SPECIAL ISSUE ARTICLE

New Onset Autoimmune Disease or

Macrophage Activation Syndrome?
J. Palmer Greene, MD; and Bridget M. Wild, MD

ferase (AST) at 52 U/L, alanine amino-

ABSTRACT transferase (ALT) at 67 U/L, albumin at
Macrophage activation syndrome (MAS) is a potentially life-threatening condition that may 2.8 g/dL and bicarbonate of 19 meq/L; a
complicate many pediatric rheumatologic diseases. Because of its similarity in presentation C-reactive protein (CRP) of 221.7 mg/L;
to other conditions with overlapping manifestations, such as flares of rheumatologic disease a urinalysis with 1+ protein and 5 red
or systemic infection, and the fact that there exists no single pathognomonic clinical finding blood cells per high power field; and
or laboratory parameter to aid in diagnosis, MAS presents a significant diagnostic challenge fibrinogen of 377 mg/dL. Additional
to the practicing pediatrician with limited access to consulting pediatric rheumatologists. sexually transmitted infections test-
Along with a review of the physiology and manifestations of the condition, we have included ing was sent on the day of admission,
the most current consensus for diagnosing MAS. [Pediatr Ann. 2019;48(10):e395-e399.] and she was observed by surgery and
gynecology.

M
acrophage activation syn- a normal appendix. She was admitted On the day after admission, the pa-
drome (MAS) is a potentially to the pediatric hospitalist service at tient was persistently febrile at 39.1°C
life-threatening complication a community hospital for observation and began describing sharp, substernal
of rheumatologic diseases that can be and serial abdominal examinations. Her chest pain exacerbated by deep respira-
difficult for the general practitioner to pain was not made worse by eating, she tions. A repeat pelvic examination pro-
recognize. This article reviews the pre- had a normal appetite, and she had no voked no cervical motion tenderness,
sentation, diagnosis, and treatment of nausea, vomiting, or diarrhea. She was although her abdomen remained exqui-
MAS. sexually active with one male partner sitely tender and distended with hypo-
and had a gonorrhea and chlamydia test active bowel sounds. A repeat CT scan
ILLUSTRATIVE CASE return negative. A pelvic examination revealed intra-abdominal and pelvic as-
A 17-year-old girl with no signifi- elicited some cervical motion tender- cites, bilateral pleural effusions, a mildly
cant past medical history presented to ness, so doxycycline and ceftriaxone enlarged liver, and a normal spleen. She
the emergency department (ED) with 3 were started for management of sus- also developed two painful papules on
days of worsening abdominal pain and pected pelvic inflammatory disease. Her the right side of her face.
fever. Physical examination revealed laboratory tests at admission were no- Given her polyserositis, thrombocy-
diffuse abdominal pain with emphasis table for a complete blood count (CBC), topenia, hematuria, and proteinuria, a
in the right lower quadrant, which was with a white count of 5,800 per mcL, battery of laboratory tests were ordered
initially concerning for appendicitis, but hemoglobin at 11.8 g/dL, and platelets to broaden her examination to include
an abdominal computed tomography at 83,000 per mcL; a complete meta- rheumatologic conditions in addition
(CT) scan obtained in the ED showed bolic panel with aspartate aminotrans- to ruling out infectious processes. As
she was ill-appearing, serial laboratory
examinations were monitored for the
J. Palmer Greene, MD, is a Medical Student. Bridget M. Wild, MD, is a Pediatric Hospitalist, NorthShore evolution of MAS. Notably her ferri-
University HealthSystem; and a Clinical Assistant Professor. Both authors are affiliation with the Pritzker tin peaked at 1,384 ng/mL and CRP at
School of Medicine, The University of Chicago. >300 mg/L. AST peaked at 111 U/L
Address correspondence to Bridget M. Wild, MD, NorthShore University HealthSystem, 2650 Ridge with ALT at 144 U/L, triglycerides were
Avenue, Office B648, Evanston, IL 60201; email: bwild@northshore.org. 151 mg/dL, and platelets remained low
Disclosure: The authors have no relevant financial relationships to disclose. but above the presenting 83,000/mcL
doi:10.3928/19382359-20190918-01 with no other significant CBC changes.

