Preclinical and clinical outcomes in patients with high rheumatoid factor levels treated with TNF inhibitors:a systematic review

OBJECTIVES: Rheumatoid factor (RF) binds to the fragment crystallisable (Fc) portion of immunoglobulin G1 and can also bind to the Fc region of biologic agents, forming immune complexes that are subsequently cleared by macrophages, contributing to reduced drug availability and diminished therapeutic response. In this systematic review, we examined the binding mechanism and impact of RF on tumour necrosis factor inhibitors (TNFis) with and without an Fc portion, along with the impact of RF levels on drug concentration and clinical outcomes in patients with rheumatoid arthritis (RA). METHODS: Searches were carried out in MEDLINE, Embase, and Cochrane CENTRAL up to January 2025 and updated in July 2025. Abstracts and full texts were screened, and discrepancies were resolved by consensus. Studies that included at least 1 group of adult patients with high RF treated with TNFis (with or without an Fc region) with outcomes of interest were considered for inclusion. RESULTS: Of the 21 studies included, 1 study reported both clinical and preclinical data, 3 studies reported preclinical data, and 18 studies reported efficacy and effectiveness outcomes in 8910 patients treated with TNFis. Clinical endpoints, such as the Clinical Disease Activity Index, the Simple Disease Activity Index, the Disease Activity Score-28 with C-reactive protein (DAS28-CRP), or erythrocyte sedimentation rate (DAS28-ESR), and Boolean remission were similar or slightly better in patients with high RF who received Fc-free TNFis, relative to those with low RF levels. CONCLUSIONS: Considering these observations, Fc-free TNFis may provide some advantages to RA patients with high RF levels.