Clinical response trajectories and drug persistence in systemic lupus erythematosus patients on belimumab treatment: A real-life, multicentre observational study

Abstract

Objective: To obtain real-world data on outcomes of belimumab treatment and respective prognostic factors in patients with systemic lupus erythematosus (SLE).

Methods: Observational study of 188 active SLE patients (median disease duration 6.2 years, two previous immunosuppressive/biological agents) treated with belimumab, who were monitored for SLEDAI-2K, Physician Global Assessment (PGA), LLDAS (lupus low disease activity state), remission (DORIS/Padua definitions), SELENA-SLEDAI Flare Index, SLICC/ACR damage index and treatment discontinuations. Group-based disease activity trajectories were modelled followed by multinomial regression for predictive variables. Drug survival was analysed by Cox-regression.

Results: At 6, 12 and 24 months, LLDAS was attained by 36.2%, 36.7% and 33.5%, DORIS-remission by 12.3%, 11.6% and 17.8%, and Padua-remission by 21.3%, 17.9% and 29.0%, respectively (attrition-corrected). Trajectory analysis of activity indices classified patients into complete (25.5%), partial (42.0%) and non-responder (32.4%) groups, which were predicted by baseline PGA, inflammatory rash, leukopenia and prior use of mycophenolate. During median follow-up of 15 months, efficacy-related discontinuations occurred in 31.4% of the cohort, especially in patients with higher baseline PGA (hazard ratio [HR] 2.78 per 1-unit; 95% CI 1.32-5.85). Conversely, PGA improvement at 3 months predicted longer drug retention (HR 0.57; 95% CI 0.33-0.97). Use of hydroxychloroquine was associated with lower risk for safety-related drug discontinuation (HR 0.33; 95% CI 0.13-0.85). Although severe flares were reduced, flares were not uncommon (58.0%) and contributed to treatment stops (odds ratio [OR] 1.73 per major flare; 95% CI 1.09-2.75) and damage accrual (OR 1.83 per mild/moderate flare; 95% CI 1.15-2.93).

Conclusions: In a real-life setting with predominant long-standing SLE, belimumab was effective in the majority of patients, facilitating the achievement of therapeutic targets. Monitoring PGA helps to identify patients who will likely benefit and stay on the treatment. Vigilance is required for the prevention and management of flares while on belimumab.

Keywords: biologics; flares; low disease activity; lupus; organ damage; remission.

Figure 1

Effect of belimumab treatment on SLE disease activity, attainment of therapeutic goals and dose of glucocorticoids. (A, B) Violin plots of SLEDAI-2K (A) and PGA (B) values at consecutive time-points during belimumab treatment. Blue lines represent median values. The non-parametric Skillings-Mack test was used to determine the statistical significance of longitudinal trends. The number of analysed patients were 178, 164, 136, 109, 74 and 48 at the 3, 6, 9, 12, 18 and 24-month time points, respectively. The number of patients with shorter follow-up were 0, 6, 16, 21, 40 and 53, respectively. (C) Rates (Lundex-corrected) of attainment of low disease activity (LLDAS (30)), remission (according to the DORIS (31) and the Zen et al. (32, 33) definitions) in belimumab-treated patients. (D) Stacked bars demonstrating the glucocorticoid dosage level (none, >0 and ≤5 mg/day, >5 to ≤7.5 mg/day, >7.5 mg/day prednisone equivalent) in patients under treatment with belimumab.

Figure 2

Distinct trajectories of disease activity (SLEDAI-2K, PGA) in SLE patients treated with belimumab. Group-based trajectory modelling of SLEDAI-2K (A) and PGA (B) during belimumab treatment was performed as described in the Methods section. Solid lines (coloured) represent the parameter estimates of each model, and dashed lines represent the 95% confidence interval of the estimates. Dots are calculated from the actual data where each individual’s responses are weighted based on the posterior probabilities of group membership. Three distinct trajectories of SLEDAI-2K and PGA are indicated with different colours (top-red, middle-blue, bottom-green). The percentages at the bottom of each panel correspond to the proportion of SLE patients belonging to each trajectory.

Figure 3

Baseline factors may predict clinical response trajectories in belimumab-treated SLE patients. Multinomial regression analysis was performed to identify baseline clinical parameters associated with the trajectory-based groups of response to belimumab. Patients with baseline PGA ≥2.0 or inflammatory rash were more likely to belong to the partial response (PR) (odds ratio [OR] 2.74; 95% confidence interval [95% CI] 1.09–6.85 and OR 2.37; 95% CI 1.05–5.35, respectively) and the non-response (NR) (OR 3.19; 95% CI 1.27–8.06 and OR 4.07; 95% CI 1.70–9.71, respectively) than the complete response (CR) group. Leukopenia was linked to reduced risk for PR as compared to CR (OR 0.07; 95% CI 0.01–0.61) and NR (OR 0.07; 95% CI 0.01–0.56). Prior use of mycophenolate was associated with lower risk for PR versus NR (OR 0.25; 95% CI 0.09–0.71).

Figure 4

Persistence of belimumab treatment in patients with active SLE. Kaplan–Meier survival curves of belimumab in active SLE patients. The number of individuals at-risk entering each time interval is shown at the bottom of the plots. One- and two-year efficacy-related retention rates were estimated at 71% and 61%, respectively. Safety-related retention rates at 1 and 2 years were estimated at 93% and 85%, respectively.