Abstract
Objective
High disease activity status (HDAS) in patients with systemic lupus erythematosus (SLE) is associated with adverse long-term outcomes. We examined the frequency of lupus low disease activity state (LLDAS) and remission (REM) attainment in HDAS patients and whether their attainment was associated with improved patient outcomes.
Methods
Demographic, clinical and outcomes data, collected prospectively from a multinational cohort between 2013 and 2020, were analysed. Disease activity was assessed using SLEDAI-2K. HDAS was defined as SLEDAI-2K ≥ 10. Patients’ first visit with SLEDAI-2K ≥ 10 was assigned as baseline. Survival analyses were performed to examine the associations between cumulative and sustained LLDAS and REM attainment in HDAS patients and subsequent organ damage accrual and flare.
Results
A total of 1029 HDAS patients with a median study duration of 2.7 years [IQR: 1.0, 4.8] were studied. LLDAS and REM were attained at least once by 71% (LLDAS-ever, n = 726) and 41% (REM-ever, n = 418) of patients. Approximately one-fifth of patients attained ≥50% cumulative time in LLDAS or REM. In total, 37% (n = 385) of patients attained ≥3months of sustained LLDAS, with progressively lower proportions of patients attaining longer periods of sustained LLDAS. Lower proportions of patients attained sustained REM. Attainment of cumulative and sustained LLDAS or REM provided significant protection against damage accrual and flare in HDAS patients. Sustained periods of LLDAS and REM were difficult to achieve and were therefore a more stringent target, but provided the most protection against damage accrual or flare.
Conclusion
LLDAS and REM were achievable targets in HDAS patients, and provided significant protection against adverse outcomes.
Keywords: systemic lupus erythematosus, high disease activity, lupus low disease activity state, outcomes
Rheumatology key messages.
We studied LLDAS and REM attainability in SLE patients following episodes of high disease activity state (HDAS).
Fewer SLE patients who had HDAS attained and sustained LLDAS or REM when compared with non-HDAS patients.
LLDAS and REM provided significant protection against damage accrual and flare regardless of prior HDAS status.
Introduction
High disease activity status (HDAS) in systemic lupus erythematosus (SLE) refers to a state of very active disease with a broad spectrum of organ involvement and an important prognostic indicator of disease severity. HDAS has been defined using the SLE Disease Activity Index (SLEDAI) where a score ≥10 marks its threshold. Being in HDAS even once is associated with worse longitudinal outcomes in patients with SLE such as more organ damage accrual and poor quality of life [1, 2]. HDAS patients frequently make up the majority of patients enrolled in clinical trials, with baseline SLEDAI ≥10 in over 70% of patients in recent phase 3 studies [3]. HDAS patients require more aggressive treatment regimens, including higher doses of glucocorticoids and immunosuppressive drugs to control disease activity.
Lupus low disease activity state (LLDAS) and remission (REM) are validated treat-to-target (T2T) endpoints that provide significant protection against adverse outcomes, such as mortality, organ damage accrual and flare [4–6]. However, the prevalence of T2T end-point attainment and their impact on long-term outcomes have not been specifically studied in HDAS patients, despite these being a group with high unmet need. Attainment of LLDAS has been shown to be a more stringent target than some of the primary endpoints in clinical trials such as BILAG-based Combined Lupus Assessment (BICLA) [7].
In this study, we sought to examine LLDAS and REM attainment in SLE patients who had HDAS, and report the impact of LLDAS and REM on adverse outcomes, irreversible organ damage accrual and flare. We carried out this study using data from the Asia Pacific Lupus Collaboration (APLC), a multi-national, multi-ethnic longitudinal prospective cohort [8]. Understanding the ability to attain LLDAS and REM, and the associated sequelae in a severe patient population is vital for clinicians and patients in the implementation of the T2T strategy in SLE.
Methods
Study population
Data from patients in 13 countries participating in the APLC, collected prospectively between 2013 and 2020 and with ≥2 study visits, were used. All patients were adults aged ≥18 years who met either the 1997 American College of Rheumatology (ACR) Modified Classification Criteria for SLE or the Systemic Lupus International Collaborating Clinics (SLICC) 2012 Classification Criteria [9, 10]. All patients provided informed consent.
Research ethics approval
Each site obtained local ethics approval to participate in the APLC research activities [11]. Storage of the central dataset and analyses of the pooled data have been approved by the Monash University Human Research Ethics Committee (MUHREC Project ID 18778).
This study is registered with ClinicalTrials.gov, NCT03138941.
