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□ CASE REPORT □

Successful Treatment of Lupus Cerebrovascular Diseasewith Mycophenolate Mofetil

Kazuhiko Higashioka 1, Kenji Yoshida 1, Kensuke Oryoji 1, Kazuo Kamada 1, Shinichi Mizuki 1,

Hiroshi Tsukamoto 2, Eisuke Yokota 1 and Koichi Akashi 2

Abstract

We report a case of neuropsychiatric systemic lupus erythematosus successfully treated with mycopheno-

late mofetil (MMF). The patient was a 40-year-old female who maintained with 7 mg of prednisolone plus

100 mg of azathioprine (AZ) per day. According to transient ischemic attack that occurred repeatedly and an

elevated level of interleukin-6 (IL-6) in spinal fluid, she was diagnosed as having neuropsychiatric systemic

lupus erythematosus (NPSLE). Initial increase in doses of prednisolone and AZ to 20 mg and 150 mg per

day, respectively, was ineffective. After switching from AZ to MMF, her symptoms of NPSLE completely re-

solved with marked improvement of the IL-6 level in her spinal fluid, suggesting that MMF was effective.

Key words: neuropsychiatric systemic lupus erythematosus, cerebrovascular disease, mycophenolate mofetil,

IL-6 in spinal fluid

(Intern Med 54: 2255-2259, 2015)(DOI: 10.2169/internalmedicine.54.4582)

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune

connective tissue disease that has multiple clinical findings.

When neuropsychiatric symptoms occur, the disease is

called neuropsychiatric systemic lupus erythematosus

(NPSLE); there is central and peripheral nervous system in-

volvement, and the syndrome is divided into 19 groups ac-

cording to clinical manifestations (1). NPSLE is an impor-

tant entity that develops during the course of the disease in

50% to 74% of SLE patients and accounts for 19% of

death (2). In cases that involve the mechanism of lupus flare

(including active vasculitis), treatment with glucocorticoid,

with or without cyclophosphamide (CY) pulse therapy, is

warranted (3). However, when CY is not effective or cannot

be administered because of adverse effects, optimal therapy

has not been established. Here we report a patient who was

affected with NPSLE and had a past history of lupus nephri-

tis with large amounts of CY. Transient ischemic attack

(TIA) occurred repeatedly on azathioprine (AZ) therapy, and

an elevated level of interleukin (IL)-6 in spinal fluid was

recognized. Mycophenolate mofetil (MMF) that was selected

as the next therapeutic agent, caused marked improvement.

There have been only a few previously reported cases in

which MMF was effective for NPSLE.

Case Report

The patient was a-40-year-old Japanese woman. She was

found to have positive antinuclear antibody (speckled pat-

tern, 320 titers), elevated anti-double-stranded (ds) DNA an-

tibody, anti-SS-A antibody and lupus nephritis (type V)

when she was 22 years old. Anti-Sm antibody was negative.

She was treated with prednisolone 50 mg plus oral CY 50

mg per day. Due to oral CY given for 28 months (the ap-

proximately cumulative dose was 43 g), the lupus nephritis

resolved and the prednisolone dose could be tapered to 10

mg per day for maintenance. The prednisolone dose was

raised to 30 mg per day due to butterfly rash and hypocom-

plementemia when she was 36. Prednisolone could be ta-

pered again and she was in remission with prednisolone 7

mg plus AZ 100 mg per day.

At the age of 40, she was referred to our department due

１Division of Rheumatology, Matsuyama Red Cross Hospital, Japan and ２Department of Medicine and Biosystemic Science, Graduate School of

Medical Science, Kyushu University, Japan

Received for publication November 24, 2014; Accepted for publication December 25, 2014

Correspondence to Dr. Kazuhiko Higashioka, higakazu1015@icloud.com

Intern Med 54: 2255-2259, 2015 DOI: 10.2169/internalmedicine.54.4582

2256

Figure　1.　Diffusion-weighted MRI image. It shows multiple high brightness legions in right cerebral hemisphere.

