Lupus low disease activity state as a treatment endpoint for systemic lupus erythematosus: a prospective validation study

Vera Golder; Rangi Kandane-Rathnayake; Molla Huq; Hieu T Nim; Worawit Louthrenoo; Shue Fen Luo; Yeong-Jian Jan Wu; Aisha Lateef; Sargunan Sockalingam; Sandra V Navarra; Leonid Zamora; Laniyati Hamijoyo; Yasuhiro Katsumata; Masayoshi Harigai; Madelynn Chan; Sean O'Neill; Fiona Goldblatt; Chak Sing Lau; Zhan Guo Li; Alberta Hoi; Mandana Nikpour; Eric F Morand; Asia-Pacific Lupus Collaboration

doi:10.1016/S2665-9913(19)30037-2

Lupus low disease activity state as a treatment endpoint for systemic lupus erythematosus: a prospective validation study

Lancet Rheumatol. 2019 Oct;1(2):e95-e102. doi: 10.1016/S2665-9913(19)30037-2. Epub 2019 Sep 6.

Authors

Vera Golder¹, Rangi Kandane-Rathnayake², Molla Huq³, Hieu T Nim², Worawit Louthrenoo⁴, Shue Fen Luo⁵, Yeong-Jian Jan Wu⁵, Aisha Lateef⁶, Sargunan Sockalingam⁷, Sandra V Navarra⁸, Leonid Zamora⁸, Laniyati Hamijoyo⁹, Yasuhiro Katsumata¹⁰, Masayoshi Harigai¹⁰, Madelynn Chan¹¹, Sean O'Neill¹², Fiona Goldblatt¹³, Chak Sing Lau¹⁴, Zhan Guo Li¹⁵, Alberta Hoi², Mandana Nikpour³, Eric F Morand²; Asia-Pacific Lupus Collaboration

Affiliations

¹ School of Clinical Sciences, Monash University, Melbourne, VIC, Australia. Electronic address: vera.golder@monash.edu.
² School of Clinical Sciences, Monash University, Melbourne, VIC, Australia.
³ Department of Rheumatology, The University of Melbourne, Melbourne, VIC, Australia.
⁴ Department of Internal Medicine, Chiang Mai University, Chiang Mai, Thailand.
⁵ Department of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Guishan Township, Taiwan.
⁶ Rheumatology Division, National University Hospital, Singapore.
⁷ Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
⁸ Joint and Bone Center, University of Santo Tomas Hospital, Manila, Philippines.
⁹ Department of Internal Medicine, University of Padjadjaran, Bandung, Indonesia.
¹⁰ Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan.
¹¹ Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore.
¹² South Western Sydney Clinical School, University of New South Wales, Sydney, NSW, Australia; Ingham Institute of Applied Medical Research, Liverpool, NSW, Australia.
¹³ Department of Rheumatology, Royal Adelaide Hospital, Adelaide, SA, Australia; Department of Rheumatology, Flinders Medical Centre, Bedford Park, SA, Australia.
¹⁴ Division of Rheumatology and Clinical Immunology, University of Hong Kong, Hong Kong Special Administrative Region, China.
¹⁵ Department of Rheumatology and Immunology, People's Hospital Peking University Health Sciences Centre, Beijing, China.

PMID: 38229349
DOI: 10.1016/S2665-9913(19)30037-2

Abstract

Background: Treat-to-target strategies have improved outcomes in single-organ diseases with simple clinical or laboratory endpoints. A lack of validated endpoints has prevented adoption of treat to target for complex multiorgan conditions, such as systemic lupus erythematosus (SLE). We report the first prospective study undertaken to specifically validate a treat-to-target endpoint for SLE.

Methods: In this prospective cohort study, patients aged 18 years or older with SLE were recruited from 13 centres in eight countries and followed prospectively. Patients with at least two visits over the study period no more than 6 months apart were included in the longitudinal analysis. Patients with no visits in the final year of the study were censored from their last visit. Attainment of the lupus low disease activity state (LLDAS) was assessed at each visit. The primary outcome measure was accrual of irreversible end-organ damage, defined as at least a 1-point increase in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. We used time-dependent hazard regression models and generalised linear models to measure the association between LLDAS (attainment at any timepoint, cumulative time in LLDAS, and sustained LLDAS) with accrual of irreversible end-organ damage or flare (key secondary outcome). This study is registered with ClinicalTrials.gov, NCT03138941.

Findings: Between May 1, 2013, and Dec 31, 2016, 1707 patients were recruited and followed for a mean of 2·2 years (SD 0·9), totalling 12 689 visits. Attainment of LLDAS at any timepoint was associated with reduction in damage accrual (hazard ratio 0·59, 0·45-0·76; p<0·0001) and subsequent flare (0·65, 95% CI 0·56-0·75; p<0·0001). Cumulative time in LLDAS was associated with improved outcomes: compared with patients with less than 50% of observed time in LLDAS, those with at least 50% of observed time in LLDAS had reduced risk of damage accrual (0·54, 0·42-0·70; p<0·0001) and flare (0·41, 0·35-0·48; p<0·0001). Similarly, increased durations of sustained LLDAS were associated with incremental reductions in the risk of damage accrual. The association of LLDAS with reduced damage accrual was observed regardless of pre-existing damage or disease activity at study entry.

Interpretation: LLDAS attainment is associated with significant protection against flare and damage accrual in SLE. These findings validate LLDAS as an endpoint for clinical studies in SLE.

Funding: The Asia Pacific Lupus Collaboration received project support grants from UCB Pharma, GlaxoSmithKline, Janssen, Bristol-Myers Squibb, and AstraZeneca.

Associated data

ClinicalTrials.gov/NCT03138941