Data collection
Data were collected during patients’ routine clinical assessments using standardized paper or electronic data-collection forms. Patient demographics (age, sex, ethnicity, years of SLE onset and diagnosis, smoking status, education level, SLE family history) and SLE classification criteria (ACR and SLICC) were collected at enrolment. Organ damage was assessed using the SLICC‐ACR Damage Index (SDI) [12], which was captured at enrolment and at annual visits. SLE Disease Activity Index (SLEDAI‐2K) [13], SELENA-SLEDAI Flare Index (SFI) [14] and Physician Global Assessment [PGA (0–3)] [15], SLE-related medications including doses (antimalarials: hydroxychloroquine, chloroquine; immunosuppressants: mycophenolate, mycophenolic acid, azathioprine, ciclosporin, methotrexate, tacrolimus, leflunomide, cyclophosphamide; biologics: rituximab, belimumab) and laboratory results were recorded at each routine visit. Details of death (date and cause) were recorded in the database at time of death. A time-adjusted mean (TAM) SLEDAI-2K was calculated as a measure of disease activity over time [16]. The TAM-PGA and TAM-prednisolone dose were similarly calculated.
Data availability
Access to APLC pooled data is subject to the specific guidelines outlined in the APLC Data Access Policy (available on request). The APLC welcomes requests for aggregate (summary) data or to perform analyses of new research questions, and such requests can be submitted to the APLC Steering Committee via the APLC Scientific Director (https://www.asiapacificlupus.com/contact-us).
Key definitions
High disease activity status (HDAS)
Patients with SLEDAI-2K ≥ 10 on at least one occasion were classified as HDAS patients. We identified HDAS patients’ first visit with SLEDAI-2K ≥ 10 as baseline, and synchronised visits subsequent to this baseline HDAS visit to report the prevalence of LLDAS attainment and outcomes at annual visits thereafter.
Lupus low disease activity state (LLDAS)
LLDAS was defined as previously published [4]. Briefly, this requires all of the following: SLEDAI-2K ≤4 with no major organ activity; absence of new SLEDAI-2K activity compared with the preceding visit; PGA ≤1; prednisolone (PNL) ≤7.5 mg/day; antimalarials and standard maintenance doses of immunosuppressants were allowed.
Remission (REM) was defined as clinical SLEDAI (disregarding serological activity)=0; PGA <0.5; antimalarials and immunosuppressants allowed, and PNL ≤5 mg/day [17].
Percent-time in LLDAS/REM was calculated as the sum of all-time intervals in LLDAS/REM divided by the total length of follow-up, multiplied by 100. Time intervals in LLDAS/REM equalled the length of time between visits if a patient was in LLDAS/REM at two consecutive visits, or half the length of time between visits if a patient was in LLDAS/REM at one visit but not the other. Although proportions of cumulative time in LLDAS as low as 20% have been shown to be protective from adverse outcomes [4], a threshold of ≥50% cumulative time in LLDAS/REM (LLDAS/REM-50) was used in line with reporting practices in other studies of these endpoints [18].
Furthermore, we derived sustained LLDAS/REM with four cut-off time points; 3 months in sustained LLDAS/REM if patients spent time in these states continuously for ≥91 days; 6-month sustained LLDAS/REM if ≥182 consecutive days, 12-month sustained LLDAS/REM if ≥365 consecutive days, and 24 months sustained LLDAS/REM if ≥730 consecutive days in LLDAS (see supplementary figure, available at Rheumatology online).
Statistical analysis
Statistical analyses were performed using Stata V. 18.0 (StataCorp, College Station, TX, USA). Continuous variables are described as median with interquartile range (IQR) due to the skewed nature of data distribution, whereas categorical variables are described as frequency and percentage (%), stratified according to HDAS/non-HDAS status. Univariable and multivariable survival analyses (Cox regression models) were carried out to examine the longitudinal associations of LLDAS/REM attainment and organ damage accrual and flare (outcomes) at subsequent visits in HDAS patients. Associations of other variables such as demographic factors with outcomes were also explored. The total time since baseline to the outcome event was fitted using the Prentice, Williams and Peterson model (PWP-TT) to set up the data to allow multiple ‘failures’ per patient, as several patients experienced damage accrual/flare in multiple visits. Clustering was specified in regression models to account for intragroup correlation [19, 20]. Multivariable regression analyses were carried to account for potential confounders. We considered a confounder as a variable that was associated with both primary exposure (e.g. LLDAS) and primary outcome (damage accrual/flare) but not in the causal pathway between these two variables. We excluded variables that were used to define LLDAS/REM, flares or damage accrual such as SLEDAI-2K and PGA. If univariable associations of covariates produced associations with P <0.1, they were considered for inclusion in at least the first multivariable models. Retention of potential confounders in the models depended on their statistical significance and the impact on magnitude of the beta coefficient of primary exposure. These results are reported as hazard ratios (HR) with corresponding 95% confidence intervals (CI). P values <0.05 were considered statistically significant.
