Modern use of 5-aminosalicylic acid compounds for ulcerative colitis

ABSTRACT

Introduction: For 30 years, 5-aminosalicylic acid (5-ASA) has been the backbone of therapeutic management in patients with ulcerative colitis (UC). In the biologic era, it still remains the treatment of choice in mild-to-moderate UC. Positioning of this therapeutic class in moderate-to-severe UC is less clear.

Areas covered: Several studies demonstrated the ability of 5-ASA to induce endoscopic remission to a similar extent as anti-TNF therapy on the moderate segment of UC. Histologic remission is achieved after induction in up to 45% of patients treated with topical 5-ASA and 30% with oral formulations. Aminosalicylates offer a favorable safety profile compared to that of immunomodulators and biologics. High-dose 5-ASA therapy may be a valuable option for patients with moderately active disease, and physicians should weigh the pros and cons of this strategy in selected patients. Whether aminosalicylates should be continued in combination with thiopurines or biologic therapy remains under debate.

Expert opinion: In the era of biologics, aminosalicylates remain the first-line therapy in patients with mild UC, and have to be considered in case of moderate UC, given their favorable risk-benefit profile. We suggest that 5-ASA should be used in moderate patients without poor prognostic factors, while biologics should be preferred otherwise.     

Anti-interleukin-23 agents for the treatment of ulcerative colitis

ABSTRACT

Introduction: Treatment of ulcerative colitis (UC) aims to control symptoms and to suppress intestinal inflammation. Despite considerable advances, a proportion of patients do not respond to currently available drugs. The interleukin (IL)-23 axis plays a significant role in the pathogenesis of UC and has thus become an important target for drug development.

Areas covered: The review briefly summarizes the pathophysiology of the IL-12/23 axis and provides a synopsis of the available evidence for efficacy and safety of ustekinumab, mirikizumab (LY3074828), risankizumab (BI655066/ABBV066), brazikumab (MEDI2070; formerly AMG139) and guselkumab (CNTO1959) in UC. We also provide an overview of ongoing and anticipated trials in this field.

Expert opinion: A Phase 2 trial with mirikizumab and a Phase 3 trial with ustekinumab have demonstrated the efficacy of anti-IL-23 agents in achieving clinical and endoscopic outcomes in UC with a favorable safety profile. Trials of other anti-IL-23 agents in UC are under way and designed to explore head-to-head efficacy with existing biologics, as well as the prospect of combination biological therapy. Apart from data on longer term efficacy and safety, future trials should also explore strategies to inform the positioning of IL-23 antagonists in therapeutic algorithms.     

Is there room for immunomodulators in ulcerative colitis?

ABSTRACT

Introduction: The management of patients with ulcerative colitis (UC) has evolved over the past few decades. While aminosalicylates remain the mainstay of induction and maintenance therapy in patients with mild-to-moderate UC, the advent of biologic agents and novel oral small molecules has substantively changed the treatment landscape for patients with moderate-to-severe disease and confounded the role of traditional immunomodulators (IMMs) such as thiopurines and methotrexate in the UC management algorithm.

Areas covered: We summarize the mechanism of action of thiopurines and methotrexate, identify clinical parameters for their use, and appraise the evidence supporting the efficacy and safety of IMMs in UC as both monotherapy and in combination with other therapies, emphasizing on prospective, controlled data.

Expert opinion: With the advent of several classes of highly effective treatments for UC, emergence of data demonstrating no benefit of IMMs over placebo, and concerns about the relative safety profile of long-term IMM exposure, we propose that the role of thiopurines or methotrexate be restricted to patients with milder disease failing to maintain corticosteroid-free remission on aminosalicylates alone or in combination therapy with tumor necrosis factor antagonists in patients with moderate-to-severe UC.     

Histological healing: should it be considered as a new outcome for ulcerative colitis?

