Measuring IFN activity in suspected SLE: a valuable step?

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by a complex immune dysregulation leading to diverse clinical phenotypes. The preclinical lupus phase (preclinical SLE) is defined as the time of emerging maladaptive immune responses prior to full-blown SLE, and is mainly applied in a retrospective manner [1]. In contrast, incomplete or suspected SLE (iSLE) is often the term used by many rheumatologists in an attempt to identify individuals at risk for clinical SLE. Another common term used is undifferentiated connective tissue disease (UCTD), which describes more broadly people with suggestive but not entirely diagnostic features of an underlying connective tissue disease, which besides SLE may include scleroderma or rheumatoid arthritis. Studies among individuals with UCTD have shown that clinical and immunologic factors, such as female sex, ANAhomogenous pattern, anti-dsDNA, anti-Sm, and anticardiolipin antibodies, portend an increased risk to transition to clinical SLE [2]. On the contrary, nonspecific markers for inflammation like the sedimentation rate and C-reactive protein are not particularly useful as predictors of disease progression [3]. Efforts to understand the intrinsic mechanisms for the development of SLE revealed that many of these patients generate and accumulate pathogenic autoantibodies, probably related to a break of B and/or T cell tolerance, many years before a clinical diagnosis is made [4]. Even though autoantibody profiling appears to be an interesting approach to detect individuals at risk, it is limited by the low percentage of autoantibody-positive healthy subjects who ultimately develop SLE. For several decades now it is known that the interferon (IFN) signaling pathway is prominently activated in SLE, with up to 50% of these patients exhibiting various IFN-inducible genes (IFIGs) linked with disease activity and severity [5–7]. Although there are available direct methods that detect interferon levels in peripheral blood, these lack sensitivity, many times, IFN activity is measured simultaneously by calculating a score from the expression of a set of IFIGs, which is commonly represented as either a categorical variable (high vs low) or a continuous one. The latter have been found to be more informative though [8]. The increased understanding of the important role of interferon in SLE led to therapeutic strategies targeting this cytokine. Despite the fact initial trials that evaluated a monoclonal antibody against interferon alpha were unsuccessful, there are some promising results with Anifrolumab, a human monoclonal antibody that blocks the common interferon alpha receptor subunit 1, especially among those SLE patients with active skin disease [9,10]. Interferons have also been found overexpressed in preclinical SLE and it is hypothesized these might be implicated in the development of clinical autoimmunity [11] (Figure 1). Therefore, ascertaining interferon status could be of value in distinguishing individuals at risk that may benefit from early preventive interventions. In this regard, hydroxychloroquine has been shown to delay the onset of SLE [12], and this effect may be connected to type I interferon suppression. Currently, hydroxychloroquine is under investigation for the prevention of SLE (NCT03030118) [13,14]. Here we center our discussion on the different types of interferons, their expression, and their role in the disease, stressing their potential as diagnostic and prognostic biomarkers in suspected SLE.