Positioning biologics in the treatment of IBD: A practical guide - Which mechanism of action for whom?

The number of available biological therapies have doubled over the last 10 years and the arrival of novel molecules (interleukin 23p19 inhibitors) is ongoing alongside the development of small molecules. As a result of this vast landscape of treatment, positioning advanced therapies (according to clinical situation, efficacy and safety) is of paramount importance to providing personalized, appropriate IBD treatment. In this publication the recent available literature is summarized for practical integration into clinical practice including comparative efficacy data, patient and disease demographics. We refer to recent publications and expert opinion in order to facilitate the decision making process of positioning biologicals IBD treatment

Utilizing Patient-Reported Outcome Measures in the Management of Inflammatory Bowel Disease

Inflammatory bowel disease, a chronic relapsing-remitting disorder, affects three million adults in the United States. One of the main therapeutic goals in patients with inflammatory bowel disease is mucosal healing, measured by endoscopy, an invasive procedure that does not always reflect patient symptomatology. To address these limitations, clinicians have developed patient-reported outcome measures, questionnaires evaluating bowel symptoms and quality of life. However, the clinical utility of these patient-reported outcome measures and their correlation to objective markers of inflammation is unclear. We will determine the efficacy of using a patient-reported outcome measure to inform treatment for inflammatory bowel disease. In a randomized clinical trial, we will compare disease metrics of patients receiving treatment guided by a patient-reported outcome measure compared to those of patients receiving standard treatment. This study will confirm the utility of patient-reported outcome measures, revolutionizing inflammatory bowel disease treatment and transitioning the field towards patient-centered care

Evaluation of anti-TNF therapeutic response in patients with inflammatory bowel disease : Current and novel biomarkers

publishedVersio

The use of unlicensed bone marrow-derived platelet lysate-expanded mesenchymal stromal cells in colitis : a pre-clinical study

Background: Mesenchymal stromal cells (MSCs) are a promising candidate for treatment of inflammatory disorders, but their efficacy in human inflammatory bowel diseases (IBDs) has been inconsistent. Comparing the results from various preclinical and clinical IBD studies is also challenging due to a large variation in study designs. Methods: In this comparative pre-clinical study, we compared two administration routes and investigated the safety and feasibility of both fresh and cryo-preserved platelet-lysate-expanded human bone marrow-derived MSCs without additional licensing in a dextran sodium sulfate (DSS) colitis mouse model both in the acute and regenerative phases of colitis. Body weight, macroscopic score for inflammation and colonic interleukin (IL)-1 beta and tumor necrosis factor (TNF)alpha concentrations were determined in both phases of colitis. Additionally, histopathology was assessed and Il-1 beta and Agtr1a messenger RNA (mRNA) levels and angiotensin-converting enzyme (ACE) protein levels were measured in the colon in the regenerative phase of colitis. Results: Intravenously administered MSCs exhibited modest anti-inflammatory capacity in the acute phase of colitis by reducing IL-1 beta protein levels in the inflamed colon. There were no clear improvements in mice treated with fresh or cryopreserved unlicensed MSCs according to weight monitoring results, histopathology and macroscopic score results. Pro-inflammatory ACE protein expression and shedding were reduced by cryopreserved MSCs in the colon. Conclusions: In conclusion, we observed a good safety profile for bone marrow-derived platelet lysate-expanded MSCs in a mouse pre-clinical colitis model, but the therapeutic effect of MSCs prepared without additional licensing (i.e. such as MSCs are administered in graft-versus-host disease) was modest in the chosen in vivo model system and limited to biochemical improvements in cytokines without a clear benefit in histopathology or body weight development.Peer reviewe

Future Therapeutic Approaches for Inflammatory Bowel Diseases

In this review, we speculate about future therapeutic approaches for inflammatory bowel diseases (IBDs), focusing on the need for better preclinical and clinical models and approaches beyond small molecules and systemically administered biologics. We offer ideas to change clinical trial programs and to use immunologic and genetic biomarkers to personalize medicine. We attempt to reconcile past therapeutic successes and failures to improve future approaches. Some of our ideas might be provocative, but we hope that the examples we provide will stimulate discussion about what will advance the field of IBD therapy

