Multicenter Study

. 2024 Aug;6(8):e528-e536.

doi: 10.1016/S2665-9913(24)00121-8. Epub 2024 Jun 11.

Association of sustained lupus low disease activity state with improved outcomes in systemic lupus erythematosus: a multinational prospective cohort study

Vera Golder¹, Rangi Kandane-Rathnayake², Ning Li², Worawit Louthrenoo³, Yi-Hsing Chen⁴, Jiacai Cho⁵, Aisha Lateef⁶, Laniyati Hamijoyo⁷, Shue Fen Luo⁸, Yeong-Jian Wu⁸, Sandra V Navarra⁹, Leonid Zamora⁹, Zhanguo Li¹⁰, Sargunan Sockalingam¹¹, Yasuhiro Katsumata¹², Masayoshi Harigai¹², Yanjie Hao¹³, Zhuoli Zhang¹⁴, Duminda Basnayake¹⁵, Madelynn Chan¹⁶, Jun Kikuchi¹⁷, Tsutomu Takeuchi¹⁸, Sang-Cheol Bae¹⁹, Fiona Goldblatt²⁰, Shereen Oon²¹, Sean O'Neill²², Kristine Ng²³, Annie Law²⁴, Nicola Tugnet²⁵, Sunil Kumar²⁶, Cherica Tee²⁷, Michael Tee²⁸, Naoaki Ohkubo²⁹, Yoshiya Tanaka²⁹, Chak Sing Lau³⁰, Alberta Hoi², Mandana Nikpour³¹, Eric F Morand²; Asia Pacific Lupus Collaboration

Affiliations

¹ Department of Medicine, Sub-Faculty of Clinical and Molecular Medicine, Monash University, Melbourne, VIC, Australia. Electronic address: vera.golder@monash.edu.
² Department of Medicine, Sub-Faculty of Clinical and Molecular Medicine, Monash University, Melbourne, VIC, Australia.
³ Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
⁴ Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan.
⁵ Rheumatology Division, National University Hospital, Singapore.
⁶ Rheumatology Division, National University Hospital, Singapore; Department of Medicine, Woodlands Health, Singapore.
⁷ Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, University of Padjadjaran, Bandung, West Java, Indonesia.
⁸ Department of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Guishan Township, Taoyuan County, Taiwan.
⁹ Section of Rheumatology, University of Santo Tomas Hospital, Manila, Philippines.
¹⁰ Department of Rheumatology and Immunology, People's Hospital Peking University Health Sciences Centre, Beijing, China.
¹¹ Department of Medicine, Faculty of Medicine, University of Malaya Medical Centre, Kuala Lumpur, Malaysia.
¹² Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan.
¹³ Rheumatology and Immunology Department, Peking University First Hospital, Beijing, China; Department of Rheumatology, St Vincent's Hospital Melbourne, VIC, Australia.
¹⁴ Rheumatology and Immunology Department, Peking University First Hospital, Beijing, China.
¹⁵ Division of Nephrology, Teaching Hospital, Kandy, Sri Lanka.
¹⁶ Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore.
¹⁷ School of Medicine, Keio University, Tokyo, Japan.
¹⁸ School of Medicine, Keio University, Tokyo, and Saitama Medical University, Saitama, Japan.
¹⁹ Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases and Hanyang University Institute for Rheumatology Research, Hanyang Institute of Bioscience and Biotechnology, Seoul, South Korea.
²⁰ Department of Rheumatology, Flinders Medical Centre, Adelaide, SA, Australia.
²¹ Department of Rheumatology, St Vincent's Hospital, Melbourne, VIC, Australia.
²² Department of Rheumatology, Liverpool Hospital, Sydney, NSW, Australia; Department of Rheumatology, Royal North Shore Hospital, Sydney, NSW, Australia; Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; Faculty of Medicine, the University of Sydney, Sydney, NSW, Australia.
²³ Department of Medicine, North Shore Hospital, Health New Zealand Waitemata, Te Whatu Ora, Auckland, New Zealand.
²⁴ Department of Rheumatology, Singapore General Hospital, Singapore.
²⁵ Department of Rheumatology, Health New Zealand Auckland, Te Whatu Ora (Greenlane Clinical Centre) Auckland, New Zealand.
²⁶ Department of Rheumatology, Health New Zealand Counties Manukau, Te Whatu Ora (Middlemore Hospital), Auckland, New Zealand.
²⁷ Department of Paediatrics, College of Medicine, University of the Philippines, Manila, Philippines.
²⁸ Department of Physiology, College of Medicine, University of the Philippines, Manila, Philippines.
²⁹ The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
³⁰ Division of Rheumatology and Clinical Immunology, Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong Special Administrative Region, China.
³¹ Faculty of Medicine, the University of Sydney, Sydney, NSW, Australia.

