Current Drug Targets - Volume 15, Issue 11, 2014

Crohn’s disease (CD) and ulcerative colitis (UC) are the two major forms of Inflammatory Bowel Disease (IBD). These progressive and disabling diseases represent a major challenge for clinicians facing complex patients. The multifaceted aspects of disease characteristics require constant update for the gastroenterologists taking care of both CD and UC patients. In this special issue of Current Drug Targets several aspects of IBD management are covered that go far beyond the classical medical therapy. First of all management in challenging cases should always cover optimization of conventional medical therapies, that is the initial and crucial step when patients are most difficult. Indeed our therapeutic armamentarium for chronic conditions is still limited depsite the arrival of new biologics such as vedolizumab and golimumab. In this regard, when biologic therapies are ongoing or are about to be started, accumulating evidence indicates that pharmacokinetics of these drugs should be monitored, considering that this is a very rapidly evolving field and evidence starts to build on key aspects that show that drug level monitoring could lead to cost savings. However, controlled trials showing a positive impact from measuring drug levels and antibodies against monoclonal antibodies on disease outcomes are still lacking in IBD. Furthermore, clinicans should always keep in mind that half of the patients with newly diagnosed CD will develop some bowel damage (strictures, abscess and/or fistulas) at 10 years. Similar to rheumatoid arthritis, a therapeutic window of opportunity is offered to both doctors and patients, and the most effective treatments should be initiated in order to stop disease progression or to prevent disease complications such as disability and bowel damage. Many other aspects of the complexity of IBD are covered in the special issue, including iron deficiency, that is the most common extraintestinal manifestation, and is frequently forgotten and thus undertreated, or nutrition, that is a key aspect of disease management. A growing body of evidence indicates that iron deficiency should be systematically screened and treated even when it is not associated with anemia. Indeed, iron deficeincy has a major impact on patients-reported outcomes such as fatigue and quality of life and leads to anemia in most of cases. Malnutrition is also underdiagnosed in adults with IBD while it concerns 75% of hospitalized patients with CD. The beneficial impact of nutrition support on disease course is well established in children with IBD. Obviously, the complexity of patient care also embraces extraintestinal manifestations that are seen in about one third of IBD patients and in particular the best strategies and evidence that try to identify the most suitable patients for response to biologic treatment, but also the critical clinical scenario of controindication to such drugs, if a patient has a cancer history. Finally, evolving aspects take care of psychotherapeutic interventions targeting the psychological factors involved in IBD, not only as therapy but expecially when patients are about to undergo surgery. The mind should be always considered as part of the medical treatment, with a multidisciplinary team. Last but not the least, many patients are using complementary medicines, that even though are little prescribed by specialists, are very popular from the patient perspective. Recognizing this issue is a prerequesite to improvement of patient-physician relationship as the only answer prodived by most of physicians is still the same: “it does not work”. Indeed, patients are using complementary medicines because they are not satisfied with their conventional treatment and tend to stop it, thus contributing to non-adherence. All the above are just few burning aspects highlighted to try to embrace disease complexity, but enough to make IBD as one of the more intriguing diseases for GI specialists.

Goals of therapy for inflammatory bowel disease have advanced beyond symptom control to the normalization of biomarkers of inflammation, and mucosal healing in particular, with the expectation that this will change the natural history of these diseases. Concurrent with higher treatment expectations has come an expanded therapeutic armamentarium to achieve these goals, and a greater ability to optimize each therapeutic class to maximize therapeutic benefits and minimize unnecessary treatment failures. In addition to these advances has come the evolution of therapeutic drug monitoring which is increasingly being utilized to optimize the use of immunomodulators and biologic therapies in particular. This review will outline the principals of optimization of the conventional medical therapies available to the clinician today.

Iron deficiency (ID) and anemia of chronic diseases (ACD) are the most common causes of anemia in inflammatory bowel disease (IBD), and frequently coexist. In these circumstances, detection of ID may be difficult as inflammation influences the parameters of iron metabolism. The prevalence of iron deficiency anemia (IDA) ranges between 36% and 76% in this population of patients. Anemia may impair physical condition, quality of life (QOL), and cognitive function, negatively affecting almost every aspect of daily life. Furthermore, it may be one of the causes of death in IBD. Consequently, iron replacement therapy should be initiated as soon as ID or IDA is detected, together with the treatment of underlying inflammation. Oral iron therapy is a simple and cheap treatment, but often is poorly tolerated and may worsen the intestinal damage. Moreover, in inflammatory states, duodenal iron absorption is blocked by a cytokine-mediated mechanism. Consequently, intravenous iron therapy is preferred in the presence of severe anemia, intolerance or lack of response to oral iron, and moderately to severely active disease. Recently, new intravenous iron compounds (iron carboxymaltose, iron isomaltoside 1000, ferumoxytol) have become available. Iron carboxymaltose has been shown to be safe and effective in IBD patients with IDA. Furthermore, it allows for rapid administration of high single doses, saving time and costs. If proven to be efficacious and well tolerated, it may become the standard therapy in the near future.

