Vedolizumab and etrolizumab for ulcerative colitis: twins or simple cousins?

ABSTRACT

Introduction: Vedolizumab is a monoclonal antibody that selectively blocks α4β7 integrin and has already been approved for use in patients with moderate-to-severe ulcerative colitis both as first and second line. Etrolizumab is a monoclonal antibody still being tested, which acts with a dual mechanism by selectively inhibiting both α4β7 and αEβ7 integrins.

Areas covered: This review provides an overview of the literature data of vedolizumab and etrolizumab, in order to define their role in the treatment of patients with moderate-to-severe ulcerative colitis.

Expert opinion: Etrolizumab and vedolizumab block the α4β7 integrin with a similar action mechanism. However, the inhibition of αEβ7 integrin by etrolizumab distinguishes the two anti-integrins making them ‘cousin’ drugs. Phase 3 clinical trials are needed to confirm the promising etrolizumab’s efficacy data and to resolve any doubts about its safety, allowing a clearer comparison with vedolizumab.     

Up-to-date surgery for ulcerative colitis in the era of biologics

ABSTRACT

Introduction: In recent decades, biologics have resulted in significantly improved medical management of ulcerative colitis (UC). Rates of surgery for UC are declining. However, there is still a controversial question of the relation of biologics to postoperative adverse outcomes and the most appropriate timing for operative intervention.

Areas covered: In this review, we explore the updated treatment algorithm of acute severe colitis, describe postoperative outcomes in patients exposed to biologics preoperatively, and discuss the primary indications for staging surgery in chronic refractory cases, largely with prolonged medical therapy.

Expert opinion: Delaying pouch construction to when patients are in better health is suggested as a safer strategy over the long term. The surgical management of UC patients in the biologic era needs to be individualized, and a case-based multidisciplinary decision is critical for improved outcomes and a reduction of morbidity and mortality.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.

     

Infliximab biosimilar CT-P13 therapy is effective and safe in maintaining remission in Crohn’s disease and ulcerative colitis – experiences from a single center

Background: CT-P13, the first biosimilar monoclonal antibody to infliximab (IFX), has been confirmed to be efficacious in inducing remission in inflammatory bowel diseases (IBD). The aim of this study was to evaluate the long-term efficacy and safety of CT-P13 therapy in Crohn’s disease (CD) and ulcerative colitis (UC), and to identify predictors of sustained clinical response during a 54-week CT-P13 treatment period.

Patients and methods: Patients with CD and UC, who were administered CT-P13, were prospectively enrolled. Clinical response was assessed at week 14 and week 54. Predictive factors for disease outcome at week 54 were evaluated.

Results: 57 CD and 57 UC patients were included; 55 CD and 49 UC patients completed the induction therapy and 50 CD and 46 UC patients completed the 54-week treatment period. Clinical remission was achieved in 65.5% of CD and 75.5% of UC patients at week 14. Rate of continuous clinical response was 51% in both CD and UC at week 54. None of the examined parameters were predictive to the clinical outcome neither in CD, nor in UC.

Conclusion: This study confirmed the long-term efficacy and safety of CT-P13 therapy in IBD. Response rates at week 54 were similar in CD and UC.     

Computed tomography-based texture analysis of bladder cancer: differentiating urothelial carcinoma from micropapillary carcinoma

Purpose

The purpose of the study is to determine the feasibility of using computed tomography-based texture analysis (CTTA) in differentiating between urothelial carcinomas (UC) of the bladder from micropapillary carcinomas (MPC) of the bladder.

Methods

Regions of interests (ROIs) of computerized tomography (CT) images of 33 MPCs and 33 UCs were manually segmented and saved. Custom MATLAB code was used to extract voxel information corresponding to the ROI. The segmented tumors were input to a pre-existing radiomics platform with a CTTA panel. A total of 58 texture metrics were extracted using four different texture extraction techniques and statistically analyzed using a Wilcoxon rank-sum test to determine the differences between UCs and MPCs.

Results

Of the 58 texture metrics extracted using the gray level co-occurrence matrix (GLCM) and gray level difference matrix (GLDM), 28 texture metrics were statistically significant (p < 0.05) for differences in tumor textures and 27 texture metrics were statistically significant (p < 0.05) for peritumoral fat textures. The remaining nine metrics extracted using histogram and fast Fourier transform analyses did not show significant differences between the textures of the tumors and their peritumoral fat.

Conclusions

CTTA shows that MPC have a more heterogeneous texture compared to UC. As visual discrimination of MPC from UC from clinical CT scans are difficult, results from this study suggest that tumor heterogeneity extracted using GLCM and GLDM may be a good imaging aid in segregating MPC from UC. This tool can aid clinicians in further sub-classifying bladder cancers on routine imaging, a process which has potential to alter treatment and patient care.

     

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.     

