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Steffens J, Michael S, Kuth K, Hollert H, Du Marchie Sarvaas M, Nesic A, Kraus T, Baumann R. Occupationally Relevant Zinc- and Copper-Containing Metal Fumes Inhibit Human THP-1 Macrophage TNF and IL-6 Responses to Bacterial Stimuli. GLOBAL CHALLENGES (HOBOKEN, NJ) 2025; 9:2400302. [PMID: 40352634 PMCID: PMC12065103 DOI: 10.1002/gch2.202400302] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 12/10/2024] [Indexed: 05/14/2025]
Abstract
Metal workers have an increased risk of severe lobar pneumonia due to exposure to metal fume particles, which lead to recent pneumococcal vaccination recommendations. To investigate the effects of metal fume-derived zinc oxide (ZnO) and copper oxide (CuO) particles on airway immune responses, human THP-1-derived macrophages are exposed in vitro to the bacterial pathogen-associated molecular patterns (PAMPs) lipopolysaccharide (LPS), lipoteichoic Acid (LTA), or peptidoglycan (PGN), together with particle suspensions. Particles are generated through metal inert gas (MIG) soldering. Spectrometric and microscopic analysis confirms CuO and ZnO as main components. Macrophage IL-6 and TNF mRNAs are quantified by qPCR and secreted protein levels by electrochemiluminescent multi-spot assay. A dose-dependent increase in macrophage TNF and IL-6 mRNA (4 h) and protein (24 h) levels following exposure to PAMPs is significantly inhibited by 2 µg mL-1 CuO/ZnO particles (n = 5). Additionally, CuO/ZnO particles significantly inhibit TNF protein expression in unstimulated macrophages, while IL-6 protein levels are unaffected (n = 5). The presented in vitro immunotoxicity approach may extend existing new approach methodology (NAM) elements for chemical risk assessment and possibly exposure limit evaluation refinements. These findings implicate that CuO/ZnO particles suppress macrophage proinflammatory responses to PAMPs, potentially compromising lung immunity, underlining current vaccine recommendations and efforts for preventive occupational health guidelines.
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Affiliation(s)
- Jan Steffens
- Institute for Translational Medicine (ITM)Medical School Hamburg (MSH)20457HamburgGermany
- Institute for Occupational, Social and Environmental MedicineMedical FacultyUniversity Hospital RWTH Aachen University52074AachenGermany
| | - Sabrina Michael
- Institute for Occupational, Social and Environmental MedicineMedical FacultyUniversity Hospital RWTH Aachen University52074AachenGermany
- Institute of Hygiene and Environmental MedicineMedical FacultyUniversity Hospital RWTH Aachen University52074AachenGermany
| | - Katharina Kuth
- Institute for Occupational, Social and Environmental MedicineMedical FacultyUniversity Hospital RWTH Aachen University52074AachenGermany
- Institute of Hygiene and Environmental MedicineMedical FacultyUniversity Hospital RWTH Aachen University52074AachenGermany
| | - Henner Hollert
- Department Evolutionary Ecology and Environmental ToxicologyInstitute of Ecology, Evolution and DiversityFaculty Biological SciencesGoethe University Frankfurt60438FrankfurtGermany
| | - Miriam Du Marchie Sarvaas
- Institute for Occupational, Social and Environmental MedicineMedical FacultyUniversity Hospital RWTH Aachen University52074AachenGermany
| | - Andrijana Nesic
- Institute for Translational Medicine (ITM)Medical School Hamburg (MSH)20457HamburgGermany
| | - Thomas Kraus
- Institute for Occupational, Social and Environmental MedicineMedical FacultyUniversity Hospital RWTH Aachen University52074AachenGermany
| | - Ralf Baumann
- Institute for Translational Medicine (ITM)Medical School Hamburg (MSH)20457HamburgGermany
- Institute for Occupational, Social and Environmental MedicineMedical FacultyUniversity Hospital RWTH Aachen University52074AachenGermany
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Adler J, Gadepalli S, Rahman M, Kim S. Early tumour necrosis factor antagonist treatment prevents perianal fistula development in children with Crohn's disease: post hoc analysis of the RISK study. Gut 2025; 74:539-546. [PMID: 39667905 DOI: 10.1136/gutjnl-2024-333280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 11/24/2024] [Indexed: 12/14/2024]
Abstract
BACKGROUND One in three children with Crohn's disease develop perianal fistula complications (PFCs), among the most disturbing and difficult-to-treat disease-related complications. Retrospective evidence suggests PFCs may be preventable. OBJECTIVE We aimed to determine if early antitumour necrosis factor-alpha (anti-TNF⍺) therapy prevents PFC development in a well-characterised prospective cohort of paediatric patients with Crohn's disease who were free from PFC at enrolment. DESIGN RISK was a multicentre inception cohort of children newly diagnosed with Crohn's disease. We included all patients who had never experienced PFCs 30 days after study enrolment. We conducted nearest-neighbour propensity score-matched triad analyses. Matching was performed to balance patient characteristics across three mutually exclusive treatment groups based on therapy prior to either PFC development or the end of the observation period. RESULTS Among 873 patients without perianal fistula, 447 matched patients were included (149 per treatment group). The presence of non-penetrating perianal lesions (large skin tags, ulcers and/or fissures) was significantly associated with PFC development, with 4-fold greater odds of PFC (OR 4.08, 95% CI (95% CI) 1.70 to 9.78; p=0.0016). Early anti-TNF⍺ therapy was associated with an 82% decrease in the odds of PFC (OR 0.18, 95% CI 0.05 to 0.66; p=0.01). Among those with perianal lesions, anti-TNF⍺ therapy was associated with 94% reduced odds of PFC development (OR 0.055, 95% CI 0.006 to 0.50; p=0.010). No other treatment group was associated with reduced risk of PFC. CONCLUSION Early anti-TNF therapy prevents perianal fistula development, especially among patients at increased risk.
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Affiliation(s)
- Jeremy Adler
- Pediatric Gastroenterology, University of Michigan, Michigan Medicine, Ann Arbor, Michigan, USA
- Susan B. Meister Child Health Evaluation and Research Center, University of Michigan, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Samir Gadepalli
- Susan B. Meister Child Health Evaluation and Research Center, University of Michigan, Michigan Medicine, Ann Arbor, Michigan, USA
- Pediatric Surgery, University of Michigan, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Moshiur Rahman
- Susan B. Meister Child Health Evaluation and Research Center, University of Michigan, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Sandra Kim
- Pediatric Gastroenterology, Cleveland Clinic, Cleveland, Ohio, USA
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Li S, Zhuge A, Chen H, Han S, Shen J, Wang K, Xia J, Xia H, Jiang S, Wu Y, Li L. Sedanolide alleviates DSS-induced colitis by modulating the intestinal FXR-SMPD3 pathway in mice. J Adv Res 2025; 69:413-426. [PMID: 38582300 PMCID: PMC11954817 DOI: 10.1016/j.jare.2024.03.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 03/28/2024] [Accepted: 03/29/2024] [Indexed: 04/08/2024] Open
Abstract
INTRODUCTION Inflammatory bowel disease (IBD) is a global disease with limited therapy. It is reported that sedanolide exerts anti-oxidative and anti-inflammatory effects as a natural phthalide, but its effects on IBD remain unclear. OBJECTIVES In this study, we investigated the impacts of sedanolide on dextran sodium sulfate (DSS)-induced colitis in mice. METHODS The mice were administered sedanolide or vehicle followed by DSS administration, after which colitis symptoms, inflammation levels, and intestinal barrier function were evaluated. Transcriptome analysis, 16S rRNA sequencing, and targeted metabolomics analysis of bile acids and lipids were performed. RESULTS Sedanolide protected mice from DSS-induced colitis, suppressed the inflammation, restored the weakened epithelial barrier, and modified the gut microbiota by decreasing bile salt hydrolase (BSH)-expressing bacteria. The downregulation of BSH activity by sedanolide increased the ratio of conjugated/unconjugated bile acids (BAs), thereby inhibiting the intestinal farnesoid X receptor (FXR) pathway. The roles of the FXR pathway and gut microbiota were verified using an intestinal FXR-specific agonist (fexaramine) and germ-free mice, respectively. Furthermore, we identified the key effector ceramide, which is regulated by sphingomyelin phosphodiesterase 3 (SMPD3). The protective effects of ceramide (d18:1/16:0) against inflammation and the gut barrier were demonstrated in vitro using the human cell line Caco-2. CONCLUSION Sedanolide could reshape the intestinal flora and influence BA composition, thus inhibiting the FXR-SMPD3 pathway to stimulate the synthesis of ceramide, which ultimately alleviated DSS-induced colitis in mice. Overall, our research revealed the protective effects of sedanolide against DSS-induced colitis in mice, which indicated that sedanolide may be a clinical treatment for colitis. Additionally, the key lipid ceramide (d18:1/16:0) was shown to mediate the protective effects of sedanolide, providing new insight into the associations between colitis and lipid metabolites.
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Affiliation(s)
- Shengjie Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Aoxiang Zhuge
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Hui Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Shengyi Han
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jian Shen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Kaicen Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jiafeng Xia
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - He Xia
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Shiman Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Youhe Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250000, China.
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Mapuskar KA, London B, Zacharias ZR, Houtman JC, Allen BG. Immunometabolism in the Aging Heart. J Am Heart Assoc 2025; 14:e039216. [PMID: 39719411 PMCID: PMC12054428 DOI: 10.1161/jaha.124.039216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 11/19/2024] [Indexed: 12/26/2024]
Abstract
Structural, functional, and molecular-level changes in the aging heart are influenced by a dynamic interplay between immune signaling and cellular metabolism that is referred to as immunometabolism. This review explores the crosstalk between cellular metabolic pathways including glycolysis, oxidative phosphorylation, fatty acid metabolism, and the immune processes that govern cardiac aging. With a rapidly aging population that coincides with increased cardiovascular risk and cancer incidence rates, understanding the immunometabolic underpinnings of cardiac aging provides a foundation for identifying therapeutic targets to mitigate cardiac dysfunction. Aging alters the immune environment of the heart by concomitantly driving the changes in immune cell metabolism, mitochondrial dysfunction, and redox signaling. Shifts in these metabolic pathways exacerbate inflammation and impair tissue repair, creating a vicious cycle that accelerates cardiac functional decline. Treatment with cancer therapy further complicates this landscape, as aging-associated immunometabolic disruptions augment the susceptibility to cardiotoxicity. The current review highlights therapeutic strategies that target the immunometabolic axis to alleviate cardiac aging pathologies. Interventions include modulating metabolic intermediates, improving mitochondrial function, and leveraging immune signaling pathways to restore cardiac health. Advances in immunometabolism thus hold significant potential for translating preclinical findings into therapies that improve the quality of life for the aging population and underscore the need for approaches that address the immunometabolic mechanisms of cardiac aging, providing a framework for future research.
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Affiliation(s)
- Kranti A. Mapuskar
- Department of Radiation OncologyUniversity of Iowa Hospitals and Clinic, University of Iowa HealthcareIowa CityIAUSA
- Holden Comprehensive Cancer Center, Carver College of MedicineUniversity of Iowa Hospitals and Clinic, University of Iowa HealthcareIowa CityIAUSA
| | - Barry London
- Holden Comprehensive Cancer Center, Carver College of MedicineUniversity of Iowa Hospitals and Clinic, University of Iowa HealthcareIowa CityIAUSA
- Department of Internal MedicineUniversity of Iowa Hospitals and Clinic, University of Iowa HealthcareIowa CityIAUSA
| | - Zeb R. Zacharias
- Holden Comprehensive Cancer Center, Carver College of MedicineUniversity of Iowa Hospitals and Clinic, University of Iowa HealthcareIowa CityIAUSA
- Human Immunology CoreUniversity of Iowa Hospitals and Clinic, University of Iowa HealthcareIowa CityIAUSA
| | - Jon C.D. Houtman
- Holden Comprehensive Cancer Center, Carver College of MedicineUniversity of Iowa Hospitals and Clinic, University of Iowa HealthcareIowa CityIAUSA
- Human Immunology CoreUniversity of Iowa Hospitals and Clinic, University of Iowa HealthcareIowa CityIAUSA
- Department of Microbiology and ImmunologyUniversity of Iowa Hospitals and Clinic, University of Iowa HealthcareIowa CityIAUSA
| | - Bryan G. Allen
- Department of Radiation OncologyUniversity of Iowa Hospitals and Clinic, University of Iowa HealthcareIowa CityIAUSA
- Holden Comprehensive Cancer Center, Carver College of MedicineUniversity of Iowa Hospitals and Clinic, University of Iowa HealthcareIowa CityIAUSA
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Lichtenstein GR, Lee SD, Feagan BG, Loftus EV, Ng S, Dehlin K, Quinn P, Coarse J, Rosario-Jansen T, Arendt C, Stark JL. Certolizumab Pegol Treatment in Patients With Crohn's Disease: Final Safety Data From the SECURE Registry. CROHN'S & COLITIS 360 2025; 7:otae083. [PMID: 39895830 PMCID: PMC11786119 DOI: 10.1093/crocol/otae083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Indexed: 02/04/2025] Open
Abstract
Background Crohn's disease (CD) treatment is associated with increased risks of infection and malignancies. Although the safety of certolizumab pegol (CZP) is well established, long-term data from community-based observational studies are lacking. Aim This study aimed to evaluate long-term safety outcomes of patients from the SECURE registry receiving CZP relative to other CD treatments, including corticosteroids, immunosuppressants, and biologics. The primary outcome of this observational study was the evaluation of malignancies. Methods Adult patients with CD were prospectively monitored for up to 8 years. Pre-specified data were collected for all enrolled patients. Adverse events of interest (AEoIs) were reported per 100 patient-years (PY) of exposure. Incidence rate ratios (IRRs) were calculated for AEoIs using multivariate regression analysis accounting for exposure to multiple treatments. Malignancies reported after any exposure to CZP were attributed to CZP. Post-hoc analyses were conducted to evaluate non-melanoma skin cancer (NMSC), lymphoma, and pregnancy outcomes. Results A total of 3072 patients were enrolled in the study. The risk of AEoIs was similar between patients with only CZP exposure versus comparator exposure. Among patients with any CZP exposure, there was a higher frequency of serious infections (IRR: 2.56 [95% confidence interval (CI): 2.00, 3.29]) and hypersensitivity or anaphylactic reactions (IRR: 4.11 [95% CI: 1.80, 9.38]) versus patients with comparator exposure. Malignancy rates were similar across groups; however, concomitant use of thiopurines was associated with higher odds of NMSC (odds ratio: 2.30 [95% CI: 1.09, 4.89]). Most cases of lymphoma (5/7) occurred in patients with exposure to thiopurines. Pregnancy outcomes were similar across groups. Conclusions No new safety signals were identified for CZP; the use of thiopurines was identified as a risk factor for NMSC. Trial registration NCT00844285.