The present article aims to review the literature on the relationship between psychology and inflammatory bowel disease (IBD). In particular, the first section is dedicated to explore the role of psychological factors in the etiopathology of the disease, its development and the efficacy of treatments, while the second analyzes existing literature on the role of psychological interventions in the care of IBD patients. Although the role of psychological factors in IBD appears controversial, literature seems to distinguish between antecedents of the disease (stress and lifestyle behavior), potential mediators of disease course (family functioning, attachment style, coping strategies, and illness perception), outcomes of IBD and concurrent factors (anxiety, depression and quality of life). Four types of psychological interventions are described: Stress management, Psychodynamic, Cognitive behavioral and Hypnosis based. Data on the role and efficacy of psychological interventions in IBD patients show little evidence both on reduction of the disease activity and benefits on psychological variables. Psychological interventions seem to be beneficial in the short term especially for adolescents. The importance of considering the connections between psychology and IBD from a broader perspective reflecting the complexity of the phenomenon at multiple levels is discussed.

Seventy five percent of hospitalized patients with Crohn’s disease suffer from malnutrition. One third of Crohn’s disease patients have a body mass index below 20. Sixty percent of Crohn’s disease patients have sarcopenia. However some inflammatory bowel disease (IBD) patients are obese or suffer from sarcopenic-obesity. IBD patients have many vitamin and nutrient deficiencies, which can lead to important consequences such as hyperhomocysteinemia, which is associated with a higher risk of thromboembolic disease. Nutritional deficiencies in IBD patients are the result of insufficient intake, malabsorption and protein-losing enteropathy as well as metabolic disturbances directly induced by the chronic disease and its treatments, in particular corticosteroids. Screening for nutritional deficiencies in chronic disease patients is warranted. Managing the deficiencies involves simple nutritional guidelines, vitamin supplements, and nutritional support in the worst cases.

The optimal care of patients with inflammatory bowel disease depends on adherence to standards of care regarding diagnosis, informing the patient of potential risks of treatment, obtaining recommended baseline studies, and monitoring the patient for efficacy and adverse effects. In clinical research as well as practice, financial conflicts of interest must be disclosed and managed to insure that patients have sufficient information to make a decision regarding participation in a study and to insure their safety. Medical education of care-givers in training carries the obligation and liability to oversee the care of the IBD patient and insure that safe and optimal care. This review addresses medicolegal issues that can arise in the care of the patient with IBD. Clinicians who provide optimal care for patients with inflammatory bowel diseases (IBD) must employ appropriate diagnostic and therapeutic options and also adhere to standards of care and ethical principles. Ethical and medicolegal issues can arise from the failure to adhere to the standards of medical care, clinical research and education. In a report in the New England Journal of Medicine in 2011, gastroenterologists in the U.S. ranked 6th out 26 subspecialities as the most commonly sued for malpractice, with the mean payment to the plaintiff of just under $200,000 [1]. It is noteworthy that two other specialties that involve invasive procedures ranked lower on the list than Gastroenterology. For example, Cardiology and Anesthesiology ranked 11th and 17th, respectively. In this review, nine of the pitfalls to adherence to the standards of practice for IBD are reviewed.

In Inflammatory Bowel Disease (IBD) patients, thiopurines promote carcinogenesis of Epstein-Barr Virus (EBV)-related lymphomas, non-melanoma skin cancers and urinary tract cancers, while anti-TNF agents could promote carcinogenesis of melanomas. Patients with IBD and previous cancer are at a higher risk of developing new or recurrent cancer than IBD patients without a history of cancer, irrespective of the use of immunosuppressants. In transplant recipients, the use of thiopurines is associated with a high rate of cancer recurrence, particularly within the first two years following transplantation. In patients with chronic inflammatory disease, limited data suggest that no dramatic incidence of cancer recurrence is associated with the use of thiopurines or anti-TNF agents. However, there is a rationale for a two-year drug holiday from immunosuppressants after the diagnosis and treatment of the majority of incident cancers, as often as possible. Extending the duration of the immunosuppressant drug holiday to 5 years in patients with previous cancers associated with a high risk of recurrence in the post-transplant state should be considered. The immunosuppressants that can be initiated or resumed after cancer treatment should be chosen according to the type of the previous cancer. All individual decisions should be made on a case-by-case basis, together with the oncologist, according to characteristics and expected evolution of the index cancer, expected impact of the immunosuppressants on cancer evolution, and intrinsic severity of IBD, with its associated risks.

