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Background: Treatment of inflammatory bowel diseases (IBD) has tremendously improved during the last 20 years; however, a substantial fraction of patients does not respond to available therapies or lose response, and new strategies are needed. Summary: Two pharmacological principles have been successfully used for IBD treatment: inhibition of cellular signaling and interference with leukocyte trafficking. Besides tumor necrosis factor, interleukin (IL)-23 is a promising drug target, and antibodies for the combined inhibition of IL-23 and IL-12 (ustekinumab and briakinumab) or selective IL-23 inhibition (brazikumab, risankizumab, and mirikizumab) seem to be effective in Crohn’s disease (CD) with emerging evidence also for ulcerative colitis (UC). Janus kinase (JAK) mediates intracellular signaling of a large number of cytokines. Tofacitinib is the first JAK inhibitor approved for UC, and the JAK inhibitors filgotinib and upadacitinib showed potential in CD. Leukocyte trafficking can be inhibited by interference with lymphocyte integrin-α4β7 or endothelial MadCAM-1. The α4β7 integrin inhibitor vedolizumab is an established treatment in IBD, and long-term data of pivotal studies are now available. Additional molecules with therapeutic potential are α4β7-specific abrilumab, β7-specific etrolizumab, and the α4-specific small molecule AJM300. PF-00547659, an antibody against endothelial MadCAM-1, also showed therapeutic potential in UC. Modulation of sphingosine-1-phosphate receptor (S1PR) activity is necessary for the egress of lymphocytes into the circulation, and S1PR modulation results in lymphocyte trapping in lymphatic organs. Ozanimod, an S1PR1 and S1PR5 inhibitor, has been successfully tested in initial studies in UC. Mesenchymal stem cell therapy has been approved for the treatment of complex, active CD fistula, and mesenchymal stem cell therapy might be a paradigm shift for this condition. Autologous stem cell transplantation (ASCT) has been successfully used in CD case series; however, in a randomized trial, a highly stringent endpoint was not met. However, considering positive effects in secondary endpoints, ASCT might be a future treatment of last resort in severe, refractory CD cases, provided that safer protocols can be provided. Key messages: New IBD treatments are successful for a significant fraction of patients. However, new strategies for patient selection, treatment combinations, and/or additional therapies must be developed to serve the need of all IBD patients.

Extraintestinal manifestations (EIMs) in patients with inflammatory bowel disease (IBD) are frequently observed. Little is known about the efficacy of anti–tumor necrosis factor (TNF) in EIM management. We assessed the effect of 3 anti-TNF agents (infliximab, adalimumab, and certolizumab pegol) on EIM evolution.MethodsData on 1249 patients from the Swiss IBD Cohort Study (SIBDCS) were analyzed. All EIMs were diagnosed by relevant specialists. Response was classified into improvement, stable disease, and clinical worsening based on the physician's interpretation.ResultsOf the 366 patients with at least 1 EIM, 213 (58.2%) were ever treated with an anti-TNF. A total of 299 treatments were started for 355 EIMs. Patients with EIM were significantly more often treated with anti-TNF compared with those without EIM (58.2% versus 21.0%, P < 0.001). Infliximab was the most frequently used drug (63.2%). In more than 71.8%, a clinical response of the underlying EIM to anti-TNF therapy was observed. In 92 patients (43.2%), anti-TNF treatments were started for the purpose of treating EIM rather than IBD. Response rates to anti-TNF were generally good and best for psoriasis, aphthous stomatitis, uveitis, and peripheral arthritis. In 11 patients, 14 EIM occurred under anti-TNF treatment.ConclusionsAnti-TNF was frequently used among patients with EIM. In more than 40%, anti-TNF treatments are started to treat EIM rather than IBD. Given the good response rates, anti-TNF seems to be a valuable option in the treatment of EIM, whereas appearance of EIM under anti-TNF does not seem to be a source of considerable concern.

