At our institution, 309 patients with SLE were treated with glucocorticoids and were followed up for more than 52 weeks between January 2006 and March 2021. Of these, 298 (96.4%) had their PSL tapered to ≤7.5 mg/day, and 75 (24.3%) discontinued glucocorticoids and completed at least 6 months of follow-up. Two patients were excluded due to missing data on prior treatment regimens. Finally, 73 patients were included in our study, of which, 49 were classified as having SLE with prior severe organ involvement and the remaining 24 were classified as having SLE without prior severe organ involvement (Figure 1). Baseline characteristics of each study group are summarized in Table 1.
Table 1
Demographic and clinical characteristics of patients with SLE with and without prior severe organ involvement
|
Patient with SLE
without prior severe organ
involvement (n = 24)
|
Patient with SLE
with prior severe organ
involvement (n = 49)
|
p value
|
Demographics
|
|
|
|
Age at time of GC discontinuation
|
44.00 [38.00, 51.75]
|
45.00 [35.00, 54.00]
|
0.97
|
Female ratio (%)
|
24 (100.0)
|
46 (93.9)
|
0.55
|
BMI
|
20.08 [18.14, 22.17]
|
19.51 [17.91, 21.11]
|
0.66
|
Ethnicity
|
|
|
|
Japanese
|
21 (87.5)
|
48 (98.0)
|
0.06
|
Non-Japanese Asian
|
3 (12.5)
|
1 (2.0)
|
Disease duration before GC discontinuation (days)
|
2379 [1547, 3345]
|
4367 [1881, 6683]
|
0.06
|
Organ involvement
|
Joints and muscles
|
22 (91.7)
|
38 (77.6)
|
0.20
|
Skin/mucous membranes
|
20 (83.3)
|
39 (81.2)
|
1
|
Hematologic abnormalities
|
14 (58.3)
|
32 (65.3)
|
0.61
|
Serositis
|
7 (29.2)
|
7 (14.3)
|
0.20
|
Renal manifestation
|
0 (0.0)
|
35 (71.4)
|
<0.01
|
Lupus nephritis class
|
|
|
|
Class III/IV
|
0 (0.0)
|
13 (37.1)
|
|
Non-class III/IV
|
0 (0.0)
|
12 (34.3)
|
No data
|
0 (0.0)
|
10 (28.6)
|
Neurological manifestation
|
0 (0.0)
|
6 (12.2)
|
0.17
|
Laboratory data
|
|
|
|
anti-dsDNA Ab
|
13 (54.2)
|
35 (71.4)
|
0.19
|
anti-Sm Ab
|
2 (8.3)
|
8 (16.7)
|
0.48
|
anti-Ro/SSA Ab
|
11 (45.8)
|
22 (46.8)
|
1
|
anti-RNP Ab
|
5 (23.8)
|
13 (31.0)
|
0.77
|
Lupus anticoagulant
|
3 (12.5)
|
8 (16.7)
|
0.74
|
anti-CL Ab
|
3 (13.6)
|
18 (37.5)
|
0.052
|
anti-CL β2GPI Ab
|
2 (9.5)
|
3 (6.5)
|
0.65
|
Prior treatment regimen
|
|
|
|
PSL 1 mg/kg/day
|
0 (0.0)
|
29 (59.2)
|
<0.01
|
mPSL pulse therapy
|
0 (0.0)
|
16 (32.7)
|
<0.01
|
Maximum GC dose (mg/day) *
|
20 [10, 25]
|
60 [40, 60]
|
<0.01
|
B-cell targeting/cytotoxic agent
|
0 (0.0)
|
4 (8.2)
|
0.30
|
RTX
|
0 (0.0)
|
1 (2.0)
|
1
|
CY
|
0 (0.0)
|
4 (8.2)
|
0.30
|
Values are number (%) or median [interquartile range]
Ab = antibody; aPL = antiphospholipid antibody; BMI = body mass index; CL = cardiolipin; CY = cyclophosphamide; GC = glucocorticoid; mPSL = methylprednisolone; PSL = prednisolone; RNP = ribonucleoprotein; RTX = rituximab; SLE = systemic lupus erythematosus
*prednisolone equivalent (mg/day)
There were no statistically significant differences in age at the time of glucocorticoid discontinuation, female ratio, body mass index, and antibody profiles (anti-dsDNA antibody, anti-Sm antibody, anti-Ro/SSA antibody, anti-RNP antibody, lupus anticoagulant, anti-CL antibody, anti-CLβ2GPI antibody) between the two groups. Although disease duration before glucocorticoid discontinuation tended to be longer in patients with prior severe organ involvement, no statistical differences were noted (4367 [1881–6683] vs. 2379 [1547–3345] days, p = 0.06). The maximum dose of glucocorticoids (PSL equivalent) was higher in patients with prior severe organ involvement than in those without (60 [40–60] vs. 20 [10–25] mg/day, p < 0.01). The detailed treatment regimen during the follow-up period is summarized in Table 2 and Additional file 1. On the day of glucocorticoid discontinuation, SLE patients with prior severe organ involvement tended to use hydroxychloroquine (HCQ), Tac, CyA, MMF, AZA, but no statistical difference was noted. MZR is an inhibitor of purine synthesis, with a mechanism of action similar to that of MMF, and is a widely used medication in Japan. Since we have proven the efficacy of MZR in IgG4-related disease with multiple organ involvement and of MZR/tacrolimus combination therapy in lupus nephritis [17, 18], the use of MZR tended to be higher in patients with prior severe organ involvement than in those without, but no statistical differences were noted. As shown in Table 3 and Additional file 2, on the day of glucocorticoid discontinuation, median SLENA-SLEDAI was 0.0 [0.0, 2.0] in patients with prior severe organ involvement and 0.0 [0.0, 0.0] in patients without prior severe organ involvement.
