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Liang G, Ma Y, Deng P, Li S, He C, He H, Liu H, Fan Y, Li Z. Role of cell-based therapies in digestive disorders: Obstacles and opportunities. Regen Ther 2025; 29:1-18. [PMID: 40124469 PMCID: PMC11925584 DOI: 10.1016/j.reth.2025.02.009] [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: 12/22/2024] [Revised: 02/01/2025] [Accepted: 02/20/2025] [Indexed: 03/25/2025] Open
Abstract
Stem cell-based therapies have emerged as a promising frontier in the treatment of gastrointestinal disorders, offering potential solutions for challenges posed by conventional treatments. This review comprehensively examines recent advancements in cell-based therapeutic strategies, particularly focusing on stem cell applications, immunotherapy, and cellular therapies for digestive diseases. It highlights the successful differentiation of enteric neural progenitors from pluripotent stem cells and their application in animal models, such as Hirschsprung disease. Furthermore, the review evaluates clinical trials and experimental studies demonstrating the potential of stem cells in regenerating damaged tissues, modulating immune responses, and promoting healing in conditions like Crohn's disease and liver failure. By addressing challenges, such as scalability, immunogenicity, and ethical considerations, the review underscores the translational opportunities and obstacles in realizing the clinical potential of these therapies. Concluding with an emphasis on future directions, the study provides insights into optimizing therapeutic efficacy and fostering innovations in personalized medicine for digestive disorders.
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Affiliation(s)
- Guodong Liang
- First Surgery Department of Colorectal, Gastric and Abdominal Tumors, Jilin Cancer Hospital, Changchun 130012, China
| | - Yuehan Ma
- First Surgery Department of Colorectal, Gastric and Abdominal Tumors, Jilin Cancer Hospital, Changchun 130012, China
| | - Ping Deng
- Medical Department, Jilin Cancer Hospital, Changchun 130012, China
| | - Shufeng Li
- First Department of Gynecological Tumor, Jilin Cancer Hospital, Changchun 130012, China
| | - Chunyan He
- Department of Anaesthesia, Jilin Cancer Hospital, Changchun 130012, China
| | - Haihang He
- Department of Otorhinolaryngology, Oral Maxillofacial, Head and Neck, Jilin Cancer Hospital, Changchun 130012, China
| | - Hairui Liu
- First Surgery Department of Colorectal, Gastric and Abdominal Tumors, Jilin Cancer Hospital, Changchun 130012, China
| | - Yunda Fan
- First Surgery Department of Colorectal, Gastric and Abdominal Tumors, Jilin Cancer Hospital, Changchun 130012, China
| | - Ze Li
- First Surgery Department of Colorectal, Gastric and Abdominal Tumors, Jilin Cancer Hospital, Changchun 130012, China
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Alizadeh M, Ali O, Cross RK. Assessing Progression of Biologic Therapies Based on Smoking Status in Patients With Crohn's Disease. Inflamm Bowel Dis 2024; 30:788-794. [PMID: 37478408 PMCID: PMC11063538 DOI: 10.1093/ibd/izad131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Indexed: 07/23/2023]
Abstract
BACKGROUND Active smoking is a well-established risk factor for developing Crohn's disease (CD) and negatively impacts overall disease progression. Patients who start or continue smoking after CD diagnosis are at risk for poor outcomes, higher therapeutic requirements, and have higher rates of relapse. However, it remains unclear if the exposure to smoking leads to increased sequencing through treatment therapies, especially biologics. METHODS The Study of Prospective Adult Research Cohort with IBD (SPARC IBD) registry has been collecting patient-reported outcomes data in real-time, as well as laboratory, endoscopic, and pathologic samples from 17 tertiary referral centers since 2016. In this study, we conducted a retrospective review of the SPARC clinical registry collected between December 2016 and January 2021 from 1 participating site, the University of Maryland School of Medicine's Inflammatory Bowel Disease Program. A total of 619 patients were enrolled in the SPARC IBD database. Four hundred twenty-five patients with CD were included for initial review of completeness of data; of these, 144 patients were excluded due to missing data on smoking status and/or biologic treatment, resulting in a final cohort of 281 patients. We collected and analyzed baseline demographic and clinical characteristics. The final cohort was categorized into 3 exposure groups: current, former, and never smokers. Our outcome of interest was number biologics used, categorized into 3 groups: 0, 1, or ≥2 biologics. RESULTS One hundred seventy-two never smokers, 70 former smokers, and 39 current smokers were identified. Current, former, and never smokers had no statistically significant differences in number of biologics used (ie, biologic sequencing). However, statistically significant independent risk factors for increased sequencing of biologics were identified. These risk factors included female sex, ileocolonic disease location, younger age at diagnosis, and prolonged disease duration; none of these factors remained significant in adjusted analyses. CONCLUSION To date, this is the first study assessing the association of smoking and sequencing of biologics. Although current or former smokers were not found to sequence through more biologics when compared with never smokers, smoking is a well-established risk factor for poor health outcomes, and efforts should be made to counsel patients to quit. Further, additional research must be done to stratify risk to patients based on amount of tobacco exposure.
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Affiliation(s)
- Madeline Alizadeh
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, Baltimore MD 21201, USA
| | - Osman Ali
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, Baltimore MD 21201, USA
| | - Raymond K Cross
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, Baltimore MD 21201, USA
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Bokemeyer B, Hlavaty T, Allez M, Selema P, Moosavi S, Cadatal MJ, Fowler H, Mueller M, Liau KF, Gisbert JP. Real-world observational cohort study of treatment patterns and safety outcomes of infliximab biosimilar CT-P13 for the treatment of inflammatory bowel disease (CONNECT-IBD). Expert Opin Biol Ther 2023; 23:791-800. [PMID: 37038897 DOI: 10.1080/14712598.2023.2200883] [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: 09/29/2022] [Accepted: 04/05/2023] [Indexed: 04/12/2023]
Abstract
BACKGROUND The objective of this non-interventional, observational prospective cohort study (CONNECT-IBD) was to assess the use of CT-P13 (Inflectra®) in the treatment of patients with Crohn's disease (CD) and ulcerative colitis (UC) in the context of treatment with reference infliximab (IFX; Remicade®). METHODS Patients (recruited April 2015 to October 2018) at 150 sites across 13 European countries were followed for up to 2 years. Primary outcomes were safety, population characteristics, and drug utilization patterns. Secondary outcomes included clinical assessment of disease activity. Data were analyzed descriptively. RESULTS Overall, 2543 patients (CD, n = 1676; UC, n = 867) were included. In the CT-P13 cohort (n = 1522), median disease duration was 63 (0-579) months and 30% of patients were IFX naïve; median duration of prior IFX treatment was 5 months. During the observation period, median duration of drug exposure was 14 (0-28) months. 41% of patients reported 912 all-causality treatment-emergent adverse events (TEAEs); 24% experienced treatment-related TEAEs. Most TEAEs were of mild-to-moderate severity. Treatment-emergent serious adverse events were reported by 17% of patients. CONCLUSION Safety information for CT-P13 in this large study was consistent with the known safety profile for IFX and did not alter the established benefit-risk profile of CT-P13.
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Affiliation(s)
- Bernd Bokemeyer
- Interdisciplinary Crohn Colitis Centre Minden, Minden, Germany
| | - Tibor Hlavaty
- 5th Department of Internal Medicine, Sub-department of Gastroenterology and Hepatology, University Hospital Bratislava and Comenius University, Bratislava, Slovakia
| | - Matthieu Allez
- Gastroenterology Department, Hôpital Saint-Louis - APHP, INSERM U1160, Université De Paris, Paris, France
| | - Pamela Selema
- Worldwide Safety and Risk Management, Pfizer, Inc, New York City, NY, USA
| | - Shahrzad Moosavi
- Worldwide Safety and Risk Management, Pfizer, Inc, New York City, NY, USA
| | - Mary Jane Cadatal
- Global Biometrics and Data Management, Pfizer, Inc, Manila, Philippines
| | - Heather Fowler
- Clinical Development and Operations, Pfizer, Inc, London, UK
| | | | | | - Javier P Gisbert
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Universidad Autónoma de Madrid (UAM), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
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Coyne M, Rinaldi A, Brigham K, Hawthorne J, Katsaros D, Perich M, Carrara N, Pericaud F, Franzese C, Jones G. Impact of Routines and Rituals on Burden of Treatment, Patient Training, Cognitive Load, and Anxiety in Self-Injected Biologic Therapy. Patient Prefer Adherence 2022; 16:2593-2607. [PMID: 36160914 PMCID: PMC9507442 DOI: 10.2147/ppa.s375037] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 09/15/2022] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Self-injection of biologics is a mainstay of chronic disease treatment, yet the process of self-injection often causes persistent apprehension and anxiety, distinct from needle phobia. While literature alludes to the role that routines and rituals play in self-injection, there is no comprehensive study on the routines and rituals self-injectors employ, nor of the process by which they are discovered and ingrained. METHODS We conducted a mixed-method, observational pilot ethnography study of 27 patients with plaque psoriasis, psoriatic arthritis, or ankylosing spondylitis with and without prior biologic self-injection experience. Patients submitted self-made videos, photos, and projective exercises of an actual biologic self-injection and completed validated instruments to assess burden of treatment. Videos and photos containing routine and ritual elements were thematically categorized based on functional and emotional benefit, and analyzed for differences based on current biologic, dosing frequency, time on current biologic, and burden of treatment measures. RESULTS During patients' initial at-home injections, training gaps became apparent, leading to a process of experimentation aimed at reducing pain/anxiety, increasing confidence, and building a consistent injection process. Routines were present in 27/27 (100%) patients and anchored the time, place, and process for injection, and incorporated approved use steps for the injection device. Ritual elements served as emotional coping strategies for patients and were present in 21/27 (77.8%) of patients. CONCLUSION Our findings suggest that providing patients device training using adult learning principles, teaching routines and rituals concurrently, and providing at-home opportunities for practice with a device trainer may be useful strategies to reduce anxiety, avoid unnecessary experimentation, and improve adherence to injection therapy. While further studies are needed to generalize our findings, we posit that routine and ritual elements can be incorporated into existing patient-clinician interactions or novel digital interventions through mobile medical applications, smart training devices, and connected injection ecosystems.