ABSTRACT

Introduction: Currently, mucosal healing is considered as a composite treatment end-point in inflammatory bowel disease (IBD) since it has been demonstrated to improve disease-related outcomes. The definition of mucosal healing has evolved and current evidence suggests that in addition to endoscopic healing the achievement of histological remission (HR) represents a potential novel target in the management of IBD in relation to better long-term disease outcomes.

Areas covered: We aimed to review the current literature on HR in ulcerative colitis and discuss its limitations and advantages when adopting this potential new target as an ultimate treatment outcome in clinical trials and routine clinical practice.

Expert opinion: HR is achievable in UC with different rates in conventional therapies, biological and novel drugs. Targeting HR in UC lowers the risk of hospitalizations, colectomy, and colorectal cancer. HR occurs later than endoscopic remission, longer treatment courses are associated with higher HR assessment. This might imply modifying monitoring time schedules and algorithms. Prospective data are needed to support histological healing as a new treatment target in UC.     

The role of integrin antagonists in the treatment of inflammatory bowel disease

Introduction: Ulcerative colitis (UC) and Crohn’s disease are chronic inflammatory diseases of the bowel associated with complex inflammatory cascades within the mucosal lining of the gut.

Areas covered: INTEGRINS and their use as therapies in UC and Crohn’s.

Expert Opinion: The anti-adhesion molecules are a welcome addition to the armamentarium of medical therapies for inflammatory bowel disease.     

The biologics of ulcerative colitis

Introduction: Tumor necrosis factor α inhibitors dramatically changed the management of moderate-to-severe phenotypes of ulcerative colitis. The recent incoming of vedolizumab, which targets gut-specific leukocyte trafficking, provides a new biologic option for these patients.

Areas covered: This review focuses on the rationale of use, efficacy, and safety profile of all biologics currently approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of ulcerative colitis, including tumor necrosis factor α inhibitors (Infliximab and biosimilars, adalimumab, and golimumab), and the more recent vedolizumab.

Expert opinion: Although biologics have been available in clinical practice for ulcerative colitis for about 15 years, there are several aspects that have not been fully understood yet: we know that they work, but we still don’t know which subsets of patients benefit more, and how to optimize their use. All these unresolved problems are at least partly due to the discrepancy observed between phase II/III clinical trials of all biologics currently used in ulcerative colitis and in clinical practice.     

Developments in liposomal gene delivery systems

ABSTRACT

Introduction: Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology. Currently approved therapies include prednisone, TNF antagonists and anti-metabolites which often are ineffective and have frequent adverse effects. Consequently, UC patients are always at risk for developing serious complications that affect their quality of life. Therefore, new treatment options are required.

Areas covered: This article discusses etrolizumab, its mechanism and the potential role it can have in the future of treating UC. Etrolizumab is a humanized monoclonal antibody that selectively blocks lymphocyte trafficking and retention in the gut. The safety and efficacy data was reviewed from all randomized placebo-controlled trials which evaluated etrolizumab for the treatment of UC.

Expert opinion: Etrolizumab is an effective and well-tolerated drug for the treatment of UC. It appears to be a promising molecule that can benefit UC patients.     

Modulation of sphingosine-1-phosphate in ulcerative colitis

ABSTRACT

Introduction: Sphingosine-1-phosphate (S1P) is a membrane-derived lysophospholipid signaling molecule implicated in various physiological and pathological processes, such as regulation of the immune, cardiovascular, pulmonary, and nervous systems and theoretical cancer-related risks, through extracellular activation of S1P1-5 receptors.

Areas covered: S1P receptor agonism is a novel strategy for the treatment of UC targeting lymphocyte recirculation, through blockade of lymphocyte egress from lymph nodes. We conducted an extensive literature review on PUBMED on currently available data on molecular aspects of S1P modulation, the mechanisms of action of S1PR agonists (fingolimod, ozanimod, etrasimod, and KRP-203), and their potential efficacy and safety for the treatment of patients with ulcerative colitis.

Expert opinion: Selective S1P modulators have emerged to enlarge the efficacy and safety profile of this class of agents. Phase 3 programs should add the potential body of evidence to prove their benefit for the management of UC patients.     

