Current Drug Targets (v.15, #11)

Crohn's disease (CD) and ulcerative colitis (UC) are the two major forms of Inflammatory Bowel Disease (IBD). Theseprogressive and disabling diseases represent a major challenge for clinicians facing complex patients. The multifaceted aspectsof disease characteristics require constant update for the gastroenterologists taking care of both CD and UC patients. In thisspecial issue of Current Drug Targets several aspects of IBD management are covered that go far beyond the classical medicaltherapy. First of all management in challenging cases should always cover optimization of conventional medical therapies, thatis the initial and crucial step when patients are most difficult. Indeed our therapeutic armamentarium for chronic conditions isstill limited depsite the arrival of new biologics such as vedolizumab and golimumab. In this regard, when biologic therapiesare 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 levelmonitoring could lead to cost savings. However, controlled trials showing a positive impact from measuring drug levels andantibodies 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 somebowel damage (strictures, abscess and/or fistulas) at 10 years. Similar to rheumatoid arthritis, a therapeutic window of opportunityis offered to both doctors and patients, and the most effective treatments should be initiated in order to stop disease progressionor 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 mostcommon extraintestinal manifestation, and is frequently forgotten and thus undertreated, or nutrition, that is a key aspect ofdisease management. A growing body of evidence indicates that iron deficiency should be systematically screened and treatedeven when it is not associated with anemia. Indeed, iron deficeincy has a major impact on patients-reported outcomes such asfatigue and quality of life and leads to anemia in most of cases. Malnutrition is also underdiagnosed in adults with IBD while itconcerns 75% of hospitalized patients with CD. The beneficial impact of nutrition support on disease course is well establishedin children with IBD. Obviously, the complexity of patient care also embraces extraintestinal manifestations that are seen inabout one third of IBD patients and in particular the best strategies and evidence that try to identify the most suitable patientsfor response to biologic treatment, but also the critical clinical scenario of controindication to such drugs, if a patient has acancer 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 ofthe 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 aprerequesite to improvement of patient-physician relationship as the only answer prodived by most of physicians is still thesame: “it does not work”. Indeed, patients are using complementary medicines because they are not satisfied with their conventionaltreatment and tend to stop it, thus contributing to non-adherence. All the above are just few burning aspects highlightedto try to embrace disease complexity, but enough to make IBD as one of the more intriguing diseases for GI specialists.

Optimizing Conventional Medical Therapies in Inflammatory Bowel Disease in 2014 by Anil Kumar Asthana, Miles P. Sparrow, Laurent Peyrin-Biroulet (1002-1010).
Goals of therapy for inflammatory bowel disease have advanced beyond symptom control to the normalization ofbiomarkers of inflammation, and mucosal healing in particular, with the expectation that this will change the natural historyof these diseases. Concurrent with higher treatment expectations has come an expanded therapeutic armamentarium toachieve these goals, and a greater ability to optimize each therapeutic class to maximize therapeutic benefits and minimizeunnecessary treatment failures. In addition to these advances has come the evolution of therapeutic drug monitoring which isincreasingly being utilized to optimize the use of immunomodulators and biologic therapies in particular. This review willoutline the principals of optimization of the conventional medical therapies available to the clinician today.

Iron Deficiency: The Hidden Miscreant in Inflammatory Bowel Disease by Mariangela Allocca, Gionata Fiorino, Silvio Danese (1011-1019).
Iron deficiency (ID) and anemia of chronic diseases (ACD) are the most common causes of anemia in inflammatorybowel disease (IBD), and frequently coexist. In these circumstances, detection of ID may be difficult as inflammationinfluences the parameters of iron metabolism. The prevalence of iron deficiency anemia (IDA) ranges between36% and 76% in this population of patients. Anemia may impair physical condition, quality of life (QOL), andcognitive function, negatively affecting almost every aspect of daily life. Furthermore, it may be one of the causes ofdeath in IBD. Consequently, iron replacement therapy should be initiated as soon as ID or IDA is detected, togetherwith the treatment of underlying inflammation. Oral iron therapy is a simple and cheap treatment, but often is poorlytolerated and may worsen the intestinal damage. Moreover, in inflammatory states, duodenal iron absorption is blockedby a cytokine-mediated mechanism. Consequently, intravenous iron therapy is preferred in the presence of severeanemia, intolerance or lack of response to oral iron, and moderately to severely active disease. Recently, new intravenousiron compounds (iron carboxymaltose, iron isomaltoside 1000, ferumoxytol) have become available. Iron carboxymaltosehas been shown to be safe and effective in IBD patients with IDA. Furthermore, it allows for rapid administrationof high single doses, saving time and costs. If proven to be efficacious and well tolerated, it may becomethe standard therapy in the near future.