PEDIATRIC ANNALS • Vol. 48, No. 10, 2019 e395


When awaiting autoimmune results, a
discoid lesion developed from the pap-
ules on the patient’s face, along with a
malar rash across the bridge of her nose.
Intravenous (IV) methylprednisolone
therapy was begun with significant im-
provement of all symptoms. Later, the
autoimmune results were notable for
positive antinuclear antibody and posi-
tive anti-Ro, negative anti-dsDNA and
anti-Smith, and normal levels of C3 and
C4 complement. Despite her urinalysis
findings, a renal biopsy was negative for
nephritis. She received the working di-
agnosis of active systemic lupus erythe-
matosus (SLE) and was discharged with
a course of oral prednisone and close
observation in the rheumatology clinic,
where further testing and management
continued for 9 months. She responded
well to steroids and hydroxychloroquine
with resolution of her symptoms. During
a trial when she was not taking hydroxy-
chloroquine 4 months after her initial
presentation, her symptoms returned;
however, she continues to be an atypical
presentation of lupus with inflammatory
features requiring ongoing testing.
DISCUSSION
Macrophage Activation Syndrome
MAS is a potentially life-threatening
condition that may complicate a number
of pediatric rheumatologic diseases. It
is classically associated with systemic
juvenile idiopathic arthritis (sJIA), al-
though it has been reported in numerous
cases of both juvenile- and adult-onset
SLE and Kawasaki disease.1,2 It is known
to occur in the setting of infection, ma-
lignancy, and immunodeficiency as well.
Although it was once considered a free-
standing diagnostic entity, today MAS is
placed on the spectrum of secondary or
acquired hemophagocytic lymphohistio-
cytosis (HLH). Its overall incidence is
unknown, but in retrospective studies of
patients with an underlying diagnosis of
e396
SPECIAL ISSUE ARTICLE
sJIA, it has been estimated to occur in at
least 10% of cases and may be present
subclinically in more than one-half of
patients with sJIA.3,4
MAS pathophysiology is character-
ized by overactivation and proliferation
of macrophages and T lymphocytes
leading to overwhelming release of pro-
inflammatory cytokines, particularly
interleukin (IL)-1 beta, IL-6, interfer-
on-gamma, and tumor necrosis factor
(TNF) alpha.3 In patients with familial
HLH, this process is known to be the
result of defective cytotoxic degranula-
tion of natural killer (NK) and cytotoxic
T cells, leading to ineffectual down-
regulation of activated macrophages and
the inflammatory response. Although
the mechanism governing the excessive
activation of macrophages in MAS and
other forms of secondary HLH has yet
to be elucidated, it is reasonable to ex-
pect it to be similar to familial versions
of the disease. The pathologic hallmark