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Affiliation(s)
- Gary R Lichtenstein
- Division of Gastroenterology and Hepatology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
| | - Scott D Lee
- Division of Gastroenterology, University of Washington School of Medicine, Seattle, WA, USA
| | - Brian G Feagan
- University of Western Ontario, Robarts Research Institute at Schulich School of Medicine and Dentistry, London, Ontario, Canada
| | - Edward V Loftus
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Samson Ng
- Ferring Pharmaceuticals, Parsippany, NJ, USA
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Liu Q, Cui Z, Deng C, Yang C, Shi T. A real-world pharmacovigilance analysis of adverse events associated with irbesartan using the FAERS and JADER databases. Front Pharmacol 2024; 15:1485190. [PMID: 39635439 PMCID: PMC11614654 DOI: 10.3389/fphar.2024.1485190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 10/28/2024] [Indexed: 12/07/2024] Open
Abstract
Objective Hypertension is a leading global risk factor for disability and death. Irbesartan, a potent angiotensin II receptor blocker, requires continuous safety monitoring. We conducted a disproportionality analysis of irbesartan-related adverse drug events (ADEs) using the FDA's FAERS and Japan's JADER databases. Methods We extracted irbesartan-related ADE reports from FAERS (Q1 2004 to Q1 2024) and JADER (Q2 2008 to Q4 2023). We used Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM) for signal detection. Sensitivity analyses were conducted to exclude comorbid medications, and subgroup analyses by age and gender were performed to explore ADE occurrence in specific populations. Th time to onset (TTO) of ADEs was assessed using Weibull distribution test and Kaplan-Meier curves. Results A total of 5,816 (FAERS) and 366 (JADER) reports were analyzed, with irbesartan-related preferred terms (PTs) involving 27 System Organ Classes (SOCs) in FAERS and 22 in JADER. Three SOCs met detection thresholds in both databases: "metabolism and nutrition disorders," "cardiac disorders," and "renal and urinary disorders." We identified 219 positive signals in FAERS and 20 in JADER, including known signals like hyperkalemia, hypotension, and acute kidney injury. Notably, newly identified signals such as acute pancreatitis (n = 50, ROR: 7.76 [5.88-10.25]) and rhabdomyolysis (n = 50, ROR: 7.76 [5.88-10.25]) in FAERS and respiratory failure (n = 7, ROR: 6.76 [3.20-14.26]) in JADER could have significant clinical implications, as they may lead to severe outcomes if not recognized and managed promptly. Subgroup analyses revealed both similarities and differences in signal detection across gender and age groups. Sensitivity analyses, excluding concomitant medications, confirmed the persistence of key positive signals, including hyperkalemia, angioedema, acute pancreatitis, and agranulocytosis. ADEs mainly occurred within 1 month (34.14%) and after 1 year (32.32%) after dosing, with a median onset of 107 days. Conclusion This study provides valuable real-world evidence on the safety profile of irbesartan. The identification of new safety signals underscores the necessity of updating drug labels, particularly for assessing and managing high-risk patients. Additionally, the TTO analysis emphasizes the importance of sustained vigilance for adverse events over time. In conclusion, our findings contribute to a more comprehensive understanding of irbesartan's safety, aiding healthcare professionals in optimizing its use in clinical practice.
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Affiliation(s)
- Qian Liu
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Zhiwei Cui
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Chao Deng
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Chao Yang
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Tao Shi
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
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Lu Y, Xiong Y, Zhang S, Wang B, Feng Y, Pu Z, Wei K, Chen J, Chen D, Zhang P. D-mannose reduces oxidative stress, inhibits inflammation, and increases treg cell proportions in mice with ulcerative colitis. Front Pharmacol 2024; 15:1454713. [PMID: 39555100 PMCID: PMC11563948 DOI: 10.3389/fphar.2024.1454713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 10/18/2024] [Indexed: 11/19/2024] Open
Abstract
Background Regulatory T (Treg) cells is required to dampen immune responses against intestinal microbiota, which aid in a healthy body to promise that the resident gut microbiota should not attract the attention of the immune system. Inflammation and inflammatory bowel disease (IBD) can be induced if the immune system fails to ignore the resident gut microbiota and targets them instead. D-mannose, a common monosaccharide in nature, has been shown to ameliorate multiple autoimmune diseases. This study aimed to investigate the therapeutic effect of D-mannose on mice ulcerative colitis (UC) induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS), and elucidate its underlying mechanisms. Methods To simulate human IBD, we constructed a mouse model of UC by injecting TNBS into the colon. Results Our results demonstrated that D-mannose treatment effectively alleviated TNBS-induced UC in mice, as evidenced by the amelioration of UC symptoms. D-mannose treatment significantly reduced inflammation by decreasing the expression of proinflammatory cytokines and inflammation mediators. D-mannose treatment also significantly inhibited oxidative stress, promoted the expression of GSH and SOD, decreased the expression of MDA. Mechanistically, D-mannose upregulated the proportion of both CD4(+) Tregs and CD8(+) Tregs. Conclusion In summary, our study provides the first evidence of the therapeutic effect of D-mannose on mice with UC, which is likely mediated by upregulating Treg proportions.
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Affiliation(s)
- Yuqing Lu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, Liaoning, China
| | - Yongjian Xiong
- Central Laboratory, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Shuangshuang Zhang
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, Liaoning, China
| | - Boya Wang
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, Liaoning, China
| | - Yuntao Feng
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Zhuonan Pu
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Kun Wei
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, Liaoning, China
| | - Jun Chen
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, Liaoning, China
| | - Dapeng Chen
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, Liaoning, China
| | - Peng Zhang
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
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Curci D, Lucafò M, Decorti G, Stocco G. Monoclonal antibodies against pediatric ulcerative colitis: a review of clinical progress. Expert Opin Biol Ther 2024; 24:1133-1144. [PMID: 39285823 DOI: 10.1080/14712598.2024.2404076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 09/10/2024] [Indexed: 09/21/2024]
Abstract
INTRODUCTION In children, ulcerative colitis (UC) is often more severe and extensive than in adults and hospitalization for acute exacerbations occurs in around a quarter of subjects. There is a need for effective drugs, which could avoid or reduce the use of corticosteroids which, especially in children, are burdened by a number of severe side effects. The introduction in therapy of monoclonal antibodies has completely changed the therapeutic scenario and the prognosis of the disease. AREAS COVERED In this review, the use of the monoclonal antibodies directed against tumor necrosis factor (TNF)α or other inflammatory targets for the treatment of pediatric UC will be discussed. A search of the literature was done using the keywords 'pediatric,' 'ulcerative colitis,' 'inflammatory bowel disease,' 'monoclonal antibodies;' 'infliximab,' 'adalimumab,' 'golimumab,' vedolizumab," 'ustekinumab' and 'risankizumab.' EXPERT OPINION The use of monoclonal antibodies has greatly increased in recent years in pediatric UC, both in patients who did not respond to conventional therapies, and, more often, as initial therapy. Thanks to therapeutic drug monitoring and to the availability of biologics with different targets, therapy has become more targeted and personalized, with a significant improvement in response, in quality of life, and with a good safety profile.
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Affiliation(s)
- Debora Curci
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
| | - Marianna Lucafò
- Department of Life Sciences, University of Trieste, Trieste, Italy
| | - Giuliana Decorti
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - Gabriele Stocco
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
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Wang K, Zhu Y, Liu K, Zhu H, Ouyang M. Adverse events of biologic or small molecule therapies in clinical trials for inflammatory bowel disease: A systematic review and meta-analysis. Heliyon 2024; 10:e25357. [PMID: 38370239 PMCID: PMC10869791 DOI: 10.1016/j.heliyon.2024.e25357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 09/20/2023] [Accepted: 01/25/2024] [Indexed: 02/20/2024] Open
Abstract
Background Biologic or small-molecule therapies are highly effective for the treatment of inflammatory bowel disease (IBD), and approval by the FDA has significantly increased both their clinical use and the development of novel regimens. However, the identification and management of their associated toxicities poses challenges for clinicians and researchers. Methods A systematic review and meta-analysis of randomized controlled trials (RCTs) published from January 1, 2000, to October 15, 2022, and in the databases. A random-effects model with logit transformation was applied to the analysis heterogeneity between studies was evaluated using the I2 statistic with incidence and 95 % confidence interval (CI) for any adverse events (AEs), and serious AEs (SAEs). Results In Crohn's disease (CD), the total AE incidence was 67.0 % (95 % CI, 66.2%-67.8 %; I2 = 97.2 %) for any AEs and 7.3 % (6.9-7.7; 97.2) for serious AEs. In ulcerative colitis (UC), the overall incidence of any and serious AEs was 63.6 % (63.0-64.3; 98.1) and 5.7 % (5.4-6.0; 88.9), respectively. The most common AEs were infections (21.5 [20.3-22.8], 32.6 [31.0-34.2], 25.9 [24.5-27.2], and 13.7 [10.7-16.7]) in CD patients that were treated with TNF antagonists, anti-integrins, anti-IL agents, and JAK inhibitors, respectively, and in UC patients also were infections (22.8 [21.7-24.0], 27.4 [25.9-28.9], and 18.4 [16.7-20.2]), respectively, as well as increases in lactic dehydrogenase levels (23.1 [20.8-25.4]) with JAK inhibitors. Conclusion This study offers a comprehensive summary of toxic side effects of IBD treatments and a useful reference for both patients and clinicians.
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Affiliation(s)
- Kailing Wang
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Youwen Zhu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Kun Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Hong Zhu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Miao Ouyang
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
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10
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Liu T, Ning Z, Liu P, Gao H. Cassane diterpenoid ameliorates dextran sulfate sodium-induced experimental colitis by regulating gut microbiota and suppressing tryptophan metabolism. Front Immunol 2023; 13:1045901. [PMID: 36741371 PMCID: PMC9893013 DOI: 10.3389/fimmu.2022.1045901] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 12/30/2022] [Indexed: 01/20/2023] Open
Abstract
Ulcerative colitis (UC) is one form of inflammatory bowel disease (IBD), characterized by chronic relapsing intestinal inflammation. As increasing morbidity of UC and deficiency of conventional therapies, there is an urgent need for attractive treatment. Cassane diterpenoids, the characteristic chemical constituents of Caesalpinia genus plants, have been studied extensively owing to various and prominent biological activities. This study attempted to investigate the bioactivity of caesaldekarin e (CA), a cassane diterpenoid isolated from C. bonduc in our previous work, on dextran sulfate sodium (DSS)-induced experimental colitis and clarify the function mechanism. The results indicated that CA ameliorated mice colitis by relieving disease symptoms, suppressing inflammatory infiltration and maintaining intestinal barrier integrity. Furthermore, 16S rRNA gene sequencing analysis indicated that CA could improve the gut microbiota imbalance disrupted by DSS and especially restored abundance of Lactobacillus. In addition, untargeted metabolomics analysis suggested that CA regulated metabolism and particularly the tryptophan metabolism by inhibiting the upregulation of indoleamine 2,3-dioxygenase 1 (IDO-1). It also been proved in IFN-γ induced RAW264.7 cells. Overall, this study suggests that CA exhibits anti-UC effect through restoring gut microbiota and regulating tryptophan metabolism and has the potential to be a treatment option for UC.
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Affiliation(s)
- Ting Liu
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China,Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Zunxi Ning
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China,Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Pengyu Liu
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China,Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Huiyuan Gao
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China,Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China,*Correspondence: Huiyuan Gao,
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11
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Jang JY, Im E, Kim ND. Therapeutic Potential of Bioactive Components from Scutellaria baicalensis Georgi in Inflammatory Bowel Disease and Colorectal Cancer: A Review. Int J Mol Sci 2023; 24:1954. [PMID: 36768278 PMCID: PMC9916177 DOI: 10.3390/ijms24031954] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/16/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
Scutellaria baicalensis Georgi (SBG), an herbal medicine with various biological activities, including anti-inflammatory, anticancer, antiviral, antibacterial, and antioxidant activities, is effective in treatment of colitis, hepatitis, pneumonia, respiratory infections, and allergic diseases. This herbal medicine consists of major active substances, such as baicalin, baicalein, wogonoside, and wogonin. Inflammatory bowel disease (IBD) comprises a group of inflammatory conditions of the colon and small intestine, with Crohn's disease and ulcerative colitis being the main types. IBD can lead to serious complications, such as increased risk of colorectal cancer (CRC), one of the most common cancers worldwide. Currently, there is no cure for IBD, and its incidence has been increasing over the past few decades. This review comprehensively summarizes the efficacy of SBG in IBD and CRC and may serve as a reference for future research and development of drugs for IBD and cancer treatment.
