A precise definition of low disease activity (LDA) in systemic lupus erythematosus (SLE) is crucial for managing patients according to a T2T strategy.¹ Lupus low disease activity state (LLDAS) was proven to be a valid outcome measure,² since its achievement is associated with a significant decrease in disease flares and damage accrual, as well as with improved HR-QoL.

Some pitfalls, however, may affect the definition of LLDAS:

1. LLDAS is not aligned with the DORIS definition of remission, particularly in the most important item - SLEDAI. Indeed, SLEDAI≤4 (including serology) is considered in the definition of LLDAS, by contrast clinical SLEDAI=0 is included in the DORIS definition. We know that a significant proportion of patients with SLEDAI≤4 has a clinical SLEDAI=0, since they are patients with serologically active clinical quiescent disease (SACQ). As a consequence, there is a great overlap between LLDAS and DORIS remission, i.e. the majority of patients in LLDAS are also in remission on therapy, according to the DORIS definition of remission.³ Thus, LLDAS cannot discriminate between patients in LDA and those in remission.⁴

2. The item that could theoretically distinguish between remission and LLDAS is physician global assessment (PGA), which has a cut-off of ≤0.5 for remission and ≤1.0 for LLDAS. It is, however, very difficult to predict the phenotype of patients with a PGA in between 0.5 and 1.0, and a poor inter-rater and intra-rater reliability of PGA has been recently confirmed in a meta-analysis, which highlighted the need for PGA standardisation.⁵ Notably, in a recent paper testing different definitions of remission, PGA did not increase the performance of clinical SLEDAI=0 in predicting damage progression.⁶

3. Thus, the remaining item able to distinguish patients in remission from those in LLDAS is glucocorticoid intake: ≤5 mg in remission according to the DORIS definition and ≤7.5 mg in LLDAS. It has, however, been shown that the great majority of patients in LLDAS receive a dosage of prednisone ≤5 mg/day; moreover, the habit of prescribing prednisone largely varies among rheumatologists,⁷ and cannot be easily standardised.

In addition, the major reason why LLDAS cannot capture patients in ‘true’ LDA is that it is based on the SLEDAI score, i.e. a binomial disease activity index that measures disease activity in each organ domain in terms of ‘present’ or ‘absent’, but it is not able to discriminate the level of disease activity within any single organ domain.

A new disease activity index named SLE-DAS (http://sle-das.eu) has recently been proposed and validated,⁸ which measures disease activity in a continuous fashion and, thus, is more sensitive to clinical changes compared with the SLEDAI. The SLE-DAS includes some items that are not considered in the SLEDAI, namely lupus enteritis, cardiac and pulmonary manifestations and haemolytic anaemia. In addition, some items that are binomial in the SLEDAI were turned into continuous in the SLE-DAS, including arthritis, proteinuria, thrombocytopenia, and leukopenia. The SLE-DAS cut-offs for defining remission and LDA have recently been derived and validated.^{9 10}

Learning Objectives

• Discuss the hurdles in defining low disease activity in SLE and the pitfalls of LLDAS

• Discuss why LLDAS does not capture patients with ‘true’ LDA

• Explain lupus LDA in clinical practice, and discuss other instruments that might identify patients in LDA better than LLDAS

References

1. Gatto M, et al. New therapeutic strategies in systemic lupus erythematosus management. Nat Rev Rheumatol 2019 Jan;15(1):30–48.

2. Franklyn K, et al. Definition and initial validation of a Lupus Low Disease Activity State (LLDAS). Ann Rheum Dis 2016 Sep;75(9):1615–1621.

3. Golder V, Tsang-A-Sjoe MWP. Treatment targets in SLE: remission and low disease activity state. Rheumatology (Oxford). 2020 Dec 5;59(Suppl5):v19–v28.

4. Zen 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 Jan;77(1):104–110.

5. Chessa E, et al. Use of Physician Global Assessment in systemic lupus erythematosus: a systematic review of its psychometric properties. Rheumatology (Oxford). 2020 Dec 1;59(12):3622–3632.

6. Saccon F, et al. Remission in systemic lupus erythematosus: testing different definitions in a large multicentre cohort. Ann Rheum Dis 2020 Jul;79(7):943–950.

7. Chen HL, et al. Cumulative Burden of Glucocorticoid-related Adverse Events in Patients with Systemic Lupus Erythematosus: Findings from a 12-year Longitudinal Study. J Rheumatol 2018 Jan;45(1):83–89.

8. Jesus D, 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 Mar;78(3):365–371.

9. Jesus D, et al. Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) enables accurate and user-friendly definitions of clinical remission and categories of disease activity. Ann Rheum Dis 2021 Dec;80(12):1568–1574.

10. Assunção H, et al. Definition of Low Disease Activity State based on the SLE-DAS: Derivation and validation in a multicentre real-life cohort. Rheumatology (Oxford). 2021 Dec 3:keab895.