Clinical Rheumatology

https://doi.org/10.1007/s10067-019-04633-y

ORIGINAL ARTICLE

Glucocorticoid, immunosuppressant, hydroxychloroquine

monotherapy, or no therapy for maintenance treatment in systemic
lupus erythematosus without major organ manifestations
Hironari Hanaoka 1 & Harunobu Iida 1 & Tomofumi Kiyokawa 1 & Yukiko Takakuwa 1 & Kimito Kawahata 1

Received: 28 February 2019 / Revised: 13 May 2019 / Accepted: 31 May 2019

# International League of Associations for Rheumatology (ILAR) 2019

Abstract
Objective To study maintenance therapy after achievement of the lowest possible disease activity in systemic lupus erythema-
tosus (SLE) without major organ manifestations.
Methods We retrospectively evaluated patients with SLE who visited our hospital from Jan 2015 to Feb 2018 and were taking
prednisolone (PSL) < 10 mg/day. After excluding those with neuropsychiatric SLE or severe lupus nephritis, patients were
divided into four groups according to their maintenance monotherapy treatment, namely, prednisolone (PSL), immunosuppres-
sant (IS), hydroxychloroquine (HCQ), and no drugs. The groups were then compared with regard to cumulative flare rate and
changes in SLE Disease Activity Index (SLEDAI).
Results There were 47 patients on PSL, 10 on IS, 5 on HCQ, and 11 on no drugs. Flare rate was higher in the no drug group, and
no patients with the IS or HCQ group experienced a flare (p = 0.003). A reduction in SLEDAI was only seen in the IS and HCQ
groups (p = 0.05 and p = 0.03, respectively). There were no differences in adverse events among groups during the study period.
Conclusions Our results suggest that the cessation of all drugs is associated with disease flare for SLE patients without major
organ manifestations. IS or HCQ monotherapy might be a reasonable maintenance strategy comparing with steroid monotherapy.

Key Point
• Immunosuppressant or hydroxychloroquine monotherapy appears to be a reasonable maintenance strategy.

Keywords Hydroxychloroquine . Immunosuppressive agents . Relapse . Systemic lupus erythematosus

Introduction disease and, if possible, complete withdrawal of GCs during

maintenance therapy [2]. This strategy further mentioned that
Glucocorticoids (GC), immunosuppressants (IS), and preventing flares should be the therapeutic goal for reducing
hydroxychloroquine (HCQ) are cornerstones of systemic lu- damage accrual. In clinical practice, physicians combine these
pus erythematosus (SLE) treatment [1], and these drugs are drugs to control disease activity and subsequently reduce the
largely used to alleviate symptoms and suppress disease ac- GC dose to as low as possible. After achieving very-low dose
tivity. According to a strategy proposed in 2014, after achiev- GC, however, it has not been clarified which drugs, including
ing clinical remission or the lowest possible disease activity, GC, IS, and HCQ, should be continued to prevent flares, es-
the goal should be the lowest GC dosage needed to control pecially in patients with nonmajor organ manifestations.
There is evidence that HCQ prevents flares, but the effect of
HCQ monotherapy on disease flare prevention has not been
well investigated [3]. Furthermore, an international task force,
* Hironari Hanaoka definitions of remission in SLE (DORIS), recently proposed
hhanaoka1208@yahoo.co.jp that complete remission should be strictly defined as the total
absence of clinical activity without the use of medication for
1
Division of Rheumatology and Allergology, Department of Internal
SLE, including GC and IS [4, 5]. However, few data are avail-
Medicine, St. Marianna University School of Medicine, able on the withdrawal of GC, IS, or even HCQ in patients
Kawasaki 216-8511, Japan with nonmajor organ manifestations [6, 7].
 Clin Rheumatol

Here, we performed a retrospective study to compare flare and the last visit. Incidence of flare during the observation
rates and changes in disease activity when these drugs were period was determined using the SLE Flare Index (SFI) by
used as monotherapy or withdrawn for maintenance therapy in chart review [12]. Patients in this study experienced moderate/
SLE patients without major organ manifestations. mild and severe flares of SFI.