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Affiliation(s)
| | - Eunok Im
- Department of Pharmacy, College of Pharmacy, Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea
| | - Nam Deuk Kim
- Department of Pharmacy, College of Pharmacy, Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea
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12
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Na SY, Choi CH, Song EM, Bang KB, Park SH, Kim ES, Park JJ, Keum B, Lee CK, Lee BI, Ryoo SB, Koh SJ, Choi M, Kim JS, on behalf of the IBD Research Group of the Korean Association for the Study of Intestinal Diseases. Korean clinical practice guidelines on biologics and small molecules for moderate-to-severe ulcerative colitis. Intest Res 2023; 21:61-87. [PMID: 35645321 PMCID: PMC9911265 DOI: 10.5217/ir.2022.00007] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 03/07/2022] [Indexed: 02/09/2023] Open
Abstract
Ulcerative colitis (UC), a relapsing-remitting chronic inflammatory bowel disease (IBD), has a variable natural course but potentially severe disease course. Since the development of anti-tumor necrosis factor (TNF) agents has changed the natural disease course of moderate-to-severe UC, therapeutic options for patients who failed conventional treatments are expanding rapidly. IBD clinical trials have demonstrated the potential efficacy and safety of novel biologics such as anti-integrin α4β7 and anti-interleukin-12/23 monoclonal antibodies and small molecules such as a Janus kinase inhibitor. Anti-TNF biosimilars also have been approved and are widely used in IBD patients. Wise drug choices should be made considering evidence-based efficacy and safety. However, the best position of these drugs remains several questions, with limited data from direct comparative trials. In addition, there are still concerns to be elucidated on the effect of therapeutic drug monitoring and combination therapy with immunomodulators. The appropriate treatment regimens in acute severe UC and the risk of perioperative use of biologics are unclear. As novel biologics and small molecules have been approved in Korea, we present the Korean guidelines for medical management of adult outpatients with moderate-to-severe UC and adult hospitalized patients with acute severe UC, focusing on biologics and small molecules.
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Affiliation(s)
- Soo-Young Na
- Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea
| | - Chang Hwan Choi
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea,Correspondence to Chang Hwan Choi, Department of Internal Medicine, Chung-Ang University College of Medicine, 102 Heukseok-ro, Dongjak-gu, Seoul 06973, Korea. Tel: +82-2-6299-1418, Fax: +82-2-6299-2064, E-mail:
| | - Eun Mi Song
- Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea
| | - Ki Bae Bang
- Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea
| | - Sang Hyoung Park
- Department of Gastroenterology and Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Eun Soo Kim
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Jae Jun Park
- Department of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Bora Keum
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Chang Kyun Lee
- Department of Gastroenterology, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Bo-In Lee
- Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung-Bum Ryoo
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Seong-Joon Koh
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Miyoung Choi
- National Evidence-based Healthcare Collaborating Agency, Seoul, Korea
| | - Joo Sung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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13
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Abd El Aziz MA, Abdalla S, Calini G, Saeed H, Stocchi L, Merchea A, Colibaseanu DT, Shawki S, Larson DW. Postoperative Safety Profile of Minimally Invasive Ileocolonic Resections for Crohn's Disease in the Era of Biologic Therapy. J Crohns Colitis 2022; 16:1079-1088. [PMID: 35045164 DOI: 10.1093/ecco-jcc/jjac012] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 12/02/2021] [Accepted: 01/14/2022] [Indexed: 12/27/2022]
Abstract
BACKGROUND There is controversy regarding the postoperative outcomes in Crohn's disease [CD] patients exposed to vedolizumab [VDZ] or ustekinumab [UST]. We aimed to describe our surgical outcomes in patients who underwent minimally invasive ileocolonic resection [MIS-ICR] for CD who had preoperative biologic therapy. METHODS All consecutive adult patients who had MIS-ICR for CD between 2014 and 2021 at our institution were included. Patients were divided into four groups: VDZ, UST, anti-tumour necrosis factor [anti-TNF], and no biologic group. Timing between the last dose of biologics and surgery was per surgeon's discretion. The primary outcome was intra-abdominal septic complications. Secondary outcomes included all 30-day complications. RESULTS A total of 274 patients were identified. Of these, 113 [41.2%] patients had received anti-TNF, 52 [19%] had received UST, and 19 [7%] had received VDZ. There was no difference between the four groups regarding baseline risk factors. There was no difference between the four groups regarding intra-abdominal septic complications [4.4% for no biologic, 5.3% for anti-TNF, 5.8% for UST, and 5.3% for VDZ; p = 0.987], surgical site infection rate, overall 30-day morbidity, overall 30-day readmission, overall surgical and medical complications, urinary tract infection, pulmonary infections, or length of stay. Those results were consistent after a subgroup analysis based on complexity of the disease. CONCLUSIONS This retrospective analysis demonstrates an equivalent postoperative safety profile for patients treated with preoperative anti-TNF, VDZ, or UST versus no biologic therapy within 3 months of MIS-ICR for Crohn's disease. Preoperative biologic therapy may not increase complications after minimally invasive ileocolonic resection in Crohn's disease. Further studies with larger sample sizes are needed to confirm results.
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Affiliation(s)
| | - Solafah Abdalla
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, MN, USA
| | - Giacomo Calini
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, MN, USA
| | - Hamadelneel Saeed
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, MN, USA
| | - Luca Stocchi
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, MN, USA
| | - Amit Merchea
- Division of Colon and Rectal Surgery, Mayo Clinic, Jacksonville, FL, USA
| | | | - Sherief Shawki
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, MN, USA
| | - David W Larson
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, MN, USA
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14
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Ferreira SDC, Parra RS, Feitosa MR, Feres O, Santana RDC, Troncon LEDA. PREVALENCE AND PREDICTIVE FACTORS ASSOCIATED WITH POSITIVITY OF SARS-COV-2 SEROLOGICAL MARKERS IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE AT AN IBD REFERRAL CENTER. ARQUIVOS DE GASTROENTEROLOGIA 2022; 59:170-176. [PMID: 35830024 DOI: 10.1590/s0004-2803.202202000-32] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 04/13/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Data related to SARS-CoV-2 exposure rates in patients with inflammatory bowel diseases (IBD) are scarce. Objective - Our aim was to determine the prevalence of serological markers of SARS-Cov-2 and the predictive factors for positivity in patients with IBD. METHODS This is a cross-sectional, observational study carried out from May to September 2020. SARS-CoV-2 serological markers were determined using chemiluminescence immunoassay in 233 IBD patients without evidence of COVID-19 symptoms. Patient age was 36.6±11.1 years, 118 patients were male (50.6%), and 63.1% had Crohn's disease. Patient clinical data were extracted from individual electronic medical records and complemented by a structured interview. RESULTS Twenty-six out of the 233 patients with IBD had positive serum markers for SARS-CoV-2 (11.2%). Female sex (P<0.003), extra-intestinal manifestations (P=0.004), use of corticosteroids (P=0.049), and previous contact with individuals with flu-like symptoms (P<0.001) or confirmed diagnosis of COVID-19 (P<0.001), were associated with a significant increased rate of positive SARS-Cov-2 serological markers. No significant difference was observed regarding to adherence to protection measures and positivity of SARS-Cov-2 serological markers (P>0.05). CONCLUSION SARS-CoV-2 previous infection in IBD patients was not that uncommon, and its prevalence was 11.2% in our series. Positivity to SARS-CoV-2 serological markers was associated with female sex, extra-intestinal manifestations, use of corticosteroids, and contact with individuals with suspected or confirmed COVID-19. Studies with longer follow-up periods are needed to confirm these findings.
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Affiliation(s)
- Sandro da Costa Ferreira
- Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Departamento de Clínica Médica, Ribeirão Preto, SP, Brasil
| | - Rogério Serafim Parra
- Faculdade de Medicina da Universidade de São Paulo, Departamento de Cirurgia e Anatomia, Ribeirão Preto, SP, Brasil
| | - Marley Ribeiro Feitosa
- Faculdade de Medicina da Universidade de São Paulo, Departamento de Cirurgia e Anatomia, Ribeirão Preto, SP, Brasil
| | - Omar Feres
- Faculdade de Medicina da Universidade de São Paulo, Departamento de Cirurgia e Anatomia, Ribeirão Preto, SP, Brasil
| | - Rodrigo de Carvalho Santana
- Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Departamento de Clínica Médica, Ribeirão Preto, SP, Brasil
| | - Luiz Ernesto de Almeida Troncon
- Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Departamento de Clínica Médica, Ribeirão Preto, SP, Brasil
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15
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Rong JM, Luo J, Huang Q, Miao YL. Individualized selection of biological agents in treatment of inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2021; 29:893-900. [DOI: 10.11569/wcjd.v29.i15.893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic non-specific inflammatory disease that can affect the ileum, colon, rectum, and even the entire digestive tract. In recent 10 years, with the in-depth understanding of its pathological mechanisms, the development of new drugs has been accelerated, and more and more biological agents have begun to be widely used in the treatment of IBD. The emergence of biological agents has significance for the treatment of IBD. This article will discuss how to individualize the selection of biologics from three aspects: The mechanism of action and clinical application of different biological agents, risk weighing, and rescue treatment for failure of anti-TNF therapy.
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Affiliation(s)
- Jia-Mei Rong
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Juan Luo
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Qi Huang
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Ying-Lei Miao
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
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16
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Miri A, Sato AI, Sewell RK, Huang-Pacheco A. Pott's Puffy Tumor in an Inflammatory Bowel Disease Patient on Anti-TNF Therapy. AMERICAN JOURNAL OF CASE REPORTS 2021; 22:e929892. [PMID: 34032782 PMCID: PMC8165497 DOI: 10.12659/ajcr.929892] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Patient: Male, 14-year-old Final Diagnosis: Pott’s puffy tumor Symptoms: Face swelling Medication: — Clinical Procedure: — Specialty: Gastroenterology and Hepatology • Infectious Diseases • Otolaryngology • Pediatrics and Neonatology
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Affiliation(s)
- Ahmad Miri
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, University of Nebraska Medical Center, Omaha, NE, USA.,Department of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital and Medical Center, Omaha, NE, USA
| | - Alice I Sato
- Department of Pediatrics Infectious Disease, University of Nebraska Medical Center, Omaha, NE, USA.,Department of Pediatrics Infectious Disease, Children's Hospital and Medical Center, Omaha, NE, USA
| | - Ryan K Sewell
- Department of Otolaryngology - Head and Neck Surgery, University of Nebraska Medical Center, Omaha, NE, USA.,Department of Ear, Nose and Throat, Children's Hospital and Medical Center, Omaha, NE, USA
| | - Andrew Huang-Pacheco
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, University of Nebraska Medical Center, Omaha, NE, USA.,Department of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital and Medical Center, Omaha, NE, USA
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17
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Kobayashi T, Motoya S, Nakamura S, Yamamoto T, Nagahori M, Tanaka S, Hisamatsu T, Hirai F, Nakase H, Watanabe K, Matsumoto T, Tanaka M, Abe T, Suzuki Y, Watanabe M, Hibi T. Discontinuation of infliximab in patients with ulcerative colitis in remission (HAYABUSA): a multicentre, open-label, randomised controlled trial. Lancet Gastroenterol Hepatol 2021; 6:429-437. [PMID: 33887262 DOI: 10.1016/s2468-1253(21)00062-5] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 02/16/2021] [Accepted: 02/17/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Anti-tumour necrosis factor (TNF) agents are the mainstay of long-term treatment for refractory ulcerative colitis. However, long-term use of anti-TNF therapy might lead to an increased risk of malignancy or infection. To date, no randomised controlled trial has evaluated whether anti-TNF agents can be safely discontinued in patients with ulcerative colitis in remission. We therefore aimed to compare outcomes in these patients who continued infliximab with those who discontinued infliximab. METHODS We did a multicentre, open-label randomised controlled trial at 24 specialist centres in Japan. We enrolled patients with ulcerative colitis who were in remission, had been treated with intravenous infliximab (5 mg/kg) every 8 weeks, and had started infliximab at least 14 weeks before study enrolment. No restrictions regarding age and comorbidities were used to exclude participation. Patients who were confirmed to be in remission for more than 6 months, to be corticosteroid-free, and to have a Mayo Endoscopic Subscore (MES) of 0 or 1 were centrally randomised. An independent organisation randomly assigned patients (1:1) into either the infliximab-continued group or infliximab-discontinued group, using a computer-generated stratified randomisation procedure. The stratified factors were the use of immunomodulators (yes or no) and MES (0 or 1). Neither patients nor health-care providers were masked to the randomisation. The primary endpoint was the remission rate at week 48 in the full analysis set, which was based on the intention-to-treat principle and excluded participants with no efficacy data after randomisation. This study was registered with the University Hospital Medical Information Network Center Trials registry, UMIN000012092. FINDINGS Between June 16, 2014, and July 28, 2017, 122 patients were eligible for screening and a total of 95 patients were randomly assigned to the infliximab-continued group (n=48) or the infliximab-discontinued group (n=47). 92 patients (n=46 for both groups) were included in the full analysis set. 37 (80·4% [95% CI 66·1-90·6]) of 46 patients in the infliximab-continued group and 25 (54·3% [39·0-69·1]) of 46 patients in the infliximab-discontinued group were in remission at week 48. The between-group difference was 26·1% (95% CI 7·7-44·5; p=0·0076) before adjustment and 27·3% (95% CI 8·0-44·1; p=0·0059) after adjustment for stratification factors. Eight (17%) of 48 patients in the infliximab-continued group and six (13%) of 47 in the infliximab-discontinued group developed adverse events (between-group difference 3·9% [95% CI -10·3 to 18·1]; p=0·59). In the infliximab-continued group, one patient had an infusion reaction and two patients had psoriatic skin lesions. Eight (66·7%, 95% CI 34·9-90·1) of the 12 patients in the infliximab-discontinuation group who were re-treated with infliximab after relapsing were in remission within 8 weeks of re-treatment; none had infusion reactions. INTERPRETATION Maintenance of remission was significantly more common in patients who continued infliximab than in those who discontinued. Discontinuing infliximab should therefore be discussed with caution, taking both risk of relapse and efficacy of re-treatment into account. FUNDING Mitsubishi Tanabe Pharma Corporation and the Intractable Disease Project of the Ministry of Health, Labour and Welfare of Japan. TRANSLATION For the Japanese translation of the abstract see Supplementary Materials section.
