Accepted Manuscript When can we cure Crohn’s? Gerassimos J. Mantzaris, MD, PhD, AGAF

PII:

S1521-6918(14)00052-3

DOI:

10.1016/j.bpg.2014.04.008

Reference:

YBEGA 1253

To appear in:

Best Practice & Research Clinical Gastroenterology

Received Date: 30 January 2014 Revised Date:

15 March 2014

Accepted Date: 13 April 2014

Please cite this article as: Mantzaris GJ, When can we cure Crohn’s?, Best Practice & Research Clinical Gastroenterology (2014), doi: 10.1016/j.bpg.2014.04.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

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When can we cure Crohn’s?

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Gerassimos J. Mantzaris, MD, PhD, AGAF

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Coordinator Consultant Gastroenterologist

Department of Gastroenterology, Evangelismos Hospital 45-47 Ypsilantou street, 10676-Athens, Greece

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E-mail: [email protected]

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Tel. +30-213-2045223, Fax. +30-213-2041604

ACCEPTED MANUSCRIPT Abstract Crohn’s disease is a life-long idiopathic inflammatory disease which affects the entire gastrointestinal tract and occasionally extra-intestinal organs. CD is thought to result

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from complex interactions between environmental factors, the gut microbes, and the genetic background and the immune system of the host. In the last decades research on these pathogenetic components, and especially on mucosal immunity,

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has led to the development of biologic agents and therapeutic strategies that have improved dramatically the treatment of CD but we are still far away from curing the

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disease. If there is a treatment for CD that will probably evolve through methodical steps towards integrating research on all the components involved in the pathogenesis of CD. This holistic and global approach may aid at unraveling the mysteries of CD and developing novel agents and therapeutic strategies which by

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hopefully to cure.

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targeting multiple pathogenetic pathways and at different stages of disease may lead

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Key words: Crohn’s disease, aminosalicylates, corticosteroids, immunosuppressants, biologics, feacal microbiota transplantation, environmental factors, gut microbiota, mucosal immunity, genetics.

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Introduction The recent English edition of Wikipedia defines ‘cure’ as ‘the end of a medical

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condition; the substance or procedure that ends the medical condition, such as a medication, a surgical operation, a change in lifestyle, or even a philosophical mindset that helps end a person's sufferings’. Crohn’s disease (CD) is an idiopathic,

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granulomatous, life-long disease that affects any part of the gastrointestinal tract

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from the mouth to the anus and runs a relapsing-remitting or continuously active course. In up to 35% of the patients the disease affects one or more extra-intestinal organs [1]. CD can impair profoundly the quality of life and can cause significant functional and/or psychological disability [2]. Despite remarkable improvement in

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the medical treatment there is still no definitive therapy for CD. Current therapeutic interventions aim at inducing and maintaining clinical and biologic remission of active disease and healing of lesions in order to restore quality of life to near normal

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levels and prevent complications which may lead to intestinal failure and disability [3]. Surgery is reserved for disease complications. In the text to follow, we shall

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review briefly what we have learned since the first descriptions of disease, what the major obstacles to curing CD are and how these can be overcome, and, finally we will discuss whether cure is a realistic option.

A. What have we learned since the first description of CD?

ACCEPTED MANUSCRIPT Eighty years after Crohn, Ginzburg and Oppenheimer presented their landmark article [4] we have improved substantially our understanding of the pathophysiology and the natural history of CD. CD is now thought to develop in genetically susceptible individuals from complex but as yet unknown interactions between

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various environmental factors, the gut microbes (gut microbiota) and the mucosal immune system of the host [5]. These interactions determine the clinical phenotypes

in the treatment of various subtypes of CD.