Statistical analysis
Materials and methods
Continuous values are shown as mean ± standard deviation.
Patients Differences between groups were analyzed using the Mann-
Whitney U test or Kruskal-Wallis test for nonparametric data
We performed a retrospective study of Japanese patients who and the chi-squared or Fisher’s exact test for categorical data.
met the American College of Rheumatology (ACR) classifica- The cumulative flare rate was calculated using the Kaplan-
tion criteria for SLE [8] and who visited St. Marianna Meier method, and differences between the two groups were
University Hospital from Jan 2015 through Feb 2018. tested using the log-rank test.
Observation was made from the earliest point to the latest point
when they visited from Jan 2015 to Feb 2018. Thus, the base-
line point in this study was the earliest point in the observational Results
periods. All the patients who were selected in this study were
treated by rheumatologist (board-certified rheumatologist in Baseline clinical characteristics
Japan College of Rheumatology) and SLE experts. Patients
who were taking prednisolone (PSL) at < 10 mg/day were se- Clinical features at baseline between patients with any drugs
lected and divided into two groups whether they were taking and no drugs are shown in Table 1, and we found no signifi-
any drugs or not. Then, they were divided into four groups cant difference between these groups. We next investigated
according to their maintenance treatment regimen, namely, baseline clinical features among the four groups depending
PSL, IS, HCQ, and no treatment. Patients with any combination on the treatments (Table 2). The length of the observation
therapy were excluded. Since HCQ was not approved in Japan periods did not significantly differ among the groups (mean
until 2015, those in the HCQ group had newly started HCQ 14.9 months). Patients in the PSL monotherapy group had
during this study period. We compared their clinical character- longer disease duration (p = 0.03) than those in the other
istics up to Feb 2018. Patients were excluded if they had neu- groups. Most patients in all groups mainly manifested skin
ropsychiatric SLE [9], lupus nephritis class III or IV [10], or any involvement, arthritis, and cytopenia. Mean PSL dose in the
manifestations that were categorized as severe activity accord- PSL mono group was 5.9 mg/day.
ing to the British Society for Rheumatology guideline for the
management of SLE in adults [1]. Among the 154 patients Cumulative flare rate and change in SLEDAI
identified as having SLE, 81 had been treated with PSL at more
than 10 mg/day or by combination treatment with PSL plus IS We next examined the flare rate between patients with any
or HCQ and were excluded. Finally, we evaluated 47 on PSL, drugs and no drugs (Fig. 1a). A significantly higher flare rate
10 on IS, 5 on HCQ, and 11 on no drugs. was observed in the no drugs group than any drugs group
This study was approved by the Ethics Committee of St. (p < 0.0001); however, there was no significant difference be-
Marianna University School of Medicine (approval number tween them in the SLEDAI change from baseline (Fig. 1b).
3305). Because the study was conducted under a retrospective We further examined the flare rate depending on the treat-
cohort design that did not conduct any investigations/ ments (Fig. 2a) and found flare rate was significantly higher
interventions besides those for clinical use, written informed in the no drugs group than other groups (p = 0.003). There was
consent was not required, in accordance with the guidelines of no significant difference among the PSL-mono, IS-mono, and
the Japanese Ministry of Health, Labour and Welfare. This HCQ-mono groups. The SLEDAI was significantly reduced
study was carried out as per routine clinical care, and medica- in the IS-mono and HCQ-mono groups compared with the no
tion was initiated at the discretion of the attending physician. drugs and PSL groups (p = 0.04 and p = 0.02, respectively)
(Fig. 2b).
Data collection
Cumulative flare rate and the last initial treatment
Clinical information was obtained at baseline and at the last before study enrolment
visit. Data included demographic and clinical features, PSL
dose, and SLE Disease Activity Index (SLEDAI) [11]. To investigate the influence of the previous treatment on
Changes in SLEDAI were compared between the baseline results, we reviewed the last initial treatment before the
Clin Rheumatol

