Accepted Manuscript

Natural History of Adult Ulcerative Colitis in Population-based Cohorts: ASystematic Review

Mathurin Fumery, Siddharth Singh, Parambir S. Dulai, Corinne Gower-Rousseau,Laurent Peyrin-Biroulet, William J. Sandborn

PII: S1542-3565(17)30722-XDOI: 10.1016/j.cgh.2017.06.016Reference: YJCGH 55298

To appear in: Clinical Gastroenterology and HepatologyAccepted Date: 8 June 2017

Please cite this article as: Fumery M, Singh S, Dulai PS, Gower-Rousseau C, Peyrin-Biroulet L,Sandborn WJ, Natural History of Adult Ulcerative Colitis in Population-based Cohorts: A SystematicReview, Clinical Gastroenterology and Hepatology (2017), doi: 10.1016/j.cgh.2017.06.016.

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A Systematic Review

Mathurin Fumery1,2,*, Siddharth Singh1,3*, Parambir S. Dulai1, Corinne Gower-Rousseau2, Laurent Peyrin-Biroulet3, William J. Sandborn1

1Division of Gastroenterology, University of California San Diego, La Jolla, California; 2Gastroenterology Unit, Epimad Registry, Amiens University Hospital, France; 3Division of Biomedical Informatics, University of California San Diego, La Jolla, California; 4LIRIC Inserm, Unit 995, Lille University, France; Epidemiology Unit, Epimad egistry, Lille University Hospital, France; 5Gastroenterology Unit, Inserm U954, Nancy University and Hospital, France;

*Both authors contributed equally to this article Short Title: Natural history of ulcerative colitis Corresponding author: Dr Mathurin Fumery, Gastroenterology Unit, Epimad Registry, Amiens, University Hospital, France; Tel: 03 22 08 88 51, Fax: 03 22 08 97 53; mathurinfumery@gmail.com Word count: Abstract – 256; Manuscript – 4751; References – 76 Tables and Figures: Tables – 5; Figures – 1 eTables (in the supplement): 1 Abbreviations: UC, Ulcerative colitis; 5ASA, 5-aminosalycilate; EIMs, Extra-Intestinal Manifestations. Disclosures and conflict of interest: Dr. Fumery is supported by the French Society of Gastroenterology (SNFGE, bourse Robert Tournut) and received lecture fees/consultant fee from Abbvie, MSD, Takeda and Ferring. Dr. Singh is supported by the NIH/NLM training grant T15LM011271 and the American College of Gastroenterology Junior Faculty Development Award and Crohn’s and Colitis Foundation of American Career Development Award. Dr. Dulai is supported by the NIDDK training grant 5T32DK007202. Dr Gower has served as speaker for Abbvie France, Ferring International, Janssen International and MSD France. Dr Peyrin-Biroulet has received consulting fees from Abbott, BMS, Boehringer Ingelheim, Celltrion, Ferring, Genentech, Hospira, Janssen, Lilly, Merck, Mitsubishi, Norgine, Pharmacosmos, Pilege, Shire, Takeda, Therakos, Tillots, UCB and Vifor, and has received lecture fees from Abbott, Ferring, HAC-pharma, Janssen, Merck, Norgine, Therakos, Tillots and Vifor. Dr Sandborn has received grant support from Exact Sciences, the American College of Gastroenterology, and the Broad Foundation; grant support and personal fees from Receptos, Amgen, Prometheus Laboratories, AbbVie, Boehringer Ingelheim, Takeda, Atlantic Pharmaceuticals, Janssen, Bristol-Myers Squibb, Genentech, Pfizer, and Nutrition Science Partners; and personal fees from Kyowa Hakko Kirin, Millennium Pharmaceuticals, Celgene Cellular

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Author Contribution: • Study concept and design: MF, SS, WJS • Acquisition of data: MF, SS • Analysis and interpretation of data: MF, SS • Drafting of the manuscript: MF, SS • Critical revision of the manuscript for important intellectual content: PSD, LPB,

CGR, WJS • Approval of the final manuscript: MF, SS, PSD, CGR, LPB, WJS • Guarantor of the article: MF

ABSTRACT

Introduction: A comprehensive knowledge of the natural history of UC helps

understand disease evolution, identify poor prognostic markers and impact of

treatment strategies and facilitates shared decision-making. We systematically

reviewed the natural history of UC in adult population-based cohort studies with long-

term follow-up.

Materials and Methods: Through a systematic literature review of MEDLINE

through March 31, 2016, we identified 60 studies performed in 17 population-based

inception cohorts reporting the long-term course and outcomes of adult-onset UC

(n=15,316 UC patients).

Results: Left-sided colitis is the most frequent location and disease extension is

observed in 10-30% patients. Majority of patients have a mild-moderate course, most

active at diagnosis and then in varying periods of remission or mild activity; about 10-

15% patients experience an aggressive course, and the cumulative risk of relapse is

70-80% at 10 years. Almost 50% patients require UC-related hospitalization, and 5-

year risk of re-hospitalization is ~50%. The 5- and 10-year cumulative risk of

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colectomy. About 50% patients receive corticosteroids, though this proportion has

decreased over time, with a corresponding increasing in the use of

immunomodulators (20%) and anti-TNF (5-10%). While UC is not associated with an

increased risk of mortality, it is associated with high morbidity and work disability,

comparable to Crohn’s disease.

Conclusion: UC is a disabling condition over time. Prospective cohorts are needed

to evaluate the impact of recent strategies of early use of disease-modifying

therapies and treat-to-target approach, with immunomodulators and biologics. Long-

term studies from low-incidence areas are also needed.

Key words: ulcerative colitis, population-based, natural history

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Ulcerative colitis (UC) is a chronic disabling inflammatory bowel disease that

generally begins in young adulthood and lasts throughout life (1). Although its

incidence and prevalence has stabilized in high-incidence areas such as Western

Europe and North America, it continues to rise in low-incidence areas such as

Eastern Europe, Asia, and much of the developing world (1,2). Besides significantly

impacting quality of life and work productivity due to debilitating symptoms, UC is

also associated with an increased risk of colorectal cancer (CRC) (1,3,4).

A detailed knowledge of the natural history of UC is essential to understand

disease evolution, evaluate the impact of treatment strategies, identify predictors for

disabling disease, and provide comprehensive information to patients to facilitate

shared decision-making (5,6). In contrast to randomized controlled trials that evaluate

specific interventions in a limited set of highly selected patients, over a short pre-

defined period, population-based observational cohort studies evaluate an entire

population in defined geographic area over an extended period of time. They are

ideal to inform natural history of disease, and also avoid selection biases associated

with referral center cohort studies (5,7,8).

