NEW ORLEANS – Three potentially useful blood-based biomarkers of relapse and of the response to glatiramer acetate treatment have been identified in patients with relapsing-remitting multiple sclerosis (RRMS).
The study was small, so much more needs to be done to move the findings to the bedside. Nonetheless, the hope is that the findings will someday help guide treatment decisions and outcomes in MS patients, Adam Kruszewski, a medical student at the University of Maryland, Baltimore, commented in a poster presentation at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Brian Hoyle/Frontline Medical News
Adam Kruszewski
The study had its roots in the researcher’s prior findings that the Response Gene to Complement (RGC)–32 is expressed by CD3+ and CD4+ T cells in peripheral blood mononuclear cells (PBMCs) and in brain tissue from RRMS patients. As well, RGC-32 regulates the expressions of Fas ligand (FasL) and interleukin-21 (IL-21), and the activities of CDC2 and Akt.
In the current study, the investigator explored the potential value of RGC-32, FasL, IL-21, CDC2, and Akt as longitudinal biomarkers of relapse and as a way of gauging the response to the treatment of RRMS patients with glatiramer acetate – one of the most common immunomodulatory approaches used in RRMS therapy.
A cohort of 15 glatiramer acetate–treated RRMS patients was enrolled over a 2-year period. The battery of inclusion criteria included an age of 18-65 years; meeting the McDonald criteria for definite MS; a disease course featuring relapses and remissions; newly diagnosed MS or MS not treated with currently used immunomodulatory drugs for 3 months prior to study entry; no exacerbations in the 4 weeks before the study; no steroid therapy for 4 weeks prior to study enrollment; no treatment with natalizumab (Tysabri), fingolimod (Gilenya), dimethyl fumarate (Tecfidera), mitoxantrone, cyclophosphamide, or investigational drugs during the prior year; and an Extended Disability Status Score (EDSS) of 0-5.5. Exclusion criteria were a history of autoimmune disorders, vascular disease, or active acute or chronic infections; use of antibiotics in the last 30 days; a history of intracranial or intraspinal tumor or metabolic myelopathy; or a history of alcohol or drug abuse.
The 15 patients were clinically monitored and PBMCs were collected at 0, 3, 6, and 12 months. mRNA expression of the five candidate biomarkers in the PBMCs was determined using real-time quantitative polymerase chain reaction testing. Nonresponders to glatiramer acetate treatment were defined as patients who exhibited two or more relapse events following the initiation of the treatment.
Acute relapse was associated with decreased expression of RGC-32 and FasL (both P less than .0001) and increased expression of IL-21 (P = .04). No relapse-associated changes in CDC2 or AKT were evident. Compared with those who did not respond to glatiramer acetate, responders displayed an increased expression of RGC-32 and FasL (both P less than .0001), and a decreased expression of IL-21 (P = .02).
Receiver operating characteristic analysis was done to find the cutoff values that best distinguished treatment responders from nonresponders for each candidate biomarker. The probability of accurately detecting relapse was 90% for RGC-32, 88% for FasL, and 75% for IL-21. The probability of accurately detecting response to glatiramer acetate was 85%, 90%, and 85% in the same respective order.
“Right now, there is no test that can help identify a responder or nonresponder in MS therapy. Often, treatment is started and then a trial and error process with time determines the treatment course,” said Mr. Kruszewski during an interview at the poster.
The aim is to expand these results with RCG-32, FasL, and IL-21 to a randomized, controlled trial with the goal of tailoring treatment at the early stage of MS.