Results
Cohort and disease characteristics
A total of 1029 patients (27%) in the APLC cohort were HDAS patients. Their demographic and disease characteristics, in comparison to non-HDAS patients, are summarized in Table 1. In brief, HDAS patients were younger, with median [IQR] age of diagnosis at 26 [20, 34] years of age, and had a median [IQR] disease duration of 7 [3, 14] years prior to enrolment into the study. The median observational time was 2.7 [1.0, 4.8] years. In this observed time, the median [IQR] TAM SLEDAI-2K was 6.0 [4.2, 8.3], which was significantly higher than the non-HDAS group. Likewise, the frequency of patients experiencing flares was significantly higher in the HDAS cohort. The majority of this group has been treated with immunosuppressants (86.2%), hydroxychloroquine (77.6%) and prednisolone (96.2%). Baseline organ damage was present in 44.8% of the HDAS group, compared with only 36.9% of the non-HDAS group (P <0.001). At the end of the study observation period, a significantly higher proportion of HDAS patients had irreversible organ damage accrual compared with non-HDAS patients (Table 1). When assessed over time (Table 2), 11.2% of HDAS patients had accrued new organ damage by 1 year after the HDAS baseline visit, which increased to 34.1% of patients by year 5. Regarding flare, 77.8% of HDAS patients had at least one flare by year 1 after the HDAS baseline visit, increasing to 96% by year 5 (Table 2).
Table 1.
Characteristics of patients with high disease activity status (HDAS)
| Non-HDAS patients | HDAS patients | ||
|---|---|---|---|
| Total = 2782 | Total = 1029 | ||
|
|
|||
| N (%) or Median [IQR] | P-valuea | ||
| Demographics | |||
| Age at enrolment (years) | 41 [32, 52] | 35 [27, 46] | <0.001 |
| Age at diagnosis (years) | 30 [22, 41] | 26 [20, 34] | <0.001 |
| SLE duration at enrolment (years) | 9 [3, 16] | 7 [3, 14] | <0.001 |
| Study duration (years) | 2.1 [1.0, 4.8] | 2.7 [1.0, 4.8] | 0.6 |
| Females | 2551 (91.7%) | 958 (93.1%) | 0.15 |
| Asian ethnicity | 2469 (89.0%) | 916 (89.2%) | 0.9 |
| Current smoker at enrolment | 143 (5.2%) | 51 (5.0%) | 0.8 |
| SLE family history | 233 (8.5%) | 70 (6.9%) | 0.10 |
| Tertiary Education level | 1430 (54.5%) | 488 (50.8%) | 0.047 |
| Gross domestic product <20 000 Int$ | 870 (31.3%) | 476 (46.3%) | <0.001 |
| SLE classification criteria | |||
| ACR classification criteria | 2548 (91.6%) | 994 (96.6%) | <0.001 |
| SLICC classification criteria | 2609 (98.2%) | 945 (97.7%) | 0.3 |
| Medications use | |||
| Prednisolone (PNL) use, ever | 2273 (81.7%) | 990 (96.2%) | <0.001 |
| Time adjusted mean (TAM) PNL | 4.8 [1.3, 7.5] | 8.5 [5.0, 12.6] | <0.001 |
| Cumulative PNL (g) | 2.7 [0.6, 7.1] | 7.0 [2.7, 13.1] | <0.001 |
| Anti-Malarials (AM) use, ever | 2213 (79.5%) | 799 (77.6%) | 0.2 |
| Immunosuppressants (IS) use, ever | 1819 (65.4%) | 887 (86.2%) | <0.001 |
| Clinical indicators | |||
| AMS (TAM-SLEDAI-2K) | 2.0 [0.8, 3.7] | 6.0 [4.2, 8.3] | <0.001 |
| TAM_PGA, median (IQR) | 0.3 [0.1, 0.6] | 0.8 [0.4, 1.1] | <0.001 |
| Mild-moderate or severe flare, ever | 1262 (45.4%) | 866 (84.2%) | <0.001 |
| No. of (any) flares | 0.0 [0.0, 1.0] | 2.0 [1.0, 4.0] | <0.001 |
| Annual flare rate | 0.0 [0.0, 0.6] | 0.9 [0.4, 1.6] | <0.001 |
| Baseline organ damage | 9,26 (36.9%) | 421 (44.8%) | <0.001 |
| Organ damage accrual during study period | 442 (17.6%) | 228 (24.3%) | <0.001 |
| LLDAS | |||
| LLDAS-ever (at least once) | 2352 (84.5%) | 726 (70.6%) | <0.001 |
| ≥50% cumulative time in LLDAS (LLDAS-50) | 1773 (63.7%) | 215 (20.9%) | <0.001 |
| ≥3months sustained LLDAS, ever | 1920 (69.0%) | 385 (37.4%) | <0.001 |
| ≥6 months sustained LLDAS, ever | 1582 (56.9%) | 301 (29.3%) | <0.001 |
| ≥12 months sustained LLDAS, ever | 1031 (37.1%) | 157 (15.3%) | <0.001 |
| ≥24 months sustained LLDAS, ever | 505 (18.2%) | 59 (5.7%) | <0.001 |
| DORIS remission (REM) | |||
| REM, ever | 1892 (68.0%) | 418 (40.9%) | <0.001 |
| REM-50 | 1773 (63.7%) | 215 (20.9%) | <0.001 |
| ≥3 months sustained REM, ever | 1448 (52.0%) | 290 (28.2%) | <0.001 |
| ≥6 months sustained REM, ever | 1196 (43.0%) | 229 (22.3%) | <0.001 |
| ≥12 months sustained REM, ever | 829 (29.8%) | 124 (12.1%) | <0.001 |
| ≥24 months sustained REM, ever | 459 (16.5%) | 42 (4.1%) | <0.001 |
P-values derived using Chi-squared tests for comparison of categorical variables and Wilcoxon Rank Sum tests for continuous variables.
