Current relevance of pharmacogenetics in immunomodulation treatment for Crohn's disease

No drug therapy is completely risk free, and the costs associated with non-response and adverse effects can exceed the cost of the therapy. The ultimate goal of pharmacogenetic research is to find robust genetic predictors of drug response that enable the development of prospective genetic tests to reliably identify patients at risk of non-response or of developing an adverse effect prior to the drug being prescribed. Currently, thiopurine S-methyltransferase (TPMT) deficiency is the only pharmacogenetic factor that is prospectively assessed before azathioprine or 6-mercaptopurine immunomodulation is commenced in patients with Crohn's disease (CD). As yet no other inherited determinant of drug response has made the transition from bench to bedside for the management of this disease. In this review we summarize what is known about TPMT deficiency and explore whether there is evidence to support a role of other genetic polymorphisms in predicting the response of CD patients to thiopurine drugs, methotrexate, and anti-tumor necrosis factor α (TNFα) therapy.     

Pharmacogenetics in inflammatory bowel disease

Pharmacogenetics is the study of the association between variability in drug response and (or) drug toxicity and polymorphisms in genes. The goal of this field of science is to adapt drugs to a patient's specific genetic background and therefore make them more efficacious and safe. In this article we describe the variants in genes that influence either the efficacy or toxicity of common drugs used in the treatment of inflammatory bowel diseases (IBD), ulcerative colitis (UC), and Crohn's disease (CD) including sulfasalazine and mesalazine, azathioprine (AZA) and 6-mercaptopurine (6-MP), methotrexate (MIX), glucocorticosteroids (CSs) and infliximab. Furthermore, difficulties with pharmacogenetic studies in general and more specifically in IBD are described. Although pharmacogenetics is a promising field that already contributed to a better understanding of some of the underlying mechanisms of action of drugs used in IBD, the only discovery translated until now into daily practice is the relation between thiopurine S-methyltransferase (TPMT) gene polymorphisms and hematological toxicity of thiopurine treatment. In the future it is necessary to organize studies in well characterized patient cohorts who have been uniformly treated and systematically evaluated in order to quantitate drug response more objectively. An effort should be made to collect genomic DNA from all patients enrolled in clinical drug trials after appropriate informed consent for pharmacogenetic studies.     

Thiopurine-induced pancreatitis in inflammatory bowel diseases

Crohn’s disease and ulcerative colitis are chronic inflammatory conditions affecting the gut and can present at any age with increased numbers of diagnoses seen in many countries in recent years. The thiopurine drugs, azathioprine and 6-mercaptopurine, are commonly used to maintain remission in Crohn’s disease and ulcerative colitis; however, the use of these drugs may be limited by the development of pancreatitis in some individuals. Recent data indicate a genetic risk factor and provides a potential immune-mediated mechanism for thiopurine-induced pancreatitis. Management of thiopurine-induced pancreatitis requires exclusion of the triggering drug, which leads to prompt resolution of symptoms. This thiopurine side-effect may limit therapeutic options for future management of patients.     

5-aminosalicylic acid is an attractive candidate agent for chemoprevention of colon cancer in patients with inflammatory bowel disease

