crohn's disease research paper

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Crohn’s disease: a clinical update

Hanan khalil.

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Email: [email protected]

Issue date 2015 Nov.

Crohn’s disease is increasing in prevalence worldwide. It arises from a complex interplay between both genetic predisposition and environmental influence. A search of databases and clinical practice guidelines was performed to provide the most up-to-date evidence-based approach for diagnosing and managing patients with Crohn’s disease. No single gold standard investigation exists. Whilst full ileocolonoscopy with biopsies remains the mainstay for diagnosis, other less invasive imaging modalities are being actively considered in the workup, as well as the use of serological markers. Management should incorporate dietary and lifestyle modifications where necessary, the use of medications in induction and remission of disease, and consideration of surgical intervention where medical therapy has failed.

Keywords: Crohn’s disease, diagnosis, inflammatory bowel disease, investigations, management, colorectal cancer, risk factors

Introduction

Crohn’s disease (CD) is a chronic relapsing inflammatory bowel disease (IBD). It is characterized by a transmural granulomatous inflammation which can affect any part of the gastrointestinal tract, most commonly the ileum, colon or both [ Thia et al. 2010 ]. Its prevalence has continually increased over the past 50 years with the highest incidence being reported in northern Europe, the United Kingdom and North America [ Cosnes et al. 2011 ]. Despite biological treatment being associated with an improved health-related quality of life [ van der Have et al. 2014 ], patients still report significant impediment on lifestyle and daily activities during both flares and remissions [ Devlen et al. 2014 ]. The mortality amongst patients with CD has been persistently higher than the general population with a meta-analysis showing a pooled estimate for the standardized mortality ratio of 1.52 [ Canavan et al. 2007 ]. No statistically significant change has occurred for this estimate over the past 30 years and thus CD remains relevant to a broad spectrum of clinicians involved in the multidisciplinary care of affected patients.

This evidence-based review derives from a comprehensive search of several databases including: Ovid Medline, Cochrane library and PubMed. MeSH terms used were “Crohn disease”, “Inflammatory Bowel Diseases” with other search terms including “epidemiology”, “risk factors”, “diagnosis”, “investigations”, “management” and “colorectal cancer”.

Clinical features

CD is a clinical diagnosis formed by correlation of clinical signs and symptoms, objective data from imaging including endoscopic with histologic information as well as laboratory studies [ Baumgart and Sandborn, 2012 ]. Chronic diarrhoea, defined as a decrease in faecal consistency for more than 4 weeks [ Juckett and Trivedi, 2011 ], is the most common presenting symptom [ Sands, 2004 ]. Abdominal pain (70%), weight loss (60%) and blood, mucus or both in stools (40–50%) are also common findings in CD [ Lennard-Jones and Shivananda, 1997 ]. Extraintestinal manifestations affect approximately a third of patients with IBD [ Trost and McDonnell, 2005 ; Lourenco et al. 2010 ]. The most commonly observed extraintestinal manifestation is primary peripheral arthritis (33%); aphthous stomatitis, uveitis, erythema nodosum and ankylosing spondylitis can be seen whilst pyoderma gangrenosum, psoriasis and primary sclerosing cholangitis are relatively uncommon [ Bernstein et al. 2001 ; Vavricka et al. 2011 ]. Fistulae, a complication of CD, occurs in up to 35% of patients with CD, with perianal fistula occurring in 20% [ Schwartz et al. 2002 ]. These clinical features associated with disease activity were found to contribute to 37% of health-related quality-of-life (HRQOL) in a systematic review analysing determinants of HRQOL in CD [ van der Have et al. 2014 ]. According to a patient-reported qualitative analysis [ Devlen et al. 2014 ], there is impact on lifestyle in regards to taking regular medication, restricting diet and avoiding certain trigger foods, as well as impact on daily activities where patients report absence from employment or school during acute flares due to pain and fatigue.

