Journal of IiME Volume 8 Issue 1 May 2014 A Biomarker in Predicting Clinical Response and Disease Activity in Patients with RA and SLE treated with Rituximab To investigate the potential of soluble CD23 as a biomarker in predicting clinical response and disease activity in patients with RA and SLE treated with Rituximab Aim: To determine whether a putative measure of B cell differentiation into memory cell phenotype can be used to inform on B cell kinetics and mechanisms of response and relapse during treatment with rituximab. Introduction: Removal of B cells with rituximab (RTX – a chimaeric monoclonal antibody recognising CD20 antigen)(1) induces clinical remission in a majority of seropositive patients with Rheumatoid arthritis (RA) (2). RTX is also used with reported success off-label in patients with SLE (3, 4). Although a randomised clinical trial in SLE did not provide clear evidence of clinical benefit, there are reasons to doubt the validity of these negative results (5). In both conditions, relapse can occur coincident with B cell return to the periphery, but in some patients may be delayed for many months (6, 7). Therefore, although B cell return precedes clinical relapse the time interval between B cell repopulation and clinical relapse is variable between patients, thus limiting the utility of B cell repopulation to accurately predict the timing of relapse. The clinical use of the B-cell depleting agent RTX in patients with RA was initiated by Professor Jonathan Edwards at UCL in 1998, with results of the first small open study published in 2001 (8). In 2006, RTX was licenced for refractory RA. Patients may be positively selected based on their serostatus as ‘good’ clinical responses (ACR>50%) are more predictable in patients with seropositive disease (2). Such an approach may limit the use of rituximab for seronegative RA, which may be better treated with alternative biological agents. Adequate B cell depletion in the peripheral blood, arbitrarily defined as CD19+ cells<5/μl, in patients with RA, and also when RTX is used off-label in SLE, is necessary for clinical response (9, 10). On the other hand, removal of the majority of peripheral B cells does not necessarily guarantee attaining a significant clinical benefit. When high sensitivity flow Geraldine Cambridge, PhD, Principal Investigator, University College London, UK Maria Leandro, MD PhD, Consultant Rheumatologist & Senior Lecturer, University College London, UK Venkat Reddy, MD, Consultant Rheumatologist, University College London, UK cytometry analysis was used (ie counting >100,000 cells), it was found that the level of depletion required to be even lower in some patients in order to achieve a ‘good’ clinical response. (11) Mechanisms underlying poor responses, in the face of good peripheral depletion, remain largely unexplored. In conjunction with studies of adequacy of peripheral B cell depletion, analysis of B cell phenotype showed that a persistence of memory B cells (usually CD27+) in peripheral blood in the weeks after rituximab therapy (12) correlated with impaired response rates in patients with RA. The analysis of B-cell phenotype has also been explored in order to suggest possible biomarkers to predict response. Several studies have now concluded that evolution of B cells towards an immunoglobulin-producing phenotype was related to whether the patient is going to respond well or not to rituximab and also whether periods of remission are going to be relatively short-lived (1315). In addition, higher percentages of switched memory B-cells in the circulation after rituximab have been associated with earlier relapse (15-17). This was supported by studies of the genetic phenotype which were possibly predictive for the strength of clinical response. In the REFLEX trial of rituximab in inadequate responders to anti-TNFα therapies, a 25% subgroup of treated subjects with elevated baseline mRNA levels of IgJ (a marker for antibody-secreting plasmablasts), showed reduced clinical response rates. There were no significant efficacy differences in the placebo arm subjects stratified by this marker. Prospective testing of IgJ, and strong IFNα signature pre-treatment in the DANCER and SERENE rituximab clinical trial cohorts confirmed the ability of these genetic markers to Invest in ME (Charity Nr. 1114035) www.investinme.org Page 13 of 52
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