Table 1 Baseline clinical

characteristics Clinical features No drugs (n = 11) Any drugs (n = 62) p

Sex (female), n (%) 10 (90.1) 57 (91.9) 0.90

Age (years) 53.8 ± 16.6 47.9 ± 15.1 0.46
Disease duration (months) 90.0 ± 70.7 181.2 ± 292.2 0.41
Observation (months) 14.0 ± 3.9 14.9 ± 5.6 0.80
WBC (× 1000/μL) 4.6 ± 2.2 5.4 ± 2.1 0.40
Hb (g/dL) 12.2 ± 1.7 12.1 ± 1.7 0.56
Plt (× 104/μL) 21.3 ± 9.5 21.7 ± 5.8 0.90
SLEDAI 2.3 ± 3.5 1.7 ± 1.5 0.89
Proteinuria (g/gCr) 0.1 ± 0.3 0.1 ± 0.2 0.91
eGFR (mL/min/1.73 m2) 70.6 ± 20.0 76.6 ± 26.2 0.85
CRP (mg/dL) 0.8 ± 2.2 0.3 ± 0.6 0.92
CH50 (U/mL) 37.3 ± 8.8 34.5 ± 10.3 0.12
Anti-Sm antibody-positive, n (%) 1 (9.1) 8 (12.9) 0.72
Anti-dsDNA antibody (IU/mL) 19.3 ± 39.2 15.3 ± 31.7 0.26
Anti-cardiolipin antibody (IU/mL) 8.8 ± 1.8 6.9 ± 3.3 0.68
Lupus anticoagulant-positive, n (%) 4 (36.3) 10 (16.1) 0.11
Organ manifestations
Skin, n (%) 2 (18.2) 14 (22.5) 0.74
Arthritis, n (%) 3 (27.3) 10 (16.1) 0.37
Cytopenia, n (%) 3 (27.3) 14 (22.6) 0.73
Serositis, n (%) 2 (18.2) 5 (8.1) 0.29
LN class II, n (%) 0 5 (8.1) 0.32
Class V, n (%) 1 (9.1) 7 (11.3) 0.82
Others, n (%) 0 7 (14.9) 0.24
PSL (mg/day) – 5.9 ± 3.0 –
MMF use, n (%) – 4 (6.4) –
TAC use, n (%) – 3 (4.8) –
CyA use, n (%) – 3 (4.8) –
MTX use, n (%) – – –
AZP use, n (%) – – –

Values indicate mean ± standard deviation unless otherwise indicated

WBC white blood cells, Hb hemoglobin, Plt platelets, GFR glomerular filtration rate, SLEDAI Systemic Lupus
Erythematosus Disease Activity Index, CRP c-reactive protein, dsDNA double-stranded DNA, LN lupus nephri-
tis, PSL prednisolone, MMF mycophenolate mofetil, TAC tacrolimus, CyA cyclosporine, MTX methotrexate, AZA
azathioprine

study period (Fig. 3). In patients in the no drugs group, experienced a flare. None of the five patients in the
three patients (27.3%) had been treated with PSL-mono, HCQ-mono group had been previously treated, and none
three (27.3%) with PSL + IS, and five (45.5%) with no of them experienced a flare.
drugs. These three subgroups showed no statistically sig- In summary of flare rate by the last treatment provided,
nificant differences in the rate of flares, albeit that num- patients in the PSL-mono group had a higher flare rate than
bers were low (66.7%, 33.3%, and 40%, respectively). those in the IS-mono group regardless of the previous treat-
Most of the PSL-mono group had been treated with ment. No patient with HCQ had been previously treated, and
PSL-mono previously (97.8%), and seven patients none experienced flare during observation.
(15.2%) experienced flare; the one patient in the PSL-
mono group who had been treated with PSL + IS also Adverse events
experienced flare during observation. Among the ten pa-
tients in the IS-mono group, two had been treated with Table 3 summarizes adverse events (AEs) over the study pe-
PSL-mono previously and the other eight had been treat- riod. There were no deaths or serious AEs. Increases in
ed with PSL and IS. No patient in the IS-mono group steroid-related metabolic markers, including low-density
 Clin Rheumatol

Table 2 Baseline clinical features

Clinical features No drugs (n = 11) PSL-mono (n = 47) IS-mono (n = 10) HCQ-mono (n = 5) p

