11 Remission and low disease activity: the new targets for treatment

In chronic inflammatory diseases such as rheumatoid arthritis, attainment of a specific cut-off of low (or even absent) disease activity has been associated with favourable long-term disease outcomes. Systemic lupus erythematosus (SLE) is a complex, systemic disease where prognosis is determined by a variety of factors including disease activity and exposure to potentially toxic drugs particularly glucocorticoids. To this end, both increased activity (either persistent or exacerbations following a period of inactivity) and continuous intake of prednisone at doses above 5–7.5 mg/day have been correlated with accrual of irreversible dysfunction or damage in a variety of organs.

Delineation of the optimal therapeutic goal in SLE is challenging, which is in part due to the inherent limitations of the available clinical instruments for monitoring the disease. Nonetheless, through an evidence- and consensus-based approach, an international expert panel has recently introduced various definitions of remission in SLE ¹ namely: (a) complete remission (with normal serological markers); (b) clinical remission (irrespective of serological markers); (c) complete remission on-treatment (allowing intake of stable maintenance immunosuppressives and/or ≤5 mg/day of prednisone); and (d) clinical remission on-treatment. In the aforementioned definitions, remission is established by combination of absent disease activity (typically, SLEDAI=0 and physician-rated global disease activity [physician global assessment-PhGA] ≤0.5). In addition, an Asia-Pacific collaborative group has proposed lupus low disease activity state (LLDAS) ² as minimally acceptable disease activity (including serological markers and allowing intake of stable maintenance immunosuppressives and/or ≤7.5 mg/day of prednisone) in patients with SLE. A SLEDAI cut-off of ≤4 with PhGA of ≤1 are included in this definition. Accordingly, a number of observational studies have shown that attainment of either remission or LLDAS is associated with improved patient outcomes such as prevention of flares and organ damage accrual.^{3 4}

However, a number of issues pertaining to the definition of therapeutic target in SLE require clarification. First, although PhGA is useful in monitoring the disease by acting as a ‘safety net’ against the drawbacks of SLEDAI, it is still subject to inter-rater variability.⁵ Second, existing definitions of remission and LLDAS comprise of a combination of features such as an objective activity index, physician-rated activity and dose of glucocorticoids. The extent to which all these components are prognostically important is not clear and recent studies suggest that SLEDAI=0 alone may suffice for the definition of remission in SLE.⁶ Finally, it has been a matter of debate whether serology (serum C3/C4, anti-dsDNA) should be included in the definition of treatment targets (remission, LLDAS) or whether the latter should be based on the clinical parameters of SLE activity. This is due to the lack of absolute concordance between clinical and serological activity and the fact, that most patients with stable abnormal serology have favourable long-term prognosis. Further studies in large, well-characterised patient registries will be required to address the abovementioned issues, thus defining the optimal treatment goal in the disease.

Learning Objectives

• Identify factors with an adverse impact on organ damage accrual in patients with SLE

• Demonstrate understanding of the existing definitions of remission and low disease activity state in SLE

• Discuss unresolved issues related to the definitions of remission and low disease activity and their implementations in clinical practice

References

1. van Vollenhoven R, Voskuyl A, Bertsias G, 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 2017;76(3):554–61.

2. Franklyn K, Lau CS, Navarra SV, et al. Definition and initial validation of a Lupus Low Disease Activity State (LLDAS). Ann Rheum Dis 2016;75(9):1615–21.

3. Petri M, Magder LS. Comparison of Remission and Lupus Low Disease Activity State in Damage Prevention in a United States Systemic Lupus Erythematosus Cohort. Arthritis Rheumatol 2018;70(11):1790–95.

4. 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.

5. Chessa E, Piga M, Arnaud L. Physician global assessment in systemic lupus erythematosus: can we rely on its reliability?Ann Rheum Dis 2020 doi: 10.1136/annrheumdis-2020-217632

6. Saccon F, Zen M, Gatto M, et al. Remission in systemic lupus erythematosus: testing different definitions in a large multicentre cohort. Ann Rheum Dis 2020 doi: 10.1136/annrheumdis-2020-217070 [published Online First: 2020/04/24].