Biologics for the treatment of pyoderma gangrenosum in ulcerative colitis

Pyoderma gangrenosum (PG) is an uncommon extra-intestinal manifestation of inflammatory bowel disease (IBD). Despite limited published literature, biologics have caused a paradigm shift in the management of this difficult-to-treat skin condition. The clinical data and outcomes of three patients with active ulcerative colitis and concurrent PG treated with biologics (infliximab two and adalimumab one) are reviewed in this report. Biologics were added because of the sub-optimal response of the colonic symptoms and skin lesions to parenteral hydrocortisone therapy. All three patients showed a dramatic response to the addition of the biologics. In view of the rapid healing of the skin lesions, superior response rate, and the additional benefit of improvement in the underlying colonic disease following treatment, anti-tumor necrosis factor blockers should be considered as a first line therapy in the management of PG with underlying IBD

Effects of Autism-associated mutations on structure and function of Epigenetic Regulator KMT5B

[Abstract Not Available

Comparison of Interferon-Gamma Release Assay and Tuberculin Skin Test for the Screening of Latent Tuberculosis in Inflammatory Bowel Disease Patients: Indian Scenario

Background. In a country like India, where the prevalence of tuberculosis is very high, the role of screening tools for detection of latent tuberculosis infection (LTBI) like TST and IGRA is still unclear, especially in inflammatory bowel disease (IBD) patients. Our study is aimed at comparing the interferon-gamma release assay (IGRA) and tuberculin skin test (TST) to determine the prevalence of LTBI in IBD patients in the Indian subset of the population. Methods. It was a prospective observational analysis. A total of 257 participants were included in the study. Both TST and IGRA were performed in consecutive patients diagnosed with IBD (131 patients) and in 126 healthy individuals. Both tests were performed on the same day. LTBI diagnosis was considered if any one of TST or IGRA was found to be positive. Results. Out of 131 IBD patients, 121 patients had ulcerative colitis and 10 patients had Crohn’s disease. 29% of the IBD patients and 22% of the control subjects had LTBI. The study demonstrated concordance between TST and IGRA. Agreement test kappa value for IBD patients was 0.656 (CI 0.50-0.81), with a p value of <0.001, suggestive of a fair agreement. Mean IFN-γ release was lower in the immunosuppressed group as compared to non-immunosuppressed individuals (0.26±0.17 vs. 0.45±0.07, p=0.02). Cohen’s kappa coefficient values in IBD cases and control subjects were 0.66 and 0.79, respectively. TST was found to be negatively correlated to BMI. Conclusion. Agreement between TST and IGRA was fair in IBD patients. For LTBI screening in IBD patients, TST and IGRA are complementary methods

Improved prognosis and evidence of enhanced immunogenicity in tumor and circulation of high-risk melanoma patients with unknown primary.

BackgroundMelanoma of unknown primary (MUP) represents a poorly understood group of patients both clinically and immunologically. We investigated differences in prognosis and candidate immune biomarkers in patients with unknown compared with those with known primary melanoma enrolled in the E1609 adjuvant trial that tested ipilimumab at 3 and 10 mg/kg vs high-dose interferon-alfa (HDI).Patients and methodsMUP status was defined as initial presentation with cutaneous, nodal or distant metastasis without a known primary. Relapse-free survival (RFS) and overall survival (OS) rates were estimated by the Kaplan-Meier method. Stratified (by stage) log-rank test was used to compare RFS and OS by primary tumor status. Gene expression profiling (GEP) was performed on the tumor biopsies of a subset of patients. Similarly, peripheral blood samples were tested for candidate soluble and cellular immune biomarkers.ResultsMUP cases represented 12.8% of the total population (N=1699) including 11.7% on the ipilimumab arms and 14.7% on the HDI arm. Stratifying by stage, RFS (p=0.001) and overall survival (OS) (p=0.009) showed outcomes significantly better for patients with unknown primary. The primary tumor status remained prognostically significant after adjusting for treatment and stage in multivariate Cox proportional hazards models. Including only ipilimumab-treated patients, RFS (p=0.005) and OS (p=0.023) were significantly better in favor of those with unknown primary. Among patients with GEP data (n=718; 102 MUP, 616 known), GEP identified pathways and genes related to autoimmunity, inflammation, immune cell infiltration and immune activation that were significantly enriched in the MUP tumors compared with known primaries. Further investigation into infiltrating immune cell types estimated significant enrichment with CD8 +and CD4+T cells, B cells and NK cells as well as significantly higher major histocompatibility complex (MHC)-I and MHC-II scores in MUP compared with known primary. Among patients tested for circulating biomarkers (n=321; 66 unknown and 255 known), patients with MUP had significantly higher circulating levels of IL-2R (p=0.04).ConclusionPatients with MUP and high-risk melanoma had significantly better prognosis and evidence of significantly enhanced immune activation within the TME and the circulation, supporting the designation of MUP as a distinct prognostic marker in patients with high-risk melanoma

Enhanced immune activation within the tumor microenvironment and circulation of female high-risk melanoma patients and improved survival with adjuvant CTLA4 blockade compared to males.

BackgroundWe hypothesized that a gender difference in clinical response may exist to adjuvant CTLA4 blockade with ipilimumab versus high-dose IFNα (HDI). We investigated differences in candidate immune biomarkers in the circulation and tumor microenvironment (TME).Patients and methodsThis gender-based analysis was nested within the E1609 trial that tested adjuvant therapy with ipilimumab 3&nbsp;mg/kg (ipi3) and 10&nbsp;mg/kg (ipi10) versus HDI in high risk resected melanoma. We investigated gender differences in treatment efficacy with ipi3 and ipi10 versus HDI while adjusting for age, stage, ECOG performance (PS), ulceration, primary tumor status and lymph node number. Forest plots were created to compare overall survival (OS) and relapse free survival (RFS) between ipi and HDI. Gene expression profiling (GEP) was performed on tumors of 718 (454 male, 264 female) patients. Similarly, serum and peripheral blood mononuclear cells (PBMC) samples were tested for soluble and cellular biomarkers (N = 321 patients; 109 female and 212 male).ResultsThe subgroups of female, stage IIIC, PS = 1, ulcerated primary, in-transit metastasis demonstrated significant improvement in RFS and/or OS with ipi3 versus HDI. Female gender was significant for both OS and RFS and was further explored. In the RFS comparison, a multivariate Cox regression model including significant variables indicated a significant interaction between gender and treatment (P = 0.024). In peripheral blood, percentages of CD3+ T cells (P = 0.024) and CD3+ CD4+ helper T cells (P = 0.0001) were higher in females compared to males. Trends toward higher circulating levels of IL1β (P = 0.07) and IL6 (P = 0.06) were also found in females. Males had higher percentages of monocytes (P = 0.03) with trends toward higher percentages of regulatory T cells (T-reg). Tumor GEP analysis supported enhanced infiltration with immune cells including gammadelta T cells (P = 0.005), NK cells (P = 0.01), dendritic cells (P = 0.01), CD4+ T cells (P = 0.03), CD8+ T cells (P = 0.03) and T-reg (P = 0.008) in the tumors of females compared to males and a higher T-effector and IFNγ gene signature score (P = 0.0244).ConclusionFemale gender was associated with adjuvant CTLA4 blockade clinical benefits and female patients were more likely to have evidence of type1 immune activation within the TME and the circulation. Trial registration ClinicalTrials.gov NCT01274338. Registered 11 January 2011, https://www.Clinicaltrialsgov/ct2/show/NCT01274338