Fecal transplantation for ulcerative colitis: current evidence and future applications

ABSTRACT

Introduction: Established evidence suggests that gut microbiota plays a role in ulcerative colitis (UC). Fecal microbiota transplantation (FMT) is clearly recognized as a highly effective treatment for patients with recurrent Clostridium difficile infection and has been investigated also in patients with UC, with promising results.

Areas covered: Literature review was performed to select publications concerning current evidence on the role of gut microbiota in the pathogenesis of UC, and on the effectiveness of FMT in this disorder.

Expert opinion: The randomized controlled trials published investigating the use of FMT suggested a potential role for FMT in the treatment of mild to moderate UC. However, given several unanswered questions regarding donor selection, dose, route of administration and duration of therapy, this is not yet recommended as a viable therapy option. FMT has allowed for more in depth investigation with regards to the role the gut microbiota may be playing in UC. This knowledge is critical to identifying where FMT may appropriately fit in the UC treatment paradigm. As our understanding of the role the microbiome plays in this chronic disease, FMT, and then eventually defined microbes, will hopefully serve in a complementary role to conventional IBD therapies.     

Certolizumab pegol for treating axial spondyloarthritis

ABSTRACT

Introduction: Axial spondyloarthritis (axSpA) is a chronic inflammatory disease of the spine and sacroiliac (SI) joints. The spectrum of axSpA includes ankylosing spondylitis (AS) and non-radiographic axSpA (nr-axSpA). Evidence has supported the use of TNF alpha inhibitors (TNFi) in treating these diseases, with good efficacy and tolerable safety profiles. Certolizumab pegol (CZP) is an anti-TNF alpha (TNFa) agent with data to support its use in both AS and nr-axSpA.

Areas covered: The pharmacologic properties of CZP were reviewed. Data regarding the use and efficacy of CZP in axSpA were reviewed. Quality of life outcomes and safety profiles of CZP in axSpA patients were discussed as well.

Expert opinion: While there are several biologics with evidence for improved outcomes in AS, there is less evidence for biologic medications that have good efficacy in nr-axSpA. CZP has good evidence of improved outcomes in terms of clinical efficacy, patient reported outcomes and imaging outcomes in both conditions, with a tolerable safety profile.     

Prevalence,incidence and mortality of inflammatory bowel disease in Catalonia. A population-based analysis

Abstract

Introduction: Few recent data on the epidemiology of inflammatory bowel disease (IBD) are available, especially in Southern Europe.

Aim: To evaluate the prevalence, incidence and mortality of IBD in Catalonia during the period 2011–2016.

Material and methods: Data on the prevalence, incidence and mortality of IBD were obtained from the Catalan Health Surveillance System (CHSS). Crude incidence and prevalence rates were calculated for all the Catalan population. Trends in age-sex-adjusted rates were also estimated, and logistic regression was used to calculate the adjusted mortality odds ratio (OR). Data for Crohn’s disease (CD) and ulcerative colitis (UC) were analyzed separately.

Results: The prevalence per 100,000 inhabitants in 2016 was 353.9 for UC and 191.4 for CD. The total number of IBD patients rose from 29543 in 2011 to 40614 in 2016. IBD was associated with significantly elevated adjusted mortality ratios: 1.28 (95% CI: 1.6–1.4) for UC and 1.85 (95% CI: 1.62–2.12) for CD.

Conclusions: IBD prevalence is very high and is increasing rapidly in Catalonia. Both CD and UC are associated with significantly higher mortality rates.

• Key message

• Crohn disease and ulcerative colitis present a small but significant increase in mortality compared to non-inflammatory bowel disease.

• The prevalence of inflammatory bowel disease is increasing rapidly in Catalonia.

• Data on prevalence and incidence suggest that the number of patients may double in approximately 10 years.

