Anti TNF-α Research Articles

Asthma Development Under Adalimumab Therapy: A Clinical Case Analysis

Adalimumab is a human monoclonal antibody against TNFa, frequently used in chronic inflammatory diseases such as inflammatory bowel disease. Anti-TNFa drugs are generally well tolerated, but in recent years their use has revealed significant adverse effects, in particular tuberculosis. Pulmonary involvement in these contexts is sometimes encountered, in association with an extra-intestinal manifestation of the disease, or secondary to therapeutics usedq such as anti TNFa. A 46-year-old female patient with cortico-dependent ulcerative colitis presented with progressive dyspnea and cough after initiation of Adalimumab therapy. Chest imaging was consistent with interstitial pathology, and functional analysis led to a diagnosis of asthma secondary to Humira. Symptoms improved a few months after discontinuation of anti-TNFa, and functional abnormalities subsequently disappeared almost completely after corticosteroid therapy. To our knowledge, this is the third clinical case of proven asthma secondary to anti-TNF therapy, with regression of symptoms on discontinuation of treatment, and after use of corticosteroid therapy. Clinicians using this treatment should be aware of this possible complication.

Anti TNF-Alpha Treatment Improves Microvascular Endothelial Dysfunction in Rheumatoid Arthritis Patients.

Nailfold capillaroscopy is a non-invasive investigation, which allows for the study of the microvasculature (anatomical and functional). Rheumatoid arthritis (RA) is associated with a high risk of cardiovascular atherosclerotic diseases, with endothelial dysfunction (macrovascular and microvascular) representing the first step in atherosclerosis development. The aim of this study is represented by the assessment of microvascular endothelial dysfunction in RA patients by means of nailfold capillaroscopy and to assess its evolution after a period of 12 months of anti TNF-alpha treatment. The study included 70 consecutive patients with RA and 70 healthy subjects, matched for age and gender, as the control group. Rheumatoid factor, anti-cyclic citrullinated peptide antibodies, serum TNF-α, C reactive protein, and erythrocytes sedimentation rate were evaluated in all patients, but in controls, only rheumatoid factor, serum TNF-α, C reactive protein, and erythrocytes sedimentation rate were measured. The RA activity was measured by DAS28. Nailfold capillaroscopy was carried out in all patients and controls, determining the baseline nailfold capillary density (Db), nailfold capillary density during reactive hyperemia (Dh), and nailfold capillary density after venous congestion (Dc). Data were presented as mean ± standard deviation. Statistical analysis was performed using ANOVA and Pearson's correlation, with p < 0.05 being statistically significant. Db, Dh, and Dc were lower in RA patients than in controls (p < 0.0001), correlating with RA activity and TNF-α (p < 0.05). After 12 months of anti TNF-α treatment, microvascular endothelial dysfunction improved (p < 0.0001). Microvascular endothelial dysfunction can be assessed by nailfold capillaroscopy, with anti TNF-α medication contributing to its improvement.

Dynamic changes in the gut microbiota composition during adalimumab therapy in patients with ulcerative colitis: implications for treatment response prediction and therapeutic targets

BackgroundWhile significant research exists on gut microbiota changes after anti-tumor necrosis factor-alpha (anti TNF-α) therapy for ulcerative colitis, little is known about the longitudinal changes related to the effects of anti TNF-α. This study aimed to investigate the dynamics of gut microbiome changes during anti TNF-α (adalimumab) therapy in patients with ulcerative colitis (UC).ResultsThe microbiota composition was affected by the disease severity and extent in patients with UC. Regardless of clinical remission status at each time point, patients with UC exhibited microbial community distinctions from healthy controls. Distinct amplicon sequence variants (ASVs) differences were identified throughout the course of Adalimumab (ADA) treatment at each time point. A notable reduction in gut microbiome dissimilarity was observed only in remitters. Remitters demonstrated a decrease in the relative abundances of Burkholderia-Caballeronia-Paraburkholderia and Staphylococcus as the treatment progressed. Additionally, there was an observed increase in the relative abundances of Bifidobacterium and Dorea. Given the distribution of the 48 ASVs with high or low relative abundances in the pre-treatment samples according to clinical remission at week 8, a clinical remission at week 8 with a sensitivity and specificity of 72.4% and 84.3%, respectively, was predicted on the receiver operating characteristic curve (area under the curve, 0.851).ConclusionsThe gut microbiota undergoes diverse changes according to the treatment response during ADA treatment. These changes provide insights into predicting treatment responses to ADA and offer new therapeutic targets for UC.

