Special Issue "Ulcerative Colitis: Current and Emerging Treatment Strategies"

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Gastroenterology & Hepatopancreatobiliary Medicine".

Deadline for manuscript submissions: closed (15 May 2020).

Special Issue Editor

Prof. Dr. Sandro Ardizzone
Website
Guest Editor
Gastrointestinal Unit, ASST Fatebenefratelli Sacco—Department of Biochemical and Clinical Sciences "L. Sacco", University of Milan, 20157 Milano, Italy
Interests: inflammatory bowel disease; digestive endoscopy; Immunomediate; inflammatory disease
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Special Issue Information

Dear Colleagues,

Ulcerative colitis (UC) is one of the two forms of inflammatory bowel disease (IBD) with a high prevalence in Western countries, whose incidence is gradually increasing in newly industrialised countries in Africa, Asia, and South America. For many years salicylates, systemic and topical steroids and immunosuppressants were the cornerstones of UC drug therapy, without however significantly affecting the clinical course of the disease and, above all, without impacting its natural history.

Although its etiology is unknown, in the last 20 years considerable progress has been made in understanding its complex pathogenesis. In particular, the identification of specific cytokines (TNFa, integrins, etc) has allowed us to define specific therapeutic targets and the relative production of anti-TNFa monoclonal antibodies (infliximab, adalimumab, golimumab) and anti-integrins (vedolizumab) , currently available in Europe and North America.

However, although these therapies have allowed us to effectively treat a larger patient audience with "difficult" UC, such as steroid-dependent patients, steroid-refractoriness, and extraintestinal manifestations, there are still various unmet needs, such as failure or loss of response, and the increased risk, albeit mild, of infections or neoplasia, which require further pharmacological treatments that are possibly faster, more effective and safe. Thus, particular emphasis tends to be placed on some of the most recent biological therapies, which are proving promising in the treatment of IBD, with therapeutic target alternatives to the selective blocking of specific cytokines, such as interleukin 12/23 and SMAD7 inhibitors, and low molecular weight drugs (small molecule drugs (SMDs)), such as inhibitors of JAK kinases, sphingosine 1 phosphate (S1P) and phosphodiesterase 4. Furthermore, particular interest is also placed on cell-based therapies (stem cell transplantation). 

Considering, therefore, the progressive enrichment of the therapeutic armament, this Special Issue, will consider the conventional therapy and the emerging treatments of UC in an attempt to place them in specific clinical contexts, in order to optimize their choice both in terms of effectiveness and safety.

Prof. Dr. Sandro Ardizzone
Guest Editor

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Keywords

  • Ulcerative colitis
  • Conventional therapy
  • Emerging treatment
  • Salicylates
  • Systemic and topical steroids
  • Immunosuppressants
  • Monoclonal anti-TNFa antibodies
  • Monoclonal anti-integrine antibodies
  • Small molecules
  • Cell-based therapies

Published Papers (9 papers)

