A new tool for detection of type I interferon activation in systemic lupus erythematosus

The IFN-I pathway is activated in systemic lupus erythematosus (SLE) and appears to be important in the pathogenesis of the disease. As a result, several clinical trials of anti-IFN monoclonal antibodies, which hold promise to control the disease, have been launched. Additionally, activation of IFN-I might be important in the prognosis and activity assessment of the disease. Therefore, new biomarkers that reflect activity of the IFN-I pathway and are simple to measure, such as the monocyte CD64 receptor, are expected to have a great impact on the management of SLE, if properly validated.

Over the past decade, numerous publications have stressed the importance of IFN-I in the pathogenesis of systemic lupus erythematosus (SLE), but their assays typically used microarrays and/or quantitative PCR (qPCR) and thus appear to be laborious and not well suited for use in clinical practice. In the previous issue of Arthritis Research Th erapy, Li and colleagues [1] have investigated a much simpler methodology to measure the level of activation of IFN-I in patients with SLE. Th ey measured the expression of CD64 (FcγRI) by fl ow cytometry on monocytes and demonstrated high levels in SLE compared with healthy controls. Th e authors also showed that CD64 levels correlated with IFN-stimulated gene (ISG) expression (by qPCR) and disease activity (by Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)) and that CD64 was downregulated in four patients who received pulse methylprednisolone therapy. As expected, CD64 was induced in normal monocytes by IFN-I in vitro. Similar fi ndings have been obtained in SLE monocytes by fl ow cytometry in another study focused on sialoadhesin (Siglec-1 or CD169), although this assay required indirect immuno fl uores cence staining [2]. Both these molecules appear promising as biomarkers of IFN-I activation in SLE.
Th e clinical signifi cance of IFN-I pathway activation in SLE is multifaceted. First, the pathway has been implicated in the pathogenesis of the disease, and therefore targeted therapies against IFN-I are currently in clinical trials. Second, IFN-I activation may identify a subset of SLE patients with potential diagnostic, prognostic and therapeutic implications. Th ird, change in IFN-I activity levels may refl ect change in disease activity and thus help clinical management of the disease. In this context, the data by Li and colleagues on CD64 expression have clinical relevance as they might facilitate research in all of the above areas with a simple tool.
Th e implication of IFN-I in SLE pathogenesis comes from multiple pieces of evidence, including genetic, gene expression association studies, and induction of SLE by therapeutic administration of IFN-I [3]. Th e potential mechanisms by which IFN-I may promote infl ammation and autoimmunity have been reviewed recently and include activation of immature dendritic cells and break of peripheral tolerance, augmentation of humoral immunity pathways with production of pathogenic antibodies, induction of Th 1 cells, chemokine production, and priming of myeloid cells for enhanced responses to infl ammatory stimuli [4]. Th e emerging evidence about the pathogenic role of IFN-I in SLE led to the recent introduction in clinical trials of several anti-IFN antibodies. Th is exciting new era of IFN-I targeting should greatly benefi t from simple biomarkers of the pathway's activity, such as CD64 and CD169 expression. Th is would facilitate stratifi cation of SLE patients according to IFN-I activation, as well as monitoring of the degree of IFN-I inhibition during therapy -adequate to suppress disease activity, but not excessive to cripple immunosurveillance.
Cross-sectional studies, including our own and the study by Li and colleagues, have shown that IFN-I activation in SLE is present in about half of adult patients and it is associated with disease activity, renal involvement, as well as autoantibodies to dsDNA, and RNA

Abstract
The IFN-I pathway is activated in systemic lupus erythematosus (SLE) and appears to be important in the pathogenesis of the disease. As a result, several clinical trials of anti-IFN monoclonal antibodies, which hold promise to control the disease, have been launched. Additionally, activation of IFN-I might be important in the prognosis and activity assessment of the disease. Therefore, new biomarkers that refl ect activity of the IFN-I pathway and are simple to measure, such as the monocyte CD64 receptor, are expected to have a great impact on the management of SLE, if properly validated. Binding Proteins (anti-Ro, La, Sm, RNP) [1,[5][6][7]. Th is group of patients might represent a diff erent subclass of the disease where the IFN-I pathway is dominant and therefore its therapeutic targeting most benefi cial. Th e design of those studies, however, leaves open the possibility that some patients may be positive for IFN only intermittently, especially during disease fl ares, and again negative after aggressive therapy, such as with pulse methylprednisolone [1,5]. More research needs to be done in this area before conclusions can be drawn. We believe that although SLE patients should be stratifi ed in clinical trials of anti-IFN therapy, patients negative for IFN-I activation should not be excluded from the trials.

© 2010 BioMed Central Ltd
Two longitudinal studies failed to show ability of IFN-I activation to parallel acute changes of disease activity [6,7]. However, one of those studies used microarray data (which is less accurate than qPCR) for their ISG score [7] and both had only few patients with more than two visits. Moreover, IFN-regulated chemokine levels did parallel disease activity in a larger study [8]. Interestingly, high baseline levels of these chemokines substantially increased the risk for lupus fl are, especially a renal one, in the next year [8]. Flares were also increased for patients with high baseline ISG scores, but in a more delayed manner [6]. In our experience, about 30 to 40% of patients, followed longi tudinally for at least 2 years, demonstrate parallel courses of SLEDAI and ISG scores [9]. Based on the above studies, it appears that the matter has not been resolved yet, but it is possible that ISG scores work as biomarkers of disease activity only in a subgroup of patients, and not necessarily the ones with high baseline IFN-I activity. Other pathway signatures or a combination of those might be eventually required to evaluate all patients [10].
Although measurement of monocyte CD64 and CD169 expression appears promising, it is likely not specifi c for either IFN-I or SLE disease activity. Similar to other ISGs, both can be induced by viral infection and IFN-γ, whereas CD64 expression may also be induced by 11,12]. Th us, at this point, none of the above gene measurements can be expected to substitute for clinical judgment to diff erentiate lupus fl are from infection. Furthermore, before these new monocyte cell surface markers can fulfi ll their promise for ease and effi ciency of IFN-I detection, they will need to be validated against currently used IFN-I molecular assays (especially qPCR) in carefully conducted large longitudinal prospective studies of SLE patients.