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Affiliation(s)
- Marty Coyne
- Matchstick, Boonton, NJ, USA
- University of Rhode Island School of Pharmacy, Kingston, RI, USA
| | | | | | - James Hawthorne
- Matchstick, Boonton, NJ, USA
- University of Rhode Island School of Pharmacy, Kingston, RI, USA
| | - Dimos Katsaros
- Matchstick, Boonton, NJ, USA
- University of Rhode Island School of Pharmacy, Kingston, RI, USA
| | - Morgan Perich
- University of Rhode Island School of Pharmacy, Kingston, RI, USA
| | | | - Flore Pericaud
- Technical Research and Development, Novartis Pharmaceuticals, Basel, Switzerland
| | - Chris Franzese
- Matchstick, Boonton, NJ, USA
- University of Rhode Island School of Pharmacy, Kingston, RI, USA
| | - Graham Jones
- Technical Research and Development, Novartis Pharmaceuticals, East Hanover, NJ, USA
- Correspondence: Graham Jones, Technical Research and Development, Novartis Pharmaceuticals, East Hanover, NJ, USA, Email
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Ferreira SDC, Nóbrega FJF, de Araújo RC, de Almeida PH, Villanova MG, Santana RDC, Zambelli Ramalho LN, Martinelli ADLC, Troncon LEDA. Histoplasmosis Related to Immunosuppression in a Patient with Crohn's Disease: A Diagnostic Challenge. AMERICAN JOURNAL OF CASE REPORTS 2021; 22:e925345. [PMID: 34495947 PMCID: PMC8438646 DOI: 10.12659/ajcr.925345] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Infliximab, a monoclonal antibody against tumor necrosis factor (TNF) alpha with proven efficacy and known safety profile, is currently widely used in the treatment of inflammatory bowel diseases. Increased risk for serious infections and malignant neoplasms secondary to immunosuppression is a major concern during therapy with this medication. Histoplasmosis is a granulomatous disease caused by the fungus Histoplasma capsulatum. Disseminated forms of the disease have immunodepression as a major risk factor. CASE REPORT A 39-years-old man had been followed with refractory fistulizing ileocolonic Crohn's disease using combination therapy (infliximab plus azathioprine) and also receiving short courses of steroids. After 2 years of this immunosuppressive therapy, the patient presented with high fever (39.5ºC) for 5 days, associated with profuse sweating, and moderate pain in the left hypochondrium. The patient was hospitalized. Diagnoses of tuberculosis, malignancy, autoimmune diseases, and bacterial and viral infections were rapidly discarded after investigation. Clinical, laboratory, and image signs of liver involvement prompted a guided percutaneous biopsy, which revealed granulomatous hepatitis, with the presence of fungal structures suggestive of Histoplasma capsulatum. Upon treatment with liposomal amphotericin followed by itraconazole, the patient showed an impressively positive clinical response. CONCLUSIONS TNF blockers, particularly when associated with other immunosuppressors, are a serious risk factor for opportunistic infections. This unusual case of disseminated histoplasmosis in a patient with Crohn's disease using infliximab in combination with azathioprine and steroids emphasizes the need for surveillance of this uncommon but potentially lethal complication before starting TNF blockers therapy.
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Affiliation(s)
- Sandro da Costa Ferreira
- Division of Gastroenterology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Fernando Jorge Firmino Nóbrega
- Division of Gastroenterology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Roberta Chaves de Araújo
- Division of Gastroenterology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Patrícia Holanda de Almeida
- Division of Gastroenterology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Márcia Guimarães Villanova
- Division of Gastroenterology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Rodrigo de Carvalho Santana
- Division of Infectious Diseases, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | | | - Ana de Lourdes Candolo Martinelli
- Division of Gastroenterology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Luiz Ernesto de Almeida Troncon
- Division of Gastroenterology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
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Marquez-Megias S, Ramon-Lopez A, Más-Serrano P, Diaz-Gonzalez M, Candela-Boix MR, Nalda-Molina R. Evaluation of the Predictive Performance of Population Pharmacokinetic Models of Adalimumab in Patients with Inflammatory Bowel Disease. Pharmaceutics 2021; 13:pharmaceutics13081244. [PMID: 34452204 PMCID: PMC8398570 DOI: 10.3390/pharmaceutics13081244] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/03/2021] [Accepted: 08/07/2021] [Indexed: 12/11/2022] Open
Abstract
Adalimumab is a monoclonal antibody used for inflammatory bowel disease. Due to its considerably variable pharmacokinetics, the loss of response and the development of anti-antibodies, it is highly recommended to use a model-informed precision dosing approach. The aim of this study is to evaluate the predictive performance of different population-pharmacokinetic models of adalimumab for inflammatory bowel disease to determine the pharmacokinetic model(s) that best suit our population to use in the clinical routine. A retrospective observational study with 134 patients was conducted at the General University Hospital of Alicante between 2014 and 2019. Model adequacy of each model was evaluated by the distribution of the individual pharmacokinetic parameters and the NPDE plots whereas predictive performance was assessed by calculating bias and precision. Moreover, stochastic simulations were performed to optimize the maintenance doses in the clinical protocols, to reach the target of 8 mg/L in at least 75% of the population. Two population-pharmacokinetic models were selected out of the six found in the literature which performed better in terms of adequacy and predictive performance. The stochastic simulations suggested the benefits of increasing the maintenance dose in protocol to reach the 8 mg/L target.
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Affiliation(s)
- Silvia Marquez-Megias
- School of Pharmacy, Miguel Hernández University, 03550 San Juan de Alicante, Spain; (S.M.-M.); (P.M.-S.); (R.N.-M.)
| | - Amelia Ramon-Lopez
- School of Pharmacy, Miguel Hernández University, 03550 San Juan de Alicante, Spain; (S.M.-M.); (P.M.-S.); (R.N.-M.)
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), 03010 Alicante, Spain;
- Correspondence:
| | - Patricio Más-Serrano
- School of Pharmacy, Miguel Hernández University, 03550 San Juan de Alicante, Spain; (S.M.-M.); (P.M.-S.); (R.N.-M.)
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), 03010 Alicante, Spain;
- Clinical Pharmacokinetics Unit, Pharmacy Department, Alicante University General Hospital, 03010 Alicante, Spain
| | - Marcos Diaz-Gonzalez
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), 03010 Alicante, Spain;
- Clinical Pharmacokinetics Unit, Pharmacy Department, Alicante University General Hospital, 03010 Alicante, Spain
| | | | - Ricardo Nalda-Molina
- School of Pharmacy, Miguel Hernández University, 03550 San Juan de Alicante, Spain; (S.M.-M.); (P.M.-S.); (R.N.-M.)
