Received: 3 April 2018 | Revised: 6 August 2018 | Accepted: 11 August 2018

DOI: 10.1111/1756-185X.13387

ORIGINAL ARTICLE

Effectiveness and safety of hydroxychloroquine therapy with

or without corticosteroid in patients with systemic lupus
erythematosus

Ippei Miyagawa | Kazuhisa Nakano | Shingo Nakayamada | Shigeru Iwata |

Kentaro Hanami | Shunsuke Fukuyo | Satoshi Kubo | Yoshino Inoue |
Masanobu Ueno | Yoshiya Tanaka

The First Department of Internal Medicine,

School of Medicine, University of
Occupational and Environmental Health,
Kitakyush, Japan
Correspondence
Yoshiya Tanaka, University of Occupational
and Environmental Health, Japan,
Kitakyushu, Japan.
Email: tanaka@med.uoeh-u.ac.jp
Funding information
This work was supported in part by
Research on rare and intractable diseases
and Research Grant‐In‐Aid for Scientific
Research by the Ministry of Health, Labor
and Welfare of Japan, the Ministry of
Education, Culture, Sports, Science and
Technology of Japan, the Japan Agency for
Medical Research and Development, and the
University of Occupational and
Environmental Health, Japan and UOEH
Grant for Advanced Research.
Abstract
Aim: The effectiveness and safety of hydroxychloroquine (HCQ) have not been fully
validated in Japanese patients with systemic lupus erythematosus (SLE) in the clini-
cal setting. This study evaluated the short‐term effectiveness and continuation rate
of HCQ therapy in Japanese patients with SLE in the clinical setting for 12 months.
Methods: The primary endpoint was defined as the continuation rate up to
12 months after the introduction of HCQ in 122 patients with SLE. The secondary
endpoints included changes in the SLE Disease Activity Index (SLEDAI) and the Bri-
tish Isles Lupus Assessment Group (BILAG) index, and the effect on concomitant
corticosteroid (CS) dose reduction.
Results: The primary endpoint, continuation rate up to 12 months after the intro-
duction of HCQ, was 79.5%. Of 25 patients who discontinued HCQ, 23 patients
terminated the therapy within 2 months. The secondary endpoints (SLEDAI, BILAG
index, and concomitant CS dose [mg/day, prednisolone equivalent]) all showed a sig-
nificant decrease. SLEDAI and BILAG index scores indicated significant improvement
during the remission induction phase, maintenance phase, and HCQ monotherapy
phase.
Conclusions: The results of this study suggested that, with attention paid to possi-
ble adverse events immediately after initiation, HCQ may be initiated as a mainstay
of SLE therapy in Japanese patients, either as a concomitant medication in the
remission induction phase, as a maintenance therapy, or as a monotherapy.

KEYWORDS
BILAG, hydroxychloroquine, safety, SLEDAI, systemic lupus erythematosus

1 | INTRODUCTION
Antimalarial agents such as hydroxychloroquine (HCQ) have long
been used as effective therapies for skin and joint symptoms, as well
as for malaise associated with cutaneous lupus erythematosus (CLE)
and systemic lupus erythematosus (SLE). In fact, these agents have
been included among the basic therapies in the treatment algorithm
for CLE and SLE,1,2 and have proven to be beneficial in treating skin
and joint symptoms as well as malaise according to the American
College of Rheumatology (ACR) guidelines and European League

