Intestinal transcriptomic analysis and prediction of biomarkers associated with mucosal healing following vedolizumab treatment in ulcerative colitis using machine learning.

Background Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). In a Phase 2 study, changes from baseline in C-reactive protein (CRP) levels as early as Week 4 and partial Mayo scores (PMS) as early as Week 2 were shown to correlate with clinical and endoscopic outcomes at Week 8 in patients with UC receiving tofacitinib.1 We aimed to determine whether CRP levels and/or PMS can be early predictors of clinical or endoscopic outcomes at Week 8 in OCTAVE Induction 1 and 2 (NCT01465763; NCT01458951).2 Methods In OCTAVE Induction 1 and 2, patients received placebo or tofacitinib 10 mg twice daily (BID) for 8 weeks. Mean CRP levels at baseline and Week 4, and PMS at baseline and Weeks 2 and 4, were analysed by secondary endpoint (clinical response, clinical remission, mucosal healing and endoscopic remission) status at Week 8. Univariate logistic regression analyses were performed to evaluate if CRP levels (log-transformed) or PMS were associated with these endpoints. Results In patients treated with tofacitinib 10 mg BID, numerically greater decreases from baseline were observed in CRP levels at Week 4 in patients who achieved a clinical response at Week 8 vs. those who did not achieve a clinical response (Table). Similarly, numerically greater decreases from baseline were observed in PMS at Weeks 2 and 4 in patients who achieved clinical response, clinical remission, mucosal healing and endoscopic remission at Week 8 vs. those who did not achieve these endpoints (Table). Logistic regression results showed that PMS at Weeks 2 and 4, and CRP levels at Week 4, were significantly (p < 0.001) associated with a clinical response at Week 8 (odds ratio [95% confidence interval] 0.578 [0.529, 0.631]; 0.483 [0.437, 0.533]; 0.631 [0.572, 0.695], respectively). This was also true for clinical remission (0.523 [0.467, 0.587]; 0.426 [0.367, 0.495]; 0.582 [0.508, 0.666]), mucosal healing (0.650 [0.600, 0.705]; 0.599 [0.548, 0.655]; 0.576 [0.515, 0.643]) and endoscopic remission (0.659 [0.574, 0.756]; 0.604 [0.513, 0.712]; 0.663 [0.549, 0.802]) at Week 8. Conclusion These post hoc analyses showed that PMS as early as Week 2 and CRP levels as early as Week 4 may be predictors of improved clinical and endoscopic outcomes in patients with moderately to severely active UC treated with tofacitinib 10 mg BID. These results are in alignment with the findings reported from the Phase 2 trial.1 References