Sex (female), n (%) 10 (90.1) 44 (93.6) 8 (80.0) 5 (100.0) 0.37

Age (years) 53.8 ± 16.6 49.0 ± 14.7 48.5 ± 18.5 36.8 ± 5.3 0.26
Disease duration (months) 90.0 ± 70.7 226.0 ± 334.3 72.1 ± 74.1 61.3 ± 75.2 0.03*
Observation (months) 14.0 ± 3.9 14.7 ± 4.5 18.1 ± 8.6 10.5 ± 7.0 0.17
WBC (× 1000/μL) 4.6 ± 2.2 5.7 ± 2.2 5.1 ± 2.2 3.7 ± 0.9 0.08
Hb (g/dL) 12.2 ± 1.7 12.4 ± 1.5 10.6 ± 2.5 12.6 ± 0.7 0.09
Plt (× 104/μL) 21.3 ± 9.5 21.5 ± 5.9 23.5 ± 5.5 20.9 ± 4.9 0.60
SLEDAI 2.3 ± 3.5 1.9 ± 3.8 1.8 ± 1.0 2.0 ± 2.2 0.12
Proteinuria (g/gCr) 0.1 ± 0.3 0.1 ± 0.3 0.4 ± 0.6 0.4 ± 0.5 0.11
eGFR (mL/min/1.73 m2) 70.6 ± 20.0 75.2 ± 27.4 77.5 ± 24.3 88.6 ± 16.6 0.50
CRP (mg/dL) 0.8 ± 2.2 0.3 ± 0.6 0.1 ± 0.1 0.1 ± 0.1 0.49
CH50 (U/mL) 37.3 ± 8.8 36.3 ± 10.7 28.4 ± 12.6 32.5 ± 12.0 0.22
Anti-Sm antibody-positive, n (%) 1 (9.1) 3 (6.3) 4 (60.0) 1 (20.0) 0.11
Anti-dsDNA antibody (IU/mL) 19.3 ± 39.2 10.9 ± 14.3 37.7 ± 70.5 11.5 ± 11.2 0.61
Anti-cardiolipin antibody (IU/mL) 8.8 ± 1.8 8.3 ± 2.7 19.5 ± 36.0 8.3 ± 0.6 0.82
Lupus anticoagulant-positive, n (%) 4 (36.3) 7 (14.8) 2 (20.0) 1 (20.0) 0.61
Organ manifestations
Skin, n (%) 2 (18.2) 11 (23.4) 1 (10.0) 2 (40.0) 0.93
Arthritis, n (%) 3 (27.3) 7 (14.9) 2 (20.0) 1 (20.0) 0.83
Cytopenia, n (%) 3 (27.3) 12 (25.5) 2 (20.0) 0 0.91
Serositis, n (%) 2 (18.2) 4 (8.5) 1 (10.0) 0 0.93
LN class II, n (%) 0 2 (4.3) 2 (20.0) 1 (20.0) 0.88
Class V, n (%) 1 (9.1) 4 (8.6) 2 (20.0) 1 (20.0) 0.97
Others, n (%) 0 7 (14.9) 0 0 0.67
PSL (mg/day) – 5.9 ± 3.0 – – –
MMF use, n (%) – – 4 (40.0) – –
TAC use, n (%) – – 3 (30.0) – –
CyA use, n (%) – – 3 (30.0) – –
MTX use, n (%) – – – – –
AZP use, n (%) – – – – –

Values indicate mean ± standard deviation unless otherwise indicated

PSL prednisolone, IS immunosuppressant, HCQ hydroxychloroquine, mono monotherapy, WBC white blood cells, Hb hemoglobin, Plt platelets, GFR
glomerular filtration rate, SLEDAI Systemic Lupus Erythematosus Disease Activity Index, CRP c-reactive protein, dsDNA double-stranded DNA, LN
lupus nephritis, PSL prednisolone, MMF mycophenolate mofetil, TAC tacrolimus, CyA cyclosporine, MTX methotrexate, AZA azathioprine
*PSL vs. IS, p < 0.05

lipoprotein cholesterol and hemoglobin A1C, were observed According to the British Society for Rheumatology
in the PSL-mono group. guideline for the management of SLE in adults [1], patients
with moderate disease activity should be treated with PSL
< 0.5 mg/kg/day plus HCQ and/or IS. After stable remis-
Discussion sion is achieved, physicians should aim to reduce and stop
drugs, except HCQ. However, the order of drug reduction
Our results suggest that patients who were treated with IS- or cessation is not specifically mentioned. One prospective
mono and HCQ-mono had a significant reduction in study reported that HCQ reduced flares, but 50% of sub-
SLEDAI. Cessation of all drugs might lead to an increased jects also used GC, and it is therefore unclear which drug is
risk of disease flare. In contrast, IS or HCQ monotherapy may more effective in reducing flare when used as monotherapy
represent reasonable maintenance strategies to prevent flares [3]. In Japan, since HCQ was not approved until 2015, we
in SLE patients without major organ manifestations for a short were able to evaluate the efficacy of IS-mono and PSL-
observation period. mono on disease flare.
Clin Rheumatol