Table 2.
LLDAS attainment and outcomes of HDAS patients at annual follow-up visits
| Year 1 | Year 2 | Year 3 | Year 4 | Year 5 | |
|---|---|---|---|---|---|
| Total=824 | Total=617 | Total=489 | Total = 354 | Total=249 | |
| n (%) | n (%) | n (%) | n (%) | n (%) | |
| LLDAS | |||||
| LLDAS-ever (at least once) | 293 (37.1%) | 330 (56.8%) | 308 (66.1%) | 251 (74.3%) | 194 (77.9%) |
| LLDAS-50 | 111 (14.1%) | 128 (22.0%) | 122 (26.2%) | 99 (29.3%) | 73 (29.3%) |
| ≥3 months sustained LLDAS, ever | 89 (11.3%) | 169 (29.1%) | 190 (40.8%) | 171 (50.6%) | 141 (56.6%) |
| ≥6 months sustained LLDAS, ever | 46 (5.8%) | 125 (21.5%) | 152 (32.6%) | 141 (41.7%) | 118 (47.4%) |
| ≥12 months sustained LLDAS, ever | 0 | 40 (6.9%) | 70 (15.0%) | 74 (21.9%) | 65 (26.1%) |
| ≥24 months sustained LLDAS, ever | 0 | 0 | 22 (4.7%) | 32 (9.5%) | 28 (11.2%) |
| REM | |||||
| REM, ever | 175 (22.2%) | 248 (42.7%) | 245 (52.6%) | 196 (58.0%) | 160 (64.3%) |
| REM-50 | 70 (8.9%) | 83 (14.3%) | 81 (17.4%) | 77 (22.8%) | 57 (22.9%) |
| ≥3 months sustained REM, ever | 64 (8.1%) | 131 (22.5%) | 153 (32.8%) | 144 (42.6%) | 123 (49.4%) |
| ≥6 months sustained REM, ever | 30 (3.8%) | 91 (15.7%) | 118 (25.3%) | 113 (33.4%) | 98 (39.4%) |
| ≥12 months sustained REM, ever | 0 | 26 (4.5%) | 51 (10.9%) | 62 (18.3%) | 57 (22.9%) |
| ≥24 months sustained REM, ever | 0 | 0 | 10 (2.1%) | 24 (7.1%) | 23 (9.2%) |
| Outcomes | |||||
| Patients with organ damage accrual | 88 (11.2%) | 106 (18.2%) | 114 (24.5%) | 98 (29.0%) | 85 (34.1%) |
| M/M/S flare ever | 614 (77.8%) | 495 (85.2%) | 411 (88.2%) | 310 (91.7%) | 239 (96.0%) |
LLDAS attainment
In the HDAS group, 70.6% patients achieved LLDAS at least once during the observation period, and 20.9% patients had at least 50% cumulative time in LLDAS (LLDAS-50). In addition, 37.4% achieved 3 months of sustained LLDAS; 29.3% achieved 6 months; 15.3% achieved 12 months and 5.7% achieved 24 months of sustained LLDAS at least once during the study period. The attainment of LLDAS was significantly lower at each threshold in HDAS patients compared with non-HDAS patients (Table 1).
Remission attainment
Approximately 41% of the HDAS cohort achieved REM at least once with about 21% achieving REM-50 at the end of the study observation period. The proportions of HDAS patients attaining 3, 6, 12 and 24 months of sustained REM were 28%, 22%, 12% and 4%, respectively (Table 1). As observed with LLDAS, significantly fewer HDAS patients attained REM when compared with non-HDAS patients.
