Suppression of Serum Interferon‐γ Levels as a Potential Measure of Response to Ustekinumab Treatment in Patients With Systemic Lupus Erythematosus

Abstract

Objective. In a previously reported phase II randomized, placebo-controlled, interventional trial, we demonstrated that treatment with ustekinumab, an anti-interleukin-12 (IL-12)/IL-23 p40 neutralizing monoclonal antibody, improved global and organ-specific measures of disease activity in patients with active systemic lupus erythematosus (SLE). Utilizing the biomarker data from this phase II clinical study, we sought to determine whether modulation of the expression of IL-12, IL-23, or both cytokines by ustekinumab is associated with clinical efficacy in patients with SLE. Methods. This phase II randomized, placebo-controlled study enrolled 102 patients with autoantibody-positive SLE whose disease remained active despite standard-of-care therapy. Patients were randomized at a 3:2 ratio to receive ~6 mg/kg ustekinumab intravenously or placebo at week 0, followed by subcutaneous injections of 90 mg ustekinumab or placebo every 8 weeks, with placebo crossover to 90 mg ustekinumab every 8 weeks. The SLE Responder Index 4 (SRI-4) at week 24 was used to determine which patients could be classified as ustekinumab responders and which could be classified as nonresponders. In addition to measurements of p40 and IL-23, serum levels of interferon-γ (IFNγ), IL-17A, IL-17F, and IL-22, as a proxy for the IL-12 and IL-23 pathways, were quantified by immunoassay. Results. Changes in the serum levels of IL-17A, IL-17F, and IL-22 at different time points after treatment were not consistently significantly associated with an SRI-4 clinical response to ustekinumab in patients with SLE. In contrast, an SRI-4 response to ustekinumab was significantly associated (P < 0.01) with durable reductions in the serum IFNγ protein levels at several time points relative to baseline, which was not observed in ustekinumab nonresponders or patients who received placebo. Conclusion. While not diminishing a potential role of IL-23, these serum biomarker assessments indicate that IL-12 blockade has an important role in the mechanism of action of ustekinumab treatment in patients with SLE. Clinicaltrials.gov identifier: NCT02349061.

Cytokines as Biomarkers in Systemic Lupus Erythematosus: Value for Diagnosis and Drug Therapy

“…Levels of IFN-γ can be modulated via other mechanisms. Interestingly, in the Phase II clinical trial of ustekinumab in SLE, the responders had declining IFN-γ levels, and this finding was suggested as a biomarker of response to anti (IL-12)/IL-23 p40 therapy [ 37 ].…”

Type I Interferons in Systemic Autoimmune Diseases: Distinguishing Between Afferent and Efferent Functions for Precision Medicine and Individualized Treatment

“…Within the limits of the relatively low number of individual tested and the sensitivity of the assays used to detect IFN-I and IFN-II, this is an important piece of evidence indicating that an adaptive immune response in SLE precedes and accompanies the initial detection of IFN-I (Lu et al, 2016). Along the same line of evidence, clinical responders, as opposed to nonresponders in a phase 2 trial assessing the efficacy and safety of ustekinumab (anti-IL-12/IL-23) in SLE had treatment-dependent reduced serum levels of IFN-gamma and not of other cytokines (van Vollenhoven et al, 2018;Cesaroni et al, 2020;van Vollenhoven et al, 2020).…”

Data Mining and Meta-Analysis of Psoriasis Based on Association Rules

“…Scholars used a multi-center randomized controlled method for clinical observation [ 30 ]. The treatment group was mainly given the prescription of cooling blood and detoxification, the liver-clearing and purging gunpowder was used for the blood-heat syndrome, the liver-releasing and qi-regulating medicine was used for the blood stasis syndrome, and the liver-softening detoxification was used for the blood-dry syndrome [ 31 – 33 ]. All were treated with medicine that was soothing to the liver and relieved depression.…”