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Affiliation(s)
- Taku Kobayashi
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
| | - Satoshi Motoya
- IBD Center, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Shiro Nakamura
- Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Nishinomiya, Japan
| | | | - Masakazu Nagahori
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shinji Tanaka
- Department of Endoscopy and Medicine, Hiroshima University Hospital, Hiroshima, Japan
| | - Tadakazu Hisamatsu
- Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Mitaka, Japan
| | - Fumihito Hirai
- Department of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Hiroshi Nakase
- Department of Gastroenterology, Sapporo Medical College, Sapporo, Japan
| | - Kenji Watanabe
- Center for Inflammatory Bowel Disease, Division of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Masanori Tanaka
- Department of Pathology, Hirosaki Municipal Hospital, Hirosaki, Japan
| | - Takayuki Abe
- Department of Data Science, Yokohama City University, Yokohama, Japan; Clinical and Translational Research Centre, Keio University School of Medicine, Tokyo, Japan
| | - Yasuo Suzuki
- Department of Internal Medicine, Toho University Sakura Medical Center, Sakura, Japan
| | - Mamoru Watanabe
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan; Advanced Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Toshifumi Hibi
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.
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18
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Ferro JM, Oliveira Santos M. Neurology of inflammatory bowel disease. J Neurol Sci 2021; 424:117426. [PMID: 33810878 DOI: 10.1016/j.jns.2021.117426] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/21/2020] [Accepted: 03/24/2021] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel diseases (IBD) are chronic inflammatory conditions affecting the digestive system, comprising two main distinctive entities, ulcerative colitis (UC) and Crohn's disease (CD). Besides gastrointestinal manifestations, IBD causes extraintestinal manifestations in the central and peripheral nervous system. The incidence of neurological complications in IBD ranges from 0.25% to 47.5%. The pathophysiology of neurological manifestations of IBD is mostly immune mediated, but dysfunction of the brain-gut axis, arterial and venous thromboembolism, infections, nutritional deficiencies and side-effects of medications (steroids, metronidazole, sulfasalazine, anti-TNF-α, anti-integrin antibodies) are other contributory mechanisms. Patients with IBD have an increased risk of arterial and venous stroke, mainly during periods of exacerbations. Vasculitis is extremely rare. There is a bidirectional association between multiple sclerosis and IBD, with a relative risk for comorbidity of 1.54, being 1.53 for the risk of multiple sclerosis in IBD and 1.55 for the risk of IBD in multiple sclerosis patients. Anti-TNF-α therapy is contraindicated in the treatment of patients who have both IBD and multiple sclerosis. Demyelinating disorders can also be a rare complication of anti-TNF-α therapy. Optic neuritis, transverse myelitis, progressive myelopathy, central nervous system infections, epilepsy and encephalopathy are among other uncommon neurological complications. Peripheral nervous system manifestations include peripheral neuropathy, either demyelination and axonal, myasthenia gravis and polymyositis/dermatomyositis and localized forms of myositis.
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Affiliation(s)
- José M Ferro
- Serviço de Neurologia, Department of Neurological Sciences and Mental Health, Hospital de Santa Maria - CHULN, Lisboa, Portugal; Faculdade de Medicina, Universidade de Lisboa, Portugal; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal.
| | - Miguel Oliveira Santos
- Serviço de Neurologia, Department of Neurological Sciences and Mental Health, Hospital de Santa Maria - CHULN, Lisboa, Portugal; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal
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19
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Comparison of Interferon-Gamma Release Assay and Tuberculin Skin Test for the Screening of Latent Tuberculosis in Inflammatory Bowel Disease Patients: Indian Scenario. Tuberc Res Treat 2021; 2021:6682840. [PMID: 33575041 PMCID: PMC7857923 DOI: 10.1155/2021/6682840] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 12/26/2020] [Accepted: 01/05/2021] [Indexed: 12/14/2022] Open
Abstract
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.
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Kearns DG, Uppal S, Chat VS, Wu JJ. Use of systemic therapies for psoriasis in the COVID-19 era. J DERMATOL TREAT 2021; 33:622-625. [PMID: 32459567 DOI: 10.1080/09546634.2020.1775774] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND In late 2019 a viral pneumonia began to spread across the world. The viral disease, COVID-19, is now officially a pandemic, causing concern for the potential risk of systemic therapies for patients with psoriasis. OBJECTIVE The purpose of this review is to analyze what is currently known about COVID-19 in regard to the safety of systemic treatment, and to provide guidelines for use in psoriasis during this pandemic. METHODS Review of guidelines from various dermatologic regulatory bodies regarding the use of systemic medications during the COVID-19 pandemic was performed and summarized. RESULTS The AAD, NPF and IPC are in agreement regarding their recommendation that patients with active COVID-19 infection should discontinue any biologic therapy. CONCLUSION Patients with active COVID-19 infections should discontinue systemic treatment for psoriasis. Patients with risk factors should discuss continuing treatment on a case by case basis.
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Affiliation(s)
| | | | - Vipawee S Chat
- Medical College of Georgia at Augusta University, Augusta, CA, USA
| | - Jashin J Wu
- Dermatology Research and Education Foundation, Irvine, CA, USA
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21
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Hansen FM, Tanzer MC, Brüning F, Bludau I, Stafford C, Schulman BA, Robles MS, Karayel O, Mann M. Data-independent acquisition method for ubiquitinome analysis reveals regulation of circadian biology. Nat Commun 2021; 12:254. [PMID: 33431886 PMCID: PMC7801436 DOI: 10.1038/s41467-020-20509-1] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 11/27/2020] [Indexed: 12/11/2022] Open
Abstract
Protein ubiquitination is involved in virtually all cellular processes. Enrichment strategies employing antibodies targeting ubiquitin-derived diGly remnants combined with mass spectrometry (MS) have enabled investigations of ubiquitin signaling at a large scale. However, so far the power of data independent acquisition (DIA) with regards to sensitivity in single run analysis and data completeness have not yet been explored. Here, we develop a sensitive workflow combining diGly antibody-based enrichment and optimized Orbitrap-based DIA with comprehensive spectral libraries together containing more than 90,000 diGly peptides. This approach identifies 35,000 diGly peptides in single measurements of proteasome inhibitor-treated cells - double the number and quantitative accuracy of data dependent acquisition. Applied to TNF signaling, the workflow comprehensively captures known sites while adding many novel ones. An in-depth, systems-wide investigation of ubiquitination across the circadian cycle uncovers hundreds of cycling ubiquitination sites and dozens of cycling ubiquitin clusters within individual membrane protein receptors and transporters, highlighting new connections between metabolism and circadian regulation.
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Affiliation(s)
- Fynn M Hansen
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Maria C Tanzer
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Franziska Brüning
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
- Institute of Medical Psychology, Faculty of Medicine, LMU, Munich, Germany
| | - Isabell Bludau
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Che Stafford
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Brenda A Schulman
- Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Maria S Robles
- Institute of Medical Psychology, Faculty of Medicine, LMU, Munich, Germany.
| | - Ozge Karayel
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.
| | - Matthias Mann
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.
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22
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Muehler A, Slizgi JR, Kohlhof H, Groeppel M, Peelen E, Vitt D. Clinical relevance of intestinal barrier dysfunction in common gastrointestinal diseases. World J Gastrointest Pathophysiol 2020; 11:114-130. [PMID: 33362939 PMCID: PMC7739114 DOI: 10.4291/wjgp.v11.i6.114] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 10/07/2020] [Accepted: 10/27/2020] [Indexed: 02/06/2023] Open
Abstract
The intestinal barrier is a complex and well-controlled physiological construct designed to separate luminal contents from the bowel wall. In this review, we focus on the intestinal barrier’s relationship with the host’s immune system interaction and the external environment, specifically the microbiome. The bowel allows the host to obtain nutrients vital to survival while protecting itself from harmful pathogens, luminal antigens, or other pro-inflammatory factors. Control over barrier function and the luminal milieu is maintained at the biochemical, cellular, and immunological level. However, disruption to this highly regulated environment can cause disease. Recent advances to the field have progressed the mechanistic understanding of compromised intestinal barrier function in the context of gastrointestinal pathology. There are numerous examples where bowel barrier dysfunction and the resulting interaction between the microbiome and the immune system has disease-triggering consequences. The purpose of this review is to summarize the clinical relevance of intestinal barrier dysfunction in common gastrointestinal and related diseases. This may help highlight the importance of restoring barrier function as a therapeutic mechanism of action in gastrointestinal pathology.
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23
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Parent Perspectives on Exclusive Enteral Nutrition for the Treatment of Pediatric Crohn Disease. J Pediatr Gastroenterol Nutr 2020; 71:744-748. [PMID: 32910623 DOI: 10.1097/mpg.0000000000002847] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
OBJECTIVES Exclusive enteral nutrition (EEN) is infrequently used in the United States but is an effective treatment for pediatric Crohn disease (CD). Limited data exists regarding patient and parent perspectives on this treatment modality. The aim of this study was to determine parent and provider perspectives regarding EEN and understand parent-cited barriers to its use. METHODS We surveyed the parents/guardians of children ages 1 through 17 with CD in our institution regarding EEN. Healthcare provider perspectives regarding reason for stopping EEN and those cited by survey respondents were compared using retrospective chart review. RESULTS One hundred fifteen (62.5%) out of 184 recipients responded to the survey. Ninety percentage of respondents had heard of EEN but of these, 26% had not discussed it with their gastroenterologist. Thirty-eight patients (33%) were treated in the past and 15 (13%) were currently on EEN. Common barriers cited by current EEN users were cost/finances and difficult social situations. Of the children who stopped EEN, most did so as parents felt it was not working (n = 14, 37%). In these cases, their primary gastroenterologist cited treatment failure for 4 cases and nonadherence for 6. CONCLUSIONS Despite the efficacy of EEN and interest in dietary treatments by patients with CD, there are many barriers surrounding effective communication and successful implementation of dietary therapies. Future research is needed regarding patient-physician communication, cost mitigation, and coping with the social limitations of dietary therapies.
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24
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Lee MH, Ng CH, Chin YH, Muthiah M, Foo FJ, Chong CS. Incidence of SARS-CoV-2 infection in inflammatory bowel disease. J Gastroenterol Hepatol 2020; 35:2021-2022. [PMID: 32779774 PMCID: PMC7404756 DOI: 10.1111/jgh.15191] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 07/20/2020] [Indexed: 01/22/2023]
Affiliation(s)
- M H Lee
- Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore
| | - C H Ng
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Y H Chin
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - M Muthiah
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore
| | - F J Foo
- Department of General Surgery, Sengkang General Hospital, Singapore
| | - C S Chong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Division of Colorectal Surgery, Department of Surgery, National University Hospital, Singapore
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25
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Healey S, Said W, Fayyaz F, Bell A. First report of paracoccidioidomycosis reactivation as a complication of immunosuppressive therapy for acute severe colitis in a caving enthusiast. BMJ Case Rep 2020; 13:13/7/e234125. [DOI: 10.1136/bcr-2019-234125] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Treatment for ulcerative colitis often requires the administration of immunosuppressive therapy. Shortly after rescue therapy with infliximab for acute severe colitis, a patient who was also taking corticosteroids, azathioprine and adalimumab became rapidly unwell with atypical pneumonia, which did not respond to conventional antimicrobials. Re-examining the travel history revealed a prior caving trip to Costa Rica. Dimorphic fungal serology was thus tested and a diagnosis of paracoccidioidomycosis was made. After a lengthy intensive care unit admission, the patient made a recovery after the administration of appropriate antifungal therapy and was discharged home on long-term oral antifungals.
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26
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Davis JS, Ferreira D, Paige E, Gedye C, Boyle M. Infectious Complications of Biological and Small Molecule Targeted Immunomodulatory Therapies. Clin Microbiol Rev 2020; 33:e00035-19. [PMID: 32522746 PMCID: PMC7289788 DOI: 10.1128/cmr.00035-19] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The past 2 decades have seen a revolution in our approach to therapeutic immunosuppression. We have moved from relying on broadly active traditional medications, such as prednisolone or methotrexate, toward more specific agents that often target a single receptor, cytokine, or cell type, using monoclonal antibodies, fusion proteins, or targeted small molecules. This change has transformed the treatment of many conditions, including rheumatoid arthritis, cancers, asthma, and inflammatory bowel disease, but along with the benefits have come risks. Contrary to the hope that these more specific agents would have minimal and predictable infectious sequelae, infectious complications have emerged as a major stumbling block for many of these agents. Furthermore, the growing number and complexity of available biologic agents makes it difficult for clinicians to maintain current knowledge, and most review articles focus on a particular target disease or class of agent. In this article, we review the current state of knowledge about infectious complications of biologic and small molecule immunomodulatory agents, aiming to create a single resource relevant to a broad range of clinicians and researchers. For each of 19 classes of agent, we discuss the mechanism of action, the risk and types of infectious complications, and recommendations for prevention of infection.