The Use of TNF-α Inhibitors in Active Ankylosing Spondylitis Treatment.

Ankylosing spondylitis (AS) is a challenging disease, characterized by chronic inflammation and structural damage primarily affecting the axial skeleton, while extra-articular manifestations may also appear. This results in the deterioration of patients' quality of life. Over the past few decades, tumor necrosis factor-α (TNF-α) inhibitors have revolutionized the management of AS, offering substantial relief from symptoms and improving patient outcomes. The aim of this review is to assess the efficacy of TNF-α inhibitors in patients with active AS. A search was performed in the PubMed database using the following keywords: ("TNF alpha inhibitors" OR "anti TNF-a" OR "TNF-a inhibitors" OR "anti TNF-alpha" OR "Etanercept " OR "Golimumab" OR "Infliximab" OR "Certolizumab pegol" OR "Adalimumab") AND "ankylosing spondylitis". The search was completed in February 2024, and 35 studies were included in this review following PRISMA guidelines. The findings reveal evidence supporting the efficacy of TNF-α inhibitors in reducing inflammation, preventing structural damage, and enhancing overall well-being in AS patients. Overall, TNF-α inhibitors have emerged as a cornerstone in the therapeutic algorithm against AS with a very satisfactory safety profile.

PERFIL LIPÍDICO DE PACIENTES COM ARTRITE REUMATOIDE EM USO DE ANTI-TNF-ALFA

Background: Rheumatoid arthritis (RA) patients have an increased risk for complications, especially cardiac, which are the main cause of deaths in this population. In this study, the lipid profile of these patients was analyzed before and after introduction of Anti-TNF-α. Methods: Retrospective study of 93 RA patients using anti-TNF-α. Epidemiological, clinical, lipid profile, disease activity data were collected before and six months after anti-TNF-α introduction. Results: 93 patients with mean age of 56.8 years with the prevalence of female were studied. Lipid profile before and after the introduction of Anti TNF-α had no differences. Changes in DAS28-PCR and DAS28-ESR showed that inflammation was controlled. Conclusion: It was not possible to demonstrate changes in the lipid profile after the use of anti-TNF-α, although these drugs have been effective in the control of the disease.

Assessment of specificity of immunologic tests for detection of tuberculosis infection in children with juvenile idiopathic arthritis

Introduction. The use of genetic engineering biological agents (GEBA) in the treatment of rheumatic diseases over the past decades has led to a significant improvement in the prognosis in this group of patients. However, against the background of anti-tumor necrosis factor α therapy (anti TNF-α), the risk of developing tuberculosis increases tenfold.Aim. To evaluate the specificity and safety of Mantoux test, recombinant tuberculosis allergen (RTA) test, IGRA tests: TB-Feron IGRA, T-SPOT.TB, QuantiFERON-TB GIT in patients from 5 to 18 years of age, who are at risk for the development of tuberculosis, due to the use of immunosuppressive therapy, including GEBP.Materials and methods. This clinical trial is a prospective single-center open-label study with 120 patients under observation. Girls predominated among the patients – 71 (59.2%), the average age was 12 years (95% CI [5.2–17.4]). As part of the treatment of the underlying disease, patients in the vast majority of cases (78.3%) received iFNO-α drugs: etanercept (67 people), adalimumab (25 people), golimumab (2 people).Results and discussion. According to the results of a comprehensive medical examination, including CT scan of the chest organs, the presence of active tuberculosis was not established in any of the patients. A positive result of the RTA sample was registered in 0.8% of the subjects, Mantoux test in 46.6%, T-SPOT.TB – 1.7%, TB-Feron IGRA and QuantiFERON-TB GIT – 0.8% each. During the safety assessment, it was noted that within 28 days after the study, none of the 120 patients had any adverse events. Patients need appropriate screening before starting treatment and regular follow-up examinations.Conclusions. The Mantoux test with 2 TE has low specificity (0.49), and the sample with RTA (0.99), TB-Feron IGRA (0.99), T-SPOT.TB (0.98) and QuantiFERON-TB GIT (0.99) are highly specific and safe as tests for detecting tuberculosis infection in children with juvenile idiopathic arthritis.