Risk factors

CD has a peak age prevalence of 30–39 years old and gender influence differs in various demographics. In a Canadian and New Zealand population, females are 10–30% more likely to acquire the disease than males [ Bernstein et al. 2006 ; Gearry et al. 2006 ], whereas males with CD are reported as up to three times more likely in Japan and Korea [ Yao et al. 2000 ; Kim et al. 2015 ]. Although the exact aetiology remains unknown, it is a complex interaction between genetic predisposition, environmental risk factors and immune dysregulation to intestinal microbiota [ Sartor and Muehlbauer, 2007 ]. A co-twin British cohort study showed concordant monozygotic twins with CD had similar disease location, disease behaviour and a moderate agreement for age at diagnosis [ Ng et al. 2012 ]. This genetic influence is consistent with previous findings from another co-twin German study [ Spehlmann et al. 2008 ]. Familial aggregation has been shown with most children acquiring the disease at an earlier time in life compared with their parents [ Bengtson et al. 2009 ]. High prevalence has also been found amongst Jewish populations although varying prevalence in different geographic locations suggests the influence of environmental factors as well [ Fireman et al. 1989 ]. Other inflammatory diseases have been implicated with CD including asthma, psoriasis, pericarditis, ankylosing spondylitis, atopic dermatitis and primary sclerosing cholangitis [ Bernstein et al. 2005 ; Lees et al. 2011 ].

Moreover, environmental risk factors have attributed to the rising incidence of CD worldwide [ Thia et al. 2008 ]. Their impact tends to be most influential during childhood [ Feeney et al . 2002 . Smoking has been confirmed to influence the phenotype of CD [ Halfvarson et al. 2006 ; Bengtson et al. 2009 ; Ng et al. 2012 ] and a meta-analysis found that smoking increased the risk of CD by more than twice [ Calkins, 1989 ]. Previous history of symptomatic mumps [ Ng et al. 2012 ] and a high dietary intake of fats, polyunsaturated fatty acids, omega-6 fatty acids and meats have both been associated with an increased risk of CD, whilst a high fibre and fruit diet has been seen to be protective [ Hou et al. 2011 ]. The oral contraceptive pill has also been associated with the development of CD; a meta-analysis [ Cornish et al. 2008 ] assessing quantitative risk of the oral contraceptive pill (OCP) in the aetiology of CD found a pooled relative risk for women currently exposed to the OCP was 1.51 (95%CI 1.17–1.96, p = 0.002).

Diagnosis and investigations

No single definitive diagnostic investigation exists for the diagnosis of CD [ Dignass et al. 2010 ]. Full ileocolonoscopy with biopsies is currently the most widely used diagnostic investigation [ Baumgart and Sandborn, 2012 ]. This can demonstrate noncaseating granulomas, though may only be detected in up to 60% of resected specimens and even less so in biopsy samples [ Nikolaus and Schreiber, 2007 ]. Cross-sectional imaging studies have been increasingly involved in the diagnostic evaluation of CD. This includes ultrasonography (US), computed tomography (CT) and magnetic resonance imaging (MRI). A systematic review [ Panes et al. 2011 ] comparing the accuracy of each cross-sectional imaging modality in the diagnosis of CD found US had a sensitivity and specificity of 85% (95% CI 83–87%) and 98% (95% CI 95–99%), respectively. This was superior to MRI which had an overall sensitivity and specificity of 78% (95% CI 67–84%) and 85% (95% CI 76–90%) respectively. Another systematic review comparing the diagnostic accuracy of magnetic resonance enterography (MRE) and computed tomography (CTE) found MRE had a diagnostic yield comparable with CTE, but does not carry the same risks of radiation exposure, especially to younger patients [ Qiu et al. 2014 ].

A normal finding on ileocolonoscopy is not sufficient to exclude the diagnosis of CD as 27% of patients have disease localized to the terminal ileum [ Cleynen et al. 2013 ], which can prove difficult to diagnose [ Doherty et al. 2011 ]. Capsule endoscopy is a relatively new, simple, noninvasive imaging technique that is gaining recognition for small bowel exploration [ Munoz-Navas, 2009 ]. The investigation involves consumption of a disposable, small, wireless camera within a capsule which passes through the gastrointestinal tract allowing direct visualization of the mucosa [ Nakamura and Terano, 2008 ]. A meta-analysis comparing the diagnostic yield of capsule endoscopy to other imaging modalities found an increased diagnostic rate of 15% over colonoscopy with ileoscopy [ Dionisio et al. 2010 ].

