**1. Introduction**

Crohn's disease (CD) is a chronic inflammatory disorder of the intestinal tract, with increasing prevalence worldwide [1,2]. It is generally accepted that CD as well as ulcerative colitis (UC) are

the result of complex interactions among environmental factors, dysregulated immune system, gu<sup>t</sup> microbiota, and disease susceptibility genes [3]. Accumulating data sugges<sup>t</sup> that oxidative stress is at the crossroad between these multiple mechanisms [4–6].

Both chronic inflammation and immune system hyperactivation are accompanied by abnormally high levels of reactive oxygen species (ROS) and decreased antioxidant defenses, resulting in oxidative stress. Oxidative stress leads to mucosal layer damage and bacterial invasion, which in turn further stimulate the immune response and contribute to disease progression [7]. One of the main advantages of oxidative modifications of cellular proteins, lipids, and nucleic acids is that they can be measured not only in the a ffected intestinal tract, but also at the systemic level; several studies have in fact reported increased levels of oxidative stress biomarkers in the serum/plasma of inflammatory bowel disease (IBD) patients [8]. This is of interest at least for two reasons: on one hand, circulating biomarkers of oxidative stress o ffer the advantage of easy collection, low costs, and the possibility to be used on a large scale; on the other hand, the systemic oxidative stress observed in CD may likely contribute to the development of extra-intestinal manifestations such as perianal fistulas, dermatologic diseases, and arthritis, which are very common in these patients [9].

Circulating antioxidant capacity also seems to be correlated with the clinical status of the patients. Plasma free thiols were recently reported to be associated with favorable outcome in CD, being negatively correlated with biomarkers of inflammation [10], and serum free thiols and uric acid were significantly lower in active CD patients with anemia [11]. Furthermore, a very strong positive correlation was found between the endoscopic activity index and the serum total oxidant status in CD patients under regular follow-up [12]. These data sugges<sup>t</sup> that the measure of circulating oxidative stress markers might be clinically useful both for early diagnosis as well for clinical monitoring. Clinical diagnosis of CD can be complex and it is often delayed. Moreover, CD patients need an adequate assessment of disease activity either to guide clinical treatment, prevent long-term complications, or induce a long-term remission after surgery.

On these bases, the aim of the present study was to explore the association between several peripheral biomarkers of oxidative stress and the clinical characteristics of a cohort of CD patients characterized by therapeutic failure and a complicated disease requiring surgery.