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Research

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Open AccessArticle
Immunomodulation of Murine Chronic DSS-Induced Colitis by Tuftsin–Phosphorylcholine
J. Clin. Med. 2020, 9(1), 65; https://doi.org/10.3390/jcm9010065 - 26 Dec 2019
Abstract
Helminths or their products can immunomodulate the host immune system, and this phenomenon may be applied as the basis of new anti-inflammatory treatments. Previously, we have shown the efficacy of tuftsin–phosphorylcholine (TPC), based on a helminth product, in four animal models of autoimmune [...] Read more.
Helminths or their products can immunomodulate the host immune system, and this phenomenon may be applied as the basis of new anti-inflammatory treatments. Previously, we have shown the efficacy of tuftsin–phosphorylcholine (TPC), based on a helminth product, in four animal models of autoimmune diseases: arthritis, colitis, systemic lupus erythematosus, and experimental autoimmune encephalomyelitis. We demonstrated that TPC reduced inflammatory process ex vivo in peripheral blood lymphocytes (PBLs) and in biopsies from giant-cell arteritis. In the present study, we assessed the therapeutic potential of TPC treatment on a chronic colitis murine model. C57BL/6 mice with chronic colitis were treated with TPC after the third cycle of 2% dextran sodium sulfate (DSS). Oral TPC treatment resulted in amelioration of the colitis clinical manifestations exemplified by reduced disease activity index (DAI) score, expansion of mesenteric lymph nodes (MLN) T regulatory cells (shown by Fluorescence Activated Cell Sorting (FACS)), significant reduction in the expression of pro-inflammatory cytokines (IL-1β, IL17, IL-6, TNFα), and elevation in the expression of anti-inflammatory cytokine IL-10 (shown by RT-PCR). This study demonstrated the potential immunomodulatory effects of oral administration of TPC in a chronic colitis murine model. Further clinical trials are needed in order to evaluate this novel approach for the treatment of patients with inflammatory bowel disease. Full article
(This article belongs to the Special Issue Ulcerative Colitis: Current and Emerging Treatment Strategies)
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Open AccessArticle
Switching between Three Types of Mesalazine Formulation and Sulfasalazine in Patients with Active Ulcerative Colitis Who Have Already Received High-Dose Treatment with These Agents
J. Clin. Med. 2019, 8(12), 2109; https://doi.org/10.3390/jcm8122109 - 02 Dec 2019
Cited by 2
Abstract
Background and aim: Oral mesalazine and sulfasalazine (SASP) are key drugs for treating ulcerative colitis (UC). The efficacy of switching from one of the several mesalazine formulations to another is largely unknown. This study assessed the efficacy of switching among three types of [...] Read more.
Background and aim: Oral mesalazine and sulfasalazine (SASP) are key drugs for treating ulcerative colitis (UC). The efficacy of switching from one of the several mesalazine formulations to another is largely unknown. This study assessed the efficacy of switching among three types of mesalazine formulation and SASP for UC therapy. Methods: UC patients receiving high-dose mesalazine/SASP who switched to other formulations due to disease activity were considered eligible. Efficacy was evaluated 2, 6, and 12 months after switching. Results: A total of 106 switches in 88 UC patients were analyzed. The efficacy at 2 months after switching was observed in 23/39 (59%) cases from any mesalazine formulation to SASP, in 18/55 (33%) cases from one mesalazine to another, and in 2/12 (17%) cases from SASP to any mesalazine formulation. Nine of 43 effective cases showed inefficacy or became intolerant post-switching. Delayed efficacy more than two months after switching was observed in four cases. Steroid-free remission was achieved in 42/106 (39%) cases—within 100 days in 35 of these cases (83%). Conclusions: Switching from mesalazine to SASP was effective in more than half of cases. The efficacy of switching between mesalazine formulations was lower but may be worth attempting in clinical practice from a safety perspective. Full article
(This article belongs to the Special Issue Ulcerative Colitis: Current and Emerging Treatment Strategies)
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Open AccessArticle
Preventive Effect of Cardiotrophin-1 Administration before DSS-Induced Ulcerative Colitis in Mice
J. Clin. Med. 2019, 8(12), 2086; https://doi.org/10.3390/jcm8122086 - 01 Dec 2019
Cited by 1
Abstract
Ulcerative colitis is a relatively frequent, chronic disease that impacts significantly the patient’s quality of life. Although many therapeutic options are available, additional approaches are needed because many patients either do not respond to current therapies or show significant side effects. Cardiotrophin-1 (CT-1) [...] Read more.
Ulcerative colitis is a relatively frequent, chronic disease that impacts significantly the patient’s quality of life. Although many therapeutic options are available, additional approaches are needed because many patients either do not respond to current therapies or show significant side effects. Cardiotrophin-1 (CT-1) is a cytokine with potent cytoprotective, anti-inflammatory, and antiapoptotic properties. The purpose of this study was to assess if the administration of CT-1 could reduce colon damage in mice with experimental colitis was induced with 5% dextran sulfate sodium (DSS) in the drinking water. Half of the mice received an i.v. dose of CT-1 (200 µg/kg) 2 h before and 2 and 4 days after DSS administration. Animals were followed during 7 days after DSS administration. The severity of colitis was measured by standard scores. Colon damage was assessed by histology and immunohistochemistry. Inflammatory mediators were measured by Western blot and PCR. CT-1 administration to DSS-treated mice ameliorated both the clinical course (disease activity index), histological damage, inflammation (colon expression of TNF-α, IL-17, IL-10, INF IFN-γ, and iNOS), and apoptosis. Our results suggest that CT-1 administration before induction of colitis improves the clinical course, tissue damage, and inflammation in DSS-induced colitis in mice. Full article