Article1 August 1954ULCERATIVE COLITIS: THERAPEUTIC EFFECTS OF CORTICOTROPIN (ACTH) AND CORTISONE IN 120 PATIENTSJOSEPH B. KIRSNER, M.D., Ph.D., F.A.C.P., WALTER L. PALMER, M.D., Ph.D., F.A.C.P.JOSEPH B. KIRSNER, M.D., Ph.D., F.A.C.P., WALTER L. PALMER, M.D., Ph.D., F.A.C.P.Author, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-41-2-232 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptINTRODUCTIONThe effects of corticotropin (ACTH) and cortisone in ulcerative colitis have been characterized as beneficial,1-5 indifferent6-8 and unfavorable.9-14 Numerous studies also have emphasized the complications of therapy and the recurrences.15-20 The observation of 40 patients in 19511 indicated that, while ACTH and cortisone do not cure ulcerative colitis, they may be useful adjuncts, initiating rapid and occasionally dramatic clinical improvement. The present report summarizes our experience with corticotropin and cortisone in 120 patients with ulcerative colitis observed during the past four years.PATIENTS STUDIEDGeneral Data:The series includes 65 females and 55 males; the majority were between 20...Bibliography1. KirsnerPalmerKlotz JBWLAP (a) : ACTH and cortisone in chronic ulcerative colitis. A comparison of clinical effects, J. Lab. and Clin. Med. 36: 846, 1950. (b) Kirsner, J. B., and Palmer, W. L.: ACTH in ulcerative colitis. Report of progress, Gastroenterology 18: 143, 1951. (c) Kirsner, J. B.: Discussion of "ACTH in chronic ulcerative colitis," Proc. Second Clinical ACTH Conference, 1951, The Blakiston Co., Philadelphia, p. 500. (d) Kirsner, J. B., and Palmer, W. L.: Effect of corticotropin (ACTH) in chronic ulcerative colitis. Observations in forty patients, J. A. M. A. 147: 541, 1951. MedlineGoogle Scholar2. 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Report of case, New England J. Med. 233: 87, 1945. (b) Jobb, E., and Finkelstein, A.: Interesting x-ray findings in a case of acute fulminating ulcerative colitis, Gastroenterology 8: 213, 1947. (c) Griffiths, L. L., and Gilchrist, L.: Fatal case of acute ulcerative colitis with multiple perforations, Brit. M. J. 1: 1366, 1951. (d) McEwen, K. L., and Lodwell, E. A.: Acute fulminating idiopathic ulcerative colitis, Radiology 59: 185, 1952. CrossrefGoogle Scholar33. JankelsonMcClureSweetsir IRCWF: Idiopathic ulcerative colitis. Perforation of the bowel, Rev. Gastroenterol. 12: 31, 1945. Google Scholar34. SalassaKeatingSprague RMFRRG: Clinical aspects of suppression of adrenal cortical function after use of cortisone, Proc. Staff Meet., Mayo Clin. 28: 662, 1953. MedlineGoogle Scholar35. Blanco HG: Considerations on the pathogenesis of ulcerative colitis: its treatment with ACTH and cortisone, Ap. de la des. Clinica No. 3-15, 1953. Google Scholar36. KirsnerPalmerMaimonRicketts JBWLSNWE: Clinical course of chronic non-specific ulcerative colitis, J. A. M. A. 137: 922, 1948. CrossrefMedlineGoogle Scholar37. LevineKirsnerKlotz MJBAP: A new concept of the pathogenesis of ulcerative colitis, Science 144: 552, 1951. CrossrefGoogle Scholar38. Machella TE: Problems in ulcerative colitis, Am. J. Med. 13: 760, 1952. CrossrefMedlineGoogle Scholar39. KirsnerPalmer JBWL: Ulcerative colitis: consideration of its etiology and treatment, J. A. M. A. 155: 341, 1954. CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Chicago, Illinois*Received for publication February 23, 1954. (Presented at Midwest Regional Meeting, American College of Physicians, Milwaukee, Wisconsin, November 21, 1953.)From the Department of Medicine, University of Chicago.†This study was supported in part by the Wallach Fund for Gastrointestinal Research.Dr. David Klein, of Wilson Laboratories, Chicago, Illinois, very generously supplied much of the corticotropin (ACTH).Merck and Company provided a portion of the cortisone. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byInflammatory bowel disease part II: Clinical and therapeutic aspectsBlood eosinophilia and ulcerative colitis--influence of ethnic origin.Clinical Observations on Inflammatory Bowel DiseaseThe Treabnent of Ulcerative ColitisChronic ulcerative colitis in elderly patientsEosinophilia in Peripheral Blood and Inflammatory Exudate in Non-specific ProctocolitisImmediate and Prolonged Therapeutic Effects of Corticotrophin and Adrenal Steroids in Ulcerative ColitisEOSINOPHIL LEUCOCYTES IN ULCERATIVE COLITISCORTICOTROPIN (ACTH) AND THE ADRENAL STEROIDS IN THE MANAGEMENT OF ULCERATIVE COLITIS: OBSERVATIONS IN 240 PATIENTS*†JOSEPH B. KIRSNER, M.D., F.A.C.P., WALTER L. PALMER, M.D., F.A.C.P., JEAN A. SPENCER, M.D., RICHARD O. BICKS, M.D., CHARLES F. JOHNSON, M.D.Response to Drugs and PsychiatryGeneralized scleroderma associated with chronic ulcerative colitisSteroid hormones in the management of chronic ulcerative colitisThe Use of ACTH and Adrenocorticosteroids in Diseases of the Digestive SystemThe Role of Acth and Adrenal Steroids in Perforation of the Colon in Ulcerative Colitis a Clinical-Pathologic StudyUlcerative Colitis; Observations on Its Etiology, Course and ManagementThe Use of the Adrenocorticosteroids in GastroenterologyThe use of ACTH, cortisone, hydrocortisone and related compounds in the management of ulcerative colitisGastroenterologyToxic Psychosis Under Cortisone and CorticotrophinObservations on the Influence of Corticotropins upon the Course of Chronic Ulcerative ColitisTHE PRESENT STATUS OF ACTH AND ADRENAL STEROID THERAPY IN MEDICINE*J. C. BECK, M.D., F.R.C.P.(C)THE RÔLE OF ACTH, CORTISONE AND HYDROCORTISONE IN SURGERY*†WILLIAM E. ABBOTT, M.D., HARVEY KRIEGER, M.D., STANLEY LEVEY, Ph.D.THE USE OF HYDROCORTISONE IN ULCERATIVE COLITIS: PRELIMINARY OBSERVATIONS 1 August 1954Volume 41, Issue 2Page: 232-250KeywordsAdrenocorticotropic hormoneResearch fundingUlcerative colitis Issue Published: 1 August 1954 PDF downloadLoading ...

