Comment on: Alexis Mathian, Suzanne Mouries-Martin, Karim Dorgham et al. Ultrasensitive serum interferon-α quantification during SLE remission identifies patients at risk for relapse. Ann Rheum Dis 2019;0:1–8. doi:10.1136/annrheumdis-2019-215571.
Commented by: Carlo Chizzolini, University of Geneva | UNIGE, Division of Immunology and Allergology.
The importance in SLE pathogenesis of type-I interferon (IFN-I) has been well documented and therapeutic strategies targeting IFN-I in SLE are currently being tested in clinical trials with promising results. IFN-I is thought to be produced mostly by plasmacytoid dendritic cells (pDC) in target organs, but also by monocyte/macrophages and other cells of the innate immune system. Immune complexes containing nucleic acids and complexes of antimicrobial peptides (such as LL-37), or other highly amphipathic peptides (such as some chemokines), with associated nucleic acids may be instrumental in concentrating DNA or RNA in endosomal compartments where they can activate toll-like receptors (TLR) leading to IFN-I production. In turn, IFN-I may influence qualitatively and quantitatively both the innate as well as the adaptive immune response finally participating to organ damage.
Under this light, it is not surprising that high levels of IFN-I are usually associated with high disease activity in SLE. However, the direct assessment of IFN-I serum levels is technically challenging, since many antigenically distinct isoforms of IFN-I may participate in the response and biological detection methods of IFN-I are insensitive. Thus, rather than assessing IFN-I serum levels, the detection IFN-I responding genes or their products is current practice. In this respect, a potentially major technical advance is the novel methodology named SIMOA (single-molecule array) which is an ultrasensitive assay enabling direct IFN-α quantification at attomolar concentrations, corresponding to a 5000-fold—increased sensitivity over classic ELISA. By using this technology Mathian and colleagues (1) report that in SLE individuals, in clinical remission, high levels of IFN-I at base-line and duration of remission are associated in an independent fashion, to a shorter time to relapse. In other words, IFN-I levels may predict relapse.
The authors based this prediction by assessing IFN-I levels in with 254 patients in remission, of which 86 (33.9%) were in complete remission off treatment, 59 (23.2%) in complete remission on treatment, 47 (18.5%) in clinical remission off treatment and 62 (24.4%) in clinical remission on treatment, where complete remission indicates SLEDAI = 0, and clinical remission indicates clinical SLEDAI (which does not take into account complement consumption and positive dsDNA antibody) = 0. Patients in ‘clinical remission on treatment’ had the highest concentration of IFN-α with a median (quartiles) of 109 fg/ mL (12–378) (vs 11 fg/mL (0–81) in patients in ‘complete remission off treatment’, p=0.0002).
Of the 254 patients in remission at day 0, 250 were followed for one year and 24 (9.6%) experienced a flare. Unadjusted cox regression showed a significantly higher risk of relapse in patients who displayed at baseline elevated IFN-α (HR 5.5 (95% CI 2.4 to 12.5), p<0.0001). Of interest, while low C3 levels at baseline were also associated with a significant risk of relapse (p<0.003), this was not the case for dsDNA antibodies detected by the Farr assay (p=0.3).
These data are new and open the possibility for clinicians to use IFN-I serum levels for predicting the risk of relapse. Limitations include the relatively low number of patients tested, which come from a single centre, and the lack of longitudinal data to confirm the robustness of the findings. Further, SIMOA technology is expensive and at the moment not available in routine laboratories. They however open new perspectives in the management of SLE patients by identifying in IFN-I an alternative biological marker which may perform better than dsDNA antibody levels to predict relapse.
References
- Mathian A, et al. Ann Rheum Dis 2019;0:1–8. doi:10.1136/annrheumdis-2019-215571