Disease heterogeneity and atypical presentations of IBD have highlighted the need for new diagnostic tools in addition to ileocolonoscopy with biopsy and other imaging studies. This has led to research of serological markers with the two most intensively studied serological markers being atypical perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) and anti Saccharomyces cerevisiae antibodies (ASCA) [ Bossuyt, 2006 ]. pANCA are antibodies formed against proteins in the nuclear lamina of neutrophils, whilst ASCA are antibodies against mannose epitopes from the yeast Saccharomyces cerevisiae [ van Schaik et al. 2013 ]. The generation of antibodies occurs most likely from abnormal response of mucosal immune system to commensal intestinal flora in genetically susceptible patients [ van Schaik et al. 2013 ]. A systematic review of the role of serological antibodies in diagnosing IBD found the most sensitive and specific test for CD was sera with positive ASCA and negative pANCA, 52–64% and 92–94%, respectively [ Prideaux et al. 2012 ]. The identification of these markers can help differentiate CD from ulcerative colitis where diagnosis remains ambiguous following clinical, histological and endoscopic grounds as well provide the opportunity for early intervention given their ability to predict development of CD [ van Schaik et al. 2013 ].

Decisions in the management of CD should always be made through discussion between the multidisciplinary team and patients themselves. Risk factors such as smoking should be ceased due to its harmful impact on the course of disease and potentially the OCP depending on the patient’s circumstances. A balanced diet of high fibre and fruits have been shown to be protective against CD and should be encouraged [ Hou et al . 2011 ].

Pharmacological management

Medications are intended to suppress the inflammatory response and a host of therapeutic agents are now available to treat CD [ Seow et al. 2008 ]. The conventional approach to managing active disease has been derived from progressive intensification of drug therapy, with the focus on inducing and maintaining clinical remission. However, there is evidence to suggest the use of aggressive treatment early to improve clinical outcomes in patients with risk factors predisposing to increased disease severity [ D’haens et al. 2014 ]. These include smoking [ Lees et al. 2011 ], initial requirement of steroid use, age below 40 years and presence of perianal disease [ Beaugerie et al. 2006 ]. Usually medications such as corticosteroids, budesonide or mesalazine are prescribed initially for induction of remission [ Dignass et al. 2010 ]. Anti-tumour necrosis factor (TNF) immunosuppressive therapies are also used in patients refractory to conventional therapy. Medical management of CD is reliant upon compliance and patient education is crucial, with patient age and follow up by a gastroenterologist being independently associated with nonadherence [ Zelante et al. 2014 ].

Corticosteroids are widely prescribed for the induction but not the maintenance of remission due to increasing resistance over time, patient dependence and adverse side effects with long-term use [ Kuenzig et al. 2014 ]. Budesonide is an alternate enteral glucocorticoid used for induction with limited systemic bioavailability due to extensive first-pass hepatic metabolism by cytochrome p-450 enzymes [ Kuenzig et al. 2014 ]. A systematic review evaluating use of budesonide for the induction of remission in CD showed budesonide to be significantly superior to placebo up to 8 weeks with a relative risk (RR) of 1.96 (95% CI, 1.19–3.23) [ Seow et al. 2008 ]. Although budesonide was shown to be inferior to conventional steroids for the induction of remission in active CD (RR 0.85; 95% CI 0.75–0.97), it had significantly fewer corticosteroid-related adverse events compared with those treated with conventional corticosteroids (RR 0.64; 95% CI 0.54–0.76) [ Seow et al. 2008 ].

5-Aminosalicylates also have a long established use in IBD [ Akobeng and Gardener, 2005 ], initially as sulfasalazine, a compound consisting of 5-aminosalicylic acid and sulfapyridine. More recently, 5-aminosalicylic acid has been isolated as a single agent being the active component without sulfapyridine, which was responsible for the majority of adverse side effects [ Ford et al. 2011 ]. However, a systematic review assessing the efficacy of 5-aminosalicylates in CD found insufficient evidence for their definitive use in either inducing remission or preventing relapse in CD [ Ford et al. 2011 ].