Figure　2.　Magnetic resonance angiography. The narrowing of the flat portion of right middle cerebral artery is shown (red arrow).

Table.　Laboratory Data.

<Complete blood count>

WBC / L

Seg 83.8 %

Lym 11.4 %

Mono 3.6 %

Eos 1.0 %

RBC 386 ×104 / L

Hb 13.3 g/dL

Ht 39.1 %

Plt 22.3 ×104/ L

<Urine>

Sugar (-)

Protein (-)

OB (-)

WBC (-)

<Chemistry>

TP

Albmin

T.Bil

AST

ALT

LDH

ALP

-GTP

CK

BUN

Cr

Na

K

Cl

Ca

7.5

4.6

0.4

17

9

164

227

12

24

9.2

0.63

145

3.9

107

10.2

g/dL

g/dL

mg/dL

U/L

U/L

U/L

U/L

U/L

U/L

mg/dL

mg/dL

mEq/L

mEq/L

mEq/L

mg/dL

Mg

BS

HbA1C

TSH

FreeT3

FreeT4

T.Chol

HDL

LDL

<Coagulation>

PT-INR

APTT

D-dimer

ProteinC

ProteinS

2.21

94

5.2

4.05

2.93

1.03

155

29.7

101

0.95

26.9

0.57

144

72.1

mg/dL

mg/dL

%

L

pg/mL

ng/dL

mg/dL

mg/dL

mg/dL

INR

sec

g/mL

%

%<Immunology>CRPC3C4CH50Anti ds-DNA Ab2-GPI Ab

LACAnti Cardiolipin IgG

0.1554.99.3

28.11.4

1.3>1.22

mg/dLmg/dLmg/dL

CH50/mL

U/mL

U/mL

5,020

to transient dysarthria and numbness in the right upper and

lower extremities.

On admission (day 0), her vital sign and the physical ex-

amination were unremarkable, including the neurological ex-

amination. Her body weight was 46.2 kg. Results of labora-

tory investigations are listed in Table. Blood cell counts

were within the normal range and anti-phospholipid anti-

body was negative, however hypocomplementemia persisted.

The brain magnetic resonance imaging (MRI) showed multi-

ple high-brightness legions in the right cerebral hemisphere

on diffusion-weighted image (DWI) (Fig. 1), indicating cere-

bral infarction in the acute or subacute phase. A narrowing

of the flat portion of the right middle cerebral artery was

shown on magnetic resonance angiography (MRA) (Fig. 2).

Initially, atherosclerotic cerebral infarction and TIA were

Intern Med 54: 2255-2259, 2015 DOI: 10.2169/internalmedicine.54.4582

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Figure　3.　Magnetic resonance angiography (a) and Diffu-sion-weighted image (b). Brain MRI showed new legions in the callosum in DWI (b, red arrow), but the narrowing of the flat portion of right middle cerebral artery had disappeared (a, red arrow).

a

b Figure　4.　Diffusion-weighted MRI image. The brain MRI re-vealed high brightness legions in right cerebellar hemisphere which had not been seen on the previous MRI (red arrow).

suspected, and we started anti-thrombin and clopidogrel af-

ter consultation with a neurologist. However, she suffered

from transient paralysis of the left upper extremity the next

day. After starting aspirin, symptoms were resolving, but

dysarthria recurred on the 19th day of admission. Brain

MRI showed new legions in the callosum on DWI, but the

narrowing of the flat portion of right middle cerebral artery

had disappeared, indicating reversibility of the vasoconstric-

tion (Fig. 3). Aspirin and clopidogrel were switched to am-

lodipine and cilostazol as stronger vasodilator. Abnormal le-

sions in the right cerebral hemisphere and callosum on MRI,

could not sufficiently explain all symptoms, such as the

dysarthria, weakness and numbness in upper and lower ex-

tremities. Also, she did not suffer from atrial fibrillation,

valvular diseases and arterial sclerosis. We then suspected

NPSLE rather than thrombosis or embolic disease. We car-

ried out lumbar puncture and an elevated level of IL-6 in

spinal fluid (33.9 pg/mL) was found. The diagnosis of

NPSLE was made, and the dose of prednisolone was raised

to 10 mg per day. She was discharged on the 32nd day of

admission.

