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ISSN 1439-7595 (print), 1439-7609 (online)

Mod Rheumatol, 2013; Early Online: 1–5

© 2013 Japan College of Rheumatology
DOI: 10.3109/14397595.2013.844402

CASE REPORT

Successful treatment of macrophage activation syndrome in a patient

with dermatomyositis by combination with immunosuppressive therapy
and plasmapheresis
Shinjiro Kaieda1, Naomi Yoshida1, Fumiya Yamashita1, Masaki Okamoto1, Hiroaki Ida1, Tomoaki Hoshino1,
and Takaaki Fukuda2
1Department of Medicine, Division of Respirology, Neurology and Rheumatology, Kurume University School of Medicine, Kurume, Japan
Mod Rheumatol Downloaded from informahealthcare.com by Kurume University on 10/22/13

and 2Center for Rheumatic Diseases, Kurume University Medical Center, Kurume, Japan

Abstract Keywords
Macrophage activation syndrome (MAS), also known as secondary hemophagocytic lymphohis- Dermatomyositis, Hypercytokinemia,
tiocytosis, is mediated by cytokine overproduction from excessive activation of T lymphocytes Macrophage activation syndrome, Plasma
and macrophages. We present a dermatomyositis patient with MAS, caused by hypercytokine- exchange, Tacrolimus
mia. The combination of tacrolimus and plasma exchange therapy was effective in this case for
treating MAS. This combination therapy is especially useful for MAS refractory to steroids. History
Received 17 June 2013
For personal use only.

Accepted 25 August 2013

Published online 18 October 2013

Introduction
Macrophage activation syndrome (MAS), also known as second-
ary hemophagocytic lymphohistiocytosis (HLH), is often life-
threatening and can be fatal, particularly if diagnosis and treatment
are delayed [1, 2]. Although MAS has been recognized as being
associated with autoimmune diseases, its development during the
course of dermatomyositis (DM) is considered to be rare [3–8].
MAS presents with clinical and laboratory features mediated by
cytokine overproduction secondary to excessive activation and
proliferation of T lymphocytes and macrophages [1, 2].
We present a DM patient with MAS, caused by hypercy-
tokinemia. The combination of an immunosuppressant, tacrolimus,
with plasma exchange led to resolution of steroid-resistant MAS in
this case.
Case report
A 57-year-old man, suffering from low-grade fever, polymyalgia
and arthralgia, noticed erythema in his face and fingers. He was
suspected of having a connective tissue disease, and was referred
to our department for detailed examination and therapy 3 months
after the disease onset.
On admission to our hospital, his height was 184 cm and weight,
104 kg. Physical examination showed a heliotrope rash around the
eyes and Gottron’s sign on the dorsum of both hands. He com-
plained of muscle weakness affecting his upper extremities. Body
temperature was elevated (38.0°C), but other vital signs were nor-
mal. His palpebral conjunctivae showed no indication of anemia.
Correspondence to: Shinjiro Kaieda, Kurume University School of
Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan. Tel:  81-942-
31-7560. Fax:  81-942-31-7703. E-mail: shinkaieda@gmail.com
On chest auscultation, heart sounds were clear. Fine crackles were
audible over both lower lung fields. The abdomen was soft and flat.
Peripheral lymphadenopathy was noted in the neck region.
Laboratory evaluation (Table 1) revealed leukocytosis (white
blood cell [WBC] count, 13400/μL; Neutrophils, 84.5%) and
marked elevations of myogenic enzymes including creatinine
phosphokinase (CPK), aldolase and myoglobin. The erythro-
cyte sedimentation rate and C-reactive protein (CRP) were both
elevated, at 93.0 mm/h and 18.1 mg/dL, respectively. Liver dys-
function was also detected: lactate dehydrogenase (LDH), 499
IU/L; alanine aminotransferase, 115 IU/L; alkaline phosphatase
(ALP), 463 IU/L. Serum albumin was mildly decreased. The
results of routine kidney function tests were normal. D-dimer and
fibrin/fibrinogen degradation products were slightly elevated, but
fibrinogen was normal on coagulation–fibrinolytic tests. Serum
ferritin was elevated (1153.1 ng/mL; normal,  183.0 ng/mL).
An immunological test revealed the patient to be positive for
anti-nuclear antibodies with a titer of 1:2560 (a speckled pattern).
Anti-DNA, anti-U1-RNP/Sm and anti-Jo-1 antibodies were all
negative. Anti-mitochondrial antibodies were not detected. Anti-
cardiolipin antibodies, lupus anticoagulant and anti-neutrophil
cytoplasmic antibodies were negative. Serum complement levels
were normal. Blood cultures were negative. Serological studies
showed no evidence of recent infection with Epstein–Barr virus
or cytomegalovirus (CMV). HBV-DNA and hepatitis C antibod-
ies were negative. Arterial blood gas analysis on room air showed
mild hypoxia (PaO2 79.6 Torr). Chest computed tomography
(CT) scans revealed consolidations and ground glass attenuations
predominantly around the bronchovascular bundles in both lower
lobes, appearing as a pattern of non-specific interstitial pneumonia
(Figure 1A). Abdominal CT detected moderate hepatosplenomegaly
(images not shown). Magnetic resonance imaging (MRI) of the
 2 S. Kaieda et al. Mod Rheumatol, 2013; Early Online: 1–5

