Guselkumab for hidradenitis suppurativa: a phase II, open-label, mode-of-action study.

BACKGROUND: The effectiveness of available biologics for the treatment of hidradenitis suppurativa (HS) is limited. Additional therapeutic options are needed. OBJECTIVES: To investigate the efficacy and mode of action of guselkumab [an anti-interleukin (IL)-23p19 monoclonal antibody] 200 mg subcutaneously every 4 weeks for 16 weeks in patients with HS. METHODS: An open-label, multicentre, phase IIa trial in patients with moderate-to-severe HS was carried out (NCT04061395). The pharmacodynamic response in skin and blood was measured after 16 weeks of treatment. Clinical efficacy was assessed using the Hidradenitis Suppurativa Clinical Response (HiSCR), the International Hidradenitis Suppurativa Severity Score System (IHS4), and the abscess and inflammatory nodule (AN) count. The protocol was reviewed and approved by the local institutional review board (METC 2018/694), and the study was conducted in accordance with good clinical practice guidelines and applicable regulatory requirements. RESULTS: Thirteen of 20 patients (65%) achieved HiSCR with a statistically significant decrease in median IHS4 score (from 8.5 to 5.0; P = 0.002) and median AN count (from 6.5 to 4.0; P = 0.002). The overall patient-reported outcomes did not show a similar trend. One serious adverse event, likely to be unrelated to guselkumab treatment, was observed. In lesional skin, transcriptomic analysis revealed the upregulation of various genes associated with inflammation, including immunoglobulins, S100, matrix metalloproteinases, keratin, B-cell and complement genes, which decreased in clinical responders after treatment. Immunohistochemistry revealed a marked decrease in inflammatory markers in clinical responders at week 16. CONCLUSIONS: Sixty-five per cent of patients with moderate-to-severe HS achieved HiSCR after 16 weeks of treatment with guselkumab. We could not demonstrate a consistent correlation between gene and protein expression and clinical responses. The main limitations of this study were the small sample size and absence of a placebo arm. The large placebo-controlled phase IIb NOVA trial for guselkumab in patients with HS reported a lower HiSCR response of 45.0-50.8% in the treatment group and 38.7% in the placebo group. Guselkumab seems only to be of benefit in a subgroup of patients with HS, indicating that the IL-23/T helper 17 axis is not central to the pathophysiology of HS.

TNFα-Signaling Modulates the Kinase Activity of Human Effector Treg and Regulates IL-17A Expression.

Maintenance of regulatory T cells CD4+CD25highFOXP3+ (Treg) stability is vital for proper Treg function and controlling the immune equilibrium. Treg cells are heterogeneous and can reveal plasticity, exemplified by their potential to express IL-17A. TNFα-TNFR2 signaling controls IL-17A expression in conventional T cells via the anti-inflammatory ubiquitin-editing and kinase activity regulating enzyme TNFAIP3/A20 (tumor necrosis factor-alpha-induced protein 3). To obtain a molecular understanding of TNFα signaling on IL-17 expression in the human effector (effTreg, CD25highCD45RA-) Treg subset, we here studied the kinome activity regulation by TNFα signaling. Using FACS-sorted naïve (naïveTreg, CD25highCD45RA+) and effTreg subsets, we demonstrated a reciprocal relationship between TNFα and IL-17A expression; effTreg (TNFαlow/IL-17Ahigh) and naïveTreg (TNFαhigh/IL-17Alow). In effTreg, TNFα-TNFR2 signaling prevented IL-17A expression, whereas inhibition of TNFα signaling by clinically applied anti-TNF antibodies led to increased IL-17A expression. Inhibition of TNFα signaling led to reduced TNFAIP3 expression, which, by using siRNA inhibition of TNFAIP3, appeared causally linked to increased IL-17A expression in effTreg. Kinome activity screening of CD3/CD28-activated effTreg revealed that anti-TNF-mediated neutralization led to increased kinase activity. STRING association analysis revealed that the TNF suppression effTreg kinase activity network was strongly associated with kinases involved in TCR, JAK, MAPK, and PKC pathway signaling. Small-molecule-based inhibition of TCR and JAK pathways prevented the IL-17 expression in effTreg. Together, these findings stress the importance of TNF-TNFR2 in regulating the kinase architecture of antigen-activated effTreg and controlling IL-17 expression of the human Treg. These findings might be relevant for optimizing anti-TNF-based therapy and may aid in preventing Treg plasticity in case of Treg-based cell therapy.

TNF-α-induced protein 3 (TNFAIP3)/A20 acts as a master switch in TNF-α blockade-driven IL-17A expression.

BACKGROUND: Anti-TNF inhibitors successfully improve the quality of life of patients with inflammatory disease. Unfortunately, not all patients respond to anti-TNF therapy, and some patients show paradoxical immune side effects, which are poorly understood. Surprisingly, anti-TNF agents were shown to promote IL-17A production with as yet unknown clinical implications. OBJECTIVE: We sought to investigate the molecular mechanism underlying anti-TNF-driven IL-17A expression and the clinical implications of this phenomenon. METHODS: Fluorescence-activated cell sorting, RNA sequencing, quantitative real-time PCR, Western blotting, small interfering RNA interference, and kinase inhibitors were used to study the molecular mechanisms in isolated human CD4+ T cells from healthy donors. The clinical implication was studied in blood samples of patients with inflammatory bowel disease (IBD) receiving anti-TNF therapy. RESULTS: Here we show that anti-TNF treatment results in inhibition of the anti-inflammatory molecule TNF-α-induced protein 3 (TNFAIP3)/A20 in memory CD4+ T cells. We found an inverse relationship between TNFAIP3/A20 expression levels and IL-17A production. Inhibition of TNFAIP3/A20 promotes kinase activity of p38 mitogen-activated protein kinase and protein kinase C, which drives IL-17A expression. Regulation of TNFAIP3/A20 expression and cognate IL-17A production in T cells are specifically mediated through TNF receptor 2 signaling. Ex vivo, in patients with IBD treated with anti-TNF, we found further evidence for an inverse relationship between TNFAIP3/A20 expression levels and IL-17A-producing T cells. CONCLUSION: Anti-TNF treatment interferes in the TNFAIP3/A20-mediated anti-inflammatory feedback loop in CD4+ T cells and promotes kinase activity. This puts TNFAIP3/A20, combined with IL-17A expression, on the map as a potential tool for predicting therapy responsiveness or side effects of anti-TNF therapy. Moreover, it provides novel targets related to TNFAIP3/A20 activity for superior therapeutic regimens in patients with IBD.