Distinct patterns of disease activity over time in patients with active SLE revealed using latent class trajectory models

John A Reynolds,Caroline Gordon,Mark Lunt,Jennifer Prattley,Ian N Bruce,Nophar Geifman,Masterplans Consortium

doi:10.1186/s13075-021-02584-x

Abstract

BackgroundSystemic lupus erythematosus (SLE) is a heterogeneous systemic autoimmune condition for which there are limited licensed therapies. Clinical trial design is challenging in SLE due at least in part to imperfect outcome measures. Improved understanding of how disease activity changes over time could inform future trial design. The aim of this study was to determine whether distinct trajectories of disease activity over time occur in patients with active SLE within a clinical trial setting and to identify factors associated with these trajectories.MethodsLatent class trajectory models were fitted to a clinical trial dataset of a monoclonal antibody targeting CD22 (Epratuzumab) in patients with active SLE using the numerical BILAG-2004 score (nBILAG). The baseline characteristics of patients in each class and changes in prednisolone over time were identified. Exploratory PK-PD modelling was used to examine cumulative drug exposure in relation to latent class membership.ResultsFive trajectories of disease activity were identified, with 3 principal classes: non-responders (NR), slow responders (SR) and rapid-responders (RR). In both the SR and RR groups, significant changes in disease activity were evident within the first 90 days of the trial. The SR and RR patients had significantly higher baseline disease activity, exposure to epratuzumab and activity in specific BILAG domains, whilst NR had lower steroid use at baseline and less change in steroid dose early in the trial.ConclusionsLongitudinal nBILAG scores reveal different trajectories of disease activity and may offer advantages over fixed endpoints. Corticosteroid use however remains an important confounder in lupus trials and can influence early response. Changes in disease activity and steroid dose early in the trial were associated with the overall disease activity trajectory, supporting the feasibility of performing adaptive trial designs in SLE.

Highlights

Systemic lupus erythematosus (SLE) is a heterogeneous systemic autoimmune condition for which there are limited licensed therapies
Whilst the SRI-4 has been used in a number of lupus trials [5, 6], there is evidence that a BILAG-based outcome might be preferable to one based on the SLEDAI score
The aim of this study was to identify whether SLE patients follow distinct disease activity trajectories within a clinical trial setting and to identify factors associated with individual trajectories

Summary

Introduction

Systemic lupus erythematosus (SLE) is a heterogeneous systemic autoimmune condition for which there are limited licensed therapies. A number of promising agents have failed to show efficacy in phase 3 randomised placebo-controlled trials [1] These failures are likely multifactorial but may be due, at least in part, to the clinical and serological heterogeneity of SLE and the choice of end-points [2, 3]. Measures need to be sensitive to changes in clinical disease activity whilst capturing the breadth of disease manifestations [3]. Composite measures such as the SLE responder index (SRI-4) which comprise objective indices (for example the SLEDAI-2K) along with more subjective measures (e.g. physician global scores) are currently favoured [4]. In the TULIP-1 study of anifrolumab, a greater difference between active drug and placebo was observed using the BILAG-based Combined Lupus Assessment (BICLA) than with the SRI-4 [7]

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