The majority of ADAs against adalimumab have neutralizing capacity and prevent the drug from interacting with its target (16). T cells in a cross-sectional adalimumab-treated RA patient cohort with a defined ADA response. The analysis revealed seven differentially expressed markers (DEMs) between the ADA+ and ADA? patients. Validation of the DEMs in an independent prospective European cohort of adalimumab treated RA patients, revealed a significant and consistent reduced frequency of signal regulatory protein (SIRP)/-expressing memory B cells in ADA+ JNJ-47117096 hydrochloride vs. ADA? RA patients. We also assessed the predictive value of SIRP/ expression in a longitudinal RA cohort prior to the initiation of adalimumab treatment. We show that a frequency of < 9.4% of SIRP/-expressing memory B cells predicts patients that will develop ADA, and consequentially fail to respond to treatment, with a receiver operating characteristic (ROC) area under the curve (AUC) score of 0.92. Thus, measuring the frequency of SIRP/-expressing memory B cells in patients prior to adalimumab treatment may be clinically useful to identify a subgroup of active RA subjects who are going to develop an ADA response and not gain substantial clinical benefit from this treatment. Keywords: B cells, rheumatoid arthritis, anti-drug antibodies, immunogenicity, SIRP, anti-TNF, adalimumab, memory B cells Introduction Rheumatoid arthritis (RA) is a chronic autoimmune disease that manifests as pain, swelling and stiffness of the joints (1), with a 0.5C1% prevalence in the adult population (2). Loss of tolerance drives disease onset and the associated excessive inflammation can lead to destruction of cartilage and bone erosion (1) as well as to systemic complications including cardiovascular disorders, if left untreated (3). Over the last few years the introduction of several biological drugs has significantly improved the treatment of RA, particularly for those patients that fail to control disease with the use of conventional disease modifying anti-rheumatic drugs (cDMARDs). Drugs neutralizing pro-inflammatory cytokines including TNF (adalimumab, infliximab, and etanercept) and IL-6 (tocilizumab) as well as depleting B cells (rituximab), and blocking T cell function (abatacept), are successfully used in the treatment of RA (4). A significant percentage of patients Rabbit Polyclonal to DDX50 with RA receiving biologics will mount an immune response against the drug (immunogenicity), leading to the production of anti-drug antibodies (ADA), often within the first 6 months of therapy (5). This is associated with lower blood drug levels, unresponsiveness to the drug, and a worse clinical outcome (6). Multiple clinical studies have shown that the incidence of ADA differs depending on the biological therapy administered. Immunogenicity occurs in around 33% of adalimumab- and 63% of infliximab-treated RA patients. A lower JNJ-47117096 hydrochloride occurrence is reported after rituximab or tocilizumab treatment with 11% and < 8% of RA patients, respectively, developing ADA (7C15). Circulating ADAs can form immune complexes that increase the clearance of the drug. The majority of ADAs against adalimumab have neutralizing capacity and prevent the drug from interacting with its target (16). Of interest, lower drug levels combined with the presence of ADA at 3 months after treatment initiation, predicted lack of response JNJ-47117096 hydrochloride to adalimumab at 12 months (17). Since not all patients treated with biological therapies develop ADA, the ability to identify a biomarker/s to predict immunogenicity would considerably improve the clinical management of RA. B cells play a prominent role in RA pathogenesis via the production of rheumatoid factor (RF) and anti-cyclic-citrullinated peptide (anti-CCP) autoantibodies, in addition to antibody-independent roles (18). B cells in the periphery can be defined according to stages of maturation: immature CD24hiCD38hi; memory CD24hiCD38lo; and mature CD24intCD38intB cells. Numerical and functional alterations in B cell subsets have been consistently reported in patients with RA (18). Of interest IgD+CD27+memory B cells are enriched in the synovium, compared to the peripheral blood, suggesting that the migration of pathogenic memory B cells into inflamed synovium may contribute to disease progression (19). Furthermore, RA patients with active disease have been reported to have a reduced frequency of regulatory B cells,.