Glucocorticoid withdrawal and risk of subsequent flare in Systemic Lupus Erythematosus

Introduction: Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease with a multifactorial pathogenesis. Glucocorticoids (GCs) play a central role in the treatment of active SLE, but their chronic use is linked to well-established side effects and GC discontinuation is a key treat-to-target endpoint in SLE management. However, data on GCs discontinuation in remitted patients are scanty. Aim: The aim of this study is to evaluate whether GCs can be safely withdrawn in patients in clinical remission and whether GC discontinuation is associated with reduced damage accrual. In addition, another aim is to identify predictors of successful GCs withdrawal, not followed by disease flares. Materials and methods: A retrospective study was conducted based on the collection of data from 570 SLE patients followed at the Rheumatology Unit of the University Padua Hospital. Patients diagnosed after 1980 and followed-up until 2023 were included in the study. We analysed the characteristics of patients achieving remission on- vs. off- GCs therapy, comparing flare rates in the two groups. Moreover, among remitted patients off-GCs predictors of disease relapse after GC discontinuation were investigated. Disease activity was assessed by the SLE Disease Activity Index-2000 (SLEDAI-2K), with remission defined according to Zen definition: SLEDAI-2K=0, stable background therapy with immunosuppressants and antimalarials, with (remission on-GCs) or without (remission off-GCs) prednisone (PDN) equivalent dose of ≤ 5 mg/day. GC withdrawal was defined as the complete discontinuation of oral GCs. Flares were defined as any increase in clinical SLEDAI-2K>0 or the need for changes in SLE medications. Organ damage was defined according to the SLICC Damage Index (SDI). Outcomes were assessed at two timepoints: last remission and first/first available remission. Kaplan-Meir curve was used to evaluate flare-free survival in on- vs- off-GCs remitted patients. Logistic regression and Cox-regression analyses were used to identify predictors of flare and predictors of flare-free remission, respectively. Results: Among 570 patients considered for our study, we could analyse data from 484 patients: at last remission, 360 achieved remission off-GCs (74.4%), while 124 on-GCs. During a mean observational time of 87 months (SD 76), 85 flares were observed, 48 in off-GCs remitted patients and 37 in on-GCs remitted patients (p<0.01). This corresponds to an annual flare rate of 1.65 flare/100 patients/year, and 8.5 flares/100 patients/year in remitted patients off- and on- GCs, respectively (p<0.001). At multivariate logistic regression analysis, flares predictors in off-GCs remission were low C3 levels (OR 0.007, CI 95% 0.00-0.188, p=0.007), arthritis (3.108, 1.096-8.811, p=0.033), leukopenia (2.146, 1.030-4.472, p=0.041), vasculitis (2.650, 1.037-6.773, p=0.042), last remission duration (0.987, 0.980-0.995, p<0.001). By Cox regression analysis, predictors of shorter flare-free remission in remitted patients off-GCs were: thrombocytopenia (HR 2.446, CI 95% 1.106-5.410, p=0.027), vasculitis (3.033, 1.262-7.432, p=0.013), disease duration (0.943, 0.892-0.998, p=0.054), and anti-U1RNP antibody positivity (1.973, 0.988-3.940, p=0.054). As damage is concerned, SDI was lower in remitted patients off-steroids, but similar in patients with or without flares, meaning that prompt restoration of therapy prevented disease-related organ damage. Conclusion: In patients with SLE in remission, gradual glucocorticoid withdrawal can be safely attempted in the majority of cases, including patients with severe organ involvement (neurological and renal). Withdrawal of GCs improves disease outcomes, reducing accrual of organ damage. According to our results, remission off-GCs is an achievable outcome in SLE, especially in patients without serological activity added to clinical quiescence and in those with less refractory disease.