Inflammatory bowel disease (IBD) is classically subdivided into ulcerative colitis (UC) and Crohn's disease (CD). Patients with IBD have increased risk for colorectal cancer. Because the pathogenesis of colorectal carcinoma has not been entirely defined yet and there is no ideal treatment for colon cancer, cancer prevention has become increasingly important in patients with IBD. The two adopted methods to prevent the development of colon cancer in clinical practice include the prophylactic colectomy and colonoscopic surveillance. But patients and physicians seldom accept colectomy as a routine preventive method and most patients do not undergo appropriate colonoscopic surveillance. Chemoprevention refers to the use of natural or synthetic chemical agents to reverse, suppress, or to delay the process of carcinogenesis. Chemoprevention is a particularly useful method in the management of patients at high risk for the development of specific cancers based on inborn genetic susceptibility, the presence of cancer-associated disease, or other known risk factors. Prevention of colorectal cancer by administration of chemopreventive agents is one of the most promising options for IBD patients who are at increased risks of the disease. The chemopreventive efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) against intestinal tumors has been well established. But with reports that NSAIDs aggravated the symptoms of colitis, their sustained use for the purpose of cancer Chemoprevention has been relatively contraindicated in IBD patients. Another hopeful candidate Chemoprevention drug for IBD patients is 5-aminosalicylic acid (5-ASA), which is well tolerated by most patients and has limited systemic adverse effects, and no gastrointestinal toxicity. 5-ASA lacks the well-known side effects of longterm NSAIDs use. Retrospective correlative studies have suggested that the long-term use of 5-ASA in IBD patients may significantly reduce the risk of development of colorectal cancer. According to the literature, this agent might well satisfy clinical expectations with respect to a safe and effective chemopreventive agent.     

Role of genetics in prediction of disease course and response to therapy

The clinical course of Crohn's disease and ulcerative colitis is highly variable between patients,and this has therapeutic implications.A number of clinical features have been identified,which predict a mild or more severe outcome.However,several of these are subjective and/or not persistent over time.With the progress in genetics research in inflammatory bowel disease(IBD),genetic markers are increasingly being proposed to improve stratification of patients.Genetics have the major advantage of being stable...     

Thiopurine S-methyltransferase polymorphisms and thiopurine toxicity in treatment of inflammatory bowel disease

AIM: To evaluate the relationship between thiopu- rine S-methyltransferase (TPMT) polymorphisms and thiopurine-induced adverse drug reactions (ADRs) in inflammatory bowel disease (IBD). METHODS: Eligible articles that compared the frequency of TPMT polymorphisms among thiopurine-tolerant and-intolerant adult IBD patients were included. Statistical analysis was performed with Review Manager 5.0. Sub-analysis/sensitivity analysis was also performed. RESULTS: Nine studies that investigated a total of 1309 part...     

The role of pharmacogenetics in nonmalignant gastrointestinal diseases

Genetic variation influences the absorption and efflux of drugs in the intestine, the metabolism of drugs in the liver and the effects of these drugs on their target proteins. Indeed, variations in genes whose products have a role in the pathophysiology of nonmalignant gastrointestinal diseases, such as IBD, have been shown to affect the response of patients to therapy. This Review provides an overview of pharmacogenetics in the management of nonmalignant gastrointestinal diseases on the basis of data from clinical trials. Genetic variants that have the greatest effect on the management of patients with IBD involve the metabolism of thiopurines. Variation in drug metabolism by cytochrome P450 enzymes also requires attention so as to avoid drug interactions in patients receiving tricyclic antidepressants and PPIs. Few genotyping tests are currently used in the clinical management of patients with nonmalignant gastrointestinal diseases, owing to a lack of data from clinical trials showing their effectiveness in predicting nonresponse or adverse outcomes. However, pharmacogenetics could have a beneficial role in enabling pharmacotherapy for nonmalignant gastrointestinal diseases to be targeted to the individual patient.     

Liver-side of inflammatory bowel diseases: Hepatobiliary and drug-induced disorders