State of the Art: Psychotherapeutic Interventions Targeting the Psychological Factors Involved in IBD by Daniela Leone, Julia Menichetti, Gionata Fiorino, Elena Vegni (1020-1029).
The present article aims to review the literature on the relationship between psychology and inflammatorybowel disease (IBD). In particular, the first section is dedicated to explore the role of psychological factors in the etiopathologyof the disease, its development and the efficacy of treatments, while the second analyzes existing literature on therole of psychological interventions in the care of IBD patients. Although the role of psychological factors in IBD appearscontroversial, literature seems to distinguish between antecedents of the disease (stress and lifestyle behavior), potentialmediators of disease course (family functioning, attachment style, coping strategies, and illness perception), outcomes ofIBD 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 ofpsychological interventions in IBD patients show little evidence both on reduction of the disease activity and benefits onpsychological 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 thecomplexity of the phenomenon at multiple levels is discussed.

Nutrition in Adult Patients with Inflammatory Bowel Disease by Xavier Hebuterne, Jerome Filippi, Stephane M. Schneider (1030-1038).
Seventy five percent of hospitalized patients with Crohn's disease suffer from malnutrition. One third ofCrohn'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 havemany vitamin and nutrient deficiencies, which can lead to important consequences such as hyperhomocysteinemia, whichis associated with a higher risk of thromboembolic disease. Nutritional deficiencies in IBD patients are the result of insufficientintake, malabsorption and protein-losing enteropathy as well as metabolic disturbances directly induced by thechronic disease and its treatments, in particular corticosteroids. Screening for nutritional deficiencies in chronic diseasepatients is warranted. Managing the deficiencies involves simple nutritional guidelines, vitamin supplements, and nutritionalsupport in the worst cases.

The optimal care of patients with inflammatory bowel disease depends on adherence to standards of care regardingdiagnosis, informing the patient of potential risks of treatment, obtaining recommended baseline studies, andmonitoring the patient for efficacy and adverse effects. In clinical research as well as practice, financial conflicts of interestmust be disclosed and managed to insure that patients have sufficient information to make a decision regarding participationin a study and to insure their safety. Medical education of care-givers in training carries the obligation and liabilityto oversee the care of the IBD patient and insure that safe and optimal care. This review addresses medicolegal issues thatcan arise in the care of the patient with IBD. Clinicians who provide optimal care for patients with inflammatory boweldiseases (IBD) must employ appropriate diagnostic and therapeutic options and also adhere to standards of care and ethicalprinciples. Ethical and medicolegal issues can arise from the failure to adhere to the standards of medical care, clinicalresearch 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 ofjust under $200,000 [1]. It is noteworthy that two other specialties that involve invasive procedures ranked lower on thelist 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 promotecarcinogenesis of melanomas. Patients with IBD and previous cancer are at a higher risk of developing new orrecurrent cancer than IBD patients without a history of cancer, irrespective of the use of immunosuppressants. Intransplant recipients, the use of thiopurines is associated with a high rate of cancer recurrence, particularly within thefirst two years following transplantation. In patients with chronic inflammatory disease, limited data suggest that nodramatic incidence of cancer recurrence is associated with the use of thiopurines or anti-TNF agents. However, there isa rationale for a two-year drug holiday from immunosuppressants after the diagnosis and treatment of the majority ofincident cancers, as often as possible. Extending the duration of the immunosuppressant drug holiday to 5 years in patientswith 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 typeof 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 immunosuppressantson cancer evolution, and intrinsic severity of IBD, with its associated risks.

Pharmacokinetics in IBD: Ready for Prime Time? by Xavier Roblin, Melanie Rinaudo, Miles Peter Sparrow, Amelie Moreau, Jean Marc Phelip, Christian Genin, Dominique Lamarque, Stephane Paul (1049-1055).
This review discusses the rationale behind recommending immunopharmacological guidance of long-termtherapies with anti-TNF-α specific biotherapies. “Arguments why therapeutic decision-making should not rely on clinicaloutcomes alone are presented. Central to this is that the use of theranostics (i.e., monitoring circulating levels of functionalanti-TNF-α drugs and antidrug antibodies) would markedly improve treatment because therapies can be tailored to individualpatients 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 individualpatients would also help industry to develop more effective and safer TNF-α inhibitors” [1].