Int J Rheum Dis. 2018;1–9. wileyonlinelibrary.com/journal/apl © 2018 Asia Pacific League of Associations for | 1
Rheumatology and John Wiley & Sons Australia, Ltd
2 |
Against Rheumatism recommendations.3,4 Furthermore, based on the
various benefits demonstrated with these agents, including preven-
tion of organ damage progression,5,6 prevention of relapse,7
8 9
improvement of prognosis, prevention of thrombosis, mitigation of
infection risk,10 and improvement of lipid profile,11 the use of anti-
malarial agents has recently been recommended for all patients with
SLE.12 However, in Japan antimalarial agents have long been unavail-
able for use in clinical practice. Recently emerging targeting treat-
ments have been developing.13 Although HCQ has been used as a
mainstay in the treatments of SLE all over the world, patients in
Japan have lost the opportunity to receive this treatment. HCQ was
approved recently (July 2015) and is yet to be fully validated for its
effectiveness and safety in the clinical setting. Furthermore, effec-
tiveness of HCQ either as a concomitant medication in the remission
induction phase, as a maintenance therapy with a small dose of cor-
ticosteroid (CS), or as a monotherapy without CS remains unclear in
patients with SLE. Accordingly, in the present study, we evaluated
HCQ therapy with or without CS in Japanese patients with SLE in
the clinical setting for 12 months, with a focus on its effectiveness
and continuation rate.
2 | PATIENTS AND METHODS
2.1 | Patients
The study included 122 patients diagnosed as having SLE according
to the ACR diagnostic criteria established in 1997 or the new Sys-
temic Lupus International Collaborating Clinics diagnostic criteria
proposed in 2012, whose course was followed for at least
12 months after the introduction of HCQ therapy at our hospital
and affiliated institutions, during the period from the domestic
launch of HCQ in September 2015 through to December 2016. All
patients underwent ophthalmologic examination before the introduc-
tion of HCQ to confirm that they had no retinopathy or maculopa-
thy before HCQ therapy initiation. The Human Ethics Review
Committee of our university reviewed and approved this study. All
persons gave their informed consent prior to their inclusion in the
study. Details that might disclose the identity of the subjects under
the study were omitted.
2.2 | Clinical measurement
To evaluate the short‐term effectiveness and safety of HCQ therapy
in Japanese patients with SLE in the clinical setting, the primary end-
point was specified as the continuation rate up to 12 months after
the introduction of HCQ in all 122 patients with SLE enrolled in this
study. The secondary endpoints were changes in the SLE Disease
Activity Index (SLEDAI), British Isles Lupus Assessment Group
(BILAG) index, anti‐double‐stranded DNA (anti‐dsDNA) titer (U/mL),
and serum complement activity (CH50, U/mL) up to 12 months, as
well as the effect on concomitant CS dose reduction.
The study further evaluated the effectiveness of HCQ as a con-
comitant drug in CS‐based remission induction therapy or
MIYAGAWA ET AL.
maintenance therapy, as well as the effectiveness of HCQ
monotherapy. Therapy with a CS at a prednisolone (PSL) equivalent
dose of 0.6 mg/kg or greater was defined as remission induction
therapy; therapy with a CS at a dose outside the definition of remis-
sion induction therapy was defined as maintenance therapy; and
therapy without a CS at the introduction of HCQ, regardless of the
use of an immunosuppressant, was defined as HCQ monotherapy.
The new occurrence of one or more items of BILAG category A or
two or more items of BILAG category B during the course, requiring
a dose increase of concomitant CS, was defined as relapse.
2.3 | Statistical analysis
Data are expressed as mean ± standard deviation. The Steel‐Dwass
test was used to detect statistically significant differences between
baseline data and those measured at months 3, 6 and 12. All
reported P values were two‐sided and were not adjusted for multiple
testing. The level of significance was set at P < 0.05. All analyses
were conducted using JMP version 10.0 (SAS Institute Inc., Cary,
NC, USA). For statistical analysis, data from discontinued cases were
complemented using the “last observation carried forward” method.
3 | RESULTS
3.1 | Baseline characteristics
Table 1 summarizes the background characteristics at the introduc-
tion of HCQ in patients who had been followed for at least
12 months after HCQ initiation. The study population had a mean
age of 41.6 years and comprised 12 men and 110 women. The mean
duration of disease was 122.3 months. Many of the patients had a
prior treatment with high‐dose CS, CS pulse, intravenous cyclophos-
phamide, and/or immunosuppressant therapy. At the introduction of
HCQ, 29 and 49 patients were receiving concomitant high‐dose CS
(remission induction therapy) and low‐dose CS (maintenance ther-
apy), respectively. HCQ was initiated as a monotherapy in 44
patients. The HCQ dose was 200 mg/d, 200/400 mg once every
2 days, and 400 mg/d via the oral route in 51, 59, and 12 patients,
respectively. For the disease activity at the introduction, the mean
SLEDAI was 7.25 and median BILAG index was 2.5. A total of 31
patients had one or more items of BILAG category A or two or more
items of BILAG category B. The median anti‐dsDNA titer was 8.0 U/
mL, and the mean CH50 level was 40.2 U/mL.
3.2 | Continuation rate up to 12 months after the
introduction of HCQ in 122 SLE patients
The continuation rate up to 12 months after the introduction of
HCQ, evaluated as the primary endpoint, was 79.5% (97 of 122
patients); HCQ was discontinued in 25 patients (Figure 1). The rea-
sons for discontinuation and the adverse events are summarized in
Table 2. HCQ was discontinued in four patients who complained of
eye symptoms, such as blurry vision and photophobia; however, no
MIYAGAWA ET AL. | 3

T A B L E 1 Baseline characteristics of 122 patients with systemic lupus erythematosus (SLE)