Infliximab biosimilar CT-P13 therapy is effective in maintaining endoscopic remission in ulcerative colitis – results from multicenter observational cohort

ABSTRACT

Background: CT-P13, the first biosimilar monoclonal antibody to infliximab (IFX), has previously been confirmed to be efficacious in inducing mucosal healing in ulcerative colitis (UC) patients. The aim of this study was to evaluate the efficacy of CT-P13 therapy in maintaining mucosal healing in UC.

Methods: CT-P13 trough levels, antibody positivity, serum inflammatory markers as CRP level, fecal calprotectin at weeks 14 and 54, concomitant steroid and azathioprine therapy at the time of induction therapy and at weeks 14 and 54, previous use of anti TNF drug and the need of dose intensification as possible predictive factors for mucosal healing at week 54 were evaluated in this prospective study.

Results: 61 patients had already completed the 54-week treatment period. Mucosal healing was shown in 65.5 % and 62.1 %, complete mucosal healing was present in 31% and 38 % at week 14 and 54, respectively. The median values of CRP, leukocytes, thrombocytes, and albumin showed significant difference between baseline and week 54. Serum antibody positivity was proved in 6.5 % and 19.7 % of cases at week 14 and 54, respectively.

Conclusion: Our study confirmed the long-term efficacy of CT-P13 therapy on mucosal healing in UC.     

Cost-effectiveness of pharmaceutical care on patients undergoing maintenance hemodialysis – a multicenter randomized controlled study

Objectives: The aim of the study is to assess the cost-effectiveness of pharmaceutical care versus usual care on the treatment costs in patients undergoing maintenance hemodialysis (HD) in the outpatient HD centers of academic, government, and corporate hospitals.

Methods: An open-labeled randomized controlled study was registered under clinical trial registry of India (Ref. no. CTRI/2014/004900). The study was conducted for a period of 12-month follow-up in patients undergoing maintenance HD. The patients were randomized into Usual Care (UC) group and Pharmaceutical Care (PC) group by the block design method. The UC group received the usual care provided by the hospital staff like physicians, nurses, and technicians whereas, the PC group received the usual care along with the pharmaceutical care delivered by a qualified registered pharmacist. The patient perspective ‘out-of-pocket expenditures’ was considered for calculating the annual cost incurred for the treatment of HD patients.

Results: Out of 153 patients, academic hospital (n = 83), government hospital (n = 18), and corporate hospital (n = 52). The incremental cost-effectiveness ratio for academic, government, and corporate hospitals HD patients of PC group compared with UC group were 86,230 Indian Rupee (INR)/Quality-adjusted life year (QALY), 231,016.66 INR/QALY, and 87,430 INR/QALY, respectively. Our study results revealed that PC group was costlier and more effective compared to the UC group.

Conclusions: It depends upon the policymakers and regulators to take the decision, if they believe that the extra cost is worth the extra QALY.     

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.     

Considerations,challenges and future of anti-TNF therapy in treating inflammatory bowel disease

ABSTRACT

Introduction: Crohn’s disease (CD) and ulcerative colitis (UC) are chronic disabling conditions. Monoclonal antibody therapy directed against tumor necrosis factor-alpha (anti-TNF) has revolutionized the care of patients with inflammatory bowel disease (IBD).

Areas covered: Considerations before starting anti-TNF therapy are highlighted: the best time to start with anti-TNF therapy, either alone or in combination with an immunomodulator, the choice of an anti-TNF agent and the contra-indications to anti-TNF therapy. Primary nonresponse and secondary loss of response are discussed. De-escalating therapy, the role of therapeutic drug monitoring and the use of biosimilars, are handled. Finally, the future directions of anti-TNF therapy are emphasized.

Expert opinion: Anti-TNF therapy remains the cornerstone in the treatment of IBD. When initiating long-term therapy, safety and cost issues are of great importance. The therapeutic armamentarium in the treatment of IBD is rapidly growing. Therefore, the challenge is to optimize the use and refine the exact position of anti-TNF therapy in the near future, with personalized medicine as the ultimate goal.     

Salivary protein biomarkers for head and neck cancer

ABSTRACT

Introduction: Saliva has gained attention as an important diagnostic fluid because it contains biomolecules that have the potential to detect early-stage cancer or to monitor the response to treatment in patients. Several saliva-based proteins have been proposed as potential biomarkers for head and neck cancers (HNC).

Areas covered: This review aims to provide an update on saliva-based protein biomarkers for HNC, often studied in observational research and clinical trials.

Expert opinion: Despite the increasing number of studies relating to salivary proteins as biomarkers for HNC, there is no consensus regarding which proteins have the best clinical utility. Most studies have analyzed individual proteins and not a protein panel approach. It must be considered that combining different proteins as a panel can increase the accuracy and will have the potential to change the current clinical practice for HNC patients.     

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.