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and the natural course of the disease. We have also made remarkable achievements

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Due to advances in molecular biology, genetics and tissue staining techniques in association with easy sampling of biologic fluids and intestinal tissues ‘bench to bedside’ research on the immune system of the host grew disproportionally faster than research on other pathogenetic components of CD. Defective innate immunity

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and pathogenic effector T helper cells were considered as the driving forces for disease activation and progression. A network of cells, key-inflammatory mediators,

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and pro- and anti-inflammatory immune pathways were implicated in the immunopathology of CD. Defective immune regulations and apoptotic mechanisms

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were incriminated for the accumulation of inflammatory cells and the perpetuation of chronic inflammation [6-10] Despite limitations, this feverish research led to the discovery and production of novel therapeutic agents, initially anti-TNFα biologics and recently anti-integrins, which target selectively key inflammatory mediators. The efficacy and safety of these agents has been elucidated in large, adequately powered randomized controlled trials (RCTs) with harder end points than simple clinical remission [11-16]. A long pipeline of non anti-TNFα biologic agents is currently being

ACCEPTED MANUSCRIPT investigated in phase II and III RCTs and is expected to further expand the pool of future therapeutic options [17-19]. Additional therapeutic interventions, such as granulocyte/monocyte apheresis [20], and autologous or allogeneic mesenchymal or hematopoietic stem cell transplantation [21-23] are also currently under

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investigation. Furthermore, pharmacokinetic studies have facilitated the initiation of therapy with appropriate doses of single drugs and/or drug combinations,

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monitoring the response and adherence to treatment, and optimizing therapy to ensure maximum efficacy and safety [24,25]. Modern imaging modalities allow

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better localization and grading of disease activity and severity. Factors predicting a disabling course of CD have been identified and call upon earlier therapeutic interventions to prevent irreversible bowel damage. Thus, we are now able to deliver highly individualized therapies based not only on disease profile but also on

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efficacy and safety of medications and on important elements of patient profiles. A ‘treat-to-target’ strategy is evolving which marries the concepts of early intervention and regular assessment of disease activity to ensure optimal control of disease using

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objective serological and faecal markers of inflammation and mucosal healing as

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surrogate markers of sustained ‘deep’ remission of CD [3]. This strategy promises excellent mid-term therapeutic outcomes, including reduced rates of hospitalizations and surgery, improvement in health-related quality of life and avoidance of disability.

Intensive research has documented the important role of each of these pathogenetic components of CD. Epidemiological studies have identified amongst others particular risk factors for developing and a disabling course of disease; geographical

ACCEPTED MANUSCRIPT gradients in the prevalence of disease; and, a dramatic increase in the incidence when former underprivileged societies adopt western dietary and life-styles and improve hygienic conditions [1,26]. A ‘clean-environment’, linked to the hygiene hypothesis, elimination of helminthes, extensive and repetitive use of antibiotics in

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early life, infections, smoking, appendectomy, and dietary modifications both qualitative and quantitatively have all been implicated with various levels of

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evidence in disease pathogenesis [1,5-7].

Our knowledge on the genetic variants of CD has truly exploded in the last decades.

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We now know that CD is a multi-genic disease; different gene variants control innate and adaptive immunity. At least in Caucasians, specific genes of the innate immunity, such as the NOD2/CARD15, are implicated in the pathogenesis of CD [27]. Childonset CD has a stronger genetic predisposition compared to adult-onset CD [28].

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Despite genetic diversity, universally distinct clinical phenotypes have been identified which may also be influenced by genetic variants [29] and have led to a

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classification of CD based on age of onset, anatomic distribution, clinical behaviour, and involvement of the perianal area; this classification has important prognostic

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and therapeutic implications [30]. The long neglected human microbiota is now attracting the interest of researchers after recent revolutionary molecular biology techniques and compositional sequence technology have enabled the culture of mixed populations of gut microbes and the genetic composition of the microbiota (microbiome)[31-33]. The gut microbiota, a huge body in the human body, comprises by trillions of microbes most of which astonishing belong only to four phyla, predominantly Firmicutes and Bacteroidetes

ACCEPTED MANUSCRIPT and to a lesser degree Proteobacteria and Actinobacteria [33]. The microbiota develops early during childhood under the influence of genetic, dietary and life-style factors, ethnicity, and geography and then remains stable throughout the adult [3436]. In adulthood, the composition and function of the microbiota may be affected

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by dietary factors, especially prebiotics (oligo- and polysaccharides), antibiotics, infections, smoking and appendectomy [34,35,37]. The gut microbes are in intimate

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and dynamic coexistence with the gut epithelium which allows selective absorption of nutrients, the regulation of fat storage [38], vitamin production, and the

probably under genetic [40].

