Targeting steroid withdrawal in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune chronic and multi organ inflammatory disease, predominantly affecting women of childbearing age. The therapeutic armamentarium for the disease consists of glucocorticoids (GC), antimalarials, conventional immunosuppressants (IS) and more recently biological drugs. Thanks to advances in the management and treatment of SLE over recent years, patient survival, disease control, and quality of life of SLE patients have significantly improved. These therapeutic advancements have opened the possibility of reducing, and in some cases discontinuing, GC therapy. While GC remain essential for the acute management of disease flares, their long-term use is associated with cumulative organ damage since cumulative GC dosage is predictive of osteoporotic fractures, coronary artery disease, cataracts, avascular necrosis and stroke In line with this, the most recent EULAR guidelines for SLE management recommend reducing GC doses to at least 5 mg/day, with discontinuation being the ideal goal when feasible. While GC tapering is a well-established practice in SLE management, there is limited guidance on how and when to stop GCs. Uncertainty remains regarding the optimal strategy, timing, and patient selection for attempting GC withdrawal. Thus, the decision to begin GC withdrawal is primarily based on the physician’s experience. Data from our SLE cohort showed that, in a real-life setting, a substantial proportion of patients can achieve GC-free remission. In our cohort of 390 SLE patients with at least 1 year of follow-up and complete clinical data, 36.2% were in GC-free remission. Furthermore, the use of today’s drugs, appears to help reduce GC dose while maintaining good disease control. Data from our patients suggest that the early introduction of biological drugs in SLE could be an effective option to help to achieve the targets proposed in the treat to target recommendations for SLE, including the use of low GC doses. Upon identifying that GC-free remission appears to be an attainable goal in clinical practice and recognizing the value of currently available pharmacological options as important tools in achieving this outcome, we started TARGET trial. This trial employs a treat-to-target approach to evaluate whether a strategy of gradual GC tapering is as effective as maintaining a low-dose regimen in patients in remission and/or LLDAS with GC dose of no more than 5 mg/day. Data from our clinical trial, despite preliminary and derived from a small cohort, suggest that in patients with these characteristics GC discontinuation does not appear to be associated with a higher risk of disease flare compared to those who continue low dose of GC. The novelty of our study lies in the fact that enrolled patients had documented adherence to hydroxychloroquine (HCQ) based on blood levels and our cohort includes both patients on conventional DMARDs and those on biologic drugs. Given the increasing use of biologics in SLE management, the findings of our study may be more broadly applicable to contemporary clinical practice. An important issue that has emerged from our preliminary data is therapy adherence, since nearly 30% of patients were found to be non-adherent to background therapy with HCQ. In conclusion, we expect that careful GC tapering before complete GC withdrawal will yield results that are not inferior to those observed with low-dose maintenance after achieving stable LLDAS or remission. In addition, we expect that in these conditions careful GC tapering will not increase the risk of disease flares. Of course, expanding the sample size and extending the follow-up period will be essential to obtain consistent results, and we need to improve medical adherence of our patients also during period of good disease control.