Table 2
Treatment regimen on the day of glucocorticoid discontinuation
Treatment regimen
|
SLE without prior severe organ involvement
(n = 24)
|
SLE with prior severe organ involvement
(n = 49)
|
P value
|
GC dosage (mg/day) *
|
0.00 [0.00, 0.00]
|
0.00 [0.00, 0.00]
|
N/A
|
HCQ
|
10 (41.7)
|
26 (53.1)
|
0.46
|
Tac
|
5 (20.8)
|
20 (40.8)
|
0.12
|
CyA
|
0 (0.0)
|
1 (2.0)
|
1.0
|
MMF
|
0 (0.0)
|
6 (12.2)
|
0.17
|
MZR
|
3 (12.5)
|
14 (28.6)
|
0.15
|
AZA
|
0 (0.0)
|
2 (4.1)
|
1.0
|
MTX
|
3 (12.5)
|
2 (4.1)
|
0.32
|
SASP
|
2 (8.3)
|
0 (0.0)
|
0.11
|
IGU
|
0 (0.0)
|
1 (2.0)
|
1.0
|
BUC
|
1 (4.2)
|
0 (0.0)
|
0.33
|
BEL/RTX/CY/PE/IVIg
|
0 (0.0)
|
0 (0.0)
|
NA
|
Values are number (%) or median [interquartile range]
AZA = azathioprine; BEL = belimumab; BUC = bucillamine; CyA = cyclosporin; CY = cyclophosphamide; GC = glucocorticoid; HCQ = hydroxychloroquine; IGU = iguratimod; IVIg = intravenous immunoglobulin; MMF = mycophenolate mofetil; MTX = methotrexate; MZR = mizoribine; PE = plasma exchange; RTX= rituximab; SASP = salazosulfapyridine; SLE = systemic lupus erythematosus; Tac = tacrolimus *prednisolone equivalent (mg/day)
Table 3
Flare ratio, complement/anti-dsDNA antibody level, and disease activity on the day of glucocorticoid discontinuation in both patient groups
|
SLE without prior severe organ involvement
(n = 24)
|
SLE with prior severe organ involvement
(n = 49)
|
p value
|
Flare-free duration after GC discontinuation (days)
|
385 [304, 2345]
|
322 [280, 1169]
|
0.33
|
Flare rate within 52 weeks after GC discontinuation*
|
4 (18.2)
|
8 (16.7)
|
1.0
|
C3 (mg/dL)
|
90.00 [81.00, 102.50]
|
82.50 [67.75, 97.25]
|
0.05
|
C4 (mg/dL)
|
20.00 [14.50, 27.50]
|
18.00 [13.50, 20.00]
|
0.03
|
Anti-dsDNA antibody (IU/mL)
|
3.50 [1.50, 5.25]
|
6.00 [3.00, 14.50]
|
0.04
|
GC dosage (mg/day) **
|
0.00 [0.00, 0.00]
|
0.00 [0.00, 0.00]
|
N/A
|
SELENA-SLEDAI
|
0.00 [0.00, 0.00]
|
0.00 [0.00, 2.00]
|
0.05
|
LLDAS achievement ratio
|
23 (95.8)
|
46 (93.9)
|
1
|
Values are number (%) or median [interquartile range]
BILAG = British Isles Lupus Assessment Group Index; GC = glucocorticoid; LLDAS = lupus low disease activity state; N/A = not applicable; SLE = systemic lupus erythematosus; SELENA-SLEDAI = Safety of Estrogens in Lupus Erythematosus National Assessment SLE Disease Activity Index; PSL = prednisolone
*We excluded 3 patients (1 patient with prior severe organ involvement and 2 patients without prior severe organ involvement) from the assessment of flare rate within 52 weeks after glucocorticoid discontinuation because of incomplete follow-up.
