An atypical case of late-onset systemic
lupus erythematosus with systemic
lymphadenopathy and severe autoimmune
thrombocytopenia/neutropenia mimicking
malignant lymphoma
Keita Tamaki, Satoko Morishima,
Sawako Nakachi, Sakiko Kitamura,
Sachie Uchibori, Shouhei Tomori, Taeko
Hanashiro, Natsuki Shimabukuro, et al.
International Journal of Hematology
ISSN 0925-5710
Int J Hematol
DOI 10.1007/s12185-016-2126-8

1 23

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Author's personal copy
Int J Hematol
DOI 10.1007/s12185-016-2126-8

CASE REPORTAn atypical case of late‑onset systemic lupus erythematosus
with systemic lymphadenopathy and severe autoimmune
thrombocytopenia/neutropenia mimicking malignant lymphoma
Keita Tamaki1 · Satoko Morishima1 · Sawako Nakachi1 · Sakiko Kitamura1 · Sachie Uchibori1 · Shouhei Tomori1 ·Taeko Hanashiro1 · Natsuki Shimabukuro1 · Iori Tedokon1 · Kazuho Morichika1 · Yukiko Nishi1 ·Takeaki Tomoyose2 · Kennosuke Karube3 · Takuya Fukushima4 · Hiroaki Masuzaki1

Received: 7 May 2016 / Revised: 1 November 2016 / Accepted: 2 November 2016
© The Japanese Society of Hematology 2016

Abstract Here, we report a rare case of systemic lupus
erythematosus (SLE) with conspicuous manifestation ofhematological abnormalities. At onset, the 52-year-old
male patient showed systemic lymphadenopathy and splenomegaly, severe autoimmune thrombocytopenia, and autoimmune neutropenia. Bone marrow examination and lymph
node biopsy excluded the possibility of malignant lymphoma. Based on laboratory findings, he was finally diagnosed with combined autoimmune cytopenia coupled with
SLE. Atypical clinical manifestations of SLE prompted us
to explore the possibility of autoimmune lymphoproliferative syndrome (ALPS). However, we did not detect anincreased number of CD4−/CD8−, CD3+, TCRαβ+ doublenegative T cells in the circulating blood or dysfunctional T
cell apoptosis in the Fas/Fas ligand pathway due to mutations in the FAS, FASLG or CASP10 genes. Combined
autoimmune cytopenia is a rare clinical entity that in some* Satoko Morishima
smorishi@med.u‑ryukyu.ac.jp* Hiroaki Masuzaki
hiroaki@med.u‑ryukyu.ac.jp
1

Division of Endocrinology, Diabetes and Metabolism,
Hematology and Rheumatology (Second Departmentof Medicine), Graduate School of Medicine, Universityof the Ryukyus, 207 Uehara, Nishihara, Okinawa 903‑0215,
Japan

2

Department of Hematology, Heartlife Hospital, Nakagusuku,
Okinawa, Japan3

Departments of Pathology and Cell Biology, Graduate Schoolof Medicine, University of the Ryukyus, Nishihara, Okinawa,
Japan

4

Laboratory of Hematoimmunology, Faculty of Medicine,
School of Health Sciences, University of the Ryukyus,
Nishihara, Okinawa, Japancases co-occurs with other autoimmune diseases. Given
that most SLE patients presenting atypical hematological manifestations at an early stage subsequently exhibit
typical systemic manifestations, the present case raises thepossibility that initial hematological abnormalities may besigns of unexpected SLE manifestations.
Keywords Systemic lupus erythematosus (SLE) · Severe
autoimmune thrombocytopenia (ITP) · Severe autoimmune
neutropenia (AIN) · Autoimmune lymphoproliferative
syndrome (ALPS) · Systemic lymphadenopathy ·Malignant lymphoma

Introduction
Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disorder with a wide range of clinical manifestation [1]. Although hematological abnormalities including
anemia, leukocytopenia, lymphopenia, thrombocytopenia
and regional lymphadenopathy are common in SLE, it has
been recognized that severe thrombocytopenia (platelet
counts ≤20,000/μL) and severe neutropenia (neutrophil
counts <500/μL) are rare manifestations [2, 3]. Noticeably,
SLE scarcely shows generalized lymphadenopathy mimicking lymphoma [4]. Therefore, systemic lymphadenopathy
accompanied by hepatosplenomegaly or B symptoms is awarning sign of malignant diseases in elderly people [5].
SLE predominantly affects women, with a high incidence
during the childbearing age. The onset of SLE over 50-yearold defined as “late-onset SLE” is uncommon, but is sometimes accompanied by insidious diseases [6]. We here reportan atypical case of SLE with conspicuous manifestationof hematological abnormalities. At the onset, the 52-yearold male patient showed systemic lymphadenopathy and13Author's personal copy
K. Tamaki et al.

splenomegaly mimicking malignant lymphoma. He simultaneously had complicated severe autoimmune thrombocytopenia (ITP) and autoimmune neutropenia (AIN).

