Clinical features

UC and CD are chronic relapsing and remitting diseases with variable evolution. These conditions have been associated with complications that greatly reduce QoL and increase anxiety and depression risk.^52,53 IBD patients also have increased risk of mortality.^54,55 Both conditions are more common in adults before middle-age, at 20-30 years for CD onset and 30-40 years for UC. Incidence peaks again between 50-60 years. About 25% of IBD cases are diagnosed in children under 18 years (pediatric-onset IBD).⁵⁶ IBD affects men and women about equally; men are only slightly more likely to develop UC. In most studies, men

9 make up about 60% of participants and women 40%. Men generally have worse outcomes than women, especially for UC. A study from Olmsted County, Minnesota, USA looked at colectomy rates and found that men were twice as likely to need colectomy than women, but could not offer a clear explanation.⁵⁷ Several studies reported that men with UC are twice as likely to develop colorectal cancer.⁵⁸ CD and UC share similarities, also differ in important ways.

2.1 CD manifestations

CD may occur in any part of the gastrointestinal tract, from the mouth to the anus. Healthy parts of the intestine may alternate with inflamed areas called skip lesions. CD is classed into four categories, by location (Montreal classification): in ileitis (L1), only the ileum is affected; in Crohn's colitis (L2), only the colon; in ileocolitis (L3), both the ileum and the colon are affected (most common form); and, in upper gastrointestinal CD (L4) only the stomach and the first part of the small intestine are inflamed. Inflammation in CD’s patients may extend through the entire thickness of the bowel wall (transmural inflammation) leading to possible serious complications including development of strictures and fistula formation, intra-abdominal abscesses and/or peritonitis.^59,60 Up to 80% of patients with CD may have at least one surgery for the disease.^59,61,62 Common symptoms of CD include diarrhea,

abdominal pain, and weight loss. Blood and mucus in the stool are present in up to 50% of patients with CD. In a cohort of newly diagnosed IBD patients, the two most commonly reported symptoms at presentation were fatigue and abdominal pain.⁶³

2.2 UC manifestations

UC is limited to the rectum and colon; inflammation occurs only in the mucosal layer of the intestine. Usual presentation is continuous inflammation with an ascending gradient from the rectum to the proximal colon. Ulcerative colitis is typed by the area of the colon affected (Montreal classification): in proctitis (E1), inflammation is limited to the rectum; in left-sided colitis (E2) the rectum is affected as far as the splenic flexure; and in pancolitis or extensive colitis (E3) the entire colon is affected. UC causes inflammation and ulceration in the large intestine, leading to loose stools or diarrhea, hematochezia or blood in stools, and bowel urgency. In a cohort of newly diagnosed IBD patients with UC, bloody bowel movements and diarrhea were the two predominant symptoms at presentation. ⁶³ About 10-15% of patients with UC will undergo proctocolectomy either for refractory colitis or because they develop colorectal cancer,⁶⁴ but the arrival of new therapies seems to be decreasing these

numbers.⁶⁵ About 10% of IBD cases exhibit features of both CD and UC; this is called indeterminate colitis (IC).

10 2.3 Extraintestinal manifestations

IBD is a systemic immune disorder not limited to the gut that can cause “extraintestinal manifestation” (EIM) in multiple other organs. The pathogenesis of EIM has not been fully described. It is unclear whether EIM is a direct product of the inflammatory process in the gut or a consequence of shared genetic background impaired leading to impaired immune responses to environmental factors. Several mechanisms have been proposed, including aberrant lymphocyte homing, upregulation of tumor necrosis factor, and cross-reactive antigen presentation.⁶⁶ A recent cohort study showed that EIM occur frequently; about 50%

of IBD patients develop an EIM at some point, which drastically reduces their QoL.^67,66 The definition of EIM is not uniform, so EIMs are classified by pathogenesis into immune-mediated manifestations caused by the same processes that drive inflammation in the gut, ⁶⁸ and non-immune-mediated IBD-associated complications like vein and arterial diseases (venous thromboembolism, ischemic heart disease, cerebral vascular disease, peripheral arterial disease), osteoporosis, anemia, and nutrient deficiency that are the result of inflammatory complications on the body.⁶⁹ EIMs can also be categorized as “specific” (the same disease as IBD but located outside the gut), “reactive” (shares pathogenic

mechanisms with IBD but has different histo-morphological characteristics), ”associated”

(EIMs more frequently observed in IBD than in controls, with an unclear pathogenic link), and “treatment induced” (appearing after IBD treatments introduction). ⁶⁸

Multiple organ systems can be involved, but musculoskeletal (arthritis type 1 or 2 and spondylarthropathy), ophthalmic (episcleritis and uveitis), dermatological (pyoderma gangrenosum, erythema nodosum, and stomatitis) and hepatobiliary disorders (non-alcoholic fatty liver disease NAFLD, primary sclerosing cholangitis (PSC)) are more

frequent.^70,71 The most common EIMs at presentation are joint pain (20% in CD; 14% in UC) and oral ulcerations (13% in CD; 6% in UC),⁷² which may or may not be linked to disease activity. Erythema nodosum, episcleritis, and type 1 arthritis are typically associated with intestinal disease; spondylarthropathy and type 2 arthritis do not correlate with intestinal inflammation. The correlation between pyoderma gangrenosum or uveitis is still not clear. ⁶⁶ Looking for EIMs is necessary to personalize care because (i) EIMs strongly affect morbidity and mortality, (ii) EIMs can indicate ongoing intestinal disease activity even if patients are asymptomatic, (iii) EIMs usually appear after IBD diagnosis (median of 92 months), but precede IBD diagnosis in 25% of patients, as highlighted in a prospective work of the Swiss IBD cohort study.⁷³ Clinicians should screen for underlying IBD in patients with EIMs to speed diagnosis. To provide the best care a close collaboration between specialists is key to success.

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