In vitro pharmacological effects of peficitinib on lymphocyte activation: a potential treatment for systemic sclerosis with JAK inhibitors

Abstract

Objectives Peficitinib, a novel Janus kinase (JAK) inhibitor, demonstrated promising results in treating RA in phase 3 clinical trials. This in vitro study was undertaken to characterize the pharmacological properties of peficitinib and investigate the involvement of JAK and signal transducer and activator of transcription (STAT) pathways in the pathological processes of SSc, which is also an autoimmune disease. Methods Phosphorylation levels of STAT molecules were assessed in peripheral blood mononuclear cells collected from patients with RA or SSc and healthy subjects, and in skin specimens obtained from 19 patients with SSc. In vitro inhibition of STAT phosphorylation and cytokine/chemokine production by peficitinib, tofacitinib and baricitinib were also characterized. Results Higher spontaneous STAT1 or STAT3 phosphorylation was observed in peripheral T-cells and monocytes from patients with RA and SSc compared with healthy subjects. In skin sections from patients with SSc, phosphorylated STAT3–positive cells were found in almost all cases, irrespective of disease subtype or patient characteristics. Conversely, phosphorylated STAT1-positive cells were observed only in samples from untreated patients with diffuse disease of short duration. Peficitinib inhibited STAT phosphorylation induced by various cytokines, with comparable efficacy to tofacitinib and baricitinib. Peficitinib also suppressed cytokine and chemokine production by peripheral blood mononuclear cells and skin fibroblasts. Conclusion Our results suggest that JAK/STAT pathways are constitutively activated in SSc and RA, and that the JAK inhibitor may represent a novel therapeutic option for SSc.

Future Treatment Options in Systemic Sclerosis—Potential Targets and Ongoing Clinical Trials

“…Therefore, interest in inhibitors of this pathway has grown. Multi-targeted cytokine signal inhibition makes it possible for these to be effective in the treatment of SSc [ 34 ]. In the phase I/II trial, 15 participants were randomized to assess the safety of tofacitinib in patients with dcSSc.…”

Impact of Different JAK Inhibitors and Methotrexate on Lymphocyte Proliferation and DNA Damage

“…Compared to healthy controls, peripheral blood isolated from patients with active RA revealed an enhanced level of activated PBMCs, which may play a direct role in disease pathogenesis [ 18 ]. Furthermore, Kitanaga et al stated constitutive activation of JAK/STAT signaling in PBMCs from patients with systemic sclerosis or RA [ 19 ].…”

TFH cells in systemic sclerosis

“…Tfh cells differentiation and activation depend on multifactorial processes and are regulated by several signalling pathways. Among them, the signal transducer and activator of transcription (STAT)3/janus kinase (JAK)2 signalling pathway is overexpressed in SSc [ 46 ]. Activated by several cytokines and growth factors, STAT3 is involved in skin fibrosis in both humans and bleomycin induced mouse model and also in Tfh cell differentiation and contributes to BCL-6 expression [ 16 , 47 , 48 ].…”

“…Moreover, in recent years, several studies have focused on JAK inhibition for the treatment of both GVHD and auto-immune diseases [ 57 ]. During in vitro experiments using peripheral blood mononuclear cells (PBMC) from SSc patients, JAK inhibitor reduces STAT phosphorylation [ 46 ], suggesting that its use should to be promising for SSc treatment. Indeed, tofacitinid, a pan inhibitor of JAK has been evaluated in early diffuse cutaneous SSc and found to be well tolerated [ 58 ].…”