Hepatobiliary disorders are among the most common extraintestinal manifestations in inflammatory bowel diseases (IBD), both in Crohn’s disease and ulcerative colitis (UC), and therefore represent a diagnostic challenge. Immune-mediated conditions include primary sclerosing cholangitis (PSC) as the main form, variant forms of PSC (namely small-duct PSC, PSC-autoimmune hepatitis overlap syndrome and IgG4-related sclerosing cholangitis) and granulomatous hepatitis. PSC is by far the most common, presenting in up to 8% of IBD patients, more frequently in UC. Several genetic foci have been identified, but environmental factors are preponderant on disease pathogenesis. The course of the two diseases is typically independent. PSC diagnosis is based mostly on typical radiological findings and exclusion of secondary cholangiopathies. Risk of cholangiocarcinoma is significantly increased in PSC, as well as the risk of colorectal cancer in patients with PSC and IBD-related colitis. No disease-modifying drugs are approved to date. Thus, PSC management is directed against symptoms and complications and includes medical therapies for pruritus, endoscopic treatment of biliary stenosis and liver transplant for end-stage liver disease. Other non-immune-mediated hepatobiliary disorders are gallstone disease, whose incidence is higher in IBD and reported in up to one third of IBD patients, non-alcoholic fatty liver disease, pyogenic liver abscess and portal vein thrombosis. Drug-induced liver injury (DILI) is an important issue in IBD, since most IBD therapies may cause liver toxicity; however, the incidence of serious adverse events is low. Thiopurines and methotrexate are the most associated with DILI, while the risk related to anti-tumor necrosis factor-α and anti-integrins is low. Data on hepatotoxicity of newer drugs approved for IBD, like anti-interleukin 12/23 and tofacitinib, are still scarce, but the evidence from other rheumatic diseases is reassuring. Hepatitis B reactivation during immunosuppressive therapy is a major concern in IBD, and adequate screening and vaccination is warranted. On the other hand, hepatitis C reactivation does not seem to be a real risk, and hepatitis C antiviral treatment does not influence IBD natural history. The approach to an IBD patient with abnormal liver function tests is complex due to the wide range of differential diagnosis, but it is of paramount importance to make a quick and accurate diagnosis, as it may influence the therapeutic management.     

Two cases of thiopurine-induced acute pancreatitis in inflammatory bowel disease

Thiopurine drugs have been widely used in the treatment of inflammatory bowel disease. However, their use is limited by adverse effect that can lead to cessation of therapy. We report 2 cases of thiopurine-induced acute pancreatitis in patients with inflammatory bowel disease. Both patients complained of abdominal pain, showed elevated pancreatic enzymes, and swollen pancreases on computed tomography. The patients' signs and symptoms resolved uneventfully after withdrawal of the thiopurine drugs. Although the mechanism of thiopurine-induced pancreatitis remains unclear, close monitoring and early recognition of acute pancreatitis is important in the management of new thiopurine users.     

Infections and inflammatory bowel disease: Challenges in Asia

The diagnosis and management of inflammatory bowel disease (IBD) in Asia can be challenging as certain infections can mimic IBD and lead to a misdiagnosis. Colitis can be caused by bacterial infections, ileitis can result from Yersinia and Salmonella infections and ileocolonic ulcers can be seen in intestinal tuberculosis and amebiasis. In addition, cytomegalovirus and Clostridium difficile infection may mimic a flare of IBD and their presence is associated with an increased risk of colectomy and mortality. Because of the increasing use of corticosteroids, immunosuppressive drugs and biological agents the risk of opportunistic infection and the reactivation of latent infection including tuberculosis and hepatitis B, are also higher in IBD patients. Screening and prevention of infection, timely vaccination and the education of the patient is paramount before initiating immunosuppressive drugs. The role of the physician lies not only in the diagnosis and management of IBD but also in the ability to prevent, recognize and treat infections.     

炎症性肠病药物联合治疗的获益与风险

目前炎症性肠病(IBD)的发病机制未完全明确，虽有越来越多的生物制剂问世，但其治疗仍存在难点，有时无法得到令人满意的疗效。在临床实践中，当常规治疗收效不佳时，将几种药物联合应用治疗IBD不失为一种重要的治疗策略，但药物联合治疗提高疗效的同时可能会增加感染及肿瘤等风险。因此应用联合治疗时需结合患者的疾病类型、病情程度、病变范围、高危因素、既往用药情况，对治疗方案进行技巧性地选择和甄别必不可少。     