of MAS, as with other forms of HLH,
is the presence of histiocytes undergo-
ing hemophagocytosis in the bone mar-
row aspirate; however, this finding may
not be present in the initial stages of the
disease.4,5
The clinical presentation of MAS
consists primarily of high, nonremit-
ting fever that can be distinguished from
the intermittent, spiking fever typical
of active sJIA. Additional features in-
clude hepatosplenomegaly, generalized
lymphadenopathy, central nervous sys-
tem (CNS) dysfunction, and hemorrhag-
ic manifestations. Heart, kidney, and
lung function may be impaired in ad-
vanced cases of the disease. Laboratory
studies may show cytopenia of multiple
cell lineages, abnormal liver function
tests, increased lactate dehydrogenase,
hypertriglyceridemia, high levels of se-
rum ferritin, elevated D-dimer, and low
fibrinogen.5 Erythrocyte sedimentation
rate may be paradoxically diminished as
well, likely secondary to the hypofibrin-
ogenemia resulting from fibrinogen con-
sumption and liver dysfunction. Special-
ized testing may reveal elevated levels of
soluble IL-2 receptor alpha chain (also
known as CD25) or CD163, a marker of
macrophage activation, although these
tests are not routinely available.6
Diagnostic Considerations
Because of its similarity in presen-
tation to other conditions with overlap-
ping manifestations, such as flares of
rheumatologic disease or systemic in-
fection, and the fact that there exists no
single pathognomonic clinical finding or
laboratory parameter to aid in diagnosis,
MAS presents a significant diagnostic
challenge to the practicing pediatrician.
Meanwhile, its reported mortality of
8%7 and the need for admission to the
intensive care unit in up to one-half of
cases means it is a diagnosis that should
be made expediently and reliably so that
appropriate management can be initiated
as promptly as possible.1,7
Developing classification and diag-
nostic criteria for MAS has proven dif-
ficult, given the lack of a gold standard
for diagnosis beyond expert opinion.
Nonetheless, several guidelines have
been proposed since MAS was first rec-
ognized as a diagnostic entity in 1993.
For instance, the similarity in clinical
presentation between MAS and HLH
led some to recommend using the HLH
diagnostic guidelines established by the
Histiocyte Society in 2004 (HLH-2004),
which based diagnosis on the fulfillment
of 5 of 8 of the following criteria: fever,
splenomegaly, cytopenia of two or more
cell lines, hypertriglyceridemia and/or
hyperfibrinogenemia, established he-
mophagocytosis, low or absent NK cell
activity, hyperferritinemia, and high sol-
uble IL-2 levels.8 However, application
of these criteria to the diagnosis of MAS
was limited by the fact that hemophago-
Copyright © SLACK Incorporated

