Methotrexate Associated with “Profound” Improvements in RA

Methotrexate therapy in patients with rheumatoid arthritis can cause significant changes in clinical disease activity, researchers say.

The study appears in the June 16 issue of RMD Open.

To date, researchers said, there have been no studies into the mechanism of action of methotrexate which look at serial prospective measures of serum cytokines and simultaneous measures of pharmacokinetics and clinical variables.

In this prospective, open-label, long-term mechanism of action study, investigators looked to describe changes in immune parameters that are observed during long-term methotrexate therapy in patients with active rheumatoid arthritis. They also wanted to explore correlations with simultaneously measured methotrexate pharmacokinetic parameters.

Led by Joel M. Kremer, M.D., from the Division of Rheumatology at Albany Medical College, researchers demonstrated that methotrexate treatment is associated with serum interleukin-6 (IL-6) and interleukin-8 (IL-8) decreases. This three-year study, conducted in the 1990s, also shows these drops correlate well with long-term, sequential measures of methotrexate pharmacokinetics and with clinical outcomes. [[{"type":"media","view_mode":"media_crop","fid":"49774","attributes":{"alt":"©JPC-PROD/Shutterstock.com","class":"media-image media-image-right","id":"media_crop_7724857889064","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"6050","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":"©JPC-PROD/Shutterstock.com","typeof":"foaf:Image"}}]]

Throughout the study, 17 patients received single, weekly 7.5 mg doses of methotrexate. The doses were adjusted for efficacy and toxicity throughout the study, and researchers gathered baseline measures for disease activity and took follow-up measurements every six months for three years. Each clinical evaluation assessed serum cytokine measurements in blood together with lymphocyte surface immunophenotypes and stimulated peripheral blood mononuclear cell cytokine production.

According to study results, cytokine concentrations revealed several significant correlations over time with disease activity measures. The two strongest were: interleukin-6 (r=0.45, p<0.0001 for swollen joints and r=0.32, p=0.002 for tender joints) and interleukin-8 (r=0.25, p=0.01 for swollen joints).

Results also found significant decreases for serum interleukin-1B, interleukin-6, and interleukin-8 from baseline measurements with interleukin-6 being the most substantial change (p<0.001). Data also revealed noteworthy increases from baseline for interleukin-2 release from peripheral blood mononuclear cells ex vivo (p<0.01). However, the change in swollen joint count correlated inversely with the changes for methotrexate (r=-0.63, p=0.007).

“These data strongly support the notion that MTX (methotrexate) mediates profound and functionally relevant effects on the immunological hierarchy in the RA lesion,” the researchers wrote.

Ultimately, investigators said, knowing methotrexate can significantly affect serum interleukin-6 will increase understanding around methotrexate’s mechanism of action. It also offers insight into further changes in transaminase levels and possible additive effects on interleukin-6 when used with biological response modifiers and Janus kinase inhibitors.

“The compelling relationship between the immune changes reported and simultaneous pharmacokinetic measures strongly suggest that the findings are related to methotrexate intervention and are not simply a surrogate for general disease improvement,” investigators said.

In addition, they said, the significant decrease in serum interleukin-6 observed with methotrexate may further explain increases in transaminase enzymes when the drug is combined with either interleukin-6 or Janus kinase inhibitors.

References:

Kremer JM, Lawrence DA, Hamilton R, et al. “Long-term study of the impact of methotrexate on serum cytokines and lymphocyte subsets in patients with active rheumatoid arthritis: correlation with pharmacokinetic measures.” RMD Open 2016; 2:e000287. doi: 10.1136/rmdopen-2016- 000287