Table 1. Laboratory Data on Admission.

[Hematology] [Blood chemistry] [Serological test]
RBC 449104/L TP 6.74 g/dL CRP 18.1 mg/dL
Hb 12.9 g/dL Alb 2.61 g/dL IgG 1700 mg/dL
Ht 39.2% T.Bil 1.19 mg/dL IgA 261 mg/dL
MCV 87 fL LDH 499 U/L IgM 79 mg/dL
MCH 28.7 pg AST 144 U/L C3 120 mg/dL
MCHC 32.9% ALT 115 U/L C4 21 mg/dL
WBC 13400/L CPK 1672 U/L RF 2 U/mL
Neutro. 84.5% ALP 463 U/L KL-6 495 U/L
Lymph. 5.5% γ-GTP 133 U/L Procalcitonin 0.33 ng/mL
Mono. 6.5% BUN 18.6 mg/dL
Eosino. 3% Cr 1.07 mg/dL Anti-Nuclear Ab. 2560 Fold
PLT 20.4 104/L Aldolase 38.8 U/L Pattern: speckled
Myoglobin 1600 ng/mL Anti-DNA Ab. (–)
Ferittin 1153.1 ng/mL Anti-U1 RNP Ab. (–)
Anti-Sm Ab. (–)
[Hemostatic data] [Virus Infection] [Serological test]
PT-INR 1.19 EBV-VCA-IgG 40 Fold Anti-Jo-1 Ab. (–)
APTT 38.6 second EBV-VCA-IgM  10 Fold Anti-CCP Ab. (–)
D-Dimer 6.9 g/mL PR3-ANCA (–)
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FDP 13.5 g/mL Parbo B19-lgM (–) MPO-ANCA (–)

Fib 224 mg/dL Lupus anti coagulant (–)
[Urinalysis] CMV-C7HRP (–) Anti-cardiolipin Ab. (–)
Protein ()
Occult blood (2)
RBC  1/HPF
WBC  1/HPF

triceps brachii demonstrated high-intensity areas in these muscles, 835 U/L; and ALP, 1016 U/L) and thrombocytopenia (platelets,
indicating inflammatory muscular lesions (Figure 1B). Electro- 8.2  104 μ/L). His hemoglobin value was maintained, but the
myogram examinations showed no myogenic alterations. On the number of WBC increased. We could not exclude the possibility
For personal use only.

