Tofacitinib Use in Rheumatoid Arthritis

Tofacitinib has demonstrated benefits in biopsies of rheumatoid arthritis patients with inadequate methotrexate response.

The oral Janus kinase (JAK) inhibitor tofacitinib can reduce metalloproteinase and interferon regulated gene expression in rheumatoid synovium, according to research published in the journal Annals of the Rheumatic Diseases.

A multifaceted team of researchers from conducted a phase II serial synovial biopsy study in patients with rheumatoid arthritis (RA) with an inadequate methotrexate response. The researchers wrote that the pathways affected by tofacitinib and the effects on gene expression in situ are currently unknown, but they aimed to examine the effects on synovial pathobiology. The patients on background methotrexate received twice daily tofacitinib 10 mg (15 patients) or a placebo (14 patients) for 28 days. The investigators performed synovial biopsies one week prior to medication initiation and on Day 28.

The patients included in the study were mostly women (26 out of 29 participants) and Caucasian (23 out of 29 patients). Ages of patients ranged from 27 to 77 years, with a mean age of 53.3 years. The mean duration of disease was 12.5 years in the tofacitinib group and 5.5 years in the placebo cohort.

The researchers found that the European League Against Rheumatism (EULAR) responses were moderate to good (11 out of 14 patients) in patients exposed to tofacitinib on Day 28. The placebo was ineffective and only 1 of 14 patients saw improvement on the EULAR response. Tofacitinib treatment reduced synovial mRNA expression of matrix metalloproteinase (MMP) 1 and MMP 3, as well as chemokines CCL 2, CXCL 10, and CXCL 13, the researchers added.

“Since cytokine inhibitors decrease disease activity in RA, blocking kinases in the signal transduction cascade could potentially have the same benefit,” the authors wrote. “Targeting JAK proteins has met with success in clinical trials, and several JAK inhibitors have demonstrated efficacy in RA, similar to biological agents, in particular, tofacitinib.”

There were no overall changes observed in synovial inflammation scores or the presence of T cells, B cells, or macrophages, the researchers continued. However, there were changes obvserved in synovial phosphorylation of signal transducer and activation of transcription 1 (STAT 1) and STAT 3, which were strongly associated with 4 month clinical responses. Finally, compared to placebo, tofacitinib significantly decreased plasma CXCL 10 by Day 28, the researchers commented.

“The data suggest that tofacitinib regulates JAK mediated events in the rheumatoid synovium,” the authors concluded. “JAK1 inhibition, with early suppression of STAT1 and STAT3, correlates well with longer term clinical benefit. The effects of tofacitinib on blood chemokines such as CXCL 10 suggest that biomarkers might be used to either predict or evaluate therapeutic response.”