Frequency of LLDAS and REM attainment over time
We examined the frequency of LLDAS and REM attainment over time following the baseline HDAS visit (Table 2). Data were available for 80% (n = 824) of the 1029 HDAS patients at year 1, 60% (n = 617) at year 2, 48% (n = 489) at year 3, 34% (n = 354) at year 4 and 24% (n = 249) at year 5. The likelihood of LLDAS and REM attainment increased with longer study observation. Only 37% (293/824) of HDAS patients attained LLDAS at least once in the first year of observation following their baseline HDAS visit, and this increased to 77.9% by year 5. Likewise, only 22% (175/824) attained REM at year 1, which increased up to 64% (160/249) by year 5. The proportions of patients achieving LLDAS-50 and REM at year 1 was 14.1% and 9%, respectively. These proportions increased over time by Year 5 (Table 2). Fewer patients achieved sustained LLDAS; for example, only 46 (5.8%) achieved ≥6 m sustained LLDAS, 32 (9.5%) achieved ≥24 m sustained LLDAS, compared with 99 (29.3%) achieving LLDAS-50 at Year 4. Even fewer patients attained sustained REM over time (Table 2).
Longitudinal associations of LLDAS and REM attainment in HDAS patients
We examined the longitudinal associations with organ damage accrual and flare of cumulative and sustained LLDAS and REM in HDAS patients. The risk of organ damage accrual subsequent to LLDAS and REM was significantly reduced by 54% [adjusted HR (95% CI)=0.46 (0.33–0.64)] and 49% [adjusted HR (95% CI)=0.51 (0.35–0.72)], respectively (Table 3). Similarly, the risk of flare subsequent to LLDAS and REM was also significantly reduced by 28% [adjusted HR (95% CI) = 0.72 (0.63, 0.81)] and 31% [adjusted HR (95% CI) = 0.69 (0.60, 0.80)], respectively.
Table 3.
Longitudinal associations of LLDAS attainment with organ damage accrual and flare at subsequent visit in HDAS patient cohorts
| Damage accrualt | Flaret | |
|---|---|---|
| HRa (95% CI), P-value | HRb (95% CI), P-value | |
| All patients with ≥2 visits | ||
| LLDASt-1 | 0.46 (0.33,0.64), <0.001 | 0.72 (0.63,0.81), <0.001 |
| LLDAS-50t-1 | 0.54 (0.34,0.86), 0.009 | 0.58 (0.48,0.70), <0.001 |
| ≥3 m sustained LLDASt-1 | 0.32 (0.20,0.52), <0.001 | 0.53 (0.44,0.63), <0.001 |
| ≥6 m sustained LLDASt-1 | 0.32 (0.18,0.56), <0.001 | 0.46 (0.37,0.57), <0.001 |
| ≥12 m sustained LLDASt-1 | 0.22 (0.09,0.56), 0.001 | 0.29 (0.21,0.40), <0.001 |
| ≥24 m sustained LLDASt-1 | 0.16 (0.02,1.20), 0.074 | 0.31 (0.19,0.51), <0.001 |
| REMt-1 | 0.51 (0.35,0.72), <0.001 | 0.69 (0.60,0.80), <0.001 |
| REM-50t-1 | 0.28 (0.15,0.53), <0.001 | 0.57 (0.46,0.70), <0.001 |
| ≥3 m sustained REMt-1 | 0.27 (0.15,0.48), <0.001 | 0.56 (0.46,0.69), <0.001 |
| ≥6 m sustained REMt-1 | 0.25 (0.12,0.49), <0.001 | 0.50 (0.40,0.64), <0.001 |
| ≥12 m sustained REMt-1 | 0.25 (0.10,0.63), 0.003 | 0.35 (0.25,0.51), <0.001 |
| ≥24 m sustained REMt-1 | 0.26 (0.06,1.17), 0.079 | 0.18 (0.09,0.36), <0.001 |
t-l indicates proceeding visit.
HRs adjusted for
age at visit, GDP and baseline damage, and
age at visit and GDP.
Furthermore, we observed a significant, dose-dependent protective response with increasing durations of sustained LLDAS and REM attainment against damage accrual and flare. For instance, hazard ratios for damage accrual subsequent to sustained LLDAS progressively decreased over time, starting at 0.32 [95% CI: 0.20, 0.52] for 3 months, reducing to 0.22 [95% CI: 0.09, 0.56] for 12 months, and further reducing to 0.16 [95% CI: 0.02, 1.20] for a period of sustained LLDAS ≥24 months (Table 3). The risk of organ damage accrual and flare subsequent to ≥50% cumulative time in LLDAS (LLDAS-50) or REM (REM-50) were also significant (Table 3). We examined the effects of sustained or cumulative LLDAS for ≥12 months in patients who had at least 12 months of follow-up and found each highly protective against organ damage accrual and flare (Fig. 1). However, the protective effect on damage accrual and flare in the patients was significantly higher in patients who sustained LLDAS compared with those who only fulfilled the definition of cumulative LLDAS (Fig. 1).
