Methotrexate and BAFF interaction prevents immunization against TNF inhibitors

Area of Science:

• Immunology
• Pharmacology
• Autoimmune Diseases

Background:

• TNF inhibitors (TNFi) can induce anti-drug antibodies (ADA), leading to treatment resistance in autoimmune diseases (AID).
• Methotrexate (MTX) is explored as a strategy to mitigate TNFi immunogenicity.

Purpose of the Study:

• To investigate the potential of methotrexate (MTX) to reduce anti-drug antibody (ADA) formation in patients treated with TNF inhibitors (TNFi).
• To explore the interaction between BAFF, MTX, and immune cells in preventing immunisation against TNFi.

Main Methods:

• BAFF transgenic (BAFFtg) mice and wild-type (WT) mice were treated with TNFi and MTX.
• B-cell surface markers, purinergic metabolism, adenosine production, and regulatory B cells (Bregs) were analyzed.
• Studies were translated to macaques and rheumatoid arthritis patients from the ABIRISK cohort.

Main Results:

• A single course of MTX prevented immunisation against TNFi in BAFFtg mice, maintaining drug levels for over 52 weeks.
• MTX induced adenosine release and increased Bregs and precursors in BAFFtg mice B-cells expressing CD73 and CD39.
• High BAFF serum levels correlated with absence of ADA to TNFi only in patients co-treated with MTX.

Conclusions:

• Methotrexate (MTX) and BAFF interact in mice and patients to prevent anti-drug antibody (ADA) formation.
• CD73, adenosine, and regulatory B cells are key mediators of MTX-induced tolerance to TNFi.