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Affiliation(s)
- Joshua S Davis
- Department of Infectious Diseases and Immunology, John Hunter Hospital, Newcastle, NSW, Australia
- Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia
- School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia
| | - David Ferreira
- School of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Emma Paige
- Department of Infectious Diseases, Alfred Hospital, Melbourne, VIC, Australia
| | - Craig Gedye
- School of Medicine, University of New South Wales, Sydney, NSW, Australia
- Department of Oncology, Calvary Mater Hospital, Newcastle, NSW, Australia
| | - Michael Boyle
- Department of Infectious Diseases and Immunology, John Hunter Hospital, Newcastle, NSW, Australia
- School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia
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27
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Conrad MA, Kelsen JR. The Treatment of Pediatric Inflammatory Bowel Disease with Biologic Therapies. Curr Gastroenterol Rep 2020; 22:36. [PMID: 32542562 DOI: 10.1007/s11894-020-00773-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW Biologics for the treatment of inflammatory bowel disease (IBD) have been transformative to the therapeutic goals in the pediatric population. We review the biologics used to treat IBD, highlighting the importance of patient selection, dosing considerations, and therapeutic drug monitoring in children. RECENT FINDINGS Infliximab is well-established as a safe and efficacious therapy for Crohn's disease and ulcerative colitis. Both dose escalation strategies and therapeutic drug monitoring increase the likelihood of response to anti-TNFα therapies. Early real-world experience of vedolizumab and ustekinumab in pediatric IBD shows promising results, including clinical response rates comparable to what is seen in adults, but there are limited data using them as first-line therapies. Biologic therapies have improved outcomes in pediatric IBD, including achieving mucosal healing as well as improved growth and pubertal development. Therapeutic drug monitoring improves likelihood of response to anti-TNFα therapies, but further studies for vedolizumab and ustekinumab are necessary.
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Affiliation(s)
- Máire A Conrad
- Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.,Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Judith R Kelsen
- Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. .,Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
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Na SY, Moon W. Perspectives on Current and Novel Treatments for Inflammatory Bowel Disease. Gut Liver 2020; 13:604-616. [PMID: 31195433 PMCID: PMC6860034 DOI: 10.5009/gnl19019] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 02/22/2019] [Accepted: 03/02/2019] [Indexed: 12/13/2022] Open
Abstract
New therapeutic strategies in inflammatory bowel disease (IBD) have shifted from symptom control towards treat-to-target algorithms in order to optimize treatment results. The treatment of IBD has evolved with the development of tumor necrosis factor-α inhibitors beyond the conventional therapies. In spite of their long-term effectiveness, many patients do not respond to or cannot sustain treatment with these drugs, which have various side effects. Therefore, the development of new drugs targeting specific pathways in the pathogenesis of IBD has become necessary. Some novel biologics and small molecule drugs have shown potential in IBD clinical trials, providing safe and effective results. In addition, clinicians are now trying to target the dysbiotic microbiome of patients with IBD using fecal microbiota transplantation. New tools such as stem cells have also been developed. The available therapeutic options for IBD are expanding rapidly. In the next few years, physicians will face an unprecedented number of options when choosing the best treatments for patients with IBD. This review provides an overview of recent advances in IBD treatment options.
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Affiliation(s)
- Soo-Young Na
- Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Korea
| | - Won Moon
- Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea
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29
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Leber A, Hontecillas R, Zoccoli-Rodriguez V, Colombel JF, Chauhan J, Ehrich M, Farinola N, Bassaganya-Riera J. The Safety, Tolerability, and Pharmacokinetics Profile of BT-11, an Oral, Gut-Restricted Lanthionine Synthetase C-Like 2 Agonist Investigational New Drug for Inflammatory Bowel Disease: A Randomized, Double-Blind, Placebo-Controlled Phase I Clinical Trial. Inflamm Bowel Dis 2020; 26:643-652. [PMID: 31077582 DOI: 10.1093/ibd/izz094] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Indexed: 12/25/2022]
Abstract
BT-11 is a new oral, gut-restricted, first-in-class investigational drug for Crohn disease (CD) and ulcerative colitis (UC) that targets the lanthionine synthetase C-like 2 (LANCL2) pathway and immunometabolic mechanisms. Oral BT-11 was assessed for safety, tolerability, and pharmacokinetics (PK) in normal healthy volunteers (n = 70) in a randomized, double-blind, placebo-controlled trial. Subjects (n = 70) were randomly assigned to one of five single ascending dose cohorts (up to 100 mg/kg, p.o.) and three multiple ascending dose cohorts [up to 100 mg/kg daily (QD) for seven days, orally]. Safety and tolerability were assessed by adverse event (AE) reporting, vital signs, electrocardiogram, hematology, and clinical chemistry. BT-11 did not increase total or gastrointestinal AE rates, as compared with placebo, and no serious adverse events were observed. Oral BT-11 dosing does not result in any clinically significant findings by biochemistry, coagulation, electrocardiogram, hematology, or urinalysis as compared with placebo. Mean fecal concentrations of BT-11 increased linearly with increasing oral doses, with 2.39 mg/g at 7.7 mg/kg on day 7 of the multiple ascending dose (MAD). Analysis of plasma pharmacokinetics indicates that maximum systemic concentrations are approximately 1/6000th of observed concentrations in feces and the distal gastrointestinal tract. Fecal calprotectin levels were lower in BT-11 treated groups as compared to placebo. BT-11 significantly decreases interferon gamma positive (IFNγ+) and tumor necrosis factor alpha positive (TNFα+) cluster of differentiation 4 positive (CD4+) T cells and increases forkhead box P3 positive (FOXP3+) CD4+ T cells in colonic lamina propria mononuclear cells from patients with CD and patients with UC at concentrations of 0.01 µM when treated ex vivo. BT-11 treatment is well-tolerated with no dose-limiting toxicities up to daily oral doses of 100 mg/kg (16 tablets); whereas the efficacious dose is a single tablet (8 mg/kg). Phase II studies in CD and UC patients are ongoing.
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Affiliation(s)
- Andrew Leber
- Landos Biopharma Inc., Blacksburg, Virginia, USA
| | | | | | - Jean-Frederic Colombel
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | | | - Marion Ehrich
- Department of Biomedical Sciences & Pathobiology, Virginia Tech, Blacksburg, Virginia, USA
| | - Nicholas Farinola
- Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia
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Alvisi P, Dipasquale V, Barabino A, Martellossi S, Miele E, Lionetti P, Lombardi G, Cucchiara S, Torre G, Romano C. Infections and malignancies risks related to TNF-α-blocking agents in pediatric inflammatory bowel diseases. Expert Rev Gastroenterol Hepatol 2019; 13:957-961. [PMID: 31490707 DOI: 10.1080/17474124.2019.1663173] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Accepted: 08/30/2019] [Indexed: 12/15/2022]
Abstract
Introduction: Tumor necrosis factor-α (TNF-α)-blocking agents are drugs approved for the treatment of inflammatory bowel diseases (IBDs). Infliximab and adalimumab are approved for the treatment of IBD in the pediatric setting with the improvement of therapeutic management. Biological agents, also in the pediatric population, can be administered either alone or in combination with immunomodulators. Their use has raised safety concerns regarding the risk of infections and malignancies.Areas covered: A broad review of the safety concerns for the use of anti-TNF-α drugs in children with IBD was performed, and information regarding the risk of infections and malignancies were updated, also in comparison with the safety of traditional drugs such as steroids and/or immunosuppressants.Expert commentary: Anti-TNF-α drugs have shown favorable safety profiles, and adalimumab treatment is associated with lower immunogenicity compared with infliximab. Heightened awareness and vigilant surveillance leading to prompt diagnosis and treatment are important for optimal management.
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Affiliation(s)
- Patrizia Alvisi
- Pediatric Gastroenterology Unit, Maggiore Hospital, Bologna, Italy
| | - Valeria Dipasquale
- Pediatric Gastroenterology Unit, Department of Human Pathology in Adulthood and Childhood "G. Barresi", University of Messina, Messina, Italy
| | - Arrigo Barabino
- Pediatric Gastroenterology Unit, Institute Giannina Gaslini, Genova, Italy
| | - Stefano Martellossi
- Pediatric Department, Gastroenterology, Digestive Endoscopy and Nutrition Unit, Institute for Maternal and Child Health I.R.C.C.S. Burlo Garofalo, Trieste, Italy
| | - Erasmo Miele
- Department of Translational Medical Science (Section of Pediatrics), and European Laboratory for the Investigation of Food-Induced Diseases, University Federico II, Naples, Italy
| | - Paolo Lionetti
- Pediatric Gastroenterology and Nutrition Unit, University of Florence-Meyer Hospital, Florence, Italy
| | - Giuliano Lombardi
- Pediatric Gastroenterology and Endoscopy Unit, Spirito Santo Hospital, Pescara, Italy
| | - Salvatore Cucchiara
- Department of Pediatrics and Infantile Neuropsychiatry, Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy
| | - Giuliano Torre
- Hepatology, Gastroenterology and Nutrition Unit, Bambino Gesù Children's Hospital, Rome, Italy
| | - Claudio Romano
- Pediatric Gastroenterology Unit, Department of Human Pathology in Adulthood and Childhood "G. Barresi", University of Messina, Messina, Italy
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Tinsley A, Navabi S, Williams ED, Liu G, Kong L, Coates MD, Clarke K. Increased Risk of Influenza and Influenza-Related Complications Among 140,480 Patients With Inflammatory Bowel Disease. Inflamm Bowel Dis 2019; 25:369-376. [PMID: 30020478 DOI: 10.1093/ibd/izy243] [Citation(s) in RCA: 114] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Diseases of immune dysregulation are associated with an increased risk of viral infections, some of which may be preventable. To date, there are very limited data on the incidence and risk of influenza and related complications in patients with inflammatory bowel disease (IBD). Furthermore, the impact of immunosuppressive medications on that risk is unclear. Therefore, the aim of this study was to estimate the incidence and severity of influenza infections in IBD patients. In addition, we looked specifically at the effect of medications on influenza risk. METHODS Using the MarketScan Database (January 2008 to December 2011), we conducted a retrospective cohort study to estimate the incidence of influenza and risk of related complications in IBD patients compared with those without IBD. We employed a nested case-control study design to evaluate the potential independent effect of IBD medications on influenza risk. RESULTS A total of 140,480 patients with IBD and non-IBD controls were studied. There were 2963 patients with influenza compared with 1941 non-IBD subjects. Inflammatory bowel disease patients had an increased influenza risk compared with those without IBD (incidence rate ratio, 1.54; 95% confidence interval [CI], 1.49-1.63). A higher rate of hospitalizations (162/2994 [5.4%] vs 36/1941 [1.85%]; P < 0.001) was noted. Systemic corticosteroids were found to be independently associated with influenza (odds ratio, 1.22; 95% CI, 1.08-1.38). CONCLUSIONS Inflammatory bowel disease patients had an increased risk of influenza compared with those without IBD and were more likely to require hospitalization. Steroids were the only medication class independently associated with flu risk.
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Affiliation(s)
- Andrew Tinsley
- Division of Gastroenterology and Hepatology, Department of Medicine, Penn State Hershey Medical Center, Hershey, Pennsylvania
| | - Seyedehsan Navabi
- Division of Gastroenterology and Hepatology, Department of Medicine, Penn State Hershey Medical Center, Hershey, Pennsylvania
| | - Emmanuelle D Williams
- Division of Gastroenterology and Hepatology, Department of Medicine, Penn State Hershey Medical Center, Hershey, Pennsylvania
| | - Guodong Liu
- Department of Public Health, College of Medicine, Penn State Hershey Medical Center, Hershey, Pennsylvania
| | - Lan Kong
- Department of Public Health, College of Medicine, Penn State Hershey Medical Center, Hershey, Pennsylvania
| | - Matthew D Coates
- Division of Gastroenterology and Hepatology, Department of Medicine, Penn State Hershey Medical Center, Hershey, Pennsylvania
| | - Kofi Clarke
- Division of Gastroenterology and Hepatology, Department of Medicine, Penn State Hershey Medical Center, Hershey, Pennsylvania
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Horneff G, Seyger MMB, Arikan D, Kalabic J, Anderson JK, Lazar A, Williams DA, Wang C, Tarzynski-Potempa R, Hyams JS. Safety of Adalimumab in Pediatric Patients with Polyarticular Juvenile Idiopathic Arthritis, Enthesitis-Related Arthritis, Psoriasis, and Crohn's Disease. J Pediatr 2018; 201:166-175.e3. [PMID: 30054164 DOI: 10.1016/j.jpeds.2018.05.042] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 05/18/2018] [Accepted: 05/25/2018] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To evaluate the safety of adalimumab in pediatric patients who participated in clinical trials of juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and pediatric enthesitis-related arthritis), psoriasis, and Crohn's disease. STUDY DESIGN This analysis included data from 7 global, randomized, and open-label AbbVie-sponsored clinical trials of adalimumab and their open-label extensions conducted between September 2002 and December 31, 2015 (cutoff date for ongoing studies). Patients who received ≥1 dose of adalimumab subcutaneously were included. Adverse events that occurred after the first dose of adalimumab and up to 70 days (5 half-lives) after the last dose were reported and events per 100 patient-years were calculated. RESULTS The analysis included 577 pediatric patients, representing 1440.7 patient-years of adalimumab exposure. Across indications, the most commonly reported adverse events (events/100 patient-years) were upper respiratory tract infections (24.3), nasopharyngitis (17.3), and headache (19.9). Serious infections (4.0 events/100 patient-years) were the most frequent serious adverse events across indications; the most commonly reported was pneumonia (0.6 events/100 patient-years). Serious infection rates were 2.7, 0.8, and 6.6 events/100 patient-years in patients with juvenile idiopathic arthritis, psoriasis, and Crohn's disease, respectively. No events of malignancies were reported. One death (accidental fall) occurred in a patient with psoriasis. CONCLUSIONS The safety profile of adalimumab in pediatric patients with polyarticular juvenile idiopathic arthritis, enthesitis-related arthritis, psoriasis, and Crohn's disease was generally similar across indications; no new safety signals were identified in the treatment of pediatric patients with adalimumab. TRIAL REGISTRATION Clinicaltrials.gov: NCT00048542, NCT00775437, NCT00690573, NCT01166282, NCT01251614, NCT00409682, and NCT00686374.