(This article belongs to the Special Issue Ulcerative Colitis: Current and Emerging Treatment Strategies)
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Open AccessArticle
The Combination of Patient-Reported Clinical Symptoms and an Endoscopic Score Correlates Well with Health-Related Quality of Life in Patients with Ulcerative Colitis
J. Clin. Med. 2019, 8(8), 1171; https://doi.org/10.3390/jcm8081171 - 05 Aug 2019
Cited by 1
Abstract
Background and aims: Patient-reported outcomes (PROs) will become increasingly important as primary endpoints in future clinical trials. We aimed to evaluate the relationship between health-related quality of life (HRQoL) and the combination of patient-reported clinical symptoms (ClinPRO2) and Mayo endoscopic subscore (MES) in [...] Read more.
Background and aims: Patient-reported outcomes (PROs) will become increasingly important as primary endpoints in future clinical trials. We aimed to evaluate the relationship between health-related quality of life (HRQoL) and the combination of patient-reported clinical symptoms (ClinPRO2) and Mayo endoscopic subscore (MES) in patients with ulcerative colitis (UC). Methods: We conducted a prospective cross-sectional study of 90 consecutive UC patients who were scheduled for sigmoidoscopy or colonoscopy. All patients completed the following questionnaires: (1) self-rated rectal bleeding and stool frequency (ClinPRO2); (2) Short Inflammatory Bowel Disease Questionnaire (SIBDQ); (3) European Quality of Life 5-Dimensions 3-Level (EQ5D3L); (4) Work Productivity and Activity Impairment questionnaire (WPAI); (5) Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F); and (6) Hospital Anxiety and Depression Scale (HADS). The endoscopic images were graded according to the MES. “No symptoms” was defined as a symptom score of 0, and “mucosal healing” was defined as MES score of 0–1. Correlations between the combined ClinPRO2 and MES with HRQoL were assessed using Spearman’s correlation coefficients. Results: The combination of the ClinPRO2 and MES was well correlated to SIBDQ (r = −0.70), EQ5D3L (r = −0.51), WPAI (r = 0.62), FACIT-F (r = −0.58), and HADS-depression (r = 0.45). SIBDQ scores had strong correlations with FACIT-F (r = 0.86), WPAI (r = −0.80), and HADS-depression (r = −0.75) (p < 0.05 for all correlations). Patients with no symptoms reported the greatest all HRQoL scores. Conclusions: In patients with ulcerative colitis, the combination of a ClinPRO2 and the MES had good correlation with the SIBDQ. In addition, SIBDQ was well correlated to the various HRQoL. Full article
(This article belongs to the Special Issue Ulcerative Colitis: Current and Emerging Treatment Strategies)
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Open AccessArticle
The Lipid Status in Patients with Ulcerative Colitis: Sphingolipids are Disease-Dependent Regulated
J. Clin. Med. 2019, 8(7), 971; https://doi.org/10.3390/jcm8070971 - 04 Jul 2019
Cited by 9
Abstract
The factors that contribute to the development of ulcerative colitis (UC), are still not fully identified. Disruption of the colon barrier is one of the first events leading to invasion of bacteria and activation of the immune system. The colon barrier is strongly [...] Read more.
The factors that contribute to the development of ulcerative colitis (UC), are still not fully identified. Disruption of the colon barrier is one of the first events leading to invasion of bacteria and activation of the immune system. The colon barrier is strongly influenced by sphingolipids. Sphingolipids impact cell–cell contacts and function as second messengers. We collected blood and colon tissue samples from UC patients and healthy controls and investigated the sphingolipids and other lipids by LC-MS/MS or LC-QTOFMS. The expression of enzymes of the sphingolipid pathway were determined by RT-PCR and immunohistochemistry. In inflamed colon tissue, the de novo-synthesis of sphingolipids is reduced, whereas lactosylceramides are increased. Reduction of dihydroceramides was due to posttranslational inhibition rather than altered serine palmitoyl transferase or ceramide synthase expression in inflamed colon tissue. Furthermore, in human plasma from UC-patients, several sphinglipids change significantly in comparison to healthy controls. Beside sphingolipids free fatty acids, lysophosphatidylcholines and triglycerides changed significantly in the blood of colitis patients dependent on the disease severity. Our data indicate that detraction of the sphingolipid de novo synthesis in colon tissue might be an important trigger for UC. Several lipids changed significantly in the blood, which might be used as biomarkers for disease control; however, diet-related variabilities need to be considered. Full article
(This article belongs to the Special Issue Ulcerative Colitis: Current and Emerging Treatment Strategies)
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Review