MATERIALS AND METHODS

Literature search

We conducted a systematic literature search of English and non-English

language publications in MEDLINE (source PUBMED, 1935 to March 31, 2016) to

identify published population-based studies in patients with UC. We searched for the

following terms: (“Inflammatory bowel diseases” OR “ulcerative colitis”) AND (“natural

history” OR “population-based” OR “long-term outcome” OR “long-term follow-up” OR

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manifestations” OR “corticosteroids” OR “immunosuppressants” OR “anti-TNF” OR

“surgery” OR “colectomy” OR “mortality” OR “cancer” OR “hospitalization” OR

“predictors”). A single reviewer screened and identified relevant studies for inclusion,

following an a priori established protocol. Additionally, a recursive search of relevant

systematic reviews was also performed. The reference lists of relevant articles were

also reviewed. Data extraction was carried out using a standardized data collection

form, by a single reviewer and confirmed by a second reviewer independently.

Inclusion and Exclusion Criteria

We included only population-based inception cohort studies of patients with

adult-onset UC (≥18y at diagnosis), based on standard clinical, endoscopic and/or

histologic criteria through medical record review, with minimum 1 year follow-up,

describing the natural history of UC in terms of the following outcomes: disease

phenotype, disease activity, complications, disease-related medications,

malignancies, morbidity, mortality and/or extra-intestinal complications.

We excluded the following studies: (i) reporting only incidence and/or

prevalence of UC, (ii) reporting phenotype, disease complications and/or treatment

only at time of diagnosis, (iii) population-based studies that relied on administrative

codes for UC diagnosis, without medical record review, (iv) reporting only on IBD,

without separate data on UC per se, (v) non-inception cohort studies, which included

patients with prevalent UC, and (vi) studies focused on patients with pediatric-onset

(<18 years) or elderly-onset (>60 years) UC. Often, one population-based cohort

reported several pertinent outcomes, in which case we only included the most recent

study with unique outcomes, with the longest follow-up.

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Outcomes of Interest

To comprehensively describe natural history of UC, we studied several UC-

related outcomes including: (a) disease phenotype (including disease location,

proximal extension and change in diagnosis); (b) disease activity and complications

(including rates of relapse, hospitalization, surgery and post-operative complications);

(c) use of UC-related medications (including 5-aminosalycilate [5-ASA],

corticosteroids, immunomodulators [IM] and anti-tumor necrosis factor [TNF]-α

agents); (d) malignancy (including CRC and extra-intestinal cancers); (e) morbidity

and mortality; and (f) extra-intestinal complications (including extra-intestinal disease

manifestations, anemia, osteoporosis, venous and arterial thromboembolic events).

The Montreal classification was used to classify and compare the phenotype

between the various studies. When data were available, we attempted to compare

and contrast differences in disease course between patients diagnosed in the pre-

biologic (before 2005) and biologic era (after 2005). Additionally, we systematically

reviewed clinical, biochemical and/or endoscopic predictors of natural history of UC.

Outcomes at different time points were generally reported in studies either as

point prevalence (at a particular time point), or as cumulative probability (over a

particular time period). Due to differences in reporting patterns, we opted not to

perform a meta-analysis, but instead systematically reported these findings using

median and interquartile range (IQR) or range or as preferred summary measures.

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Through a systematic literature review, we identified 60 studies reporting on

17 population-based cohorts. Key characteristics of these cohorts and corresponding

studies are detailed in Table 1 . These included 12 European cohorts, two North-

American cohorts and two Asia-Oceania cohorts. Patients were recruited from 1940

to 2014. Sample sizes of these studies ranged from 63 to 3117 patients (total 15,316)

and median follow-up ranged from one to 20 years. Salient aspects of study

methodology of each population-based cohort are detailed in Supplementary Table

1. Main results of each evaluated outcome are summarized in Tables 2, 3 and 4 and

Figure 1.

I. Disease Phenotype

Disease Extension

At diagnosis, the majority of patients had left-sided colitis (median 40.1%; IQR,

32.6-44.6); 30.5% (29.8-32.6) and 29.4% (25.3-34.7) were diagnosed with extensive

colitis and proctitis, respectively (9-17). Overall rates of disease extension were

comparable across cohorts, regions, and over time (including the pre-biologic and

biologic era) (Table 2 ). Rate of progression from proctitis to left-sided colitis was 28-

30%, and to extensive colitis was 14-16%; rate of progression from left-sided colitis

to extensive colitis was 21-34% (9,10,18). Overall rates of progression ranged from

12-30%, with cumulative 5-year risk of progression being approximately 13%

(10,13,14). At the end of follow-up, left-sided colitis (44-53%) was the most common

site of disease involvement, followed by extensive colitis (24-28%) and proctitis (22-

28%). Extra-intestinal manifestations (EIMs) (odds ratio (OR), 3.6; confidence interval

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follow-up, were significantly associated with extensive disease (13,15).

Change of diagnosis

In the EC-IBD cohort, the original diagnosis of UC remained unchanged in

98% of cases after 4 years of follow-up (19); in 1% patients, the diagnosis was

changed to Crohn’s disease (CD), and in another 1%, to indeterminate colitis. In the

South-Limburg cohort, the diagnosis of UC was changed in 3% of patients, after a

median follow-up of 7 years (16).

II. Disease Activity and Complications

Disease Relapse

In the 10y follow-up study of the IBSEN cohort, four different profiles of

disease activity were reported by patients: remission or mild severity after initial

period of high activity (55%), chronic intermittent symptoms (37%), chronic

continuous symptoms (6%) and increase activity after period of low activity (1%) (18).

In studies evaluating changes in disease activity within the first 1-2 years of

diagnosis, most studies observed improvement in disease activity in 50-70% patients

(14,20,21). In the Uppsala cohort, 50% patients remained in remission within the first

year after initial disease flare, 43% of patients experienced relapse and 5% had

chronic symptoms without remission (21). Similarly, in the Asia-Pacific cohort, during

the 1-year after diagnosis, 65% patients were in clinical remission (UC Simple

Clinical Colitis Activity Index (SCCAI) ≤2), 18% had mild to moderate disease (SCCAI

3-4), and 17% had severe disease (SCCAI ≥5), respectively (14). On longer follow-

up, rates of remission remained stable. In the EC-IBD cohort (19), after 4 years

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risk of relapse ranged from 67% to 83% at 10 years (median, 70.0%; IQR, 68.5-76.5)

(19,21,22).

There has been limited comparison of disease activity trends between the pre-

biologic and biologic era, though there seems to be a shift towards improved early

disease course, perhaps related to availability and early adoption of more effective

therapies. In a cohort of patients diagnosed in Copenhagen county between 1962-93,

disease course was characterized as indolent, moderate or aggressive in 13%, 73%

and 14% of patients, respectively, within the first 5-years of diagnosis; in the same

region, in a cohort of patients diagnosed between 2003-04, early disease activity was

characterized as mild in 76%, and moderate-to-severe in 24% (23,24).

Young age at disease onset (hazard ratio (HR), 1.3; 95% CI, 1.0–1.6), female

sex (HR, 1.4; 95% CI, 1.1–1.7) and high level of education (HR 1.4; 95% CI, 1.1-1.8)

has been associated with disease relapse, while smoking may be protective (HR 0.7;

95%CI, 0.6-0.9) (9,16,21). Conflicting data on the association between serological

markers and risk of relapse were observed (25,26) (Table 5 ).