P731 Relapse rate following withdrawal of anti-TNF therapy in patients with inflammatory bowel disease: A single-center experience

Abstract Background Discontinuation of anti–tumor necrosis factor alpha treatment (anti-TNFα) in patients with inflammatory bowel disease (IBD) poses a significant risk for relapse. The aim of this study is to analyze relapse rates and to possibly identify factors associated with relapse in IBD patients after treatment cessation with anti-TNFα. Methods This is a prospective study conducted at University Clinic of Gastroenterology in Albania from 2019-2022. IBD patients who discontinued biologic therapy with infliximab (IFX) or adalimumab (ADA) were included. All the patients discontinued therapy due to reimbursement issues. Demographic, clinical,laboratory and endoscopic data were collected for each patient. Relapse rates and predictors for relapse were studied using survival and Cox regression analysis. Results A total of 52 IBD patients, mean age 50.8±14.7 years (46 UC and 6 CD), 25(48%) males, were included in the study. Mean follow-up was 29 months. 47.4% were treated with ADA and 51.5 % with IFX. The mean period of biologic therapy was 33.3 months for all patients. Upon treatment cessation, 55.8% of patients were in complete clinical remission, and 30.8% were in partial clinical remission. Cumulative relapse rates at 6, 12, 24 and 36 months were 23.9%, 39.1%, 44.2% and 69.7% respectively for all UC patients while 66.7% of CD patients relapsed within 6 months. The mean time to relapse was 13 months for UC and 5 months for CD patients. Among all IBD patients in complete clinical remission at the time of treatment discontinuation, the cumulative relapse rates at 6, 12, 24 and 36 months, were: 6.9%, 24.8%, 57.7%, and 58% respectively. Significantly higher cumulative relapse rates were found in patients with partial remission, the at the same time points: 37.5%, 50%, 75%, and 81.2% respectively (p=0.01). Multivariable Cox analysis revealed that the only factor associated with lower risk of relapse was mucosal healing (vs nonmucosal healing: HR, 0.322; 95% CI, 1.26 to 6.677; p=0.012). Conclusion The majority of IBD patients relapsed within 3 years after anti TNFα discontinuation, Mucosal healing was the only factor associated with a lower risk of relapse. These results emphasise the crucial role of mucosal healing in guiding treatment decisions for IBD patients.

P807 HLA type impact on immunization and efficacy of ustekinumab in IBD patients: a multicenter study

Abstract Background About 30% of patients treated with ustekinumab will present primary or secondary failure. Outcomes and frequency of ustekinumab immunization are still controversial. Some HLA types (especially DQA1*05) appear to be predictive factors of anti TNFα immunization. This study aimed to assess the impact of HLA type on the risk of immunization and on the efficacy of ustekinumab. Methods IBD patients treatede with ustekinumab in Saint-Etienne and Lyon hospitals were included between 2017 and 2023. Ustekinulab through level was measured by ELISA and HLA type (DQA1, DQB1, DRB1) determined by PCR. Anti-drug antibodies (ADA) detection was done using both a "drug sensitive" assay (ELISA) and an innovative "drug tolerant" method based on anti human lambda chain. Data about clinical, biological (CRP, fecal calprotectin) and endoscopic responses were retrospectively collected. Results Among the 115 patients included (43% males, mean age of 40 years old), 98 had Crohn disease. Nighty-eight percent of the patients were previously treated with at least one anti-TNFα and 33% of them were immunized. In this study, 43 patients were immunized against ustekinumab with the "drug tolerant" assay and only 2 with the "drug sensitive" method. Immunization tended to reduce (not significatively) clinical, biological and endoscopic responses. Ustekinumab through level was significately higher for patients with good clinical (p = 0.009) and biological (p = 0.036). HLA DQA1*05 or DRB1*03 carriage was associated with higher risk of immunization (OR = 5.13, p = 0.048 / OR = 5.36, p = 0.006) and with a trend to decrease clinico-biological response. Other HLA types, notable DQA1*01 tended to be associated with a lower immunization (OR = 0.7, p=0.3) and a better response (OR = 2.55, p = 0.018). A small group involved (26 patients), combination therapy at induction had no significant benefit in terms of immunization prevention or therapeutic response. Sub-groups analysis seemed to confirm some HLA types involvement, by breaking free of imbalances due to haplotype transmission. Conclusion Our study suggests the usefulness of ustekinumab monitoring and a more common immunization than previously described. HLA type seem to influence immunization and ustekinumab response. Some specific HLA types and patients profiles tend to be associated with a higher risk of immunization not only to anti-TNFα but also to ustekinumab.

