JRA (15). NK cell activity in peripheral blood samples
collected during the acute stage and after the resolution
of MAS was profoundly depressed in all patients. In
some patients, low NK cell activity was associated with
very low numbers of NK cells but mildly increased levels
of perforin expression in NK T cells and cytotoxic CD8⫹
T lymphocytes, a pattern somewhat similar to that in
virus-associated HLH. In contrast, in other patients,
very low NK cell activity was associated with only mildly
decreased numbers of NK cells but very low levels of
perforin expression in all cytotoxic cell types, a pattern
indistinguishable from that in carriers of familial HLH.
Remarkably, most of the patients with low perforin
expression had a history of previous episodes of MAS.
It has also been reported that decreased absolute
numbers of NK cells (17) and decreased NK cell function (18) might be features that distinguish patients with
Table 2. Immunologic abnormalities in HLH and MAS*
Familial HLH
NK cell function
NK cell number
% of perforin-expressing NK cells
% of perforin-expressing CD8⫹ cells
Biallelic mutations
in PRF1 gene
PRF1 gene
Normal or 2
Normal or 2
Normal or 2
* NK (natural killer) cell function is defined as cytolytic activity against the K562 cell line. HLH ⫽ hemophagocytic lymphohistiocytosis; MAS ⫽
macrophage activation syndrome.
systemic JRA from those with other forms of JRA. This
observation may be another clue to the understanding of
the reasons for the increased incidence of MAS in
patients with systemic-onset JRA. These data also suggest that the pathway common to both MAS and HLH is
likely to be associated with abnormal cytolytic function
(see Table 2).
NK cell function and cellular immune responses
The exact mechanisms that would link deficient
NK cell and cytotoxic T lymphocyte functions with
expansion of activated macrophages are not clear. Two
alternative explanations have been suggested in the
literature. One is related to the fact that HLH/MAS
patients appear to have a diminished ability to control
some infections (41,51). More specifically, NK cells and
cytotoxic T lymphocytes fail to kill infected cells and,
thus, fail to remove the source of antigenic stimulation.
Such persistent antigen stimulation leads, in turn, to
persistent antigen-driven activation and proliferation of
T cells associated with escalating production of cytokines that stimulate macrophages. The fact that HLH/
MAS episodes are often triggered by viruses from the
herpesvirus group supports this hypothesis. The herpesviruses, including CMV and EBV, have evolved evasion
mechanisms to down-regulate or sequester class I major
histocompatibility complex (MHC) molecules, thus preventing efficient cytolytic CD8⫹ T cell responses. In
contrast, such down-regulation of the expression of class
I MHC molecules serves as an activating signal for NK
cells that triggers their cytolytic activity against infected
cells. Therefore, NK cells become particularly important
in the defense against herpesviruses. Consistent with this
idea, infection of NK-depleted or perforin-deficient
mice with murine CMV does result in an exaggerated
immune response associated with more persistent expansion of cytotoxic CD8⫹ T cells that secrete IFN␥, an
important macrophage activator (52,53).
In many cases of MAS, however, attempts to
identify an infectious trigger have not been successful,
and some episodes appear to be triggered by modifications in drug therapy rather than infection. Furthermore,
the importance of NK cells and perforin-based systems
in the down-regulation of the cellular immune responses
has been demonstrated in experimental animal systems,
in which immune responses were elicited by anti-CD3
antibodies or staphylococcal toxins instead of viruses.
For instance, Kagi et al demonstrated that the injection
of staphylococcal enterotoxin B into perforin-deficient
mice resulted in dramatically increased selective expansion and prolonged persistence of CD8⫹ but not CD4⫹
staphylococcal enterotoxin B–reactive T cells (54). The
results of these experiments suggest that there likely is a
more direct effect of perforin-based systems on the
survival of activated lymphocytes.
It has been hypothesized by some authors that
abnormal cytotoxic cells may fail to provide appropriate
apoptotic signals for removal of the antigen-presenting
cells and/or activated T cells after infection is cleared
(55). Such T cells may continue to secrete cytokines,
including IFN␥ and granulocyte–macrophage colonystimulating factor (GM-CSF), 2 important macrophage
activators. Subsequently, the sustained macrophage activation results in tissue infiltration and in the production of high levels of TNF␣, IL-1, and IL-6, which play a
major role in the various clinical symptoms and tissue
damage. A report on successful treatment of JRAassociated MAS by cyclosporin A with transient exacerbation of MAS by conventional-dose G-CSF supports
this hypothesis (11).