This review discusses the rationale behind recommending immunopharmacological guidance of long-term therapies with anti-TNF-α specific biotherapies. “Arguments why therapeutic decision-making should not rely on clinical outcomes alone are presented. Central to this is that the use of theranostics (i.e., monitoring circulating levels of functional anti-TNF-α drugs and antidrug antibodies) would markedly improve treatment because therapies can be tailored to individual patients and provide more effective and economical long-term clinical benefits while minimising risk of side effects. Large-scale immunopharmacological knowledge of the pharmacokinetics of TNF-α biopharmaceuticals in individual patients would also help industry to develop more effective and safer TNF-α inhibitors” [1].

Crohn’s disease (CD) is a chronic, disabling, progressive and destructive disease. The general goal of conventional step-up strategy in CD treatment is to treat and control symptoms. This strategy did not change the disease course and is now being replaced with a treat-to-target approach. Achieving deep remission (clinical remission and absence of mucosal ulcerations) is the target in CD in 2014. Inducing and maintaining deep remission is needed to prevent long-term outcomes such as bowel damage and disability in CD. Diagnostic delay is a common issue in CD and is associated with an increased risk of bowel damage over time. Identification of poor prognostic factors, risk stratification together with the development of “red flags” may result in early intervention with disease-modifying agents such as anti-TNF agents with the final aim of preventing overtreatment and avoiding undertreatment. Similar to rheumatoid arthritis, by catching the therapeutic window of opportunity in early CD and achieving deep remission, this could be the best way to change disease course (hospitalizations, surgeries, bowel damage, and disability) and patients’ life.

Extraintestinal manifestations (EIM) in inflammatory bowel disease (IBD) occur frequently and may present themselves before or after IBD diagnosis. They most commonly affect the eyes, skin, and joints, but can also involve other organs such as the liver. Some EIM are associated with intestinal disease activity and ameliorate by treatment of the underlying IBD. This is seen in patients with peripheral Type 1 arthritis, oral aphthous ulcers, episcleritis, and erythema nodosum. Other EIM are intestinal disease activity-independent such as uveitis, and ankylosing spondylitis. Finally, some EIM (e.g. pyoderma gangrenosum and primary sclerosing cholangitis) may or may not be associated with the underlying IBD. Successful therapy of EIM is important for improving quality of life of IBD patients. TNF antibody therapy is an important treatment option for EIM in IBD patients whereas no such beneficial effect was reported for alpha 4 beta 7 integrin antibodies such as vedolizumab so far. This article reviews the therapeutic experience with TNF antibodies for the treatment of EIM in IBD patients.

Surgery has been associated with variable effect on the quality of life of inflammatory bowel disease (IBD) patients, depending on clinical patterns and baseline disease characteristics. However, surgical treatment is often conceived by these patients with distress and considered as the failure of their therapies. Lack of control, risk of complications, defacement of the body image, need of ostomy and hospitalization may be triggering concerns leading to anguish and anxiety. Even though the quality of life in most cases generally improves after surgery, some particular aspects such as sexual activity, bowel movements and the ability to deal with a possible stoma may present a slower amelioration trend. These problems represent common causes of distress and may lead to an heightened risk of depression and anxiety with respect to background population. The psychological impact and apprehension surrounding surgery will be discussed in this review. Pros and cons of the surgical treatment in various IBD populations and its long-term sequelae in terms of quality of life and psychological well-being will be highlighted. Furthermore the tools to encompass these issues such as complete patient information, gastroenterologist/surgeon synergy and psychological counseling will be explored analyzing their respective roles.

Complementary and alternative therapies (CAM) are defined as therapies that are presently not considered part of conventional medical practice. They are termed “complementary” when used in addition to conventional therapies and termed “alternative” when used instead of conventional therapies. CAM includes many different practices, for example Ayurveda, acupuncture or traditional Chinese medicine (TCM), phytotherapy, homeopathy, probiotics and dietary supplements. While some evidence of benefit exists regarding some therapies, for most of these therapeutic approaches, the therapeutic efficacy and safety have not been proven in well-designed scientific studies. However, the use of complementary and alternative medicine among IBD patients is common, and physicians are frequently confronted with questions about their use. As most of the reported studies contain methodological problems, it is often difficult for physicians to inform their patients adequately. Nevertheless, the widespread use of CAM needs to be recognized. Some of these agents exert plausible biological effects in IBD patients and warrant further investigation. Controlled trials in IBD are warranted to show therapeutic benefits and safety of CAM. This review aims to give a brief overview on the current use of various complementary and alternative treatment options in IBD patients.