Clinical phenotyping and predicting treatment responses in Systemic Lupus Erythematosus (SLE) patients is challenging. Extensive blood transcriptional profiling has identified various gene modules that seem promising for stratification of SLE patients. This study was undertaken to translate transcriptomic data into gene signatures suitable for introduction into clinical practice and to associate these signatures with disease activity.
RT-PCR of multiple genes from the Interferon M1.2, Interferon M5.12, neutrophil (NPh)- and plasma cell (PLC) modules followed by a principle component analysis was used to identify indicator genes per gene signature. Gene signatures were measured in longitudinal samples from two childhood onset SLE cohorts (n=101 and n=34, respectively) and associated with clinical features. Disease activity was measured using SELENA-SLEDAI. Cluster analysis subdivided patients into three fingerprint groups termed 1) all-signatures-low, 2) only IFN high (M1.2 and/or M5.12) and 3) high NPh and/or PLC.
All gene signatures were significantly associated with disease activity in cross-sectionally collected samples. The PLC signature showed the highest association with disease activity. Also, in longitudinally collected samples, the PLC signature was associated with disease activity and showed a decrease over time. When patients were divided into fingerprints, the highest disease activity was observed in the high NPh and/or PLC group. The lowest disease activity was observed in the all-signatures-low group. The same distribution could be reproduced in samples from an independent SLE cohort.
Gene signatures are associated with disease activity and can be suitable tools to sub-classify SLE patients into groups with similar pathogenically activated immunological pathways.
We aimed to investigate early changes in B cell subsets in relation to flare during standard therapy plus belimumab or placebo within the frame of three phase III clinical trials of belimumab in SLE.
We analyzed pooled 52-week data from BLISS-76 (N=819), BLISS-SC (N=836), and BLISS North-East Asia (N=60). B cell subsets were determined with flow-cytometry. Severe flares were evaluated according to the SELENA-SLEDAI Flare Index. We investigated B cell changes relative to baseline using proportional hazards regression.
Decreases in CD19+CD20-CD138+ long-lived (HR: 0.7; 95% CI: 0.56–0.98; P=0.034) and CD19+CD38brightCD27bright SLE-associated plasma cells (HR: 0.7; 95% CI: 0.50–0.87; P=0.003) from baseline through week 24 were negatively associated with the development of severe flare through week 52, and decreases in naïve CD19+CD20+CD27- B cells showed a similar trend (HR: 0.7; 95% CI: 0.56–1.00; P=0.051). No such association was observed for early changes in CD19+CD20+CD27+ memory B cells, CD19+CD20+CD69+ activated B cells or CD19+CD20-CD27bright short-lived plasma cells. The association with CD19+CD38brightCD27bright SLE-associated plasma cells held true for patients treated with belimumab (HR: 0.7; 95% CI: 0.47–0.97; P=0.032) but not placebo, while placebo receivers showing reductions in CD19+CD20-CD138+ long-lived plasma cells displayed lower probability to flare (HR: 0.6; 95% CI: 0.38–0.87; P=0.009).
Early decreases in long-lived circulating plasma cells were negatively associated with severe flares in patients with active SLE treated with standard immunosuppression with or without add-on belimumab, while reductions in circulating CD19+CD38brightCD27bright plasma cells may prove a useful early marker of favorable response to belimumab therapy.