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), 03010 Alicante, Spain;
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Kim B, Chae J, Kim EH, Yang HI, Cheon JH, Kim TI, Kim WH, Jeon JY, Park SJ. Physical activity and quality of life of patients with inflammatory bowel disease. Medicine (Baltimore) 2021; 100:e26290. [PMID: 34232167 PMCID: PMC8270579 DOI: 10.1097/md.0000000000026290] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 02/22/2021] [Accepted: 05/20/2021] [Indexed: 01/04/2023] Open
Abstract
ABSTRACT This study examined the association between physical activity (PA) and quality of life (QOL) in Korean patients with inflammatory bowel disease (IBD).We enrolled 158 patients with IBD (81 men and 47 women). PA levels were assessed using the International PA questionnaire. Using self-reported frequency (day) and duration (h) of physical activities, the patients were categorized into 3 groups based on their total metabolic equivalent (MET-h/wk) values: least, moderate, and most active. The QOL of patients with IBD was assessed using the inflammatory bowel disease questionnaire (IBDQ), the Medical Outcomes Study 36-Item Short Form Version 2 (SF36v2), the EuroQOL five dimensions questionnaire (EQ5D), and the EuroQOL visual analog scale (EQ-VAS).Of 158 patients, 62, 73, and 23 patients with Crohn disease, ulcerative colitis, and intestinal Behçet disease, respectively, were included. The mean age was 45.96 ± 17.58 years, and 97 (61.4%) patients were men. Higher PA levels correlated with higher EQ5D and EQ-VAS scores (P < .001 and P = .004 respectively). In addition, depending on the type of PA, the amount of leisure activity was associated with higher IBDQ (κ = 0.212, P = .018), physical function of SF36v2 (κ = 0.197, P = .026), EQ5D (κ = 0.255, P = .002), and EQ-VAS (κ = 0.276, P = .001) scores. The frequency of sweat-inducing exercise showed an inverse correlation with IBDQ (κ = -0.228, P = .011), physical function of SF36v2 (κ = -0.245, P = .006), EQ5D (κ = -0.225, P = .007), and EQ-VAS (κ = -0.246, P = .004) scores.Increased PA levels were associated with improved QOL in patients with IBD. More leisure activity and non-sweat-inducing exercise were associated with improved QOL in patients with IBD.
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Affiliation(s)
- Bun Kim
- Department of Medicine, The Graduated School, Yonsei University College of Medicine, Seoul
- Center for Colon Cancer, Center for Cancer Prevention and Detection, National Cancer Center, Goyang
| | - Jisuk Chae
- Department of Sport and Leisure Studies, Yonsei University
| | - Eun Hye Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyuk In Yang
- Department of Sport and Leisure Studies, Yonsei University
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Tae Il Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Won Ho Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Justin Y. Jeon
- Department of Sport and Leisure Studies, Yonsei University
| | - Soo Jung Park
- Department of Sport and Leisure Studies, Yonsei University
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Wang Y, Zhang J, Gao X, Li Q, Sun D. In vitro and in vivo anti-inflammatory effect of Zaluzanin D isolated from Achillea acuminate. Int Immunopharmacol 2021; 90:107130. [PMID: 33218937 DOI: 10.1016/j.intimp.2020.107130] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 10/17/2020] [Accepted: 10/19/2020] [Indexed: 11/23/2022]
Abstract
The present study was investigated to verify anti-inflammatory and immune regulation effect of Zaluzanin D on LPS-induced macrophages and acute lung injury. NR8383 macrophages were pre-treated with Zaluzanin D and stimulated by LPS. Zaluzanin D reduced the production of nitric oxide in NR8383 macrophages and decreased the secretions of inflammatory cytokines. In addition, intravenous of Zaluzanin D to LPS-induced rats reduced the infiltrations of macrophages into BALF and the histological inflammatory changes in lung tissues. Furthermore, Z.D inhibited lipid peroxidation and effectively recruit the anti-oxidative defense system, regulated the levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6 in the lungs by inhibitory expression of nuclear factor-kappa B pathway. These findings suggested that Zaluzanin D attenuated pulmonary inflammatory responses by inhibiting the expression of diverse inflammatory mediators in vitro and in vivo.
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Affiliation(s)
- Yongjie Wang
- Department of Pharmacy, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China
| | - Jiaozhen Zhang
- Department of Natural Products Chemistry, Key Lab of Chemical Biology of Ministry of Education, Shandong University, Jinan, Shandong 250012, PR China
| | - Xinli Gao
- Department of Pharmacy, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China
| | - Qiang Li
- Department of Pharmacy, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China.
| | - Deqing Sun
- Department of Pharmacy, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China; Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, PR China.
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Cross RK, Chiorean M, Vekeman F, Xiao Y, Wu E, Chao J, Wang AW. Assessment of the real-world safety profile of vedolizumab using the United States Food and Drug Administration adverse event reporting system. PLoS One 2019; 14:e0225572. [PMID: 31800627 PMCID: PMC6892509 DOI: 10.1371/journal.pone.0225572] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 11/06/2019] [Indexed: 12/26/2022] Open
Abstract
Vedolizumab is the first gut-selective integrin blocker indicated for patients with Crohn's disease (CD) and ulcerative colitis (UC). This study aimed to examine the adverse events (AEs) profile of vedolizumab compared to anti-tumor necrosis factors (anti-TNFs) indicated for CD and UC using the FDA Adverse Event Reporting System (FAERS) database. AE reports with vedolizumab (5/20/2014-6/30/2015) and CD/UC-indicated anti-TNF drugs (adalimumab, infliximab, certolizumab pegol, and golimumab, during 8/1/1998-6/30/2015) as primary suspects were extracted from the FAERS database. AEs associated with vedolizumab were compared for signals of disproportionate reporting against anti-TNF drugs and all other drugs (1969-6/30/2015), using the proportional reporting ratio (PRR) and the empirical Bayesian geometric mean (EBGM) algorithms. The search retrieved 499 reports for vedolizumab and 119,620 reports for anti-TNFs, with 35.9% and 32.1% of these, respectively, being serious AEs. With the PRR approach, vedolizumab-associated reports had signals for 22 groups of AEs (9 were associated with serious outcomes) relative to anti-TNFs and had 34 signals relative to all other drugs. Signals detected included those reported as warnings in prescribing information and new AEs related to cardiovascular disease. Due to the voluntary nature of FAERS, this finding should be considered hypothesis generating (rather than hypothesis testing). Longer-term observational studies are required to evaluate the safety of vedolizumab.
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Affiliation(s)
- Raymond K. Cross
- University of Maryland School of Medicine, Baltimore, Maryland, United States of America
| | - Michael Chiorean
- Virginia Mason Medical Center, Seattle, Washington, United States of America
| | | | | | - Eric Wu
- Analysis Group, Inc., Boston, Massachusetts, United States of America
| | - Jingdong Chao
- AbbVie Inc., North Chicago, Illinois, United States of America
| | - Anthony W. Wang
- AbbVie Inc., North Chicago, Illinois, United States of America
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Epidemiology and Clinical Outcomes of Inflammatory Bowel Disease: A Hospital-Based Study in Central Taiwan. Gastroenterol Res Pract 2019; 2019:4175923. [PMID: 31312216 PMCID: PMC6595318 DOI: 10.1155/2019/4175923] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 05/05/2019] [Accepted: 05/15/2019] [Indexed: 02/07/2023] Open
Abstract
The incidence and prevalence of inflammatory bowel disease (IBD) are low but increasing in Taiwan. We aimed to investigate the epidemiology and clinical outcomes of IBD in central Taiwan. We retrospectively analyzed patients with IBD diagnosed at our hospital between January 2000 and September 2018. The diagnostic criteria were based on endoscopic and pathologic findings. Clinical characteristics, treatment regimens, and treatment outcomes were analyzed. A total of 190 patients with IBD were enrolled (80 with Crohn's disease (CD) and 110 with ulcerative colitis (UC)). The mean age at diagnosis was 38.4 years (CD: 36 years, UC: 40 years). Male patients accounted for the majority of patients (71.1%). The male-to-female ratio was 3 : 1 for CD and 2.1 : 1 for UC. Current and ever smokers accounted for 30.5% of all patients. Only 4.2% of patients had a family history of IBD. Extraintestinal manifestations (EIMs) were reported in 7.9%, and colorectal cancers (CRCs) were reported in 2.1% of all patients. In patients with CD, the ileal type was the most common disease phenotype (57.5%), and the stricturing type was the most common disease behavior (60.0%). In patients with UC, left-sided colitis was the predominant disease extent (42.7%). The seroprevalence of hepatitis B virus (HBV) was 13.3%. The incidence of perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) in patients with UC was 22%. 5-Aminosalicylic acids were the preferred treatment for UC, whereas corticosteroids, immunomodulators, and biologic agents were preferred for CD. In patients with CD, the bowel resection rate was 38.8%, and the incidence of hip avascular necrosis was 3.8%. In Taiwan, patients with IBD showed a male predominance, lack of familial clustering, a higher prevalence of HBV infection, and a lower prevalence of p-ANCA, EIMs, and CRC. Moreover, a higher incidence of the ileal type with poor outcomes of CD and left-sided predominance in UC were found.
