A large observational study identified specific gut microbiome alterations occurring up to 10 months before the clinical onset of rheumatoid arthritis, potentially offering new insights into disease progression.
In research published in Annals of the Rheumatic Diseases, investigators found that individuals who later developed rheumatoid arthritis (RA) showed significant gut microbiome instability—characterized by the accumulation of multiple bacteria, including specific Prevotellaceae strains—approximately 10 months before clinical disease onset.
The cross-sectional and longitudinal study examined 124 anti-cyclic citrullinated protein (anti-CCP) positive individuals at risk for RA, of whom 30 progressed to clinical disease. The research also included 7 participants with new-onset RA (NORA) and 22 healthy controls. In the at-risk cohort, 70% were female with a median anti-CCP antibody titre of 73 IU/mL.
Clinical characteristics differed significantly between progressors and non-progressors. RF positivity was present in 70% of progressors versus 30% of non-progressors. HLA positivity appeared in 63% of progressors compared to 51% of non-progressors. Power Doppler positivity was detected in 43% of progressors versus 14% of non-progressors.
Risk stratification, based on a validated RA risk severity score, revealed that among progressors, 10% were low risk, 50% moderate risk, and 40% high risk. In contrast, non-progressors showed 37% low risk, 55% moderate risk, and 7% high risk.
The longitudinal component followed 19 participants over 15 months at five timepoints, with 5 progressing to RA. These individuals showed significant microbiome instability (Bray-Curtis dissimilarity >0.6) approximately 10 months before clinical RA onset.
Metabolic pathway analysis demonstrated that individuals with NORA showed increased activity in several pathways compared to healthy controls, including L-lysine degradation, L-threonine metabolism, tricarboxylic acid cycle, glycol metabolism, phenylacetate degradation, and putrescine degradation.
The study revealed that anti-CCP positive at-risk individuals exhibited significantly reduced gut microbiome diversity compared to healthy controls, with this reduction stratified by anti-CCP antibody levels. High and very high levels of anti-CCP antibodies were associated with the lowest diversity, a pattern also linked to RF positivity.
Medication use was similar between groups, with NSAIDs used by 60% of progressors versus 50% of non-progressors, and steroids used by 33% of progressors versus 34% of non-progressors. Both groups averaged 3.6 medications per person.
The researchers noted study limitations, including a small longitudinal sample size and lack of 1:1 longitudinal comparison between at-risk and healthy control groups, suggesting a need for larger confirmatory studies.
Conflicts of interest disclosures include research funding, consulting fees, and honoraria from various pharmaceutical companies, including AbbVie, Lilly, Pfizer, AstraZeneca, and others; complete disclosures can be found in the original study.