Catching the Therapeutic Window of Opportunity in Early Crohnµs Disease by Silvio Danese, Gionata Fiorino, Carlos Fernandes, Laureal Peyrin-Biroulet (1056-1063).
Crohn's disease (CD) is a chronic, disabling, progressive and destructive disease. The general goal of conventionalstep-up strategy in CD treatment is to treat and control symptoms. This strategy did not change the disease courseand is now being replaced with a treat-to-target approach. Achieving deep remission (clinical remission and absence ofmucosal ulcerations) is the target in CD in 2014. Inducing and maintaining deep remission is needed to prevent long-termoutcomes such as bowel damage and disability in CD. Diagnostic delay is a common issue in CD and is associated with anincreased risk of bowel damage over time. Identification of poor prognostic factors, risk stratification together with thedevelopment of “red flags” may result in early intervention with disease-modifying agents such as anti-TNF agents withthe final aim of preventing overtreatment and avoiding undertreatment. Similar to rheumatoid arthritis, by catching thetherapeutic window of opportunity in early CD and achieving deep remission, this could be the best way to change diseasecourse (hospitalizations, surgeries, bowel damage, and disability) and patients' life.

Biologics for Extraintestinal Manifestations of IBD by Stephan R. Vavricka, Michael Scharl, Martin Gubler, Gerhard Rogler (1064-1073).
Extraintestinal manifestations (EIM) in inflammatory bowel disease (IBD) occur frequently and may presentthemselves before or after IBD diagnosis. They most commonly affect the eyes, skin, and joints, but can also involveother organs such as the liver. Some EIM are associated with intestinal disease activity and ameliorate by treatment of theunderlying IBD. This is seen in patients with peripheral Type 1 arthritis, oral aphthous ulcers, episcleritis, and erythemanodosum. Other EIM are intestinal disease activity-independent such as uveitis, and ankylosing spondylitis. Finally, someEIM (e.g. pyoderma gangrenosum and primary sclerosing cholangitis) may or may not be associated with the underlyingIBD. Successful therapy of EIM is important for improving quality of life of IBD patients. TNF antibody therapy is animportant treatment option for EIM in IBD patients whereas no such beneficial effect was reported for alpha 4 beta 7 integrinantibodies such as vedolizumab so far. This article reviews the therapeutic experience with TNF antibodies for thetreatment of EIM in IBD patients.

Psychological Perspectives of Inflammatory Bowel Disease Patients Undergoing Surgery: Rightful Concerns and Preconceptions by Antonino Spinelli, Michele Carvello, Andre D'Hoore, Francesco Pagnini (1074-1078).
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 conceivedby these patients with distress and considered as the failure of their therapies. Lack of control, risk of complications, defacementof 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 sexualactivity, bowel movements and the ability to deal with a possible stoma may present a slower amelioration trend. Theseproblems represent common causes of distress and may lead to an heightened risk of depression and anxiety with respectto 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 oflife and psychological well-being will be highlighted. Furthermore the tools to encompass these issues such as completepatient information, gastroenterologist/surgeon synergy and psychological counseling will be explored analyzing their respectiveroles.

Complementary Therapies in Inflammatory Bowel Diseases by Philip Esters, Axel Dignass (1079-1088).
Complementary and alternative therapies (CAM) are defined as therapies that are presently not considered partof conventional medical practice. They are termed “complementary” when used in addition to conventional therapies andtermed “alternative” when used instead of conventional therapies. CAM includes many different practices, for exampleAyurveda, 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, thetherapeutic efficacy and safety have not been proven in well-designed scientific studies. However, the use of complementaryand alternative medicine among IBD patients is common, and physicians are frequently confronted with questionsabout their use. As most of the reported studies contain methodological problems, it is often difficult for physicians to informtheir patients adequately. Nevertheless, the widespread use of CAM needs to be recognized. Some of these agentsexert plausible biological effects in IBD patients and warrant further investigation. Controlled trials in IBD are warrantedto show therapeutic benefits and safety of CAM. This review aims to give a brief overview on the current use of variouscomplementary and alternative treatment options in IBD patients.