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Lynch KD, Keshav S, Chapman RW. The Use of Biologics in Patients with Inflammatory Bowel Disease and Primary Sclerosing Cholangitis. CURRENT HEPATOLOGY REPORTS 2019; 18:115-126. [PMID: 31008013 PMCID: PMC6445403 DOI: 10.1007/s11901-019-00456-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE OF REVIEW Biologics are well established in the treatment of many immuno-inflammatory diseases including inflammatory bowel disease (IBD). However, although primary sclerosing cholangitis (PSC) is closely associated with IBD, the role of biologics in PSC remains uncertain. Many new biologics are becoming available to treat IBD, and this review aims to use the experience of biologics in PSC so far to guide more effective evaluation of emerging therapies in the future. RECENT FINDINGS Antibodies to TNF-α were the first biologics used in IBD, and retrospective analysis suggests that they may have some benefit in PSC, even though an early randomised controlled trial (RCT) showed no effect. Mechanistic studies suggest that TNF-α may have a pathogenic role in PSC. An antibody to integrin α4β7 is effective in IBD, and there are emerging data on its effects in PSC, although no RCT data are available. Mechanistic studies suggest that interrupting the migration of lymphocytes is relevant in PSC. Two biologics, targeting vascular adhesion protein-1 (VAP-1), and lysyl oxidase-like 2 (LOXL2) have been tested in RCTs. The trial of anti-VAP1 is ongoing, whilst the anti-LOXL2 trial was negative. SUMMARY Anti-TNF antibodies may benefit PSC when used to treat concomitant IBD, and this may be a direct effect on the liver in a subgroup of patients, or may be an indirect effect of treating IBD. Similarly, anti-integrin therapy may benefit a subset of patients with IBD and PSC. RCTs could decide the role of emerging biologics in PSC, although future trials should be guided by biomarkers that could predict response to the pathway being targeted.
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Affiliation(s)
- Kate D. Lynch
- Translational Gastroenterology Unit, Nuffield Department of Medicine, Level 5, John Radcliffe Hospital, University of Oxford, Headley Way, Headington, Oxford, OX3 9DU UK
| | - Satish Keshav
- Translational Gastroenterology Unit, Nuffield Department of Medicine, Level 5, John Radcliffe Hospital, University of Oxford, Headley Way, Headington, Oxford, OX3 9DU UK
| | - Roger W. Chapman
- Translational Gastroenterology Unit, Nuffield Department of Medicine, Level 5, John Radcliffe Hospital, University of Oxford, Headley Way, Headington, Oxford, OX3 9DU UK
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12
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Dubé PE, Liu CY, Girish N, Washington MK, Polk DB. Pharmacological activation of epidermal growth factor receptor signaling inhibits colitis-associated cancer in mice. Sci Rep 2018; 8:9119. [PMID: 29904166 PMCID: PMC6002410 DOI: 10.1038/s41598-018-27353-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 05/30/2018] [Indexed: 12/15/2022] Open
Abstract
Current treatments for inflammatory bowel disease (IBD) target the overactive immune response of the intestinal mucosa. However, epidermal growth factor (EGF), an activating ligand of the EGF receptor (EGFR), has been shown to induce disease remission through direct targeting of intestinal mucosal healing. Despite promising preclinical and clinical results, this EGFR-activating therapy has not progressed, in part due to the potential for carcinogenesis associated with long-term use and the increased risk of colitis-associated cancer (CAC) in IBD. Here we tested whether pharmacological modulation of EGFR altered outcomes of CAC in the murine azoxymethane/dextran sulfate sodium model. We found that administering EGF during the period of maximum colitis severity ("early"), coincident with the initiation and early promotion of tumors, improved outcomes of colitis and reduced tumor size. In contrast, daily EGF administration beginning ~2 months after tumor initiation ("late") increased tumor size. Administration of the EGFR kinase inhibitor gefitinib increased the tumor size when the drug was given early and decreased the tumor size when the drug was administered late. EGF administration not only reduced colonic cytokine and chemokine expression during injury, but also baseline chemokine expression in homeostasis. These results suggest that EGFR activation during acute bouts of colitis may reduce the long-term burden of CAC.
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Affiliation(s)
- Philip E Dubé
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, CA, USA
- Taconic Biosciences, Hudson, NY, USA
| | - Cambrian Y Liu
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - Nandini Girish
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - M Kay Washington
- Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - D Brent Polk
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, CA, USA.
- Department of Biochemistry and Molecular Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA.
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Gisbert JP, Chaparro M. Ustekinumab to treat Crohn's disease. GASTROENTEROLOGIA Y HEPATOLOGIA 2017; 40:688-698. [PMID: 29042094 DOI: 10.1016/j.gastrohep.2017.08.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 08/21/2017] [Indexed: 12/14/2022]
Abstract
Ustekinumab is a monoclonal antibody directed against the p40 subunit, which is part of interleukins IL-12 and IL-23. The efficacy of ustekinumab versus placebo in terms of clinical response and remission of induction has been shown in phase3 clinical trials. When used as subcutaneous maintenance therapy, the therapeutic benefit of ustekinumab over placebo has been confirmed in both clinical response and remission in patients who have responded clinically to induction therapy. In addition, ustekinumab has demonstrated an improvement in mucosal healing parameters. The safety profile of the drug has been good, with low infection rates (without reactivation of tuberculosis) and absence of tumour reporting. The development of drug immunogenicity appears to be rare. In summary, ustekinumab is a promising treatment option in patients with Crohn's disease, as an alternative to anti-TNFα drugs.
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Affiliation(s)
- Javier P Gisbert
- Servicio de Aparato Digestivo, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid y Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España.
| | - María Chaparro
- Servicio de Aparato Digestivo, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid y Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España
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Anti-NKG2D mAb: A New Treatment for Crohn's Disease? Int J Mol Sci 2017; 18:ijms18091997. [PMID: 28926962 PMCID: PMC5618646 DOI: 10.3390/ijms18091997] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 08/24/2017] [Accepted: 09/11/2017] [Indexed: 01/09/2023] Open
Abstract
Crohn’s disease (CD) and ulcerative colitis (UC) are immunologically-mediated, debilitating conditions resulting from destructive inflammation of the gastrointestinal tract. The pathogenesis of IBD is incompletely understood, but is considered to be the result of an abnormal immune response with a wide range of cell types and proteins involved. Natural Killer Group 2D (NKG2D) is an activating receptor constitutively expressed on human Natural Killer (NK), γδ T, mucosal-associated invariant T (MAIT), CD56+ T, and CD8+ T cells. Activation of NKG2D triggers cellular proliferation, cytokine production, and target cell killing. Research into the NKG2D mechanism of action has primarily been focused on cancer and viral infections where cytotoxicity evasion is a concern. In human inflammatory bowel disease (IBD) this system is less characterized, but the ligands have been shown to be highly expressed during intestinal inflammation and the following receptor activation may contribute to tissue degeneration. A recent phase II clinical trial showed that an antibody against NKG2D induced clinical remission of CD in some patients, suggesting NKG2D and its ligands to be of importance in the pathogenesis of CD. This review will describe the receptor and its ligands in intestinal tissues and the clinical potential of blocking NKG2D in Crohn’s disease.
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15
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Yu Y, Song EM, Lee KE, Joo YH, Kim SE, Moon CM, Kim HY, Jung SA, Jo I. Therapeutic potential of tonsil-derived mesenchymal stem cells in dextran sulfate sodium-induced experimental murine colitis. PLoS One 2017; 12:e0183141. [PMID: 28854223 PMCID: PMC5576698 DOI: 10.1371/journal.pone.0183141] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Accepted: 07/23/2017] [Indexed: 02/06/2023] Open
Abstract
The therapeutic potential of tonsil-derived mesenchymal stem cells (TMSC) prepared from human tonsillar tissue has been studied in animal models for several diseases such as hepatic injury, hypoparathyroidism, diabetes and muscle dystrophy. In this study, we examined the therapeutic effects of TMSC in a dextran sulfate sodium (DSS)-induced colitis model. TMSC were injected in DSS-induced colitis mice via intraperitoneal injection twice (TMSC[x2]) or four times (TMSC[x4]). Control mice were injected with either phosphate-buffered saline or human embryonic kidney 293 cells. Body weight, stool condition and disease activity index (DAI) were examined daily. Colon length, histologic grading, and mRNA expression of pro-inflammatory cytokines, interleukin 1β (IL-1β), IL-6, IL-17 and tumor necrosis factor α, and anti-inflammatory cytokines, IL-10, IL-11 and IL-13, were also measured. Our results showed a significant improvement in survival rates and body weight gain in colitis mice injected with TMSC[x2] or TMSC[x4]. Injection with TMSC also significantly decreased DAI scores throughout the experimental period; at the end of experiment, almost complete reversal of DAI scores to normal was found in colitis mice treated with TMSC[x4]. Colon length was also significantly recovered in colitis mice treated with TMSC[x4]. However, histopathological alterations induced by DSS treatment were not apparently improved by injection with TMSC. Finally, treatment with TMSC[x4] significantly reversed the mRNA levels of IL-1β and IL-6, although expression of all pro-inflammatory cytokines tested was induced in colitis mice. Under our experimental conditions, however, no apparent alterations in the mRNA levels of all the anti-inflammatory cytokines tested were found. In conclusion, our findings demonstrate that multiple injections with TMSC produced a therapeutic effect in a mouse model of DSS-induced colitis.
