Superior Discrimination Between LLDAS and DORIS Remission with Modification of Prednisolone Dose Threshold

Eric Morand¹, Vera Golder², Worawit Louthrenoo³, Shue Fen Luo⁴, Yeong-Jian Wu⁵, Aisha Lateef⁶, Sargunan Sockalingam⁷, Sandra Navarra⁸, Leonid Zamora⁹, Laniyati Hamijoyo¹⁰, Yasuhiro Katsumata¹¹, Masayoshi Harigai¹², Madelynn Chan¹³, Sean O'Neill¹⁴, Fiona Goldblatt¹⁵, Yi-Hsing Chen¹⁶, Yanjie Hao¹⁷, Zhuoli Zhang¹⁷, Jun Kikuchi¹⁸, Tsutomu Takeuchi¹⁹, Chak Sing Lau²⁰, Zhanguo Li²¹, Alberta Hoi²², Mandana Nikpour²³ and Rangi Kandane-Rathnayake², ¹Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Australia, ²Monash University, Clayton, Victoria, Australia, ³Chiang Mai University Hospital, Muang, Thailand, ⁴Chang Gung Memorial Hospital-Linkou, Taoyuan, Taipei, Taiwan (Republic of China), ⁵Chang Gung Memorial Hospital, Guishan, Taiwan (Republic of China), ⁶National University Hospital, Singapore, Singapore, ⁷University of Malaya, Kuala Lumpur, Malaysia, ⁸University of Santo Tomas, Manila, Philippines, ⁹University of Santo Thomas, Manila, Philippines, ¹⁰University of Padjadjaran, Bandung, Indonesia, ¹¹Tokyo Women's Medical University School of Medicine, Tokyo, Japan, ¹²Department of Rheumatology, Tokyo Women’s Medical University School of Medicine, Shinjuku-ku, Tokyo, Japan, ¹³Tan Tock Seng Hospital, Singapore, Singapore, ¹⁴Sydney University, Sydney, Australia, ¹⁵Royal Adelaide Hospital, Adelaide, Australia, ¹⁶Taichung Veterans General Hospital, Taichung, Taiwan (Republic of China), ¹⁷Peking University First Hospital, Beijing, China (People's Republic), ¹⁸Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan, ¹⁹Division of Rheumatology, Department of internal Medicine, School of Medicine, Keio University, Tokyo, Japan, ²⁰Hong Kong University, Hong Kong, Hong Kong, ²¹Department of Rheumatology and Immunology, Peking University People’s Hospital, Beijing, China (People's Republic), ²²Monash University, Melbourne, Victoria, Australia, ²³The University of Melbourne at St. Vincent's Hospital, Melbourne, Victoria, Australia

Meeting: ACR Convergence 2020

Keywords: longitudinal studies, Systemic lupus erythematosus (SLE)

Session Information

Date: Friday, November 6, 2020

Title: SLE – Diagnosis, Manifestations, & Outcomes Poster I: Clinical Manifestations

Session Type: Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Treat-to-target (T2T) approaches to rheumatic disease require the definition and validation of low disease activity and remission endpoints that should be concentrically more stringent. The Lupus Low Disease Activity State (LLDAS) has been established as a low-disease activity endpoint for SLE, but multiple possible definitions for remission arise from the Definition of Remission in SLE (DORIS) framework. LLDAS and all remission definitions are associated with improved long term outcomes in terms of damage accrual and flare, but previous analyses suggested that Clinical Remission on Treatment (CROT) allowing 5mg/day prednisolone was insufficiently different from LLDAS (≤7.5 mg/day) to be used separately. Therefore, we examined a more stringent threshold, requiring daily prednisolone < 5mg (CROT< 5), a dose which requires physician and patient to change from standard 5 mg tablets.

Methods: Data from a prospective multinational cohort study of patients with SLE (ACR or SLICC criteria) undertaken in 17 centres between 2013-2017 were used. Time-dependent Cox proportional hazards models were used to compare LLDAS and DORIS definitions of remission in terms of impact on flares (SELENA flare index) and organ damage (SLICC damage index (SDI)). LLDAS and DORIS CROT were defined as described in Golder et al, 2019: CROT requires clinical SLEDAI-2K = 0 and physician global assessment (PGA) (0-3) < 0.5; CROT allows prednisolone ≤5 mg/day; whereas CROT< 5 excludes patients taking 5mg/day. LLDAS allows SLEDAI-2K ≤4 with no new/major organ activity, PGA ≤1, and prednisolone ≤7.5 mg.

