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Off Target: The Long-Term Sequelae of Inadequate Disease Control in SLE

As treatment options expand in SLE with an increasing number of targeted therapeutics, we can be optimistic about the potential to improve disease outcomes.

The management of SLE has until recently been complicated by a paucity of effective treatment targets to guide clinicians in making decisions about treatment efficacy. Inadequate disease control may be associated with increased long-term morbidity related to disease activity and high steroid requirements. Lupus Low Disease Activity State (LLDAS) represents a clinically meaningful disease activity measure which may provide a viable treatment target. Previous work has demonstrated associations between the attainment of LLDAS and improved quality of life and clinical outcomes.1,2 Moreover, the use of LLDAS in clinical trials may several issues related to the problematic SLE Responder Index (SRI4) used previously.

A recent paper in Arthritis Research and Therapy aims to quantify the impact of suboptimal disease control with a multinational observational cohort study of 3384 lupus patients with 30,313 total visits.3 Investigators collected data from 23 sites in 13 countries within the Asia-Pacific region between 2013-2019. At each visit, disease activity was assessed using the SLE Disease Activity Index 2000 (SLEDAI-2K) score and Systemic Lupus Erythematosus National Assessment (SELENA)-SLEDAI flare index alongside the physician global assessment. Accrual of organ damage was assessed using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC-ACR) Damage Index (SDI). Quality of life outcomes were assessed using the 36-Item Short Form Health Survey (SF-36) questionnaire.

Investigators identified 3 patient groups of concern. Within the study, 24% of patients never achieved LLDAS (LLDAS-never), 34% had a time-adjusted mean SLEDAI-2K score >4 (AMS>4), and 25% had at least 1 period of high disease activity state (HDAS) defined as a SLEDAI-2K ≤10 (HDAS-ever). Membership of any of these 3 groups was associated with higher levels of glucocorticoid usage, higher damage accrual, and worse quality of life outcomes. Furthermore, the LLDAS-never, AMS>4, and HDAS-ever states were all associated with significant increases in mortality. Approximately a 5-fold increase in mortality was observed in the LLDAS-never and HDAS-ever groups.

Further analysis of the AMS>4 group revealed a higher proportion of patients with Asian heritage, younger age, and higher serological activity within this group. Similar analysis of the HDAS-ever group revealed these patients to be younger with higher serological activity relative to those who never experienced a high disease activity state but showed no association with ethnicity. The limited ethnic diversity within the cohort (87.4% Asian ethnicity) was noted as a limitation of the study.

Investigators analyzed whether undertreatment may be a driver of poorer outcomes within these groups of concern. Over 70% of patients in the 3 groups of concern were treated with a regimen consisting of ≥2 out of antimalarials, glucocorticoids, and immunosuppressants compared to 65% within the whole cohort. This suggests that significance of disease activity within these patients is not being overlooked by clinicians, even if management options currently remain limited.

As treatment options expand in SLE with an increasing number of targeted therapeutics, we can be optimistic about the potential to improve disease outcomes. Approximately 1/4 (24%) of patients recruited to this study never achieved LLDAS and this was associated with a 5-fold increase in mortality. This sobering fact illustrates both the scale of the problem in SLE and the necessity of identifying these patients to prevent long-term morbidity/mortality. Hopefully, clinicians can bring to bear the expanding therapeutic complement and allow more and more patients to reap the benefits of a low disease activity state.


1. Golder V, Kandane-Rathnayake R, Hoi AYB, Huq M, Louthrenoo W, An Y, et al. Association of the lupus low disease activity state (LLDAS) with health-related quality of life in a multinational prospective study. Arthritis Res Ther. 2017 Mar 20;19(1).

2. Ugarte-Gil MF, Gamboa-Cardenas RV, Reátegui-Sokolova C, Pimentel-Quiroz VR, Medina M, Elera-Fitzcarrald C, et al. LLDAS (lupus low disease activity state) and/or remission are associated with less damage accrual in patients with systemic lupus erythematosus from a primarily Mestizo population: data from the Almenara Lupus Cohort. Lupus Sci Med [Internet]. 2022 Feb 1 [cited 2022 Jul 15];9(1):e000616. Available from: https://lupus.bmj.com/content/9/1/e000616

3. Kandane-Rathnayake R, Louthrenoo W, Hoi A, Luo SF, Wu YJJ, Chen YH, et al. “Not at target”: prevalence and consequences of inadequate disease control in systemic lupus erythematosus-a multinational observational cohort study. Arthritis Res Ther [Internet]. 2022 Dec 1 [cited 2022 Jun 15];24(1). Available from: https://pubmed.ncbi.nlm.nih.gov/35287720/

4. Van Vollenhoven R, Voskuyl A, Bertsias G, Aranow C, Aringer M, Arnaud L, et al. A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS). Ann Rheum Dis [Internet]. 2017 Mar 1 [cited 2022 Jul 15];76(3):554–61. Available from: https://pubmed.ncbi.nlm.nih.gov/27884822/

5. Parra Sánchez AR, Voskuyl AE, van Vollenhoven RF. Treat-to-target in systemic lupus erythematosus: advancing towards its implementation. Nat Rev Rheumatol [Internet]. 2022 Mar 1 [cited 2022 Jul 15];18(3):146–57. Available from: https://pubmed.ncbi.nlm.nih.gov/35039665/