Frequency of latent tuberculosis in patients receiving Anti-TNF-Alpha therapy.

In this study, it was aimed to reveal the incidence of tuberculosis development in patients receiving tumor necrosis factor-alpha (TNF-α) blocker therapy, despite tuberculosis chemoprophylaxis. 520 patients who were receiving anti TNF-α treatment in the last 3 years were evaluated retrospectively. Radiological imaging tuberculin skin test (TST), history of tuberculosis, BCG vaccine, chemoprophylaxis administration, used anti TNF-α drugs were recorded. There were 265(51.0%) of the patients with ankylosing spondylitis (AS), 175(33.7%) with rheumatoid arthritis, 35(6.7%) with Crohn's, 10(1.9%) with ulcerative colitis (UC), 21(4.0%) with psoriatic arthritis, 14(2.7%) with psoriasis vulgaris. In total, 455 (79.6%) patients were given INH prophylaxis. Active tuberculosis development was observed in five patients (4: pulmonary,1: extrapulmonary; 3: UC, 2:AS) who all received anti TNF-α treatment (0.96%), infliximab. Three patients had tuberculosis disease in the 6th month, and the other 2 patients in the 5th and 24th month of their anti TNF-α treatments, and two had 9-month, and 1 had 6-month chemoprophylaxis history. The incidence of tuberculosis development in patients treated with anti TNF-α was found to be higher than the general population. In our country, where tuberculosis is still prevalent, patients receiving Anti TNF-α treatment (especially infliximab) should be carefully questioned and examined about tuberculosis.

Infliximab Inhibits Colitis Associated Cancer in Model Mice by Downregulating Genes Associated with Mast Cells and Decreasing Their Accumulation

Inflammatory bowel diseases (IBDs), such as Crohn's disease or ulcerative colitis, can be treated with anti TNF-alpha (TNF-α) antibodies (Abs), but they also put patients with IBDs at risk of cancer. We aimed to determine whether the anti TNF-α Ab induces colon cancer development in vitro and in vivo, and to identify the genes involved in colitis-associated cancer. We found that TNF-α (50 ng/mL) inhibited the proliferation, migration, and invasion of HCT8 and COLO205 colon cancer cell lines and that anti TNF-α Ab neutralized TNF-α inhibition in vitro. The effects of anti TNF-α Ab, infliximab (10 mg/kg) were investigated in mouse models of colitis-associated cancer induced by intraperitoneally injected azoxymethane (AOM: 10 mg/kg)/orally administered dextran sodium sulfate (DSS: 2.5%) (AOM/DSS) in vivo. Infliximab significantly attenuated the development of colon cancer in these mice. Microarray analyses and RT-qPCR revealed that mast cell protease 1, mast cell protease 2, and chymase 1 were up-regulated in cancer tissue of AOM/DSS mice; however, those mast cell related genes were downregulated in cancer tissue of AOM/DSS mice with infliximab. These results suggested that mast cells play a pivotal role in the development of cancer associated with colitis in AOM/DSS mice.