Hospitalization

Almost half the patients with UC require hospitalization at some point during

disease course, with 1-, 5-, 10-year cumulative probabilities ranging from 17-29%,

29-54% and 39-66%, respectively; 10-15% may be hospitalized at time of diagnosis

(11,12,20,27). Among patients who are hospitalized once, cumulative probability of

re-hospitalization 1-, 5- and 10-years after index hospitalization ranges from 24%, 51-

56% and 59-75%, respectively (11,12,20,27). Overall, the rate of hospitalization may

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134/1,000 py in 1970–79 to 88/1,000 py from 2000-04 (12).

Disease extent at diagnosis (HR, 1.8, p=0.02), need for corticosteroids (HR,

2.0, p<0.001), immunomodulators (HR, 1.6, p=0.038) and/or anti-TNF agents (HR,

2.3, p<0.001) have been associated with an increased risk of UC-related

hospitalization (12,27); early need for hospitalization (<90 days after diagnosis) was

an independent predictor for future hospitalization (HR, 1.5; 95%CI, 1.0-2.4) (12).

Surgery

Risk of colectomy in adults with UC has been extensively studied and is

summarized in Table 2 . In an early report of colectomy from the Stockholm County

cohort in patients diagnosed between 1966-1984, cumulative colectomy rate at 5-,

10- and 25y after diagnosis was 20%, 28% and 45%, respectively (28). Subsequent

studies have reported lower rates of colectomy, with 1, 5, 10 and 20-y cumulative

colectomy rate ranging from 0.5-6%, 3-13%, 8.5-19%, and 11-20%, respectively (10-

12,14,17,18,20,23,29-33). A recent meta-analysis of population-based studies

observed a cumulative risk of surgery in adults of 4.4%, 10.1%, and 14.6%,

respectively 1, 5, and 10 years after UC diagnosis, with a significant decrease over

time (34). In a contemporary Copenhagen County cohort of patients diagnosed

between 2003-04, cumulative risk of colectomy at 5 years was 10% (23); similarly, in

a recently established Oceania cohort, less than 2% of patients in Asia and 6% in

Australia underwent a colectomy after median 1.5 year of follow-up (11,14). In the

Dutch population-based South Limburg cohort, patients diagnosed with UC between

1991-97 had an early colectomy (within 6 months) rate of 1.5%, compared to a rate

of 0.5% in a contemporary cohort from 2006-10; late colectomy rates in these cohorts

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appears to have changed over time. In Olmsted County, among colectomies

performed before 1990, 90% were performed for medically refractory disease, 5% for

fulminant colitis, and 5% for colorectal neoplasia. In contrast, among surgeries

performed after 1990, 56% were performed for medically refractory disease, 26% for

fulminant colitis and 12% for colorectal neoplasia. The types of surgery were total

protocolectomy with ileal pouch anal anastomosis in 54%, total proctocolectomy with

end-ileostomy in 33% and subtotal colectomy and ileostomy in 12% (12).

Disease extent consistently influences risk of colectomy (OR 2.2; 95% CI, 1.1–

4.3), with significantly higher risk in patients with extensive colitis (10y cumulative

risk, 19%), followed by left-sided colitis (8%) and ulcerative proctitis (5%) (16,18,20).

Young age (age <40y: OR, 2.8; 95% CI, 1.3–5.9), male gender (HR, 2.1; 95% CI,

1.3–3.5) and elevated CRP/erythrocyte sedimentation rate (ESR) (CRP≥30 mg/l or

ESR≥30 mm/h: OR, 3.3, 95% CI 1.7–6.5) at diagnosis have been associated with an

increase risk of colectomy (11,12,21). In the IBSEN cohort, patients younger than 40

years with extensive colitis, who were treated with systemic corticosteroids and had

ESR≥30 mm/h or CRP≥30 mg/l at diagnosis had a probability of colectomy of 40% as

compared to 8% for same age patient with proctitis or left-sided colitis and ESR<30

mm/h or CRP<30 mg/l at diagnosis (36). In a Norwegian cohort, achieving

endoscopic mucosal healing within one year of disease onset was associated with a

78% lower risk of future colectomy, as compared to continued endoscopic disease

activity (RR 0.2, 95% CI, 0.1-0.8) (37). However, the majority of the colectomies

occurred during the first 3 months after endoscopic assessment, which limit the

interpretation of long-term impact of MH in UC.

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Postoperative complications

In the EC-IBD cohort, 32% of patients operated on between 1993 and 2004

developed postoperative complications without difference between acute and elective

surgery, and 6% died postoperatively (38). Among the 33 deaths observed in the

1962-1987 cohorts from Copenhagen, 19 (58%) resulted from postoperative

complications. A meta-analysis of both administrative and inception population-based

studies recently observed a pooled mortality rate of respectively 0.7% and 5.3% for

elective and emergent surgery, respectively without significant decrease over time

(39).

In summary, the majority of patients with UC have a mild-moderate course,

generally most active at diagnosis and then in varying periods of remission or mild

activity; about 14-17% of patients may experience an aggressive course. Median

cumulative risk of relapse is 70.0% (IQR, 68.5-76.5) by 10 years. Almost half the

patients require UC-related hospitalization at some point during disease course, and

among those hospitalized once, 5-year risk of re-hospitalization is about 50%. The 5-

and 10-year cumulative risk of surgery is 10-15%, and though rates of early

colectomy have declined, long-term colectomy rates have generally remained stable

over time; contemporary cohorts with early use of biologic agents are lacking.

III. UC related medications

No IBD-medications

In the Uppsala inception cohort, 97% patients were exposed to either 5-ASA,

or steroids during the first year after diagnosis (21). The prevalence of no IBD

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in the Dutch-SL cohort (16).

5-aminosalcylic acid

Approximately 88-97% patients received 5-ASA within 1 year of diagnosis

(14,20,21) (Table 3 ). On long-term follow-up, 60-87% patients continued 5-ASA use

at 11-15 years after diagnosis, without significant change over time (10,16,23).

Corticosteroids

In the Copenhagen Cohort, 50% patients received corticosteroids after a

median follow-up of 15 years (23). Among patients with corticosteroid exposure,

cumulative rates of second course of CS at 1-, 5- and 10 years was 13%, 41% and

48%, respectively, in the IBSEN cohort; however, the likelihood of steroid exposure

decreases with time since UC diagnosis, with reported 1-, 5- and 11-year point

prevalence of corticosteroid use of 20%, 18% and 12%, respectively (16).

Implications and outcomes of corticosteroid exposure were studied in the Olmsted

County cohort, in a prebiologic era. Faubion and colleagues observed that within 30

days of a course of corticosteroids, 54% patients achieved complete remission, 30%

were in partial remission, and 16% were non-responders; one year after initiation of

corticosteroids, 49% were in sustained clinical remission, 22% were steroid-

dependent, and 29% underwent colectomy (40). Among patients diagnosed between

2003-2004 in the Copenhagen County cohort, steroid dependency was observed in

9% of patients after a follow-up of 5 years. The risk of corticosteroid exposure

appears to be decreasing in the biologic era. In the same Copenhagen county cohort,

exposure to corticosteroids was significantly higher in patients diagnosed between

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years later 59% of patients were exposed to corticosteroids (10).