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Affiliation(s)
- Yeonsil Yu
- Department of Molecular Medicine, College of Medicine, Ewha Womans University, Seoul, South Korea
| | - Eun Mi Song
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, South Korea
| | - Ko Eun Lee
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, South Korea
| | - Yang-Hee Joo
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, South Korea
| | - Seong-Eun Kim
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, South Korea
| | - Chang Mo Moon
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, South Korea
| | - Ha Yeong Kim
- Department of Molecular Medicine, College of Medicine, Ewha Womans University, Seoul, South Korea
| | - Sung-Ae Jung
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, South Korea
- * E-mail: (IJ); (SAJ)
| | - Inho Jo
- Department of Molecular Medicine, College of Medicine, Ewha Womans University, Seoul, South Korea
- * E-mail: (IJ); (SAJ)
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Short article: The effect of implementation of a treatment algorithm for infliximab on remission rates and drug costs in inflammatory bowel disease patients. Eur J Gastroenterol Hepatol 2017; 29:169-173. [PMID: 27749780 DOI: 10.1097/meg.0000000000000763] [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: 12/20/2022]
Abstract
INTRODUCTION The effective, but expensive, drug infliximab is used in patients with inflammatory bowel disease (IBD). Monitoring infliximab trough levels and anti-infliximab antibody (ATI) formation can lead to a more cost-effective use of infliximab therapy. The aim of our study was to investigate the effect of implementation of a treatment algorithm for infliximab in a single-centre IBD cohort, focussing on remission rates and drug costs. METHODS IBD patients aged 18 years or older treated with infliximab were asked to participate in this study. Remission rates were assessed using faecal calprotectin levels and a validated questionnaire. Infliximab trough levels and ATIs were determined at baseline and at the third infliximab infusion. According to the advice given by the treatment algorithm, infliximab dosage adjustments were performed at the second infliximab infusion. RESULTS Between January and December 2015 a total of 62 IBD patients in our centre were treated with infliximab, of whom 33 (53%) patients agreed to participate in this study. The number of patients in remission was 28 (85%) at baseline and there were 13 dose adaptations suggested by the treatment algorithm for the successive second infusion. Four patients possessed undetectable infliximab levels and positive ATI status at baseline. After the second infusion, there were 29 (88%) patients in remission at the third infusion. All of this resulted in an annual drug cost reduction of &OV0556;47 026 (7.4%). CONCLUSION Our developed treatment algorithm of infliximab led to optimization of infliximab therapy in IBD patients by increasing remission rates and reducing drug costs.
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17
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Kadivar M, Petersson J, Svensson L, Marsal J. CD8αβ+ γδ T Cells: A Novel T Cell Subset with a Potential Role in Inflammatory Bowel Disease. THE JOURNAL OF IMMUNOLOGY 2016; 197:4584-4592. [PMID: 27849165 DOI: 10.4049/jimmunol.1601146] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 10/13/2016] [Indexed: 01/27/2023]
Abstract
γδ T cells have been attributed a wide variety of functions, which in some cases may appear as contradictory. To better understand the enigmatic biology of γδ T cells it is crucial to define the constituting subpopulations. γδ T cells have previously been categorized into two subpopulations: CD8αα+ and CD8- cells. In this study we have defined and characterized a novel subset of human γδ T-cells expressing CD8αβ. These CD8αβ+ γδ T cells differed from the previously described γδ T cell subsets in several aspects, including the degree of enrichment within the gut mucosa, the activation status in blood, the type of TCRδ variant used in blood, and small but significant differences in their response to IL-2 stimulation. Furthermore, the novel subset expressed cytotoxic mediators and CD69, and produced IFN-γ and TNF-α. In patients with active inflammatory bowel disease the mucosal frequencies of CD8αβ+ γδ T cells were significantly lower as compared with healthy controls, correlated negatively with the degree of disease activity, and increased to normal levels as a result of anti-TNF-α therapy. In conclusion, our results demonstrate that CD8αβ+ γδ T cells constitute a novel lymphocyte subset, which is strongly enriched within the gut and may play an important role in gut homeostasis and mucosal healing in inflammatory bowel disease.
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Affiliation(s)
| | - Julia Petersson
- Immunology Section, Lund University, S-22184 Lund, Sweden; and
| | - Lena Svensson
- Immunology Section, Lund University, S-22184 Lund, Sweden; and
| | - Jan Marsal
- Immunology Section, Lund University, S-22184 Lund, Sweden; and .,Department of Gastroenterology, Skåne University Hospital, S-22185 Lund, Sweden
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Leung G, Papademetriou M, Chang S, Arena F, Katz S. Interactions Between Inflammatory Bowel Disease Drugs and Chemotherapy. ACTA ACUST UNITED AC 2016; 14:507-534. [DOI: 10.1007/s11938-016-0109-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Dziechciarz P, Horvath A, Kierkuś J. Efficacy and Safety of Adalimumab for Paediatric Crohn's Disease: A Systematic Review. J Crohns Colitis 2016; 10:1237-44. [PMID: 26995184 DOI: 10.1093/ecco-jcc/jjw077] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Accepted: 03/11/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIM Adalimumab is well-established therapy for adults with Crohn's disease [CD]. The aim of the study was to systematically assess the published evidence on the efficacy and safety of adalimumab for Crohn's disease in children. METHODS MEDLINE, EMBASE, the Cochrane Library, and abstracts from the main gastroenterological meetings in the past 5 years were systematically searched up to July 2015 for randomised controlled trials and observational studies on the efficacy and safety of adalimumab for Crohn's treatment in children and adolescents. RESULTS A total of 14 studies [1 randomised controlled trial, 13 case series], altogether including 664 patients [age: 1.9 to 21 years] were available for analysis. The studies differed with respect to patients' characteristics, including percentage of infliximab-naïve patients, disease duration, site of the disease, adalimumab doses, treatment duration, and follow-up period. The pooled remission rates were: 30% [n = 93/309] at 4 weeks, 54% [n = 79/145] at 3 months, 45% [n = 18/40] at 4 months, 42% [n = 146/345] at 6 months, 57% [n = 20/35] at 8 months, and 44% [n = 169/383] at 12 months. Of the total patients, 6% [n = 13/207] were classified as primary non-responders and 12% [n = 69/599] had severe adverse events reported including 2 deaths and 1 medulloblastoma. Withdrawal rate due to adverse events reported in one study was 35% [n = 64/182]. CONCLUSION According to low-quality evidence based mainly on case series, approximately half of children with Crohn's disease on adalimumab therapy achieve remission during the first year of the therapy with reasonable safety profile. There is still a need for high-quality evidence on effectiveness and safety of adalimumab for paediatric Crohn's disease.
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Affiliation(s)
- Piotr Dziechciarz
- Department of Paediatrics Medical University of Warsaw, Warsaw, Poland
| | - Andrea Horvath
- Department of Paediatrics Medical University of Warsaw, Warsaw, Poland
| | - Jaroslaw Kierkuś
- Department of Gastroenterology, Hepatology and Feeding Disorders, Child's Health Memorial Institute, Warsaw, Poland
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Vadstrup K, Galsgaard ED, Gerwien J, Vester-Andersen MK, Pedersen JS, Rasmussen J, Neermark S, Kiszka-Kanowitz M, Jensen T, Bendtsen F. Validation and Optimization of an Ex Vivo Assay of Intestinal Mucosal Biopsies in Crohn's Disease: Reflects Inflammation and Drug Effects. PLoS One 2016; 11:e0155335. [PMID: 27171179 PMCID: PMC4865152 DOI: 10.1371/journal.pone.0155335] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2016] [Accepted: 04/27/2016] [Indexed: 12/22/2022] Open
Abstract
Crohn’s disease (CD) is a chronic illness demanding better therapeutics. The marketed biologics only benefit some patients or elicit diminishing effect over time. To complement the known methods in drug development and to obtain patient specific drug responses, we optimized and validated a known human explant method to test drug candidates and pathophysiological conditions in CD intestinal biopsies. Mucosal biopsies from 27 CD patients and 6 healthy individuals were collected to validate an explant assay test where the polarized tissue was cultured on a novel metal mesh disk, slightly immersed in medium imitating an air-liquid interphase. After culture in high oxygen for 24 hours with or without biological treatment in the medium, biopsy integrity and penetration of antibodies was measured by immunohistochemistry (IHC). Nine cytokines were quantified in the conditioned medium as a read-out for degree of inflammation in individual biopsies and used to evaluate treatment efficacy. The biopsies were well-preserved, showing few structural changes. IHC revealed tissue penetration of antibodies demonstrating ability to test therapeutic antibodies. The cytokine release to the medium showed that the assay can distinguish between inflammation states and then validate the known effect of two treatment biologics confirmed by a detection panel of five specific cytokines. Our data also suggest that the assay would be able to indicate which patients are responders to anti-TNF-α therapeutics, and which are non-responders. This study demonstrates this version of an ex vivo culture as a valid and robust assay to assess inflammation in mucosal biopsies and test of the efficacy of novel drug candidates and current treatments on individual patients–potentially for a personalized medicine approach.
