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.