Background A LLDAS definition has received preliminarily validation. Achieving low disease activity by this definition is associated with protection from damage accrual for patients (pts) with SLE.1 However, it has not been evaluated as an endpoint in randomized controlled trials (RCTs).
Objectives We evaluated LLDAS as an RCT endpoint in a post-hoc analysis of the MUSE trial of anifrolumab in pts with moderate to severe SLE.2
Methods During the 52-week MUSE study, pts with active SLE received intravenous placebo, anifrolumab 300 mg, or 1,000 mg, in addition to standard of care, every 4 weeks for 48 weeks. LLDAS requires all of the following: SLEDAI–2K ≤4 without major organ activity, no new disease activity, PGA (0–3) ≤1, prednisolone ≤7.5 mg/day, and tolerance of standard immunosuppressant dosages.1 LLDAS utility, its association with other endpoints, and discrimination between anifrolumab- and placebo-treated pts, were explored using descriptive statistics, logistic regression, and Gray's test. All randomized pts in MUSE were included in the analyses, and non-response imputation was performed after dropout.
Results For pts receiving placebo (n=102), anifrolumab 300 mg (n=99), or anifrolumab 1,000 mg (n=104), LLDAS criteria were met at least once by 35%, 52%, and 46% of pts, respectively (odds ratio [OR] vs. placebo; 300 mg: 1.97, 95% CI 1.08, 3.58; p=0.027; 1,000 mg: 1.63, 95% CI 0.90, 2.95; p=0.103). Positive associations were observed between LLDAS and both the SLE Responder Index (SRI) and BILAG-based Composite Lupus Assessment (BICLA), with 87% and 74% of pts attaining LLDAS at Week 52 also being SRI(4) and BICLA responders, respectively (χ2=57.61 and 55.18; both p<0.0001). However, only 47% and 51% of SRI(4) and BICLA responders reached LLDAS. Increased LLDAS attainment from Week 12 (300 mg) or 28 (1,000 mg) was associated with anifrolumab treatment, compared with placebo (OR range; 300 mg: 1.7–3.6; 1,000 mg: 1.7–2.5). LLDAS was attained earlier (300 mg: χ2=6.39, p=0.012; 1,000 mg: χ2=2.44, p=0.119) in anifrolumab-treated pts (Figure 1). At Week 52, more anifrolumab-treated pts attained a LLDAS (OR vs. placebo; 300 mg: 3.41, 95% CI 1.73, 6.76, p<0.001; 1,000 mg: 2.03, 95% CI 1.01, 4.07, p=0.046). More anifrolumab-treated pts spent ≥50% of observed time in LLDAS (OR vs. placebo; 300 mg: 3.04, 95% CI 1.34, 6.92; p=0.008; 1,000 mg: 2.17, 95% CI 0.93, 5.03; p=0.072), and the OR of sustained LLDAS for at least six consecutive visits from Week 12 to 52 were 4.02 (95% CI 1.38, 11.73; p=0.011) (300 mg) and 2.95 (95% CI 0.99, 8.78; p=0.052) (1,000 mg).
Conclusions LLDAS is associated with validated treatment response measures, SRI(4) and BICLA, but is more stringent than either. Anifrolumab was associated with ≤3.6-fold OR increases in LLDAS attainment, as well as greater aggregate and sustained time in LLDAS. This LLDAS definition should be considered as a study endpoint in SLE RCTs.
Franklyn K, et al. Ann Rheum Dis. 2015;75:1615–21.
Furie R, et al. Arthritis Rheumatol. 2017;69:376–86.
Acknowledgements Funded by MedImmune. Medical writing support: R Plant, QXV Comms, an Ashfield company, funded by MedImmune.
Disclosure of Interest E. Morand Grant/research support from: Astra Zeneca, Janssen, UCB, BristoMyersSquibb, Consultant for: AstraZeneca, Pfizer, Merganser, Baxalta, BristoMyersSquibb, UCB, A. Berglind Shareholder of: AstraZeneca, Employee of: AstraZeneca, T. Sheytanova Employee of: AstraZeneca, R. Tummala Employee of: AstraZeneca, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune LLC