basis of the presence of DM-specific skin alterations, including
the heliotrope rash and Gottron’s sign, myalgia, arthritis, elevated
myogenic enzymes and CRP, the patient met the Japanese criteria
for the diagnosis of DM (revised in 1992). We thus diagnosed DM
complicated by interstitial pneumonia. The MRI findings of myo-
sitis supported this diagnosis. Investigations including a CT scan
of the whole body, upper endoscopy and colonoscopy excluded
malignancy.
After admission, the patient’s temperature rose to approxi-
mately 38°C and an evolving maculopapular rash appeared over
his trunk and upper arms (Figure 2). A drug eruption was excluded
because the skin rash did not improve in response to discontinu-
ation of medications possibly causing rash as a side effect, such
as proton pump inhibitors and non-steroidal anti-inflammatory
drugs. Skin biopsy was not performed. Treatment was initiated
with 500 mg intravenous methylprednisolone (mPSL) for 3 days,
followed by 50 mg/day of oral PSL and 50 mg/day cyclosporine.
During steroid pulse therapy, the fever, polymyalgia and arthralgia
showed amelioration; however, 5 days after therapy initiation, the
patient developed a spiking fever, exceeding 39°C. Furthermore,
he showed progressive liver dysfunction (ALT, 442 U/L; LDH,
that cyclosporine was causing his liver dysfunction as an adverse
effect. Thus, this immunosuppressant was discontinued. We con-
sidered the spiking fever, cutaneous rash and liver dysfunction to
be complications of HLH. In addition, levels of soluble forms of
the interleukin-2 receptor (sIL-2R) were markedly elevated (6300
U/mL; normal,  519 U/mL) and hypertriglyceridemia was also
noted (268 mg/dL; normal,  149 mg/dL). Although we did not
examine bone marrow or other organs to detect hemophagocytosis,
this patient met the diagnostic criteria for HLH published by the
Histiocyte Society in 2004, based on the presence of fever, sple-
nomegaly, hypertriglyceridemia, hyperferritinemia and marked
elevation of sIL-2R [9]. It is now recognized that MAS is a form
of secondary HLH [1]. Thus, we diagnosed this patient as having
developed MAS/secondary HLH as a complication of DM, which
was refractory to steroid therapy because ferritin levels worsened
after steroid pulse therapy while CRP was reduced (Figure 3).
MAS presents with clinical and laboratory features mediated by
cytokine overproduction secondary to excessive activation and
proliferation of T lymphocytes and macrophages [1, 2]. There-
fore, we investigated serum inflammatory cytokine levels. IL-6
and TNF-α were increased to 310 and 61.0 pg/mL, respectively