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Affiliation(s)
- Kasper Vadstrup
- Gastro Unit, Medical Division, Hvidovre University Hospital, Hvidovre, Denmark
- Faculty of Health Sciences, The Panum Institute, University of Copenhagen, Copenhagen N, Denmark
- Biopharmaceutical Research Unit, Novo Nordisk A/S, Maaloev, Denmark
- * E-mail:
| | | | - Jens Gerwien
- Biopharmaceutical Research Unit, Novo Nordisk A/S, Maaloev, Denmark
| | | | | | - Julie Rasmussen
- Gastro Unit, Medical Division, Hvidovre University Hospital, Hvidovre, Denmark
| | - Søren Neermark
- Gastro Unit, Medical Division, Hvidovre University Hospital, Hvidovre, Denmark
| | | | - Teis Jensen
- Biopharmaceutical Research Unit, Novo Nordisk A/S, Maaloev, Denmark
| | - Flemming Bendtsen
- Gastro Unit, Medical Division, Hvidovre University Hospital, Hvidovre, Denmark
- Faculty of Health Sciences, The Panum Institute, University of Copenhagen, Copenhagen N, Denmark
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Detrez I, Dreesen E, Van Stappen T, de Vries A, Brouwers E, Van Assche G, Vermeire S, Ferrante M, Gils A. Variability in Golimumab Exposure: A 'Real-Life' Observational Study in Active Ulcerative Colitis. J Crohns Colitis 2016; 10:575-81. [PMID: 26738756 PMCID: PMC4957447 DOI: 10.1093/ecco-jcc/jjv241] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 12/18/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Golimumab has been approved recently to treat refractory moderate-to-severe ulcerative colitis [UC]. To date it is not clear why a considerable fraction of patients do not respond, or lose initial response, to golimumab therapy. Our aim was to investigate whether a low golimumab serum concentration and/or a positive anti-golimumab antibody status reduces the efficacy of this drug in patients with UC. METHODS Serum samples of 21 patients with moderate-to-severe UC were collected during the first 14 weeks of golimumab therapy. For measurement of golimumab serum concentrations, both a tumour necrosis factor [TNF]-coated enzyme-linked immunosorbent assay [ELISA] and a sandwich-type ELISA were developed. Anti-golimumab antibodies were measured using a bridging ELISA and a newly-developed drug-tolerant immunoassay. Clinical response and mucosal healing were assessed 14 weeks after start of treatment. RESULTS Out of 21 patients, 10 [48%] reached partial clinical response at Week 14. Median [interquartile range] serum golimumab concentration was significantly higher in partial clinical responders than in non-responders: 10.0 [7.8-10.5] µg/ml versus 7.4 [4.8-8.3] µg/ml at Week 2 [p = 0.035] and 5.1 [4.0-7.9] µg/ml versus 2.1 [1.8-4.2] µg/ml at week 6 [p = 0.037]. Four out of 21 UC patients developed anti-golimumab antibodies, detectable only using a drug-tolerant immunoassay, and three had a partial clinical response at that time. Clinical non-responders had a significantly more severe colitis, indicated by a higher endoscopic Mayo score at baseline compared with partial clinical responders [p = 0.048]. CONCLUSION Adequate exposure to golimumab drives clinical response. A worse disease at baseline influences clinical response rate negatively.
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Affiliation(s)
- Iris Detrez
- Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Therapeutic and Diagnostic Antibodies, KU Leuven, Leuven, Belgium
| | - Erwin Dreesen
- Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Therapeutic and Diagnostic Antibodies, KU Leuven, Leuven, Belgium
| | - Thomas Van Stappen
- Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Therapeutic and Diagnostic Antibodies, KU Leuven, Leuven, Belgium
| | - Annick de Vries
- Sanquin Diagnostic Services, Biologicals Laboratory, Amsterdam, The Netherlands
| | - Els Brouwers
- Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Therapeutic and Diagnostic Antibodies, KU Leuven, Leuven, Belgium
| | - Gert Van Assche
- Department of Gastroenterology, Translational Research in Gastrointestinal Disorders, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Department of Gastroenterology, Translational Research in Gastrointestinal Disorders, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Marc Ferrante
- Department of Gastroenterology, Translational Research in Gastrointestinal Disorders, University Hospitals Leuven, KU Leuven, Leuven, Belgium,Joint senior authors
| | - Ann Gils
- Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Therapeutic and Diagnostic Antibodies, KU Leuven, Leuven, Belgium,Joint senior authors
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Kolios G. Bin1 Antibodies for IBD Therapy: Is Permeability the Answer BAR None? Dig Dis Sci 2016; 61:330-1. [PMID: 26694171 DOI: 10.1007/s10620-015-3997-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
- George Kolios
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, Dragana, 68100, Alexandroupolis, Greece.
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Chidrawar VR. Exploiting the role of various types of ion-channels against chemically induced inflammatory bowel disease in male Wistar rats. ASIAN PACIFIC JOURNAL OF TROPICAL DISEASE 2016. [DOI: 10.1016/s2222-1808(15)60992-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Isaacs JD, Cutolo M, Keystone EC, Park W, Braun J. Biosimilars in immune-mediated inflammatory diseases: initial lessons from the first approved biosimilar anti-tumour necrosis factor monoclonal antibody. J Intern Med 2016; 279:41-59. [PMID: 26403380 DOI: 10.1111/joim.12432] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The introduction of targeted biological therapies has revolutionised the management of immune-mediated inflammatory diseases (IMIDs) such as rheumatoid arthritis, ankylosing spondylitis, psoriasis and inflammatory bowel disease. Following treatment with these therapies, many patients experience significant improvements in different aspects of their disease, including symptoms, work productivity and other outcomes relevant for individuals and society. However, due to the complexity of biological drug development and manufacturing processes, the costs of these therapies are relatively high. Indeed, the financial burden on healthcare systems due to biological therapies is considerable and lack of patient access to effective treatment remains a concern in many parts of the world. As many reference biological therapies have now reached or are near to patent expiry, a number of 'biosimilar' drugs have been developed for use in various clinical settings, and some of these drugs are already in use in several countries. While the potential pharmacoeconomic benefits of cost-effective biosimilars seem clear, several issues have been raised regarding, for example, the definition of biosimilarity and the validity of indication extrapolation, as well as the 'switchability' and relative immunogenicity of biosimilars and their reference drugs. In this review, these issues will be discussed with reference to CT-P13, a biosimilar of the anti-tumour necrosis factor monoclonal antibody infliximab, which is approved in Europe and elsewhere for the treatment of various IMIDs. Other important issues, including those related to data collection during nonclinical and clinical development of biosimilars, are also discussed.
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Affiliation(s)
- J D Isaacs
- Institute of Cellular Medicine, NIHR Newcastle Biomedical Research Centre, Newcastle Hospitals NHS Trust and Newcastle University, Newcastle upon Tyne, UK
| | - M Cutolo
- Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - E C Keystone
- Division of Rheumatology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - W Park
- Division of Rheumatology, Department of Internal Medicine, Inha University Hospital, Incheon, Republic of Korea
| | - J Braun
- Rheumazentrum Ruhrgebiet, Herne, Germany
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25
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Moon W. Golimumab Therapy in Ulcerative Colitis. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2016; 67:64-73. [DOI: 10.4166/kjg.2016.67.2.64] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- Won Moon
- Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea
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Klare P, Nigg J, Nold J, Haller B, Krug AB, Mair S, Thoeringer CK, Christle JW, Schmid RM, Halle M, Huber W. The impact of a ten-week physical exercise program on health-related quality of life in patients with inflammatory bowel disease: a prospective randomized controlled trial. Digestion 2015; 91:239-47. [PMID: 25823689 DOI: 10.1159/000371795] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Accepted: 12/30/2014] [Indexed: 02/04/2023]
Abstract
BACKGROUND Improving health-related quality of life is a primary target of therapy for patients with inflammatory bowel disease. Physical activity has been demonstrated to improve health-related quality of life in several patient populations with chronic disease. There are very few studies investigating the effects of physical activity on health-related quality of life in inflammatory bowel disease. The primary purpose of this study is to investigate the effects of 10 weeks of moderate physical activity on health-related quality of life in patients with inflammatory bowel disease. METHODS Thirty patients with mild to moderate IBD (Crohn's Disease Activity Index (CDAI) <220 or Rachmilewitz Index (RI) <11) were randomized 1:1 to either supervised moderate-intensity running thrice a week for 10 weeks or a control group who were not prescribed any exercise. Health-related quality of life, symptoms, and inflammation were assessed at baseline and after 10 weeks. RESULTS Participants were 41 ± 14 years (73% female), had a body mass index of 22.8 ± 4.1 kg/m(2), and an average CDAI or RI of 66.8 ± 42.4 and 3.6 ± 3.1. No adverse events occurred during the 10-week training period. Health-related quality of life, reported as IBDQ total score, improved 19% in the intervention group and 8% in the control group. Scores for the IBDQ social sub-scale were significantly improved in the intervention group compared with controls (ΔIBDQsocial = 6.27 ± 5.46 vs. 1.87 ± 4.76, p = 0.023). CONCLUSION Patients suffering from moderately active IBD are capable of performing symptom-free regular endurance exercise. Our data support the assumption that PA is feasible in IBD patients. PA may furthermore improve quality of life through improvements in social well-being, and may, therefore, be a useful adjunct to IBD therapy.