Purine antimetabolites azathioprine and 6-mercaptopurine have both been used in patients with active CD, although evidence has been conflicting and controversial. A Cochrane review found 48% of patients receiving antimetabolites achieved remission compared with 37% of placebo patients, with no statistically significant difference between the two groups [ Chande et al. 2013 ]. Evidence remains sparse in regards to whether purine analogues are superior to placebo for maintenance of surgically-induced remission in patients with CD [ Gordon et al. 2014 ]. Methotrexate, another antimetabolite with antagonistic action against folic acid, was superior to placebo in maintenance of remission at 40 weeks; 65% of patients receiving intramuscular methotrexate maintained remission compared to 39% in the placebo group (RR 1.67 95% CI 1.05–2.67) [ Patel et al. 2014 ].

Anti-TNF immunosuppressive therapies, most commonly infliximab and adalimumab, are another group of agents generally reserved for patients refractory to conventional therapies. A randomized controlled trial [ Colombel et al. 2010 ] evaluating the efficacy of infliximab monotherapy, azathioprine monotherapy and combination of both found 56.8% of patients receiving combination therapy achieved corticosteroid-free clinical remission at week 26 compared with 44.4% receiving infliximab alone ( p = 0.02) and 30.0% receiving azathioprine alone ( p < 0.001). Superiority of combination therapy compared with monotherapy of adalimumab remains unclear.

More recently, the novel agent vedolizumab, a monoclonal antibody targeting α4β7 [ Bryant et al. 2015 ], has shown efficacy in a randomized controlled trial for the induction of remission of CD compared with placebo (14.5% and 6.8%, respectively, p = 0.02) as well as maintenance of remission [ Sandborn et al. 2013 ]. Vedolizumab has also demonstrated similar efficacy to natalizumab, another anti-α4 integrin, although it does not pose the risk of progressive multifocal leukoencephalopathy as natalizumab does. However, a network meta-analysis found adalimumab to be superior to vedolizumab in maintenance of remission and its role in the stepwise management of CD still needs to be defined in further trials [ Hazlewood et al. 2015 ]. Ustekinumab, a monoclonal antibody against interleukin-12, has also demonstrated a role in maintenance of remission of CD [ Sandborn et al. 2012 ] and these biologic agents are likely to change the approach to medical management in the near future.

Surgical management

The majority of patients diagnosed with CD will have a surgical resection within 10 years of their diagnosis [ Bernell et al. 2000 ]. Surgical treatment is required for failed medical therapy, recurrent intestinal obstruction, malnutrition and for septic complications such as perforations and abscesses [ Dasari et al. 2011 ]. It has a role in limiting other complications including complex perianal disease and internal fistulas [ Baumgart and Sandborn, 2012 ] as well as improving quality of life [ Delaney et al. 2003 ]. However, the underlying pathology still persists resulting in high recurrence of disease, ranging from 28 to 45% at 5 years and 36 to 61% at 10 years [ Buisson et al. 2012 ]. Surgical admissions account for more than half of all hospitalizations and accounts for almost 40% of total financial costs to patients [ Cohen et al. 2000 ].

Laparoscopy has been widely accepted in gastrointestinal surgery over open surgery in CD [ Duepree et al. 2002 ]. Whilst laparoscopy offers certain advantages of smaller abdominal wounds, lower risk of hernia and decreased rate of small bowel obstruction, there are concerns that occult segments of disease and severe strictures can be missed due to limited tactile ability [ Dasari et al. 2011 ]. However, a meta-analysis on perioperative complications and long-term outcomes between open surgery and laparoscopic surgery found a nonsignificant difference in rate of surgical recurrence and a decreased risk of perioperative complications in the laparoscopic group compared to the open surgery group (12% to 18%, RR = 0.71 CI = 0.58–0.86, p = 0.001) [ Patel et al. 2013 ]. The overall cost including hospital stay costs and costs associated with lost working days between laparoscopic-assisted bowel resection and open surgery was no different [ Scarpa et al. 2009 ]. Despite the evidence for the advantages of laparoscopic surgery, further randomized controlled trials with adequate follow up are required prior to firm recommendations being made [ Patel et al. 2013 ].