The treatment effect of Infliximab on Spondyarthritis patients

Background: Biologic drugs, especially anti TNF-α drugs, are revolutionary in the treatment of Spondyloarthritis when the conventional DMARDs have proved ineffective. Research objective: To evaluate the effectiveness of Infliximab treatment on Spondyloarthritis patients. Materials and method: Longitudinal follow-up study with Infliximab treatment on 27 patients with Spondyloarthritis. Results: The effectiveness of Infliximab on patients with Spondyloarthritis is demonstrated by clinical indicators; inflammatory markers: CRP, ESR in the first hour and the disease activity level according to ASDAS-CRP and ASDAS-ESR in the first hour at the time of T2, T6 compared to T0 were statistically significant (p &lt; 0.05)). After excluding the data of 2 patients with flare at T14, all the above-mentioned indicators improved, the difference was statistically significant with p &lt; 0.05. Conclusion: Infliximab is effective in improving clinical symptoms, inflammatory markers and disease activity score in patients with Spondyloarthritis. Key words: spondyloarthritis, Infliximab.

P590 ADVANCED-UC TRIAL: AppenDectomy Vs ANti TNF-a in inducing Clinical and EnDoscopic remission in left-sided Ulcerative Colitis – A Randomized Clinical Trial

Abstract Background A considerable amount of evidence supports the immunomodulatory role of the appendix in the development and course of Ulcerative Colitis. Indeed, the appendix could act as either a reservoir for commensal bacteria or as the "priming site” for the cytokine production and the immunological cascade triggering inflammation in the colon. Therefore a potential role of the appendix in etiopathogenesis, treatment, prophylaxis and in the colectomy rate in UC has been hypothesized. Given the lack of randomized data on the topic, the ADVANCED-UC trial aims to assess to role of appendectomy in inducing remission in refractory left sided Ulcerative Colitis. Methods Consecutive patients with left-sided UC refractory to conventional treatment and candidate to biologics will be randomized in the standard group (anti-TNF alpha) or in the intervention group (laparoscopic appendectomy). Primary endpoints: Steroid Free Clinical Remission, Endoscopic remission and Assessment of Quality of Life at 3 and 12 months. Secondary endpoints: Clinical Response, Failure Rate, Complication rate and Histological Remission at 3 and 12 months; Colectomy rate at 12, 24 and 60 months. To obtain a significance level of 5% and a test power of 90%, it is required a sample size of 148 patients (74 patients per group), assuming a 25% success rate in the control group and a 50% success rate in the experimental group. The study has been already approved by our local IRB (num. 340/21) and has been granted with the Spring Award from the Surgical Research Network by the Crohn’s and Colitis Foundation (CCF). We plan to start the enrollment in 2023 and we are currently recruiting potential participating centers, to run a multicenter, randomized controlled trial Results The findings of this study could support a change of treatment paradigm for patients refractory to conventional therapy: indeed, while an appendectomy can protect UC patients from the future use of expensive or potentially dangerous drugs, or even major surgery, the initial additional costs and potential side effects of appendectomy will be offset by substantial health gains and reduced costs later in time. On the other hand, patients undergoing appendectomy which do not experience disease remission and are forced to start biologics will be followed up for the evaluation of the colectomy rate to evaluate the possible synergic effect of appendectomy and biologics in reducing the need for total colectomy in the long term. Conclusion The aim of this study is to define the role and effects of laparoscopic appendectomy as a therapeutic option in patients with UC refractory to conventional therapy who are candidates, in the first instance, for biologic anti-TNF-a therapy.