Fig. 2 Cumulative flare rate and change in SLEDAI for each treatment.
Cumulative flare rate (a) and SLEDAI change from baseline (b) are
shown. PSL, prednisolone; IS, immunosuppressant; HCQ,
hydroxychloroquine; SLEDAI, Systemic Lupus Erythematosus Disease
Activity Index
Fig. 1 Cumulative flare rate and change in SLEDAI for patients with no
drugs and any drugs. Cumulative flare rate (a) and SLEDAI change from
baseline (b) are shown. SLEDAI, Systemic Lupus Erythematosus study comparing PSL monotherapy with no drugs in patients
Disease Activity Index with lupus nephritis class III/IV/V in maintenance phase
concluded that there was no significant difference in flare
Our results suggest that IS and HCQ monotherapy rate [13]. Regarding nonmajor organ manifestations, howev-
might have superior efficacy to PSL monotherapy re- er, the possibility of a complete withdrawal of therapy while
garding reduction of flare incidence and SLEDAI. Since minimizing the risk of flare remains unclear. Few data are
the last treatment before this study might have influenced available about withdrawal of therapy in SLE without major
the results, we also analyzed flare rates by the previous organ manifestation [14–17]. In a cohort of 667 SLE pa-
treatment. In that analysis, regardless of any previous tients, 156 (23%) were able to stop therapy and maintain
treatment, patients treated with IS monotherapy experi- remission for a mean of 5.8 years. Steiman et al. reported
enced the lowest flare rate for the maintenance phase that 2.4% of SLE patients took no medications for ≥ 5 years,
among monotherapies. No patient with HCQ had been while Zen et al. reported the complete withdrawal of therapy
previously treated, and none experienced flare during ob- in 7.1% of SLE patients for ≥5 years. Our results suggest
servation. IS or HCQ monotherapy therefore appears to that patients who had been previously treated with PSL
be the most effective in suppressing flare in our study. monotherapy or PSL + IS experienced a 50% risk of flare
Discontinuation of all drugs without disease flare is a over a mean observation period of 14.0 months if they
desirable outcome in SLE treatment. DORIS recently de- discontinued all drugs. Allowing that patient number in the
fined complete remission to include a clinical SLEDAI = 0, HCQ monotherapy group was low (n = 5), our findings may
physician’s global assessment < 0.5 cm, PSL = 0 mg/day, no suggest that HCQ monotherapy should be used as minimal
IS, and serological stability [4, 5]. One randomized pilot maintenance therapy [1, 4, 5].
 Clin Rheumatol

Fig. 3 Cumulative flare rate by

previous treatment. Previous
treatment (a) and cumulative flare
rate in patients who had
previously been treated with PSL
+ IS (b), PSL-mono (c), and no
drugs (d). PSL, prednisolone; IS,
immunosuppressant; HCQ,
hydroxychloroquine

This study is limited by its single-center nature, retro- small; therefore, adverse events were not accurately col-
spective observational design, relatively short observation lected. Confirmation of our findings will require a multi-
period, and small sample size. Statistical significance center prospective study.
might not have been reached because of the small sample In conclusion, these findings suggest that cessation of all
size. Furthermore, treatment strategy was changed at the drugs increases the risk of disease flare for SLE patients with-
discretion of the attending physicians, which may have out major organ manifestations. As monotherapy, IS or HCQ
influenced the results. Since the flare was counted by chart may be a reasonable maintenance strategy comparing with
review, it poses the risk of missing flares. This study was steroid, but further insight into this aspect is left to future
conducted retrospectively, and enrolled patients were very work.

Table 3 Adverse events

No drugs (n = 11) PSL mono (n = 47) IS mono (n = 10) HCQ mono (n = 5) p

Death 0 0 0 0 –
Serious adverse event 0 0 0 0 –
Infection (total) 1 (9.1) 3 (6.4) 1 (10.0) 0 0.87
Respiratory infection 1 (9.1) 1 (2.1) 1 (10.0) 0 0.52
Urinary tract infection 0 2 (4.2) 0 0 0.53
Gastrointestinal –
Nausea 0 0 1 (10.0) 1 (20.0) 0.61
Diarrhea 0 0 0 0 –
Laboratory data
Leukopenia, WBC count < 4000/μL 1 (10.0) 1 (2.1) 3 (30.0) 0 0.09
Anemia, Hb < 11.0 g/dL 0 2 (4.2) 1 (10.0) 0 0.90
Thrombocytopenia, Plt count < 10 × 104/μL 0 0 0 0 –
Abnormal liver function test 0 1 (2.1) 1 (10.0) 0 0.71
HbA1c increasing 0 3 (6.4) 0 0 0.89
LDL-C increasing 0 6 (12.8) 0 0 0.77

WBC white blood cells, Hb hemoglobin, Plt platelets, HbA1c hemoglobin A1C, LDL-C low-density lipoprotein cholesterol
Clin Rheumatol

Compliance with ethical standards international task force on definitions of remission in SLE
(DORIS). Ann Rheum Dis 76:554–551
This study was approved by the Ethics Committee of St. Marianna 6. Zahr ZA, Fang H, Magder LS, Petri M (2013) Predictors of corti-
University School of Medicine (approval number 3305). costeroid tapering in SLE patients: the Hopkins lupus cohort. Lupus
22:697–701
7. Mosca M, Tani C, Aringer M (2013) Withdrawal of therapy in non-
Disclosures None.
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