cytosis in the bone marrow is not always
demonstrable in cases of secondary HLH
or may be present only late in the disease
course. Furthermore, decreases in white
blood cell count, platelets, and fibrino-
gen may require a different threshold in
the hyperinflammatory state associated
with sJIA or other rheumatologic causes
of secondary HLH.
A later set of diagnostic criteria de-
veloped specifically for MAS in the set-
ting of sJIA (MAS-2005) emphasized
clinical and laboratory features with-
out requiring tissue confirmation of the
disease, while also accounting for CNS
involvement, hemorrhaging, and hepa-
tomegaly as important clinical features
that may aid diagnosis.9 These criteria
outperformed the HLH-2004 guidelines
in a comparative analysis that assessed
their ability to distinguish MAS from the
potentially confusable conditions of ac-
tive sJIA without MAS and systemic in-
fection.10 For distinguishing MAS-2005
from sJIA without MAS, the MAS-2005
criteria had a sensitivity and specific-
ity of 86%, as opposed to a sensitivity
of 79% and specificity of 75% for the
HLH-2004 criteria.10 For distinguishing
MAS from systemic infection, adding
the criterion of ferritin level greater than
500 ng/mL to the other MAS-2005 cri-
teria was the best diagnostic performer
of all, with a sensitivity of 86% and a
specificity of 95%.10
In 2016, the European League
Against Rheumatism (EULAR) and the
American College of Rheumatology
(ACR) sponsored the largest effort yet to
create an updated set of criteria based on
international expert consensus, evidence
from the medical literature, and analy-
sis of patient data (MAS-2016).5 After
candidate criteria had been selected by
statistical analyses of data from 1,111
patients with sJIA-associated MAS and
two potentially confusable conditions,
the project culminated in a consensus
PEDIATRIC ANNALS • Vol. 48, No. 10, 2019
SPECIAL ISSUE ARTICLE
conference for the selection of final clas-
sification criteria.5 These MAS-2016
criteria are listed in Table 1. In addi-
tion to the inherent advantage that the
MAS-2016 criteria were developed
with the participation of 95 pediatric
rheumatologists and data from patients
in 33 different countries, they improve
on the previous diagnostic guidelines in
their reliance entirely on widely avail-
able laboratory studies. They eschew the
criteria for NK cell activity and soluble
IL-2 levels included in the HLH-2004
guidelines, which must be tested in a
specialized laboratory. Furthermore,
bone marrow aspirate demonstrating he-
mophagocytosis, which has shown poor
sensitivity and specificity for diagnosing
HLH, is not included as a criterion.11
Clinical findings that typically develop
only late in the disease course, such as
hepatosplenomegaly, CNS dysfunction,
and hemorrhages, are excluded as well.
Finally, hyperferritinemia, which is
shown to be the single greatest discrimi-
nator between MAS and disease states
with similar clinical presentation, is set
as the sine qua non of diagnosis.5
The bulk of the effort toward estab-
lishing reliable criteria for MAS diag-
nosis has focused on MAS in the set-
ting of sJIA. However, one preliminary
guideline does exist for the diagnosis of
MAS in patients with underlying SLE,
which was developed in 2009 as a retro-
spective study of 38 patients with under-
lying SLE diagnosed with MAS based
on “typical clinical and laboratory pic-
ture of the syndrome.”1 These patients
were subdivided into cases of “definite
MAS” and “probable MAS” based on
the presence or absence, respectively, of
macrophage hemophagocytosis on bone
marrow aspiration. Similar to other stud-
ies5,8,9 in which elevated serum ferritin
level was found to be among the most
reliable markers of the disease, the labo-
ratory feature with the best sensitivity
and specificity was hyperferritinemia,
and clinical features were found to
have greater specificity than sensitiv-
ity—aside from fever, which was highly
sensitive but had poor specificity. How-
ever, it should be noted that ferritin is an
acute-phase reactant and mild to moder-
ate elevations of ferritin can be seen with
inflammation from any cause (including
infection).
The preliminary diagnostic criteria
proposed in the study are included in
Table 2.1 Of note, sJIA in the absence
of MAS is typically characterized by
thrombocytosis. However, thrombocy-
topenia is frequently noted in SLE at
baseline, even in the absence of MAS.
Thus, a lower threshold for thrombo-
cytopenia is suggested in the 2009 pre-
liminary criteria for MAS as a compli-
cation of juvenile SLE, as compared to
sJIA-associated MAS.1 Limitations of
the study include the comparatively low
number of patients used to develop the
criteria and the fact that cases of system-
ic infection were not included as a con-
trol group to ensure ability to distinguish
MAS from infection.
OPTIONS FOR TREATMENT
Unfortunately, to the best of our
knowledge, no controlled studies on
therapies for MAS have been published,
and evidence for effective management
of the disease is anecdotal. Common
practice is to consider high-dose IV cor-
ticosteroids as first-line therapy, with
cyclosporine as an appropriate second-
line medication in refractory cases.3 The
emergence of biologic agents as thera-
peutic options for a variety of disease
states provides further potential avenues
for MAS treatment. Indeed, there are
several reports of effective treatment
with the TNF-inhibitor etanercept, the
IL-1 inhibitor anakinra, the IL-6 recep-
tor monoclonal antibody tocilizumab,
and cytotoxic T-lymphocyte-associated
e397

