# Autoantibodies as predictors of progression to rheumatoid arthritis: a systematic review and meta-analysis

## TL;DR

This study finds that certain autoantibodies, especially CCP2 and IgM-RF with arthralgia, strongly predict the risk of developing rheumatoid arthritis.

## Contribution

The study identifies specific combinations of autoantibodies and symptoms that most strongly predict progression to RA.

## Key findings

- Autoantibody presence increases RA risk by 3.1--19.3-fold compared to negative individuals.
- CCP2 positive individuals with arthralgia and IgM-RF had a 35.2% cumulative RA incidence at 12 months.
- Individuals with arthralgia are at highest risk of RA progression within the first 24 months.

## Abstract

The aim of this systematic review and meta-analysis was to examine autoantibody positive individuals and define: (a) the relative risk of rheumatoid arthritis (RA) compared with autoantibody negative individuals and (b) the cumulative incidence of RA over time, in different populations.

A systematic literature search was performed in August 2025. Retrospective case control studies of individuals with RA and healthy matched controls were identified and relative risk of RA was calculated. Prospective observational studies or randomised controlled trials of autoantibody positive individuals were identified and pooled survival models were used to estimate cumulative incidence of progression to arthritis.

293 full-text articles fulfilled screening criteria and 26 were eligible for meta-analysis. The presence of serum autoantibodies confers between a 3.1--19.3-fold increase risk of developing RA. Prospective studies of anticyclic citrullinated peptide 2 (CCP2) or CCP3 positive individuals were grouped according to additional criteria; presence of arthralgia, presence/absence of immunoglobulin M rheumatoid factor (IgM-RF) and first-degree or second-degree relatives with RA. The estimated cumulative incidence of RA at 12 months was highest for CCP2 positive individuals with arthralgia and IgM-RF, at 35.2% (95% CI 29.3% to 41.2%).

A considerable number of autoantibodies have been examined as predictors for RA; however, the fastest rate of progression to RA in this study occurred in those with CCP2 and IgM-RF in combination with arthralgia. Importantly, the risk of developing RA changes over time for individuals with arthralgia, and they are at the highest risk of progression within the first 24 months of follow-up.

CRD42021231245.