Inflammatory Bowel Disease Clinical

Background/AimsThe efficacy and safety of vedolizumab in moderate to severely active ulcerative colitis (UC) have been demonstrated in the GEMINI 1 study (NCT00783718). This post-hoc exploratory analysis sought to establish the efficacy and safety of vedolizumab in a subgroup of patients from Asian countries with UC from GEMINI 1.MethodsEfficacy outcomes of interest were clinical response, clinical remission and mucosal healing at week 6 (induction phase); and clinical remission, durable clinical response, durable clinical remission, mucosal healing and glucocorticoid-free remission at week 52 (maintenance phase). Differences in outcome rates between vedolizumab and placebo in Asian countries (Hong Kong, India, Malaysia, Singapore, South Korea, and Taiwan) were assessed using descriptive analyses, and efficacy and safety compared between Asian and non-Asian countries.ResultsDuring induction, in Asian countries (n = 58), clinical response rates at week 6 with vedolizumab and placebo were 55.2% and 24.1%, respectively (difference 31.0%; 95% confidence interval: 7.2%–54.9%). In non-Asian countries (n = 316), response rates at week 6 with vedolizumab and placebo were 45.9% and 25.8%, respectively. During maintenance, in Asian countries, clinical remission rates at 52 weeks with vedolizumab administered every 8 weeks, vedolizumab administered every 4 weeks and placebo were 9.1%, 36.8%, and 31.6%, respectively; corresponding rates for mucosal healing were 45.5%, 47.4%, and 47.4%, respectively. Vedolizumab was well-tolerated; adverse event frequency was comparable in Asian and non-Asian countries.ConclusionsIn patients from Asian countries, the efficacy and safety of vedolizumab in treatment of UC were broadly consistent with that in the overall study population.

Mucosal healing is an important therapeutic endpoint in the management of Crohn's disease (CD) and ulcerative colitis (UC). Limited data exist regarding the comparative efficacy of various therapies in achieving this outcome. To perform a systematic review and meta-analysis of biologics for induction and maintenance of mucosal healing in Crohn's disease and ulcerative colitis. We performed a systematic review and meta-analysis of randomised controlled trials (RCT) examining mucosal healing as an endpoint of immunosuppressives, anti-tumour necrosis factor α (anti-TNF) or anti-integrin monoclonal antibody therapy for moderate-to-severe CD or UC. Pooled effect sizes for induction and maintenance of mucosal healing were calculated and pairwise treatment comparisons evaluated using a Bayesian network meta-analysis. A total of 12 RCTs were included in the meta-analysis (CD - 2 induction, 4 maintenance; UC - 8 induction, 5 maintenance). Duration of follow-up was 6-12weeks for induction and 32-54weeks for maintenance trials. In CD, anti-TNFs were more effective than placebo for maintaining mucosal healing [28% vs. 1%, Odds ratio (OR) 19.71, 95% confidence interval (CI) 3.51-110.84]. In UC, anti-TNFs and anti-integrins were more effective than placebo for inducing (45% vs. 30%) and maintaining mucosal healing (33% vs. 18%). In network analysis, adalimumab therapy was inferior to infliximab [OR 0.45, 95% credible interval (CrI) 0.25-0.82] and combination infliximab-azathioprine (OR 0.32, 95% CrI 0.12-0.84) for inducing mucosal healing in UC. There was no statistically significant pairwise difference between vedolizumab and anti-TNF agents in UC. Anti-TNF and anti-integrin biological agents are effective in inducing mucosal healing in UC, with adalimumab being inferior to infliximab or combination therapy. Infliximab and adalimumab were similar in CD.