P795 Impact of anxiety and depression on inflammatory bowel disease patients

Abstract Background IBD patients may complain of stress and emotional disorders (anxiety and depression), impacting their quality of life. Anxiety and depression has been reported to be more common in IBD than in the general population. The aim of study was to estimate the prevalence and severity of anxiety and depression among IBD patients and to identify their impact on IBD related features. Methods Consecutive IBD patients presented from January 2021 to February 2022 at our outpatient IBD clinic, were included in this study. Demographic data, disease activity scores, endoscopic scores, disease duration, localization, hospitalization, laboratory data, were collected for each patient. Based on Hospital Anxiety and Depression Scale (HADS) patients were divided in 2 groups: those with symptoms of anxiety and depression and those without. Total Mayo Score (TMS) was used to evaluate UC disease activity while Crohn’s disease activity index (CDAI) for CD patients. CD was considered active when CDAI score &amp;gt; 150; UC was considered active when TMS &amp;gt;2. Results A total of 48 IBD patients (30F: 18M), mean age 41.2±15.6 years were included. 43 (89.6%) patients were diagnosed with UC, and 5 (10.4%) with CD. Mean disease duration was 5.1±4.6 years.37.2% of UC patients were in remission, 20.9% had mild disease, 32.6% moderate, and 9.3% severe disease.40% of CD patients were in remission while 60% had active disease.27.1% of patients were anti TNF-α naïve,43.8% on cortisone, 45.8% were on adalimumab and 27.1% on infliximab treatment. Anxiety and depression symptoms were present in 45.8% and 27.1% of patients, respectively.These symptoms were found combinedin 27%of the patients. No statistically significant difference was observed on the presence and scores of anxiety and depression between UC and CD patients.Presence of anxiety was significantly associated with female gender (p=0.052), UC disease extent (p=0.078), cortisone use (p=0.077), and previous hospitalizations (p=0.01.8). A significant correlation was observed between anxiety score and CDAI score (p=0.006, r=0.971); UC Mayo score (p=0.013, r=0.376) and CRP level (p=0.053, r=0.281). Presence of depression was associated with female gender (p=0.052) and UC disease activity (p=0.097).Depression score was only associated with UC Mayo score (p=0.062). On multiple linear regression,only TMS was correlated to anxiety and depression score (p=0.022, p=0.048, respectively). Conclusion Anxiety and depression are disorders frequently encountered in IBD patients, especially among females. When anxiety and/or depression were present, IBD patients demonstrated a more active disease. Addressing these psychological problems would be helpful achieving a better treatment and quality of life.

P870 What had the greatest impact on the quality of life of IBD patients on intravenous biological therapy in Montenegro during COVID-19?

Abstract Background COVID-19 has affected the quality of life (QoL) of patients with chronic diseases, including patients with IBD. The aim of this study is to evaluate the QoL of patients with IBD on intravenous biological therapy (IvBT), through the Short Inflammatory Bowel Disease Questionnaire (sIBDQ), and to correlate the results with sociodemographic data of the patients. Methods This study was comprised of patients older than 18 years of age, with a pathohistologically confirmed diagnosis of IBD (Ulcerative Colitis (UC), and Crohn’s Disease (CD)). The study was conducted on September and October 2020, during one of the highest incidences period of COVID-19 in our country. Patients completed the sIBDQ, and DASS-21 (Depression, Anxiety and Stress Score-21) questionnaire too, assessing their level of depression, anxiety and stress. For significant symptoms (DASS-21), we used at least moderate DASS-21 subscale score: DASS-21 Depression (≥ 14), DASS-21 Anxiety (≥ 10) and DASS-21 Stress (≥19). The Simple Clinical Colitis Activity Index was used to assess the disease activity of UC; for CD, the Harvey-Bradshaw Index was used. Patients who scored below 50 on the sIBDQ were those labeled with worse QoL. We also examined demographic data, data on IBD characteristics and COVID-19 data and their impact on quality of life. Results Of the total number of patients (94), there were 40 (42.5%) females, 42 (44.6%) with CD. All patients have been receiving IvBTh (anti TNFα: infliximab-originator and biosimilar (59 patients) and anti-integrins: vedolizumab (35 patients)) for at least 6 months prior. The results indicated worse QoL in 25 (27%) patients. Multivariate analysis showed that the greatest impact on poor QoL during the COVD-19 pandemic were: active disease (p= 0.002), significant symptoms on the DASS21 score (p= 0.013), patients who did not regularly go to work or were not employed (p=0.017), if they had a patient with COVID-19 in their immediate environment (p=0.024) and those who had a higher degree of health concerns about coming to regular admission to biological therapy at the IBD unit. (p=0.046). Conclusion 27% of IBD patients on IvBT had worse QoL during the COVID 19 pandemic. In addition to disease activity and significant psychological disturbances, other reasons for lower QoL were identified during the pandemic and are directly related to it.