All (n = 122)
Gender, M/F 12/110
Age, years, 41.6 ± 14.6
mean ± SD
Disease 122.3 ± 109.7
duration,
mean ± SD
Treatment High dose CS, 51; low dose
history, n CS, 23; CS pulse, 8; IV‐CY,
31; TAC/CsA, 25; AZ, 17;
MTX, 16; MMF, 8, RTX, 7; IA/
PE, 6
No. of Once, 18; twice, 2; four times,
relapses 1 1
before
introduction
of HCQ
Concomitant High dose CS, 29; CS pulse, 9;
treatment, n low dose CS, 49; IV‐CY, 17;
MTX, 8; MMF, 17; AZ, 19;
TAC/CsA, 26; MZ, 5 HCQ
monotherapy (without CS), 44
Concomitant Median 4 mg, range 0‐90 mg/d
CS dose (PSL equivalent)
HCQ dose, n 200 mg, 51; 200/400 mg, 59;
400 mg, 12
SLEDAI, 7.25 ± 6.73
mean ± SD
SLEDAI [Psychiatric symptom] 4,
[organic encephalopathy] 1,
[cranial neuropathy] 2,
[headache] 4, [cerebrovascular
disorder] 5, [vasculitis] 1,
[arthritis] 49, [myositis] 1,
[urinary casts] 16, [hematuria]
13, [proteinuria] 25, [pyuria]
6, [skin eruption] 54, [hair
loss] 28, [mucosal ulceration]
13, [pleuritis] 2, [pericarditis]
2, [hypocomplementemia] 49,
[anti‐ds DNA antibody] 49,
[pyrexia] 17, [platelet count
decrease] 22, [white blood cell
count decrease] 25
BILAG index median 2.5, range 0‐44
BILAG [General symptoms] A: 12, B:
category 13, C: 12; [mucocutaneous] A:
7, B: 30, C: 17;
[neuropsychiatric] A: 11, B: 3,
C: 2; [musculoskeletal] A: 1, B:
9, C: 29;[renal] A: 13, B: 8, C:
6; [hematological] A: 6, B: 11,
C: 44;[cardiorespiratory] A: 2,
B: 1, C: 1; [gastrointestinal] B:
3, [ocular] B: 1
Remission induction therapy
(n = 29)
3/26
45.0 ± 18.3
125.9 ± 127.4
High dose CS, 20; low dose
CS, 2; CS pulse, 3; IV‐CY, 12;
TAC/CsA, 9; AZ, 2; MTX, 3;
MMF, 3; RTX, 4; IA/PE, 3
Once, 10; twice, 2; four times,
High dose CS, 29; CS pulse, 9;
low dose CS, 0; IV‐CY, 13;
MTX, 0; MMF, 13; AZ, 3;
TAC/CsA, 4; MZ, 0
Median 50 mg, range 30‐
90 mg/d (PSL equivalent)
200 mg, 18; 200/400 mg, 6;
400 mg, 5
15.0 ± 7.57
[Psychiatric symptom] 3,
[organic encephalopathy] 1,
[cranial neuropathy] 2,
[headache] 4, [cerebrovascular
disorder] 3, [vasculitis] 0,
[arthritis] 10, [myositis] 1,
[urinary casts] 15, [hematuria]
6, [proteinuria] 13, [pyuria] 5,
[skin eruption] 19, [hair loss]
10, [mucosal ulceration] 4,
[pleuritis] 2, [pericarditis] 2,
[hypocomplementemia] 24,
[anti‐ds DNA antibody] 20,
[pyrexia] 13, [platelet count
decrease] 10, [white blood cell
count decrease] 10
Median 16, range 16‐44
[General symptoms] A: 12, B:
9, C: 3; [mucocutaneous] A: 4,
B: 12, C: 4;
[neuropsychiatric] A: 10, B: 3,
C: 2; [musculoskeletal] A: 1, B:
4, C: 5;
[renal] A: 12, B: 5, C: 0
[hematological] A: 4, B: 7, C:
14; [cardiorespiratory] A: 1, B:
1, C: 1; [gastrointestinal] B: 2,
[ocular] 0
Maintenance therapy (n = 49)
4/45
40.0 ± 13.8
134.8 ± 109.0
High dose CS, 23; low dose CS.
17; CS pulse, 3; IV‐CY, 15;
TAC/CsA, 10; AZ, 9; MTX, 8;
MMF, 4; RTX, 1; IA/PE, 2
Once, 7; twice, 0; four times, 0
High dose CS, 0; CS pulse, 0;
low dose CS, 49; IV‐CY, 4;
MTX, 3; MMF, 4; AZ, 11;
TAC/CsA, 14; MZ, 2
Median 5 mg, range 0.5‐12 mg/
d (PSL equivalent)
200 mg, 17; 200/400 mg, 28;
400 mg, 4
7.25 ± 6.73
[Psychiatric symptom] 1,
[organic encephalopathy] 0,
[cranial neuropathy] 0,
[headache] 0, [cerebrovascular
disorder] 2, [vasculitis] 1,
[arthritis] 14, [myositis] 0,
[urinary casts] 1, [hematuria]
6, [proteinuria] 7, [pyuria] 1,
[skin eruption] 14, [hair loss]
9, [mucosal ulceration] 4,
[pleuritis] 0, [pericarditis] 0,
[hypocomplementemia] 13,
[anti‐ds DNA antibody] 16,
[pyrexia] 2, [platelet count
decrease] 5, [white blood cell
count decrease] 5
Median 1, range 0‐10
[General symptoms] A: 0, B: 3
C: 1; [mucocutaneous] A: 3, B:
5, C: 7;
[neuropsychiatric] A: 1, B: 0,
C: 0; [musculoskeletal] A: 0, B:
2, C: 9;
[renal] A: 0, B: 1, C: 5;
[hematological] A: 1, B: 2, C:
15; [cardiorespiratory] A: 0 B:
0, C: 0; [gastrointestinal] B: 0,
[ocular] 0
HCQ monotherapy (n = 44)
5/39
41.1 ± 12.3
106.1 ± 95.6
High dose CS, 8; low dose CS,
4; CS pulse, 2; IV‐CY, 4; TAC/
CsA, 6; AZ, 6; MTX, 5; MMF,
1; RTX, 2; IA/PE, 1
Once, 1; twice, 0; four times, 0
High dose CS, 0; low dose CS,
0; CS pulse, 0; IV‐CY, 0;
MTX, 5; MMF, 0; AZ, 5; TAC/
CsA, 8; MZ, 3
(Without CS)
200 mg, 16; 200/400 mg, 25;
400 mg, 3
5.00 ± 3.50
[Psychiatric symptom] 0,
[organic encephalopathy] 0,
[cranial neuropathy] 0,
[headache] 0,
[cerebrovascular disorder] 0,
[vasculitis] 0, [arthritis] 25,
[myositis] 0, [urinary casts] 0,
[hematuria] 1, [proteinuria] 5,
[pyuria] 0, [skin eruption] 21,
[hair loss] 9, [mucosal
ulceration] 5, [pleuritis] 0,
[pericarditis] 0,
[hypocomplementemia] 12,
[anti‐ds DNA antibody] 13,
[pyrexia] 2, [platelet count
decrease] 7, [white blood cell
count decrease] 10
2.0 (0‐13)
[General symptoms] A: 0, B: 1,
C: 8; [mucocutaneous] A: 0,
B: 13, C: 6;
[neuropsychiatric] A: 0, B: 0,
C: 0; [musculoskeletal] A: 0,
B: 3, C: 15;
[renal] A: 1, B: 2, C: 1
[hematological] A: 1, B: 2, C:
15; [cardiorespiratory] A: 1,
B: 0, C: 0; [gastrointestinal] B:
1, [ocular] B:1

