Understanding Crohn’s disease

Epidemiology

Prevalence and incidence

Crohn’s disease is an inflammatory bowel disease (IBD), characterised by chronic inflammation which can occur at any point along the gastrointestinal tract¹. A growing body of evidence suggests that the prevalence and incidence of this debilitating condition is increasing globally, with some regional variation^2–5.

While prevalence describes actual numbers of cases, incidence measures rates of new cases, and most epidemiological studies suggest that the incidence of IBD is increasing⁶.

Until recently, IBD was widely regarded as a disease of the western world⁴. The prevalence of IBD in westernised countries increased considerably over the course of the 20^th century and today exceeds 0.3% in many regions of Europe, North America, and Oceania⁴. Interestingly, although this figure now appears to be stabilising or even decreasing in some of these countries, the beginning of the 21^st century has seen a similar increase in the number of cases reported in newly industrialised nations, with incidence of IBD on the rise in South America, eastern Europe, Asia, and Africa (Figure 1)⁴. In Brazil, for example, an annual percentage increase in incidence of Crohn’s disease of 11.1% (95% confidence interval 4.8–17.8) has been reported ⁴.

Figure 1. Worldwide incidence of Crohn’s disease per 100,000 person years, 1990–2016 (Adapted⁴).

Nevertheless, the results of a large systematic review suggest that the prevalence of Crohn’s disease remains highest in Europe (322 cases per 100,000 individuals in Germany) and North America (319 cases per 100,000 individuals in Canada)^4,7. More recently, similar findings were reported by a study based on data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD)². This revealed that between 1990 and 2017 the highest age-standardised prevalence rate of IBD was recorded in high-income North America (344.8 cases per 100,000 individuals [95% UI 331.7 – 359.3] in 1990; 422.0 cases per 100,000 individuals [95% UI 398.7 – 466.1] in 2017)². Meanwhile, the lowest age-standardised prevalence rates were reported in the Caribbean (6.7 cases per 100,000 individuals [95% UI 6.3 – 7.2] in 2017)². Other regions with low rates of IBD included Andean Latin America and parts of sub-Saharan Africa².

Disease development

Among adults, Crohn’s disease affects more women than men^8,9. It can develop at any point from early childhood but the median age of onset is 30 years^6,10. Onset tends to occur in two peaks – mainly between 20 and 30 years of age, but also around 50 years¹⁰.

Aetiology

Genetic susceptibility

Though the exact aetiology of Crohn’s disease remains unknown, familial aggregation studies and twin studies indicate a strong genetic component^11,12. A family history of the condition has been reported by approximately 12% of patients and concordance rates among monozygotic twins are estimated to be around 50%^1,3. 

Further evidence of a genetic component can be found in differences in the prevalence of Crohn’s disease between ethnic groups. Caucasians and African Americans are among those most commonly affected, while individuals of Hispanic and Asian descent are considered to be at lower risk¹¹. Of note, risk of developing Crohn’s disease is reportedly 3–fold higher in Jewish compared with non-Jewish individuals¹².

To date, genome-wide association studies have identified over 200 susceptibility loci for IBD¹³. In Crohn’s disease, these include polymorphisms in the NOD2 gene, which is expressed in a range of cell types and encodes a protein with a role in innate immunity, as well as in autophagy-related genes^14–16.

Gut flora

Dysbiosis is thought to play a key role in IBD pathogenesis, and Crohn’s disease is associated with the presence of specific pathogens in the gut microbiota and a reduction in gut microbial diversity compared to healthy individuals¹⁷. Alterations in the composition of the intestinal microbiota in patients with Crohn’s disease include changes in the relative abundance of Bacteroides and Firmicutes, and an increased proportion of Gammaproteobacteria and Enterobacteriales, as well as a decrease in Clostridiales¹⁷.

Environmental factors

A range of environmental factors influence the onset and progression of Crohn’s disease in genetically susceptible individuals¹.

Cigarette smoking is the best-studied environmental risk factor. Among smokers, risk of developing Crohn’s disease is reportedly double that of non-smokers and smoking has been linked to an earlier onset of disease, need for immunosuppression, increased need for surgical intervention and higher rates of postoperative recurrence^1,3.