**prednisolone equivalent (mg/day)
SLE flare rate (overall)
Prior severe organ involvement did not affect the time to first flare after glucocorticoid discontinuation, as this time was 322 (280–1169) days in patients with prior severe organ involvement vs. 385 (304–2345) days in those without prior severe organ involvement (p = 0.33; Table 3).
As shown in Figure 2a, more than 80% of the patients achieved 52 weeks of flare-free remission and more than 70% achieved 1000 days of flare-free remission after glucocorticoid discontinuation. When we compared patients by the presence or absence of prior severe organ involvement, the flare-free rate after glucocorticoid discontinuation in patients with prior severe organ involvement was lower than that in patients without prior severe organ involvement in the first year. However, the flare rate stabilized over time (Figure 2a), and the log rank test results showed that there was no statistical difference between the two groups by the end of the follow-up period (p = 0.73).
We defined resuming glucocorticoids as another definition of flare and assessed glucocorticoid-free remission rate. As shown in Figure 2b, although patients with prior severe organ involvement tended to restart glucocorticoids, no statistical difference was noted between the two groups (p = 0.74).
SLE flare rate (52 weeks)
Of the 73 patients, 1 patient with prior severe organ involvement and 2 patients without prior severe organ involvement did not complete the entire 52-week follow-up after glucocorticoid discontinuation, and these patients could not be monitored for SLE flares during the follow-up. Therefore, we excluded these 3 patients from the 52-week evaluation for SLE flare rates. Of the remaining 70 patients, 8 (16.7%) with prior severe organ involvement and 4 (18.2%) without prior severe organ involvement had flares during the 52 weeks of follow-up after glucocorticoid discontinuation; however, no statistical difference was noted between these patients (p = 1.0; Table 3).
A detailed electronic record search revealed that most flares were mild. However, 3 patients (6.3%) with prior severe organ involvement and 1 patient (4.5%) without prior severe organ involvement experienced a lupus nephritis flare or a lupus flare that necessitated re-initiation of glucocorticoid therapy at a dose of >0.5 mg/kg/day. Of the 3 patients with prior severe organ involvement, 1 experienced a lupus nephritis flare 280 days after glucocorticoid discontinuation and was managed by restarting PSL at 25 mg/day, adding tacrolimus, and subsequently tapering prednisolone to 2.5 mg/day. The second patient experienced a flare of lupus myopathy 313 days after glucocorticoid discontinuation. Although the patient had to start PSL at 40 mg/day, the dose was subsequently decreased to 6 mg/day. The third patient experienced a mild flare of lupus nephritis 70 days after glucocorticoid discontinuation and was initiated on belimumab.
The one patient without prior severe organ involvement experienced fever, arthritis, leukocytopenia, and thrombocytopenia on day 301 after glucocorticoid discontinuation and was managed by restarting mPSL at 30 mg/day. Prednisolone was discontinued 251 days after the occurrence of first flare. The details of each flare are summarized in Additional file 3.
Risk factors for flares after glucocorticoid discontinuation
We evaluated the risk factors for flares after glucocorticoid discontinuation. As shown in Table 4, flare rate was not affected by the presence of prior severe organ involvement (patients with flare 68.4% vs. patients without flare 66.7%, p = 1.0), renal manifestation (47.4% vs. 48.1%, p = 1.0) or neurological manifestation (0.0% vs. 11.1%, p = 0.33), history of PSL treatment more than 1 mg/kg/day (42.1% vs. 38.9%, p = 1.0), mPSL pulse therapy (21.1% vs. 22.2%, p = 1.0), or B cell targeting/cytotoxic agent (0.0% vs. 7.4%, p = 0.57).
Factors that negatively affected flare-free remission after discontinuation were: hypocomplementemia (patient with flare 50.0% vs. patient without flare 23.1%, p = 0.04), elevated anti-dsDNA antibody titer at more than twice the upper limit of the laboratory reference range on the day of glucocorticoid discontinuation (55.6% vs. 12.0%; p = 0.02), positive anti-Sm (31.6% vs. 7.5%, p = 0.02), and anti-RNP antibodies (64.7% vs. 15.2%, p < 0.01).