(Continues)
4 | MIYAGAWA ET AL.

TABLE 1 (Continued)
Remission induction therapy
All (n = 122) (n = 29) Maintenance therapy (n = 49) HCQ monotherapy (n = 44)
Anti‐dsDNA Median 8, range 1.2‐400 Median 26.7, range 2.3‐400 Median 7.9, range 1.2‐400 Median 3.5, range 1.2‐171
antibody, U/
mL
CH50, U/mL, 40.2 ± 17.9 32.2 ± 19.3 42.7 ± 16.9 43.4 ± 16.4
mean ± SD

AZ, azathioprine; BILAG, British Isles Lupus Assessment Group index; CS, corticosteroid; CsA, cyclosporine; HCQ, hydroxychloroquine; IA/PE, immuno‐
absorption/plasma exchange; IVCY, intravenous cyclophosphamide pulse therapy; MMF, mycophenolate mofetil; MTX, methotrexate; MZ, mizoribine;
RTX, rituximab; SD, standard deviation; SLEDAI, SLE Disease Activity Index; TAC, tacrolimus.

abnormalities were detected on ocular examination performed at the 12 months after the introduction of HCQ, the results were as fol-
introduction or at the onset of eye symptom in any cases. Other lows: the mean SLEDAI was 7.25 ± 6.73, 4.24 ± 5.15, 3.77 ± 5.05,
adverse events included common cold/upper airway inflammation/ and 3.76 ± 5.28 at 0, 3, 6, and 12 months (as observed analysis:
pharyngitis (12 events), gastrointestinal symptoms (diarrhea/vomiting) 7.25 ± 6.73, 3.55 ± 4.12, 3.04 ± 3.90 and 3.04 ± 4.21 at 0, 3, 6 and
(four events), influenza infection/bronchitis/herpes zoster/urinary 12 months), respectively; the BILAG index was 6.24 ± 8.55,
tract infection/gastroenteritis (two events each), and cerebellar hem- 2.98 ± 6.06, 3.14 ± 6.34, and 3.26 ± 6.57 at 0, 3, 6, and 12 months
orrhage/hyponatremia (one event each). Five patients experienced (as observed analysis: 6.24 ± 8.55, 2.39 ± 5.49, 2.35 ± 5.42 and
relapse. 2.48 ± 5.73 at 0, 3, 6 and 12 months), respectively; and the con-
comitant CS dose was 14.5 ± 22.1, 8.80 ± 14.4, 7.82 ± 14.0, and
7.30 ± 13.7 mg/d as PSL equivalent dose at 0, 3, 6, and 12 months
3.3 | Effect of HCQ on the improvement of disease
(as observed analysis: 14.5 ± 22.1, 7.08 ± 11.5, 6.09 ± 10.9 and
activity in all 122 SLE patients
5.56 ± 10.3 at 0, 3, 6 and 12 months), respectively, all exhibiting a
For the secondary endpoints of changes in SLEDAI and BILAG index significant reduction. The anti‐dsDNA antibody titer was
as well as the effect on concomitant CS dose reduction at 42.4 ± 87.2, 23.9 ± 59.3, 22.0 ± 43.8, and 20.9 ± 43.2 U/mL at 0, 3,

F I G U R E 1 Continuation rate up to 12 mo after the introduction of hydroxychloroquine (HCQ). A, Continuation rate up to 12 mo in all of
the 122 patients, B, in 29 patients with remission induction therapy, C, in 49 patients with corticosteroid (CS)‐based maintenance therapy and
D, in 44 patients with HCQ monotherapy
MIYAGAWA ET AL. | 5

T A B L E 2 Reasons for hydroxychloroquine discontinuation

Reasons for discontinuation

Timing of Remission induction Maintenance therapy Hydroxychloroquine

discontinuation All (n = 122) therapy (n = 29) (n = 49) monotherapy (n = 44)
Wk 1 Suspected hemocyte decrease (1), dizziness Dizziness (1) Suspected hemocyte
(1), worsening of renal disorder (primary decrease (1), worsening of
disease) (1) renal disorder (primary
disease) (1)
Wk 2 Numbness of the extremities/lips (1), skin Skin eruption (1) Numbness of the Skin eruption (1)
eruption (2) extremities/lips (1)
Wk 3 Diarrhea/skin eruption (1) Diarrhea/skin eruption (1)
Mo 1 Skin eruption (3), diarrhea (1), worsening of Skin eruption (1), Worsening of arthritis/ Skin eruption (2), diarrhea
arthritis/myositis (1), prolonged proteinuria prolonged proteinuria myositis (1) (1), blurry vision (1)
(1), hepatic disorder (1), blurry vision (1) (1), hepatic disorder
(1)
Mo 2 Gastrointestinal symptom (2), platelet count Suspected platelet Gastrointestinal symptom Gastrointestinal symptom (1),
decrease/bad mood (1), suspected platelet count decrease (1), (1), malaise/blood pressure platelet count decrease/bad
count decrease (1), hypoglycemia (1), hypoglycemia (1), increase/insomnia/ mood (1), photophobia/
herpes zoster (1), photophobia/blurry herpes zoster (1) headache/tremor (1) blurry vision (1)
vision (1), malaise/blood pressure increase/
insomnia/headache/tremor (1)
Mo 5 Diarrhea (1) Diarrhea (1)
Mo 6 Pruritus (1) Pruritus (1)

6, and 12 months (as observed analysis: 42.4 ± 87.2, 16.8 ± 35.6, significant reduction. CH50 was 32.2 ± 19.3, 40.6 ± 16.4,
13.0 ± 21.0 and 10.7 ± 19.6 at 0, 3, 6, 12 months), respectively, 43.5 ± 16.6, and 44.0 ± 16.9 U/mL at 0, 3, 6, and 12 months (as
demonstrating a significant reduction. CH50 was 40.2 ± 17.9, observed analysis: 32.2 ± 19.3, 42.8 ± 16.0, 46.6 ± 15.6 and
42.7 ± 16.6, 44.5 ± 16.1, and 44.2 ± 15.9 U/mL at 0, 3, 6, and 47.2 ± 15.8 at 0, 3, 6 and 12 months), respectively, exhibiting a sig-
12 months (as observed analysis: 40.2 ± 17.9, 43.4 ± 18.1, nificant increase from the lower limit of normal at 0 month (Fig-
45.2 ± 15.5 and 44.9 ± 15.3 at 0, 3, 6, 12 months), respectively, ure 3A).
indicating a significant increase (Figure 2).

