There is converging and increasing evidence, but also uncertainty, for the role of abnormal intestinal epithelial barrier function in the origin and development of a growing number of human gastrointestinal and extraintestinal inflammatory disorders, and their related complaints. Despite a vast literature addressing factors and mechanisms underlying changes in intestinal permeability in humans, and its connection to the appearance and severity of clinical symptoms, the ultimate link remains to be established in many cases. Accordingly, there are no directives or clinical guidelines related to the therapeutic management of intestinal permeability disorders that allow health professionals involved in the management of these patients to carry out a consensus treatment based on clinical evidence. Instead, there are multiple pseudoscientific approaches and commercial propaganda scattered on the internet that confuse those affected and health professionals and that often lack scientific rigor. Therefore, in this review we aim to shed light on the different therapeutic options, which include, among others, dietary management, nutraceuticals and medical devices, microbiota and drugs, and epigenetic and exosomes-manipulation, through an objective evaluation of the scientific publications in this field. Advances in the knowledge and management of intestinal permeability will sure enable better options of dealing with this group of common disorders to enhance quality of life of those affected.
Inflammatory bowel disease (IBD) is a chronic immune-mediated condition of the gastrointestinal tract that requires chronic treatment and strict surveillance. Development of new monoclonal antibodies targeting one or a few single cytokines, including anti-tumor necrosis factor agents, anti-IL 12/23 inhibitors, and anti-α4β7 integrin inhibitors, have dominated the pharmacological armamentarium in IBD in the last 20 years. Still, many patients experience incomplete or loss of response or develop serious adverse events and drug discontinuation. Janus kinase (JAK) is key to modulating the signal transduction pathway of several proinflammatory cytokines directly involved in gastrointestinal inflammation and, thus, probably IBD pathogenesis. Targeting the JAK-STAT pathway offers excellent potential for the treatment of IBD. The European Medical Agency has approved three JAK inhibitors for treating adults with moderate to severe Ulcerative Colitis when other treatments, including biological agents, have failed or no longer work or if the patient cannot take them. Although there are currently no approved JAK inhibitors for Crohn’s disease, upadacitinib and filgotinib have shown increased remission rates in these patients. Other JAK inhibitors, including gut-selective molecules, are currently being studied IBD. This review will discuss the JAK-STAT pathway, its implication in the pathogenesis of IBD, and the most recent evidence from clinical trials regarding the use of JAK inhibitors and their safety in IBD patients.
Background Ustekinumab (UST), an inhibitor of the p40 subunit of interleukins 12 and 23, is an effective treatment for patients with Crohn’s disease (CD) and ulcerative colitis (UC). There is limited data on therapeutic outcomes and UST trough levels (UTL). We aimed to evaluate the association between UTL and corticosteroid-free clinical remission. We also assessed the relationship between UTL and endoscopic remission as a secondary outcome. Methods We performed a cross-sectional study on IBD patients receiving maintenance therapy with UST (>6 months). We included UTL, C reactive protein (CRP), faecal calprotectin (FC), and clinical and endoscopic indexes (Harvey Bradshaw [HBI] and simple endoscopic score [SES-CD] for CD patients; and partial Mayo score [PMS] and endoscopic Mayo score [EMS] for UC patients). Corticosteroid-free clinical remission (CSF-CR) was defined as HBI<5 or PMS<2 plus normal CRP and/or FC values without corticosteroids. Endoscopic remission was defined as SES-CD<3 or EMS<2. Results We included 105 patients; the mean age was 50 years, and 59% were female (Figure 1). Eighty-seven patients had CD, and 92% had previously received an anti-TNF. The median time on UST was 121 weeks at inclusion. Sixty-four patients received 90mg subcutaneous (SC) every 4 weeks, 40 patients 90mg SC every 8 weeks, and 1 patient 90mg SC every 12 weeks. Eighty percent were in CSF-CR, and 53% were in endoscopic remission. Median UTL were 2,7µg/mL (IQR: 1,7-4,1µg/mL); UST antibodies were not detected. Patients in CSF-CR and endoscopic remission did not show significantly higher UTL (3,4µg/mL vs. 2,5µg/mL, p=0,147; and 3,6µg/mL vs. 3,7µg/mL, p=0,903, respectively). No differences in UTL were detected between patients on monotherapy and combination therapy (2,9µg/mL vs. 3,3µg/mL, p=0,456). Conclusion No association between UTL and clinical or endoscopic activity was observed in our predominantly biologic-experienced cohort. Further prospective studies are needed to determine the role of therapeutic drug monitoring while on UST.
Background Current guidelines in inflammatory bowel disease (IBD) advocate for endoscopic biopsies to confirm cytomegalovirus (CMV) colitis by means of immunohistochemistry (IHC) or tissue polymerase chain reaction (tPCR). Clinical usefulness of whole-blood PCR (bPCR) remains controversial. Our aim was to asses diagnostic accuracy of bPCR to predict CMV colitis. Methods We extracted data from all patients between 2017 and 2022 with ulcerative colitis (UC), Crohn’s disease (CD) or unclassified colitis presenting with a moderate-to-severe flare of IBD, and who were tested for CMV infection with both IHC and bPCR at the same time. IHC was considered reference standard and was used to evaluate diagnostic accuracy of bPCR. Results 89 patients were included, of which 44 (49,4%) were women, and median age was 49 years (Figure 1). 48 (50,6%) had UC, 16 (19,1%) had CD, and 25 (29,2%) had unclassified colitis. 46 (51,7%) were receiving any IBD treatment by the time of enrolment, of which 34 (67,4%) were on corticosteroids. Among patients in the CMV colitis group we found a higher proportion of leucocyte counts in the normal concentration range (p=0,035) and higher endoscopic activity using the Mayo endoscopic score in CU (p=0,027). Of the study subjects, 25 (28,2%) had CMV colitis; and bPCR was positive in 23 (25,8%). Diagnostic accuracy of bPCR was 75,3%, being sensitivity and specificity 52% and 84,4%, respectively. The positive predictive value and negative predictive value were 56,5% and 81,8%. Numerically, patients in the CMV colitis group showed higher concentrations of CMV DNA PCR without reaching statistical significance (6416,2 copies/mL vs. 2256 copies/mL, p=0,295). The area under the receiver operating characteristic curve value was 0,646 (p=0,239). When setting a threshold of above 1336 copies/mL, sensitivity and specificity values were 40% and 92,2%, respectively, and the positive likelihood ratio (LR+) was 5,13 (Figure 2). Conclusion Although bPCR showed high specificity for diagnosing CMV colitis, the sensitivity values were low. In agreement with current guidelines, blood-based tests should not replace IHC or tPCR for detecting CMV reactivation in IBD. A threshold of above 1336 copies/mL showed a moderately high LR+, thus it should prompt consideration of early antiviral treatment.
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