The following is a summary of “Multifaceted immune dysregulation characterizes individuals at-risk for rheumatoid arthritis,” published in the November 2023 issue of Rheumatology by James et al.

In the context of rheumatoid arthritis (RA), the detection of autoimmunity-associated molecular markers, specifically antibodies to citrullinated protein antigens (ACPA), precedes the onset of inflammatory arthritis (IA) and may delineate a phase deemed ‘at-risk’ for future RA development. This study undertook a cross-sectional comparative analysis involving three distinct groups: ACPA-positive individuals lacking IA (termed At-Risk), ACPA-negative individuals, and individuals with early clinical RA demonstrating ACPA positivity (referred to as Early RA).

The differential methylation analysis conducted among these groups unveiled a broad, non-specific dysregulation present in peripheral B cells, memory T cells, and naïve T cells within the At-Risk participants. In contrast, individuals with Early RA displayed more specific abnormalities in immunological pathways. Tetramer studies conducted in the At-Risk cohort showcased an increased abundance of T cells recognizing citrullinated (cit) epitopes, notably an expansion of T cells reactive to citrullinated cartilage intermediate layer protein I (cit-CILP). These particular T cells exhibited phenotypes akin to Th1, Th17, and T stem cell memory.

Furthermore, analyses using antibody-antigen arrays demonstrated elevated antibodies targeting cit-clusterin, cit-fibrinogen, and cit-histone H4 among At-Risk and Early RA participants. The highest antibody levels were observed in those diagnosed with Early RA.

These findings collectively highlight that the ACPA-positive at-risk state is associated with multifaceted immune dysregulation. This intricate immune profile, evident before the onset of inflammatory arthritis, presents a potential window for targeted intervention strategies.

The study underscores the complexity of immune dysregulation in individuals deemed at risk for RA due to ACPA positivity. The identified immune abnormalities across various cell types and specific antibody profiles suggest a potential early intervention opportunity before the onset of clinically apparent disease. These insights contribute to a better understanding of the immune landscape preceding RA and lay the groundwork for prospective intervention strategies targeting individuals in the at-risk phase.

Source: nature.com/articles/s41467-023-43091-8