Seronegative Rheumatoid Arthritis: A Distinct Immunopathological Entity with Erosive Potential.

Area of Science:

• Rheumatology
• Immunology
• Clinical Medicine

Background:

• Seronegative rheumatoid arthritis (SNRA) accounts for 20-30% of rheumatoid arthritis (RA) cases.
• Previously thought to be milder, SNRA is now recognized as heterogeneous, with some patients showing significant structural progression.
• Standard RF and ACPA tests may miss unconventional autoimmune responses in SNRA patients, as indicated by the broader anti-modified protein antibody (AMPA) family.

Purpose of the Study:

• To review current knowledge on SNRA epidemiology, immunopathology, diagnosis, and treatment.
• To emphasize the distinction between erosive and non-erosive SNRA phenotypes.
• To explore the implications of the AMPA paradigm for understanding SNRA.

Main Methods:

• Comprehensive literature search of PubMed, Cochrane Library, and Google Scholar.
• Focus on randomized trials, observational cohorts, and systematic reviews from the past decade.
• Synthesis of contemporary insights into SNRA.

Main Results:

• SNRA exhibits distinct immune features, including differences in lymphoid structures and innate inflammatory circuits.
• Unconventional humoral responses against non-classical post-translational modifications may be present in some RF/ACPA-negative patients.
• While ACPA predicts erosions, up to one-third of SNRA patients develop them; current diagnostic criteria may delay SNRA diagnosis. Therapies like cytokine and JAK inhibitors show similar efficacy across serostatuses, but B-cell and T-cell therapies are less effective in SNRA.

Conclusions:

• SNRA is clinically and immunologically diverse, necessitating the integration of the AMPA framework for improved classification and prognostication.
• Differentiating erosive from non-erosive SNRA is crucial for guiding treatment decisions.
• Future research should focus on identifying biomarkers for predicting SNRA progression and treatment response.