The brain MRI taken after one month from discharge

(day 67) showed the disappearance of lesions in the callo-

sum. We regarded this as the benefit of treatment, but tran-

sient weakness recurred about once a week from the next

month (day 94). The prednisolone dose was raised to 20 mg

per day (day 107), then the symptoms resolved. The IL-6

level in spinal fluid had improved (20 pg/mL) (day 127),

but she came to our department complaining of transient

weakness and sensory dysfunction in the right upper and

lower extremities and dysarthria (day 135). We diagnosed

flare of NPSLE due to a new lesion with high signal inten-

sity on DWI, fluid attenuation inversion recovery (FLAIR),

T2-weighted image (T2WI) in the right cerebellar hemi-

sphere on brain MRI (Fig. 4). The level of IL-6 in spinal

fluid remained higher than the normal range (14.9 pg/mL).

We measured the level of β2-glycoprotein (β2-GPI) Ab, lu-

pus anticoagulant (LAC) and anti-cardiolipin IgG again to

rule out antiphospholipid syndrome. The level of β2-GPI Ab

was 1.3> U/mL, LAC was 1.2 and anti-cardiolipin IgG was

1 U/mL. The results were all negative again and antiphos-

pholipid syndrome was ruled out. AZ was raised to 150 mg

per day and she was discharged on the 14th day of admis-

sion (day 148). However, she was admitted to our hospital

due to recurrence of the TIA (day 170). The brain MRI was

normal, but the level of IL-6 spinal fluid level was increased

to 19.8 pg/mL. Since prednisolone 20 mg plus AZ 150 mg

per day was considered to be ineffective, we switched to

prednisolone 40 mg plus MMF 2 g per day. After the

switch, her symptoms disappeared completely and the pred-

nisolone dose could be tapered to 25 mg per day. She was

discharged on the 31st day of admission (day 200). Predni-

solone was tapered to 20 mg per day (day 210). The level

of IL-6 in spinal fluid showed marked improvement (6.0 pg/

mL) (day 225). At the time of this writing (day 322), her

symptoms have not recurred.

The clinical course is depicted in Fig. 5.

Intern Med 54: 2255-2259, 2015 DOI: 10.2169/internalmedicine.54.4582

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Figure　5.　Clinical course of the current patient. Prednisolone plus azathioprine could not control the cerebrovascular disease of NPSLE, but symptoms disappeared and the level of IL-6 in spinal fluid markedly improved on prednisolone plus MMF. The level of complement tended to rise.

Discussion

NPSLE is a major cause of morbidity and mortality in pa-

tients with SLE (4). Cerebrovascular diseases occurred in 3-

30% of NPSLE (5) and more than 80% of cerebrovascular

disease comprises ischemic stroke and TIA (6). The level of

IL-6 in spinal fluid has high specificity and sensitivity to di-

agnose NPSLE if the cut off level is 4.3 pg/mL (7) and it is

effective for evaluating disease progress.

In this case, TIA happened repeatedly. Her clinical state

could be the cerebrovascular disease due to vasculitis or

autoantibody associated with NPSLE, because of the up-

regulated spinal level of IL-6 and absence of anti-

phospholipid antibody, atrial fibrillation, valvular diseases

and atrial sclerosis. Hypertension and a high cumulative

dose of glucocorticoids were risk factors for NPSLE (6, 8).

