Lupus low disease activity state attainment in the phase 3 TULIP trials of anifrolumab in active systemic lupus erythematosus

Abstract

Objectives: In patients with systemic lupus erythematosus (SLE), lupus low disease activity state (LLDAS) attainment is associated with improved outcomes. We investigated LLDAS attainment in anifrolumab-treated patients.

Methods: We performed post hoc analysis of pooled Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP-1) (NCT02446912) and TULIP-2 (NCT02446899) anifrolumab phase 3 trial data in patients with moderate to severe SLE receiving standard therapy. LLDAS was defined as: SLE Disease Activity Index 2000 ≤4 without major organ activity, no new disease activity, Physician's Global Assessment ≤1, prednisone ≤7.5 mg/day and no non-standard immunosuppressant dosing. Time to first LLDAS attainment was compared between groups using Cox regression modelling; responses were compared using logistic regression.

Results: Agnostic to treatment, 205/819 (25.0%) patients attained LLDAS at week 52; 186/205 (90.7%) were also British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA)-responders. Among BICLA-responders at week 52, 186/318 (58.5%) attained LLDAS; 203/380 (53.4%) SLE Responder Index-4 (SRI(4)) responders attained LLDAS. Improvements from baseline in patient global assessment scores at week 52 were threefold greater in LLDAS-attainers. At week 52, 30.0% of anifrolumab-treated patients and 19.6% of placebo were in LLDAS (OR 1.8, 95% CI 1.3 to 2.5, p=0.0011). Compared with placebo, anifrolumab treatment was associated with earlier LLDAS attainment (time to first LLDAS, HR 1.76, 95% CI 1.35 to 2.30, p<0.0001), increased cumulative time in LLDAS (p<0.0001) and higher likelihood of sustained LLDAS (p<0.001). Anifrolumab treatment was also associated with higher rates of Definition of Remission in SLE remission at week 52 (15.3% vs 7.6%; OR 2.2, 95% CI 1.4 to 3.6, p=0.0013).

Conclusions: LLDAS attainment was highly associated with, but more stringent than, BICLA and SRI(4) responses. Compared with placebo, anifrolumab treatment was associated with earlier, more frequent, and more prolonged and sustained LLDAS.

Trial registration numbers: NCT02446912 and NCT02446899.

Keywords: autoimmune diseases; biological therapy; glucocorticoids; lupus erythematosus, systemic.

Figure 1

Association of LLDAS attainment and BICLA response, agnostic to treatment or dose level, at week 52. (A) Participants who attained LLDAS and were BICLA responders. (B) BICLA responders who attained LLDAS. (C) Participants who attained LLDAS and were SRI(4) responders. (D) SRI(4) responders who attained LLDAS. BICLA, British Isles Lupus Assessment Group-based Composite Lupus Assessment; LLDAS, lupus low disease activity state; SRI(4), SLE Responder Index-4.

Figure 2

Heat map of LLDAS attainment. Each row represents an individual patient, treated with either intravenous anifrolumab 300 mg or placebo every 4 weeks, and each column represents the LLDAS response at each time point from week 4 to week 52. The anifrolumab group (n=360) had fewer patients than the placebo group (n=366); therefore, the anifrolumab heat map panel has fewer rows making it appear to have a different height. Purple indicates LLDAS non-attainment and yellow indicates LLDAS attainment. Patients are sorted by LLDAS response status at each visit from week 4 to week 52. LLDAS, lupus low disease activity state.

Figure 3

Attainment of LLDAS across 52 weeks. LLDAS attainment from weeks 0 to 52 in patients treated with intravenous anifrolumab 300 mg or placebo every 4 weeks. Responder rates (percentages) were weighted and calculated using a stratified Cochran-Mantel-Haenszel approach, with stratification factors SLEDAI-2K score at screening, day 1 glucocorticoid dose, type I IFN gene signature test result at screening and study. Nominal p values were calculated using logistic regression with the same stratification factors. **p<0.01; ***p<0.001. IFN, interferon; LLDAS, lupus low disease activity state; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000.

Figure 4

Cumulative time in LLDAS. Percentages of patients attaining LLDAS for (A) at least 20%, 50% or 70% of observed time from weeks 0 to 52 or (B) for at least three, at least five or at least seven consecutive visits in patients treated with intravenous anifrolumab 300 mg or placebo every 4 weeks. Responder rates (percentages), the difference in estimates and associated 95% CIs were weighted and calculated using a stratified Cochran-Mantel-Haenszel approach, with stratification factors SLEDAI-2K score at screening, Day 1 glucocorticoid dose, type I IFN gene signature test result at screening and study. Nominal p values were calculated using the same stratification factors. IFN, interferon; LLDAS, lupus low disease activity state; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000.

Figure 5

Attainment of DORIS remission across 52 weeks. Remission attainment from weeks 0 to 52 in patients treated with intravenous anifrolumab 300 mg or placebo every 4 weeks. Responder rates (percentages) were weighted and calculated using a stratified Cochran-Mantel-Haenszel approach, with stratification factors SLEDAI-2K score at screening, Day one glucocorticoid dose, type I IFN gene signature test result at screening. Nominal p values were calculated using logistic regression with the same stratification factors. *p<0.05; **p<0.01; ***p<0.001. DORIS, Definition of Remission in Systemic lupus erythematosus; IFN, interferon; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000.