Response to ustekinumab treatment in patients with systemic lupus erythematosus is linked to suppression of serum interferon gamma levels.

OBJECTIVE We previously reported that treatment with ustekinumab, an anti-interleukin (IL)-12/23 p40 neutralizing monoclonal antibody, improved global and organ-specific measures of disease activity in a randomized, placebo-controlled study of patients with active systemic lupus erythematosus (SLE). Here, we utilized biomarker data from this clinical study to determine whether modulation of IL-12, IL-23, or both were associated with clinical efficacy. METHODS A Phase 2, placebo-controlled study enrolled 102 patients with autoantibody positive SLE and active disease despite standard-of-care therapy. Patients were randomized (3:2) to receive intravenous ustekinumab ~6 mg/kg or placebo at week 0, then subcutaneous injections of 90 mg ustekinumab or placebo every 8 weeks. SLE Responder Index 4 at week 24 was used to determine which patients were ustekinumab responders and non-responders. In addition to measuring p40 and IL-23, serum interferon (IFN)-γ, IL-17A, IL-17F and IL-22 levels were quantified by immunoassay as a proxy for the IL-12 and IL-23 pathways. RESULTS Changes in serum IL-17A, IL-17F and IL-22 levels did not associate consistently with ustekinumab response. In contrast, response to ustekinumab was associated with a durable reduction in IFN-γ serum protein levels relative to baseline, which was not observed in ustekinumab non-responders or placebo patients. CONCLUSIONS These data indicate an important role of IL-12 blockade in the mechanism of action of ustekinumab in SLE.