Combination of Ursodeoxycholic Acid and Glutathione Improves Intestinal Morphology in Cholestasis by Downregulating TNF-α Expression

BACKGROUND: Cholestasis caused by obstruction of the common bile duct and may developed gut-derived sepsis due to reactive oxygen species (ROS) accumulation. Ursodeoxycholic acid (UDCA) and glutathione are widely known for their antioxidant properties, that might be beneficial against ROS. However, the effects of UDCA-glutathione combination against ROS have not been well elucidated in previous studies. Thus, this study was conducted to evaluate tumor necrosis factor (TNF)-α level and height of terminal ileal mucosal villus after UDCA-glutathione administration in cholestasis rat model.METHODS: Twenty-eight male Sprague Dawley rats were randomly grouped into four treatment groups, each group consisted of seven rats that had previously undergone bile duct ligation. Three groups received treatment of UDCA-glutathione combination on stratified dose, while the other one only received UDCA. Each treatment was given for 21 days. Ileal samples were collected from the rats and stained with mouse anti TNF-a antibody and hematoxylin-eosin (HE). Immunohistochemistry and histopathological examination were done using microscope and then calculated with ImageJ.RESULTS: The combination of UDCA and glutathione treatment decreased the TNF-α expression (p&lt;0.05) compared to UDCA only group, particularly in group that received 20 mg UDCA and 15 mg glutathione supplementation (p&lt;0.05) and group that received 30 mg UDCA and 20 mg glutathione supplementation (p&lt;0.05). The height of the mucosa villous was higher in the UDCA-glutathione combination groups for all the three dosage variations given (p&lt;0.05) compared to UDCA only group.CONCLUSION: UDCA-glutathione combination downregulates TNF-α expression and improves ileum mucosal villus height in cholestasis.KEYWORDS: cholestasis, glutathione, intestinal villus height, TNF-α, UDCA

Immune cells and their inflammatory mediators modify β cells and cause checkpoint inhibitor-induced diabetes.

Checkpoint inhibitors (CPIs) targeting programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have revolutionized cancer treatment but can trigger autoimmune complications, including CPI-induced diabetes mellitus (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration. In the NOD mouse model, anti–PD-L1 but not anti–CTLA-4 induced diabetes rapidly. RNA sequencing revealed that cytolytic IFN-γ+CD8+ T cells infiltrated islets with anti–PD-L1. Changes in β cells were predominantly driven by IFN-γ and TNF-α and included induction of a potentially novel β cell population with transcriptional changes suggesting dedifferentiation. IFN-γ increased checkpoint ligand expression and activated apoptosis pathways in human β cells in vitro. Treatment with anti–IFN-γ and anti–TNF-α prevented CPI-DM in anti–PD-L1–treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway resulted in transcriptional changes in β cells and immune infiltrates that may lead to the development of diabetes. Inhibition of inflammatory cytokines can prevent CPI-DM, suggesting a strategy for clinical application to prevent this complication.

Evaluation of Safety and Immunogenicity of BNT162B2 mRNA COVID-19 Vaccine in IBD Pediatric Population with Distinct Immune Suppressive Regimens.

Patients affected by Inflammatory Bowel Disease (IBD) present higher risk for infection and suboptimal response upon vaccination. The immunogenicity of SARS-CoV2 vaccination is still largely unknown in adolescents or young adults affected by IBD (pIBD). We investigated the safety and immunogenicity of the BNT162B2 mRNA COVID-19 vaccine in 27 pIBD, as compared to 30 healthy controls (HC). Immunogenicity was measured by anti-SARS-CoV2 IgG (anti-S and anti-trim Ab) before vaccination, after 21 days (T21) and 7 days after the second dose (T28). The safety profile was investigated by close monitoring and self-reported adverse events. Vaccination was well tolerated, and short-term adverse events reported were only mild to moderate. Three out of twenty-seven patients showed IBD flare after vaccination, but no causal relationship could be established. Overall, pIBD showed a good humoral response upon vaccination compared to HC; however, pIBD on anti-TNFα treatment showed lower anti-S Ab titers compared to patients receiving other immune-suppressive regimens (p = 0.0413 at first dose and p = 0.0301 at second dose). These data show that pIBD present a good safety and immunogenicity profile following SARS-CoV-2 mRNA vaccination. Additional studies on the impact of specific immune-suppressive regimens, such as anti TNFα, on immunogenicity should be further investigated on larger cohorts.