Extensive colitis and EIMs (OR, 3.1; 95% CI, 1.7–5.5) have been significantly

associated with need for corticosteroids (13,16).

Immunomodulators

The use of immunomodulators has increased incrementally since 1990s

(10,16). In the pre-biologic era, the point prevalence of immunomodulator

medications use at 1, 5 and 10 years after diagnosis was 5%, 12% and 12%,

respectively (16). In contemporary cohorts, immunomodulator use has increased 2-3-

fold, with reported use in 11-20% at 1 year, and 17-27% by 7 years (10,11,14

20,23,27). In the Dutch-SL cohort, the 5-year cumulative probability of using

thiopurines increased from 8% in patients diagnosed between 1991-1997 to 23% in

patients diagnosed between 1998-2010. Over time, thiopurines have also been

initiated earlier during disease course, from median 23 months (1991-1997) to

10 months after UC diagnosis (2006-2010) (35). About 10% experienced adverse

events after at a median of 1 month (range 1–24 months) (11). Likelihood of

exposure to immunomodulator is significantly higher in patients with extensive colitis

(HR, 2.9; 95% CI, 1.7–4.9) and EIMs (OR 2.6; CI 95%, 1.4-4.9) (14,13).

Anti-TNF

Limited studies have evaluated patterns of anti-TNF use in population-based

cohorts. In contemporary cohorts, at 1 year, 1-5% patients were treated with anti-

TNF (11,14,20,21). More long-term results are available from the Copenhagen

County and Hungary, where 4% patients have been treated with anti-TNF at 5 years

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anti-TNF exposure increased from 4% in patients diagnosed between 1998-2005, to

10% in patients diagnosed between 2006-2010, and the median time to initiation

decreased from 44 to 12 months; 37% received combination therapy with

azathioprine (35).

In the EPICOM cohort, most of the patients treated with anti-TNF (65%) had

extensive colitis. Young age at time of disease onset (<40y: HR, 2.5; 95% CI, 1.1–

5.7) was associated with anti-TNF exposure (20).

To summarize, almost all patients with UC are exposed to 5-ASA within 1 year

of diagnosis, though 30-40% are not on 5-ASA on long-term follow-up. About 50% of

patients eventually receive a treatment course of corticosteroids, although this

proportion has decreased over time, with a corresponding increasing in the use of

immunomodulators (20% patients), and anti-TNF (5-10%).

IV. Malignancies

Colorectal cancer

Since the recognition of increased risk of CRC in patients with UC in a

Swedish population-based cohort (standardized incidence ratio (SIR) 5.7; 95% CI,

4.6-7.0) (41), several studies have confirmed increased CRC rates in UC patients,

with a pooled SIR of 2.4 (95% CI, 2.1-2.7) and an average 1.6% patients are

diagnosed with CRC during 14 years of follow-up (42) (Table 4 ). Cumulative

probability of CRC at 10, 20, and 30 years after UC diagnosis was 0.4-0.6%, 1.1-

5.4%, and 2.1-7.5%, respectively (43,44). This risk is increased in patients with

pancolitis (SIR, 2.4-14.8) and left-sided colitis (SIR, 1.4-2.8), but not in patients with

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duration and concomitant primary sclerosing cholangitis have been consistently

identified as risk factors of CRC. The risk of CRC was similar in users and non-users

of 5-ASA and thiopurines in Denmark (30). One population-based study suggested

that CRC complicating UC is more aggressive than sporadic CRC; unadjusted overall

mortality (47/100,000py) was almost 2-fold higher as compared to patients with

sporadic CRC (standardized mortality ratio, 1.8; 95% CI, 1.4-2.2) (17).

Extra-intestinal cancer

Population-based studies have shown no consistent increase in the risk of

overall- or extra-intestinal cancers in patients with UC, as compared to the general

population (Table 4 ) (30,43,47-49). On meta-analysis of population-based inception

cohorts, patients with UC were noted to have a lower risk of lung cancer (SIR, 0.4;

95% CI, 0.2-0.7) and overall cancers of the respiratory tract (SIR, 0.7; 95% CI, 0.5 -

1.0), and a higher risk of liver and biliary tract cancers (SIR, 2.6; 95% CI, 1.6-4.2),

and leukemia (SIR, 2.0; 95% CI, 1.3-3.1) (50). No consistent increase in the risk of

prostate or cervical cancer, melanoma or Hodgkin’s lymphoma or non-Hodgkin’s

lymphoma was observed (50). In the Danish North-Jutland cohort, overall cancer risk

was similar among women and men, across age groups, across disease localization,

among smokers and non-smokers, and among ever users and never users of 5-ASA

and thiopurines (30).

V. Morbidity and Mortality

Patients reported outcomes, quality of life and dis ability

In the Manitoba cohort, patients with UC reported high rates of fatigue and

sleep difficulties, particularly those with active symptoms (67% and 72%,

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and these rates were not significantly different than in patients with CD (51). This

high rate of fatigue was confirmed in the Dutch-SL cohort, and was associated with

lower quality of life. Disease activity, anemia and female sex were independent

determinants of fatigue (52). Health-related quality of life scores generally improved

from diagnosis to 1-year of disease, and baseline high Short Inflammatory Bowel

Disease Questionnaire scores, limited disease extent, absence of EIMs, non-receipt

of biologic therapy and no need for surgery, were predictive of superior health-related

quality of life on follow-up (53,54).

Overall disability burden was lower in patients with UC, as compared to

patients with CD, and was associated with long-term active disease, but not IBD-

related surgeries or hospitalizations (55). In a contemporary Australian cohort, 25%

patients were classified as having disabling disease defined by at least one of the

following criteria present at 12 months: >2 courses of steroids, further hospitalization

after diagnosis, ongoing active disease, or colectomy (11). Work disability, defined as

all patients who had applied or had been granted for rehabilitation benefits, was

evaluated in the IBSEN cohort. Patients with UC had 1.8 times higher risk of work

disability (95% CI, 1.4-2.3) as compared to general population, and was comparable

to that seen in patients with CD (56). Male sex, disease relapse, need for

corticosteroids or surgery within one year of disease onset, and elevated CRP or

ESR have been associated with work disability (11,56).

Mortality

UC has not been associated with an increased mortality, as compared to the

general population, except in one cohort (23, 57-62). When assessing the specific

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related mortality, partly attributed to an increased mortality from liver diseases, and

inconsistent increase in risk of CRC-related mortality, and to respiratory-related

mortality primarily due to asthma-related deaths, despite a decrease in risk of

respiratory tract cancers. Overall, there has been no increase in risk of cancer-

related or cardiovascular mortality (47,57,59-63).