Factors that tended to decrease the flare-free ratio, but without statistical significance possibly due to the small sample size, were: SLE duration of more than 5000 days (patient with flare 15.8% vs. patient without flare 38.9%, p = 0.09), HCQ treatment on the day of glucocorticoid discontinuation (36.8% vs. 53.7%, p = 0.29), and LLDAS achievement on the day of glucocorticoid discontinuation (89.5% vs. 96.3%, p = 0.28). We then evaluated these variables using the Cox proportional hazard model, which showed that flare rate was not influenced by the presence of prior severe organ involvement (hazard ratio [HR] 1.19, 95% confidence interval [CI] 0.44–3.17, p = 0.73), renal manifestations (HR 1.22, 95% CI 0.48–3.10, p = 0.67), neurologic manifestations (not applicable), history of PSL treatment more than 1 mg/kg/day (HR 1.16, 95% CI 0.46–2.91, p = 0.76), mPSL pulse therapy (HR 0.97, 95% CI 0.32–2.95, p = 0.95), or B-cell targeting or cytotoxic agent use (not applicable).
Cox proportional hazard model analysis also demonstrated that hypocomplementemia on the day of glucocorticoid discontinuation (HR 3.77, 95% CI 1.43–9.90, p < 0.01), elevated anti-dsDNA antibody titer more than twice the upper limit of the laboratory reference range (HR 4.84, 95% CI 1.27–18.41, p = 0.02), anti-Sm antibody positivity (HR 3.50, 95% CI 1.31–9.35, p = 0.01), and anti-RNP antibody positivity (HR 6.80, 95% CI 2.36–19.63, p < 0.01) were risk factors for flares after glucocorticoid discontinuation. Cox proportional hazard model analysis suggested that SLE duration of >5000 days (HR 0.43, 95% CI 0.12–1.48, p = 0.18), HCQ use (HR 0.75, 95% CI 0.29–1.97, p = 0.56), and LLDAS achievement (HR 0.25, 95% CI 0.06–1.1, p = 0.07) on the day of glucocorticoid discontinuation were possible protective factors for flare-free remission after discontinuation; however, significant differences were not noted.
Table 4
Risk factors for flares after glucocorticoid discontinuation
Factor
|
Fisher’s exact test
|
Cox proportional hazard model
|
|
Flare (−)
(n = 54)
|
Flare (+)
(n = 19)
|
p value
|
Hazard ratio
|
p value (95% CI)
|
Prior severe organ involvement
|
36 (66.7)
|
13 (68.4)
|
1.0
|
1.19
|
0.73 (0.44–3.17)
|
Renal manifestations
|
26 (48.1)
|
9 (47.4)
|
1.0
|
1.22
|
0.67 (0.48–3.10)
|
Neurological manifestations
|
6 (11.1)
|
0 (0.0)
|
0.33
|
N/A
|
N/A
|
History of treatment with PSL 1 mg/kg/day
|
21 (38.9)
|
8 (42.1)
|
1.0
|
1.16
|
0.76 (0.46–2.91)
|
History of treatment with mPSL pulse therapy
|
12 (22.2)
|
4 (21.1)
|
1.0
|
0.97
|
0.95 (0.32–2.95)
|
History of treatment with:
B-cell targeting/cytotoxic medication
|
4 (7.4)
|
0 (0.0)
|
0.57
|
N/A
|
N/A
|
Hypocomplementemia
on the day of glucocorticoid discontinuation
|
12 (23.1)
|
9 (50.0)
|
0.04
|
3.77
|
<0.01 (1.43–9.90)
|
Elevated anti-dsDNA antibody of twice above ULN of laboratory reference range on the day of glucocorticoid discontinuation
|
3 (12.0)
|
5 (55.6)
|
0.02
|
4.84
|
0.02 (1.27-18.41)
|
Duration of SLE >5000 days
|
21 (38.9)
|
3 (15.8)
|
0.09
|
0.43
|
0.18 (0.12–1.48)
|
Anti-Smith antibody
|
4 (7.5)
|
6 (31.6)
|
0.02
|
3.50
|
0.01 (1.31–9.35)
|
Anti-Ro/SSA antibody
|
22 (42.3)
|
11 (57.9)
|
0.29
|
2.19
|
0.10 (0.87–5.55)
|
Anti-RNP antibody
|
7 (15.2)
|
11 (64.7)
|
<0.01
|
6.80
|
<0.01 (2.36-19.63)
|
HCQ use on the day of glucocorticoid discontinuation
|
29 (53.7)
|
7 (36.8)
|
0.29
|
0.75
|
0.56 (0.29–1.97)
|
Achievement of LLDAS on the day of glucocorticoid discontinuation
|
52 (96.3)
|
17 (89.5)
|
0.28
|
0.25
|
0.07 (0.06–1.1)
|
Values are number (%) unless otherwise specified.
HCQ = hydroxychloroquine; LLDAS = lupus low disease activity state; mPSL = methylprednisolone; N/A = not applicable; PSL = prednisolone; RNP = ribonucleoprotein; SLE = systemic lupus erythematosus, ULN = upper limit of normal