Background Close monitoring of disease activity is essential for the therapeutic management of inflammatory bowel disease. A minimally invasive and reliable serum biomarker is desirable, but its reliability and validity have not yet been fully evaluated. The purpose of this study (UMIN000043185) was to investigate the utility of leucine-rich α-2-glycoprotein (LRG) in the management of vedolizumab therapy in patients with ulcerative colitis (UC), and to identify mucosal signatures and surrogate biomarkers by using serum cytokine and mucosal transcriptome analysis. Methods Serum LRG, C-reactive protein (CRP), serum Mucosal Vascular Addressin Cell Adhesion Molecule 1(MadCAM1), serum vedolizumab levels, 19 serum cytokines, and fecal calprotectin (fCal) were measured over 54 weeks (week 0, 2, 6, 14, 30, and 54) (n=21). Clinical remission (Mayo score <= 2, all subscore < = 1) and mucosal healing (Mayo endoscopic subscore <= 1) at week 14 were compared between the clinical remission (CR) group (n=11) and non-clinical remission (non-CR) group (n=10), and between the mucosal healing (MH) group (n=14) and non-mucosal healing (non-MH) group (n=7). Differentially expressed gene (DEG) extraction was performed by stratifying data at week 0 and comparing two groups: CR (n=10) and non-CR (n=3), and complete MH (Mayo endoscopic subscore = 0) (n=8) and non-complete MH (n=6) at week 14. Results Serum LRG concentrations were significantly lower in CR group compared to the non-CR group at week 0 (19.0 vs. 29.0 ug/mL, p=0.027) and week 6 (13.4 vs. 19.6 ug/mL, p=0.034) and significantly lower in MH group compared to the non-MH group at week 6 (13.7 vs. 21.6 ug/mL, p=0.033). In contrast, there were no significant differences in serum CRP and fecal calprotectin levels at any time point for either CR or MH. Serum MCP-1 levels showed significant differences between CR and non-CR at week 0 (609.0 vs 403.4 pg/mL, p=0.0018), between MH and non-MH at week 0 (587.2 vs 358.9 pg/mL, p<0. 001), week 6 (606.9 vs 451.6 pg/mL, p=0.015). DEGs extracted from colon tissue included LRG1 and LRG-related cytokines, MCP-1, reflecting the effect of vedolizumab treatment. Conclusion Both serum LRG (lower in CR/ MH group) and serum MCP-1 (higher in CR/MH group) were suggested to be promising predictive biomarkers of vedolizumab treatment response in patients with UC. Further studies are needed to assess their reliability and validity as indicators of treatment effectiveness.

Nutritional status could affect clinical outcomes in critical patients. We aimed to determine the prognostic accuracy of the modified Nutrition Risk in Critically Ill (mNUTRIC) score for hospital mortality and treatment outcomes in patients with severe community-acquired pneumonia (SCAP) compared to other clinical prediction rules. We enrolled SCAP patients in a multi-center setting retrospectively. The mNUTRIC score and clinical prediction rules for pneumonia, as well as clinical factors, were calculated and recorded. Clinical outcomes, including mortality status and treatment outcome, were assessed after the patient was discharged. We used the receiver operating characteristic (ROC) curve method and multivariate logistic regression analysis to determine the prognostic accuracy of the mNUTRIC score for predicting clinical outcomes compared to clinical prediction rules, while 815 SCAP patients were enrolled. ROC curve analysis showed that the mNUTRIC score was the most effective at predicting each clinical outcome and had the highest area under the ROC curve value. The cut-off value for predicting clinical outcomes was 5.5. By multivariate logistic regression analysis, the mNUTRIC score was also an independent predictor of both clinical outcomes in SCAP patients. We concluded that the mNUTRIC score is a better prognostic factor for predicting clinical outcomes in SCAP patients compared to other clinical prediction rules.