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Affiliation(s)
- Gerd Horneff
- Centre of Paediatric Rheumatology, Department of General Paediatrics, Asklepios Klinik Sankt Augustin, Sankt Augustin, Germany.
| | - Marieke M B Seyger
- Department of Dermatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
| | | | | | | | - Andreas Lazar
- AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany
| | | | | | | | - Jeffrey S Hyams
- Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, CT
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Reinglas J, Gonczi L, Kurt Z, Bessissow T, Lakatos PL. Positioning of old and new biologicals and small molecules in the treatment of inflammatory bowel diseases. World J Gastroenterol 2018; 24:3567-3582. [PMID: 30166855 PMCID: PMC6113721 DOI: 10.3748/wjg.v24.i32.3567] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 05/09/2018] [Accepted: 06/25/2018] [Indexed: 02/06/2023] Open
Abstract
The past decade has brought substantial advances in the management of inflammatory bowel diseases (IBD). The introduction of tumor necrosis factor (TNF) antagonists, evidence for the value of combination therapy, the recognition of targeting lymphocyte trafficking and activation as a viable treatment, and the need for early treatment of high-risk patients are all fundamental concepts for current modern IBD treatment algorithms. In this article, authors review the existing data on approved biologicals and small molecules as well as provide insight on the current positioning of approved therapies. Patient stratification for the selection of specific therapies, therapeutic targets and patient monitoring will be discussed as well. The therapeutic armamentarium for IBD is expanding as novel and more targeted therapies become available. In the absence of comparative trials, positioning these agents is becoming difficult. Emerging concepts for the future will include an emphasis on the development of algorithms which will facilitate a greater understanding of the positioning of novel biological drugs and small molecules in order to best tailor therapy to the patient. In the interim, anti-TNF therapy remains an important component of IBD therapy with the most real-life evidence and should be considered as first-line therapy in patients with complicated Crohn's disease and in acute-severe ulcerative colitis. The safety and efficacy of these 'older' anti-TNF therapies can be optimized by adhering to therapeutic algorithms which combine clinical and objective markers of disease severity and response to therapy.
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Affiliation(s)
- Jason Reinglas
- Department of Gastroenterology, McGill University Health Center, Montreal, Québec H4A 3J1, Canada
| | - Lorant Gonczi
- First Department of Medicine, Semmelweis University, H-1083, Budapest, Koranyi S. 2A, Hungary
| | - Zsuzsanna Kurt
- First Department of Medicine, Semmelweis University, H-1083, Budapest, Koranyi S. 2A, Hungary
| | - Talat Bessissow
- Department of Gastroenterology, McGill University Health Center, Montreal, Québec H4A 3J1, Canada
| | - Peter L Lakatos
- Department of Gastroenterology, McGill University Health Center, Montreal, Québec H4A 3J1, Canada
- First Department of Medicine, Semmelweis University, H-1083, Budapest, Koranyi S. 2A, Hungary
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Turner D, Ruemmele FM, Orlanski-Meyer E, Griffiths AM, de Carpi JM, Bronsky J, Veres G, Aloi M, Strisciuglio C, Braegger CP, Assa A, Romano C, Hussey S, Stanton M, Pakarinen M, de Ridder L, Katsanos K, Croft N, Navas-López V, Wilson DC, Lawrence S, Russell RK. Management of Paediatric Ulcerative Colitis, Part 1: Ambulatory Care-An Evidence-based Guideline From European Crohn's and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2018; 67:257-291. [PMID: 30044357 DOI: 10.1097/mpg.0000000000002035] [Citation(s) in RCA: 316] [Impact Index Per Article: 45.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND The contemporary management of ambulatory ulcerative colitis (UC) continues to be challenging with ∼20% of children needing a colectomy within childhood years. We thus aimed to standardize daily treatment of pediatric UC and inflammatory bowel diseases (IBD)-unclassified through detailed recommendations and practice points. METHODS These guidelines are a joint effort of the European Crohn's and Colitis Organization (ECCO) and the Paediatric IBD Porto group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). An extensive literature search with subsequent evidence appraisal using robust methodology was performed before 2 face-to-face meetings. All 40 included recommendations and 86 practice points were endorsed by 43 experts in Paediatric IBD with at least an 88% consensus rate. RESULTS These guidelines discuss how to optimize the use of mesalamine (including topical), systemic and locally active steroids, thiopurines and, for more severe disease, biologics. The use of other emerging therapies and the role of surgery are also covered. Algorithms are provided to aid therapeutic decision-making based on clinical assessment and the Paediatric UC Activity Index (PUCAI). Advice on contemporary therapeutic targets incorporating the use of calprotectin and the role of therapeutic drug monitoring are presented, as well as other management considerations around pouchitis, extraintestinal manifestations, nutrition, growth, psychology, and transition. A brief section on disease classification using the PIBD-classes criteria and IBD-unclassified is also part of these guidelines. CONCLUSIONS These guidelines provide a guide to clinicians managing children with UC and IBD-unclassified management to provide modern management strategies while maintaining vigilance around appropriate outcomes and safety issues.
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Affiliation(s)
- Dan Turner
- Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Frank M Ruemmele
- Université Paris Descartes, Sorbonne Paris Cité, APHP, Hôpital Necker Enfants Malades, Paris, France
| | | | - Anne M Griffiths
- The Hospital for Sick Children, University of Toronto, Toronto, Canada
| | | | - Jiri Bronsky
- Department of Paediatrics, University Hospital Motol, Prague, Czech Republic
| | - Gabor Veres
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Marina Aloi
- Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy
| | - Caterina Strisciuglio
- Department of Woman, Child and General and Specialistic Surgery, University of Campania "Luigi Vanvitelli," Napoli, Italy
| | | | - Amit Assa
- Schneider Children's Hospital, Petach Tikva, Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Claudio Romano
- Pediatric Department, University of Messina, Messina, Italy
| | - Séamus Hussey
- National Children's Research Centre, Royal College of Surgeons of Ireland and University College Dublin, Dublin, Ireland
| | | | - Mikko Pakarinen
- Helsinki University Children's Hospital, Department of Pediatric Surgery, Helsinki, Finland
| | - Lissy de Ridder
- Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
| | | | - Nick Croft
- Barts and the London School of Medicine, Queen Mary University of London, London, UK
| | - Victor Navas-López
- Pediatric Gastroenterology and Nutrition Unit. Hospital Materno, IBIMA, Málaga, Spain
| | - David C Wilson
- Child Life and Health, University of Edinburgh, Edinburgh, UK
| | - Sally Lawrence
- BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada
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Monasterio C, Kreisel W, Hasselblatt P. [Severe lymphopenia in a patient with Crohn's disease]. Internist (Berl) 2018; 59:857-860. [PMID: 29356833 DOI: 10.1007/s00108-017-0363-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
We report on a 25-year-old female patient with Crohn's disease and profound lymphocytopenia while receiving corticosteroids and azathioprine. Discontinuation of azathioprine only resulted in a mild increase in CD4+ T cell numbers; however, therapy with the TNFα inhibitor adalimumab was initiated for a clinical flare and resulted in long-lasting clinical remission and rapid normalization of the lymphocytopenia including the respective lymphocyte subsets. Lymphocytopenia is frequently observed as a side effect of immunosuppressive therapy. This case illustrates that lymphocytopenia may also occur in relation to Crohn's disease activity as an extraintestinal manifestation and may then be efficiently treated by escalation of immunosuppressive therapy.
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Affiliation(s)
- C Monasterio
- Klinik für Innere Medizin II, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Hugstetter Str. 55, 79106, Freiburg, Deutschland.
| | - W Kreisel
- Klinik für Innere Medizin II, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Hugstetter Str. 55, 79106, Freiburg, Deutschland
| | - P Hasselblatt
- Klinik für Innere Medizin II, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Hugstetter Str. 55, 79106, Freiburg, Deutschland
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Ylisaukko-Oja T, Aaltonen J, Nuutinen H, Blomster T, Jussila A, Pajala M, Salminen K, Moilanen V, Hakala K, Kellokumpu M, Toljamo K, Rautiainen H, Kuisma J, Peräaho M, Molander P, Silvennoinen J, Liukkonen V, Henricson H, Tillonen J, Esterinen M, Nielsen C, Hirsi E, Lääne M, Suhonen UM, Vihriälä I, Mäkelä P, Puhto M, Punkkinen J, Sulonen H, Herrala S, Jokelainen J, Tamminen K, Sipponen T. High treatment persistence rate and significant endoscopic healing among real-life patients treated with vedolizumab - a Finnish Nationwide Inflammatory Bowel Disease Cohort Study (FINVEDO) . Scand J Gastroenterol 2018;53:158-167. [PMID: 29258369 DOI: 10.1080/00365521.2017.1416160] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES The efficacy and tolerability of vedolizumab in the treatment of inflammatory bowel diseases (IBD) has been demonstrated in an extensive GEMINI clinical trial programme. Clinical trials represent highly selected patient populations and, therefore, it is important to demonstrate effectiveness in real-life clinical practice. We set out to assess real-world treatment outcomes of vedolizumab in a nationwide cohort of treatment refractory Finnish Crohn's disease (CD) and ulcerative colitis (UC) patients. METHODS This was a nationwide, retrospective, non-interventional, multi-centre chart review study. All adult patients from 27 Finnish gastroenterology centers with a diagnosis of UC or CD who had at least one vedolizumab infusion since the availability of the product in Finland, were included in the study. Data were collected retrospectively from medical charts at baseline, week 14, and month 6. The primary outcome measure was treatment persistence 24 weeks post-vedolizumab initiation. RESULTS A total of 247 patients were included (108 CD, 139 UC). A total of 75.0% (n = 81) of all CD patients and 66.2% (n = 92) of all UC patients, were persistent on vedolizumab therapy for 6 months post treatment initiation. At month 6, 41.8% (28/67) of the treatment persistent CD patients and 73.3% (63/86) of the treatment persistent UC patients achieved clinical remission. Significant improvement in endoscopic scores were observed among treatment persistent patients (CD, n = 17, ΔSES-CD=-5.5, p = .008; UC, n = 26, ΔMayo endoscopic score =-0.5, p = .003) at month 6. CONCLUSIONS Vedolizumab provides an effective and well-tolerated treatment option in real-world clinical practice even among treatment refractory IBD patients.
