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Nowadays anti-TNF-α antibodies are used for the treatment of perianal Crohn's disease (CD). Nevertheless, this treatment is effective in only a part of these patients and recent studies suggested a role for other cytokines in chronic bowel inflammation. The aim of this study was to assess the cytokine profile in the rectal mucosa of patients affected by perianal CD and to understand its relations with the systemic cytokine profile and inflammatory parameters and the need for surgery.Seventeen patients affected by perianal CD, 7 affected by CD without perianal involvement, and 17 healthy controls were enrolled and underwent blood sampling and endoscopy. During endoscopy rectal mucosal samples were taken and the expression of TNF-α, IL-6, IL-1β, IL-12, and TGF-β1 was quantified with enzyme-linked immunosorbent assay (ELISA). Local cytokine levels were compared and correlated with diagnosis, therapy, phenotype (fistulizing and stenosing), and disease activity parameters.In the group with perianal CD, rectal mucosal IL-1β, IL-6, and serum IL-6 and TNF-α were higher than in patients with small bowel CD and healthy controls. IL-12 and TGF-β1 mucosal levels did not show any differences among the 3 groups. Mucosal IL-6 significantly correlated with the Perianal Crohn's Disease Activity Index and mucosal TNF-α and IL-1β. Mucosal TNF-α and IL-1β showed a direct correlation with the histological grade of disease activity.The cytokines network analysis in perianal CD shows the important involvement of IL-1β, IL-6, and TNF-α. Furthermore, mucosal levels of IL-6 and IL-12 are predictors of recurrence and of need for surgery in perianal CD patients.