Evaluation and Prediction of Relapse Risk in Stable Systemic Lupus Erythematosus Patients after Glucocorticoid Withdrawal (PRESS): An Open- Label, Multicentre, Non-Inferiority, Randomized Controlled Study in China

Background: Low dose glucocorticoid (GC) maintenance in stable systemic lupus erythematosus (SLE) is universally adopted to prevent disease relapse which is associated with increased accumulated disease damage. The relapse risk of glucocorticoid withdrawal in stable SLE patients and whether hydroxychloroquine (HCQ) can substitute for GC as maintenance are unclear.Methods: The PRESS trial is a multicentre, 33-week, open-label, three-arm, non-inferiority design, randomized controlled trial conducted in China. SLE patients without severe organ disfunction and with sustained stabilized disease for more than one year who were maintained on low-dose GC plus HCQ therapy, were screened for eligibility. Qualified patients were sequentially recruited and assigned to three groups. Drug-free Group: both GC and HCQ withdrawal management; HCQ Group: discontinued GC but maintained HCQ dosage; Dual Maintenance Group: both GC and HCQ continued without change. The primary endpoint was to compare the proportion of patients experiencing a flare as defined by the SELENA-­SLEDAI flare index (SFI) by week 33. Two parallel non-inferiority analysis were performed (Drug-free Group vs. Dual Maintenance Group and HCQ Group vs. Dual Maintenance Group) to explore the difference of relapse risk. This trial is registered with ClinicalTrials.gov, NCT 02842814.Findings: From November 3rd, 2016 through August 13th, 2021, 352 patients fulfilling the inclusion criteria were randomized, and a total of 333 participants who practically implemented the intervention according to the protocol after randomization were analysed. The average age was 37.35±10.34, and the gender ratio of F:M being 21.2:1. The flare rates in the three groups (Drug-free Group, HCQ Group, and Dual Maintenance Group) were 26.1%, 11.2% and 4.7%, respectively. Compared with Dual Maintenance Group, Drug-free Group failed to achieved non-inferiority significance in relapse rate (rate difference 21.4%; 95% CI 11.4%-31.4%; Pnon-inferiority=0.2381), whereas HCQ Group achieved noninferiority in the relapse rate as compared with Dual Maintenance Group (rate difference 6.5%; 95% CI 1.4%-14.4%; Pnon-inferiority=0.0336). HCQ Group also exhibited fewer flares than Drug-free Group (P=0.0059). The SLE damage index and adverse events were similar among all three groups.Interpretation: Over two-thirds of long-term stable and quiescent SLE patients could enjoy GC-free or even drug-free for at least 33 weeks when sustained remission had obtained over 1 year. HCQ maintenance may exert a protective role in preventing disease relapse after GC withdrawal. Keywords: relapse risk; systemic lupus erythematosus; glucocorticoid withdrawal; hydroxychloroquine maintenanceTrial Registration: This trial is registered with ClinicalTrials.gov, NCT 02842814.Funding: This study was supported by the National Natural Science Foundation of China (82230060, 81788101, 82271856, 82071840), the Key R&D plan of the Ministry of Science and Technology (2022YFC3602000), Chinese Academy of Medical Science Innovation Fund (CIFMS 2020-I2M-C & T-A-002, 2021-1-I2M-017, 2021-1-I2M-047), and the National High-Level Hospital Clinical Research Funding (2022-PUMCH-C-039, 2022-PUMCH-B-013, 2022-PUMCH-A-108, BJ-2022-116).Declaration of Interest: The authors declared no interests of conflicts.Ethical Approval: Five geographically representative tertiary rheumatology centres across China, including Peking Union Medical College Hospital (PUMCH) (Central), the First Affiliated Hospital of University of Science and Technology of China (East), People’s Hospital of Xinjiang Uygur Autonomous Region (West), Shengjing Hospital (North), and Xiangya Hospital (South), participated in this trial. Ethics approval for this study was obtained from the ethics committees of all five centres. Written informed consent was obtained from all participants.