The association between CD and malignancy is well documented, although the risk of colorectal cancer is decreasing [ Soderlund et al. 2009 ]. A meta-analysis of population-based cohort studies found a pooled standardized incidence ratio (SIR) of 1.7 amongst patients with CD in the general population (95% CI 1.01–2.5) and a pooled SIR of 4.4 in referral centres (95% CI 1.5–7.2) [ Lutgens et al. 2013 ]. For patients with chronic perianal fistula, there is possibility of malignant transformation and it should not be overlooked by the treating clinician [ Thomas et al. 2010 ]. There is a lack of consensus in regards to the frequency of colonoscopic surveillance. The American Gastroenterological Association (AGA) recommends surveillance intervals of 1–3 years for a maximum of 8 years after diagnosis [ Farraye et al. 2010 ] whilst the British Society of Gastroenter-ology (BSG) recommends yearly, 3-yearly or 5-yearly intervals depending on risk factors after ten years [ Cairns et al. 2010 ]. Chromoendoscopy is also a relatively recent technique that uses topical application of dyes or pigments to improve detection of subtle mucosal aberrations compared with usual white light endoscopy. A meta-analysis showed that, although chromoendoscopy had a 7% increase in dysplasia detection (95% CI 3.2–11.3) compared with white light endoscopy, it is uncertain as to whether this confers a survival benefit in patients given most were low grade dysplasia [ Subramanian et al. 2011 ]. The SCENIC consensus statement (Surveillance for Colorectal Endoscopic Neoplasia Detection and Manage-ment in Inflammatory Bowel Disease Patients: International Consensus Recommendations) nevertheless recommends chromoendoscopy as the preferred technique for surveillance for dysplasia in IBD [ Laine et al. 2015 ].

There are still certain gaps in the evidence regarding the diagnosis and management of CD. Each patient must be assessed individually to determine which investigation is most appropriate, taking into consideration age, suspected location of disease, disease severity and likelihood of recurrence. Numerous diagnostic techniques, be it serological markers or imaging modalities, have assisted both diagnosis and monitoring of CD. Further research is needed to assess the efficacy of certain novel therapeutic agents including vedolizumab and ustekinumab, and their role in active CD compared with classic anti-TNF therapy.

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement: The authors declare no conflicts of interest in preparing this article.

Contributor Information

Francis Ha, Faculty of Medicine, Nursing and Health Science, Monash University, Australia.

Hanan Khalil, School of Rural Health, Monash University, Ollerton Rd, Moe, Victoria, Australia.

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A comprehensive review and update on Crohn's disease

Affiliations.

1 Department of Internal Medicine, Texas Tech University Health Science Center El Paso, 2000B Transmountain Road, El Paso, TX 79911, United States. Electronic address: [email protected].
2 Department of Internal Medicine, Texas Tech University Health Science Center El Paso, 2000B Transmountain Road, El Paso, TX 79911, United States.
3 Department of Family Medicine, Texas Tech University Health Science Center El Paso, 2000B Transmountain Road, El Paso, TX 79911, United States.
4 Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, M2, C Wing, 200 Lothrop Street, Pittsburgh, PA 15213, United States.
PMID: 28826742
DOI: 10.1016/j.disamonth.2017.07.001