VI. Extra-intestinal Complications

Extra-intestinal Manifestations

Overall risk of EIMs in patients with UC ranges from 7-17%, probably lower as

compared to patients with CD, and approximately 1% patients may present with EIMs

before UC diagnosis (13,16,64). Articular manifestations are the most frequently

observed EIMs (8%), including peripheral arthritis (5.5%), and ankylosing spondylitis

(1%), followed by cutaneous EIMs (1.3%), PSC (0.6%) and ocular manifestations

(0.6%) (64,65). The cumulative incidence of spondyloarthropathy was 5%, 14%, and

22% at 10, 20 and 30y after UC diagnosis (66) and in the IBSEN cohort, 11% of UC

patients experienced peripheral arthritis within the 6y after diagnosis, with 20% of

these being observed prior to UC diagnosis (65). Interestingly, risk of hidradenitis

suppuritiva may be 6-fold higher in patients with UC, as compared to the general

population (67). Patients with left-sided and extensive may be at increased risk of

EIMs as compared to patients with proctitis (15% vs 6%) (64).

Other Extra-intestinal Complications

Approximately 20-24% of patients with UC are anemic at diagnosis, including

8% with severe anemia (<10g/dl). This rate generally decreases on follow-up, to 8-

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prevalence of anemia was higher at 30% after 7 years of disease (13). Disease

extent, and high disease activity (based on elevated CRP or ESR, or need for

corticosteroids) were significantly associated with anemia (68,69).

In both Manitoba and Olmsted cohorts, there was no significant increase in

risk of fractures in patients with UC, and patients had normal hip and lumbar spine

bone density scores (71,72).

Incidence rate of venous thromboembolism ranged from 1.1-2.0/1000 py, with

a 5- and 10- cumulative probability of 0.8% and 1.2%, respectively, may be higher in

patients with UC, as compared to patients with CD (73,74). High disease burden and

disease activity, as measured by presence of extensive colitis (OR 3.3; 95% CI, 1.1-

9.4), fulminant colitis (OR 4.2; 95%CI, 1.3-13.5), and need for corticosteroids (OR

3.0; 95%CI, 1.0-8.9), as well as smoking (OR 3.5; 95%CI, 1.1–10.5) were

significantly associated with risk of venous thromboembolism (73,74). No population-

based data on risk of arterial cardiovascular events was available from inception

cohorts.

DISCUSSION

We have systematically summarized the current knowledge on the natural

history of UC from 17 population-based inception cohorts reported in 60 studies,

across multiple domains including disease extent, activity, EIMs, medication use,

requirement for surgery, etc. We observed that the diagnosis of UC generally

remains stable over time, and infrequently evolves into CD (<5%). Though left-sided

colitis is most frequently observed at diagnosis in approximately 40% patients, about

10-30% of patients may develop proximal extension on follow-up. The majority of

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varying periods of remission or mild activity; about 10-15% of patients may

experience an aggressive course, and the cumulative risk of relapse is 70-80% at 10

years. Almost half the patients require UC-related hospitalization at some point

during disease course. The 5- and 10-year cumulative risk of surgery in patients with

UC is 10-15%, and though rates of early colectomy have declined, long-term

colectomy rates have generally remained stable over time. We observed that almost

all patients with UC are exposed to 5-ASA within 1 year of diagnosis, though 30-40%

are not on 5-ASA on long-term follow-up. About 50% of patients receive

corticosteroids, though this proportion has decreased over time, with a corresponding

increasing in the use of immunomodulators (20%), and anti-TNF (5-10%).

Approximately 1.5% patients are diagnosed with colorectal cancer after 15 years of

follow-up, particularly those with young age at disease onset, extensive disease and

concomitant PSC. Ulcerative colitis is not associated with an increased risk of all-

cause mortality. However, gastrointestinal-specific mortality, but not cancer-specific

mortality, may be increased. Ulcerative colitis is associated with high morbidity, with

high rates of fatigue, inferior health-related quality of life, and high disability, generally

comparable to levels observed in patients with CD. Consistent predictors of

aggressive UC disease course are young age at diagnosis, extensive disease, early

need for corticosteroids and elevated biochemical markers; achieving mucosal

healing early may be strongly associated with a decreased risk of future colectomy.

We note that these variables are all easily determined and monitored with electronic

medical records, and create a future opportunity to risk stratify patients and focus

health resource utilization on the subgroup of patients at high risk for a worse

disease outcome.

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essential to initiate personal therapeutic strategy according to risk stratification. High-

risk patients may benefit to early combination therapy and low risk patients to rapid

step-up therapy (77). However, we identified several areas of knowledge gap on

natural history of UC. First, while several risk factors associated with a generally

aggressive disease course have been identified, an impact of treatment based on

early stratification of high- and low-risk patients on the natural history of disease is

not well studied. Second, there is limited data on the course and outcomes of UC in

newly industrialized nations and Asia-Oceania region; with the creation of recent

population-based cohorts, this knowledge is anticipated to increase in the coming

years. Third, contemporary population-based cohorts of patients diagnosed in the

biologic era are lacking. These may inform us on the population-level impact of

paradigm shifts in approach to UC management over the last decade, such as early

use of disease-modifying biologic therapy, and treat-to-target strategy. Fourth, slight

differences were observed in different outcomes, particularly in risks of surgery and

hospitalizations in different cohorts. Whether this is due to differences in medical

practices, particularly access of newer therapies, or to true differences in underlying

disease behavior and biology in different populations, needs to be explored. With

creation of large, collaborative population-based networks, these gaps will be bridged

in the coming decade.

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ACCEPTED MANUSCRIPT 52. Romberg-Camps MJ, Bol Y, Dagnelie PC, et al. Fatigue and health-related quality of life in inflammatory bowel disease: results from a population-based study in the Netherlands: the IBD-South Limburg cohort. Inflamm Bowel Dis. 2010;16:2137-47. 53. Burisch J, Weimers P, Pedersen N, et al. Health-related quality of life improves during one year of medical and surgical treatment in a European population-based inception cohort of patients with inflammatory bowel disease--an ECCO-EpiCom study. J Crohns Colitis. 2014;8:1030-42. 54. Bernklev T, Jahnsen J, Schulz T et al. Course of disease, drug treatment and health-related quality of life in patients with inflammatory bowel disease 5 years after initial diagnosis. Eur J Gastroenterol Hepatol. 2005;17:1037-45. 55. Israeli E, Graff LA, Clara I, et al. Low prevalence of disability among patients with inflammatory bowel diseases a decade after diagnosis. Clin Gastroenterol Hepatol. 2014;12:1330-7.e2 56. Høivik ML, Moum B, Solberg IC, Henriksen M, Cvancarova M, Bernklev T. Work disability in inflammatory bowel disease patients 10 years after disease onset: results from the IBSEN Study. Gut. 2013;62:368-75. 57. Höie O, Schouten LJ, Wolters FL, et al. Ulcerative colitis: no rise in mortality in a European-wide population based cohort 10 years after diagnosis. Gut. 2007;56:497-503. 58. Hovde Ø, Småstuen MC, Høivik ML, et al. Mortality and Causes of Death in Ulcerative Colitis: Results from 20 Years of Follow-up in the IBSEN Study. Inflamm Bowel Dis. 2016;22:141-5. 59. Romberg-Camps M1, Kuiper E, Schouten L, et al. Mortality in inflammatory bowel disease in the Netherlands 1991-2002: results of a population-based study: the IBD South-Limburg cohort. . Inflamm Bowel Dis. 2010;16:1397-410. 60. Masala G, Bagnoli S, Ceroti M, et al. Divergent patterns of total and cancer mortality in ulcerative colitis and Crohn's disease patients: the Florence IBD study 1978-2001. Gut. 2004;53:1309-13. 61. Manninen P, Karvonen AL, Huhtala H, et al. Mortality in ulcerative colitis and Crohn's disease. A population-based study in Finland. J Crohns Colitis. 2012;6:524-8. 62. Jess T, Loftus EV Jr, Harmsen WS, et al. Survival and cause specific mortality in patients with inflammatory bowel disease: a long term outcome study in Olmsted County, Minnesota, 1940-2004. Gut. 2006;55:1248-54. 63. Persson PG, Bernell O, Leijonmarck CE, Farahmand BY, Hellers G, Ahlbom A. Survival and Cause-Specific Mortality in Inflammatory Bowel Disease: A Population-Based Cohort Study. Gastroenterology 1996;110:1339-45.