Figure 1. Chest CT and MRI of

muscle. A. Plain chest CT scans
shows consolidations and ground
glass attenuations predominantly
around the bronchovascular bundles
in both lower lobes. B. High signal
intensity can be seen in the triceps
muscle of the arm and in adipose
tissue on STIR-weighted MRI
(arrow).
 DOI 10.3109/14397595.2013.844402
Figure 2. An evolving maculopapular
rash on the trunk (A) and upper arms
(B).
(Figure 2). Plasma exchange therapy, which was expected to rap-
idly reduce cytokine levels in peripheral blood, was performed
using 30 units of fresh frozen plasma six times (twice a week  3
weeks). We administered 80 mg of mPSL intravenously with 3
mg of oral tacrolimus. The dose of tacrolimus, 3 mg/day, led to a
Mod Rheumatol Downloaded from informahealthcare.com by Kurume University on 10/22/13
blood concentration of approximately 5 ng/dl and was well toler-
ated. Repeated therapeutic plasmapheresis improved both clinical
symptoms and laboratory abnormalities. As shown in Figure 2, his
clinical symptoms, including the fever and cutaneous rash, showed
dramatic improvement after plasma exchange therapy. Laboratory
data, including the levels of liver enzymes, CRP and ferritin, were
also improved. Intravenous mPSL was changed to 80 mg of oral
PSL, and the doses were tapered as soon as possible. The patient
was discharged from our hospital in an improved condition and
has since been monitored on an outpatient basis. He has remained
well for 12 months, to date, and his PSL dose has been reduced to
For personal use only.
12.5 mg/day with 3 mg of oral tacrolimus. Low-dose oral tacroli-
mus may help maintain MAS remission while exerting a steroid-
sparing effect.
Plasma
August exchange
Successful treatment of macrophage activation syndrome 3
Discussion
MAS, a serious complication of systemic juvenile idiopathic
arthritis (sJIA) and other childhood systemic inflammatory
disorders, is thought to be caused by excessive activation and
proliferation of T lymphocytes and macrophages. It is also a
complication of autoimmune diseases including systemic lupus
erythematosus (SLE) and adult-onset Still’s disease (AOSD)
[1, 10]. It has been established that MAS is a secondary form
of HLH [1, 2, 9]. The current classification of MAS in patients
with autoimmune disease is imprecise, but MAS is included
among the reactive hemophagocytic syndromes, and the case
definition generally proceeds according to the HLH-2004 diag-
nostic criteria [1]. The development of MAS during the course
of DM is rare [3–8]. Epstein–Barr virus, CMV, and the usage
of gold, methotrexate, and tumor necrosis factor blockers, have
been recognized as triggering MAS [2, 11]. Our present case
had none of these factors, suggesting that he had developed
MAS as a complication of DM.
September
B.T(ഒ 11 14 20 25 27 30 1
40
39
38
Skin
eruption mPSL
500mg PSL PSL
Steroids mPSL 80mg/day
50mg/day 80mg/day

Cyclosporin 50mg/day
Tacrolimus 3 mg/day

Ferritin
40 4000
CRP (mg/dL)

Ferritin (ng/mL)