     

Anti-MADCAM therapy for ulcerative colitis

ABSTRACT

Introduction: The mucosal addressin cell adhesion molecule-1 (MAdCAM-1) plays a key role in the endothelial adhesion and migration of lymphocytes to sites of inflammation in inflammatory bowel disease. Therapies that target this pathway appear to be a promising therapeutic approach in the management of ulcerative colitis (UC).

Areas covered: This review provides a summary of the preclinical and available clinical data on the safety and efficacy of ontamalimab (SHP647), a fully human monoclonal antibody that binds and inhibits the action of MAdCAM-1.

Expert opinion: Intestinal immune cell trafficking is emerging as an important component in the pathogenesis of UC. Ontamalimab (SHP647) inhibits this process by preventing the binding of integrins found on the surface of lymphocytes and the endothelial ligand adhesion molecule MAdCAM-1. This monoclonal antibody has already demonstrated safety and efficacy in phase II clinical trials. Its targeted mechanism of action suggests a superior safety profile as compared with the current systemic immunosuppressive therapies. Results from the phase III trials are awaited to establish ontamalimab (SHP647) as a therapeutic option in the management of UC.     

Targeting B cells with biologics in systemic lupus erythematosus

Importance of the field: The use of biologics as immune modulators in several autoimmune diseases has provided new tools to the physician's therapeutic armamentiarium and has led to improved patients' outcomes and quality of life. By producing autoantibodies, B cells in systemic lupus erythematosus (SLE) are key players in the pathogenesis of the disease and in its clinical manifestations. Therefore, biologics that target B cells in SLE aim at reducing the activity of these cells for the induction of remissions and/or amelioration of disease activity, reduction of organ involvement, and limitation of the complications and side effects caused by immunosuppressive therapies.

Areas covered in this review: This review describes the past and current clinical trials with B-cell-targeted biologics in SLE, to provide a historical perspective and the state-of-the-art on the topic.

What the reader will gain: We review how the disappointment in the field from promising agents has been instrumental in providing valuable lessons leading to an improved design of new trials that are now giving encouraging results.

Take home message: In systemic lupus erythematosus (SLE), the use of B-cell-based biologics in clinical trials has shown both disappointment and promise.     

Epidemiological data and utilization patterns of anti-TNF alpha therapy in the Hungarian ulcerative colitis population between 2012-2016

ABSTRACT

Background: Anti-TNF therapy is efficacious in the maintenance of remission in ulcerative colitis (UC); however, long-term data on real-life use of these agents are lacking.

Methods: This observational, retrospective, epidemiological study using the National Health Insurance Fund social security database aimed to understand patient characteristics and therapeutic patterns of anti-TNF therapy. Data of adult Hungarian, UC patients treated with anti-TNF agents (IFX-infliximab, ADA-adalimumab) between 2012 and 2016 were analyzed.

Results: Five hundred and sixty-eight UC patients were identified. Approximately 70-80% of the patients reached maintenance therapy. A large proportion of patients stopped therapy after 10 to 12 months due to the reimbursement policy. Corticosteroid use decreased significantly after the initiation of biological therapy. The dose-escalation rate was 19.8% for ADA and 10.9% for IFX, respectively, and was performed earlier along the treatment timeline for patients on ADA. In the present study, the rate of primary non-response (PNR) was 11.6% and the rate of secondary loss of response (LOR) was 36.5%.

Summary: Treatment length is in correspondence with the Hungarian reimbursement policies. The mandatory stop of treatment in the reimbursement policy is suboptimal in UC patients requiring biological therapy. The corticosteroid-sparing effect of biological therapy was demonstrated.     

Early postoperative physical therapy for improving short-term gross motor outcome in infants with cyanotic and acyanotic congenital heart disease

Purpose: We analysed the gross motor recovery of infants and toddlers with cyanotic and acyanotic congenital heart disease (CHD) who received early postoperative physical therapy to see whether there was any difference in the duration to recovery.

Methods: This study retrospectively evaluated the influence of early physical therapy on postoperative gross motor outcomes of patients with CHD. The gross motor ability of patients with cyanotic (n?=?25, average age: 376.4 days) and acyanotic (n?=?26, average age: 164.5 days) CHD was evaluated using our newly developed nine-grade mobility assessment scale.