Harnessing machine learning to personalize web-based health care content

Web-based health care content has emerged as a primary source for patients to access health information without direct guidance from health care providers. The benefit of this approach is dependent on the ability of patients to access engaging high-quality information, but significant variability in the quality of web-based information often forces patients to navigate large quantities of inaccurate, incomplete, irrelevant, or inaccessible content. Personalization positions the patient at the center of health care models by considering their needs, preferences, goals, and values. However, the traditional methods used thus far in health care to determine the factors of high-quality content for a particular user are insufficient. Machine learning (ML) uses algorithms to process and uncover patterns within large volumes of data to develop predictive models that automatically improve over time. The health care sector has lagged behind other industries in implementing ML to analyze user and content features, which can automate personalized content recommendations on a mass scale. With the advent of big data in health care, which builds comprehensive patient profiles drawn from several disparate sources, ML can be used to integrate structured and unstructured data from users and content to deliver content that is predicted to be effective and engaging for patients. This enables patients to engage in their health and support education, self-management, and positive behavior change as well as to enhance clinical outcomes

PRN OPINION PAPER: Application of precision medicine across pharmacy specialty areas

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149551/1/jac51107_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149551/2/jac51107.pd

Development of Novel Therapies for the Treatment of Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic and remittent inflammation of the gastrointestinal tract (GIT). Despite extensive research efforts, there is no cure nor a well-defined pathogenesis for IBD. Loss of epithelial barrier function, increased colonic immune cell infiltration and upregulation of pro-inflammatory cytokines are the hallmarks of IBD. Despite treatments like painkillers, aminosalicylates, steroids, and biologics, almost 70% patients require surgery at least once in their life time. The main limitation with most of the current treatments is they are either absorbed systemically or administered systemically resulting in adverse side effects. As a result, there is a huge unmet need for therapies that can be safely and locally delivered to treat inflammation. Chloroquine (CQ) has been used as an anti-malarial for a long time and recently it has found anti-inflammatory applications. However, long term administration of CQ results in severe side effects like retinopathy because of systemic absorption. In this dissertation, we have re-designed CQ into a polymer (pCQ) and evaluated its potential as an orally administered IBD therapeutic. We found that pCQ showed preferential localization in the GIT which almost negligible systemic levels. We further evaluated the anti-inflammatory activity of pCQ in a mouse model of IBD and found reduction in colon v inflammation. We achieved this while reducing the systemic absorption almost 100 times which translates into an increased safety profile. We then assessed the effect of local delivery of combination of TNFα siRNA and polymeric CXCR4 antagonist (PCXA) via chitosan (CS) nanoparticles (NPs) in vivo. We found that the particles not only demonstrated a desirable size but also protected the siRNA against biorelevant conditions which are usually encountered in the GIT. Our results also indicate uptake of these particles by macrophages which are target cells and infiltrated the inflamed colon tissue in IBD. We tested the particles in vivo in a mouse model of colitis. We observed the therapeutic effect due to CXCR4 inhibition as well as observed TNFα silencing in the colon. Both these systems showed promise as local anti-inflammatory therapies. However, further development is needed to enhance their anti-IBD potential

Molecular serum portraits - A step towards personalized medicine

Antibody microarray technology has the potential for playing a large roll in identifying serological biomarker panels for personalized medicine. The aim of this thesis, based on four original papers, was to investigate if information in the serum proteome could be extracted and used for diagnostic, classificational, prognostic or treatment predictive purposes in a range of diseases. In two studies (paper I and paper IV), the diagnosis and prognosis of breast cancer was addressed, also being the main focus of this thesis. In paper I, we identified a biomarker panel capable of stratifying serum samples from metastatic breast cancer patients from those of healthy controls. In paper IV, another panel, pre-validated in the same study, was deciphered that could be used to identify patients destined for metastatic disease in a group of newly diagnosed breast cancer patients. Paper II and III targeted immunotherapy of glioblastoma multiforme and the diagnosis and sub- stratification of two autoimmune diseases (SLE and SSc), respectively. Also in these cases, multiple biomarker panels were identified, each capable of separating predefined cohorts of patients with relevance for applications within personalized medicine. In conclusion, this thesis introduces the concept of personalized medicine; details the antibody microarray technology in general and the platform used for the experiments in paper I to IV; and describes the subsequent microarray data analysis

Supplement: Abstracts from Rambam Research Day, December 29, 2011

(Excerpt) This Supplement of the Rambam Maimonides Medical Journal presents the abstracts from Rambam Research Day. These abstracts represent the newest basic and clinical research coming out of Rambam Health Care Campus—research that is the oxygen for education and development of today‘s generation of physicians. Hence, the research presented on Rambam Research Day is a foundation for future generations to understand patient needs and improve treatment modalities. Bringing research from the bench to the bedside and from the bedside to the community is at the heart of Maimonides‘ scholarly and ethical legacy. We hope you will appreciate the potential represented in these abstracts, which touch on nearly every aspect of clinical practice