The term inflammatory bowel disease (IBD) refers principally to two major categories of chronic relapsing inflammatory intestinal disorders: Crohn's disease (CD) and ulcerative colitis (UC). In the United States, it is currently estimated that about 1.5 million people suffer from IBD, causing considerable suffering, mortality and economic loss every year. Yet the cause of IBD is unknown, and until we understand more, prevention or cure will not be possible. There is a lot of variation in the incidence and prevalence of CD based on geographic region, environment, immigrant population, and ethnic groups. The annual incidence of CD in North America is reported to be 3.1-20.2 per 100,000 with a prevalence of 201 per 100,000 population. Based on the epidemiological, genetic and immunological data, CD is considered to be a heterogeneous disorder with multifactorial etiology in which genetics and environment interact to manifest the disease. Several genes have been studied so for with respect to CD, but thus far the strong and replicated associations have been identified with NOD2, IL23R and ATG16L1 genes. The risk factors implicated with CD include smoking, low fiber- high carbohydrate diet, altered microbiome and medications such as non-steroidal anti-inflammatory drugs. CD is typically characterized by transmural inflammation of the intestine and could affect any part of the gastrointestinal tract from mouth to perianal area. In terms of distribution of the disease 25% of the patients have colitis only, 25% is ileitis only and 50% have ileocolitis. The Montreal classification is based on the age at diagnosis (<16, 17-40, > 40), disease location (Ileal, colonic, Ileocolonic) and the disease behavior (nonstricturing/nonpenetrating, stricturing, penetrating). The key features for diagnosing CD comprises a combination of radiographic, endoscopic and pathological findings demonstrating focal, asymmetric, transmural or granulomatous features. Abdominal Computed tomography (CT) enterography is the most preferred first-line radiologic study used in the assessment of small bowel CD. The diagnostic accuracy of magnetic resonance enterography/enteroclysis is similar to that of CT scans and also prevents exposure to ionizing radiation. Endoscopic scores are considered to be the gold standard tool to measure the activity of CD and they are used more commonly in the clinical trials to measure the efficacy of various drugs on inducing and maintaining mucosal healing. The most common scoring systems used to measure clinical disease activity include Crohn's Disease Activity Index (CDAI), HBI- Harvey-Bradshaw index (HBI), short inflammatory bowel disease questionnaire (SIBDQ) and Lehmann score. Management of Crohn's disease has been seen as an evolving challenge owing to its widely heterogeneous manifestations, overlapping characteristics with other inflammatory disorders, often elusive extraintestinal manifestations and uncertain etiology. Therapeutic interventions are tailored to address symptomatic response and subsequent tolerance of the intervention. Chronology of treatment should favor treatment dose acute disease or "induction therapy", followed by maintenance of adequate response or remission, i.e. "maintenance therapy". The medications which are highly effective in inducing remission include steroids and Tumor Necrosis Factor (TNF) inhibitors. Medications used to maintain remission include 5-aminosalicyclic acid products, immunomodulators (Azathioprine, 6-mercaptopurine, methotrexate) and TNF inhibitors (infliximab, adalimumab, certolizumab and golimumab). Surgical interventions like bowel resection, stricturoplasty or drainage of abscess is required in up to two thirds of CD patients during their lifetime. The most common indications for surgical resection are medically refractory disease, perforation, persisting or recurrent obstruction, abscess not amenable to percutaneous drainage, intractable hemorrhage, dysplasia or cancer. Endoscopic recurrence in postoperative CD patients, as defined by Rutgeers score i2-i4 occur in 30-90% of the patients at the neoterminal ileum within 12 months of surgery and almost universally by 5 years. Treating CD requires a comprehensive care team including the patient, primary care provider, and gastroenterologist. In summary CD is a chronic inflammatory condition with a remitting and relapsing course primarily affecting relatively younger population with significant socioeconomic effects.

Keywords: Crohn's disease; Diagnosis; Epidemiology; Management; Postoperative; Surgery.

Publication types

Combined Modality Therapy
Crohn Disease* / diagnosis
Crohn Disease* / epidemiology
Crohn Disease* / etiology
Crohn Disease* / therapy
Digestive System Surgical Procedures
Gastrointestinal Agents / therapeutic use
Genetic Markers
Induction Chemotherapy
Maintenance Chemotherapy
North America / epidemiology
Risk Factors
Severity of Illness Index
Tomography, X-Ray Computed
Gastrointestinal Agents

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Published: 02 April 2020

Crohn's disease

Nature Reviews Disease Primers volume 6 , Article number: 23 ( 2020 ) Cite this article

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This PrimeView highlights the epidemiology, mechanisms and management of Crohn’s disease, a progressive, destructive, chronic inflammatory bowel disease of unclear aetiology.