Mucosal healing is the endoscopic treatment target in inflammatory bowel disease. The treat-to-target strategy, emphasizing proactive assessment and optimizing treatment, is commonly applied in the clinical setting. Although colonoscopies are essential for this strategy to be successful, bowel preparation and sedative drugs are required for paediatric patients. We attempted to verify the usefulness of sigmoidoscopy, which is less invasive than colonoscopy, combined with faecal calprotectin, to assess mucosal healing. A total of 58 paediatric patients diagnosed with ulcerative colitis and followed up at Severance Children's Hospital from March 2015 to May 2018 were enrolled. Clinical data and laboratory findings (including faecal calprotectin and endoscopic data) were collected from medical records. The predictive power of mucosal healing of sigmoid colon and rectum (s-MH) combined with faecal calprotectin to predict mucosal healing throughout the colon was analysed. Among 58 patients (mean age 16.13 ± 2.88 years), 18 (31.0%) were in mucosal healing status. The median faecal calprotectin level was 486.5 μg/g. The faecal calprotectin cutoff value for predicting mucosal healing, identified using receiver-operating characteristic analyses, was 148 μg/g (area under the curve, 0.81). Sensitivity, specificity, positive predictive value, and negative predictive value of s-MH in predicting mucosal healing were 1.0, 0.82, 0.72, and 1.0, respectively. When we combined s-MH with faecal calprotectin less than the cutoff value, the sensitivity, specificity, positive predictive value, and negative predictive value were 0.56, 1.0, 1.0, and 0.83, respectively. For patients with a low faecal calprotectin level, sigmoidoscopy might be sufficient to assess mucosal healing.

The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Surgical Management of Ulcerative Colitis.

Single-cell and bulk transcriptomics reveals M2d macrophages as a potential therapeutic strategy for mucosal healing in ulcerative colitis.

P140 The relation between resistin and insulin resistance in inflammatory bowel disease patients

BackgroundFecal calprotectin (FC) is well accepted as a non-invasive biomarker which objectively reflects colonic inflammation in ulcerative colitis (UC). However, its value as a marker of response during the early phase of remission induction treatment has not been well studied. The aim of this study is to evaluate the significance of FC for predicting the short-term outcomes of remission induction treatment in patients with UC.MethodsA prospective observational study was conducted among 31 patients with active UC. FC was monitored with two-item patient-reported outcome (PRO2), partial Mayo score (PMS), and Lichtiger clinical activity index (CAI) during the first 4 weeks of remission induction treatment. Clinical response was defined as a decrease in CAI of 3 or more points below baseline. Mucosal healing (MH) was defined as Mayo endoscopic subscore 0 or 1. Within-day and within-stool variability of FC were assessed during the first week of treatment.ResultsIn week 4-clinical responders, PRO2, PMS, and CAI significantly decreased from day 3, however, FC did not show significant reduction until week 2. Among all markers, the decrease in PRO2 at week 4 most accurately predicted MH at week 12. Within-day variability of FC was remarkably wide even at the first week in clinical responders. Within-stool variability was extremely small.ConclusionsPRO2 predicted the short-term outcomes of remission induction treatment earlier than FC possibly because of the wide within-day variability of FC in active UC.

