Glucocorticoids-free zone in SLE? Save

For over 70 years, glucocorticoids, (GC) have been a part of standard therapy in SLE. They are classically used to not only induce remission or treat an acute flare, but also as maintenance therapy. They are a valuable 'friend' if used wisely, and can become a 'foe' if used excessively. However, many people with SLE continue unacceptable doses of GC, which leads to detrimental effects on the accrual of organ damage, infection, morbidity and mortality.

With rapid advancement in licensing of new therapies in SLE over the last 3 years, are we any closer to a “GC-free” zone? In this article, we will preview some selected data that will be presented at this year’s ACR Convergence 2023 in the sunny San Diego. 

Lupus nephritis (LN) is one of the most severe manifestations of SLE and traditionally, treatment regimens for proliferative or membranous lupus nephritis (LN) often involve the use high dose oral GC (i.e. up to 1.0 mg/kg/day prednisone equivalent) with or without a preceding intravenous (IV) methylprednisolone pulse. Dr. Saxena (Abstract 0781) will present data from a pooled analysis of patients from the standard of care arms (consisted of either therapy with mycophenolate mofetil or Euro-Lupus cyclophosphamide followed by azathioprine) from four RCTs. The objective was to compare the renal responses and safety between the use of concurrent initial high dose vs low dose (i.e. up to 5mg/kg/day) with these SOC therapies. The study showed that there was no significant efficacy difference between both groups with fewer adverse events in the latter group, thus supporting the use of lower oral GC doses in remission induction of LN.

One contributing factor in the failure of many promising therapies when investigated in SLE RCTs was the high placebo response rates, i.e., some were well above 40%, even when composite indices such SRI-4 and BICLA were used as primary endpoints. This high placebo rate was attributed to the use of active comparator including high dose GC in the SOC arm. Therefore, since concurrent GC is often used or permitted at the start of the study, a) should we incorporate low dose GC or even better cessation as co-primary endpoint ?; and b) could this strategy reduce the placebo response rate?

Dr. Merill (Abstract 2488) will present the efficacy and safety data from a Phase 2 RCT of ABBV-599 High Dose, a novel combination of elsubrutinib (a selective BTK-inhibitor) and upadacitinib (JAK-inhibitor) that targets non-overlapping signaling pathways, upadacitinib alone and placebo. The study included achieving steroid dose ≤10 mg/day, in addition to the SRI-4 as the primary composite endpoint. At Week 24, the primary endpoint was met in both the ABBV-599 (48.5%) and upadacitinib alone (43.5%) groups vs placebo group (32%). There appeared to be no statistical significant advantage by combining elsubrutinib compared to upadacitinib alone over placebo over various efficacy and safety endpoints. 

Dr. Shen (Abstract 2487) will present an interim analyses of the efficacy and safety data of a novel BAFF-receptor inhibitor, ianalumab which provides both B-cell depleting and BAFF-inhibition mode of actions. In this Phase 2 RCT, the primary composite endpoint was the SRI-4 and notably, even lower bar of GC dose target, i.e., the ability to sustain prednisolone tapering to ≤5 mg/day or ≤ BL dose from Week 16 to Week 28. Significantly more patients in the ianalumab-treated group met this primary composite endpoint vs placebo (15/34 [44%] vs 3/33 [9%] respectively) at Week 28. 

The data above have shown that concurrent low dose GC +/- 1-3 day pulses of IV methylprednisolone should be used instead of high dose GC to complement the initiation of immunosuppressant for remission induction in SLE. Once the GC has been initiated, we should be proactive in tapering the GC dose with the aim to reduce or withdraw glucocorticoids once SLE is controlled. Tapering or cessation of GC should also be considered as a target and co-primary endpoint to reduce the placebo rate response in RCTs, which would open the door to licensing of more therapies and improve the overall outcomes of people with SLE.