Elsevier

The Lancet

Volume 389, Issue 10080, 29 April–5 May 2017, Pages 1741-1755
The Lancet

Seminar
Crohn's disease

https://doi.org/10.1016/S0140-6736(16)31711-1Get rights and content

Summary

Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract, with increasing incidence worldwide. Crohn's disease might result from a complex interplay between genetic susceptibility, environmental factors, and altered gut microbiota, leading to dysregulated innate and adaptive immune responses. The typical clinical scenario is a young patient presenting with abdominal pain, chronic diarrhoea, weight loss, and fatigue. Assessment of disease extent and of prognostic factors for complications is paramount to guide therapeutic decisions. Current strategies aim for deep and long-lasting remission, with the goal of preventing complications, such as surgery, and blocking disease progression. Central to these strategies is the introduction of early immunosuppression or combination therapy with biologicals in high-risk patients, combined with a tight and frequent control of inflammation, and adjustment of therapy on the basis of that assessment (treat to target strategy). The therapeutic armamentarium for Crohn's disease is expanding, and therefore the need to develop biomarkers that can predict response to therapies will become increasingly important for personalised medicine decisions in the near future. In this Seminar, we provide a physician-oriented overview of Crohn's disease in adults, ranging from epidemiology and cause to clinical diagnosis, natural history, patient stratification and clinical management, and ending with an overview of emerging therapies and future directions for research.

Introduction

Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract with symptoms evolving in a relapsing and remitting manner. It is also a progressive disease that leads to bowel damage and disability. All segments of the gastrointestinal tract can be affected, the most common being the terminal ileum and colon. Inflammation is typically segmental, asymmetrical, and transmural. Most patients present with an inflammatory phenotype at diagnosis, but over time complications (strictures, fistulas, or abscesses) will develop in half of patients, often resulting in surgery.1, 2 Current therapeutic strategies aim for deep and prolonged remission, with the goal of preventing complications and halting the progressive course of disease.

Section snippets

Epidemiology

There is no sex-specific distribution in adult Crohn's disease. The onset of the disease usually occurs in the second to fourth decade of life with a smaller peak that has been described from 50 to 60 years.3 Crohn's disease has increased steadily in most regions worldwide (appendix).3 Incidence and prevalence of Crohn's disease are greater in developed countries than in developing countries, and in urban areas than in rural areas.3 The highest annual incidence is in Canada (20·2 per 100 000),

Cause and pathophysiology

Crohn's disease is believed to result from the interplay between genetic susceptibility, environmental factors, and intestinal microflora, resulting in an abnormal mucosal immune response and compromised epithelial barrier function.

Clinical presentation and diagnosis

Presenting symptoms can be heterogeneous and insidious. Clinical presentation depends on disease location, severity of inflammation, and disease behaviour (figure 2). The most common scenario is a young patient presenting with right lower quadrant abdominal pain, chronic diarrhoea, and weight loss. Fatigue and anorexia are common symptoms. In patients with colonic involvement, rectal bleeding or bloody diarrhoea might be the major symptoms. High fever should always raise the suspicion of a

Diagnostic investigations

Typical laboratory findings include thrombocytosis, increased acute phase proteins (particularly C-reactive protein), and anaemia. C-reactive protein is a biomarker used to monitor disease activity, but correlates poorly with endoscopic findings, and a third of patients never present with increased concentrations.55 Hypoalbuminaemia and vitamin deficiencies might be present, especially in extensive small bowel disease. About 60–70% of patients might have antimicrobial antibodies in their serum,

Definition of disease activity and severity

Disease activity refers to the assessment of disease at a given timepoint, and it is important for choosing the induction therapy, assessing the need for admission to hospital, or efficacy of a drug. A more clinical classification categorises disease into mild, moderate, or severe depending on response to therapy, presence of malnutrition, dehydration or systemic toxicity, presence of abdominal tenderness, mass or obstruction, and degree of weight loss and anaemia (appendix).68 Symptoms do not

Natural history and predictive factors for complications

Crohn's disease is characterised by periods of clinical remission alternating with periods of recurrence. However, there is a disconnect between clinical symptoms and mucosal disease activity, which might explain why conventional strategies have failed to alter the course of the disease.71 Persistent subclinical inflammation that occurs during clinical remission is thought to lead to complications (strictures, fistulas, and abscesses) and progressive bowel damage (figure 3).72 Disease location

Risk factors for complicated disease

With various definitions of complicated disease, the predictors of a worse outcome identified in population-based studies are ileal or ileocolonic disease location, extensive small bowel disease, severe upper gastrointestinal disease, rectal disease, perianal lesions, early stricturing or penetrating disease, a young age at diagnosis, and smoking.78 Smoking is also the most important risk factor for postoperative recurrence and need for second surgery.79 These clinical risk factors have poor

Treatment goals and therapeutic strategies

In the past, patients were started on aminosalicylates, steroids, or thiopurine, with escalation to more effective treatments only after these lines of therapy had failed (step-up therapy). This strategy failed to change the course of disease as reflected by high rates of surgery. Therefore, the treatment framework evolved from mere control of symptoms towards blocking progression of the disease that leads to complications, bowel damage, and disability. Endoscopic healing, usually defined as no

Evolving therapeutic strategies and treatment goals

The concept of targeting early Crohn's disease is emerging. Post-hoc data suggest that biological drug therapy is effective if introduced earlier in the disease course.137 Controlled trials in this specific population, using a treat-to-target approach and seeking prospective evidence regarding the need to achieve and maintain mucosal healing and deep remission, are eagerly awaited.138

Personalisation of therapy and drug monitoring

The need to develop biomarkers that can predict response to therapies will become increasingly important for

Search strategy and selection criteria

We searched for relevant manuscripts using PubMed, MEDLINE, Embase, and the Cochrane library from their inception until March 1, 2016. The search combined the MeSH terms “Crohn's disease” and “inflammatory bowel disease” with the sub-headings “epidemiology”, “aetiology”, “physiopathology”, “innate AND adaptive immunity”, “genetics”, “diagnosis”, “endoscopy”, “therapy”, “surveillance”, “prevention”, and “complications”. We searched bibliographies of included articles and consulted experts in

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