Introduction: Patients with la/m TNBC have poor prognosis and limited effective treatment options. Clinical guidelines recommend testing for biomarkers, including PD-L1 expression, to inform clinical decision making and eligible treatments. This study describes treatment patterns and clinical outcomes in patients with la/m TNBC treated in US community and academic health systems. Methods: This observational, cohort study used deidentified person-level NorstellaLinQ EMR/lab and supplemental claims data. Patients were required to have diagnosis of la/m TNBC followed by initiation of 1L mTNBC anti-cancer treatment between 1/1/ 2020 and 12/31/2023. Patients were followed from initiation of 1L treatment (index date) until earliest of death, end of EMR, or end of study period (12/31/2024). Patients were stratified by PD-L1 status closest to the index date. Tumor PD-L1 status were assessed using the PD-L1 assays in EMR laboratory results or evidence of PD-L1 tumor status in unstructured clinical notes. Clinical outcomes included real-world time on treatment (rwTOT) and real-world time to next treatment (rwTTNT). Results: A total of 724 patients met criteria for analysis (PD-L1 Negative: 163, PD-L1 Positive: 398, Unknown/did not receive IO in la/m setting: 163). Mean(sd) age at index: 59(13) years. Demographics were comparable across PD-L1 Negative/Positive subgroups. Less than 5% of study patients were exposed to IO therapy in (neo)adjuvant setting. Among all patients, there were over 30 distinct 1L treatment agent-based regimens observed. Among patients with PD-L1 negative tumors, most common 1L regimens were chemotherapy monotherapy (“chemo mono”) (73.6%) and chemotherapy + immunotherapy (chemo + IO) (17.2%)). Among patients with PD-L1 positive tumors, most common 1L regimens were chemo + IO (60.6%) and chemo mono (31.7%). Approximately 34% of study patients cycled through at least 3 LOTs during the study period. rwTOT and rwTTNT were described in Table 1. Conclusions: In this real-world study of US patients with la/m TNBC and confirmed PD-L1 status, there is variability in 1L, 2L and 3L regimens. The majority of the PD-L1 positive cohort received 1L chemo (+/- IO) followed by chemo + IO or ADCs in 2L/3L. Negative PD-L1 cohort was largely prescribed 1L chemo followed by ADCs or chemo in 2L/3L, while there is a proportion of patients who used chemo+ IO combination therapy that is higher than previously published literature. The proportion of patients receiving subsequent LOTs was low, highlighting the need for new and efficacious frontline treatment options. Citation Format: X. Wang, Y. Zhang, A. Petrilla, S. McElwee, B. Momani, J. Dinoso, B. Stwalley, C. Lai, A. Brufsky. Variations in lines of treatment and clinical outcomes in US health system patients with locally advanced, inoperable or metastatic triple negative breast cancer (la/m TNBC) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-02-27.

Subcutaneous Golimumab Induces Clinical Response and Remission in Patients With Moderate-to-Severe Ulcerative Colitis

Purpose This study was aimed at identifying hub genes and ceRNA regulatory networks linked to prognosis in hepatocellular carcinoma (HCC) and to identify possible therapeutic targets. Methods Differential expression analyses were performed to detect the differentially expressed genes (DEGs) in the four datasets (GSE76427, GSE6764, GSE62232, and TCGA). The intersected DEmRNAs were identified to explore biological significance by enrichment analysis. We built a competitive endogenous RNA (ceRNA) network of lncRNA-miRNA-mRNA. The mRNAs of the ceRNA network were used to perform Cox and Kaplan-Meier analyses to obtain prognosis-related genes, followed by the selection of genes with an area under the curve >0.8 to generate the random survival forest model and obtain feature genes. Furthermore, the feature genes were subjected to least absolute shrinkage and selection operator (LASSO) and univariate Cox analyses were used to identify the hub genes. Finally, the infiltration status of immune cells in the HCC samples was determined. Results A total of 1923 intersected DEmRNAs were identified in four datasets and involved in cell cycle and carbon metabolism. ceRNA network was created using 10 lncRNAs, 67 miRNAs, and 1,923 mRNAs. LASSO regression model was performed to identify seven hub genes, SOCS2, MYOM2, FTCD, ADAMTSL2, TMEM106C, LARS, and KPNA2. Among them, TMEM106C, LARS, and KPNA2 had a poor prognosis. KPNA2 was considered a key gene base on LASSO and Cox analyses and involved in the ceRNA network. T helper 2 cells and T helper cells showed a higher degree of infiltration in HCC. Conclusion The findings revealed seven hub genes implicated in HCC prognosis and immune infiltration. A corresponding ceRNA network may help reveal their potential regulatory mechanism.