MAS is a serious complication of systemic JRA
and is associated with considerable morbidity and mortality. Therefore, early recognition of this syndrome and
immediate therapeutic intervention to produce a rapid
clinical response are critical. Thus, in a patient with
persistently active systemic-onset JRA, a fall in the ESR
and platelet count, particularly in combination with an
increase in D-dimer levels, should raise suspicion of
impending MAS. Prompt administration of more aggressive treatment in these patients may, in fact, prevent
development of the full-blown syndrome. In our clinic,
to achieve rapid reversal of coagulation abnormalities,
we often start with intravenous methylprednisolone
pulse therapy (30 mg/kg/day for 3 consecutive days)
followed by 2–3 mg/kg/day in 4 divided doses. After
normalization of hematologic abnormalities and resolution of coagulopathy, we taper steroids slowly to avoid
relapses of macrophage activation. Not uncommonly,
however, MAS appears to be corticosteroid resistant,
with deaths being reported even among patients treated
with massive doses of steroids.
Parenteral administration of cyclosporin A in
patients with corticosteroid-resistant MAS was recently
proposed by Mouy et al (9). From the primary effect of
cyclosporin A, largely but not entirely confined to T
cells, a wide variety of other effects are mediated,
leading to profound and therapeutically useful immunosuppression (56). In the patients with MAS described by
Mouy et al (9) and Ravelli et al (10), parenteral administration of cyclosporin A (2–8 mg/kg/day) not only
provided rapid control of symptoms but also allowed
avoidance of excessive use of corticosteroids.
There have been anecdotal reports on the use of
etoposide, a podophyllotoxin derivative that inhibits
DNA synthesis by forming a complex with topoisomerase II and DNA. For instance, etoposide was successfully used to treat EBV-induced MAS in a 21-year-old
woman with longstanding systemic-onset JRA (8) but
induced severe bone marrow suppression in another
patient with MAS (6).
Of note is the fact that the combination of
steroids, cyclosporin A, and etoposide is the major
component of the HLH treatment protocol (HLH-94)
developed by the international Histiocyte Society (57).
This protocol includes a combination of etoposide and
CNS-penetrating dexamethasone (with or without intrathecal methotrexate), followed by a maintenance course
of cyclosporin A and less frequent pulses of etoposide
once clinical remission has been established. In accordance with the protocol, patients with familial HLH and
patients who experience a relapse after initially responding to HLH-94 should proceed to definitive therapy with
allogeneic hematopoietic stem cell transplantation.
A suggested role for TNF␣ in the development of
coagulation abnormalities provided a rationale for the
use of TNF inhibitors in corticosteroid-resistant cases of
MAS (12,58), which resulted in a good clinical response.
However, other reports describe patients in whom MAS
developed while they were being treated with TNF
inhibitors (15,33). In most of those cases, MAS was
triggered by infections. Because TNF-inhibiting agents
may increase susceptibility to infections, including those
that trigger MAS, these medications should be considered only when an infectious etiology has been ruled out.
In other words, it appears that although TNF inhibitors
may help control some of the downstream pathways of
MAS, these drugs do not provide protection against
triggering of this syndrome.
The analysis of pathophysiologic similarities between HLH and MAS leads to the hypothesis that
impaired cytotoxic functions and the lack of an immunoregulatory role of NK cells are relevant to the development of both syndromes. It appears likely that an
intrinsic cytolytic defect is responsible for the failure to
down-regulate cellular immune responses triggered by
either infection or some other environmental factors.
Furthermore, profound NK dysfunction may be a feature that distinguishes systemic JRA from other clinical
forms of JRA as well as other rheumatic conditions. If
this hypothesis were proven, it would explain the increased incidence of MAS in patients with systemiconset JRA and provide a basis for further mechanistic
studies of MAS and HLH. Both conditions are rare;
therefore, cooperative efforts from pediatric rheumatologists in the US and around the world will be necessary to better understand the nature of MAS and its
relationship to other HLH syndromes.
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dysfunction, syndrome, common, systemic, activation, killer, onset, cells, macrophage, natural, arthritis, juvenile, hemophagocytic, lymphohistiocytosis, pathways, rheumatoid
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