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maturation and function of the immune system [6,38,39]. This ‘cross-talking’ is

The unequivocal role of the microbiota in the development of intestinal inflammation in CD has been demonstrated in animal models, improvement of

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colonic involvement after faecal diversion followed by relapse when ileostomy effluents are infused into the diverted colon or by infusion of intestinal contents in

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the excluded ileum, the post-operative recurrence and the effect of antibiotics for post-operative prophylaxis [26,41-43]. In CD, there is reduced diversity and altered

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function of the microbiota (dysbiosis) [35,44-46]. Numbers of firmicutes, lactobacilli, bifidobacteria, and bacteroidetes decrease whereas Faecalibacterium prausnitzii, an anti-inflammatory commensal which consists 5% of the normal microbiota, is reduced [47,48]. In contrast, number of facultative bacteria, proteobacteria and adherent-invasive Escherichia coli increase. The composition of the microbiota in relatives of patients with CD is more similar to patients than healthy individuals [49].

ACCEPTED MANUSCRIPT Metagenomics have shown that dysbiosis alters fundamental metabolic functions of the microbiota [37]. Finally, many surgical dogmas have been challenged in the last 35 years. Indications

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and timing for surgical intervention have been revised, surgical techniques have improved, new techniques have been introduced, and the number of operations has probably declined. Complicated rather than medically intractable disease is now the

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main drive for surgical therapy; strictureplasty has replaced intestinal resection for short intestinal strictures; examination under anaesthesia, abscess drainage, and

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seton placement under pelvic MRI guidance has become the first intervention in a stepwise multidisciplinary approach to complex perianal fistulae; and, early surgery may be a valid option for patients with limited stricturing ileocolonic disease [26,28]. Meta-analyses of RCTs and non-RCTs have shown that laparoscopic surgery is equally

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safe to the open operation but decreases the rates of perioperative complications

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and incisional hernia [50].

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B. Why have we not achieved ‘cure’ of CD?

Despite great achievements in the pathophysiology and treatment important questions relevant to ‘curing’ CD remain unanswered: what causes the disease, why is innate immune defective, what drives flares and spontaneous remission, how the microbiota influences immune regulation, why the disease is discontinuously and unevenly distributed in the gut, why a proportion of patients develop perianal

ACCEPTED MANUSCRIPT disease or extra-intestinal manifestations, etc. Current medical therapy can ensure at best a mid-term ‘honeymoon’ rather than ‘cure’. Dietary modifications, exclusive elemental nutrition, modifiers of the microbiota (antibiotics, probiotics, prebiotics, synbiotics, faecal microbiota transplantation) cannot ‘cure’ the disease [26,28,51-

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59]. Corticosteroids can induce clinical remission in a proportion of patients but cannot effectively heal lesions and are associated with serious adverse events.

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Remission rates on thiopurines fall as time goes by and disease will relapse if treatment is withdrawn [26,60,61]. Approximately one fourth of patients will be

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primary non responders to anti-TNFα agents and another third may lose response overtime or develop serious allergic or infectious complications [26]. Co-morbidities may not allow administration of the ‘best’ medical therapy, especially in aged patients. Biosimilars can only promise access of a proportion of underprivileged

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patients to biologics. Based on available data, non-anti-TNFα’ biologics may be helpful for patients with disease refractory to prior therapies but do not seem to offer ‘cure’. Failure of current medical therapy is best underscored by lack of

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adherence, and use of therapies of questionable efficacy and safety. Interestingly,

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approximately one fifth of patients in RCTs will respond or achieve remission on placebo [62-64] and a small group of patients in the community may not need any treatment [26]. Last but not least, despite ‘curative’ surgical resection and postoperative prophylaxis CD will inevitably recur [28]. Faecal diversion may alleviate only temporarily symptoms of colitis and complicated perianal disease. Yet, CD remains an incurable disease. Why?