PMID: 38876129
DOI: 10.1016/S2665-9913(24)00121-8

Multicenter Study

Association of sustained lupus low disease activity state with improved outcomes in systemic lupus erythematosus: a multinational prospective cohort study

Vera Golder et al. Lancet Rheumatol. 2024 Aug.

. 2024 Aug;6(8):e528-e536.

doi: 10.1016/S2665-9913(24)00121-8. Epub 2024 Jun 11.

Authors

Affiliations

¹ Department of Medicine, Sub-Faculty of Clinical and Molecular Medicine, Monash University, Melbourne, VIC, Australia. Electronic address: vera.golder@monash.edu.
² Department of Medicine, Sub-Faculty of Clinical and Molecular Medicine, Monash University, Melbourne, VIC, Australia.
³ Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
⁴ Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan.
⁵ Rheumatology Division, National University Hospital, Singapore.
⁶ Rheumatology Division, National University Hospital, Singapore; Department of Medicine, Woodlands Health, Singapore.
⁷ Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, University of Padjadjaran, Bandung, West Java, Indonesia.
⁸ Department of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Guishan Township, Taoyuan County, Taiwan.
⁹ Section of Rheumatology, University of Santo Tomas Hospital, Manila, Philippines.
¹⁰ Department of Rheumatology and Immunology, People's Hospital Peking University Health Sciences Centre, Beijing, China.
¹¹ Department of Medicine, Faculty of Medicine, University of Malaya Medical Centre, Kuala Lumpur, Malaysia.
¹² Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan.
¹³ Rheumatology and Immunology Department, Peking University First Hospital, Beijing, China; Department of Rheumatology, St Vincent's Hospital Melbourne, VIC, Australia.
¹⁴ Rheumatology and Immunology Department, Peking University First Hospital, Beijing, China.
¹⁵ Division of Nephrology, Teaching Hospital, Kandy, Sri Lanka.
¹⁶ Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore.
¹⁷ School of Medicine, Keio University, Tokyo, Japan.
¹⁸ School of Medicine, Keio University, Tokyo, and Saitama Medical University, Saitama, Japan.
¹⁹ Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases and Hanyang University Institute for Rheumatology Research, Hanyang Institute of Bioscience and Biotechnology, Seoul, South Korea.
²⁰ Department of Rheumatology, Flinders Medical Centre, Adelaide, SA, Australia.
²¹ Department of Rheumatology, St Vincent's Hospital, Melbourne, VIC, Australia.
²² Department of Rheumatology, Liverpool Hospital, Sydney, NSW, Australia; Department of Rheumatology, Royal North Shore Hospital, Sydney, NSW, Australia; Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; Faculty of Medicine, the University of Sydney, Sydney, NSW, Australia.
²³ Department of Medicine, North Shore Hospital, Health New Zealand Waitemata, Te Whatu Ora, Auckland, New Zealand.
²⁴ Department of Rheumatology, Singapore General Hospital, Singapore.
²⁵ Department of Rheumatology, Health New Zealand Auckland, Te Whatu Ora (Greenlane Clinical Centre) Auckland, New Zealand.
²⁶ Department of Rheumatology, Health New Zealand Counties Manukau, Te Whatu Ora (Middlemore Hospital), Auckland, New Zealand.
²⁷ Department of Paediatrics, College of Medicine, University of the Philippines, Manila, Philippines.
²⁸ Department of Physiology, College of Medicine, University of the Philippines, Manila, Philippines.
²⁹ The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
³⁰ Division of Rheumatology and Clinical Immunology, Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong Special Administrative Region, China.
³¹ Faculty of Medicine, the University of Sydney, Sydney, NSW, Australia.

PMID: 38876129
DOI: 10.1016/S2665-9913(24)00121-8

Abstract

Background: Validation of protective associations of the lupus low disease activity state (LLDAS) against flare, irreversible damage, health-related quality of life, and mortality has enabled the adoption of treat-to-target strategies in patients with systemic lupus erythematosus (SLE). Previous validation studies were of short duration, limiting the ability to detect longer term signals in flare rate and irreversible damage. In addition, previous studies have focused on percent time at target, rather than actual periods of time that are more useful in clinical practice and trials. We assessed long-term protective associations of LLDAS and remission, and specifically examined protective thresholds of sustained LLDAS and remission.