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Open AccessReview
Revisiting Inflammatory Bowel Disease: Pathology, Treatments, Challenges and Emerging Therapeutics Including Drug Leads from Natural Products
J. Clin. Med. 2020, 9(5), 1273; https://doi.org/10.3390/jcm9051273 - 28 Apr 2020
Cited by 6
Abstract
Inflammatory bowel disease (IBD) is a chronic and life-long disease characterized by gastrointestinal tract inflammation. It is caused by the interplay of the host’s genetic predisposition and immune responses, and various environmental factors. Despite many treatment options, there is no cure for IBD. [...] Read more.
Inflammatory bowel disease (IBD) is a chronic and life-long disease characterized by gastrointestinal tract inflammation. It is caused by the interplay of the host’s genetic predisposition and immune responses, and various environmental factors. Despite many treatment options, there is no cure for IBD. The increasing incidence and prevalence of IBD and lack of effective long-term treatment options have resulted in a substantial economic burden to the healthcare system worldwide. Biologics targeting inflammatory cytokines initiated a shift from symptomatic control towards objective treatment goals such as mucosal healing. There are seven monoclonal antibody therapies excluding their biosimilars approved by the US Food and Drug Administration for induction and maintenance of clinical remission in IBD. Adverse side effects associated with almost all currently available drugs, especially biologics, is the main challenge in IBD management. Natural products have significant potential as therapeutic agents with an increasing role in health care. Given that natural products display great structural diversity and are relatively easy to modify chemically, they represent ideal scaffolds upon which to generate novel therapeutics. This review focuses on the pathology, currently available treatment options for IBD and associated challenges, and the roles played by natural products in health care. It discusses these natural products within the current biodiscovery research agenda, including the applications of drug discovery techniques and the search for next-generation drugs to treat a plethora of inflammatory diseases, with a major focus on IBD. Full article
(This article belongs to the Special Issue Ulcerative Colitis: Current and Emerging Treatment Strategies)
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Open AccessReview
Management of Acute Severe Colitis in the Era of Biologicals and Small Molecules
J. Clin. Med. 2019, 8(12), 2169; https://doi.org/10.3390/jcm8122169 - 08 Dec 2019
Cited by 2
Abstract
Acute severe ulcerative colitis (ASUC) is a medical emergency which occurs in about 20%–30% of patients with ulcerative colitis during their lifetime, and does carry a mortality risk of 1%. The management of inflammatory bowel diseases has evolved with changes in objective patient [...] Read more.
Acute severe ulcerative colitis (ASUC) is a medical emergency which occurs in about 20%–30% of patients with ulcerative colitis during their lifetime, and does carry a mortality risk of 1%. The management of inflammatory bowel diseases has evolved with changes in objective patient monitoring, as well as the availability of new treatment options with the development of new biological and small molecules; however, data is limited regarding their use in the context of ASUC. This review aims to discuss the emerging data regarding biologicals and small molecules therapies in the context of ASUC. Full article
(This article belongs to the Special Issue Ulcerative Colitis: Current and Emerging Treatment Strategies)
Open AccessReview
History of Inflammatory Bowel Diseases
J. Clin. Med. 2019, 8(11), 1970; https://doi.org/10.3390/jcm8111970 - 14 Nov 2019
Cited by 15
Abstract