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Affiliation(s)
- Tero Ylisaukko-Oja
- a Takeda Oy , Helsinki , Finland.,b MedEngine Oy , Helsinki , Finland.,c Faculty of Medicine , Center for Life Course Health Research University of Oulu , Oulu , Finland
| | | | - Heikki Nuutinen
- d Division of Gastroenterology, Department of Medicine , Turku University Hospital , Turku , Finland
| | - Timo Blomster
- e Division of Gastroenterology, Department of Medicine , Oulu University Hospital , Oulu , Finland
| | - Airi Jussila
- f Department of Gastroenterology and Alimentary Tract Surgery , Tampere University Hospital , Tampere , Finland
| | - Markku Pajala
- g Department of Internal Medicine , Kuopio University Hospital , Kuopio , Finland
| | - Kimmo Salminen
- d Division of Gastroenterology, Department of Medicine , Turku University Hospital , Turku , Finland
| | - Veikko Moilanen
- h Department of Internal Medicine , Satakunta Central Hospital , Pori , Finland
| | - Kalle Hakala
- i Department of Internal Medicine , Kanta-Häme Central Hospital , Hämeenlinna , Finland
| | - Mikko Kellokumpu
- j Department of Internal Medicine , Lapland Central Hospital , Rovaniemi , Finland
| | - Kari Toljamo
- k Department of Internal Medicine , TYKS Salo Hospital , Salo , Finland
| | - Henna Rautiainen
- l Department of Gastroenterology , Helsinki University Hospital/Jorvi Hospital , Espoo , Finland
| | - Juha Kuisma
- m Department of Internal Medicine , HUS Hyvinkää Hospital , Hyvinkää , Finland
| | - Markku Peräaho
- n Department of Internal Medicine , Central Hospital of Central Finland , Jyväskylä , Finland
| | - Pauliina Molander
- o Department of Gastroenterology , Helsinki University Hospital/Peijas Hospital , Vantaa , Finland
| | - Jouni Silvennoinen
- p Department of Gastroenterology , North Karelia Central Hospital , Joensuu , Finland
| | - Ville Liukkonen
- p Department of Gastroenterology , North Karelia Central Hospital , Joensuu , Finland
| | - Hans Henricson
- q Department of Internal Medicine , Hospital Pietarsaari , Pietarsaari , Finland
| | - Jyrki Tillonen
- r Department of Internal Medicine , Päijät-Häme Central Hospital , Lahti , Finland
| | - Mirva Esterinen
- s Department of Internal Medicine , Savonlinna Central Hospital , Savonlinna , Finland
| | - Christian Nielsen
- t Department of Internal Medicine , Vaasa Central Hospital , Vaasa , Finland
| | - Eija Hirsi
- u Department of Internal Medicine , South Karelia Central Hospital , Lappeenranta , Finland
| | - Margus Lääne
- v Department of Internal Medicine , Seinäjoki Central Hospital , Seinäjoki , Finland
| | - Ulla-Maija Suhonen
- w Department of Internal Medicine , Kainuu Central Hospital , Kajaani , Finland
| | - Ilkka Vihriälä
- x Department of Internal Medicine , Central Ostrobothnia Central Hospital , Kokkola , Finland
| | - Petri Mäkelä
- y Department of Internal Medicine , Turku City Hospital , Turku , Finland
| | - Mika Puhto
- z Department of Internal Medicine , Mikkeli Central Hospital , Mikkeli , Finland
| | - Jari Punkkinen
- aa Department of Internal Medicine , HUS Porvoo Hospital , Porvoo , Finland
| | - Hannu Sulonen
- ab Department of Internal Medicine , Forssa Hospital , Forssa , Finland
| | | | - Jari Jokelainen
- b MedEngine Oy , Helsinki , Finland.,c Faculty of Medicine , Center for Life Course Health Research University of Oulu , Oulu , Finland.,ac Unit of Primary Health Care , Oulu University Hospital , Oulu , Finland
| | | | - Taina Sipponen
- ad Department of Gastroenterology , Helsinki University Hospital and University of Helsinki , Helsinki , Finland
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Eriksson C, Marsal J, Bergemalm D, Vigren L, Björk J, Eberhardson M, Karling P, Söderman C, Myrelid P, Cao Y, Sjöberg D, Thörn M, Karlén P, Hertervig E, Strid H, Ludvigsson JF, Almer S, Halfvarson J. Long-term effectiveness of vedolizumab in inflammatory bowel disease: a national study based on the Swedish National Quality Registry for Inflammatory Bowel Disease (SWIBREG). Scand J Gastroenterol 2017; 52:722-729. [PMID: 28362144 DOI: 10.1080/00365521.2017.1304987] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Clinical trials have demonstrated the efficacy of vedolizumab in inflammatory bowel disease (IBD). However, these findings may not reflect the clinical practice. Therefore, we aimed to describe a vedolizumab-treated patient population and assess long-term effectiveness. MATERIALS AND METHODS Patients initiating vedolizumab between 1 June 2014 and 30 May 2015 were identified through the Swedish National Quality Registry for IBD. Prospectively collected data on treatment and disease activity were extracted. Clinical remission was defined as Patient Harvey Bradshaw index <5 in Crohn's disease (CD) and Patient Simple Clinical Colitis Activity index <3 in ulcerative colitis (UC). RESULTS Two-hundred forty-six patients (147 CD, 92 UC and 7 IBD-Unclassified) were included. On study entry, 86% had failed TNF-antagonist and 48% of the CD patients had undergone ≥1 surgical resection. After a median follow-up of 17 (IQR: 14-20) months, 142 (58%) patients remained on vedolizumab. In total, 54% of the CD- and 64% of the UC patients were in clinical remission at the end of follow-up, with the clinical activity decreasing (p < .0001 in both groups). Faecal-calprotectin decreased in CD (p < .0001) and in UC (p = .001), whereas CRP decreased in CD (p = .002) but not in UC (p = .11). Previous anti-TNF exposure (adjusted HR: 4.03; 95% CI: 0.96-16.75) and elevated CRP at baseline (adjusted HR: 2.22; 95% CI: 1.10-4.35) seemed to be associated with discontinuation because of lack of response. Female sex was associated with termination because of intolerance (adjusted HR: 2.75; 95% CI: 1.16-6.48). CONCLUSION Vedolizumab-treated patients represent a treatment-refractory group. A long-term effect can be achieved, even beyond 1 year of treatment.
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Affiliation(s)
- Carl Eriksson
- a Department of Gastroenterology, Faculty of Medicine and Health , Örebro University , Örebro , Sweden
| | - Jan Marsal
- b Immunology Section , Lund University , Lund , Sweden.,c Department of Gastroenterology , Skåne University Hospital , Lund , Sweden
| | - Daniel Bergemalm
- a Department of Gastroenterology, Faculty of Medicine and Health , Örebro University , Örebro , Sweden
| | - Lina Vigren
- d Department of Internal Medicine , Ystad Hospital , Ystad , Sweden
| | - Jan Björk
- e Department of Medicine , Center for Digestive Diseases, Karolinska University Hospital , Karolinska Institutet , Solna , Stockholm , Sweden
| | - Michael Eberhardson
- e Department of Medicine , Center for Digestive Diseases, Karolinska University Hospital , Karolinska Institutet , Solna , Stockholm , Sweden
| | - Pontus Karling
- f Department of Public Health and Clinical Medicine , Umeå University , Umeå , Sweden
| | - Charlotte Söderman
- g Department of Internal Medicine , St Göran Hospital , Stockholm , Sweden
| | | | - Pär Myrelid
- h Department of Clinical and Experimental Medicine, Linköping University and Department of Surgery , Linköping University Hospital , Linköping , Sweden
| | - Yang Cao
- i Department of Clinical Epidemiology and Biostatistics, School of Medical Sciences , Örebro University , Örebro , Sweden.,j Department of Medical Epidemiology and Biostatistics , Karolinska Institutet , Stockholm , Sweden
| | - Daniel Sjöberg
- k Center for Clinical Research Dalarna , Uppsala University , Falun , Sweden
| | - Mari Thörn
- l Department of Medical Sciences, Section of Gastroenterology and Hepatology , Uppsala University , Uppsala , Sweden
| | - Per Karlén
- m Department of Internal Medicine , Danderyd Hospital , Stockholm , Sweden
| | - Erik Hertervig
- c Department of Gastroenterology , Skåne University Hospital , Lund , Sweden
| | - Hans Strid
- n Department of Internal Medicine , Södra Älvsborgs Sjukhus , Borås , Sweden
| | - Jonas F Ludvigsson
- j Department of Medical Epidemiology and Biostatistics , Karolinska Institutet , Stockholm , Sweden.,o Department of Pediatrics , Örebro University Hospital , Örebro , Sweden
| | - Sven Almer
- e Department of Medicine , Center for Digestive Diseases, Karolinska University Hospital , Karolinska Institutet , Solna , Stockholm , Sweden
| | - Jonas Halfvarson
- a Department of Gastroenterology, Faculty of Medicine and Health , Örebro University , Örebro , Sweden
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Singh S, Andersen NN, Andersson M, Loftus EV, Jess T. Comparison of Infliximab and Adalimumab in Biologic-Naive Patients With Ulcerative Colitis: A Nationwide Danish Cohort Study. Clin Gastroenterol Hepatol 2017; 15:1218-1225.e7. [PMID: 27913244 PMCID: PMC5447492 DOI: 10.1016/j.cgh.2016.11.024] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 11/02/2016] [Accepted: 11/15/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS This study compares the effectiveness and safety of infliximab and adalimumab in biologic-naive patients with ulcerative colitis (UC), in a nationwide register-based propensity score-matched cohort study. METHODS From 1719 adults with UC, between ages 15 and 75 years in Denmark treated with either infliximab or adalimumab as their first biologic agent, we compared rates of all-cause hospitalization, UC-related hospitalization, major abdominal surgery, and serious infections after a variable 2:1 propensity score matching, accounting for baseline clinical characteristics, disease severity, health care utilization, and use of UC-related medications. RESULTS As compared with infliximab-treated patients, adalimumab-treated patients had higher rate of all-cause hospitalization (hazard ratio [HR], 1.84; 95% CI, 1.18-2.85) and a trend toward higher rate of UC-related hospitalization (HR, 1.71; 95% CI, 0.95-3.07), particularly in a stratum of patients on concomitant immunomodulator therapy. However, risk of abdominal surgery (HR, 1.35; 95% CI, 0.62-2.94) was not different between the 2 treatment groups. Risk of serious infection requiring hospitalization was significantly higher in adalimumab-treated patients (HR, 5.11; 95% CI, 1.20-21.80). CONCLUSIONS In this nationwide propensity score matched-cohort study of biologic-naive adults with UC, use of adalimumab as first-line biologic over infliximab was associated with higher risk of hospitalization and serious infections, although risk of surgery was not different. In the absence of head-to-head trials, this evidence may assist patients, health care providers, purchasers, and policy makers to make informed decisions that may improve health care in UC.
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Affiliation(s)
- Siddharth Singh
- Division of Gastroenterology, University of California San Diego, La Jolla, California.
| | - Nynne Nyboe Andersen
- Department of Epidemiology Research, Statens Serum Institute, Copenhagen, Denmark
| | - Mikael Andersson
- Department of Epidemiology Research, Statens Serum Institute, Copenhagen, Denmark
| | - Edward V Loftus
- Divison of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Tine Jess
- Department of Epidemiology Research, Statens Serum Institute, Copenhagen, Denmark; Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
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Perretti M, Di Filippo C, D’Amico M, Dalli J. Characterizing the anti-inflammatory and tissue protective actions of a novel Annexin A1 peptide. PLoS One 2017; 12:e0175786. [PMID: 28407017 PMCID: PMC5391094 DOI: 10.1371/journal.pone.0175786] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 03/31/2017] [Indexed: 12/13/2022] Open
Abstract
Inflammation in now appreciated to be at the centre of may diseases that affect Western civilization. Current therapeutics for managing these conditions may interfere with the host response leading to immune suppression. We recently developed an annexin (Anx) A1-derived peptide, coined CR-AnxA12-50, which displays potent pro-resolving and tissue protective actions. Herein, we designed a novel peptide using CR-AnxA12-50 as a template that was significantly more resistant to neutrophil-mediated degradation. This peptide, termed CR-AnxA12-48, retained high affinity and specificity to the pro-resolving Lipoxin A4 receptor (ALX) with an IC50 of ~20nM. CR-AnxA12-48 dose dependently (100fM-10nM) promoted the efferocytosis of apoptotic neutrophils, an action that was mediated by the murine orthologue of human ALX. The neutrophil-directed actions were also retained with human primary cells were CR-AnxA12-48 reduced human neutrophil recruitment to activated endothelial cells at concentrations as low as 100 pM. This protective action was mediated by human ALX, since incubation of neutrophils with an anti-ALX antibody reversed this anti-inflammatory actions of CR-AnxA12-48. Administration of this peptide to mice during dermal inflammation led to a significant and dose dependent decrease in neutrophil recruitment. This reduction in neutrophil numbers was more pronounced than that displayed by the parent peptide CR-AnxA12-50. CR-AnxA12-48 was also cardioprotecitve reducing infarct size and systemic chemokine (C-C motif) ligand 5 concentration following ischemia reperfusion injury. These findings identify CR-AnxA12-48 as a new ALX agonist that regulates phagocyte responses and displays tissue-protective actions.
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Affiliation(s)
- Mauro Perretti
- The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London, United Kingdom
| | - Clara Di Filippo
- Department of Experimental Medicine, Second University of Naples, Naples, Italy
| | - Michele D’Amico
- Department of Experimental Medicine, Second University of Naples, Naples, Italy
| | - Jesmond Dalli
- The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London, United Kingdom
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40
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Demethyleneberberine alleviates inflammatory bowel disease in mice through regulating NF-κB signaling and T-helper cell homeostasis. Inflamm Res 2016; 66:187-196. [PMID: 27900412 DOI: 10.1007/s00011-016-1005-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Revised: 10/24/2016] [Accepted: 10/28/2016] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE The activation of NF-κB signaling and unbalance of T-helper (Th) cells have been reported to play a key role in the pathogenesis of colitis. Cortex Phellodendri Chinensis (CPC) is commonly used to treat inflammation and diarrhea. Demethyleneberberine (DMB), a component of CPC, was reported to treat alcoholic liver disease as a novel natural mitochondria-targeted antioxidant in our previous study. In this study, we investigated whether DMB could protect against dextran sulfate sodium (DSS)-induced inflammatory colitis in mice by regulation of NF-κB pathway and Th cells homeostatis. METHODS Inflammatory colitis mice were induced by 3% DSS, and DMB were orally administered on the doses of 150 and 300 mg/kg. In vitro, DMB (10, 20, 40 μM) and N-acetyl cysteine (NAC, 5 mM) were co-cultured with RAW264.7 for 2 h prior to lipopolysaccharide (LPS) stimulation, and splenocytes from the mice were cultured ex vivo for 48 h for immune response test. RESULTS In vivo, DMB significantly alleviated the weight loss and diminished myeloperoxidase (MPO) activity, while significantly reduced the production of pro-inflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor-α (TNF-α), and inhibited the activation of NF-κB signaling pathway. Furthermore, DMB decreased interferon (IFN)-γ, increased IL-4 concentration in the mice splenocytes and the ratio of IgG1/IgG2a in the serum. In vitro, ROS production and pro-inflammation cytokines were markedly inhibited by DMB in RAW264.7 cell. CONCLUSIONS Our findings revealed that DMB alleviated mice colitis and inhibited the inflammatory responses by inhibiting NF-κB pathway and regulating the balance of Th cells.