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Affiliation(s)
- Peter Klare
- II. Medizinische Klinik, Klinikum rechts der Isar, Technischen Universität München, München, Germany
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Diallyl trisulfide inhibits naphthalene-induced oxidative injury and the production of inflammatory responses in A549 cells and mice. Int Immunopharmacol 2015; 29:326-333. [DOI: 10.1016/j.intimp.2015.10.033] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Revised: 10/20/2015] [Accepted: 10/29/2015] [Indexed: 12/24/2022]
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Krauss AH, Corrales RM, Pelegrino FSA, Tukler-Henriksson J, Pflugfelder SC, de Paiva CS. Improvement of Outcome Measures of Dry Eye by a Novel Integrin Antagonist in the Murine Desiccating Stress Model. Invest Ophthalmol Vis Sci 2015; 56:5888-95. [PMID: 26348638 DOI: 10.1167/iovs.15-17249] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
PURPOSE We investigated the effects of GW559090, a novel, competitive, and high-affinity α4 integrin antagonist, in a murine model of dry eye. Through interaction with vascular cell adhesion molecule 1 (VCAM-1) and fibronectin α4β1 integrin is involved in leukocyte trafficking and activation. METHODS Female C57BL/6 mice, aged 6 to 8 weeks, were subjected to desiccating stress (DS). Bilateral topical twice daily treatment with GW559090 was compared to vehicle-treated controls. Treatment was initiated at the time of DS induction. Treatment effects were assessed on corneal staining with Oregon Green Dextran (OGD) and expression of inflammatory markers in ocular surface tissues by real time PCR. Dendritic cell activation was measured in draining cervical lymph nodes (CLN) by flow cytometry. Separate groups of mice received GW559090 subcutaneously to evaluate the effects of systemic administration on corneal staining and cells in CLN. RESULTS Topical GW559090 significantly reduced corneal uptake of OGD compared to vehicle-treated disease controls in a dose-dependent manner (1, 3, 10, and 30 mg/mL) with 30 mg/mL showing the greatest reduction in OGD staining. When administered topically, corneal expression of IL-1α, matrix metalloproteinase (MMP)-9, chemokine ligand 9 (CXCL9), and TGF-β1 was reduced in GW559090-treated eyes. Topical treatment with GW559090 decreased dendritic cell activation in lymph nodes. The effects on corneal staining and cellular composition in CLN were not reproduced by systemic administration of GW559090, suggestive of a local role for integrin antagonism in the treatment of dry eye. CONCLUSION The novel α4 integrin antagonist, GW559090, improved outcome measures of corneal staining and ocular surface inflammation in this murine model of dry eye. These results indicate the potential of this novel agent for the treatment of dry eye disease.
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Affiliation(s)
- Achim H Krauss
- GSK Ophthalmology King of Prussia, Pennsylvania, United States
| | - Rosa M Corrales
- Ocular Surface Center, Cullen Eye Institute, Deptartment of Ophthalmology, Baylor College of Medicine, Houston, Texas, United States
| | - Flavia S A Pelegrino
- Ocular Surface Center, Cullen Eye Institute, Deptartment of Ophthalmology, Baylor College of Medicine, Houston, Texas, United States
| | - Johanna Tukler-Henriksson
- Ocular Surface Center, Cullen Eye Institute, Deptartment of Ophthalmology, Baylor College of Medicine, Houston, Texas, United States
| | - Stephen C Pflugfelder
- Ocular Surface Center, Cullen Eye Institute, Deptartment of Ophthalmology, Baylor College of Medicine, Houston, Texas, United States
| | - Cintia S de Paiva
- Ocular Surface Center, Cullen Eye Institute, Deptartment of Ophthalmology, Baylor College of Medicine, Houston, Texas, United States
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Wei P, Yang Y, Ding Q, Li X, Sun H, Liu Z, Huang J, Gong Y. Oral delivery of Bifidobacterium longum expressing α-melanocyte-stimulating hormone to combat ulcerative colitis. J Med Microbiol 2015; 65:160-168. [PMID: 26567174 DOI: 10.1099/jmm.0.000197] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
α-Melanocyte-stimulating hormone (α-MSH) is a tridecapeptide derived from pro-opiomelanocortin that exhibits potent anti-inflammatory properties by regulating the production of inflammatory mediators. This peptide has been well established in several inflammatory models, including inflammatory bowel disease (IBD). However, its extremely short duration in vivo limits its clinical application. To address this limitation, Bifidobacterium was used here as a carrier to deliver α-MSH. We utilized α-MSH-engineered Bifidobacterium against IBD, which is closely linked to immune and intestinal microbiota dysfunction. First, we constructed a Bifidobacterium longum secreting α-MSH (B. longum-α-MSH). We then tested the recombinant α-MSH expression and determined its bioactivity in HT-29 cells. To assess its effectiveness, B. longum-α-MSH was used against an ulcerative colitis (UC) model in rats induced by dextran sulfate sodium. The data showed that α-MSH expression in B. longum-α-MSH was effective, and its biological activity was similar to the synthesized one. This UC model experiment indicated that B. longum-α-MSH successfully colonized the intestinal gut, expressed bioactive α-MSH and had a significant anti-inflammatory effect. The results demonstrate the feasibility of preventing IBD by using B. longum-α-MSH.
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Affiliation(s)
- Pijin Wei
- Institute of Genomic Medicine Research, College of Pharmacy, Jinan University, Guangzhou, 510632, PR China
| | - Yan Yang
- Institute of Genomic Medicine Research, College of Pharmacy, Jinan University, Guangzhou, 510632, PR China
| | - Qing Ding
- Institute of Genomic Medicine Research, College of Pharmacy, Jinan University, Guangzhou, 510632, PR China
| | - Xiuying Li
- Institute of Genomic Medicine Research, College of Pharmacy, Jinan University, Guangzhou, 510632, PR China
| | - Hanxiao Sun
- Institute of Genomic Medicine Research, College of Pharmacy, Jinan University, Guangzhou, 510632, PR China
| | - Zhaobing Liu
- Institute of Genomic Medicine Research, College of Pharmacy, Jinan University, Guangzhou, 510632, PR China
| | - Junli Huang
- Institute of Genomic Medicine Research, College of Pharmacy, Jinan University, Guangzhou, 510632, PR China
| | - Yahui Gong
- Institute of Genomic Medicine Research, College of Pharmacy, Jinan University, Guangzhou, 510632, PR China
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Gómez-Gómez GJ, Masedo &A, Yela C, Martínez-Montiel MDP, Casís B. Current stage in inflammatory bowel disease: What is next? World J Gastroenterol 2015; 21:11282-11303. [PMID: 26525013 PMCID: PMC4616205 DOI: 10.3748/wjg.v21.i40.11282] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 07/12/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
In recent years, the incidence of inflammatory bowel disease (IBD) has been on the rise, extending to countries where it was infrequent in the past. As a result, the gap between high and low incidence countries is decreasing. The disease, therefore, has an important economic impact on the healthcare system. Advances in recent years in pharmacogenetics and clinical pharmacology have allowed for the development of treatment strategies adjusted to the patient profile. Concurrently, new drugs aimed at inflammatory targets have been developed that may expand future treatment options. This review examines advances in the optimization of existing drug treatments and the development of novel treatment options for IBD.
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Abstract
PURPOSE OF REVIEW Many patients with psoriatic arthritis (PsA) have additional medical problems that can have an impact on morbidity and mortality. The goal of this review is to summarize the available evidence to date on the association of medical comorbidities with PsA and the implications these comorbidities have on prognosis, therapy selection and treatment response. RECENT FINDINGS Cardiovascular disease, metabolic syndrome, obesity, diabetes, fatty liver disease Crohn's disease, ophthalmic disease, depression and anxiety are common comorbidities associated with PsA. Additional comorbidities may include an elevated risk for malignancy and osteoporosis; however, fewer studies have addressed these issues and the data available are sometimes conflicting. SUMMARY All clinicians caring for patients with PsA should be aware of the relevant comorbidities affecting patients with PsA and should have an understanding of how these comorbidities affect management.
