A newly developed plasma cell (PC) 5-gene signature accurately measures PC levels in patients with scleroderma and other autoimmune diseases, including lupus and rheumatoid arthritis (RA). This work paves the way for identification of subsets of patients who may benefit from PC-depleting therapy, according to investigators (Streicher K, et al. Arthritis Rheumatol. 2014;66: 173-184).
“At this point, additional studies are needed to fully understand the utility of the PC signature and whether or not measuring PC levels at baseline before treatment or evaluating the extent of PC depletion following treatment would have an impact on clinical care in autoimmune diseases,” lead author Katie Streicher, PhD, MedImmune, Gaithersburg, MD, told Value-Based Care in Rheumatology.
“Plasma cells are responsible for secreting autoantibodies that are critical to the pathogenesis of autoimmune diseases,” she added. “Previously, the impact of different treatments on this cell population has been difficult to measure in large clinical trials. Our work not only developed a reliable method for monitoring this cell population but also identified diseases where PCs may be especially important, including lupus, RA, and scleroderma,” Dr Streicher continued.
A sensitive gene expression–based method was developed to measure PCs, which is not readily done using flow cytometry. Using whole genome microarray analysis of subsets of cellular fractions, the investigators were able to identify 5 genes predominantly expressed in PCs: IGHAI, IGJ, IGKC, IGKV4-1, and TNFRSF17. Then, they assessed the ability of the PC-enriched genes to be reliably detected in whole blood to verify that this signature would have routine applicability in a clinical setting.
The sensitivity and specificity of this signature was validated using ex vivo experiments and its utility was confirmed using samples from patients with scleroderma enrolled in a phase 1 dose-escalation trial of MEDI-551, an anti-CD19 monoclonal antibody. MEDI-551 exerted a robust reduction of the PC signature in whole blood, with maximum and sustained PC depletion to day 85 posttreatment. Patients in the placebo group had little or no change in the PC signature at all time points. This is an early study with small numbers of patients, but suggests that the concept of PC depletion has promise.
In addition, the investigators also identified multiple autoimmune diseases with increases in the PC signature in blood and diseased tissue, which is possibly indicative of a relationship between PCs and the pathogenesis of these diseases. Increased levels of PCs were observed in 30% to 35% of patients with lupus and RA.
“Many therapies [for autoimmune diseases] that are FDA [US Food and Drug Administration]-approved or in development are not specifically designed to target the PC. However, using the PC signature we developed allows sensitive and specific assessment of various treatments on PCs in large clinical trials,” Dr Streicher explained.
“This highlights the importance of measuring PCs prior to therapy and, potentially, understanding their pattern of depletion and recovery following B-cell depletion therapy,” Dr Streicher concluded, citing recent findings that patients with RA who have high PC plasma levels were less likely to respond to treatment with anti-CD20 B-cell–depleting therapy. n