Case presentation
A 52-year-old male with neither significant past medical
history nor appreciable family history presented with systemic lymphadenopathy and splenomegaly and showedexaggerated uptake of 18F-fluorodeoxyglucose (FDG) on
positron-emission tomography/computed tomography(PET/CT) scan (Fig. 1). The values for SUV max, SUV
mean and SUV peak at the left axillary lymph node were
8.8, 5.0 and 5.9, respectively (Fig. 1). As he did not havesignificant symptoms other than lymphadenopathy, hestopped going to the regular outpatient clinic on his own
accord.
Nine months later, he came to our outpatient unit withgum bleeding, night sweat and fever of unknown origin.
Blood examination revealed severe thrombocytopenia, neutropenia and polyclonal hyper-γ globulinemia with elevation of circulating soluble interleukin-2 receptor (Table 1).
Enhanced CT scan showed systemic lymphadenopathy
and splenomegaly. As we initially suspected hematological malignancies, bone marrow examination and left axillary lymph node biopsy were performed. However, lymph
node biopsy revealed hyperplastic reactive changes without specific etiologies. Bone marrow examination also did
not show specific changes other than slight hyperplasia.

Fig. 1  Images of PET/CT
scan in the present case. PET/CT scan showed systemic lymphadenopathy (black rightward
arrowhead) and splenomegaly(heavy wide-headed rightward)
exaggerated abnormal uptakesof FDG. The values for SUV
max, SUV mean and SUV peakat the left axillary lymph node
were 8.8, 5.0 and 5.9, respectively

13

Therefore, we suspected that a kind of autoimmunity would
be responsible for symptoms. Expectedly, it was revealed
that anti-neutrophil antibody, direct antiglobulin test, platelet-associated IgG, anti-platelet antibody, anti-GPIIb/IIIa
antibody and anti-human leukocyte antigen autoantibody
were positive in circulating blood (Table 1). We therefore
tentatively diagnosed him with ITP and AIN. He showed
mild anemia without obvious hemolytic changes. We also
detected other multiple autoantibodies including antinuclear antibody, anti-cardiolipin antibody and anti-SS-A/
Ro antibody. During his hospitalization, refractory cheilitis
and mono-neuropathy in the right leg emerged. As patient’s
physical and laboratory findings met the diagnostic criteria for SLE, we finally diagnosed him with SLE. Although
there was prolonged liver dysfunction, liver biopsy did notshow specific findings except mild chronic hepatitis.
To prevent possible severe hemorrhage, we administeredintravenous immunoglobulin (IVIG) at the dose of 400 mg/
kg for 5 days. However, the IVIG therapy was not effective(Fig. 2). Severe thrombocytopenia and neutropenia were
improved expeditiously by administration of prednisolone(PSL) at the dose of 1 mg/kg. During tapering of PSL, thenumber of platelets in the circulating blood was decreased
by about 2 × 104/μL. We therefore appended eltrombopag
as a second-line therapy. As eltrombopag showed excellent
effectiveness at the minimal dose of 12.5 mg, the numberof platelets in the circulating blood was increased around
10 × 104/μL. Two months later, PET/CT scan revealed significant improvement in the exaggerated uptake of FDG bylymph nodes and spleen. Furthermore, the value of solubleAuthor's personal copy
An atypical case of late-onset systemic lupus erythematosus with systemic lymphadenopathy…
Table 1  Laboratory findings of the present case on the first admission
CBC
WBC
  Baso
  Eo
  Seg
  Ly
  Mono  At-Ly
RBC
Hb
Hct
MCV
MCH
MCHC
Plt
Ret
Biochemistry
TP
Alb
AST
ALT
LDH
ALP
γ-GTP
T-bil
BUN
Cre
ESR
Serum protein fraction
Polyclonal hyper γ globulinemia
Hyaluronic acid
Coagulation
PT%
APTT
Fib
d-Dimer
FDP
Urea breath test