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Devadason D, Jones K, Rodrigues A. The use of biologicals in paediatric onset inflammatory bowel disease. PAEDIATRICS AND CHILD HEALTH 2016; 26:441-444. [DOI: 10.1016/j.paed.2016.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Orsini D, Narcisi A, Arcese A, Costanzo A. Long-term safety of etanercept in psoriasis: Retrospective study focused on infections. J Int Med Res 2016; 44:58-60. [PMID: 27683141 PMCID: PMC5536529 DOI: 10.1177/0300060515593252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Objective Retrospective study to evaluate the incidence of infectious adverse events in patients with psoriasis treated with etanercept. Methods Patients with psoriasis or psoriatic arthritis who were treated with etanercept (50 mg, administered weekly via subcutaneous injection) for ≥48 weeks were retrospectively enrolled. Patients were screened for occult infections before treatment commenced, and then every 12 months thereafter. Minor (not requiring hospitalization and/or discontinuation of treatment) and major (requiring hospitalization and/or discontinuation of treatment) infectious events were recorded. Results The study included 50 patients. Minor infectious events included self-limiting upper respiratory tract infections (six patients), lower urinary tract infections (one patient) and recurrent herpes simplex labialis (two patients). Major infections occurred in only two cases. Conclusion These data support the good safety profile of etanercept in patients with psoriasis or psoriatic arthritis.
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Affiliation(s)
- Diego Orsini
- Dermatology Unit, Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), University of Rome "La Sapienza", Rome, Italy
| | - Alessandra Narcisi
- Dermatology Unit, Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), University of Rome "La Sapienza", Rome, Italy
| | - Annalisa Arcese
- Dermatology Unit, Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), University of Rome "La Sapienza", Rome, Italy
| | - Antonio Costanzo
- Dermatology Unit, Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), University of Rome "La Sapienza", Rome, Italy
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Dávila-Seijo P, Dauden E, Descalzo MA, Carretero G, Carrascosa JM, Vanaclocha F, Gómez-García FJ, De la Cueva-Dobao P, Herrera-Ceballos E, Belinchón I, López-Estebaranz JL, Alsina M, Sánchez-Carazo JL, Ferrán M, Torrado R, Ferrandiz C, Rivera R, Llamas M, Jiménez-Puya R, García-Doval I. Infections in Moderate to Severe Psoriasis Patients Treated with Biological Drugs Compared to Classic Systemic Drugs: Findings from the BIOBADADERM Registry. J Invest Dermatol 2016; 137:313-321. [PMID: 27677836 DOI: 10.1016/j.jid.2016.08.034] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 07/29/2016] [Accepted: 08/31/2016] [Indexed: 12/12/2022]
Abstract
Information regarding the safety of biological drugs prescribed to psoriasis patients on daily and long-term bases is insufficient. We used data from the BIOBADADERM registry (Spanish Registry of Adverse Events for Biological Therapy in Dermatological Diseases) to generate crude rates of infection during therapy with systemic drugs, including biological drugs (infliximab, etanercept, adalimumab, and ustekinumab) and nonbiological drugs (acitretin, cyclosporine, and methotrexate). We also calculated unadjusted and adjusted risk ratios (RRs) (with propensity score adjustment) of infection, serious infections, and recurrent infections of systemic therapies compared with methotrexate, using Poisson regression. Our study included records of 2,153 patients (7,867.5 person-years). The adjusted RR of overall infection was significantly increased in the groups treated with adalimumab with methotrexate (adjusted RR = 2.13, 95% confidence interval [CI] = 1.2-3.7), infliximab (adjusted RR = 1.71, 95% CI = 1.1-2.65), cyclosporine (adjusted RR = 1.58, 95% CI = 1.17-2.15), ustekinumab with methotrexate (adjusted RR = 1.56, 95% CI = 1.08-2.25), and etanercept (adjusted RR = 1.34, 95% CI: 1.02-1.76) compared with methotrexate alone. Cyclosporine had a significant risk of serious infection (adjusted RR = 3.12, 95% CI = 1.1-8.8), followed by adalimumab combined with methotrexate (adjusted RR = 3.28, 95% CI = 0.8-13.5). Adalimumab in combination with methotrexate had the highest risk of infection recurrence (adjusted RR = 4.33, 95% CI = 2.27-8.24).
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Affiliation(s)
- Paula Dávila-Seijo
- Research Unit, Fundación Academia Española de Dermatología y Venereología, Madrid, Spain; Dermatology and Venereology Department, Umeå University Hospital, Umeå, Sweden.
| | - Esteban Dauden
- Dermatology Department, Hospital Universitario La Princesa, Madrid, Spain
| | - M A Descalzo
- Research Unit, Fundación Academia Española de Dermatología y Venereología, Madrid, Spain
| | - Gregorio Carretero
- Dermatology Department, Hospital Universitario de Gran Canaria Dr Negrín, Las Palmas de Gran Canaria, Spain
| | | | | | | | | | | | - Isabel Belinchón
- Dermatology Department, Hospital General Universitario de Alicante, Departamento de Medicina Clínica, Universidad Miguel Hernández, ISABIAL-FISABIO, Alicante, Spain
| | | | - Merce Alsina
- Dermatology Department, Hospital Clinic de Barcelona, Barcelona, Spain
| | | | - Marta Ferrán
- Dermatology Department, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
| | - Rosa Torrado
- Dermatology Department, Hospital Universitario de Gran Canaria Dr Negrín, Las Palmas de Gran Canaria, Spain
| | - Carlos Ferrandiz
- Dermatology Department, Hospital Universitario Germans Trias i Pujol, Badalona, Spain
| | - Raquel Rivera
- Dermatology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Mar Llamas
- Dermatology Department, Hospital Universitario La Princesa, Madrid, Spain
| | | | - Ignacio García-Doval
- Research Unit, Fundación Academia Española de Dermatología y Venereología, Madrid, Spain; Dermatology Derpartment, Complexo Hospitalario Universitario de Vigo, Vigo, Spain
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Moćko P, Kawalec P, Pilc A. Safety Profile of Biologic Drugs in the Treatment of Inflammatory Bowel Diseases: A Systematic Review and Network Meta-analysis of Randomized Controlled Trials. Clin Drug Investig 2016; 37:25-37. [DOI: 10.1007/s40261-016-0459-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Pouillon L, Bossuyt P, Peyrin-Biroulet L. Considerations, challenges and future of anti-TNF therapy in treating inflammatory bowel disease. Expert Opin Biol Ther 2016; 16:1277-90. [PMID: 27329436 DOI: 10.1080/14712598.2016.1203897] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Crohn's disease (CD) and ulcerative colitis (UC) are chronic disabling conditions. Monoclonal antibody therapy directed against tumor necrosis factor-alpha (anti-TNF) has revolutionized the care of patients with inflammatory bowel disease (IBD). AREAS COVERED Considerations before starting anti-TNF therapy are highlighted: the best time to start with anti-TNF therapy, either alone or in combination with an immunomodulator, the choice of an anti-TNF agent and the contra-indications to anti-TNF therapy. Primary nonresponse and secondary loss of response are discussed. De-escalating therapy, the role of therapeutic drug monitoring and the use of biosimilars, are handled. Finally, the future directions of anti-TNF therapy are emphasized. EXPERT OPINION Anti-TNF therapy remains the cornerstone in the treatment of IBD. When initiating long-term therapy, safety and cost issues are of great importance. The therapeutic armamentarium in the treatment of IBD is rapidly growing. Therefore, the challenge is to optimize the use and refine the exact position of anti-TNF therapy in the near future, with personalized medicine as the ultimate goal.
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Affiliation(s)
- Lieven Pouillon
- a Department of Hepato-Gastroenterology , University Hospitals Leuven, Uz Gasthuisberg , Leuven , Belgium
| | - Peter Bossuyt
- b Imelda GI Clinical Research Centre , Imeldaziekenhuis Bonheiden , Bonheiden , Belgium
| | - Laurent Peyrin-Biroulet
- c Inserm U954 and Department of Gastroenterology , Nancy University Hospital, Université de Lorraine , Vandœuvre-lès-Nancy , France
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Atreya R, Neurath MF. Predicting Therapeutic Response by in vivo Molecular Imaging in Inflammatory Bowel Diseases. Dig Dis 2016; 34:552-7. [PMID: 27333283 DOI: 10.1159/000445262] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND Different invasive and non-invasive imaging modalities are indispensable tools in the management of inflammatory bowel disease (IBD) patients. Standard imaging procedures like white light endoscopy or MRI are used to define gut inflammation based on structural changes and altered morphology of the mucosa. Nevertheless, it has thus far not been possible to analyse biological processes at the cellular level, which drive intestinal inflammation in IBD patients. The recent advent of molecular imaging in the field of IBD has opened new promising avenues to allow personalized medicine approaches based on in vivo-detected molecular findings. KEY MESSAGES Recent clinical studies have attempted to address the issue of predicting therapeutic response to anti-tumor necrosis factor (TNF) treatment in IBD patients based on the molecular mechanism of action of these agents and corresponding in vivo assessment of mucosal immune responses. Several experimental studies have indicated that one of the main functions of efficacious anti-TNF therapy in IBD is the induction of intestinal cell apoptosis. Fittingly, a corresponding molecular-imaging study using single-photon emission CT for the localization and quantification of cell apoptosis, demonstrated that induction of mucosal T-cell apoptosis correlated with the therapeutic response to anti-TNF therapy in Crohn's disease patients. There was moreover a predictive capacity regarding therapeutic efficacy. As the main biological properties of anti-TNF antibodies in IBD are mediated through binding to membrane-bound TNF (mTNF) expressing intestinal cells, another study used molecular imaging for in vivo visualization of these cells via fluorescent anti-TNF antibodies to predict therapeutic efficacy of these agents. It could be shown that patients with high amounts of mTNF positive cells showed significantly better response rates compared to patients with low amounts of mTNF positive cells. CONCLUSION In vivo molecular imaging in IBD has the potential to have an impact on our current treatment approaches and may allow us to individualize specific therapies based on molecular level analysis.
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Affiliation(s)
- Raja Atreya
- Medical Clinic I, Friedrich-Alexander Universitx00E4;t Erlangen-Nx00FC;rnberg, Erlangen, Germany
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Waterland P, Athanasiou T, Patel H. Post-operative abdominal complications in Crohn’s disease in the biological era: Systematic review and meta-analysis. World J Gastrointest Surg 2016; 8:274-283. [PMID: 27022455 PMCID: PMC4807329 DOI: 10.4240/wjgs.v8.i3.274] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 10/27/2015] [Accepted: 01/04/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To perform a systematic review and meta-analysis on post-operative complications after surgery for Crohn’s disease (CD) comparing biological with no therapy.
METHODS: PubMed, Medline and Embase databases were searched to identify studies comparing post-operative outcomes in CD patients receiving biological therapy and those who did not. A meta-analysis with a random-effects model was used to calculate pooled odds ratios (OR) and confidence intervals (CI) for each outcome measure of interest.
RESULTS: A total of 14 studies were included for meta-analysis, comprising a total of 5425 patients with CD 1024 (biological treatment, 4401 control group). After biological therapy there was an increased risk of total infectious complications (OR = 1.52; 95%CI: 1.14-2.03, 8 studies) and wound infection (OR = 1.73; 95%CI: 1.12-2.67; P = 0.01, 7 studies). There was no increased risk for other complications including anastomotic leak (OR = 1.19; 95%CI: 0.82-1.71; P = 0.26), abdominal sepsis (OR = 1.22; 95%CI: 0.87-1.72; P = 0.25) and re-operation (OR = 1.12; 95%CI: 0.81-1.54; P = 0.46) in patients receiving biological therapy.
CONCLUSION: Pre-operative use of anti-TNF-α therapy may increase risk of post-operative infectious complications after surgery for CD and in particular wound related infections.
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Ryoo JY, Yang HJ, Ji E, Yoo BK. Meta-analysis of the Efficacy and Safety of Secukinumab for the Treatment of Plaque Psoriasis. Ann Pharmacother 2016; 50:341-51. [PMID: 26783352 DOI: 10.1177/1060028015626545] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND In January 2015, US FDA approved secukinumab, a human interleukin-17A (IL-17A) antagonist, for the treatment of plaque psoriasis. OBJECTIVE To provide unbiased drug information about the efficacy and safety of secukinumab for the treatment of moderate to severe plaque psoriasis by performing meta-analysis. METHODS PubMed and EMBASE database searches were conducted. Among the literatures retrieved, relevant Phase III clinical trials were analyzed. Statistical analysis of the data was performed by RevMan. RESULTS Four pivotal and three non-pivotal Phase III clinical trials were retrieved. All the trials evaluated the efficacy and safety of secukinumab for the treatment of moderate to severe plaque psoriasis with two co-primary endpoints: proportions of Psoriasis Area and Severity Index (PASI) responders and Investigator's Global Assessment (IGA) responders. The overall odd ratios for proportions of PASI responders and IGA responders in secukinumab-containing arm were 65.6 and 62.5 compared to the placebo arm, respectively. Secukinumab was superior to etanercept resulting in both of the odd ratios being 3.7 compared to the etanercept. Secukinumab was generally well tolerated during the one year trial. However, as with other monoclonal antibody medications, vulnerability of respiratory infection (especially nasopharyngitis) was reported as most common adverse event. CONCLUSIONS Meta-analysis of the seven Phase III clinical trials resulted in superiority of secukinumab over etanercept in terms of the efficacy and safety. However, long-term safety data is lacking at this time so post-marketing surveillance should be performed for any adverse events associated with the use of this new biological medication.
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Recomendaciones del Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU) sobre el cribado y tratamiento de la tuberculosis latente en pacientes con enfermedad inflamatoria intestinal. ACTA ACUST UNITED AC 2015. [DOI: 10.1016/j.eii.2015.09.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Safety Profile of Certolizumab Pegol in Patients with Immune-Mediated Inflammatory Diseases: A Systematic Review and Meta-Analysis. Drug Saf 2015; 38:869-88. [DOI: 10.1007/s40264-015-0336-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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