Management of liver and gastrointestinal toxicity induced by immune checkpoint inhibitors: Position statement of the AEEH–AEG–SEPD–SEOM–GETECCU / Manejo de las toxicidades digestivas secundarias al tratamiento con inhibidores de checkpoint: documento de posicionamiento de la AEEH-AEG-SEPD-SEOM-GETECCU

The development of the immune checkpoint inhibitors (ICI) is one of the most remarkable achievements in cancer therapy in recent years. However, their exponential use has led to an increase in immune-related adverse events (irAEs). Gastrointestinal and liver events encompass hepatitis, colitis and upper digestive tract symptoms accounting for the most common irAEs, with incidence rates varying from 2% to 40%, the latter in patients undergoing combined ICIs therapy. Based on the current scientific evidence derived from both randomized clinical trials and real-world studies, this statement document provides recommendations on the diagnosis, treatment and prognosis of the gastrointestinal and hepatic ICI-induced adverse events.(AU)

El descubrimiento de los inhibidores de checkpoint inmunológicos (ICI) es uno de los logros más importantes en los últimos años en Oncología. Sin embargo, su uso en aumento ha conlllevado a un incremento de los efectos adversos inmunomediados (irAEs). Los eventos hepáticos y gastrointestinales incluyen la hepatitis, colitis y síntomas de tracto digestivo superior, que son de los irAEs más frecuentes, con incidencias entre el 2 y 40%, ésta última en paciente tratados con combo de ICI. Basados en la evidencia científica tanto de ensayo clínicos randomizados como de estudio de vida real, este documento de consenso aporta recomendaciones sobre el diagnóstico, tratamiento y pronóstico de los efectos adversos hepáticos y gastrointestinales asociados con la inmunoterapia.(AU)

Idiopathic mesenteric phlebosclerotic colitis associated with Chinese herbal medicine

Idiopathic mesenteric phlebosclerotic colitis(IMP) is a rare disease. At present, the etiology and pathogenesis are not clear, but the main patients are Asian people, and most of them have a history of taking Chinese herbal medicines. The disease has characteristic endoscopic and imaging manifestations. This paper shares a case of IMP, The patient came to our hospital for one year because of intermittent abdominal pain and diarrhea. It conforms to the typical manifestations of IMP. For patients who take Chinese herbal medicine for a long time, if they have clinical manifestations of gastrointestinal tract, it is necessary to consider the possibility of the disease to avoid serious consequences due to missed diagnosis. (AU)

Knockdown of TRIM8 alleviates dextran sulfate sodium-induced colitis in mice by inhibiting the NF-kB signaling pathway

Background: Although TRIpartite Motif containing 8 (TRIM8) gene plays an important role in a number of biological processes, such as inflammation, its function and mechanism in ulcerative colitis (UC) remain unknown. Methods: The UC model was established by feeding mice with 3.5% dextran sulfate sodium (DSS). The animals were divided into the following four groups: control group, DSS group, DSS+short hairpin (sh)-NC group, and DSS+sh-TRIM8 group. Changes in body weight and disease activity index (DAI) score of mice in all the groups were recorded for 7 days. The animals were executed at the end of the experiment, and the expression of TRIM8 in colon tissue was detected by polymerase chain reaction and Western blot assays. The length of colon was measured, and the histopathological changes in mice colon were examined by hematoxylin and eosin staining. The expression of pro-inflammatory factors in mice serum and colonic tissue homogenate was detected by enzyme-linked-immunosorbent serologic assay. The expression of nuclear factor kappa B (NF-κB) pathway-related proteins in colonic tissues was detected by Western-blot analysis. Results: TRIM8 was highly expressed in the colonic tissues of UC mice. Knockdown of TRIM8 improved DSS-induced weight loss, increased DAI score, shortened colon length, and alleviated colonic injury and inflammation in mice. Western-blot experiments showed that knockdown of TRIM8 inhibited DSS-induced phosphorylation of p65 and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) protein but increased IκBα expression. Conclusion: Knockdown of TRIM8 inhibits UC injury and inflammatory response caused by DSS. This could be related to the regulation of NF-κB signaling pathway by TRIM8 protein (AU)

TRIM52 aggravated inflammation and pyroptosis in dextran sulfate sodium-induced inflammatory bowel disease through activation of the TLR4/NF-kBs pathway

Introduction: Inflammatory bowel disease (IBD), which mainly leads to diarrhea, fatigue, stool blood, abdominal pain, and cramping, is threatening public health. Tripartite motif-containing 52 (TRIM52) has been reported to play an important role in inflammatory responses via activating the toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway. However, the causes of IBD need to be elucidated, and the function of TRIM52 in IBD remains unclear. Here, we demonstrated that TRIM52 aggravated inflammation and pyroptosis in dextran sulfate sodium (DSS)-induced IBD by activating TLR4/NF-κBs pathway. Methods: The colitis model was established on mice through DSS induction. For the TRIM52 knockdown, the mice were infected with a recombinant adenoviral vector expressing sgRNAs targeting TRIM52. RT-qPCR, western blot, and immunohistochemistry were performed to verify TRIM52 expression in DSS-induced IBD. The body weight, disease activity index, colon length, and H&E staining were used to assess the IBD symptoms in mice with TRIM52 knockdown. The inflammatory responses were examined by RT-qPCR and ELISA measuring tumor necrosis factor-α (TNF-α), inter-leukin 6 (IL-6), and interleukin 1β (IL-1β). Furthermore, the pyroptosis in colon tissue was detected by western blot. Finally, the TLR4/NF-κBs pathway activity was also examined by western blot. Results: TRIM52 expression was up-regulated in DSS-induced IBD, and knockdown of TRIM52 could alleviate the symptoms of IBD. TRIM52 knockdown retarded DSS-induced inflammatory response and inhibited DSS-induced pyroptosis in colon tissue. In addition, TRIM52 played a role in activating TLR4/NF-κBs pathway. Conclusion: Knockdown of TRIM52 alleviated inflammation and pyroptosis in IBD by regulating TLR4/NF-κBs pathway. TRIM52 is expected to be a novel diagnostic indicator for IBD and a target of therapeutic treatment (AU)