Results: Physical therapy was started at an average of five days after surgery, during which each patient’s gross motor ability was significantly decreased compared with the preoperative level. Patients (who received early postoperative physical therapy) with cyanotic (88.0%) and acyanotic CHD (96.2%) showed improved preoperative mobility grades by the time of hospital discharge. However, patients with cyanotic CHD had a significantly prolonged recovery period compared to those with acyanotic CHD (p?Conclusions: Our findings suggested that infants with cyanotic CHD are likely at a greater risk of gross motor delays, the recovery of which might differ between infants with cyanotic and acyanotic CHD after cardiac surgery. Early postoperative physical therapy promotes gross motor recovery.

• Implications of Rehabilitation

• Infants and toddlers with cyanotic congenital heart disease are likely at greater risk of gross motor delays and have a prolonged recovery period of gross motor ability compared to those with acyanotic congenital heart disease.

• Early postoperative physical therapy for patients with congenital heart disease after cardiac surgery promoted gross motor recovery.

• The postoperative recovery period to preoperative mobility grade was affected by pre-, intra-, and postoperative factors.

• Rehabilitation experts should consider the risk of gross motor delays of patients with congenital heart disease after cardiac surgery and the early postoperative physical therapy to promote their gross motor recovery.

     

Positioning ustekinumab in moderate-to-severe ulcerative colitis: new kid on the block

ABSTRACT

Introduction: Ulcerative colitis (UC) is a chronic relapsing disorder of the colonic tract. Dysregulated innate and adaptive immune pathways contribute to intestinal inflammation in IBD, and cytokines, including IL-12 and IL-23, play a key role. The blockade of both IL-12 and IL-23 may have an impact on different pathways of inflammation and could be effective for the treatment of inflammatory bowel diseases.

Ustekinumab is a fully human IgG1κ monoclonal antibody which binds to the shared p40 protein subunit of IL-12 and ?23. It is currently approved for several immune-mediated diseases such as moderate to severe plaque psoriasis, psoriatic arthritis, and Crohn’s disease, and has shown promising results in UC.

Areas covered: A review of the literature was performed to understand several aspects including the role of IL-12 and ?23 in UC, the potential therapeutic role of ustekinumab in inflammatory bowel disease, and the positioning of ustekinumab in the therapeutic algorithm of UC, based on extrapolated data from available randomized clinical trials.

Expert opinion: Ustekinumab is effective and safe in UC, and shows potential advantages compared to other drugs in moderate-to-severe UC.     

My Treatment Approach to the Management of Ulcerative Colitis

Ulcerative colitis diagnosis and management represent a challenge for clinicians. The disguises of ischemia and acute infectious colitis continue to confound the diagnosis. The therapeutic options have remarkably expanded in the way of immunomodulators, biologics, or ileoanal pouch surgery, yet all carry potential considerable risks. These risks can confuse and impair patient acceptance, particularly elderly patients and men younger than 30 years. Predictors of outcome of medical and surgical therapy have improved but are far from complete. Nevertheless, therapies focused on the specific patient's condition continue to offer hope.     

New biologic therapeutics for ulcerative colitis and Crohn's disease

Introduction: Some inflammatory bowel disease (IBD) patients especially those with refractory Crohn's disease (CD) or relapsing ulcerative colitis (UC) do not respond to current therapies. The newly introduced biological drugs have got some interest due to their specificity and selectivity in modulation of inflammatory elements.

Areas covered: In 46 included randomized, placebo-controlled clinical trials, the efficacy and safety of different biologic drugs have been evaluated in moderately to severely active CD or UC patients. Current investigated drugs include new anti-TNF drugs (adalimumab, certolizumab pegol, etanercept, onercept and golimumab), anti-CD20 (rituximab), T-cell inhibitors (abatacept) and anti-α4 integrins (natalizumab and vedolizumab). Adalimumab, certolizumab, and golimumab showed significant efficacy in induction of remission and maintenance in CD and UC patients with a rate of adverse events similar to placebo in the major trials. Natalizumab and vedolizumab were effective in the treatment of moderately to severely active CD and UC patients. However, vedolizumab caused less adverse effects than natalizumab. onercept, etanercept, rituximab and abatacept were all well tolerated but were not effective in CD or UC patients.