3.5 | Effectiveness of HCQ in CS‐based

3.4 | Effectiveness of HCQ therapy as a
concomitant drug in remission induction therapy
Next, the effectiveness of HCQ as a concomitant drug in remission
induction therapy was evaluated. In 29 patients who received HCQ
as a concomitant drug in remission induction therapy, the SLEDAI
was 15.0 ± 7.57, 5.66 ± 7.37, 5.90 ± 7.31, and 5.55 ± 7.40 (as
observed analysis: 15.0 ± 7.57, 2.18 ± 3.08, 2.50 ± 3.23
2.05 ± 3.00 at 0, 3, 6 and 12 months) and the BILAG index was
18.1 ± 9.64, 6.45 ± 10.6, 7.41 ± 11.1, and 6.52 ± 10.5 (as observed
analysis: 18.1 ± 9.64, 1.40 ± 2.88, 2.66 ± 5.93 and 1.50 ± 2.44 at 0,
3, 6 and 12 months), both showing a significant reduction at and
after 3 months. Similarly, the concomitant CS dose (PSL equivalent)
was 51.8 ± 13.3, 26.0 ± 19.2, 22.3 ± 20.3, and 19.7 ± 21.5 mg/d at
0, 3, 6, and 12 months (as observed analysis: 51.8 ± 13.3,
18.4 ± 11.6, 11.5 ± 6.97 and 7.86 ± 5.54 at 0, 3, 6 and 12 months),
respectively, indicating a significant reduction at and after 3 months.
The anti‐dsDNA antibody titer was 82.5 ± 125.0, 29.9 ± 47.4,
27.5 ± 46.1, and 26.8 ± 46.4 U/mL at 0, 3, 6, and 12 months respec-
tively (as observe analysis: 82.5 ± 125.0, 22.1 ± 48.0, 10.2 ± 14.5
and 9.50 ± 14.9 at 0, 3, 6 and 12 months), demonstrating a
maintenance therapy
In 44 patients who received HCQ during CS‐based maintenance
therapy, the SLEDAI was 4.67 ± 4.71, 3.33 ± 4.22, 3.10 ± 4.82, and
3.10 ± 4.82 at 0, 3, 6, and 12 months (as observed analysis:
4.67 ± 4.71, 2.67 ± 3.59, 2.11 ± 3.20 and 2.40 ± 4.08 at 0, 3, 6,
12 months), respectively, indicating a significant improvement. The
and BILAG index was 1.85 ± 2.32, 1.12 ± 1.62, 1.30 ± 2.05, and
1.92 ± 4.97 at 0, 3, 6, and 12 months (as observed analysis:
1.85 ± 2.32, 0.78 ± 0.95, 0.97 ± 1.66 and 1.64 ± 5.06 at 0, 3, 6 and
12 months), respectively, demonstrating a significant improvement.
The anti‐dsDNA antibody titer was 29.4 ± 69.3, 19.5 ± 36.3,
19.3 ± 36.0, and 17.3 ± 33.6 U/mL at 0, 3, 6, and 12 months respec-
tively (as observed analysis: 29.4 ± 69.3, 13.2 ± 25.9, 13.0 ± 25.4
and 10.8 ± 20.7 at 0, 3, 6 and 12 months), demonstrating a signifi-
cant reduction by 12 months. CH50 was 42.7 ± 16.9, 43.5 ± 18.2,
44.7 ± 16.3, and 45.4 ± 17.2 U/mL at 0, 3, 6, and 12 months (as
observed analysis: 42.7 ± 16.9, 44.2 ± 18.3, 45.6 ± 16.0 and
46.3 ± 17.0 at 0, 3, 6 and 12 months), respectively, exhibiting a sig-
nificant increase, but stayed within the normal range without mean-
ingful changes (Figure 2). On the other hand, the concomitant CS
6 | MIYAGAWA ET AL.

F I G U R E 2 Effect of
hydroxychloroquine (HCQ) in 122 patients
with systemic lupus erythematosus (SLE).
Changes in the SLEDAI (N = 122), BILAG
index (N = 122), anti‐double‐stranded DNA
(anti‐dsDNA) antibody titer (U/mL,
n = 106), and serum complement activity
(CH50: U/mL, n = 97), as well as the effect
on corticosteroid (CS) dose reduction
(N = 122) up to 12 months after the
introduction. ***P < 0.001, **P < 0.01,
*P < 0.05, Steel‐Dwass test vs baseline
(last observation carried forward). SLEDAI,
SLE Disease Activity Index; BILAG, British
Isles Lupus Assessment Group