TABLE 1.
MAS-2016 Diagnostic
Criteria
• Platelets <181,000 per mL
• AST >48 IU/dL
• Triglycerides >156 mg/dL
• Fibrinogen <360 mg/L
Abbreviations: AST, aspartate aminotransferase; MAS,
macrophage activation syndrome.
Adapted from Ravelli et al.5
protein 4 immunoglobulin.3 However,
some investigators12-14 also recount in-
stances of MAS that were likely trig-
gered by these drugs. Further clinical
experience and dedicated research trials
with these agents may elucidate their
role in the management of MAS.
An additional consideration in treat-
ing cases of probable MAS in the acute
setting is the potentially confounding
diagnosis of systemic infection, which
may proceed rapidly and with devas-
tating consequences in the event of de-
layed diagnosis or misdiagnosis. Thus,
the authors of this article propose that
concurrent treatment with empiric anti-
biotics be a reasonable course of action
until an infectious process can be defini-
tively ruled out.
CONCLUSION
The establishment of these MAS-
2016 criteria, which have been ap-
proved by both the EULAR and ACR
after validation against an independent
data set, should make it easier for pe-
diatricians practicing in the commu-
nity with limited immediate access to
a consulting pediatric rheumatologist
to diagnose and treat MAS. Its param-
eters are consistently reliable and eas-
ily measured without specialized testing
facilities. Furthermore, they do away
with the need to perform bone marrow
aspiration, as pathologic evidence of he-
mophagocytosis is often not sufficiently
e398
SPECIAL ISSUE ARTICLE
TABLE 2.
Preliminary Diagnostic
Guidelines for MAS as a
Complication of Juvenile
SLE
Clinical criteria
Fever >38℃
Hepatomegaly
Splenomegaly
Hemorrhagic manifestations (purpura,
easy bruising, or mucosal bleeding)
CNS dysfunction (irritability, disorienta-
tion, lethargy, headache, seizures, or
coma)
Laboratory criteria
Cytopenia affecting ≥2 cell lineages
(white blood cell count ≤4 × 109/L, he-
moglobin ≤90 g/L, or platelet count ≤150
× 109/L)
Increased aspartate aminotransferase
(>40 units/L)
Increased lactate dehydrogenase
(>567 U/L)
Hypofibrinogenemia (fibrinogen
≤1.5 g/L)
Hypertriglyceridemia (triglycerides
>178 mg/dL)
Hyperferritinemia (ferritin >500 mcg/L)
Abbreviations: CNS, central nervous system; MAS,
macrophage activation syndrome; SLE, systemic lupus
erythematosus.
Adapted from Parodi et al.1
sensitive, specific, or practical to be use-
ful in a community setting.11
These guidelines are not without lim-
itations, which are necessary to keep in
mind when suspicion for MAS is high.
For one, it is important to note the rela-
tively low sensitivity of 79% and high
specificity of 99% of the MAS-2016
criteria.5 The classification criteria were
created primarily for use in research
studies and clinical trials and may miss
some instances of MAS seen in the
community setting—especially those
with incomplete clinical expression.
Furthermore, although the proj-
ect did examine the role of changes in
laboratory values over time for their
potential usefulness in the detection of
MAS, there was not sufficient data in
the control group to include them in
consideration as candidate criteria.15
Therefore, the final diagnostic criteria
include only “snapshot” values from
the single point in time of the patients’
initial presentation, and do not account
for the concept of MAS as a “moving
target.” In the acute setting, a propor-
tional drop in white blood cell count and
platelet counts or an increase in ferritin
level should alert the pediatrician that
MAS may be evolving, especially in pa-
tients who exhibit high white blood cell
counts and platelet levels as a baseline
function of their underlying sJIA.16
Finally, and perhaps most relevant to
the above illustrative case, these crite-
ria were developed specifically for the
classification of MAS in the setting of
sJIA. The applicability to MAS in other
disease states, such as SLE or Kawasaki
disease or in patients whose underlying
disease state is unknown, has not been
tested.
The patient in the illustrative case
was ultimately diagnosed and managed
as SLE, and she made rapid clinical
improvement with systemic steroids.
Throughout her hospital stay, MAS was
held by the primary pediatric team as
a “must not miss” diagnosis and was
monitored for actively. As you can see
in the discussion above, by some stan-
dards, she met MAS criteria. The fact
that MAS can occur as the initial, pre-
senting manifestation of rheumatic
disease (and thus occur in a patient
similar to the patient in the illustrative
case, who did not have a previously
established diagnosis of an autoim-
mune condition), and that MAS can so
closely mimic classic presentations of
other—potentially related—conditions
such as flare of active SLE or sJIA, or
even systemic infection, make MAS
Copyright © SLACK Incorporated

an exceptionally challenging diagnosis
to make in the inpatient setting.17 But
with a mortality rate as high as 8%, it is
an important diagnosis to make or ex-
clude with confidence and in a timely
fashion.7
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