Prevalence,predictors, and clinical consequences of medical adherence in IBD： How to improve it？

Inflammatory bowel diseases （IBD） are chronic diseases with a relapsing-remitting disease course necessitating lifelong treatment. However, non-adherence has been reported in over 40% of patients, especially those in remission taking maintenance therapies for IBD. The economical impact of non-adherence to medical therapy including absenteeism, hospitalization risk, and the health care costs in chronic conditions, is enormous. The causes of medication non-adherence are complex, where the patient-doctor relationship, treatment regimen, and other disease-related factors play key roles. Moreover, subjective assessment might underestimate adherence. Poor adherence may result in more frequent relapses, a disabling disease course, in ulcerative colitis, and an increased risk for colorectal cancer. Improving medication adherence in patients is an important challenge for physicians. Understanding the different patient types, the reasons given by patients for non-adherence, simpler and more convenient dosage regimens, dynamic communication within the health care team, a self-management package incorporating enhanced patient education and physician-patient interaction, and identifying the predictors of non-adherence will help devise suitable plans to optimize patient adherence. This editorial summarizes the available literature on frequency, predictors, clinical consequences, and strategies for improving medical adherence in patients with IBD.     

Review of inflammatory bowel disease and COVID-19

The first cases of a novel corona virus infection were reported in Wuhan China in December of 2019, followed by the declaration of an international pandemic by the World Health Organization in March 2020. Early reports of the virus, now known as severe acute respiratory syndrome coronavirus 2, and its clinical disease coronavirus disease 2019(COVID-19), has shown higher rates of morbidity and mortality in the elderly and those with pre-existing medical conditions. Of particular concern is the safety of those with compromised immune systems. Inflammatory Bowel disease(IBD) is itself caused by a disordered immune response, with the most effective medical therapies being immune suppressing or modifying. As such, the risk of COVID-19, virus related outcomes, and appropriate management of IBD patients during the global pandemic is of immediate concern to gastroenterologists worldwide. There has been a rapid accumulation of clinical data and expert opinion on the topic. This review will highlight the latest source information on clinical observation/outcomes of the IBD population and provide a concise summary of the most up to date perspectives on IBD management in the age of COVID-19.     

Advances in the Diagnosis and Management of Inflammatory Bowel Disease: Challenges and Uncertainties

Over the past two decades, several advances have been made in the management of patients with inflammatory bowel disease (IBD) from both evaluative and therapeutic perspectives. This review discusses the medical advancements that have recently been made as the standard of care for managing patients with ulcerative colitis (UC) and Crohn''s Disease (CD) and to identify the challenges associated with implementing their use in clinical practice. A comprehensive literature search of the major databases (PubMed and Embase) was conducted for all recent scientific papers (1990–2013) giving the recent updates on the management of IBD and the data were extracted. The reported advancements in managing IBD range from diagnostic and evaluative tools, such as genetic tests, biochemical surrogate markers of activity, endoscopic techniques, and radiological modalities, to therapeutic advances, which encompass medical, endoscopic, and surgical interventions. There are limited studies addressing the cost-effectiveness and the impact that these advances have had on medical practice. The majority of the advances developed for managing IBD, while considered instrumental by some IBD experts in improving patient care, have questionable applications due to constraints of cost, lack of availability, and most importantly, insufficient evidence that supports their role in improving important long-term health-related outcomes.     