dose (PSL equivalent) was 5.37 ± 2.99, 5.26 ± 5.14, 5.68 ± 8.47, and 3.32 ± 3.74 at 0, 3, 6, and 12 months (as observed analysis:
5.85 ± 7.85 mg/day at 0, 3, 6, and 12 months (as observed analysis: 5.00 ± 3.50, 3.83 ± 3.32, 2.75 ± 2.68 and 2.64 ± 2.86 at 0, 3, 6,
5.37 ± 2.99, 5.36 ± 5.39, 5.84 ± 8.98 and 6.04 ± 8.31 at 0, 3, 6 and 12 months), respectively, indicating a significant improvement. Simi-
12 months), respectively, indicating no effect in dose reduction larly, the BILAG index was 3.27 ± 3.57, 2.77 ± 3.88, 2.38 ± 3.40,
(Figure 3B). and 2.61 ± 3.55 at 0, 3, 6, and 12 months (as observed analysis:
3.27 ± 3.57, 2.35 ± 3.38, 1.86 ± 2.62 and 2.19 ± 2.89 at 0, 3, 6 and
12 months), respectively, demonstrating a significant improvement at
3.6 | Effectiveness of HCQ monotherapy
and after 3 months. The anti‐dsDNA antibody titer was 17.3 ± 32.5,
In 44 patients for whom HCQ was initiated without concomitant CS, 16.5 ± 28.6, 13.4 ± 21.1, and 12.8 ± 21.3 U/mL at 0, 3, 6, and
the SLEDAI was 5.00 ± 3.50, 4.30 ± 3.89, 3.41 ± 3.61, and 12 months (as observed analysis: 17.3 ± 32.5, 18.3 ± 33.0,