78.5%
27.9 s
280 mg/dL
1.4 μg/mL
4 μg/mL

Serum immunology
IgG
IgA
IgM
IgG4
CRP
sIL-2R
β2MG
Haptoglobin
Type IV collagen
RF
ANA
  Homogeneous
C3
C4
CH50
Anti-dsDNA antibody
Anti-ssDNA antibody
Anti-RNP antibody
Anti-Sm antibody
Anti-cardiolipin antibody
Anti-SS-A/Ro antibody
Anti-SS-B/La antibody
AMA2 antibody
DAT
PAIgG
Anti-platelet antibody
Anti-GPIIb/IIIa antibody
Anti-HLA antibody
Anti-neutrophil antibody
HBs antigen
Anti-HBs antibody
Anti-HBc antibody
Anti-HCV antibody
Anti-HIV antibody
Anti-HTLV-1 antibody
CMV antigenemia(−)

EBV-PCR

2000/μL
2.5%
3.5%
9%
60%
21%
4%
373 × 104/μL
12.0 g/dL
35.2%
94.4 fl32.2 pg
34.1%
0.9 × 104/μL
16‰
8.3 g/dL
2.9 g/dL
50 IU/L47 IU/L
212 IU/L
934 IU/L
132 IU/L
0.6 mg/dL
13 mg/dL
0.81 mg/dL
69 mm/h

300 ng/mL (≤50)

3443 mg/dL (870–1700)
360 mg/dL (110–410)
301 mg/dL (33–190)
85 mg/dL (4–108)
1.73 mg/dL
3068 U/mL (127–582)
3.51 mg/L (0.00–2.00)
169 mg/dL (19–170)
14 ng/mL (≤6)
7 IU/mL (0–14)(+)
×160 (<×20)
138 mg/dL (65–135)
8 mg/dL (13–35)
41 U/mL (31–58)
7 IU/mL (0–20)
23 AU/mL (0–40)
0.1 Index (<1.0)
0.5 Index (<1.0)
16.1 U/mL (<10.0)
29.0 Index (<10.0)
2.0 Index (<15.0)
1.6 Index (<7)
IgG (3+), C3b, d (−)
883 ng/107 cells (≤46)
(+)
(+)
(+)
(+)
(−)
(−)
(−)
(−)
(−)
(−)
(−)
2 × 102 copy/mL (<2 × 102)

Peripheral blood testing showed severe thrombocytopenia and neutropenia, polyclonal γ globulinemia, hepatic disorder and multiple autoantibodies (anti-neutrophil antibody, direct antiglobulin test, platelet-associated IgG, anti-platelet antibody, anti-GPIIb/IIIa antibody, anti-humanleukocyte antigen autoantibody, anti-nuclear antibody, anti-cardiolipin antibody and anti-SS-A/Ro antibody). In the table each normal value isshown in parenthesis
CBC complete blood count, WBC white blood cell, Baso basophil, Eo eosinophil, Seg segmented neutrophil, Ly lymphocyte, Mono monocyte,
At-Ly atypical lymphocyte, RBC red blood cell, Hb hemoglobin, Hct hematocrit, MCV mean corpuscular volume, MCH mean corpuscularhemoglobin, MCHC mean corpuscular hemoglobin concentration, Plt platelet, Ret reticulocyte, TP total protein, Alb albumin, AST aspartatetransaminase, ALT alanine transaminase, LDH lactate dehydrogenase, ALP alkaline phosphatase, γ-GTP gamma-glutamyl transpeptidase, T-bil
total-bilirubin, BUN blood urea nitrogen, Cre creatinine, ESR erythrocyte sedimentation rate, PT prothrombin, APTT activated partial thromboplastin time, Fib fibrinogen, FDP fibrin degradation products, IgG immunoglobulin G, IgA immunoglobulin A, IgM immunoglobulin M, IgG4
immunoglobulin G4, CRP C-reactive protein, sIL-2R soluble interleukin-2 receptor, β2MG beta-2 microglobulin, RF rheumatoid factor, ANA
anti-nuclear antibody, AMA2 anti-mitochondria M2 antibody, DAT direct antiglobulin test, PAIgG platelet-associated immunoglobulin G, HBs
antigen hepatitis B surface antigen, HBc antibody hepatitis B core antibody, HCV antibody hepatitis C virus antibody, HIV human immunodeficiency virus, HTLV-1 human T cell leukemia virus type 1, CMV cytomegalovirus, EBV Epstein–Barr virus, PCR polymerase chain reaction, (+)
positive, (−) negative13

Author's personal copy
K. Tamaki et al.
Fig. 2  Clinical course of thepresent case. As the IVIG
therapy was not effective, we
administered PSL at the doseof 1 mg/kg. Pancytopenia
was improved expeditiously.
However, the number of plateletin the circulating blood was
decreased by about 2 × 104/μL
during tapering of PSL. After
we added eltrombopag at theminimal dose of 12.5 mg, thenumber of platelets in the circulating blood was successfullyincreased around 10 × 104/μL.
PSL prednisolone, WBC whiteblood cell, Neu neutrophil, Hbhemoglobin, Plt platelet, IVIG
intravenous immunoglobulininterleukin-2 receptor in the circulating blood decreased to
603 U/mL.
Approximately 2 years after the first admission, he experienced relapse while he was taking PSL 5 mg per day(Table 2). He was again treated with PSL at the dose of
1 mg/kg. His hematological findings improved, and PSL isnow being tapered slowly.

