The immune system and environmental factors are involved in various diseases, such as inflammatory bowel disease (IBD), through their effect on genetics, which modulates immune cells. IBD encompasses two main phenotypes, Crohn’s disease, and ulcerative colitis, which are manifested as chronic and systemic relapse-remitting gastrointestinal tract disorders with rising global incidence and prevalence. The pathophysiology of IBD is complex and not fully understood. Epigenetic research has resulted in valuable information for unraveling the etiology of this immune-mediated disease. Thus, the main objective of the present review is to summarize the current findings on the role of epigenetic mechanisms in IBD to shed light on their potential clinical relevance. This review focuses on the latest evidence regarding peripheral blood mononuclear cells and epigenetic changes in histone modification, DNA methylation, and telomere shortening in IBD. The various identified epigenetic DNA profiles with clinical value in IBD could be used as biomarkers for more accurately predicting disease development, treatment response, and therapy-related adverse events. Ultimately, the information presented here could be of potential relevance for future clinical practice in developing more efficient and precise medicine to improve the quality of life for patients with IBD.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the digestive tract usually characterized by diarrhea, rectal bleeding, and abdominal pain. IBD includes Crohn’s disease and ulcerative colitis as the main entities. IBD is a debilitating condition that can lead to life-threatening complications, involving possible malignancy and surgery. The available therapies aim to achieve long-term remission and prevent disease progression. Biologics are bioengineered therapeutic drugs that mainly target proteins. Although they have revolutionized the treatment of IBD, their potential therapeutic benefits are limited due to large interindividual variability in clinical response in terms of efficacy and toxicity, resulting in high rates of long-term therapeutic failure. It is therefore important to find biomarkers that provide tailor-made treatment strategies that allow for patient stratification to maximize treatment benefits and minimize adverse events. Pharmacogenetics has the potential to optimize biologics selection in IBD by identifying genetic variants, specifically single nucleotide polymorphisms (SNPs), which are the underlying factors associated with an individual’s drug response. This review analyzes the current knowledge of genetic variants associated with biological agent response (infliximab, adalimumab, ustekinumab, and vedolizumab) in IBD. An online literature search in various databases was conducted. After applying the inclusion and exclusion criteria, 28 reports from the 1685 results were employed for the review. The most significant SNPs potentially useful as predictive biomarkers of treatment response are linked to immunity, cytokine production, and immunorecognition.

Background/Objectives: Crohn’s disease (CD) is a chronic immune-mediated disorder with heterogeneous response to biologic therapies. Ustekinumab (UST), an anti-IL-12/23 monoclonal antibody, is effective in CD, but predictive biomarkers of treatment response remain lacking. This study aimed to investigate cytokine dynamics during UST induction and to evaluate their association with clinical and biochemical outcomes in an observational cohort of CD patients. Methods: We prospectively recruited 31 adult patients with moderate-to-severe active CD initiating UST therapy at a tertiary referral center. Peripheral blood and stool samples were collected at baseline and weeks 4, 8, and 16. UST trough concentrations, C-reactive protein (CRP), fecal calprotectin (FC), hemoglobin, albumin, and 13 serum cytokines (including IL-1β, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17, IL-23, TNF-α, and OSM) were analyzed. Response was defined as a ≥70% reduction in FC at week 16, or, alternatively, CRP < 5 mg/L or a Harvey–Bradshaw Index < 3. Results: Eighteen patients (58%) achieved response at week 16. Responders showed significant reductions in FC, CRP, and disease activity, while non-responders exhibited limited biochemical improvement. Overall, UST induction was associated with a global decrease in proinflammatory cytokines, particularly TNF-α and IL-1β. Responders displayed distinct cytokine patterns, with higher IL-13 levels at week 8 and lower IL-8 concentrations at week 16 compared with non-responders. UST trough levels tended to be higher in responders, and inverse correlations were observed between drug concentrations and several cytokines, including IL-6, IL-8, IL-13, and IL-23. Conclusions: UST induction leads to measurable immunological changes in CD, with differential cytokine dynamics distinguishing responders from non-responders. These findings support the potential of cytokine signatures, in combination with therapeutic drug monitoring, as pharmacodynamic biomarkers to optimize personalized treatment strategies in CD.

Background: Upadacitinib (UPA) is the first oral Janus kinase (JAK) inhibitor approved for the treatment of Crohn's disease (CD). Real‐world data, particularly from large nationwide cohorts, remain limited. This study aimed to evaluate the real‐world effectiveness, safety, and treatment persistence of UPA in patients with CD. Methods: Multicenter observational study including patients with CD who received UPA, using data from a nationwide registry. Patients were classified according to active luminal disease, extraintestinal manifestations (EIMs), or combination therapy with another biological therapy. Disease activity was assessed using the Harvey–Bradshaw Index (HBI), C‐reactive protein (CRP), and fecal calprotectin (FC) at baseline and weeks 12, 24, and 52. Endoscopic outcomes were evaluated when available. Adverse events (AEs), hospitalizations, and treatment discontinuations were recorded. Results: 300 patients were included, representing a highly treatment‐refractory population, with 98% previously exposed to anti‐TNF agents and 59% to three or more advanced therapies. In those treated for active luminal disease, corticosteroid‐free clinical remission was achieved in 60%–62% of patients at weeks 12, 24 and 52. CRP normalization increased from 64% at week 12%–74% at week 52, while FC normalization improved from 48% to 64%. Patients treated for EIMs achieved high and sustained remission rates with excellent treatment persistence. Early remission at week 12 was strongly associated with sustained remission and meaningful endoscopic improvement. UPA was discontinued in 98 patients (39%). AEs were reported in 71 patients (24%). Conclusions: In this large real‐world cohort, UPA demonstrated sustained clinical and biochemical effectiveness, meaningful endoscopic response, and a safety profile consistent with clinical trial data. Early response emerged as a key predictor of long‐term outcomes, supporting the clinical utility of UPA.

The relationship between smoking and inflammatory bowel disease (IBD), which has been widely studied for years, is complex and different in Crohn's disease (CD) and ulcerative colitis (UC). The negative effect on CD, not only on disease progression and post-surgical recurrence, but also on post-surgical complications after intestinal resection, on its influence on the reservoir and on the modification of the natural evolution of CD towards fistulizing and stenosing forms, makes a proper approach to the problem imperative. With the rise of biologics, the influence of smoking on the response to these drugs has been studied. Although some studies have found a worse response to these treatments in patients who smoke, it is unclear whether the response to biologics worsens, or whether it is simply a worsening of the underlying disease with a consequent reduced response to the drugs used. Furthermore, regarding the safety of biologics and small molecule drugs in smokers, smoking may worsen adherence to these treatments, increase their adverse effects and contribute to an increased risk of thrombosis in patients with Janus-kinase (JAK) inhibitors. Because of its high preventable morbidity and mortality, it is essential that patients with CD stop smoking. Patients should be informed by their physician and governmental strategies should be promoted to facilitate both cessation and to reduce the risk of relapse.