F I G U R E 3 Effectiveness of hydroxychloroquine (HCQ) in remission induction therapy, corticosteroid (CS)‐based maintenance therapy and
monotherapy. A, Changes in the SLEDAI (n = 29), BILAG index (n = 29), anti‐ds DNA antibody titer (U/mL, n = 29), CH50 (U/mL, n = 29) and
CS dose (n = 29) in remission induction therapy B, Changes in the SLEDAI (n = 49), BILAG index (n = 49), anti‐double‐stranded DNA (anti‐
dsDNA) antibody titer (U/mL, n = 41), serum complement activity (CH50: U/mL, n = 35) and CS dose (n = 49) in CS‐based maintenance
therapy C, Changes in the SLEDAI (n = 44), BILAG index (n = 44), anti‐dsDNA antibody titer (U/mL, n = 36), CH50 (U/mL, n = 33) in HCQ
monotherapy. ***P < 0.001, **P < 0.01, *P < 0.05, Steel‐Dwass test vs baseline (last observation carried forward). SLEDAI, SLE Disease
Activity Index; BILAG, British Isles Lupus Assessment Group
MIYAGAWA ET AL. | 7
8 |
13.8 ± 23.5 and 13.1 ± 23.7 at 0, 3, 6 and 12 months), respectively,
demonstrating a significant decrease by 12 months. On the other
hand, CH50 was 43.4 ± 16.4, 42.6 ± 15.1, 44.1 ± 15.5, and
42.5 ± 14.3 U/mL at 0, 3, 6, and 12 months (as observed analysis:
43.4 ± 16.4, 43.3 ± 15.5, 45.5 ± 15.9 and 43.5 ± 14.6 at 0, 3, 6 and
12 months), respectively, showing no significant change from the
level at 0 month (Figure 3C).
4 | DISCUSSION
In the present study, we introduced HCQ therapy in 122 Japanese
patients with SLE and followed them for 6 months to assess the treat-
ment continuation rate and the improvement of disease activity. Our
results confirmed a high continuation rate of HCQ therapy in Japanese
patients with SLE. In addition, HCQ therapy led to improvement of SLE
disease activity, either as a concomitant drug in remission induction
therapy, in CS‐based maintenance therapy, or as monotherapy.
In Japan, Yokogawa et al14 conducted a double‐blind, randomized
parallel‐group clinical trial in 103 patients with CLE, and demon-
strated a reduction in the primary endpoint, that is, Cutaneous Lupus
Area and Severity Index activity score after 16 weeks of treatment.
They also demonstrated the safety profile as well as the efficacy and
tolerability of HCQ in patients with CLE in Japan. However, there
remain insufficient data on the use of HCQ for the treatment of SLE
in the clinical setting. The present study particularly focused on the
continuation rate of HCQ therapy and identified 25 patients who
discontinued HCQ; the most common reasons for discontinuation
were gastrointestinal and/or skin symptoms, accounting for nearly
half of the patients (11 patients), and 23 of these 25 patients discon-
tinued HCQ in as short as 2 months from HCQ initiation. In some
patients, HCQ was discontinued because of concerns about potential
decrease in platelet count and prolonged proteinuria, but was later
resumed as these effects were ruled out. These findings indicate that
physicians should exercise caution in relation to early adverse events
up to about 2 months after HCQ initiation, as well as evaluate
patients for potential organ damage due to the primary disease and
fully assess the possibility of adverse events due to other therapeu-
tic and concomitant medications, before initiating HCQ in patients
with highly active SLE and to determine whether or not to continue
the HCQ therapy. There were also some patients for whom HCQ
was discontinued because of eye symptoms; however, no abnormal
findings were identified in examinations by an ophthalmologist in
any of these patients. However, it should be noted that the inci-
dence of retinopathy under HCQ therapy is often reported to
15,16
increase as the dose and treatment period increase. This may
mean that ocular safety cannot be evaluated in a short follow‐up
period as in the present study. Further research will be required to
accumulate evidence of the long‐term safety, including the risk of
retinopathy, in Japanese patients with SLE.