Vasculitis is a rare cause of cerebrovascular diseases in

NPSLE (6), but there are a few reported cases which proved

to be vasculitis pathologically by brain biopsy or autopsy of

the lesions recognized as cerebral infarction on CT or

MRI (9, 10). In addition, autoantibodies against the nerve

cell body, axon, endothelial cells and histone, for example,

are frequently recognized in NPSLE patients (11, 12). One

of the pathogenic mechanisms is thought to be that these an-

tibodies induce apoptosis and alter expression level of adhe-

sion molecules of endothelial cells in the blood-brain-

barrier, allowing the passage of toxic components and anti-

neuronal antibodies into the central nervous system (12). In

the current case, anti-ds DNA antibody and anti-

phospholipid antibody were negative, but there may be other

autoantibodies as yet undetected. Anti-SS-A antibody was

positive in this case, however the significance of this anti-

body with regard to NPSLE is controversial (13, 14).

The narrowing of right cerebral artery was reversible in

the present case. The reversibility of narrowing was involved

in the diagnostic criteria of reversible cerebral vasoconstric-

tion syndrome (RCVS) that Calabrese et al. proposed (15),

but she did not meet the criteria because she did not have

severe, acute headache, called “thunderclap headache” and

MRA did not reveal multifocal segmental cerebral artery

narrowing. It is difficult to distinguish RCVS from vasculi-

tis (16), but in this case, it is suggested that the narrowing

of right middle cerebral artery was caused by vasculitis be-

cause the recurrence has been suppressed by MMF.

The acute management of cerebrovascular diseases in

NPSLE is similar to that in the general population (6) such

as antiplatelet and anticoagulant therapy. In cases where an

inflammation mechanism such as vasculitis is associated

with NPSLE, glucocorticoid is selected as an initial treat-

ment. If glucocorticoid is ineffective or disease activity is

high, addition of CY, which has been proven effective in

some clinical trials (3, 17, 18), may be considered (3). We

could not use CY in the present case, because of the cumu-

lative dose in the past. AZ and MMF have been used as

second-line immunosuppressive drugs, but their efficacy has

never been tested in clinical trials. In this case, we switched

the immunosuppressant to MMF, because 150 mg of AZ per

day was ineffective against NPSLE. MMF reversibly inhibits

inosine-5'-monophosphate dehydrogenase (IMPDH) that

controls the rate of synthesis of guanine monophosphate in

the de novo pathway of purine synthesis used in the prolif-

eration of T and B lymphocytes (19). In addition, the type II

isoform of IMPDH, which predominates in proliferating B

Intern Med 54: 2255-2259, 2015 DOI: 10.2169/internalmedicine.54.4582

2259

and T lymphocytes, is about four times more sensitive to in-

hibition by mycophenolic acid (MPA), the prodrug of MMF,

than is the type I isoform, expressed in most cell type (20).

MMF is mainly used for active lupus nephritis, but there are

a few reports that MMF was effective for NPSLE. There is

a report that MMF significantly decreased Systemic Lupus

Erythematosus Disease Activity Index (SLEDAI) and had a

glucocorticoid sparing effect among 13 SLE patients, includ-

ing 2 NPSLE patients (21). And there are two case reports

of MMF effectiveness for NPSLE (one myelitis, one psy-

chosis.) (22, 23). However, to our knowledge, there has

never been a report that MMF is effective for cerebrovascu-

lar disease in NPSLE.

In this case, various symptoms of cerebrovascular disease,

such as numbness, weakness and dysarthria completely re-

solved and the level of IL-6 in spinal fluid decreased. Al-

though the prednisolone dose was raised from 20 mg to 40

mg per day as induction therapy, it was tapered smoothly

and has maintained the resolution of symptoms for about

four months. We have not increased the prednisolone dose

since MMF was started; currently, the prednisolone dose is

19 mg per day, suggesting that MMF was effective. MMF

could be an option in the treatment of NPSLE.

The authors state that they have no Conflict of Interest (COI).

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