Pragmatic targets for moderate/severe SLE and their implications for clinical care and trial design: sustained DORIS or LLDAS for at least 6 months is sufficient while their attainment for at least 24 months ensures high specificity for damage-free progression

Abstract

Objectives: Treatment targets in systemic lupus erythematosus (SLE) have been validated in unselected-in terms of severity-cohorts, which limits their generalisability. We assessed remission (Definition of Remission in SLE (DORIS)) and Lupus Low Disease Activity State (LLDAS) in a historical cohort of 348 patients with active moderate-to-severe disease and median follow-up of 5 years.

Methods: Active SLE was defined as Physician Global Assessment ≥1.5 and/or SLE Disease Activity Index 2000 ≥6, requiring therapy intensification. DORIS/LLDAS, organ damage, flares and adverse events were monitored. Shared frailty survival, generalised linear models and K-means clustering were applied.

Results: Sustained DORIS and LLDAS for ≥6 months occurred in 41.1% and 80.4%, respectively, and resulted in reduced damage accrual (HR: 0.58; 95% CI 0.36 to 0.93 and 0.61; 0.43 to 0.86) and severe flares (HR: 0.14; 0.08 to 0.27 and 0.19; 0.13 to 0.27). LLDAS without DORIS was also protective (HR: 0.65; 0.43 to 0.98 for damage, 0.49; 0.36 to 0.67 for flares). Models fitting increasing duration of targets showed that DORIS ≥50% and LLDAS ≥60% of time, or alternatively, ≥24 and ≥36 months, achieved optimal balance between feasibility (20.2-41.7%) and specificity (73.3-86.1%) for damage-free outcome. These targets were linked to reduced serious adverse events (risk ratio (RR): 0.56-0.71), hospitalisation (RR: 0.70) and mortality (RR: 0.06-0.13). Patients with predominant arthritis and mucocutaneous disease experienced reduced DORIS/LLDAS, compared with counterparts with major organ involvement. Conventional drugs were more frequently used in the former group, whereas potent immunosuppressive/biological agents in the latter.

Conclusions: In moderate-to-severe SLE, sustained DORIS/LLDAS for at least 6 months is sufficient, while attainment for at least 24 months ensures higher specificity for damage-free progression, thus facilitating treat-to-target strategies and clinical trials. Arthritis and skin disease represent unmet therapeutic needs that could benefit from novel biologics.

Keywords: Lupus Erythematosus, Systemic; Outcome Assessment, Health Care; Therapeutics.

Figure 1

Attainment of treatment targets above specific exposure thresholds results in significant reduction of organ damage accrual. (A,B) Survival plot of new organ damage-free time according to achievement of (A) DORIS ≥50% of observation time or not (HR 0.51; 95% CI 0.31 to 0.84, multiple-failures Cox-proportional hazards), and (B) LLDAS ≥60% of time or not (HR 0.47; 0.32 to 0.69). Banded areas represent 95% CI. (C,D) Survival plot of new organ damage-free time according to sustained attainment of (C) DORIS ≥24 months or not (HR 0.49; 0.29 to 0.84, multiple-failures Cox-proportional hazards) and (D) LLDAS ≥36 months or not (HR 0.43; 0.28 to 0.68). Banded areas represent 95% CI. (E) The same plot as above according to accomplishment of DORIS ≥50% of time (with or without LLDAS ≥60% of time), LLDAS ≥60%/DORIS <50% and LLDAS <60%/DORIS <50%. Using the latter condition as reference, LLDAS ≥60%/DORIS <50% had reduced hazard for organ damage accrual (HR 0.60; 0.38 to 0.95, p=0.030). (F) The same plot as above according to sustained attainment of DORIS ≥24 months (with or without LLDAS ≥36 months), LLDAS ≥36 months/DORIS <24 months and LLDAS <36 months. Using the latter condition as reference, LLDAS ≥36 months/DORIS <24 months had reduced hazard for organ damage accrual (HR 0.54; 0.30 to 0.97, p=0.038). DORIS, Definition of Remission in SLE; LLDAS, Lupus Low Disease Activity State.

Figure 2

Clinically defined SLE patient clusters correspond to differential attainment of the DORIS and LLDAS treatment targets. (A) K-means clustering was used to group patients according to the proportion of follow-up time exhibiting activity in each one of the items/domains included in the SLEDAI-2K. Clusters 1 (n=87, 25.0% of the study cohort), 2 (n=139, 39.9%) and 3 (n=122, 35.1%) were identified. Heatmap illustrating the fold changes of the proportion of time with actively involved SLEDAI-2K items, across the patients’ clusters. Z-score transformation of the fold change values was applied, ranging from −1 (dark blue) to +1 (dark red) as shown in the legend on top right. ‘Serositis’ includes ‘pericarditis’ and ‘pleuritis’; ‘renal features’ include ‘urinary casts’, ‘haematuria’, ‘proteinuria’ and ‘pyuria’; and ‘neurological features’ include ‘seizure’, ‘psychosis’, ‘organic brain syndrome’, ‘visual disturbances’, ‘cranial nerve disorder’ and ‘lupus headache’. (B) Dot plots demonstrating the attainment (% of cumulative time) of DORIS and LLDAS by each patient across the three clusters. The black dot with blue error bars represents the median (IQR) attainment in each cluster. Comparisons between the clusters were performed with the Kruskal-Wallis non-parametric test followed by Dunn’s test for multiple comparisons. *P<0.05; ***P<0.001; ****p<0.0001. (C) Stacked bar plots illustrating the proportion of patients within each cluster who met the target thresholds DORIS ≥50% (with or without LLDAS ≥60%), LLDAS ≥60%/DORIS <50% and LLDAS <60%/DORIS <50%. DORIS, Definition of Remission in SLE; LLDAS, Lupus Low Disease Activity State; SLE, systemic lupus erythematosus; SLEDAI-2K, SLE Disease Activity Index 2000.