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.

Trial registration: ClinicalTrials.gov NCT02349061.

© 2020 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.

Figures

Figure 1

Assessment of serum levels of p40 and interleukin‐23 (IL‐23). A and B, Serum levels of p40 (A) and IL‐23 (B) were determined in healthy controls (n = 60) and at baseline in patients with systemic lupus erythematosus (SLE) in the placebo (PBO) or ustekinumab (UST) treatment groups (subject numbers at week 0 shown at bottom of C and D) by response status at week 24 (responder [R] versus nonresponder [NR]). Data are shown as box plots. Each box represents the 25th to 75th percentiles. Lines inside the boxes represent the median. Lines outside the boxes represent the 10th and 90th percentiles. Circles indicate outliers. C and D, Longitudinal serum concentrations of p40 (C) and IL‐23 (D) were compared between the ustekinumab and placebo groups of SLE patients by response status. Results are shown as the median change from baseline with median absolute deviation of the change. Numbers of subjects with available samples are indicated at each time point. * = P < 0.05; ** = P < 0.01; *** = P < 0.001; **** = P < 0.0001 versus baseline within group in C and D or as indicated in A. Asterisk color in C and D matches the treatment response group in which a significant difference was achieved. P values were computed using t‐tests.

Figure 2

Assessment of serum levels of interferon‐γ (IFNγ). A, Serum levels of IFNγ were determined in healthy controls (n = 60) and at baseline in patients with SLE in the placebo or ustekinumab treatment groups (subject numbers at week 0 shown at bottom of B) by response status at week 24. Data are shown as box plots. Each box represents the 25th to 75th percentiles. Lines inside the boxes represent the median. Lines outside the boxes represent the 10th and 90th percentiles. Circles indicate outliers. B, Longitudinal serum concentrations of IFNγ were compared between the ustekinumab and placebo groups of SLE patients by response status. Results are shown as the median change from baseline with median absolute deviation of the change. Numbers of subjects with available samples are indicated at each time point. ** = P < 0.01; *** = P < 0.001; **** = P < 0.0001 versus baseline within group in B or as indicated in A. † = P < 0.05 for responders versus nonresponders. Footnote symbol color matches the treatment response group in which a significant difference was achieved. P values were computed using t‐tests. See Figure 1 for other definitions.

Figure 3

Assessment of serum levels of IL‐17A, IL‐17F, and IL‐22 through week 24 in the placebo and ustekinumab treatment groups of SLE patients according to response status. Results are shown as the median change from baseline with median absolute deviation of the change. Numbers of subjects with available samples at each time point are indicated below the graphs. * = P < 0.05; ** = P < 0.01 versus baseline within group. Asterisk color indicates the treatment response group in which a significant difference was achieved. P values were computed using t‐tests. See Figure 1 for definitions.