30 3000
IL-6 310pg/ml
20 TNF-α 61pg/ml 2000
CRP
10 1000

0 0
11 18 24 29 1
August September
PLT (x104/μL 15.5 8.2 5.8 8.1 20.5
ALT (U/L) 91 442 185 176 120
T.Bil (mg/dL) 1.19 1.75 2.12 1.24 0.86
CPK (U/L) 1110 1412 1104 493 357
Figure 3. Clinical course of the patient. B.T, body temperature; mPSL, methylprednisolone; and PSL, prednisolone.
 4 S. Kaieda et al.
Although MAS is a rare complication of DM, characteristics
of four patients with DM complicated by MAS/HPS have been
reported in the literature [7]. The patients were all male, and the
complication of interstitial pneumonitis was seen in three cases.
Substantial increase in sIL-2R levels were reported as observed
in the present case. Furthermore, these patients received a com-
bination of high-dose of glucocorticoids and immunosuppres-
sive therapy with intravenous immunoglobulin because of poor
responses to steroids alone. Consistent with previous observations,
the present case was also steroid resistant.
MAS can be difficult to diagnose, despite its well-recognized
clinical features. The recognition of incipient MAS in patients
with rheumatic disease requires a high index of suspicion. Hall-
mark features of MAS include hyperferritinemia, liver dysfunc-
tion, hypertriglyceridemia, splenomegaly and bone marrow
aspirates showing active hemophagocytosis. Measurement of the
serum ferritin, derived from activated macrophages, may facilitate
the diagnosis and may be a useful indicator of disease activity,
therapeutic response and prognosis. Ferritin levels correlated with
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disease activity in the present case. Cutaneous rash, as observed
in our case, is one of the specific clinical features associated with
MAS as a complication of sJIA [1]. In general, in a patient with
persistently active underlying rheumatologic disease, a fall in the
platelet count, particularly in combination with persistently high
CRP and increasing levels of ferritin and sIL-2R, should raise
suspicion of impending MAS. The diagnosis of MAS is usually
confirmed by the demonstration of hemophagocytosis in several
organs, including bone marrow and the liver, as well as lympha-
nodes. However, false negatives may occur owing to sampling
errors, particularly in the early stages of this syndrome, and failure
For personal use only.
to demonstrate hemophagocytosis does not rule out the diagnosis
of MAS [8]. Although we did not identify hemophagocytosis in
bone marrow or other organs, this patient met the HLH criteria.
Even with treatment, MAS is associated with a high mortality rate,
approximately 50% [12]. Prompt diagnosis of MAS based on the
full clinical picture is thus essential because early treatment favors
a better outcome.
The central role of T cells in hemophagocytic disorders is
further illustrated by the diagnostic and prognostic significance
of elevated serum sIL-2R levels [13]. sIL-2R is now increas-
ingly being recognized as an important biomarker of MAS [14,
15]. Assessment of sIL-2R levels in serum may facilitate timely
diagnosis of MAS. Although mild elevation of sIL-2R has been
reported in several rheumatic diseases including sJIA and SLE, a
several-fold increase in sIL-2R is highly suggestive of MAS [15,
16]. In the present case, marked elevation of sIL-2R was noted,
thus suggesting the presence of aberrant T-cell activation.
As shown in Figure 3, the serum concentrations of IL-6 and
TNF-α were elevated in the present case. Elevations of several
macrophage-driven pro-inflammatory cytokines, including IL-6,
IL-12, IL-18 and TNF-α, are present in many cases [17–19]. Fur-
thermore, TNF-α and IL-6 expressions by CD68 macrophages
have been demonstrated in the hepatic parenchyma of patients
with hemophagocytic syndromes [20]. MAS is usually managed
with eradication of triggers and immunosuppressive therapy.
Plasma exchange has been reported to be useful for treating MAS
accompanying other connective tissue diseases, such as AOSD,
sJIA and SLE [21–23]. Whereas plasma exchange was effective
because it rapidly decreased circulating cytokine levels, addi-
tional immunosuppressive therapy would be required to suppress
immunocompetent cells activated by DM to secrete inflammatory
cytokines, which trigger macrophages to release inflammatory
cytokines, such as TNF-α. As shown in Figure 3, administration
of tacrolimus also contributed to reducing CPK levels, suggesting
that it contribute to DM remission. Thus, combining an immuno-
suppressive agent, tacrolimus, with plasma exchange therapy led
Mod Rheumatol, 2013; Early Online: 1–5
to resolution of corticosteroid-resistant MAS in the present case.
Plasma exchange therapy should be considered as a form of rescue
treatment in patients with life-threatening MAS, associated with
hypercytokinemia.
Tacrolimus, a potent T-cell inhibitor, has been successfully
administered for the treatment of inflammatory bowel disease, SLE
and rheumatoid arthritis [24–27]. While various immune response
abnormalities have been identified in patients with MAS, aberrant
T-cell activation is recognized as one of the most important factors
in disease development [1, 2]. On the basis of these findings, T-cell
blockade is thought to be a potential therapeutic target for MAS.
Cyclosporine has also been shown to be effective MAS [28, 29].
However, this immunosuppressant was discontinued due to suspi-
cion of side effects, specifically liver dysfunction. Tacrolimus is
also reportedly useful for treating MAS/secondary HLH [30, 31].
Thus, this immunosuppressive agent was administered to our cur-
rent patient. Although an improvement in MAS may result from
plasma exchange, low-dose oral tacrolimus has also been shown to
contribute to the maintenance of MAS remission while exerting a
steroid-sparing effect. Furthermore, tacrolimus was considered to
promote remission of DM while exerting a steroid-sparing effect
after withdrawal of plasmapheresis. Tacrolimus has the potential
to be an additional or alternative modality for treating MAS asso-
ciated with DM.
In conclusion, MAS is rare in patients with DM. It is impor-
tant to rapidly diagnose MAS based on the clinical features. The
present case demonstrated that combining immunosuppression
and plasmapheresis is an effective therapeutic strategy for MAS,
complicated by hypercytokinemia, in patients with DM.
Conflicts of interest
None.
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