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ACCEPTED MANUSCRIPT 64. Isene R, Bernklev T, Høie O, et al. Extraintestinal manifestations in Crohn's disease and ulcerative colitis: results from a prospective, population-based European inception cohort. Scand J Gastroenterol. 2015;50:300-5. 65. Palm Ø, Moum B, Jahnsen J, Gran JT. The prevalence and incidence of peripheral arthritis in patients with inflammatory bowel disease, a prospective population-based study (the IBSEN study). Rheumatology (Oxford). 2001;40:1256-61. 66. Shivashankar R, Loftus EV Jr, Tremaine WJ, et al. Incidence of Spondyloarthropathy in patients with ulcerative colitis: a population-based study. J Rheumatol. 2013;40:1153-7. 67. Yadav S, Singh S, Edakkanambeth Varayil J, et al. Hidradenitis Suppurativa in Patients With Inflammatory Bowel Disease: A Population-Based Cohort Study in Olmsted County, Minnesota. Clin Gastroenterol Hepatol. 2016;14:65-70. 68. Høivik ML, Reinisch W, Cvancarova M, Moum B. Anaemia in inflammatory bowel disease: a population-based 10-year follow-up. Aliment Pharmacol Ther. 2014;39:69-76. 69. Sjöberg D, Holmström T, Larsson M, Nielsen AL, Holmquist L, Rönnblom A. Anemia in a population-based IBD cohort (ICURE): still high prevalence after 1 year, especially among pediatric patients. Inflamm Bowel Dis. 2014;20:2266-70. 70. Ott C, Liebold A, Takses A, Strauch UG, Obermeier F. High prevalence but insufficient treatment of iron-deficiency anemia in patients with inflammatory bowel disease: results of a population-based cohort. Gastroenterol Res Pract. 2012;2012:595970. 71. Loftus EV Jr, Achenbach SJ, Sandborn WJ, Tremaine WJ, Oberg AL, Melton LJ 3rd. Risk of fracture in ulcerative colitis: a population-based study from Olmsted County, Minnesota. Clin Gastroenterol Hepatol. 2003;1:465-73. 72. Leslie WD, Miller N, Rogala L, Bernstein CN. Body mass and composition affect bone density in recently diagnosed inflammatory bowel disease: the Manitoba IBD Cohort Study. Inflamm Bowel Dis. 2009;15:39-46. 73. Isene R, Bernklev T, Høie O, et al. Thromboembolism in inflammatory bowel disease: results from a prospective, population-based European inception cohort. Scand J Gastroenterol. 2014;49:820-5. 74. Vegh Z, Golovics PA, Lovasz BD, et al. Low incidence of venous thromboembolism in inflammatory bowel diseases: prevalence and predictors from a population-based inception cohort. Scand J Gastroenterol. 2015;50:306-11. 75. Stewénius J, Adnerhill I, Anderson H, et al. Incidence of colorectal cancer and all cause mortality in non-selected patients with ulcerative colitis and indeterminate colitis in Malmö, Sweden. Int J Colorectal Dis. 1995;10:117-22.

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• A detailed knowledge of the natural history of ulcerative colitis (UC) is essential to understand disease evolution, evaluate the impact of treatment strategies, and identify predictors for disabling disease.

• Population-based observational cohort studies are ideal to inform natural history of disease.

What is new here:

• Majority of patients have a mild-moderate course; about 10-15% patients experience an aggressive course, and the cumulative risk of relapse is 70-80% at 10 years.

• Almost 50% patients require UC-related hospitalization. The 5- and 10-year cumulative risk of colectomy is 10-15%

• While UC is not associated with an increased risk of mortality, it is associated with high morbidity and work disability.

• Consistent predictors of aggressive disease course are young age at diagnosis, extensive disease, early need for corticosteroids and elevated biochemical markers; achieving mucosal healing early may be strongly associated with a decreased risk of future colectomy.

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Cohort Country Study period and follow-up UC Population References

Multicentric European (EC-IBD)

Greece, Israel, Italy, Spain, Denmark, Netherlands,

Norway Diagnosis between 1991 and 1993; follow-up ranging from 4 to 10 y 328 to 781

9,19, 25,38,57,64,

73

Copenhagen County Denmark Diagnosis ranging from 1962 to 2005; follow-up ranging from 1 to 19 y 87 to 1160 10,23,24,26,43

North-Jutland County Denmark Diagnosis between 1978 and 2002; follow-up: 15 y 1575 30

IBSEN cohort Norway Diagnosis between 1990 and 1993; follow-up ranging from 5 to 20 y 328 to 519 15,18,36,3754,56,58,65,

68

Veszprem province Hungary Diagnosis between 1974 to 2012; follow-up ranging from 5 to 13 y 220 to 1060 13,27,33,44,74,76

Malmo Sweden Diagnosis between 1958 and 1982, median follow-up: 15 y 471 22,32,75

Stockholm county Sweden Diagnosis between 1955 and 1984; follow-up ranging from 13 to 16.5 y 1547 to 1586 17,28,47,63

Uppsala Region Sweden Cohort 1.Diagnosis between 1922 and 1983 Cohort 2. Diagnosis between 2005 and 2009; follow-up ranging from 1 to 11 y 496 to 3117 17,21,41,69

Florence Area Italia Diagnosis between 1978 and 1992; follow-up ranging from 11 to 15 y 689 48,60 Dutch IBD -South Limburg

cohort The Netherlands Diagnosis between 1991 and 2010; follow up ranging from 3 to 17 y 368 to 1161 16,35,52,59

Area of Tampere University Hospital Finland Study period between 1986-2007 (diagnosis period not defined); follow-up of

13 y 1254 46,61

Olmsted County USA Diagnosis ranging from 1940 to 2011; follow-up ranging from 1 to 21 y 63 to 462 12,40,45,49,62,66,67,71

Manitoba IBD cohort Canada Diagnosis after 1995; follow-up up to 12.3 y 45 to 158 51,55,61

Asia-Pacific Crohn’s and Colitis Epidemiology

Study

China, Hong Kong, Indonesia, Sri Lanka, Macau, Malaysia,

Singapore, Thailand and Australia

Diagnosis between 2011 and 2013; follow-up 1.5 y 222 14

Barwon area Australia Diagnosis between 2007–2008 and 2010–2013; follow-up of 1.5 y 96 11

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ECCO-EPICOM cohort European Multicentric (14 countries, 31 centers) Diagnosis in 2011, follow-up of 1 y 575 to 710 20,53

Oberpfalz, Bavaria Germany Diagnosis between 2004 and 2009, follow-up > 1 y 90 70

Table 1. Characteristics of the 17 population based cohorts included. Y, year.