Dietary changes and associated gut dysbiosis has also been implicated in the development of Crohn’s disease¹. While high fibre diets are thought to reduce risk of Crohn’s disease, diets rich in sugar, fat, and meat have been shown to increase risk in several studies¹⁰.

Crohn’s disease risk is also held to be increased by exposure to certain drugs, including oral contraceptives, aspirin and non-steroidal anti-inflammatory drugs (NSAIDs), as well as use of antibiotics such as penicillins, cephalosporins, metronidazole and fluoroquinolones, particularly during childhood^1,10,18. 

Pathophysiology

Pathogenesis

The pathogenesis of Crohn’s disease is not well understood, involving inflammatory processes of the intestinal tract, the origins of which are unknown^19,20. This being said, it is thought that both the innate and adaptive immune responses play a role²¹. Indeed, massive infiltration of the mucosa by innate and adaptive immune cells is considered a key characteristic of active IBD in general²². This may be related to either overactivation of effector T cells and/or alteration of T cell-mediated tolerance²². An abnormal and sustained host immune response against intestinal microbiota is key to the development of IBD²².

In patients with Crohn’s disease, damage to the intestinal barrier leads to translocation of commensal microorganisms into the bowel wall. Innate immune cells respond to microbes and their mediators, resulting in immune cell activation and the production of cytokines and chemokines. Innate immunity is then activated as a result of disruptions to gut homeostasis and recruitment of additional immune cells to the bowel wall and causes activation of adaptive immune cells. Activated immune cells produce mediators, including cytokines, which, along with immune cells themselves, cause damage to epithelial cells, impair barrier function resulting in dysbiosis, and perpetuate gut inflammation (Figure 2)²⁰ .

Figure 2. Pathogenesis of Crohn’s disease (Adapted²³).

Crohn’s disease is a chronic progressive disease, with half of all patients developing intestinal complications, including strictures and fistulae, within 10 years of diagnosis¹.

IBD therapy

Crohn’s disease is characterised by patchy, transmural inflammation, known as “skip lesions”^1,20. The lesions that typically occur in Crohn’s disease are “cobblestone appearance” and “longitudinal ulcers”²⁴. It can occur at any point along the gastrointestinal tract, where it causes chronic, relapsing transmural inflammation, which is associated with a range of debilitating symptoms including diarrhoea, abdominal pain, fever, and fatigue^1,10,20.

At diagnosis, an estimated 81% of patients with Crohn’s disease present with a luminal inflammatory phenotype, though this may change as the disease progresses^10,25,26. Extraintestinal manifestations of the disease may impact patient quality of life, long-term outcomes, risk of hospitalisation, complications and surgery¹. Numerous factors are thought to affect quality of life in patients with Crohn’s disease, including¹:

• Physical status and ability to function (e.g. pain, defecation, sleep loss, fatigue)
• Psychological status and wellbeing (e.g. body image, emotional status)
• Economic and/or vocational factors (e.g. ability to participate in educational/recreational activities or to work and earn money)
• Social factors (e.g. relationships and sexual function)

Treatment goals

Evolution of treatment goals and treat-to-target

In the past, standard of care for patients with IBD was limited to managing their symptoms. Today, treatment goals in Crohn’s disease are evolving and a treat-to-target approach is now encouraged. This strategy promotes personalised care and early intervention²⁷.

A treat-to-target approach involves careful monitoring of specific and objective improvement in measures of inflammation^27,28.

Currently mucosal healing represents an important treatment target in Crohn’s disease and has been associated with improved patient outcomes¹. In the future, transmural healing, which can be assessed using cross-sectional imaging techniques, is expected to become another key treatment target for patients with Crohn’s disease (Figure 3)^1,29.

Figure 3. Evolution of treatment targets in Crohn’s disease (Adapted³⁰).

Consensus definition of targets in Crohn’s disease: STRIDE

The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) programme assessed potential treatment targets for patients with IBD to be used in a treat-to-target strategy³¹. For Crohn’s disease, the expert-consensus definition of treatment targets that was generated by STRIDE and published in 2015, combines clinical (patient-reported) remission and endoscopic (clinician-reported) remission^31,32.

The original STRIDE statements define clinical remission as resolution of abdominal pain and normalisation of bowel habit, while absence of ulceration at ileocolonoscopy is used to confirm endoscopic remission³¹.