ACCEPTED MANUSCRIPT • Progress in medicine is slow. A characteristic example is the discovery of H. pylori, a simple infectious agent as a cause of peptic ulcer disease, a plague of mankind for thousands of years and a monumental failure of epidemiologists, biologists

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and pathologists.

• Medical education probably no longer produces this species, ‘researcher-

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physicians’. In many countries, medical students are exposed to cataclysmic information during a rather strictly specialty-orientated training rather than

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proper medical education that would aim at creating personalities with restless minds and influences from various medical and nonmedical disciplines. Separation created a chasm in communication and cooperation between basic scientists and clinicians which has resulted in partition and isolation of the

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medical disciplines and inevitably to ‘paucity of convergent thinking’ or luck of

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‘thinking across the boundaries of traditional disciplines’ [39].

• Universal lack of adequate funding and strong competition for the limited

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resources has further intensified fragmentation and privacy in the medical science.

• Implementation of market rules and practices in the Academic Society in association with the evaluation of the scientific work on the basis of publication records and impact factors (‘publish or perish’) is leading young investigators to

ACCEPTED MANUSCRIPT massive research of questionable quality leaving aside the innovative and pioneering research. All these are not applicable exclusively to IBD. In addition, what we have witnessed

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in CD is an isolated and disproportionally allocated research mainly on those components of disease pathogenesis that are especially related to the host. However, as Fiocchi points out in a recent excellent editorial, the isolated

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modulation of each of the pathogenetic components of CD is unlikely to lead to ‘cure’ [65]. Thus,

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• for many years, epidemiological studies have documented strong relations between various environmental factors and CD but have failed to correlate aetiopathogenetically any of these factors to mechanisms underlying and/or

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potentially implicated in the pathogenesis of this disease [39].

• the human genome has not changed in the last 100 years! Although ‘cases’ of

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intestinal involvement resembling CD were described centuries ago, CD as is

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known today was described convincingly nearly 100 years ago. Genetics studies have revealed an astonishing number of genetic loci associated with CD but these associations can explain only a limited proportion of cases. CD is a multi-genic disease and no single genetic association can explain its diverse clinical phenotypes. Recent experimental work has shown that manipulating some important genetic variants, such as NOD2, may alleviate symptoms of chemicallyinduced colitis [66] but in humans none of these associations can offer

ACCEPTED MANUSCRIPT convincingly solid ground for a practical approach to patient treatment let alone ‘cure’ of CD.

• although there are numerous animal models of CD, none of these addresses the

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complexity of the interactions between the microbiota, the immune system and the environmental factors in CD. This is evidenced by disparity in the results of

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their efficacy to treat acute experimental colitis.

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RCTs and meta-analyses of probiotics in the treatment of human CD [26,56] and

• the limitations of treatments aiming at resetting disordered mucosal immune mechanisms have been underscored earlier. The activation of the mucosal immune system in CD resembles sequential explosions (activation of immune

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pathways) after firing a single firework (the initial trigger). Targeting each individual immune pathway, especially those that are activated late in the cascade of immune events may control to a certain degree the inflammatory

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response but cannot cure CD. Blocking some immune pathways with biologics

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may lead onto paradoxical inflammation which may be more severe that CD itself [7,68]

• manipulating the microbiota has proven efficacious in the prevention and treatment of several conditions, such as pouchitis, hepatic encephalopathy, Listeria infections and travelers’ diarrhoea. In a mouse model of colitis administration of F. Prausnitzii strain A2-165 protected against 2,4,6trinitrobenzenesulfonic acid (TNBS)-induced colitis [48]. However, CD is a much

ACCEPTED MANUSCRIPT more complex disease characterized by severe dysbiosis. Hopes that empirical treatment with a single probiotic or combinations of probiotics may restore a

C. What should be done to achieve ‘cure’ of CD?

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healthy microbiota and ‘cure’ CD is in itself a childish naivety.