Figure 1.
Kaplan–Meier survival estimates of organ damage accrual (A and C) and flare (B and D) in patients spending ≥365 days in sustained (dark green) vs cumulative LLDAS (light green) (A and B), and in patients spending ≥365 days in sustained (dark blue) vs cumulative remission (REM) (light blue) (C and D)
Discussion
This multinational cohort study examined the ability of HDAS patients to achieve LLDAS and REM, and its impact on outcomes. HDAS has been previously demonstrated to be associated with multiple indicators of worse outcome in SLE, including rates of flare, damage accrual and mortality [1, 21]. HDAS patients comprised a quarter of all SLE patients in this study cohort, and in clinical trial cohorts, HDAS patients comprise the majority of patients. We found that after even a single episode of high disease activity during observation, HDAS patients demonstrated an inherently more severe phenotype. Similar to a previous observation in a single centre cohort [1], HDAS patients had higher disease activity, flares and damage accrual, and treatment burden shown in this multinational cohort.
A T2T strategy has now been accepted as a key recommendation and overarching principle of management for the care of SLE patients [22]. Attainment of T2T endpoints such as LLDAS and REM has been validated to provide protection against adverse outcomes, including organ damage accrual and flare [4, 5]. In this multinational cohort study, we found that, for example, over two-thirds of HDAS patients were able to achieve LLDAS at least once over the observation period. However, the rate of LLDAS and REM attainment was significantly lower than in non-HDAS patients, further underscoring the importance of HDAS assessing the severity of SLE.
By synchronizing patients’ first HDAS visit as baseline, we examined the hazard risk reduction of LLDAS and REM attainment on adverse outcomes such as damage accrual and flare. Compared with the protective effect seen in an earlier prospective validation study, where attainment of LLDAS at any time point was associated with 41% protection from damage accrual [4], the current study has shown a greater damage accrual risk reduction in HDAS patients of 54%. There was also observation of a dose-dependent protective effect. This indicates that patients in HDAS who attain LLDAS or REM have considerable advantages compared with those who do not, and confirms that the benefits of the treat-to-target approaches are not limited to patients who intrinsically have lower disease activity.
Sustained LLDAS or REM attainment was a more stringent measure compared with ≥50% cumulative time in LLDAS (LLDAS-50) or REM-50, and offered a greater protection from adverse outcomes. Increasing durations of sustained LLDAS have been associated with a dose-dependent reduction in damage accrual [23]. The protective effect of as little as 3 months of sustained LLDAS was a 68% reduction in risk of damage accrual, further increasing to an 84% reduction in risk if patients were able to sustain LLDAS for a period of 24 months or more. This further highlights the importance of not only attaining but sustaining a treat-to-target state in patients with high disease activity.
Conceptually, as therapeutic strategies are generally tailored to maintain patients at low disease activity, in a sustained manner is an ambitious but highly protective goal. In this population with a severe phenotype, a clear message that the treatment goal of sustained LLDAS is beneficial emerges from our results, and such findings could be used to encourage adherence. The proportion of patients achieving LLDAS-50 was higher than the corresponding ‘equivalent’ sustained LLDAS, which suggests that loss of disease control is common. For example, 14% in the first-year cohort achieved LLDAS-50, compared with only 5.8% who achieved 6 m sustained LLDAS. In the first 2 years, 22% achieved LLDAS-50, compared with only 6.9% who achieved 12 m LLDAS.
There are some limitations to this study. The analysis undertaken was retrospective, although data were collected prospectively in a study specifically designed to evaluate the outcomes associated with LLDAS. The number of patients with long periods of observation was fewer, although the proportion of patients that achieved LLDAS increased with length of observation, suggesting the possibility of increased dropouts of patients with worse outcomes.
In summary, this study confirms that HDAS is a poor prognostic indicator in SLE, but in this severe group of patients, protective effects of LLDAS or REM attainment were clearly evident. Sustained LLDAS or REM was a more stringent but also more protective target than LLDAS-50 or REM-50, and is conceptually simpler for patient and physicians to monitor. Even though the attainment of these targets was lower in HDAS patients, this patient subgroup had greater uncontrolled disease activity and burden of treatment and should be the priority group for consideration of emerging therapies available for SLE in order to achieve treat-to-target goals.
Supplementary Material
Acknowledgements
The authors extend their gratitude to the patients enrolled in the Asia Pacific Lupus Collaboration cohort and to all the research support staff involved in data collection and entry.
