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Gut dysbiosis is associated with difficult-to-treat rheumatoid arthritis
Patricia Ruiz-Limón1,2,3, Natalia Mena-Vázquez1,4, Isabel Moreno-Indias1,2,3
1The Biomedical Research Institute of Malaga and Platform in Nanomedicine (IBIMA BIONAND Platform), Málaga, Spain.
Background:
Difficult-to-treat rheumatoid arthritis (D2T RA) refers to a subset of patients who fail to achieve adequate disease control after the use of two or more biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) with different mechanisms of action, while maintaining active inflammatory disease. This presents a therapeutic challenge and highlights the need to explore contributing factors such as the potential role of the gut microbiota. Therefore, the aim of this study was to analyze the gut microbiota and inflammation in patients with D2T RA in comparison to patients with easy-to-treat RA (E2T RA).
Objective:
To analyze the gut microbiota and inflammation in patients with D2T RA.
Methods:
We performed an observational study of a prospective cohort between 2007 and 2011 and analyzed the gut microbiota. In 2022, we identified 2 extreme patient phenotypes: (1) D2T RA, which was defined as failure of ≥2 biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) (with different mechanisms of action) plus signs of active disease; and (2) easy-to-treat RA (E2T RA), i.e., stable disease managed with a single treatment. The gut microbiota was analyzed using 16S rRNA gene sequencing; bioinformatics analysis was performed using QIIME2, and its functionality was inferred through PICRUSt. We recorded data on clinical findings, inflammation, and cytokines. A Cox multivariate analysis was performed to identify factors related to D2T RA.
Results:
The study population comprised 39 patients: 13 (33%) with D2T RA and 26 (66%) with E2T RA. The families Lachnospiraceae and Pasteurellaceae, and their genera Coprococcus and Haemophilus were more abundant in E2T RA patients, while the genus Megasphaera was more abundant in D2T RA patients. The Firmicutes/Bacteroidetes ratio decreased in D2T RA patients. The metabolic profile of the gut microbiota was characterized by differences in Degradation/Utilization/Assimilation pathway and the Biosynthesis pathway. The factors associated with D2T RA were inflammatory activity according to DAS28-ESR (HR, 2.649; p = 0.013), prednisone (HR, 3.794; p = 0.008), and the Firmicutes/Bacteroidetes ratio (HR, 0.288; p = 0.033).
Conclusion:
The composition of the gut microbiota of patients with D2T RA differed from that of E2T RA patients, as did the metabolic pathways.
Insights
Difficult-to-treat rheumatoid arthritis (D2T RA) patients exhibit distinct gut microbiota compositions and metabolic profiles compared to easy-to-treat RA (E2T RA) patients. These gut microbiome differences may influence treatment resistance in D2T RA.
Area of Science:
- Microbiome Research
- Rheumatology
- Immunology
Background:
- Difficult-to-treat rheumatoid arthritis (D2T RA) is defined by inadequate disease control despite multiple b/tsDMARDs.
- Identifying factors contributing to D2T RA, such as gut microbiota alterations, is crucial for therapeutic advancement.
- This study compared gut microbiota and inflammation in D2T RA versus easy-to-treat RA (E2T RA) patients.
Purpose of the Study:
- To analyze and compare the gut microbiota composition and function in patients with D2T RA and E2T RA.
- To identify specific microbial taxa and metabolic pathways associated with treatment-resistant RA.
- To explore the relationship between gut microbiota, inflammation, and clinical factors in D2T RA.
Main Methods:
- Observational study of a prospective cohort (2007-2011), with 2022 analysis.
- Gut microbiota analyzed via 16S rRNA gene sequencing and PICRUSt for functional inference.
- Clinical data, inflammation markers (DAS28-ESR), cytokines, and medication use were recorded. Cox multivariate analysis was employed.
Main Results:
- Significant differences in gut microbiota composition were observed between D2T RA and E2T RA patients.
- Abundant genera like Megasphaera were associated with D2T RA, while Coprococcus and Haemophilus were more prevalent in E2T RA.
- Lower Firmicutes/Bacteroidetes ratio, altered metabolic pathways, higher inflammatory activity, and prednisone use were linked to D2T RA.
Conclusions:
- Gut microbiota composition and function differ significantly between D2T RA and E2T RA patients.
- Specific microbial alterations and metabolic pathways may contribute to RA treatment resistance.
- Inflammatory activity, prednisone use, and the Firmicutes/Bacteroidetes ratio are key factors associated with D2T RA.
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