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.

     

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.     

MRI features of perianal fistulas: is there a difference between Crohn’s and non-Crohn’s patients?

Purpose

Though perianal fistulas are commonly seen in patients with Crohn’s disease, they can also be seen in patients without inflammatory bowel disease. The purpose of this study was to evaluate MR imaging differences of perianal fistulas in patients with and without Crohn’s disease.

Methods

Our retrospective search from January 2012 to December 2015 of the Radiology database for perianal fistula yielded 207 patients. Only patients with dedicated MR fistula protocol studies were included, whereas patients with previous anal surgery or anastomosis, anorectal tumors, and equivocal findings that could not be definitely assessed as a fistula were excluded. The following features were assessed: anatomic type of fistula (Parks Classification), luminal origin (hour clock position), anal verge distance, signs of acute inflammation, circumference of anus involved by inflammation, presence of rectal inflammation. and abscess.

Results

One hundred and twenty six of 207 patients met inclusion criteria. Of these, 96 (76.2%) had Crohn’s disease and 30 (23.8%) did not. The most common fistulas identified were transphincteric (38.5% of Crohn’s and 50% of non-Crohn’s) and intersphincteric (33.3% of Crohn’s and 35.4% of non-Crohn’s). An abscess was associated in 41 cases, 32 (33.3%) in the Crohn’s group and 9 (30.0%) in the non-Crohn’s group. Rectal inflammation was present in 29 patients with Crohn’s disease (29.2%) and in 2 without Crohn’s (6.7%). This finding was statistically significant (p = 0.0009).

Conclusions

Our study demonstrates that while both groups can have similar MR imaging features, accompanying rectal inflammation was more commonly seen in Crohn’s 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.     

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.     

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.     

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.     

Rheumatologic and extraintestinal manifestations of inflammatory bowel diseases

Inflammatory bowel diseases (IBDs) often present as a complex inflammatory process wherein colon lesions (ulcerative colitis, UC) or widespread ulceration and fissure (Crohn’s disease, CD) might be accompanied by ancillary extraintestinal manifestations (EIMs) that could involve almost every organ system, but also by autoimmune disorders ranging from psoriasis and rheumatoid arthritis to connective tissue diseases. Certain EIMs are more common related to the activity of the IBD (joint, skin, ocular and oral manifestations), other EIMs typically run a course independent of the IBD activity (hepatobiliary disorders) and some are non-specific disorders (osteoporosis and amyloidosis). This paper reviews the most common extraintestinal and rheumatologic manifestations of UC and CD. They may produce greater morbidity than the underlying intestinal disease and may even be the initial presenting symptoms of the IBD. Thus, early recognition of these manifestations should help guide therapy that will reduce overall morbidity in affected patients.

• Key Message

• A complete review on the most common extraintestinal and rheumatologic manifestations of ulcerative colitis and Crohn’s disease.

     

Special considerations for biologic medications in pediatric ulcerative colitis

ABSTRACT

Introduction: More extensive disease, high rates of corticosteroid refractory and dependent disease, and the potential impact of disease on growth and development differentiate inflammatory bowel disease in children from adults. This is particularly evident in ulcerative colitis where pancolitis predominates, success of mesalamine alone in achieving remission is less than 50%, and there is a high need for immunomodulator or biologic therapies.

Areas Covered: This review describes the use of infliximab, adalimumab, golimumab, and vedolizumab in the treatment of children with ulcerative colitis but is limited in scope due to the paucity of controlled clinical trials. A search of existing literature with keywords of these specific biological therapies as well as ‘pediatric’, ‘ulcerative colitis,’ and ‘inflammatory bowel disease’ was used to complete this review.

Expert Opinion: Therapeutic drug monitoring has become standard of care when assessing dosing and changes in therapy and will play a role in future treatment planning.     

Inflammatory bowel disease: new therapies from antisense oligonucleotides

Inflammatory bowel diseases (IBD) are chronic inflammatory conditions of the gastrointestinal tract encompassing two main clinical entities: Crohn’s disease (CD) and ulcerative colitis (UC). These disorders are characterized by various grades of tissue damage and development of local complications and extra-intestinal manifestations. The cause of IBD remains unknown but accumulating evidence indicates that both CD and UC arise in genetically predisposed individuals as a result of the action of multiple environmental factors, which ultimately trigger excessive and poorly controlled immune response against antigens of the luminal flora. Despite this realization, a full understanding of IBD pathogenesis is still out of reach and, consequently, treatment is far from optimal. However, in recent years, several pathways of intestinal damage have been delineated and the improved knowledge has contributed to the development of new therapies. Various approaches have been used to either inhibit the expression and/or function of inflammatory molecules or enhance counter-regulatory mechanisms. This review summarizes the available pre-clinical and clinical data for antisense oligonucleotides and oligonucleotide-based therapy to provide a comprehensive understanding of the rationale and mechanism of action of these compounds in IBD.