Contributor Information
Rangi Kandane-Rathnayake, Department of Medicine, Sub-faculty of Clinical and Molecular Medicine, Monash University, Clayton, VIC, Australia.
Vera Golder, Department of Medicine, Sub-faculty of Clinical and Molecular Medicine, Monash University, Clayton, VIC, Australia; Department of Rheumatology, Monash Health, Clayton, VIC, Australia.
Worawit Louthrenoo, Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
Yi-Hsing Chen, Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan.
Jiacai Cho, Rheumatology Division, University Medical Cluster, National University Hospital, Singapore.
Aisha Lateef, Rheumatology Division, University Medical Cluster, National University Hospital, Singapore; Department of Medicine, Woodlands Health, Singapore.
Laniyati Hamijoyo, Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, University of Padjadjaran, Bandung, Indonesia.
Shue-Fen Luo, Department of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Taipei, Taiwan.
Yeong-Jian J Wu, Department of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Taipei, Taiwan.
Sandra V Navarra, Rheumatology Center, University of Santo Tomas Hospital, Manila, Philippines.
Leonid Zamora, Rheumatology Center, University of Santo Tomas Hospital, Manila, Philippines.
Zhanguo Li, Department of Rheumatology and Immunology, People’s Hospital Peking University Health Sciences Centre, Beijing, China.
Sargunan Sockalingam, Department of Medicine, Faculty of Medicine Building, University of Malaya Medical Centre, Kuala Lumpur, Malaysia.
Yasuhiro Katsumata, Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan.
Masayoshi Harigai, Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan.
Yanjie Hao, Rheumatology and Immunology Department, Peking University First Hospital, Beijing, China; Department of Rheumatology, St Vincent’s Hospital, Melbourne Victoria, Australia.
Zhuoli Zhang, Rheumatology and Immunology Department, Peking University First Hospital, Beijing, China.
B M D B Basnayake, Department of Nephrology, Teaching Hospital, Kandy, Sri Lanka.
Madelynn Chan, Department of Rheumatology, Allergy & Immunology, Tan Tock Seng Hospital, Singapore.
Jun Kikuchi, Division of Rheumatology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Tsutomu Takeuchi, Division of Rheumatology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan; Department of Internal Medicine, Saitama Medical University, Saitama, Japan.
Sang-Cheol Bae, Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea; Hanyang University Institute for Rheumatology Research and Hanyang Institute of Bioscience and Biotechnology, Seoul, South Korea.
Sheeran Oon, Department of Rheumatology, St Vincent’s Hospital, Melbourne Victoria, Australia.
Sean O’Neill, Rheumatology Department, Liverpool Hospital and the University of Sydney, New South Wales, Australia.
Fiona Goldblatt, Department of Rheumatology, Flinders Medical Centre, Bedford Park, SA, Australia.
Kristine (Pek Ling) Ng, Department of Rheumatology, Health New Zealand Waitemata, Te Whatu Ora (North Shore Hospital), Auckland, New Zealand.
Annie Law, Department of Rheumatology and Immunology, Singapore General Hospital and Asia Arthritis and Rheumatology Centre, Singapore.
Nicola Tugnet, Department of Rheumatology, Health New Zealand Auckland, Te Tofa Tumai (Greenlane Clinical Centre), Auckland, New Zealand.
Sunil Kumar, Department of Rheumatology, Health New Zealand Counties Manukau, Te Whatu Ora (Middlemore Hospital), Auckland, New Zealand.
Cherica Tee, Department of Paediatrics, University of the Philippines, Manila, Philippines.
Michael Tee, Department of Paediatrics, University of the Philippines, Manila, Philippines.
Naoaki Ohkubo, The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Yoshiya Tanaka, The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Chak Sing Lau, Division of Rheumatology & Clinical Immunology, Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong.
Mandana Nikpour, Department of Rheumatology, St Vincent’s Hospital, Melbourne Victoria, Australia; The University of Sydney School of Public Health, Camperdown, NSW, Australia.
Eric F Morand, Department of Medicine, Sub-faculty of Clinical and Molecular Medicine, Monash University, Clayton, VIC, Australia; Department of Rheumatology, Monash Health, Clayton, VIC, Australia.
Alberta Hoi, Department of Medicine, Sub-faculty of Clinical and Molecular Medicine, Monash University, Clayton, VIC, Australia; Department of Rheumatology, Monash Health, Clayton, VIC, Australia.
Supplementary material
Supplementary material is available at Rheumatology online.
Data availability
The data underlying this article cannot be publicly shared due to the strict protocols and procedures outlined in the Asia Pacific Lupus Collaboration (APLC) Data Access Policy to protect patients’ privacy and to maintain data security and ethical principles. Access to APLC pooled data is subject to the specific guidelines outlined in the APLC Data Access Policy (available on request). The APLC welcomes requests for aggregate (summary) data or to perform analyses of new research questions, and such requests can be submitted to the APLC Steering Committee via the APLC Project Manager via the APLC website (www.asiapacificlupus.com).
