Background/Purpose: We previously reported that treatment with ustekinumab (UST), an anti-IL-12/23 p40 neutralizing monoclonal antibody, improved global and organ-specific measures of disease activity in a randomized, placebo (PBO)-controlled study of patients with active SLE (NCT02349061)¹. Type I interferon (IFN-I) and type II IFN (IFN-g) are elevated in a subset of SLE patients. The comparative effects of IFN-I and IFN-g in SLE remain uncertain, although targeting IFN-I (anifrolumab) has demonstrated clinical efficacy, whereas a preliminary study with anti-IFN-g mAb (AMG811) failed to establish benefit^2,3. Given the potential importance of the IFN-I and IFN-g pathways in SLE pathogenesis, we studied the effects of UST treatment on both IFN-I and IFN-g in patients with active SLE.

Methods: We conducted a phase 2, PBO-controlled study in 102 adults with seropositive SLE by SLICC criteria and active disease (baseline SLEDAI score ≥6 and ≥1 BILAG A and/or ≥2 BILAG B scores) despite standard-of-care therapy¹. Gene expression analysis using a previously published 21 gene IFN-I gene signature (IGS)⁴ was performed by microarray analysis using whole blood PAXgene RNA samples. Analysis of serum protein levels of IFN-g and IFN-α was performed using MSD (IFN-g) and Quanterix (IFN-α) platforms.

Results: Serum levels of IFN-g and IFN-α and the IGS were significantly elevated at baseline versus healthy controls (p<0.0001). Approximately 67% of the SLE patients were IGS high at baseline. At 4 weeks, patients who received UST, but not PBO, exhibited decreased IFN-g protein levels (p=0.0032). Despite non-significant differences at baseline, there was a trend toward greater reduction in IFN-g levels in UST-treated patients who achieved an SRI-4 response at wk24 compared to non-responders. There was no decrease in IFN-α protein levels or the IGS after treatment with either UST or PBO. Whereas the proportion of patients achieving an SRI-4 response at wk24 was numerically greater in the IGS low patients (81.8% UST vs. 54.5% PBO) versus the IGS high (48.6% UST vs. 20% PBO) population, the magnitude of the treatment effect (UST vs. PBO) was similar in both subsets (IGS low effect size= 27.3% vs. IGS high effect size = 28.6%).

Conclusion: In this SLE trial population which had significant upregulation of IFN-I protein and IGS at baseline, clinical response to UST was not associated with IFN-I reduction. In contrast, a significant decrease in IFN-g protein levels was associated with UST treatment. These findings suggest that a broad population of SLE patients may respond to UST regardless of baseline IFN status. Moreover, an effect of UST treatment on TH1 responses manifested by IFN-g levels in SLE patients was suggested, a finding that will be tested in a phase 3 trial.

¹ACR 2017 Abstract # 6L

²Furie, R., et al., Arthritis Rheumatol, 2017. 69(2): p. 376-386.1.

³Boedigheimer, M.J., et al., Lupus Sci Med, 2017. 4(1): p. e000226.

⁴Yao, Y., et al., HGP, 2009.

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