Crucial steps in the natural history of inflammatory bowel disease

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic, progressive and disabling disorders. Over the last few decades, new therapeutic approaches have been introduced which have led not only to a reduction in the mortality rate but also offered the possibility of a favorable modification in the natural history of IBD. The identification of clinical, genetic and serological prognostic factors has permitted a better stratification of the disease, thus allowing the opportunity to indicate the most appropriate therapy. Early treatment with immunosuppressive drugs and biologics has offered the opportunity to change, at least in the short term, the course of the disease by reducing, in a subset of patients with IBD, hospitalization and the need for surgery. In this review, the crucial steps in the natural history of both UC and CD will be discussed, as well as the factors that may change their clinical course. The methodological requirements for high quality studies on the course and prognosis of IBD, the true impact of environmental and dietary factors on the clinical course of IBD, the clinical, serological and genetic predictors of the IBD course (in particular, which of these are relevant and appropriate for use in clinical practice), the impact of the various forms of medical treatment on the IBD complication rate, the role of surgery for IBD in the biologic era, the true magnitude of risk of colorectal cancer associated with IBD, as well as the mortality rate related to IBD will be stressed; all topics that are extensively discussed in separate reviews included in this issue of World Journal of Gastroenterology.     

Seronegative spondyloarthropathy-associated inflammatory bowel disease

Seronegative spondyloarthropathy (SpA) usually starts in the third decade of life with negative rheumatoid factor, human leukocyte antigen-B27 genetic marker and clinical features of spinal and peripheral arthritis, dactylitis, enthesitis and extra-articular manifestations (EAMs). Cases can be classified as ankylosing spondylitis, psoriatic arthritis, reactive arthritis, enteropathic arthritis, or juvenile-onset spondyloarthritis. Joint and gut inflammation is intricately linked in SpA and inflammatory bowel disease (IBD), with shared genetic and immunopathogenic mechanisms. IBD is a common EAM in SpA patients, while extraintestinal manifestations in IBD patients mostly affect the joints. Although individual protocols are available for the management of each disease, the standard therapeutic guidelines of SpA-associated IBD patients remain to be established. Nonsteroidal anti-inflammatory drugs are recommended as initial therapy of peripheral and axial SpA, whereas their use is controversial in IBD due to associated disease flares. Conventional disease-modifying anti-rheumatic drugs are beneficial for peripheral arthritis but ineffective for axial SpA or IBD therapy. Anti-tumor necrosis factor monoclonal antibodies are effective medications with indicated use in SpA and IBD, and a drug of choice for treating SpA-associated IBD. Janus kinase inhibitors, approved for treating SpA and ulcerative colitis, are promising therapeutics in SpA coexistent with ulcerative colitis. A tight collaboration between gastroenterologists and rheumatologists with mutual referral from early accurate diagnosis to appropriately prompt therapy is required in this complex clinical scenario.     

Venous thrombosis and prothrombotic factors in inflammatory bowel disease

Patients with inflammatory bowel disease(IBD)may have an increased risk of venous thrombosis(VTE).PubMed,ISI Web of Knowledge and Scopus were searched to identify studies investigating the risk of VTE and the prevalence of acquired and genetic VTE risk factors and prothrombotic abnormalities in IBD.Overall,IBD patients have a two-to fourfold increased risk of VTE compared with healthy controls,with an overall incidence rate of 1%-8%.The majority of studies did not show significant differences in the risk of VTE between Crohn’s disease and ulcerative colitis.Several acquired factors are responsible for the increased risk of VTEin IBD:inflammatory activity,hospitalisation,surgery,pregnancy,disease phenotype(e.g.,fistulising disease,colonic involvement and extensive involvement)and drug therapy(mainly steroids).There is also convincing evidence from basic science and from clinical and epidemiological studies that IBD is associated with several prothrombotic abnormalities,including initiation of the coagulation system,downregulation of natural anticoagulant mechanisms,impairment of fibrinolysis,increased platelet count and reactivity and dysfunction of the endothelium.Classical genetic alterations are not generally found more often in IBD patients than in nonIBD patients,suggesting that genetics does not explain the greater risk of VTE in these patients.IBD VTE may have clinical specificities,namely an earlier first episode of VTE in life,high recurrence rate,decreased efficacy of some drugs in preventing further episodes and poor prognosis.Clinicians should be aware of these risks,and adequate prophylactic actions should be taken in patients who have disease activity,are hospitalised,are submitted to surgery or are undergoing treatment.