Validation of the Lupus Low Disease Activity State (LLDAS) in the Asia Pacific Region

Overview

Lupus Low Disease Activity State (LLDAS) study is an international, multi-centre prospective study, developed by the Asia Pacific Lupus Collaboration (APLC) to investigate whether the attainment of LLDAS is associated with improved outcomes in patients with Systemic Lupus Erythematosus (SLE). SLE, or lupus, is the archetypal multisystem autoimmune disease, with an estimated incidence of 5-50 cases per 100,000 people. Patients with SLE, usually young women, suffer a marked loss of life expectancy, and severe morbidity, due to a heterogeneous range of clinical manifestations caused by autoimmune-mediated inflammation of multiple organs. The most severe manifestations of SLE are the accrual of irreversible organ damage, especially renal and central nervous system (CNS) involvement. As there is no effective targeted monotherapy for SLE, patients also suffer severe toxicity from the use of glucocorticoids and broad-spectrum immunosuppressive therapies. Despite combination therapy with current drugs, many studies show that the majority of patients suffer inadequate disease control and inexorably accrue permanent organ damage over time. The diversity of clinical features of active SLE has made quantification of disease activity problematic. Although there are a number of published systems in use to measure SLE disease activity, there are widely acknowledged problems with these instruments. Published definitions of remission are so stringent that they are met by less than 5% of patients. This lead to the realisation that rather than lupus remission, a lupus low disease activity state target may be more feasible, and that patients with low disease activity are more homogeneous than patients with active disease. Thus, the development of a definition of lupus low disease activity, which is feasible and has face validity, escapes the complexity of attempts to quantify heterogeneous states of active disease. In this study, the investigators will prospectively collect longitudinal data on consecutive SLE patients at each centre to evaluate the LLDAS definition. Protection from organ damage accrual as the primary endpoint.

Detailed description

In this study, patients with SLE will be followed for \~ 5 years. Regular recordings of the data needed to score LLDAS (disease activity and treatment domains, see Franklyn L et al, Ann Rheum Dis 2016) will be collected, as well as annual recording of lupus-related damage using the SLICC\_ACR Damage Index (SDI) and quality of life using the Short Form 36 version 2 (SF36v2).

At conclusion of primary data collection, the associate of LLDAS attainment, or sustained attainment, with protection from organ damage accrual will be ascertained.

Primary outcome measures

• SLICC-ACR Damage Index [Time frame: Approximately 5-10 years]

Secondary outcome measures (2)

• SFv2-36 [Time frame: Approximately 5-10 years]
• Mortality [Time frame: Approximately 5-10 years]

Eligibility criteria

Inclusion criteria

• All patients have to meet either the 1997 American College of Rheumatology (ACR) Modified Classification Criteria for SLE, with at least four of the 11 items; or alternatively, fulfil the Systemic Lupus International Collaborating Clinics (SLICC) 2012 Classification Criteria, with at least four of the 17 items (at least one clinical and one immunological criterion) or with lupus nephritis in the presence of at least one immunological criteria. Patients can be either newly diagnosed or longstanding lupus patients.

All patients must be over the age of 18 and competent to provide written consent.

Exclusion criteria

• Patients less than 18 years of age and patients who are unable to consent are excluded from the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Australia · 4 centers

• Rheumatology Unit, Royal Adelaide Hospital — Adelaide
• Department of Rheumatology, Flinders Medical Centre — Adelaide
• School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing & Health Scienc — Clayton
• Department of Rheumatology, St Vincent's Hospital (Melbourne) — Fitzroy

Japan · 3 centers

• The First Department of Internal Medicine, School of Medicine, University of Occupational — Kitakyushu
• Division of Rheumatology, Department of Internal Medicine, School of Medicine, Keio Univer — Tokyo
• Institute of Rheumatology, Tokyo Women's Medical University — Tokyo

China · 2 centers

• Department of Rheumatology and Immunology, People's Hospital Peking University Health Scie — Beijing
• Rheumatology and Immunology department, Peking University First Hospital — Beijing

Philippines · 2 centers

• Joint and Bone Center, University of Santo Tomas Hospital — Manila
• University of the Philippines — Quezon City

Singapore · 2 centers

• Rheumatology Division, University Medical Cluster, National University Hospital — Singapore
• Department of Rheumatology, Allergy & Immunology, Tan Tock Seng Hospital — Tan Tock Seng

Taiwan · 2 centers

• Department of Rheumatology, Allergy and Immunology Chang Gung Memorial Hospital Chang Gung — Guishan
• Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital — Taichung

Hong Kong · 1 center

• Division of Rheumatology & Clinical Immunology, Department of Medicine, Queen Mary Hospita — Pok Fu Lam