Methods: Patients aged 18 years or older with SLE were followed up from May 1, 2013, to Dec 31, 2020 in a prospective, multinational, longitudinal cohort study. Patients were recruited from 25 centres in 12 countries. Multi-failure time-to-event analyses were used to assess the effect of sustained LLDAS on irreversible damage accrual (primary outcome; measured with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index) and flare (key secondary outcome; measured with the SELENA Flare Index), with dose exposure and threshold effects studied. Sustained LLDAS or remission were defined as two or more consecutive visits over at least 3 months in the respective state. This study is registered with ClinicalTrials.gov, NCT03138941.

Findings: 3449 patients were followed up for a median of 2·8 years (IQR 1·1-5·6), totalling 37 662 visits. 3180 (92·2%) patients were women, and 3031 (87·9%) were of Asian ethnicity. 2506 (72·7%) patients had sustained LLDAS at least once. Any duration of sustained LLDAS or remission longer than 3 months was associated with reduced damage accrual (LLDAS: hazard ratio 0·60 [95% CI 0·51-0·71], p<0·0001; remission: 0·66 [0·57-0·76], p<0·0001) and flare (LLDAS: 0·56 [0·51-0·63], p<0·0001; remission: 0·66 [0·60-0·73], p<0·0001), and increasing durations of sustained LLDAS corresponded to increased protective associations. Sustained DORIS remission or steroid-free remission were less attainable than LLDAS.

Interpretation: We observed significant protective associations of LLDAS and remission against damage accrual and flare, establish a threshold of 3 months sustained LLDAS or remission as protective, and demonstrate deepening protection with longer durations of sustained LLDAS or remission.

Funding: The Asia Pacific Lupus Collaboration receives project support grants from AstraZeneca, Bristol Myers Squibb, EMD Sereno, GSK, Janssen, Eli Lilly, and UCB.

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Conflict of interest statement

Declaration of interests RK-R received grants from GSK and Novartis. SVN received consulting fees from Biogen, Boehringer Ingelheim, Astra Zeneca, Idorsia; payment for lectures from AstraZeneca, Boehringer Ingelheim, GSK, and Roche; participation in advisory board for Biogen; and leadership of societies, unpaid (CEO of Rheumatology Educational Trust Foundation, and Head of the SLE Special Interest Group at the Philippine Rheumatology Association). ZL received consulting fees from Pfizer, Roche, Janssen, Abbott, AbbVie, Bristol Myers Squibb, MSD, Celgene, Eli Lilly, GSK, Novartis, and UCB, and has royalties with Pfizer, Roche, Janssen, Abbott, AbbVie, Bristol Myers Squibb, MSD, Celgene, Eli Lilly, GSK, Novartis, and UCB. SS received consulting fees from Pfizer, AstraZeneca, and ZP Therapeutics. YK received payment or honoraria from GlaxoSmithKline, AstraZeneca, Sanofi, Pfizer Japan, Janssen Pharmaceutical, Chugai Pharmaceutical, Asahi Kasei Pharma, Astellas Pharma, and Mitsubishi Tanabe Pharma Corporation. MH received institutional research grants from GSK and Novartis; and honoraria for lectures from AstraZeneca and Astellas Pharma. ZZ received payment or honoraria from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GSK, Novartis, Pfizer, Roche, Sanofi, Janssen, and UCB; and participation in advisory board for Beigene. JK received speaker fees from GSK and Asahi Kasei. TT received grants from Astellas, Asahi Kasei, Chugai, and Mitsubishi Tanabe, and consulting fees from Astellas and Chugai. FG is Director of the Board of the Australian Rheumatology Association. KN received Advisory Board participation fees from AbbVie. YT received research grants from Boehringer Ingelheim, Taisho, and Chugai; and speaker fees or honoraria from AbbVie, Eisai, Chugai, Eli Lilly, Boehringer Ingelheim, GSK, Taisho, AstraZeneca, Daiichi-Sankyo, Gilead, Pfizer, UCB, Asahi-kasei, and Astellas. AH received a research grant from AstraZeneca; consulting fees from EUSA Pharma (UK); and speaker fees or honoraria from Limbic, Novartis, Moose Republic, AbbVie, and Eli Lilly. MN received an Investigator Grant from the National Health and Medical Research Council of Australia (NHMRC GNT1176538); research grants from Janssen and Boehringer Ingelheim; consulting fees from AstraZeneca and GSK; honoraria for presentations from AstraZeneca, GSK, and Boehringer Ingelheim; and support for conference attendance from Boehringer Ingelheim. EFM received consulting fees from AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, Genetech, Janssen, Novartis, Servier, and EMD Serono. All other authors declare no competing interests.

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Association of sustained lupus low disease activity state with improved outcomes in systemic lupus erythematosus: a multinational prospective cohort study

Affiliations

Association of sustained lupus low disease activity state with improved outcomes in systemic lupus erythematosus: a multinational prospective cohort study

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