Expert opinion: Anti-TNF drugs, except for onercept and etanercept, and anti-α4 integrins exhibit beneficial therapeutic effects. Although they were all well tolerated, the incidence of progressive multifocal leukoencephalopathy associated with natalizumab should not be missed.     

Adalimumab in ulcerative colitis – efficacy,safety and optimization in the era of treat-to target

Introduction: Active ulcerative colitis is associated with significant morbidity and impairment to quality of life. Adalimumab is a welcome addition to the therapeutic armamentarium for clinicians treating patients with moderate-severe ulcerative colitis refractory to conventional therapies, an indication with few prior treatment options. It offers the convenience of self-injection and is most appropriate for outpatients with moderate disease activity.

Areas covered: This review briefly summarizes data from well-designed clinical trials and observational real-life studies that demonstrate the safety and efficacy of adalimumab in UC. Particular attention is paid to newer studies, including those with objective treatment endpoints and pharmacokinetic outcomes that incorporate a treat to target approach in inflammatory bowel disease.

Expert opinion: Adalimumab is effective for the induction and maintenance of remission in patients with moderate-severe ulcerative colitis refractory to conventional therapies. At currently approved doses, it is most suitable for use in outpatients with moderate disease activity; higher doses may be required for patients with more severe disease. The convenience of self-injection will make it popular for remote patients and it may be an appropriate option in patients in whom monotherapy, rather than combination therapy with an immunomodulator, is preferred.     

Effects of perioperative statins on patient outcomes after noncardiac surgery: a meta-analysis

Background: Cardiovascular complications are strongly correlated with a higher risk of mortality during follow-up after noncardiac surgery. However, controversy remains regarding whether perioperative administration of hydroxymethylglutaryl-CoA reductase inhibitors (statins) has a beneficial effect on patient outcomes.

Objective: We performed a meta-analysis to validate the hypothesis that perioperative statins improve patient outcomes after noncardiac surgery.

Methods: Electronic databases (PubMed, Web of Science, EMBASE, and the Cochrane Library) were searched for randomized controlled trials (RCTs) published up to 10 November 2017. RCTs were eligible for inclusion if they compared perioperative statin treatment with control treatment in patients scheduled for noncardiac surgery and reported data pertaining to clinical outcomes.

Results: Twelve RCTs involving 4707 patients (2371 in the perioperative statin group and 2336 in the control group) were ultimately included in this meta-analysis. The incidences of postoperative myocardial infarction, composite of death/myocardial infarction/stroke and new cases of atrial fibrillation were all lower in patients treated with statins than in control group patients, as shown by the fixed-effects model (odds ratio (OR)?=?0.460, 95% confidence interval (CI)?=?0.324–0.653, p?=?0 for myocardial infarction; OR?=?0.617, 95% CI?=?0.476–0.801, p?=?0 for composite of death/myocardial infarction/stroke; OR?=?0.406, 95% CI?=?0.247–0.666, p?=?0 for new atrial fibrillation). No significant differences in the incidences of stroke or transient ischemic attack, all-cause mortality and cardiovascular mortality were observed between the statin and control arms.

Conclusions: This meta-analysis supports the hypothesis that perioperative statins effectively reduce the incidences of postoperative myocardial infarction, composite of death/myocardial infarction/stroke and new cases of atrial fibrillation in patients undergoing noncardiac surgery.

• Key Messages

• Cardiovascular complications are strongly correlated with a higher risk of mortality during follow-up after noncardiac surgery.

• We performed a meta-analysis to confirm the hypothesis that perioperative statins improve patient outcomes after noncardiac surgery.