• Key messages

• Preclinical studies and clinical trials show that antisense oligonucleotide (ASO)-based therapy could be of benefit in inflammatory bowel diseases.

• ASOs have an excellent safety profile.

• Technical issues emerged from clinical trials suggest that changes in drug formulation and/or route of administration could improve ASO efficacy.

     

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.     

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.     

The use of ustekinumab in autoimmune disease

Importance of the field: The advent of biologic therapies has revolutionized the treatment of autoimmune diseases including psoriasis, autoimmune arthritides and inflammatory bowel disease. With recent advances in our understanding of the immunogenetic pathways involved in the pathogenesis of these conditions, newer, more targeted biologic therapies have been developed. Ustekinumab is an antibody to the common p40 subunit of IL-12 and IL-23, which has been studied in the treatment of psoriasis, psoriatic arthritis, Crohn's disease and multiple sclerosis.

Areas covered in this review: This review details the efficacy and safety of ustekinumab in all clinical studies to date, using PubMed listed publications and official product websites.

What the reader will gain: Readers will gain a comprehensive understanding of the mechanism of action of ustekinuamb, its pharmacodynamic and pharmacokinetic profile, and its clinical efficacy and safety in the treatment of psoriasis, psoriatic arthritis, Crohn's disease and multiple sclerosis.

Take home message: Ustekinumab has shown significant efficacy in the treatment of chronic plaque psoriasis in Phase III studies, and promising results in Phase II studies in psoriatic arthritis. Efficacy has been shown in Crohn's disease only in non-responders to infliximab. Ustekinumab did not show benefit in the treatment of multiple sclerosis.     

Infliximab and ulcerative colitis

Tumour necrosis factor (TNF)-α is an inflammatory cytokine that plays a main role in the inflammatory process underlying inflammatory bowel disease (IBD). Despite the fact that the cytokine profiles associated with ulcerative colitis (UC) and Crohn’s disease (CD) are classically considered different (a Th2 pattern in UC and a Th1 pattern in CD), there are several evidences in vitro and in vivo that TNF-α has an important role in UC. For this reason, infliximab, the chimeric monoclonal antibody to TNF-α, has been evaluated in the therapy of UC. The drug has been evaluated in different clinical settings both in adults and in children: in moderate–severe steroid-dependent UC, in severe refractory UC as rescue therapy, in active non-steroid-refractory UC, in resistant pouchitis and in maintenance of moderate–severe UC responsive to infliximab. On the basis of the randomised controlled trials (RCTs), it is possible to draw the following conclusions for adults: infliximab seems active in severe steroid-refractory UC, allowing colectomy to be spared even if further controlled trials are needed with a larger sample of patients adopting strict and well-defined inclusion criteria. The drug seems active in inducing remission after 8 weeks in steroid-refractory patients, in patients taking steroids (even if it is not clear at which dosage of steroid dependence the drug is more active) and also in patients failing aminosalicylates therapy. The long-term response of infliximab in comparison to placebo in these subgroups of patients is not clinically impressive even if it is statistically significant. Further trials are warranted in order to establish the role of infliximab in steroid-dependent UC (defined with clear criteria), in maintaining remission after severe UC, in non-steroid-dependent moderate–severe UC and in refractory pouchitis. For children it is not possible to draw the same conclusions, due to a lack of RCTs, despite the encouraging data coming from open studies, mainly in steroid-refractory UC.     

Crohn’s disease diagnosis,treatment approach,and management paradigm: what the radiologist needs to know

Crohn’s disease is one of the major subtypes of idiopathic inflammatory bowel disease and is characterized by chronic transmural intestinal inflammation of the gastrointestinal tract anywhere from mouth to the anus, with a predilection for the small bowel. Cross-sectional imaging with computed tomography and magnetic resonance enterography plays a key role in confirming diagnosis, identifying and managing complications, assessing disease severity, and identifying response to medical therapy. This review will focus on the role of radiologists in the diagnosis and assessment of Crohn’s disease. Additionally, a review of current medical therapy approaches, available medications, and side effects will be discussed. The review will also highlight key complications of medical therapy and associated diseases that should be evaluated by the radiologist with cross-sectional imaging.