Discussion
We experienced an atypical case of late-onset SLE withsevere ITP, AIN and marked systemic lymphadenopathy andsplenomegaly, closely mimicking malignant lymphoma. At
the onset, the patient showed no typical manifestations of
SLE including skin lesion, mucous membrane lesions, arthritis or nephritis. In contrast, from the beginning, the patient
had systemic lymphadenopathy, night sweat, neutropenic
fever and gum bleeding due to severe thrombocytopenia.
However, bone marrow examination and lymph node biopsy
clearly excluded the possibility of malignant lymphoma. In
minor cases, SLE is known to resemble malignant lymphoma
or lymphoproliferative disorder [5]. According to Systemic
Lupus International Collaboration Clinics (SLICC) criteria[7], he met 2 of 11 clinical criteria (leukopenia and thrombocytopenia) and 4 of 6 immunologic criteria (ANA positivity,
antiphospholipid antibody positivity, hypocomplementemia
and direct antiglobulin test positivity) for the diagnosis of
SLE. Therefore, the patient was finally diagnosed with SLE.
SLE is an autoimmunity-based chronic inflammatory
disease that causes a wide variety of organ damages and13

resultant clinical manifestations [8]. Notably, it is uncommon that the onset of SLE is over 50 years of age (lateonset SLE) [6]. Previous reports on patients with late-onset
SLE demonstrated that female to male ratio was low [9]and the frequency of cutaneous, neuropsychiatric manifestations and lupus nephritis was also low, but the frequency
of cytopenia was high compared with young patients withSLE [10].
According to the literature, severe ITP coupled with
SLE is associated with severe hemorrhagic complications[2]. Although conventional immunosuppressive agents suchas corticosteroid and calcineurin inhibitor remain the mainstay against such a situation, thrombopoietin receptor agonist is a novel, promising therapeutic modality [11]. In thepresent case, the combination therapy of PSL with eltrombopag showed excellent effectiveness.
Of note, the combination of ITP and AIN, as observedin the present case, has been considered as “combined
autoimmune cytopenias” [12]. To date, unlike Evans syndrome (ES), there have been only a few reports on combined autoimmune cytopenias. ES is characterized by theco-existence of autoimmune hemolytic anemia (AIHA) and
ITP and/or AIN [13]. On the other hand, combined autoimmune cytopenia consists of ITP, AIN and/or AIHA [12]. A
recent study reported that approximately half of the adult
ES patients have a variety of underlying diseases including collagen diseases, immunodeficiency diseases, lymphomas and lymphoproliferative disorders [14]. Similarly,
combined autoimmune cytopenia is often complicated byunderlying diseases [12]. As in the present case, the majority of late-onset SLE patients who limitedly exemplified

Author's personal copy
An atypical case of late-onset systemic lupus erythematosus with systemic lymphadenopathy…
Table 2  Laboratory findings ofthe present case on the second
admission

CBC
WBC
  Eo
  Myelo
  Meta  Stab
  Seg
  Ly
  Mono
RBC
Hb
Hct
MCV
MCH
MCHC
Plt
Ret
Biochemistry
TP
Alb
AST
ALT
LDH
ALP
γ-GTP
T-Bil
D-Bil
BUN
Cre
ESR

3400/μL
2.0%
(+)
1.0%
14.0%
2.0%
53%
28%
429 × 104/μL
13.8 g/dL
40.1%
93.5 fl32.2 pg
34.4%
0.6 × 104/μL
36.5‰
7.6 g/dL
3.7 g/dL
63 IU/L
103 IU/L
229 IU/L
636 IU/L
164 IU/L
2.9 mg/dL
1.1 mg/dL
16 mg/dL
1.01 mg/dL

Coagulation
PT%
APTT
Fib
d-Dimer
FDP
Serum immunology
IgG
IgA
IgM
CRP
sIL-2R
Haptoglobin
RF
ANA
  Homogeneous
C3
C4
CH50
Anti-dsDNA antibody
Anti-ssDNA antibody
Anti-cardiolipin antibody
Anti-SS-A/Ro antibody
Anti-SS-B/La antibody
DAT
PAIgG
Anti-platelet antibody