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Cohort Disease extension (1) Relapse/ Disease Activity Colectomy Hospitalizatio n

IBSEN

E1 to E2: 28%, E1 to E3: 14%,

E2 to E3: 21% at 10y

- Relapse: 83% by 10y

- Disease course: remission/mild severity after initial period of high activity 55%, chronic

intermittent symptoms 37%, chronic continuous symptoms 6% and increase activity after period

of low activity 1% 5%, 9.5% and 11% by 2, 10 and 20 y

-

Copenhagen

E1 to E2: 30% E1 to E3: 16% E2 to E3: 34%

Overall extension by 7.5y: 30%

Indolent course 13%, moderate 73% and aggressive 14%

24% by 10y (1963-1993), 10% by 5y (2003-2004) -

EC-IBD cohort

Disease location at 10y: E1 22%, E2 53%, E3 24%

Relapse: 67% by 10 y 8.5% by 10y -

Hungary/ Veszprem

Extension by 1, 3, and 5 y: 2.9%, 9.4%, and 12.7%.

Disease location at 7y: E1 28%, E2 44%, E3: 28%

- 0.5%, 1.8%, and 2.8% by 1, 3, and 5y

29%, 54% and 66% by 1, 5 and 10y

Asia-Pacific cohort

Overall extension: 11.5% (by 1.5y)

During 1st y: remission (UC-SCCAI of ≤ 2) 65%, mild to moderate disease (3-4) 18%, and severe

disease (≥5) 17%

1.6% (Asia) and 5.9% (Australia) by 1.5y -

Malmo - Relapse: 70% by 10y 23% by 15y -

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Table 2. Risk of disease extension, relapse, colectomy and hospitalizations in population based studies.

(1) According to the Montreal classification

cohort

Uppsala - During 1st year: Relapse 43%, chronic activity 5%, remission 50% 16%, 20% and 25%

by 10, 20 and 30y

-

Stockholm County - -

South -Limburg - -

3%, 6%, and 7% by 1, 3, and 5 y -

Olmsted - - 3.8%, 13%, 19%, and 25% by 1, 5,

10 and 20y

29%, 39%, 49%, 52% by 5, 10, 20 and 30y

EPICOM - Remission: 11% at diagnosis, 73% at 1 y 3% by 1 y 13% by 1 y

Barwon - - 6% at 1y, 13% by 5y 23% by 5y

North Jutland County

- -

1991-1997: 4.1%, 5.6%, and 7.5% by 1, 2, 5y,

1998-2005: 0.9%, 2.1%, and 5.7%, 2006-2010: 1.0%, 2.8%,

and 4.1%

1991-1997: 12%, 17%, and 22%, by 1, 2, 5y 1998-2005: 8.6%, 12%, and 19.5%

2006-2010: 8.7%, 11%, and 18%

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Cohort No medications 5-ASA Steroids Immunosuppressants Anti-TNFs

IBSEN 3% by 1y (CP) - 13%, 41% and 48% by 1, 5

and 10y (CP of second course)

7% by 10y (CP) -

Copenhagen -

87% by 15y (CP), with no change over time

(1962-2004) 78% by 1y, 85% by 5y

(CP) (2003-2004)

50% by 15y (CP) with no change over time (1962-2004)

43% by 1y, 59% by 5y (CP) (2003-2004)

27% by 7 y (CP) (2003-2004)

4% at 5y and 6% by 7y (CP) (2003-2004)

EC-IBD cohort 11 to 35% (prevalence at 4y) - - - -

Veszprem - - 40% by 7 y (CP) 17% by 7y (CP) 7.5% by 7y (CP)

Asia-Pacific cohort - 88% by 1.5 y (CP) 25% by 1.5y (CP) 13% by 1.5y (CP) 1% by 1y (CP)

Uppsala - 97% by 1 y (CP) 64% by 1 y (CP) 12% by 1y (CP) 5% by 1y (CP)

South-Limburg 26%, 32% and 40%

by 1, 5 and 11y (prevalence)

73%, 65% and 60% at 1, 5 and 11 y (prevalence)

20%, 18% and 12% by 1, 5 and 11y (prevalence)

1991-1997: 8% by 5y (CP) 1998-2005: 23% by 5y (CP) 2006-2010: 23% by 5y (CP)

1998-2005: 5% by 5y (CP) 2006-2010: 10% by 5y (CP)

EPICOM - 97% by 1 y (CP) 46% by 1y 20% by 1y 5% by 1y (CP)

Barwon - - 63% by 1.5y 19% by 1.5y 2% by 1.5y (CP)

Table 3. Exposure to UC-related medications.

Abbreviations: 5ASA, 5 aminosalycilic acid; Y, years; CP, cumulative probability

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Cohort EIMs Colorectal Cancer Extra-digestive canc er Mortality

IBSEN Peripheral arthritis: 11%, AS: 2.6% by 6y - - Overall: HR 1.1 (95 CI%, 0.9–1.4)

Copenhagen -

Overall: SMR 1.1 (95% CI, 1.0-1.2),

0.4%, 1.1%, and 2.1% by 10, 20 and 30y

Overall cancer: SMR 0.9 (95% CI, 0.7-1.1) Melanoma: SMR 3.4 (95% CI, 1.4 -7.1) Overall: SIR 1.1 (95% CI, 1.0-1.2)

EC-IBD cohort

10% by 10y. Articular 8%,

Iridocyclitis/Uveitis 0.6%, cutaneous 1.3%,

PSC 0.6%.

- 3.3% by 10 y

Overall: SMR 1.1 (95% CI, 0.9-1.4), Pulmonary diseases: SMR 2.0

(95% CI, 1.0-3.6), Cancer: SMR 1.0 (95% CI, 0.6–1.6),

CV: SMR 1.1 (95% CI, 0.7–1.5), GI diseases: SMR 2.0

(95% CI, 0.7–4.7)

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Hungary/Veszprem 17% at 7y - NHL: SIR 1.35 (95% CI, 0.34–5.42),

NHL in male: SIR 2.4 (95% CI, 0.77-7.47)

0.6%, 5.4%, 7.5% by 10, 20 and 30y.

