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 Teresa 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 & 2 others Mandana Nikpour, Eric F. Morand

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)e95-e102
Number of pages8
JournalThe Lancet Rheumatology
Volume1
Issue number2
DOIs
Publication statusPublished - Oct 2019

Cite this

Golder, Vera ; Kandane-Rathnayake, Rangi ; Huq, Molla ; Nim, Hieu T. ; Louthrenoo, Worawit ; Luo, Shue Fen ; Jan Wu, Yeong Jian ; Lateef, Aisha ; Sockalingam, Sargunan ; Navarra, Sandra Teresa V. ; Zamora, Leonid ; Hamijoyo, Laniyati ; Katsumata, Yasuhiro ; Harigai, Masayoshi ; Chan, Madelynn ; O'Neill, Sean ; Goldblatt, Fiona ; Sing Lau, Chak ; Li, Zhan Guo ; Hoi, Alberta ; Nikpour, Mandana ; Morand, Eric F. / Lupus low disease activity state as a treatment endpoint for systemic lupus erythematosus: a prospective validation study. In: The Lancet Rheumatology. 2019 ; Vol. 1, No. 2. pp. e95-e102.
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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.",
author = "Vera Golder and Rangi Kandane-Rathnayake and Molla Huq and Nim, {Hieu T.} and Worawit Louthrenoo and Luo, {Shue Fen} and {Jan Wu}, {Yeong Jian} and Aisha Lateef and Sargunan Sockalingam and Navarra, {Sandra Teresa V.} and Leonid Zamora and Laniyati Hamijoyo and Yasuhiro Katsumata and Masayoshi Harigai and Madelynn Chan and Sean O'Neill and Fiona Goldblatt and {Sing Lau}, Chak and Li, {Zhan Guo} and Alberta Hoi and Mandana Nikpour and Morand, {Eric F.}",
year = "2019",
month = "10",
doi = "10.1016/S2665-9913(19)30037-2",
language = "English",
volume = "1",
pages = "e95--e102",
journal = "The Lancet Rheumatology",
issn = "2665-9913",
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Golder, V, Kandane-Rathnayake, R, Huq, M, Nim, HT, Louthrenoo, W, Luo, SF, Jan Wu, YJ, Lateef, A, Sockalingam, S, Navarra, STV, Zamora, L, Hamijoyo, L, Katsumata, Y, Harigai, M, Chan, M, O'Neill, S, Goldblatt, F, Sing Lau, C, Li, ZG, Hoi, A, Nikpour, M & Morand, EF 2019, 'Lupus low disease activity state as a treatment endpoint for systemic lupus erythematosus: a prospective validation study', The Lancet Rheumatology, vol. 1, no. 2, pp. e95-e102. https://doi.org/10.1016/S2665-9913(19)30037-2

Lupus low disease activity state as a treatment endpoint for systemic lupus erythematosus: a prospective validation study. / Golder, Vera; Kandane-Rathnayake, Rangi; Huq, Molla; Nim, Hieu T.; Louthrenoo, Worawit; Luo, Shue Fen; Jan Wu, Yeong Jian; Lateef, Aisha; Sockalingam, Sargunan; Navarra, Sandra Teresa V.; Zamora, Leonid; Hamijoyo, Laniyati; Katsumata, Yasuhiro ; Harigai, Masayoshi ; Chan, Madelynn; O'Neill, Sean; Goldblatt, Fiona; Sing Lau, Chak; Li, Zhan Guo; Hoi, Alberta; Nikpour, Mandana; Morand, Eric F.

In: The Lancet Rheumatology, Vol. 1, No. 2, 10.2019, p. e95-e102.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Lupus low disease activity state as a treatment endpoint for systemic lupus erythematosus: a prospective validation study

AU - Golder, Vera

AU - Kandane-Rathnayake, Rangi

AU - Huq, Molla

AU - Nim, Hieu T.

AU - Louthrenoo, Worawit

AU - Luo, Shue Fen

AU - Jan Wu, Yeong Jian

AU - Lateef, Aisha

AU - Sockalingam, Sargunan

AU - Navarra, Sandra Teresa V.

AU - Zamora, Leonid

AU - Hamijoyo, Laniyati

AU - Katsumata, Yasuhiro

AU - Harigai, Masayoshi

AU - Chan, Madelynn

AU - O'Neill, Sean

AU - Goldblatt, Fiona

AU - Sing Lau, Chak

AU - Li, Zhan Guo

AU - Hoi, Alberta

AU - Nikpour, Mandana

AU - Morand, Eric F.

PY - 2019/10

Y1 - 2019/10

N2 - 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.

AB - 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.

U2 - 10.1016/S2665-9913(19)30037-2

DO - 10.1016/S2665-9913(19)30037-2

M3 - Article

VL - 1

SP - e95-e102

JO - The Lancet Rheumatology

JF - The Lancet Rheumatology

SN - 2665-9913

IS - 2

ER -