Funding
The APLC received funding from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, EMD Serono, GSK, Janssen and UCB Biopharma in support of its research activities such as data collection. S.-C.B. is supported in part by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2021R1A6A1A03038899).
Disclosure statement: R.K.-R. received research grants from GSK and Novartis. S.V.N. received consulting fees from AstraZeneca, Biogen, Boehringer Ingelheim; lecture/speaker fees from AstraZeneca, Biogen, Boehringer Ingelheim, Pfizer and GSK; research grants from Aurinia, Biogen, Idorsia, Novartis. Z.L. received consulting fees from Pfizer, Roche, Janssen, Abbott, AbbVie, Bristol Myers, Squibb, MSD, Celgene, Eli Lilly, GSK, Novartis, UCB Pharma, and have royalties with Pfizer, Roche, Janssen, Abbott, AbbVie, Bristol Myers Squibb, MSD, Celgene, Eli Lilly, GSK, Novartis, UCB Pharma. S.S. received consulting fees from Pfizer, AstraZeneca, ZP Therapeutics. Y.K. received payment/Honoria from Asahi Kasei Pharma, Astellas Pharma Inc., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd, GlaxoSmithKline K.K., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Pfizer Japan Inc., and Sanofi K.K. M.H. received speaker’s fee from AbbVie Japan GK, Ayumi Pharmaceutical Co., Boehringer Ingelheim Japan, Inc.,Bristol Myers Squibb Co., Ltd, Chugai Pharmaceutical Co., Ltd, Eisai Co., Ltd, Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kissei Pharmaceutical Co., Ltd, Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd, and Teijin Pharma Ltd; consultant fees from AbbVie, Boehringer-ingelheim, Bristol Myers Squibb Co., Kissei Pharmaceutical Co.,Ltd and Teijin Pharma & research grants from AbbVie Japan GK, Asahi Kasei Corp., Astellas Pharma Inc., Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd, Chugai Pharmaceutical Co., Daiichi-Sankyo, Inc.,Eisai Co., Ltd, Kissei Pharmaceutical Co., Ltd, Mitsubishi Tanabe Pharma Co., Nippon Kayaku Co., Ltd, Sekiui Medical, Shionogi & Co., Ltd, Taisho Pharmaceutical Co., Ltd, Takeda Pharmaceutical Co., Ltd, and Teijin Pharma Ltd. T.T. received grants from Astellas, Asahi Kasei, Chugai, Mitsubishi Tanabe, and consulting fees from Astellas, Chugai. S.-C.B. supported in part by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2021R1A6A1A03038899). K.(P.L.)N. received Advisory Board participation fees from Abbvie. Y.T. received research grants from Mitsubishi-Tanabe, Eisai, Chugai, Taisho; payment/honoraria from Eli Lilly, AstraZeneca, Abbvie, Gilead, Chugai, Behringer-Ingelheim, GlaxoSmithKline, Eisai, Taisho, Bristol-Myers, Pfizer, Taiho. M.N. received research grant from Boehringer Ingelheim and Janssen; consulting fees from AstraZeneca, Boehringer Ingelheim, GSK, Janssen, and speaker fees from AstraZeneca, Boehringer Ingelheim, GSK, Janssen. E.F.M. received research grants and/or consulting fees from AbbVie, AstraZeneca, Biogen, BristolMyersSquibb, Eli Lilly, Galapagos, Gilead, Genentech, GSKGenetech, Janssen, Novartis, Servier, EMD Serono, Takeda and UCB. A.H. received research grant from AstraZeneca, and consulting fees from EUSA Pharma (UK), and Speaker/Honoraria from Limbic, Novartis, Moose Republic, AbbVie, Eli Lilly. All other co-authors report no conflicts of interest.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Access to APLC pooled data is subject to the specific guidelines outlined in the APLC Data Access Policy (available on request). The APLC welcomes requests for aggregate (summary) data or to perform analyses of new research questions, and such requests can be submitted to the APLC Steering Committee via the APLC Scientific Director (https://www.asiapacificlupus.com/contact-us).
The data underlying this article cannot be publicly shared due to the strict protocols and procedures outlined in the Asia Pacific Lupus Collaboration (APLC) Data Access Policy to protect patients’ privacy and to maintain data security and ethical principles. Access to APLC pooled data is subject to the specific guidelines outlined in the APLC Data Access Policy (available on request). The APLC welcomes requests for aggregate (summary) data or to perform analyses of new research questions, and such requests can be submitted to the APLC Steering Committee via the APLC Project Manager via the APLC website (www.asiapacificlupus.com).