Impact of low disease activity, remission, and complete remission on flares following tapering of corticosteroids and immunosuppressive therapy in patients with systemic lupus erythematous: a multinational cohort study

Cho J 1 , Shen L 2 , Huq M 3 , Kandane-Rathnayake R 4 , Golder V 4 , Louthrenoo W 5 Show all authors , Chen YH 6 , Hamijoyo L 7 , Luo SF 8 , Wu YJ 8 , Zamora L 9 , Li Z 10 , Sockalingam S 11 , Katsumata Y 12 , Harigai M 12 , Hao Y 13 , Zhang Z 13 , Basnayake D 14 , Chan M 15 , Kikuchi J 16 , Takeuchi T 17 , Bae SC 18 , Oon S 19 , O'Neill S 20 , Goldblatt F 21 , Ng KPL 22 , Law A 23 , Tugnet N 24 , Kumar S 25 , Tee C 26 , Tee M 26 , Ohkubo N 27 , Tanaka Y 27 , Navarra SV 9 , Lau CS 28 , Hoi A 4 , Morand EF 4 , Nikpour M 3 , Lateef A 29 , Asia-Pacific Lupus Collaboration

Affiliations 

  • 1 National University Hospital, Singapore. Electronic address: jiacai_cho@nuhs.edu.sg
  • 2 National University of Singapore, Singapore
  • 3 The University of Melbourne, Melbourne, VIC, Australia
  • 4 Monash University, Melbourne, VIC, Australia
  • 5 Chiang Mai University, Chiang Mai, Thailand
  • 6 Taichung Veterans General Hospital, Taichung, Taiwan
  • 7 University of Padjadjaran, Bandung, Indonesia
  • 8 Chang Gung Memorial Hospital, Taoyuan, Taiwan
  • 9 University of Santo Tomas Hospital, Manila, Philippines
  • 10 People's Hospital Peking University Health Sciences Centre, Beijing, China
  • 11 University of Malaya, Kuala Lumpur, Malaysia
  • 12 Tokyo Women's Medical University, Tokyo, Japan
  • 13 Peking University First Hospital, Beijing, China
  • 14 Teaching Hospital, Kandy, Sri Lanka
  • 15 Tan Tock Seng Hospital, Singapore
  • 16 Keio University and Saitama Medical University, Saitama, Tokyo, Japan
  • 17 Keio University, Tokyo, Japan
  • 18 Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea
  • 19 Department of Medicine, The University of Melbourne at St Vincent's Hospital, Fitzroy, VIC, Australia
  • 20 Department of Medicine, University of New South Wales, Kensington, NSW, Australia
  • 21 Royal Adelaide Hospital and Flinders Medical Centre, Adelaide, SA, Australia
  • 22 Waitemata District Health Board, Auckland, New Zealand
  • 23 Singapore General Hospital, Singapore
  • 24 Auckland District Health Board, Auckland, New Zealand
  • 25 Middlemore Hospital, Auckland, New Zealand
  • 26 University of the Philippines, Manila, Philippines
  • 27 University of Occupational and Environmental Health, Kitakyushu, Japan
  • 28 University of Hong Kong, Hong Kong Special Administrative Region, China
  • 29 National University Hospital, Singapore
Lancet Rheumatol, 2023 Oct;5(10):e584-e593.
PMID: 38251484 DOI: 10.1016/S2665-9913(23)00209-6

Abstract

BACKGROUND: Targets of treatment for systemic lupus erythematosus (SLE) include the Lupus Low Disease Activity State (LLDAS), remission, and complete remission. Whether treatment can be tapered after attaining these targets and whether tapering is safer in patients in complete remission compared with LLDAS are unknown. We aimed to assess the odds of disease flares after treatment tapering in stable disease, versus continuing the same therapy. We also aimed to examine whether tapering in complete remission resulted in fewer flares or longer time to flare compared with tapering in LLDAS or remission.

METHODS: This multinational cohort study was conducted at 25 sites across 13 Asia-Pacific countries. We included adult patients aged 18 years or older with stable SLE who were receiving routine clinical care, had two or more visits and had attained stable disease at one or more visits. We categorised stable disease into: LLDAS (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K] score ≤4, Physician Global Assessment [PGA] ≤1, and prednisolone ≤7·5 mg/day); Definitions of Remission in SLE (DORIS) remission (clinical SLEDAI-2K score 0, PGA <0·5, and prednisolone ≤5 mg/day); or complete remission on therapy (SLEDAI-2K score 0, PGA <0·5, and prednisolone ≤5 mg/day). Stable disease categories were mutually exclusive. Tapering was defined as any decrease in dose of corticosteroids or immunosuppressive therapy (mycophenolate mofetil, calcineurin inhibitors, azathioprine, leflunomide, or methotrexate). Using multivariable generalised estimating equations, we compared flares (SELENA-SLEDAI Flare Index) at the subsequent visit after drug tapering. We used generalised estimating equations and Cox proportional hazard models to compare tapering attempts that had begun in LLDAS, remission, and complete remission.

FINDINGS: Between May 1, 2013, and Dec 31, 2020, 4106 patients were recruited to the cohort, 3002 (73·1%) of whom were included in our analysis. 2769 (92·2%) participants were female, 233 (7·8%) were male, and 2636 (88·1%) of 2993 with ethnicity data available were Asian. The median age was 39·5 years (IQR 29·0-50·0). There were 14 808 patient visits for patients in LLDAS, or remission or complete remission, of which 13 140 (88·7%) entered the final multivariable model after excluding missing data. Among the 9863 visits at which patients continued the same therapy, 1121 (11·4%) flared at the next visit, of which 221 (19·7%) were severe flares. Of the 3277 visits at which a patient received a tapering of therapy, 557 (17·0%) flared at the next visit, of which 120 (21·5%) were severe flares. Tapering was associated with higher odds of flare compared with continuing the same therapy (odds ratio [OR] 1·24 [95% CI 1·10-1·39]; p=0·0005). Of 2095 continuous tapering attempts, 860 (41·1%) were initiated in LLDAS, 596 (28·4%) in remission, and 639 (30·5%) in complete remission. Tapering initiated in LLDAS (OR 1·37 [95% CI 1·03-1·81]; p=0·029) or remission (1·45 [1·08-1·94]; p=0·013) had higher odds of flare in 1 year compared with complete remission. Tapering in LLDAS (hazard ratio 1·24 [95% CI 1·04-1·48]; p=0·016) or remission (1·30 [1·08-1·56]; p=0·0054) had a significantly shorter time to first flare than tapering initiated in complete remission. Attaining sustained LLDAS, remission, or complete remission for at least 6 months just before the time of taper was associated with lower odds of flare at next visit, flares in 1 year, and longer time to flare.

INTERPRETATION: Tapering of corticosteroids or immunosuppressive therapy in patients with stable SLE was associated with excess flares. Our findings suggest that drug tapering should be carefully considered, weighing the risks and benefits, and is best exercised in complete (clinical and serological) remission and after maintaining stable disease for at least 6 months.

FUNDING: AstraZeneca, BMS, Eli Lily, Janssen, Merck Serono, GSK, and UCB.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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