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Ward MM, Deodhar A, Akl EA, Lui A, Ermann J, Gensler LS, Smith JA, Borenstein D, Hiratzka J, Weiss PF, Inman RD, Majithia V, Haroon N, Maksymowych WP, Joyce J, Clark BM, Colbert RA, Figgie MP, Hallegua DS, Prete PE, Rosenbaum JT, Stebulis JA, van den Bosch F, Yu DTY, Miller AS, Reveille JD, Caplan L. American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis Rheumatol 2015; 68:282-98. [PMID: 26401991 DOI: 10.1002/art.39298] [Citation(s) in RCA: 300] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 07/21/2015] [Indexed: 12/15/2022]
Abstract
OBJECTIVE To provide evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS A core group led the development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946-2014), PubMed (1966-2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework. RESULTS In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS. CONCLUSION These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas.
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Affiliation(s)
- Michael M Ward
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland
| | | | - Elie A Akl
- American University of Beirut, Beirut, Lebanon, and McMaster University, Hamilton, Ontario, Canada
| | | | - Joerg Ermann
- Brigham and Women's Hospital, Boston, Massachusetts
| | | | | | | | | | - Pamela F Weiss
- Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia
| | | | | | | | | | - Janet Joyce
- American College of Rheumatology, Atlanta, Georgia
| | | | - Robert A Colbert
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland
| | | | | | - Pamela E Prete
- VA Long Beach Medical Center, Long Beach, California, and University of California, Irvine
| | - James T Rosenbaum
- Oregon Health & Science University and Legacy Devers Eye Institute, Portland
| | | | | | | | - Amy S Miller
- American College of Rheumatology, Atlanta, Georgia
| | | | - Liron Caplan
- Denver VA Medical Center, Denver, Colorado, and University of Colorado, Aurora
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Ward MM, Deodhar A, Akl EA, Lui A, Ermann J, Gensler LS, Smith JA, Borenstein D, Hiratzka J, Weiss PF, Inman RD, Majithia V, Haroon N, Maksymowych WP, Joyce J, Clark BM, Colbert RA, Figgie MP, Hallegua DS, Prete PE, Rosenbaum JT, Stebulis JA, Van Den Bosch F, Yu DTY, Miller AS, Reveille JD, Caplan L. American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis Care Res (Hoboken) 2015; 68:151-66. [PMID: 26401907 DOI: 10.1002/acr.22708] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 07/21/2015] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To provide evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS A core group led the development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946-2014), PubMed (1966-2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework. RESULTS In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS. CONCLUSION These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas.
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Affiliation(s)
- Michael M Ward
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland
| | | | - Elie A Akl
- American University of Beirut, Beirut, Lebanon, and McMaster University, Hamilton, Ontario, Canada
| | | | - Joerg Ermann
- Brigham and Women's Hospital, Boston, Massachusetts
| | | | | | | | | | - Pamela F Weiss
- Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia
| | | | | | | | | | - Janet Joyce
- American College of Rheumatology, Atlanta, Georgia
| | | | - Robert A Colbert
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland
| | | | | | - Pamela E Prete
- VA Long Beach Medical Center, Long Beach, California, and University of California, Irvine
| | - James T Rosenbaum
- Oregon Health & Science University and Legacy Devers Eye Institute, Portland
| | | | | | | | - Amy S Miller
- American College of Rheumatology, Atlanta, Georgia
| | | | - Liron Caplan
- Denver VA Medical Center, Denver, Colorado, and University of Colorado, Aurora
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Abstract
Epidemiologic studies have shown that, in patients with psoriatic arthritis (PsA), associated comorbidities may occur more frequently than expected. This article discusses related comorbidities in patients with PsA. Identifying these comorbidities may affect the management and treatment decisions for these patients to ensure an optimal clinical outcome. All health care providers caring for patients with PsA should be aware of the relevant comorbidities and should have an understanding of how these comorbidities affect management. The common comorbidities include cardiovascular disease, metabolic syndrome, obesity, diabetes, fatty liver disease, inflammatory bowel disease, ophthalmic disease, kidney disease, osteoporosis, depression, and anxiety.
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High Spatiotemporal Resolution Dynamic Contrast-Enhanced MR Enterography in Crohn Disease Terminal Ileitis Using Continuous Golden-Angle Radial Sampling, Compressed Sensing, and Parallel Imaging. AJR Am J Roentgenol 2015; 204:W663-9. [PMID: 26001254 DOI: 10.2214/ajr.14.13674] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE The purpose of this article was to assess the feasibility of golden-angle radial acquisition with compress sensing reconstruction (Golden-angle RAdial Sparse Parallel [GRASP]) for acquiring high temporal resolution data for pharmacokinetic modeling while maintaining high image quality in patients with Crohn disease terminal ileitis. MATERIALS AND METHODS Fourteen patients with biopsy-proven Crohn terminal ileitis were scanned using both contrast-enhanced GRASP and Cartesian breath-hold (volume-interpolated breath-hold examination [VIBE]) acquisitions. GRASP data were reconstructed with 2.4-second temporal resolution and fitted to the generalized kinetic model using an individualized arterial input function to derive the volume transfer coefficient (K(trans)) and interstitial volume (v(e)). Reconstructions, including data from the entire GRASP acquisition and Cartesian VIBE acquisitions, were rated for image quality, artifact, and detection of typical Crohn ileitis features. RESULTS Inflamed loops of ileum had significantly higher K(trans) (3.36 ± 2.49 vs 0.86 ± 0.49 min(-1), p < 0.005) and v(e) (0.53 ± 0.15 vs 0.20 ± 0.11, p < 0.005) compared with normal bowel loops. There were no significant differences between GRASP and Cartesian VIBE for overall image quality (p = 0.180) or detection of Crohn ileitis features, although streak artifact was worse with the GRASP acquisition (p = 0.001). CONCLUSION High temporal resolution data for pharmacokinetic modeling and high spatial resolution data for morphologic image analysis can be achieved in the same acquisition using GRASP.
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Vedolizumab en el tratamiento de la enfermedad de Crohn. GASTROENTEROLOGIA Y HEPATOLOGIA 2015; 38:338-48. [DOI: 10.1016/j.gastrohep.2014.12.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Accepted: 12/05/2014] [Indexed: 12/22/2022]
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Perrillo RP, Gish R, Falck-Ytter YT. American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology 2015; 148:221-244.e3. [PMID: 25447852 DOI: 10.1053/j.gastro.2014.10.038] [Citation(s) in RCA: 387] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Robert P Perrillo
- Hepatology Division, Baylor University Medical Center, Department of Medicine, University of Texas Southwestern, Dallas, Texas
| | - Robert Gish
- Division of Gastroenterology and Hepatology, Department of Medicine,Stanford University, Palo Alto, California; Hepatitis B Foundation, Doylestown, Pennsylvania
| | - Yngve T Falck-Ytter
- Division of Gastroenterology and Hepatology, Department of Medicine, Case and VA Medical Center, Case Western Reserve University, Cleveland, Ohio
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Stone RH, Hong J, Jeong H. Pharmacokinetics of monoclonal antibodies used for inflammatory bowel diseases in pregnant women. ACTA ACUST UNITED AC 2014; 4. [PMID: 26539323 DOI: 10.4172/2161-0495.1000209] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Inflammatory bowel disease (IBD) is a condition of chronic immune response and inflammation of the gastrointestinal tract. Most women with IBD are affected during their reproductive years, and untreated IBD can have detrimental maternal and fetal outcomes. In recent years, many biological therapies including anti-TNF agents (infliximab, adalimumab, and certolizumab) have been developed for the treatment of IBD. An increasing number of IBD patients are treated with these agents during pregnancy. Sporadic reports suggest an absence of negative pregnancy outcomes related to use of anti-TNF agents in women with IBD. However, it is unclear if the physiological changes occurring in pregnancy alter mAb dose requirements for optimal maternal disease management and minimal fetal exposure to therapeutic antibodies. Based on current understanding of the pharmacokinetic profiles for anti-TNF agents in nonpregnant subjects, it appears very likely that physiological changes accompanying pregnancy can alter pharmacokinetics of anti-TNF agents. This review focuses on how such physiological changes may impact disposition of anti-TNF agents during pregnancy. Further improvement in pregnancy outcomes may be achieved in women with IBD by better understanding of pregnancy-mediated changes in the pharmacokinetics of anti-TNF agents.
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Affiliation(s)
- Rebecca H Stone
- Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA
| | - James Hong
- Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA
| | - Hyunyoung Jeong
- Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA ; Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA
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