Genetic Variants and Therapeutic Response to Anti-TNF-α Agents in Juvenile Idiopathic Arthritis: An Updated Systematic Review and Meta-analysis.

Genetic Variants and Therapeutic Response to Anti-TNF-α Agents in Juvenile Idiopathic Arthritis: An Updated Systematic Review and Meta-analysis.

Direct effects of anti‐inflammatory medication on barrier function in intestinal epithelial cells

An impaired intestinal epithelial barrier (IEB) is a hallmark in the pathogenesis of inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn’s disease. Most of the IBD patients are treated with anti‐inflammatory reagents including glucocorticoids, anti TNFα (tumor necrosis factor alpha) antibodies and mesasalazine. While the Immune‐modulating effects of those therapies are well documented, we hypothesized whether there are direct effects of those reagents on enterocytes and the IEB.To address this hypothesis we used Caco2 cells as well as 2D and 3D murine organoids and performed analysis of intestinal epithelial barrier function. Inflammation‐induced alterations were mimicked using cytomix for 24h (TNFα, Interleukin 1 beta and Interferon gamma). The enterocytes were treated with 100ng/ml anti‐TNFα antibody Infliximab, 1mM prednisolone or 5mM mesasalazine, respectively following the challenge with cytomix. Epithelial permeability as revealed by measurements of 4kDa FITC Dextran flux and of transepithelial electric resistance showed that Infliximab and a pre‐incubation with prednisolone for 24h attenuated inflammation‐induced breakdown of the IEB. This was not the case after application of mesasalazine or a simultaneous incubation of prednisolone. The functional changes in intestinal epithelial barrier function following incubation with Cytomix were paralleled by alterations in the expression of “leaky” tight junction protein Claudin2, as revealed by Western blots. Furthermore, immunostainings demonstrated an altered distribution of barrier sealing proteins such as Claudin1, Desmoglein2 and E‐Cadherin. All of these effects were blocked by infliximab and prednisolone.In summary, our data indicate that infliximab and prednisolone have direct effects on the IEB that may contribute to the efficacy in the treatment of IBD.

Pediatric inflammatory bowel disease: Fecal calprotectin response to Anti-tumor necrosis factor alpha.

Fecal calprotectin (FC) is a marker of mucosal inflammation in inflammatory bowel disease (IBD). We aimed to assess the effect of anti-tumor necrosis factor alpha (TNFα) therapy on FC levels in children with IBD. The medical records of pediatric patients treated with anti-TNFα agents (2015-2020) were reviewed retrospectively. 63 patients had FC levels measured prior to anti TNFα induction with sequential measurements during follow-up. The main outcome measures were time to FC response according to cutoffs of 250, 150, 100 and 50 µgr/gr. Mean age was 13.6 ± 3 years [females 28 (44.4%), Crohn's 55 (87%)]. Outcomes of < 250, < 150, < 100 and < 50 µgr/gr were achieved by 52 (82%), 51 (81%), 44 (70%) and 32 (50%), respectively. The median time for achieving these cutoffs was 4.8 (1.8-15.6), 7.9 (2.6-16.4), 10.0 (3.5-20.5) and 18.5 (7.0-64.7) months, respectively. Shorter time from diagnosis to treatment was associated with achievement of FC < 50 µgr/gr (p = 0.03). There was no association between age, disease type, anti-TNFα type, inflammatory markers, disease activity indices at baseline and induction anti-TNFα trough concentration and FC response. FC response was achieved by the majority of patients treated with anti-TNFα within a short period of time. FC normalization in responders required almost one year. Fecal calprotectin response was achieved by the majority of pediatric patients within a relatively short period of time after anti-TNFα induction and maintenance therapy. Fecal calprotectin normalization required an average period of approximately one year in responders. The faster response of fecal calprotectin is associated with shorter time from diagnosis to anti-TNFα treatment. Inflammatory bowel disease treating physicians should be aware of the relatively prolonged time to fecal calprotectin normalization and to allow enough time for anti-TNFα therapy to express its full potential prior to significant interventions.