Results:

18.659 visits of 2,384 patients collected over a mean (SD) 2.26 (1.34) years were analysed. LLDAS was attained in 8,883 (47.6%) visits, CROT in 6,521 (35.0%) and CROT< 5 in 4,373 (23.4%; mean (SD) daily prednisolone 1.16 (1.32) mg)), confirming that lowering the prednisolone threshold resulted in a more stringent remission definition compared to CROT. LLDAS was protective from flare and damage accrual whether assessed visit by visit or cumulatively using a 50% of time exposed threshold. Visit by visit analysis revealed that CROT< 5 was associated with slightly greater protection from future flare (HR (95% CI) 0.48 (0.42,0.54)) than CROT (HR 0.54 (0.49,0.60)). Similarly, future damage risk was slightly less with CROT< 5 (HR 0.60 (0.47,0.78)) than CROT (0.62 (0.50,0.78)). When measured cumulatively using a 50% of time exposed threshold, CROT < 5 was more protective from flare (HR 0.40 (0.35,0.46)) than CROT (0.45 (0.40,0.50)) but not from damage. The effect of cumulative LLDAS on damage accrual overtime remained significant after excluding patients in CROT< 5 (HR 0.74 (0.57,0.96), p=0.022) but not after excluding CROT. Cumulative LLDAS was independently associated with flare excluding either CROT or CROT< 5.

Conclusion: A remission definition requiring a ceiling dose of prednisolone less than 5 mg (CROT< 5) is more stringent than CROT (allowing 5 mg/day) and its effects are independent of LLDAS, while CROT is insufficiently distinct from LLDAS. Confirmation in other cohorts should be undertaken prior to agreeing on a definition of remission for SLE.

Disclosure: E. Morand, AstraZeneca, 2, 5, 8, Bristol-Myers Squibb, 2, 5, Eli Lilly, 2, 5, GlaxoSmithKline, 2, 5, Janssen, 2, 5, Merck Serono, 2, 5, Neovacs, 5, Sandoz, 5, Novartis, 8, AbbVie, 5, Amgen, 5, Biogen, 5; V. Golder, None; W. Louthrenoo, None; S. Luo, None; Y. Wu, None; A. Lateef, None; S. Sockalingam, None; S. Navarra, Eli Lilly, 5, 8, Astra-Zeneca, 5, 8, Astellas, 8, Janssen, 5, 8, Novartis, 8, Pfizer, 8, Biogen, 2, 5; L. Zamora, None; L. Hamijoyo, None; Y. Katsumata, None; M. Harigai, AbbVie Japan GK, 1, 2, Asahi Kasei Corp., 1, Astellas Pharma Inc., 1, Ayumi Pharmaceutical Co. Ltd., 1, 2, Bristol Myers Squibb Co., Ltd, 1, 2, 3, Chugai Pharmaceutical Co. Ltd., 1, 2, Daiichi-Sankyo, Inc., 1, Eisai Pharmaceutical, 1, 2, Nippon Kayaku Co. Ltd., 1, Mitsubishi Tanabe Pharma Co., 1, Taisho Pharmaceutical Co. Ltd., 1, Takeda Pharmaceutical Co. Ltd., 1, 2, Eli Lilly Japan K.K, 1, Pfizer Japan Inc, 1, AbbVie, 1; M. Chan, None; S. O'Neill, None; F. Goldblatt, None; Y. Chen, None; Y. Hao, None; Z. Zhang, None; J. Kikuchi, None; T. Takeuchi, Astellas Pharma Inc., 2, 5, 8, Daiichi Sankyo Company, Limited, 2, 5, 8, Takeda Pharmaceutical Company Limited, 2, 5, 8, AbbVie GK., 2, 5, 8, Asahi Kasei Pharma Corporation, 2, 5, 8, Mitsubishi Tanabe Pharma Corporation, 2, 5, 8, Eisai Co., Ltd., 2, 5, 8, Nippon Kayaku Co., Ltd., 2, 5, 8, Chugai Pharmaceutical Co., Ltd., 2, 5, 8, Eli Lily Japan K.K, 2, 5, 8, Gilead Sciences, Inc., 2, 5, 8, Pfizer Japan, Inc., 2, 5, 8, Bristol-Myers Squibb, 2, 5, 8, AYUMI Pharmaceutical Corporation, 2, 5, 8, Novartis Pharma K.K., 2, 5, 8, UCB, 2, 5, 8, Dainippon Sumitomo Co., 2, 5, 8, Shionogi & Co., Ltd., 2, 5, 8; C. Lau, None; Z. Li, None; A. Hoi, None; M. Nikpour, Actelion, 2, 5, 8, GSK, 2, 5, 8, Boehringer Ingelheim, 5; R. Kandane-Rathnayake, None.

To cite this abstract in AMA style:

Morand E, Golder V, Louthrenoo W, Luo S, Wu Y, Lateef A, Sockalingam S, Navarra S, Zamora L, Hamijoyo L, Katsumata Y, Harigai M, Chan M, O'Neill S, Goldblatt F, Chen Y, Hao Y, Zhang Z, Kikuchi J, Takeuchi T, Lau C, Li Z, Hoi A, Nikpour M, Kandane-Rathnayake R. Superior Discrimination Between LLDAS and DORIS Remission with Modification of Prednisolone Dose Threshold [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/superior-discrimination-between-lldas-and-doris-remission-with-modification-of-prednisolone-dose-threshold/. Accessed .

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