Inflammatory bowel diseases (IBD) are characterized by chronic inflammation of the intestinal mucosa and unknown etiology. In this review, we identified three main eras in the IBD history. Between the 19th and the 20th century, the primary task had been the definition of [...] Read more.
Inflammatory bowel diseases (IBD) are characterized by chronic inflammation of the intestinal mucosa and unknown etiology. In this review, we identified three main eras in the IBD history. Between the 19th and the 20th century, the primary task had been the definition of the diagnostic criteria in order to differentiate the new entity from intestinal tuberculosis. In the 20th century, an intense and prolific therapeutic research prevailed, culminating in the introduction of biological drugs in the clinical setting. Since the beginning of the 21st century, traditional definition criteria have been challenged by holistic criteria in an effort to seek a still unattained cure. Centuries of worldwide efforts on IBD etiology and therapy search have culminated in this novel strategy. Full article
(This article belongs to the Special Issue Ulcerative Colitis: Current and Emerging Treatment Strategies)
Open AccessReview
Preclinical Study in Vivo for New Pharmacological Approaches in Inflammatory Bowel Disease: A Systematic Review of Chronic Model of TNBS-Induced Colitis
J. Clin. Med. 2019, 8(10), 1574; https://doi.org/10.3390/jcm8101574 - 01 Oct 2019
Cited by 4
Abstract
The preclinical studies in vivo provide means of characterizing physiologic interactions when our understanding of such processes is insufficient to allow replacement with in vitro systems and play a pivotal role in the development of a novel therapeutic drug cure. Chemically induced colitis [...] Read more.
The preclinical studies in vivo provide means of characterizing physiologic interactions when our understanding of such processes is insufficient to allow replacement with in vitro systems and play a pivotal role in the development of a novel therapeutic drug cure. Chemically induced colitis models are relatively easy and rapid to develop. The 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitis model is one of the main models in the experimental studies of inflammatory bowel disease (IBD) since inflammation induced by TNBS mimics several features of Crohn’s disease. This review aims to summarize the existing literature and discuss different protocols for the induction of chronic model of TNBS-induced colitis. We searched MEDLINE via Pubmed platform for studies published through December 2018, using MeSH terms (Crohn Disease.kw) OR (Inflammatory Bowel Diseases.kw) OR (Colitis, Ulcerative.kw) AND (trinitrobenzenesulfonic acid.kw) AND (disease models, animal.kw) AND (mice.all). The inclusion criteria were original articles, preclinical studies in vivo using mice, chronic model of colitis, and TNBS as the inducer of colitis and articles published in English. Chronic TNBS-induced colitis is made with multiple TNBS intrarectal administrations in an average dose of 1.2 mg using a volume lower than 150 μL in 50% ethanol. The strains mostly used are Balb/c and C57BL/6 with 5–6 weeks. To characterize the preclinical model the parameters more used include body weight, stool consistency and morbidity, inflammatory biomarkers like interferon (IFN)-γ, myeloperoxidase (MPO), tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10, presence of ulcers, thickness or hyperemia in the colon, and histological evaluation of the inflammation. Experimental chronic colitis is induced by multiple rectal instillations of TNBS increasing doses in ethanol using Balb/c and C57BL/6 mice. Full article
(This article belongs to the Special Issue Ulcerative Colitis: Current and Emerging Treatment Strategies)
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