Genetic risk factors, intestinal microbiota and a dysregulated immune system contribute to the pathogenesis of inflammatory bowel disease (IBD). We have previously demonstrated that dysfunction of protein tyrosine phosphatase non-receptor type 2 (PTPN2) and PTPN22 contributes to alterations of intestinal microbiota and the onset of chronic intestinal inflammation in vivo. Here, we investigated the influence of PTPN2 and PTPN22 gene variants on intestinal microbiota composition in IBD patients. Bacterial DNA from mucosa-associated samples of 75 CD and 57 UC patients were sequenced using 16S rRNA sequencing approach. Microbial analysis, including alpha diversity, beta diversity and taxonomical analysis by comparing to PTPN2 (rs1893217) and PTPN22 (rs2476601) genotypes was performed in QIIME, the phyloseq R package and MaAsLin pipeline. In PTPN2 variant UC patients, we detected an increase in relative abundance of unassigned genera from Clostridiales and Lachnospiraceae families and reduction of Roseburia when compared to PTPN2 wild-type (WT) patients. Ruminoccocus was increased in PTPN22 variant UC patients. In CD patients with severe disease course, Faecalibacterium, Bilophila, Coprococcus, unclassified Erysipelotrichaeceae, unassigned genera from Clostridiales and Ruminococcaceae families were reduced and Bacteroides were increased in PTPN2 WT carriers, while Faecalibacterium, Bilophila, Coprococcus, and Erysipelotrichaeceae were reduced in PTPN22 WT patients when compared to patients with mild disease. In UC patients with severe disease, relative abundance of Lachnobacterium was reduced in PTPN2 and PTPN22 WT patients, Dorea was increased in samples from PTPN22 WT carriers and an unassigned genus from Ruminococcaceae gen. was increased in patients with PTPN2 variant genotype. We identified that IBD-associated genetic risk variants, disease severity and the interaction of these factors are related to significant alterations in intestinal microbiota composition of IBD patients.

Inflammatory bowel disease (IBD) is increasingly diagnosed among elderly persons (older than 60 years). Epidemiological studies show that late-onset IBD is characterized by predominance of colonic disease, milder disease course, and less frequent occurrence of extraintestinal manifestations. However, due to comorbidities, polypharmacy and reduced resistance to severe disease course elderly patients have an increased risk of mortality. Drug treatment generally follows the same algorithms as in the younger IBD patients. This is challenging for the treating physician as this population is usually underrepresented in clinical trials and treatment outcomes as well as safety data on the elderly population are scarce. Choice of drugs should consider risk of infections, skin cancer, lymphoma, and metabolic as well as cardiovascular side effects. Considering comorbidities, surgical interventions such as colectomy with ileo-anal pouch anastomosis for refractory ulcerative colitis can be performed safely provided that the anal sphincter function is adequately maintained. Special attention should be given in this age group to general health issues, including nutrition, vaccination, bone, muscle, and mental health as well as colorectal and skin cancer screening.

Patients with inflammatory bowel disease (IBD) are predisposed to pneumococcal infections due to their underlying disease and iatrogenic immunosuppression. Vaccination with the 13-valent pneumococcal conjugated vaccine (PCV13) is recommended, but with poor take-up and few data available. We performed an open-label, phase IV, multicenter study to evaluate the safety and immunogenicity of PCV13 in adults with IBD and to analyze the influence of immunomodulating treatments on anti-pneumococcal seroresponses. We enrolled 306 patients with IBD from March 2014 through February 2016, with the following exclusion criteria: current IBD flare, pregnancy, pneumococcal immunization in the previous 5 years, and influenza immunization in the previous 4 weeks. PCV13 was administered intramuscularly. Serotype-specific vaccine responses were evaluated using an opsonophagocytic assay. Adverse events were monitored by diary cards and standardized phone interviews. The median seroprotection rate increased significantly from 43.9% (95% confidence interval [CI], 42.3-45.5) at inclusion to 90.4% (95% CI, 89.5-91.3%; P < 0.001) after vaccination. Patients receiving anti-tumor necrosis factor agents achieved a slightly lower seroprotection rate (from 44.5% [95% CI, 42.3%-46.8%] to 86.6% [95% CI, 84.9%-88.1%]) than patients treated with other types of immunosuppressive regimens (thiopurine, methotrexate, oral corticosteroids; from 44.7% [95% CI, 41.7%-47.7%] to 93.8% [95% CI, 92.1%-95.2%]) or nonimmunosuppressive treatment (5-aminosalicylate, topical corticosteroids, vedolizumab; from 41.3% [95% CI, 37.9%-44.8%] to 95.2% [95% CI, 93.4%-96.6%]). There were no safety issues. Overall, the administration of PCV13 was highly immunogenic and well tolerated, irrespective of the baseline treatment, and should be encouraged in all adults with IBD.