     

The alternate effects of anti-TNFα therapeutics and their role in mycobacterial granulomatous infection in Crohn’s disease

Introduction: Crohn’s disease is an inflammatory bowel disease that has been debated to be associated with bacterial triggers such as Mycobacterium avium subspecies paratuberculosis (MAP). Standard treatment of Crohn’s disease (CD) patients includes a family of immunomodulators and biologics such as Anti-Tumor Necrosis Factor alpha (Anti-TNFα). This cytokine in particular has been known to play vital roles in fighting microbial infections through formation and maintenance of granulomas.

Areas covered: This perspective is focused on elucidating the negative effects of using Anti-TNFα therapeutic agents as a treatment option in CD patients who are more likely suspected to have MAP infection, and the role of other immunomodulators in MAP infection.

Expert commentary: While treatment with Anti-TNFα is beneficial to reduce inflammation and to provide short term relief to the patients, it also compromises the immune system causing susceptibility to microbial infection. More than 50% of CD patients have shown no response to Anti-TNFα treatment which indicates a demand for introducing novel CD treatment in combination with antibiotics as a future CD treatment plan.     

Optimization of biologic therapy in Crohn’s disease

Introduction: Crohn’s disease (CD) is a manifestation of inflammatory bowel disease (IBD), which can result in significant morbidity. Biologic therapy with anti-TNF medication has been effective in treating inflammation and reducing complications in CD. It is important for clinicians to have better knowledge of the various biologic therapies including mechanisms of action and optimization strategies.

Areas covered: The review describes optimization of biologic therapy in CD including different mechanisms of loss of response, therapeutic drug monitoring in CD, clinical implications and management strategies which utilize drug monitoring, and areas of future development and research in optimization of biologic therapy.

Expert opinion: Achieving adequate levels of the drug (antibody unbound) is one of the most important determinants of attaining clinical remission and mucosal healing. Drug level is also critical in determining if a patient requires combination therapy with an immunomodulator. Certain populations, including those with active perianal disease, may require higher serum levels to achieve healing or closure. Treat to target level is an algorithm that is not universally accepted and more data is need. Additionally, there are numerous assays that don’t always correlate, especially regarding measuring anti-drug antibodies.     

Antimicrobial treatment with the fixed-dose antibiotic combination RHB-104 for Mycobacterium avium subspecies paratuberculosis in Crohn’s disease: pharmacological and clinical implications

Introduction: Crohn’s disease (CD) is an inflammatory bowel disease of unknown etiology. However, increasing evidence suggests Mycobacterium avium subspecies paratuberculosis (MAP) as a putative causative agent: 1) MAP is the etiological agent of Johne’s disease, a granulomatous enteritis affecting ruminants, which shares clinical and pathological features with CD; 2) MAP has been detected in tissues and blood samples from CD patients; 3) case reports have documented a favorable therapeutic response to anti-MAP antibiotics.

Area covered: This review provides an appraisal of current information on MAP characteristics, diagnostic methodologies and emerging drug treatments. The authors focus on RHB-104, a novel oral formulation containing a fixed-dose combination of clarithromycin, clofazimine and rifabutin, endowed with synergistic inhibitory activity on MAP strains isolated from CD patients.

Expert opinion: Based on encouraging in vitro data, RHB-104 has entered recently the clinical phase of its development, and is being investigated in a randomized, placebo-controlled phase III trial aimed at evaluating its efficacy and safety in CD. Provided that the overall clinical development will support the suitability of RHB-104 for inducing disease remission in CD patients with documented MAP infection, this novel antibiotic combination will likely take a relevant position in the therapeutic armamentarium for CD management.     

Top-down approach to biological therapy of Crohn’s disease

Introduction: Crohn’s disease (CD) is a chronic, immune-mediated condition with a potentially disabling and destructive course. Despite growing data on when to use a therapeutic ‘top-down’ strategy, clinical management of this complex disorder is still challenging. Currently, the discussion of ‘top-down’ strategy in CD mostly includes biological therapy alone or in combination.

Areas covered: This article is based on a review of existing literature regarding the use of biological therapy in a ‘top-down’ approach for the treatment of Crohn’s disease. The authors reviewed all the major databases including MEDLINE as well as DDW and ECCO abstracts, respectively.

Expert opinion: A ‘top-down’ therapeutic approach in Crohn’s disease is strongly supported by existing data in patients with several risk factors for a severe course of disease. Moreover, there is an increasing amount of published data recommending a more individualised therapeutic strategy to identify candidates for ‘top-down’ treatment, based on enhanced diagnostics using biomarkers. Emerging therapeutic approaches besides existing therapy concepts using biologicals may possibly redefine the ‘top-down’ therapeutic strategy for Crohn’s disease in the future.