Indonesia · 1 center

• Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Padjadjara — Bandung

South Korea · 1 center

• Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases — Seoul

Sri Lanka · 1 center

• Division of Nephrology, Teaching Hospital Kandy, Sri Lanka — Kandy

Thailand · 1 center

• Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai — Chiang Mai

Publications

• Golder V, Huq M, Franklyn K, Calderone A, Lateef A, Lau CS, Lee ALH, Navarra STV, Godfrey T, Oon S, Hoi AYB, Morand EF, Nikpour M. Does expert opinion match the operational definition of the Lupus Low Disease Activity State (LLDAS)? A case-based construct validity study. Semin Arthritis Rheum. 2017 Jun;46(6):798-803. doi: 10.1016/j.semarthrit.2017.01.007. Epub 2017 Jan 18. PMID 28216192
• Golder V, Kandane-Rathnayake R, Hoi AY, Huq M, Louthrenoo W, An Y, Li ZG, Luo SF, Sockalingam S, Lau CS, Mok MY, Lateef A, Franklyn K, Morton S, Navarra ST, Zamora L, Wu YJ, Hamijoyo L, Chan M, O'Neill S, Goldblatt F, Nikpour M, Morand EF; Asia-Pacific Lupus Collaboration. Association of the lupus low disease activity state (LLDAS) with health-related quality of life in a multinational prospective PMID 28320433
• Golder V, Kandane-Rathnayake R, Hoi AY, Huq M, Louthrenoo W, An Y, Li ZG, Luo SF, Sockalingam S, Lau CS, Lee AL, Mok MY, Lateef A, Franklyn K, Morton S, Navarra ST, Zamora L, Wu YJ, Hamijoyo L, Chan M, O'Neill S, Goldblatt F, Morand EF, Nikpour M; Asia-Pacific Lupus Collaboration. Frequency and predictors of the lupus low disease activity state in a multi-national and multi-ethnic cohort. Arthriti PMID 27829463
• Franklyn K, Lau CS, Navarra SV, Louthrenoo W, Lateef A, Hamijoyo L, Wahono CS, Chen SL, Jin O, Morton S, Hoi A, Huq M, Nikpour M, Morand EF; Asia-Pacific Lupus Collaboration. Definition and initial validation of a Lupus Low Disease Activity State (LLDAS). Ann Rheum Dis. 2016 Sep;75(9):1615-21. doi: 10.1136/annrheumdis-2015-207726. Epub 2015 Oct 12. PMID 26458737
• Kandane-Rathnayake R, Golder V, Louthrenoo W, Luo SF, Jan Wu YJ, Li Z, An Y, Lateef A, Sockalingam S, Navarra SV, Zamora L, Hamijoyo L, Katsumata Y, Harigai M, Chan M, O'Neill S, Goldblatt F, Hao Y, Zhang Z, Al-Saleh J, Khamashta M, Takeuchi T, Tanaka Y, Bae SC, Lau CS, Hoi A, Nikpour M, Morand EF. Development of the Asia Pacific Lupus Collaboration cohort. Int J Rheum Dis. 2019 Mar;22(3):425-433. PMID 30398013
• Golder V, Kandane-Rathnayake R, Huq M, Nim HT, Louthrenoo W, Luo SF, Wu YJ, Lateef A, Sockalingam S, Navarra SV, Zamora L, Hamijoyo L, Katsumata Y, Harigai M, Chan M, O'Neill S, Goldblatt F, Lau CS, Li ZG, Hoi A, Nikpour M, Morand EF; Asia-Pacific Lupus Collaboration. Lupus low disease activity state as a treatment endpoint for systemic lupus erythematosus: a prospective validation study. Lancet R PMID 38229349
• Golder V, Kandane-Rathnayake R, Huq M, Louthrenoo W, Luo SF, Wu YJ, Lateef A, Sockalingam S, Navarra SV, Zamora L, Hamijoyo L, Katsumata Y, Harigai M, Chan M, O'Neill S, Goldblatt F, Lau CS, Li ZG, Hoi A, Nikpour M, Morand EF; Asia Pacific Lupus Collaboration. Evaluation of remission definitions for systemic lupus erythematosus: a prospective cohort study. Lancet Rheumatol. 2019 Oct;1(2):e103-e110 PMID 38229337
• Kandane-Rathnayake R, Zolio L, Choi JI, Golder V, Louthrenoo W, Chen YH, Cho J, Lateef A, Hamijoyo L, Luo SF, Wu YJ, Navarra SV, Zamora L, Li Z, Sockalingam S, Katsumata Y, Harigai M, Hao Y, Zhang Z, Chan M, Kikuchi J, Takeuchi T, Oon S, Bae SC, Goldblatt F, O'Neill S, Ng KPL, Law A, Basnayake BMDB, Tugnet N, Kumar S, Tee C, Tee M, Tanaka Y, Lau CS, Hoi A, Nikpour M, Morand EF. Predictors of damag PMID 41252474

Identifiers

NCT: NCT03138941 · APLC LLDAS Study

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