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• Great achievements in Medicine came from people who had global influences from various disciplines and had time to think in a simple way. We must rethink

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CD! Why the disease was unknown just a century ago? What has truly changed in our internal and external environment that has led to the appearance of this horrible disease? Why the disease has a predilection for Caucasians and particular ethnicities? What drives the dramatic increase in prevalence in societies that are

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rapidly westernized? Is the inverse epidemiological association of tuberculosis to CD simply the result of improved hygienic conditions or they are connected

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aetiologically? Is CD truly a multifactorial disease or what we see at the time of diagnosis is a complex phenotype that is being built gradually on a background

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platform set by a single infectious agent?

• These simple questions make crystal clear that we see the tree and miss the forest. We are lost in the curling corridors of the labyrinth of research that is compartmentalized in narrow, isolated, and strictly demarcated scientific fields without an Ariadne’s thread! This myopic approach has resulted in the accumulation of a huge load of information on each of the pathogenetic

ACCEPTED MANUSCRIPT components of CD, especially mucosal immunity, but not to global knowledge that can be transformed into revolutionary research towards a cure of CD. We need to ‘U-turn’, rethink, design and execute cooperative, integrated research that will include all the pathogenetic components of CD [65]. Hopefully, we have

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recently begun to witness research moving towards this direction [37].

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• An important first step could be to orchestrate national and international interdisciplinary consortiums of scientists from medical and nonmedical

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disciplines. These will have the difficult task to review what is known, identify missing links between the factors associated with the pathogenesis of CD, and then prioritize the next essential steps of innovative, pioneering integrated research which would address the unanswered questions in the pathogenesis and

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treatment of CD. Focusing on societies which undergo rapid and dynamic environmental changes as well as on early childhood during crucial changes in the composition of the microbiota and maturation of immune system rather than late

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adulthood may be more appropriate targets.

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• Research on the human microbiota should drive this integrated research. The microbiota may be the ‘missing link’ between external environmental factors, the genetic background and the mucosal immune system of the host. The interplay between external environmental factors and dysbiosis in genetically predisposed subjects may initiate immune reactions that lead onto gut damage. Indeed, environmental factors, especially diet and antibiotics, may cause dysbiosis during early, critical developmental stages of the immune system. Metagenomis have

ACCEPTED MANUSCRIPT shown that dysbiosis alters fundamental metabolic functions of the microbiota [37]: breaks down the gut barriers and impacts severely on the host immune response to microbes by inducing activation of effector T helper cells or suppressive T regulatory cells, the IL-23/Th1/Th17 pathway, and autophagy

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[69,70]. Dysbiosis-induced impairment in the enzymatic activity of the microbiota modifies the composition of luminal bile acids which may erase the anti-

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inflammatory effects of some bile acids contributing to chronic inflammation in IBD [71]. Noteworthy, mutant genes implicated in the pathogenesis of CD can

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regulate the host immune response to environmental factors (e.g. autophagy genes) and code for sensors of intestinal bacteria (e.g. NOD2) [6,39,72]. Recent experimental data suggests that NOD2 deficiency causes dysbiosis which renders the colonic epithelium vulnerable to chemical injury and colitis [73].

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Consequently, disease-related dysbiosis can be manipulated by targeting the NOD2 gene [66]. Manipulation of these pathogenetic pillars of CD is more likely to work in child-onset CD, during crucial changes in the composition of the

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microbiota and maturation of immune system. Furthermore, human microbiota-

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driven excess fat storage may trigger pro-inflammatory immune effects offering a theoretical bridge between improved socio-economic conditions, altered dietary habits and rapid changes in the epidemiology of CD [39].