More recently, an updated version of the original STRIDE statements, STRIDE-II, has been made available²⁸. Clinical response and remission, endoscopic healing, and normalisation of C-reactive protein/erythrocyte sedimentation rate and calprotectin were all listed as key therapeutic targets²⁸.

As well as confirming the long-term treatment targets of clinical remission and endoscopic healing that were outlined in STRIDE I, STRIDE-II also introduced several additional targets including absence of disability, restoration of quality of life and normal growth in children²⁸. Symptomatic relief and normalisation of serum and faecal markers were also identified as short-term targets²⁸.

Role of early intervention

Although the majority of patients with Crohn’s disease initially present with uncomplicated disease, for many, chronic intestinal inflammation ultimately leads to the development of irreversible bowel damage and complications, which could necessitate surgery, leading to further permanent bowel damage^3,20,33. Nevertheless, experts have now identified a “window of opportunity” in the early stages of the disease, during which appropriate therapeutic intervention has the potential to stop the inflammatory cascade and alter disease progression in many patients^32,34.

It is therefore thought that early intervention with effective agents may allow many patients to achieve complete disease control by resolving local inflammation and potentially preventing disease progression and the associated irreversible bowel damage^33,35–37.

The potential benefits of early intervention with biological therapies have been highlighted in several publications, including a recent systematic review and meta-analysis in which a total of 18,471 patients were studied³⁸. This study reported that, compared with later biological intervention, early initiation of biological therapy was associated with higher rates of clinical remission (OR 2.10 [95% CI:1.69 – 2.60], n = 2763, p<0.00001) and mucosal healing (OR 2.37 [95% CI: 1.78 – 3.16], n=994, P<0.00001), as well as lower rates of relapse (OR 0.31 [95% CI: 0.14 – 0.68], n=596, p=0.003)³⁸.

Similarly, in another study, higher rates of clinical remission were observed in patients who received early treatment with adalimumab (within 1 year of diagnosis) (66.25%) compared with patients for whom initiation of adalimumab treatment was delayed for 1 year or more (33.77%) (p<0.001)³⁹. In total, 53.75% of patients receiving early adalimumab treatment achieved mucosal healing, compared to 20.78% of those whose treatment was delayed (p<0.001)³⁹. Dose escalation was also required less frequently in patients receiving early (30.00%) compared to late (66.23%) treatment (p<0.01) and the proportion of non-responders was 7.50% and 22.08% respectively (p<0.01)³⁹.

Further insight was provided by a study which reported a significantly lower Lémann Index (a measure of cumulative bowel damage in patients with Crohn’s disease) in patients who were treated with an anti-TNF agent within two years of diagnosis compared to those whose treatment was delayed beyond 2 years (p=0.015)⁴⁰.

The Lémann Index is used to assess cumulative structural bowel damage in patients with Crohn’s disease^40,41.

Nevertheless, in a study that included 16,260 patients with Crohn’s disease, it was reported that less than 5% were initially treated with biologics⁴². Although conventional therapy is only effective in approximately 20–40% of patients with IBD, the most common initial treatment for Crohn’s disease were found to be corticosteroid monotherapy (42%) and 5-aminosalicylic acid monotherapy (35%)⁴².

Role of mucosal healing

Recognition of the fact that disease activity often persists in the absence of clinical manifestations highlighted a need for more stringent treatment targets for patients with Crohn’s disease, including mucosal healing³⁰.

Achieving mucosal healing has several important benefits for patients with Crohn’s disease and is now widely considered to be an important therapeutic endpoint. Mucosal healing is associated with sustained clinical remission and a reduced risk of both hospitalisation and surgery^30,43.

Nevertheless, it should be noted that given the transmural nature of Crohn’s diseases, there is some debate as to whether or not mucosal healing is an adequate measure of the inflammatory burden and prognosis in patients with this condition. This highlights the need for further investigation of transmural healing as a potential therapeutic target⁴⁴. Currently available research suggests that transmural healing may represent a deeper level of healing than mucosal healing²⁹. It is hoped that stronger therapeutic intervention earlier in the disease course could lead to increased rates of transmural healing among patients with Crohn’s disease²⁹. The reported benefits of achieving transmural include lower rates of hospitalisation and surgery, as well as an association with favourable longer-term outcomes²⁹.

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