The evaluation of disease activity in 122 patients with SLE
demonstrated a significant reduction in the SLEDAI and BILAG index
scores at and after 3 months.
MIYAGAWA ET AL.
Considering the differences in the background characteristics of
patients, including disease activity, organ damage, and concomitant
CS dose, we separately analyzed the effectiveness of HCQ as a con-
comitant drug in remission induction therapy and in maintenance
therapy, and as monotherapy.
In remission induction therapy, the SLEDAI, BILAG index, anti‐
dsDNA antibody titer, and CH50 all significantly improved at and
after 3 months along with a significant reduction in the concomitant
CS dose. In 49 patients in whom HCQ was initiated during CS‐based
maintenance therapy, the SLEDAI, BILAG index, anti‐dsDNA anti-
body titer, and CH50 significantly improved. Nevertheless, HCQ did
not lead to a significant reduction of the concomitant CS dose. Con-
sidering the fact that disease activity and anti‐dsDNA antibody titer
significantly improved, the lack of significant effects on the reduction
of concomitant CS dose is likely attributable to the impact of
relapse, that is, inclusion of three patients who required a substantial
increase in CS dose in this study. Future accumulation of data from
many patients and an extended follow‐up period will provide details
on the effect of HCQ on CS dose reduction during CS‐based mainte-
nance therapy.
Similarly, in 44 patients who received HCQ monotherapy, the
SLEDAI and BILAG index significantly improved and the anti‐dsDNA
antibody titer significantly decreased. The serum complement activ-
ity did not indicate a significant increase probably because the level
was already normal at the initiation of HCQ.
In summary, the results of this study suggest that, with attention
to potential adverse events immediately after initiation, HCQ may be
useful as a mainstay of SLE therapy in Japanese patients, either as a
concomitant medication in the remission induction phase, as mainte-
nance therapy, or as monotherapy. However, a limitation of this
study was that the follow‐up period was insufficient to evaluate
long‐term outcomes, including the effect of HCQ on the prevention
of relapse and organ damage or on prognostic improvement. Future
accumulation of data from a larger number of patients and continued
follow‐up is warranted to evaluate the proper effectiveness of HCQ
in Japanese patients with SLE.
ACKNOWLEDGEMENTS
The authors thank the study participants, without whom this study
would never have been accomplished, as well as the investigators
for their participation in the study, especially those in Kitakyushu
General Hospital, Saiseikai Shimonoseki General Hospital, Fukuoka
Yutaka Central Hospital, Nakama Municipal Hospital, and Steel
Memorial Yawata Hospital.
CONFLICT OF INTEREST
Y. Tanaka has received speaking fees and/or honoraria from Daiichi‐
Sankyo, Astellas, Pfizer, Mitsubishi‐Tanabe, Bristol‐Myers, Chugai, YL
Biologics, Eli Lilly, Sanofi, Janssen, UCB and has received research
grants from Mitsubishi‐Tanabe, Takeda, Bristol‐Myers, Chugai, Astel-
las, Abbvie, MSD, Daiichi‐Sankyo, Pfizer, Kyowa‐Kirin, Eisai, Ono.
MIYAGAWA ET AL.
AUTHORS’ CONTRIBUTIONS
IM contributed to the study design, overall review, writing of the
manuscript, and the other authors were involved in the performance
of the study and review of the manuscript. YT, KN, SN participated
in the study design and coordination. All authors read and approved
the final manuscript.
ORCID
Ippei Miyagawa http://orcid.org/0000-0002-9071-145X
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How to cite this article: Miyagawa I, Nakano K, Nakayamada
S, et al. Effectiveness and safety of hydroxychloroquine
therapy with or without corticosteroid in patients with
systemic lupus erythematosus. Int J Rheum Dis. 2018;00:1–9.
https://doi.org/10.1111/1756-185X.13387