• The human microbiota may be used for mining new drugs and identify biomarkers to monitoring the effect of treatment on the course of disease [37,39,45]. These biomarkers are expected to be of higher specificity and sensitivity than traditional serological or faecal biomarkers.

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• Furthermore, the effect of current medical treatments on the composition and function of the gut microniota and the secondary effects of this particular dysbiosis on the response to treatment and the course of CD should be

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thoroughly investigated longitudinally. There is preliminary evidence that treatment-induced disordered composition and function of the microbiota may

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affect metabolism and nutrient availability in the presence of oxidative stress and tissue injury [45]. Exploring these interactions may help in explaining primary non

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response or secondary loss of response to medications and treatment-induced paradoxical inflammation, and may select patients for treatment optimization or switch to alternative therapies.

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• Research should expand to incorporate additional fields. For instance, the function of the mucosal immune system is not controlled exclusively by environmental factors, the microbiota and genetic variants of the host but also by

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neurophysiological and neuroendocrine mechanisms. The role of neural

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regulation of the immune system in various intestinal diseases, especially irritable bowel syndrome, has been recognized for many years and vagal-induced/cytokine mediated inhibition of active intestinal inflammation is a known homeostatic mechanism. Although elements of psychological, social and physical stress have been incorporated in measurements of quality of life in CD and anti-depressants consist often an integral part of the therapy research probably underestimates the importance of the brain-gut axis in IBD.

ACCEPTED MANUSCRIPT • Unfortunately, pioneer research is nowadays very costly and cannot be adequately funded by independent sources. Funding for clinical research comes mainly from the Pharmaceutical Industry. However, the priorities of the Industry cannot usually meet the needs of pure Science. Industry initiated trials are

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subjected to market forces and barriers from Regulatory Authorities. For instance, a recent publication claimed that many ‘real-life’ patients would never qualify for

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inclusion in any trial of anti-TNFα biologics [74]. As it is likely that in foreseeable future the industry will continue to invest on novel agents that modulate immune

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pathways hoping for fast rewards we should urgently strive for independent studies targeting unmet needs in CD pathogenesis and therapy.

• Funding should originate from independent sources: scientific, governmental or

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international organizations, patient associations, but also where possible by the corporate members of scientific organizations. Research protocols that involve all the pathogenetic components of CD should be preferentially funded. Research

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products should be accessible to enhance productive criticism and creative

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brainstorming.

D. Is cure of Crohn’s disease a realistic option?

To ‘cure’ CD we must learn from and correct our mistakes. Instead of accumulating irrelevant and redundant data on each individual pathogenetic component following the trends of time we should orchestrate globally integrated research to study

ACCEPTED MANUSCRIPT concurrently the functional interplay between environmental factors, the dysbiotic microbiota, the mucosal immune system, the genetic background of the host and the neuroendocrine control of the gut function taking advantage of recent revolutionary technological advances, such as proteomics, metagenomics, transcriptomics,

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metabolomics, epigenetics, etc. The effect of any acquired disorder affecting each of these components, for instance the effect of smoking or prolonged antibiotic use on

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the microbiota, should be longitudinally studied to assess its impact(s) on the other pathogenetic components. Mining novel and disease specific biomarkers from the

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dysbiotic microbiota will aid at following up the course of disease and linking these effects to measurable outcomes of disease. In this way, we will probably be able to conceive new ideas, produce novel therapeutic agents, and apply novel therapeutic strategies addressing multiple pathogenetic pathways which may be used either to

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prevent or to ‘cure’ CD.

