Association between intestinal permeability, systemic inflammation, and response to anti-TNF therapy in patients with rheumatoid arthritis: a prospective controlled study

Objectives: To evaluate the association between biomarkers related to intestinal epithelial barrier integrity, systemic inflammation, and clinical response to anti-TNF therapy in patients with rheumatoid arthritis (RA). Methods: A prospective controlled 24-week study of patients with active RA receiving anti-TNF therapy was performed. Findings were compared with those of age- and sex-matched healthy controls. Values of tight junction proteins (occludin, claudin-1), zonulin, lipopolysaccharide (LPS), and LPS-binding protein (LBP) were determined in serum and feces at baseline and at 6 months. The associations with clinical, inflammatory, and remission parameters (DAS28-CRP ≤2.6) were analyzed. Multivariate models explored links between intestinal, inflammatory, and treatment response biomarkers. Results: The study population comprised 70 patients with RA and 70 controls. Baseline serum levels of occludin and claudin-1 were lower in patients than in controls (p<0.001). After 6 months, systemic inflammation had improved significantly, and values of several biomarkers had returned to normal in patients who achieved clinical remission. In multivariate analysis, higher baseline occludin and claudin-1 levels were associated with a greater probability of achieving remission (OR = 1.04, and 1.02, respectively). Average HAQ was inversely associated with remission (OR = 0.26). Increased occludin after anti-TNF was associated with baseline DAS28-CRP (β=0.314) and IL-1β (β=0.416); claudin-1 with male sex (β=-0.342); and zonulin with lower IL-1β (β=-0.313) and higher resistin (β=0.294). Conclusions: Biomarkers of intestinal integrity, especially serum occludin, are altered in patients with RA and were associated with response to anti-TNF. Disruption of the intestinal barrier, as reflected by these indirect markers, is associated with systemic inflammation, thus reinforcing the gut-joint axis as a potential therapeutic target.