73.0%
28.7 s
558 mg/dL
0.9 μg/mL
5 μg/mL
1592 mg/dL (861–1747)
326 mg/dL (93–393)
169 mg/dL (33–183)
11.56 mg/dL
827 U/mL (127–582)
118 mg/dL (19–170)<5 IU/mL (0–14)(+)
×40 (<×20)
142 mg/dL (65–135)
21 mg/dL (13–35)
59 U/mL (31–58)
3 IU/mL (0-12)
5 AU/mL (0-25)
1.1 U/mL (<10.0)
1.3 Index (<10.0)
0.9 Index (<15.0)
IgG (−), C3b, d (−)
142 ng/107 cells (≤46)(−)

69 mm/hHis blood test revealed marked severe thrombocytopenia and neutropenia. In the table each normal value isshown in parenthesis
CBC complete blood count, WBC white blood cell, Baso basophil, Eo eosinophil, Myelo myelocyte, Meta
metamyelocyte, Stab stab neutrophil, Seg segmented neutrophil, Ly lymphocyte, Mono monocyte, RBC
red blood cell, Hb hemoglobin, Hct hematoclit, MCV mean corpuscular volume, MCH mean corpuscularhemoglobin, MCHC mean corpuscular hemoglobin concentration, Plt platelet, Ret reticulocyte, TP total
protein, Alb albumin, AST aspartate transaminase, ALT alanine transaminase, LDH lactate dehydrogenase,
ALP alkaline phosphatase, γ-GTP gamma-glutamyl transpeptidase, T-Bil total-bilirubin, D-Bil direct-bilirubin BUN blood urea nitrogen, Cre creatinine, ESR erythrocyte sedimentation rate, PT prothrombin, APTT
activated partial thromboplastin time, Fib fibrinogen, FDP fibrin degradation products, IgG immunoglobulin G, IgA immunoglobulin A, IgM immunoglobulin M, CRP C-reactive protein, sIL-2R soluble interleukin-2 receptor, RF rheumatoid factor, ANA anti-nuclear antibody, DAT direct antiglobulin test, PAIgG
platelet-associated immunoglobulin G, (+) positive, (−) negative

atypical hematological manifestations without typical lupus
signs are less likely to be diagnosed with SLE. Therefore, it
is required to periodically monitor autoantibodies such as
ANA and ds-DNA, indicating the disease activity of SLE.
Atypical clinical manifestations of SLE in the present
case tempted us to explore the possibility of autoimmune
lymphoproliferative syndrome (ALPS) as a plausible differential diagnosis. ALPS is an immune-deficient diseasecaused by dysfunction of T cell apoptosis in the Fas/Fas

ligand pathway due to mutations in the FAS, FASLG and
CASP10 genes [15]. ALPS is characterized by the presenceof chronic, non-malignant, non-infectious lymphadenopathy
and/or splenomegaly. In circulating blood from patients with
ALPS, CD4−/CD8−, CD3+ and TCRαβ+ double-negative T
cell (DNT) counts were reported to increase in many cases[15]. Although the onset of ALPS is typically observed inchildhood, some cases of ALPS were reported to be diagnosed during adulthood [16]. We therefore investigated the13Author's personal copy
K. Tamaki et al.

DNT counts and possible gene mutations via the Internet
web site of Primary Immunodeficiency Database in Japan(http://pidj.rcai.riken.jp/). However, increased number of
DNT counts as well as gene mutations for FAS, FASLG and
CASP10 was not detected, and hence the exclusion of ALPS.
In summary, we reported a 52-year-old male SLE patientpresenting with severe ITP, AIN and systemic lymphadenopathy without typical manifestations of SLE. The present case raises the alarm of considering the possibility that
initial hematological abnormalities may be signs of unexpected SLE manifestation.
Acknowledgements Investigation of the DNT counts and the genemutations for the Fas/Fas ligand pathway was executed via Primary
Immunodeficiency Database in Japan. We express our sincere thanks
to Dr. T. Wada and Prof. A. Yachie at the Department of Pediatrics,
Kanazawa University, for helpful advices and analyses on the number
of DNT counts. We also thank Y. Murayama, M. Shimoji, Y. Kishimoto, I. Asato, M. Hirata and C. Noguchi for excellent assistance.
Compliance with ethical standards
All authors follow the compliance with ethical standards.
Conflict of interest All authors declare no conflict of interest.

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