Identifying novel predictors of future disease, genetic, immune, environmental,

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microbiota-derived may help in selecting patients at a pre-clinical stage for

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appropriate preventive interventions. One such approach in off-springs of affected families may be to select those with established susceptibility genes and manipulate any culprit environmental factor(s) during the early, crucial developmental stages of the microbiota or even colonize the offspring using faecal microbiota transplantation from unaffected individuals to prevent dysbiosis-initiated immune events leading onto CD. Identifying novel microbiota-derived antigens from patients with CD, especially affected family members, may also open another avenue of disease prevention or treatment using oral immunization as we have done in the past for

ACCEPTED MANUSCRIPT orally transmitted intestinal and systemic infections. These therapeutic strategies may also apply for patients who have undergone ‘therapeutic’ resection for irreversible bowel damage.

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CD is not a single entity but consists of various subsets/clinical phenotypes (Crohn’s diseases) with unpredictable clinical course and response to treatment. If cure is ‘a

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substance or procedure that ends a medical condition’ it is probably naïve to believe that in the foreseeable future ‘cure’ of CD will be a Procroustes bed, an ‘one-fit-all’

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single regimen that can apply to all patients independently of the stage of disease and the accumulated intestinal damage. Therefore, timing of intervention may continue to be crucial. This is more important for childhood CD because children will live with the disease for longer periods and avoidance of surgeries and disability is

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much more important than in adulthood CD [75]. Using a variety of combination therapies we could target in a highly individualized way the particular clinical phenotype at different stages of the evolution of CD in the particular patient. Thus,

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patients with established disease may be treated by blocking all the involved

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pathogenetic components and prolonged follow up using microbiota-derived biomarkers may ensure ‘cure’. For instance, attacking crucial genetic variants linked to CD, such as NOD2, in association with dietary modifications, immune modulation and manipulation of the microbiota [66]. Alternatively, production of fibrolytic agents may substitute for surgical strictureplasty or resection of stenotic bowel areas and decrease the need for surgical intervention in patients with irreversible bowel damage.

ACCEPTED MANUSCRIPT Any ‘realistic’ option assumes that is potentially valid, has been adopted as working hypothesis by the international scientific society, and is generously financed. How long it will take such an effort is purely conjectural. The ‘Craft is long’ but although the pace of any such innovative research effort is unpredictable, random events as in

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the H. pylori story, may accelerate tremendously the sequence of events towards ‘seeing light at the end of the tunnel’ as long as we are keeping the train on the

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tracks.

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We should be dreamers but we must also be realistic. Currently, we cannot give our patients their lives back. However, until the mysteries of CD are unraveled and because a universal lack of quality of care in IBD has been documented [76,77], every effort should be made to offer patients a safe, timely administered, effective,

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evidence-based, and patient-centered healthcare [78]. Amongst others, this includes universally agreed structure, process and outcome measures based on solid quality indicators; expansion of centers of excellent care for easy access of patients to

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multidisciplinary expert teams and regular audits for continuous improvement;

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allocation of sufficient time in motivational interviews to express expectations of life and concerns for their disease and treatments; interactive education for groups of patients with similar disease burden rather than incomprehensible leaflets. Furthermore, medical therapy should be personalized and administered by better drug delivery systems as early as possible to prevent irreversible gut damage. Treatment should aim beyond symptomatic control to include normalization of markers of inflammation, mucosal healing and, if possible, histologic remission. Combination therapies targeting different inflammatory pathways may achieve

ACCEPTED MANUSCRIPT tighter control of disease. Patients should be monitored regularly so that treatment is adapted to the state of disease. These mid-term outcome measures are expected to relieve the physical and psychological burden of CD and allow patients to run a

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normal life under a safe treatment until definitive therapy is found. Summary

For many years medical treatment of CD was empiric and surgery was reserved for

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incapacitating symptoms and complications. After the 1980s surgery moved to the

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backstage; corticosteroids became the mainstay of therapy for active disease and thiopurines the drugs of choice for remission maintenance and post-operative prophylaxis. The advent of anti-TNF was a breakthrough in the management of patients with disease refractory to prior treatments. Advanced technology, novel

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markers of inflammation, pharmacokinetic and genetic studies have allowed better localization of disease and close monitoring of response to treatment over time. Non-anti-TNFα biologics are under investigation and approval of safer anti-integrins

