Assessment of the prognostic impact of including standard serological markers in the definitions of remission and low lupus disease activity in patients with SLE

Assessment of the prognostic impact of including standard serological markers in the definitions of remission and low lupus disease activity in patients with SLE

Systemic Lupus Erythematosus (SLE) is the prototype systemic autoimmune disease causing inflammation in multiple organs such as the joints, skin, kidneys and other. The disease typically runs a chronic course with alternating periods of active (also known as flare) and inactive (also known as remission) state. In SLE, adequate control of disease activity has been recognised as an important target in the management of the disease. Depending on the number of afflicted organs and the severity of inflammation in each involved organ, disease activity can vary from remission (i.e., absence of signs of inflammation) to low, moderate or high activity, quantifiable according to the physician assessment (Physician Global Assessment [PhGA] ranging from 0 to maximum activity of 3) and objective clinical indices such as the SLEDAI-2K (SLE Disease Activity Index-2K, ranging from 0 to maximum activity of 105). In this context, collaborative groups of experts have introduced tentative definitions for remission and low disease activity, which have been associated with improved patient outcomes including lowered risk for flares and organ damage accrual. Remission is defined as SLEDAI-2K = 0, PhGA <0.5 and intake of ≤5 mg/day of prednisone, whereas the Lupus Low Disease Activity State (LLDAS) is defined as SLEDAI-2K ≤4, PhGA ≤1 and intake of ≤7.5 mg/day of prednisone. Serological blood markers are integral part of the assessment of SLE activity and typically include anti-double stranded DNA (anti-dsDNA) autoantibodies and the complement fractions C3 and C4, which are proteins produced by the immune system to fight infection and are reduced during high SLE activity. Although these serological markers (anti-dsDNA, serum C3/C4) are part of the SLEDAI-2K index, it remains elusive whether they should be considered in the aforementioned definitions of remission and LLDAS. To this end, no studies have so far examined for the independent effects of abnormal serological markers and accordingly, their contribution to the prognostic impact of remission and LLDAS in patients with SLE. In this proposal, we plan to utilise data from the belimumab phase III controlled trials in SLE in order to investigate whether inclusion of the serological markers (serum C3/C4, anti-dsDNA) in the definitions of remission and LLDAS affects their prognostic significance in terms of prevention of flares and/or organ damage accrual. Specifically, patients belonging to all treatment arms from three controlled trials (GSK-HGS1006-C1057, GSK-HGS1006-C1056, GSK-HGS1006-C1115) will be merged into a single dataset, and variables from each patient pertaining to disease activity, serological markers, flares, organ damage and ongoing treatments will be collected at baseline and at 4-weekly intervals until week 52. We will employ time-dependent hazard regression models and generalised linear models to assess the association between various definitions (including or excluding serology) of LLDAS and remission with the primary (flares) and secondary (organ damage) outcome measures. Taking advantage of the large sample size, a comparative analysis between alternative LLDAS/remission definitions will also be performed. These findings will determine whether, in the context of treating active SLE, normalisation of serological markers has an independent prognostic effect on clinically relevant patient outcomes such as flares and organ damage. The results of the research proposal may inform existing initiatives towards optimisation of therapeutic targets in SLE.

[{ "PostingID": 1416, "Title": "GSK-HGS1006-C1056", "Description": "A Phase 3, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, 76-Week Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006, LymphoStat-B™), a Fully Human Monoclonal Anti-BLyS Antibody, in Subjects with Systemic Lupus Erythematosus (SLE)" },{ "PostingID": 1417, "Title": "GSK-HGS1006-C1057", "Description": "A Phase 3, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, 52-Wk Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006, LymphoStat-B™), a Fully Human Monoclonal Anti-BLyS Antibody, in Subjects With Systemic Lupus Erythematosus (SLE)" },{ "PostingID": 14488, "Title": "GSK-HGS1006-C1115", "Description": "A Phase 3, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, 52-Week Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006) Administered Subcutaneously (SC) to Subjects with Systemic Lupus Erythematosus (SLE)" }]