From bench to bedside: the personalization of biological therapy in patients with inflammatory bowel diseases

Inflammatory bowel diseases (IBD) are chronic relapsing diseases involving the digestive tract. In recent years, their incidence and prevalence are increasing, affecting a significant proportion of young individuals. Indeed, IBD development is particularly frequent from the second to the fourth decade of life. Since their pathogenesis is not completely clear, current treatment is focused on immune-suppression, by using conventional therapy (corticosteroids, 5-aminosalicilic acid or immunosuppressants like azathioprine) or, in the most severe cases, biological therapies directed against specific inflammatory pathways. The first class of biological drugs proposed for IBD treatment have been anti-tumor necrosis factor (TNF), but other drugs with different mechanisms of action have been approved recently. Moreover, other drugs that are currently on evaluation in registration trials could significantly improve the therapeutic armamentarium. At the same time, they would open the issue of the choice of the right drug for the right patient. Indeed, biological therapies are characterized by high costs and high rates of loss of response over time, and several patients even experience primary non-response. At the same time, side effects, although uncommon, can occur at every biologic administration, thus suggesting to optimize as much as possible the risk/benefit ratio. The present PhD thesis reports 9 original studies carried out during my 3-year PhD course, with the common thread of the personalization of biological therapy in patients with IBD, trying to identify one or more biomarkers of therapeutic response. Chapter 2 focuses on two biomarkers currently available at every hospital: fecal calprotectin (FC), which is the most used biomarker for monitoring IBD activity, and neutrophil-to-lymphocyte (NLR) ratio, which is derived by a simple blood count. We showed that both these biomarkers were able to predict therapeutic response to biological therapies in patients with ulcerative colitis, evaluated in terms of mucosal healing. In particular, FC seemed to be reliable for every biological treatment, whereas we tested NLR only in patients treated with anti-TNF in a multicenter study involving the Universities of Padua and Genoa. On the other hand, NLR was able to predict mucosal healing even at baseline, while FC was reliable only after the induction of biological therapies. Chapter 3 reports five studies evaluating serum biomarkers of therapeutic outcome to different biological therapies. Four of them were aimed to assess the putative role of serum cytokines as prospective biomarkers of mucosal healing. We also studied the correlation of immunoglobulin (Ig) glycosylation with ulcerative colitis activity and therapeutic outcome of anti-TNF in this disease. The most interesting biomarker identified by these studies was oncostatin M: indeed, its levels at baseline were able to predict therapeutic outcome to anti-TNF therapies in patients with IBD with a very high reliability, whereas they were not correlated to therapeutic response to vedolizumab (VDZ). Therefore, oncostatin M appears to be a drugspecific biomarker, ideal in the perspective of a tailored management of biological therapies in IBD. With 4 regard to the other cytokines, we showed that IL-6 and IL-8 levels could be able to predict therapeutic response to VDZ, especially in ulcerative colitis. In particular, higher levels of baseline IL-8 were associated with higher probability of mucosal healing in patients with ulcerative colitis, whereas the decrease in the first weeks of treatment of IL-6 and IL-8 levels was able to predict therapeutic outcome to VDZ in patients with both IBD. It is worth to mention that some of the studies presented in this section of the thesis were conducted in collaboration with the University of Turin and Padua, increasing the number of patients enrolled and thereby increasing the significance of the results. Conversely, the study concerning Ig glycosylation was carried out in collaboration with another PhD student of our University, specialized in immunology, and showed that a reduction of Jacalin binding to anti-TNF antibodies was seen only in responders. Furthermore, Jacalin binding seemed to be inversely correlated to ulcerative colitis activity. Finally, the two studies presented in Chapter 4 were aimed to evaluate the putative correlation of the body composition with therapeutic outcome in IBD. Indeed, we assessed by bioelectrical impedance analysis (BIA) the body composition in patients with Crohn’s disease treated with ustekinumab (UST) at baseline and during a one-year follow up, showing that responders increase their phase angle over time. This seems to be particularly relevant, since phase angle represents the most clinically established impedance parameter and it might be considered as a reliable and optimal marker of nutritional status. Moreover, we showed that the assessment of serum IL-23 at baseline could be able to predict therapeutic response to UST. The last study conducted during this PhD course in collaboration with the Catholic University of Rome (Columbus Complex) took into consideration elderly patients with IBD, showing that serum triiodothyronineto-thyroxine (T3/T4) ratio at baseline was able to therapeutic outcome to biological therapies. T3/T4 ratio could be a surrogate marker of lean muscle mass, since T4 is converted in T3 by peripheral deiodinases, located mainly in lean muscles. Therefore, patients with low T3/T4 ratio have reasonably a lower lean muscle mass, configuring a condition known as sarcopenia, which is associated with worse outcome of IBD. However, the correlation of a serum biomarker of sarcopenia with therapeutic outcome in elderly patients with IBD was never been assessed. In conclusion, the studies discussed in this PhD thesis supports the hypothesis that a personalized management of biological therapy in IBD could be possible through evaluation of one or more biomarkers. Future studies with larger cohorts should be performed in order to confirm and validate the results presented, with the purpose to include as many biomarkers as possible in clinical practice, thus favoring a tailored approach of biological therapy