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01 T2T, LLDAS and remission: operational definitions meet reality?
  1. Andrea Doria
  1. University of Padova, Italy


In the wake of the effect of the treat-to-target (T2T) approach in rheumatoid arthritis and other rheumatic conditions, remission and low disease activity (LDA) have recently been the objective of a number of studies in systemic lupus erythematosus (SLE), where the validity of some definitions for their effect on organ damage were tested.

Remission An agreement on the principles that should guide the development of the definition of remission was published in 2017,1 and some new definitions of remission have been proposed.1-3

All definitions distinguish two subtypes of remission, namely complete (no serological and clinical activity) and clinical (serologically active clinical quiescent disease). They differ in terms of allowed therapies and disease activity indices used. To be defined as a therapeutic goal, a potential target should be achievable by a significant proportion of patients. Prolonged remission was rarely reported in the past, but in the last few years it has been shown that durable remission might be not anymore rare in SLE.3-6 Discrepancy can be due to the application of definitions of remission different from those used in the past, together with improved knowledge and management of the disease.

All the aforementioned definitions of remission succeeded in identifying patients with a better disease outcome.

DORIS and Zen definitions are close on several aspects,1 3 with the substantial difference of excluding the physician global assessment (PGA) by Zen et al. PGA has the known limitation of having relevant inter-observer variability7 and, moreover, a significant difference between pre-laboratory and post-laboratory PGA was highlighted.8

Interestingly, comparable results in terms of prevalence of remission and of protective effect on damage progression were obtained using either Zen’s3 4 or DORIS’ definition,2 4 suggesting that exclusion of PGA might not alter the ability to identify patients with better prognosis and that achievement of clinical SLE disease activity index (SLEDAI)-2K equal to zero is probably the main driver of the protective effect of remission.

Low disease activity The concept of LDA has recently been proposed in SLE and preliminary data suggest that patients achieving LDA have better outcomes.2 9-11

Three definitions of LDA have recently been set up: Those by Franklyn et al.9 (10) and Ugarte et al.2 are similar, although the latter does not consider PGA. These definitions were tested in different cohorts with promising results, with patients in LDA having lower damage progression than those without LDA.

The definition by Polachek et al . is quite different, with the cut off for definition being a clinical SLEDAI-2K ≤2, and antimalarials the only medications allowed.10 This definition was associated with improved outcomes in the original cohort, but it has not been validated in other cohorts.

Notably, measurement of disease activity should be continuous for defining LDA and not categorical (item present/absent) as SLEDAI is, being thus inadequate to capture low-intermediate activity in each single organ domain. In fact, LDA should not only correspond to milder lupus manifestations, but it should identify patients with low activity irrespective of the type of manifestations (e.g. low persistent proteinuria, low-active arthritis). Thus, SLEDAI is not adequate to define LDA and to separate remission from LDA on a continuum. In this regard, PGA, which is indeed a continuous index, could be helpful in complementing SLEDAI; however, PGA does not include objective measure of disease activity and, as mentioned above, it has a number of substantial limitations.

A new disease activity index named SLE-DAS (‘’) has recently been proposed and validated,12 which is a continuous disease activity index with a higher sensitivity to change than SLEDAI. This new index is very promising in the evaluation of a treatment response and in discriminating LDA from remission.

Learning objectives

  • Describe definitions of remission in SLE

  • Identify patients who can achieve SLE remission

  • Identify patients who can achieve SLE LDA


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  2. Ugarte-Gil MF, Wojdyla D, Pons-Estel GJ, et al. Remission and Low Disease Activity Status (LDAS) protect lupus patients from damage occurrence: data from a multiethnic, multinational Latin American Lupus Cohort (GLADEL). Annals of the Rheumatic Diseases 2017;76(12):2071–74.

  3. Zen M, Iaccarino L, Gatto M, et al. Prolonged remission in Caucasian patients with SLE: prevalence and outcomes. Annals of the Rheumatic Diseases 2015;74(12):2117–22.

  4. Mok CC, Ho LY, Tse SM, et al. Prevalence of remission and its effect on damage and quality of life in Chinese patients with systemic lupus erythematosus. Ann Rheum Dis 2017;76(8):1420–25.

  5. Tsang ASMW, Bultink IE, Heslinga M, et al. Both prolonged remission and Lupus Low Disease Activity State are associated with reduced damage accrual in systemic lupus erythematosus. Rheumatology (Oxford, England) 2017;56(1):121–28.

  6. Zen M, Iaccarino L, Gatto M, et al. The effect of different durations of remission on damage accrual: results from a prospective monocentric cohort of Caucasian patients. Annals of the Rheumatic Diseases 2016;76(3):562–65.

  7. Isenberg DA, Allen E, Farewell V, et al. An assessment of disease flare in patients with systemic lupus erythematosus: a comparison of BILAG 2004 and the flare version of SELENA. Ann Rheum Dis 2011;70(1):54–9.

  8. Aranow C. A pilot study to determine the optimal timing of the Physician Global Assessment (PGA) in patients with systemic lupus erythematosus. Immunologic Research 2015;63(1–3):167–69.

  9. Franklyn K, Lau CS, Navarra SV, et al. Definition and initial validation of a Lupus Low Disease Activity State (LLDAS). Annals of the Rheumatic Diseases 2015;75(9):1615–21.

  10. Polachek A, Gladman DD, Su J, et al. Defining Low Disease Activity in Systemic Lupus Erythematosus. Arthritis care & research 2017;69(7):997–1003.

  11. Zen M, Iaccarino L, Gatto M, et al. Lupus low disease activity state is associated with a decrease in damage progression in Caucasian patients with SLE, but overlaps with remission. Ann Rheum Dis 2018;77(1):104–10.

  12. Jesus D, Matos A, Henriques C, et al. Derivation and validation of the SLE Disease Activity Score (SLE-DAS): a new SLE continuous measure with high sensitivity for changes in disease activity. Ann Rheum Dis 2019;78(3):365–71.

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