A systematic literature review informing the 2023 update of the European Alliance of Associations for Rheumatology recommendations for managing systemic lupus erythematosus found high-quality evidence supporting the efficacy of biologic agents and defined treatment targets.
In the review, published in Annals of the Rheumatic Diseases, investigators analyzed studies from 2018 to 2022 across five key areas of lupus management. They screened 10,889 articles, ultimately including 439 for data extraction. The majority were observational studies of low or moderate quality, highlighting the continued need for high-quality randomized controlled trials (RCTs) in lupus research.
The review identified robust data from RCTs demonstrating the efficacy of anifrolumab and belimumab for treating extrarenal lupus compared with standard of care. For lupus nephritis, high-quality RCTs showed improved outcomes with belimumab and voclosporin plus standard therapy.
Multiple observational studies confirmed that achieving clinical remission or low disease activity was associated with reduced risk of damage accrual, flares, mortality, and other adverse outcomes in patients with lupus. The investigators found evidence supporting gradual tapering of glucocorticoids in patients with stable disease; however, randomized studies showed higher relapse rates after complete discontinuation.
For lupus nephritis, the review highlighted two pivotal phase III RCTs. The BLISS-LN trial found that adding belimumab to standard therapy significantly increased renal response rates at 2 years (43% vs 32%, odds ratio [OR] = 1.6, 95% confidence interval [CI] = 1.0–2.3). The AURORA trial showed higher complete renal response rates at 1 year with voclosporin plus mycophenolate mofetil vs placebo (41% vs 23%, OR = 2.65, 95% CI = 1.64–4.27).
Regarding biologic therapies for extrarenal disease, a meta-analysis of six RCTs found belimumab increased the risk of BILAG-defined skin response at 52 weeks vs placebo (OR = 1.44, 95% CI = 1.20–1.74). For anifrolumab, pooled analysis of the TULIP trials showed greater CLASI-50 skin responses vs placebo (treatment difference = 21.0%, 95% CI = 8.1%–34.0%).
The review identified a lack of high-quality data on treating specific organ manifestations outside of lupus nephritis. For neuropsychiatric lupus, only one meta-analysis on rituximab in refractory disease was found, reporting a 90% complete response rate for neuropsychiatric manifestations (95% CI = 53%–99%).
Safety data showed slightly increased rates of herpes zoster reactivation with anifrolumab compared with (6.4% vs 1.4%). A phase IV trial raised potential concerns about increased depression and suicidality risk with belimumab, although pooled safety analyses showed similar overall adverse event rates vs placebo.
The review provided new insights on hydroxychloroquine (HCQ) use in lupus. A meta-analysis of 21 studies (26,037 patients) found HCQ use was associated with reduced mortality risk (pooled hazard ratio = 0.46). Regarding retinal toxicity, two large retrospective cohort studies reported retinopathy rates of 0.8% and 4.3%, with longer duration of use and higher cumulative dose confirmed as risk factors.
For glucocorticoid use, the review found most observational studies pointed to thresholds of mean 5 to 7.5 mg/day prednisone associated with various side effects. The investigators noted that lowering the recommended maximum maintenance dose to 5 mg/day was not based on randomized trial evidence comparing different maintenance doses.
The systematic review provided an updated evidence base supporting the efficacy of newer biologic therapies and defined treatment targets in lupus. However, it also highlighted continued gaps in high-quality data for treating various organ-specific manifestations. The findings informed the 2023 update of European Alliance of Associations for Rheumatology (EULAR) recommendations to guide optimal management of this complex autoimmune disease.
A conflict of interest statement can be found in the guidelines.