Disease Duration >1 y: OR 14.3 (95% CI, 1.8-110.5),

Chronic continuous disease: OR 6.4 (95% CI, 1.9-21.6),

Extensive vs left-sided colitis: OR 5.3 (95% CI, 1.7-16.4),

PSC: OR 27.1 (95% CI, 7.9-92.0)

Malmo cohort - Overall SIR 2.1 (95% CI, 1.0-4.1) - -

Uppsala -

Overall: SIR 5.7 (95% CI, 4.6-7.0), Proctitis: SIR 1.7 (95% CI, 0.8-3.2),

LSC: SIR 2.8 (95% CI, 1.6-4.4),

Age <15 y at diag: SIR 4.0 (95% CI, 2.07-7.85), Pancolitis: SIR 14.8 (95% CI, 11.4-18.9)

-

NHL: SIR 1.1 (95% CI, 0.6–1.8),

HL: SIR 0.4 (95% CI, 0.0–2.2),

Overall leukaemia: SIR 2.3 (95% CI, 1.4–3.7),

Acute myeloid leukaemia: SIR 2.5 (95% CI, 1.2–4.8)

-

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Stockholm County -

Proctitis: SIR 1.1 (95% CI, 0.7–1.7),

LSC: SIR 1.4 (95% CI, 1.1–1.9),

Pancolitis: SIR 1.4 (95% CI, 1.0–1.9)

Extra-colonic cancer: SMR 1.1 (95% CI,

0.9–1.3), Hepato-Biliary (men): SMR 6.0 (95% CI,

2.8-11.1), Pulmonary:

SMR 0.3 (95% CI, 0.1-

0.9)

Overall: SMR 1.4 (95% CI, 1.2–1.5), Cancer: SMR 1.2 (95% CI, 0.9–1.6),

CRC: SMR 2.9 (95 CI%, 1.6–4.7), Respiratory disease: SMR 1.9

(95% CI, 1.1–2.9), Liver disease: SMR 4.8

(95% CI, 2.1-9.5)

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South-Limburg 7% at 7y - -

Overall: SMR 0.9 (95% CI, 0.7-1.2), GI causes: SMR 3.4 (95% CI, 1.4-7.0), GI causes (Women): SMR 8.6

(95% CI, 2.8–20.0), GI causes (<19y) SMR 537.3 (95% CI, 7.0-

2989)

Olmsted Cumulative incidence of SpA: 14% at 20y

Overall SIR 1.1 (95% CI, 0.4-2.4), Proctitis SIR 0

(95% CI, 0.0-3.5), Pancolitis SIR 2.4 (95% CI, 0.6–6.0)

Overall cancer: 5% by 10 years, Overall cancer: SIR 1.1 (95% CI, 0.8-1.4),

Overall cancer (women): SIR 1.6 (95% CI, 1.1-2.3),

Overall cancer (men): SIR 0.9 (95% CI, 0.6-1.2),

Hemato malignant tumors: SIR 2.7 (95% CI, 1.2-5.3),

Melanoma: SIR 2.0 (95% CI, 0.7-4.4), Hepatobiliary: SIR 11.4 (95% CI, 2.4-33.2),

Lung: SIR 0.3 (95% CI, 0.1-0.9)

Overall: SMR 0.8 (95% CI, 0.6–1.0), GI diseases: SMR 2.0

(95% CI, 0.8–4.4), GI cancer: SMR 2.2 (95% CI, 0.7–5.2),

CV Death: SMR 0.6 (95% CI, 0.4–0.9)

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EPICOM - - - 0.3% at 1y

North Jutland County -

SIR 0.8 (95% CI, 0.5-1.4). Young age at diagnosis SIR

17.1 (95% CI, 0.4 -95.1)

Overall cancer: SIR 1.1 (95 % CI, 0.9-1.2), Prostate: SIR 1.8 (95% CI, 1.1-2.7) -

Florence - Overall: SIR 1.7 (95% CI, 0.8–3.2), Extensive colitis: SIR 3.1 (95% CI, 1.5–5.8)

Overall cancer: SIR 1.0 (95% CI, 0.7–1.3), Respiratory tract: SIR 0.2 (95% CI, 0.0–0.8)

Overall: SMR 0.7 (95% CI, 0.6–0.9), CV: SMR 0.7 (95% CI, 0.5–1.0),

Overall cancer: SMR 0.7 (95% CI, 0.5–1.0), Lung cancer mortality:

SMR 0.3 (95% CI, 0.1–1.0), CRC: SMR 1.3 (95% CI, 0.3–3.2), GI

disease: SMR 1.6 (95% CI, 0.8–2.8)

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Area of Tampere

University Hospital

-

Overall: SIR 2.0 (95% CI, 1.1–3.3), Proctitis: SIR 0.0

(CI 95%, 0.0–2.8), Left sided colitis: SIR 1.8

(95% CI, 0.7–3.8), Pancolitis: SIR 3.1 (95% CI,

1.5–5.8)

- Overall: SMR 0.9 (95% CI, 0.8-1.1),

CV: SMR 1.0 (95% CI, 0.8–1.4), CRC: SMR 1.8 (95% CI, 0.7–3.7)

Table 4. Risk of extra-intestinal manifestations, colorectal cancer, extra-intestinal cancer and mortality in population based studies.

Abbreviations: Dis, disease; Diag, diagnosis; AS, Ankylosing Spondylitis, SpA, Spondylarthropathy; EN, Erythema Nodosum; PG, Pyoderma Gangrenosum; PSC,

Primary Sclerosing Cholangitis; SIR; Standardized Incidence Ratio; SMR; Standardized Mortality Ratio; OR, Odds Ratio; HR, Hazard Ratio; PSC, Primary sclerosing

cholangitis; NHK, Non Hodgkin Lymphoma; HL, Hodgkin Lymphoma; LSC, Left Side Colitis; CV, Cardiovascular; GI, Gastrointestinal.

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Outcome Clinical variables

Disease Relapse

Age < 40 years at diagnosis Female sex

Extra-intestinal manifestations High level of education

Non smoker pANCA + ASCA +

Hospitalizations Extensive disease

Need for corticosteroids, azathioprine or anti-TNF Early need for hospitalization

Colectomy

Age <40 years at diagnosis Male sex

Extensive disease CRP>10 mg/L, ESR>30 mm Absence of mucosal healing

Initiation of anti -TNF therapy Age <40 years

Table 5. Predictors of natural history in Ulcerative colitis.

Abbreviations: HR, Hazard Ratio; OR, Odds Ratio; RR, Relative Risk; CS, Corticosteroids; DIag, Diagnosis, CRP, C reactive protein; ESR, Erythrocyte

sedimentation rate; ANCA, Perinuclear Anti-Neutrophil Cytoplasmic Antibodies; ASCA, anti-Saccharomyces cerevisiæ anti-body; MH, Mucosal healing.

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Figure 1. Cumulative risk of main outcomes on disease phenotype, disease activity and colorectal cancer in

population-based studies.

Abbreviations: LSC, left side colitis; CRC, colorectal cancer; y, year.

Supplementary Figure 1. Cumulative probabilities of colectomy in population-based studies.

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