Afectación intestinal secundaria a tocilizumab / Intestinal disease secondary to tocilizumab

Se presenta un caso clínico sobre una paciente con estenosis benigna del colon secundario a tratamiento con tocilizumab. (AU)

Cinnamtannin D1 ameliorates DSS-induced colitis by preventing Th17/Treg imbalance through activation of the AMPK/mTOR pathway

Background: Inflammatory bowel disease (IBD) is a chronic idiopathic gastrointestinal dis-ease, including ulcerative colitis (UC) and Crohn’s disease (CD), which is typically charac-terized by chronicity and relapse. Cinnamtannin D1 (CTD1), extracted from Cinnamomum tamala, has been found to exert good immunosuppressive activity. However, the role of CTD1 in IBD is unclear. Methods: The colitis mice model was established by dextran sulfate sodium (DSS) treat-ment. Protein levels (p-STAT3/STAT3, ROR-γt, p-STAT5/STAT5, FOXP3, p-AMPK/AMPK, and p-mTOR/mTOR) were examined using Western blotting analysis. Changes in histopathol-ogy were detected through hematoxylin and eosin staining. The proportion of T helper 17 (Th17) cells and regulatory T (Treg) cells was measured by flow cytometry analysis.Results: CTD1 improved body weight and colon length, and alleviated inflammation and histological damage in DSS-induced colitis mice model. DSS treatment also demonstrated a negative effect on Th17–Treg cells balance whereas CTD1 restored the balance of Th17–Treg cells in DSS-induced colitis mice model. Regulatory factors (such as STAT3, ROR-γt, STAT5, and FOXP3) that closely related to the balance of Th17–Treg cells were regulated by CTD1. In addition, AMPK phosphorylation was increased and mTOR phosphorylation was inhibited by CTD1 in DSS-induced colitis mice model. Conclusion: These findings established that CTD1 improved DSS-induced colitis by suppress-ing Th17–Treg cells balance by activating the AMPK/mTOR pathway. This study provided a new strategy for developing novel treatments for patients with IBD (AU)

Radon exposure and inflammatory bowel disease in a radon prone area

Introduction: inflammatory bowel disease (IBD) is a multifactorial pathology with an increasing incidence. There is no study that has assessed a possible relationship with very high residential radon exposure in the study area. The aim of the study was to analyze if residential radon concentration is associated with a higher incidence of IBD.Material and methods: an ecological study was performed. All incident cases of inflammatory bowel disease in the area of Santiago de Compostela were included between January and December 2017. Radon levels at a municipal level were correlated with demographic factors and type of IBD.Results: ninety-six patients were included, 63 (65.6 %) with ulcerative colitis, 29 (30.25) with Crohn's disease and four (4.2 %) with indeterminate colitis. The incidence rate per 100,000 inhabitants-year was 21.6 cases. There were no statistically significant differences in the type of disease developed regarding radon levels (p > 0.05). No correlation between radon levels and the cumulative incidence of inflammatory bowel disease at the municipal level was observed (Spearman's rho = 0.13, p-value 0.5).Conclusion: in the area of Santiago de Compostela, there is a higher incidence of IBD in comparison with previous studies using western countries as reference. However, there was no correlation with the municipal average radon concentration and incidence of IBD or any of its types in this study. (AU)

Inducción de remisión con gentamicina y vancomicina oral en enfermedad inflamatoria intestinal de inicio temprano / Very early onset inflammatory bowel disease remission induced with oral gentamicin and vancomycin

La enfermedad inflamatoria intestinal de inicio temprano se manifiesta en pacientes pediátricos antes de los 6 años de edad. Habitualmente se asocia a diversas causas, siendo descrita frecuentemente la disbiosis como factor desencadenante. Esta población presenta comúnmente refractariedad a los tratamientos inmunosupresores más empleados.Presentamos el caso de un paciente con colitis no clasificable y corticodependiente de un año de evolución ingresado en nuestro centro que no había respondido a terapia inmunosupresora intensificada. Se plantea terapia con antibióticos orales como inducción de la remisión del brote de actividad en combinación con su tratamiento inmunomodulador habitual. Si bien inicialmente se obtiene la remisión clínica, el paciente experimenta posteriormente al alta un nuevo brote de actividad siendo necesaria una segunda reinducción con antibióticos que no resulta eficaz, motivando su suspensión. (AU)

Very early onset inflammatory bowel disease occurs in children under 6 years age. It is frequently associated to a diverse ethiology, dysbiosis being usually described as a triggering factor. Commonly, this population is highly resilient to inmmunosuppressant therapies.We report here a medical case of a patient diagnosed with unclassified and steroid-dependent colitis, with a year of evolution, who had no responded to intensified therapy at home, and, therefore, was hospitalized at our centre. Treatment with oral antibiotics was intended as remission induction in combination with his usual inmmunomodulator treatment. Although clinical remission was observed at first stage, a new activity outbreak emerged requiring a second round of antibiotics therapy, which was unsuccessful and currently withdrawned. (AU)