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is pending. As for rheumatoid arthritis, a ‘teat-to-target’ strategy is evolving for CD and promises better long-term outcomes through tighter control of inflammation

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and mucosal healing by continuous fine adjustments of treatment. However, CD remains incurable. This is probably because research has focused exclusively on the host and on isolated pathogenetic components of disease. Recent advances have shifted our interest to the lumen: the gut microbiota, a huge organ within the human body, co-existing and continuously interacting with the immune system and the genetic constituents of the host, emerges as a new therapeutic target, a source for novel biomarkers, and a goldmine for new drug development. However, focusing

ACCEPTED MANUSCRIPT only on the microbiota will undoubtedly lead to the same mistakes, i.e. accumulating information on another pathogenetic pillar. Using effectively the available resources consortiums of basic and clinical medical and nonmedical scientists should prioritize and execute integrated ‘holisitc’ research to include all factors that are relevant to

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the pathogenesis of CD. This global approach may lead to the development of novel agents and therapeutic strategies destined to ‘cure’ CD. However, until the mysteries

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of CD are uncovered every effort should be made to ensure that excellent patientcentered healthcare is delivered in appropriately organized Centers of Excellent Care

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by multidisciplinary expert teams.

Practice points

Crohn’s disease is a life-long idiopathic inflammatory bowel disease

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There is no definitive medical or surgical therapy.

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Current medical therapy aims at inducing ‘deep’ clinical, biologic and

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•

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endoscopic remission; deep remission is associated with reduced rates of

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complications, hospitalization and surgeries at least in the short-term. •

The long-term efficacy of a ‘treat-to-target’ therapeutic strategy needs to be investigated in prospective controlled trials.

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Until CD is cured every effort should be undertaken to ensure the delivery of personalized, holistic, effective, and safe therapy to patients by multidisciplinary teams of experts in centers of excellent care.

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Although structure and process measures are central to the delivery of optimal treatment, universally applied outcome measures is all that matters

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to patients and need to be defined.

Research agenda •

Epidemiological and genetic studies and research focusing on the host have

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been unable to discover what causes the disease and lead to ‘cure’.

The gut microbiota emerges as a novel field for innovative research.

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The interactions between constituents of the gut microbiota, dietary factors,

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genes, and the mucosal immune system of the host need to be defined. •

Research should also assess whether the microbiota can be used for mining

•

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new drugs and/or as a biomarker to monitoring the effect of treatment. However, continuing isolated research on each of the pathogenetic components of CD in our struggle to identify the aetiopathogenesis of CD is

•

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expected to be counter-productive. Consortiums of scientists from different disciplines should be involved in

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innovative integrated research focusing on the functional interplay between the components involved in the pathogenesis of CD.

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Early age and societies undergoing rapid environmental and socioeconomic changes should be the focus of this research.

ACCEPTED MANUSCRIPT References

[1]. Langholz E. Current trends in inflammatory bowel disease: the natural history.

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Therap Adv Gastroenterol 2010;3:77-86. [2]. Peyrin-Biroulet L, Cieza A, Sandborn WJ et al. Development of the first disability index for inflammatory bowel disease based on the international classification of

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functioning, disability and health. Gut 2012;61:241-247.

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[3]. Bouguen G, Levesque BG, Feagan BG et al. Treat to Target: A Proposed New Paradigm for the Management of Crohn's Disease. Clin Gastroenterol Hepatol ‘(In press)’.

*[4]. Crohn BB, Ginzburg L & Oppenheimer GD. Regional ileitis: A pathologic and

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Conflicts of interest statement

Dr. Mantzaris has received advisory board fees from Centocor Ortho Biotech, MSD,

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Schering-Plough, AbbVie, and Danon; consulting fees from Danon; lecture fees from Ferring International, MSD, AbbVie, FALK Pharma, and Angelini; research support

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from AstraZeneca, AbbVie, Menarini, and Genesis.