Prevalence and Characteristics of Extra-intestinal Manifestations in a Large Cohort of Greek Patients with Inflammatory Bowel Disease

Abstract

Background and Aims:

Extraintestinal manifestations [EIMs] are common in inflammatory bowel disease [IBD]. Data on epidemiology and risk factors of EIMs in IBD patients are limited. The aim of this study was to investigate the prevalence of EIMs in a large cohort of Greek IBD patients and identify risk factors for their development.

Methods:

The study population consisted of IBD patients, who were followed in eight tertiary Greek hospitals. Demographic and clinical characteristics of patients were analysed. The diagnosis of EIMs was based on standard criteria and on specialist consultation.

Results:

In total, 1860 IBD patients (1001 with Crohn’s disease [CD], 859 with ulcerative colitis [UC]) were registered. Among them 615 [33.1%] exhibited at least one EIM; 238 patients [38.6%] developed an EIM before IBD diagnosis. An association between active IBD and presence of an EIM was established in 61.1% of the patients. Arthritic [peripheral arthritis], mucocutaneous [erythema nodosum], and ocular [episcleritis] were the most common manifestations. EIMs were more prevalent in females, patients with CD, smokers [for all p <0.0001], patients with extensive UC [ p = 0.007], and patients with a previous appendectomy [ p < 0.0001] or a major IBD-related surgery [ p = 0.012].

Conclusions:

About one-third of Greek IBD patients developed at least one EIM. Of those, more than one-third had their EIM diagnosed before IBD, and in about two-thirds it was related to disease activity. EIMs were more frequently present in females and patients with extensive UC in multivariate analysis.

Extraintestinal manifestations, inflammatory bowel disease

1. Introduction

Patients with inflammatory bowel disease [IBD] often develop one or more extraintestinal manifestations [EIMs] during the course of disease. The most frequent EIMs are musculoskeletal, mucocutaneous, and ocular. Many other organs may also infrequently be affected, including liver, biliary tract, pancreas, lungs, and kidneys. ¹ Moreover, certain diseases or abnormal conditions are observed in IBD patients more frequently than the general population, but these are not strictly classified as EIMs. Cholelithiasis, non-alcoholic fatty liver disease, pancreatitis, nephrolithiasis, anaemia, thromboembolic events, diabetes mellitus, osteopathy, cardiopulmonary disease, and several autoimmune disorders are included in this group. ^{2 , 3 , 4 , 5 , 6}

The prevalence of EIMs ranges between 16% and 40%, depending on the definition applied, when multiple EIMs are being studied. ^{7 , 8 , 9 , 10 , 11} Occurrence of one EIM predisposes to the development of additional EIMs. ^{8 , 9} EIMs may precede IBD diagnosis by several years or manifest for the first time after intestinal resection. ¹² Certain EIMs, like aphthous stomatitis, episcleritis, erythema nodosum, and peripheral arthritis are related to IBD activity whereas others, like pyoderma gangrenosum, primary sclerosing cholangitis [PSC], uveitis, and ankylosing spondylitis, predominantly progress in an independent manner. ¹ Pathogenesis of EIMs is largely unknown, but there is evidence that environmental [smoking], ¹³ autoimmune [p-ANCA, memory T-cells], ¹⁴ and genetic [NOD2/CARD15 mutations, HLA-B8/DR3, HLA-DRB1*0103, HLA-B27, or HLA-B58 phenotypes] ^{15 , 16 , 17} factors are implicated.

The aims of the present multicentre retrospective cohort study were: [i] to investigate the frequency of EIMs in a Greek population of IBD patients; and [ii] to identify risk factors for the development of EIMs.

2. Materials and Methods

Data were extracted retrospectively from clinical files and electronic medical records of IBD patients attending the outpatient clinics of eight Greek tertiary referral centres. Inclusion criteria were age ≥ 17 years and diagnosis of IBD at least 3 months prior to inclusion. Diagnosis was based on the Lennard-Jones criteria. ¹⁸ Only patients with a definite diagnosis of Crohn’s disease [CD] or ulcerative colitis [UC] were included. Demographic [age, gender, place of birth, residency, educational level, marital status, smoking] as well as disease [age at IBD and EIMs diagnosis, IBD and EIMs duration at study entry, precedence or not of EIMs in relation to IBD, number of different EIMs, IBD activity at EIMs diagnosis, IBD-related surgical procedures, familial IBD, EIMs history, and present treatment] characteristics were registered in a standardised database. Montreal classification was used for registering IBD location and behaviour ¹⁹ and disease activity was clinically judged according to treating physician’s assessment (presence of related symptoms in combination with elevated inflammatory markers, mainly C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR], despite appropriate treatment at the time of EIM diagnosis). Smoking status was captured at the time of first EIM diagnosis. Active smoking was defined as the consumption of any tobacco product either daily or occasionally [more than 100 cigarettes in lifetime]. Patients provided informed consent to data processing.

2.1. Diagnosis of extra-intestinal manifestations

The term EIMs was used to define IBD-associated disorders appearing in distant sites in regard to the digestive tract. Arthralgia was recorded based on patients self-reporting peripheral joint pain and motility restriction without any objective sign of active inflammation detected either by the treating physician or by a consulting rheumatologist. Diagnosis of peripheral arthritis was made on clinical findings of painful and/or swollen joints with exclusion of other types of arthritis such as osteoarthritis, rheumatoid arthritis, and arthritis associated with connective tissue diseases based on specialist’s consultation. Ankylosing spondylitis and sacroiliitis were diagnosed after a thorough physical examination by a rheumatologist [low back and pelvic pain and stiffness persisting for more than 3 months, worsening with immobility especially at night and early in the morning, showing a positive response to non-steroidal anti-inflammatory drugs, and presenting with a positive Schober’s test] and radiological changes on X-ray or magnetic resonance imaging. Mucocutaneous manifestations were diagnosed by an experienced dermatologist based on their clinical characteristics and skin biopsy where necessary. Ocular manifestations were established by a consulting ophthalmologist. Diagnosis of PSC was established by magnetic resonance cholangiopancreatography and/or liver biopsy, when persistent abnormal liver function tests were present and other common causalities of liver or biliary disorders were excluded. Certain EIMs, not feasible to be classified in any of the above mentioned categories, were registered as ‘rare EIMs’. Chronological data regarding diagnosis of an EIM prior to IBD were retrieved from respective specialists’ reports and patients’ recall information.

Manifestations not characterized as ‘classic’ EIMs, but rather as common abnormal conditions not strictly related to IBD, were also captured. Deep venous thrombosis [DVT] was diagnosed on clinical findings [most commonly swelling, pain, or tenderness in the leg, frequently accompanied by red or discoloured skin] and imaging with ultrasound or venography, whereas pulmonary embolism was diagnosed by helical computed tomography. Asthma and chronic bronchitis were sought only in non-smokers and were diagnosed by critical evaluation of clinical, radiological, and spirometric results by a lung specialist. The diagnosis of cholelithiasis was based either on a history of cholecystectomy for true cholelithiasis or on characteristic sonographic findings. Non-alcoholic fatty liver disease [NAFLD] was considered when compatible histological and/or sonographic findings were detected in the absence of other diagnoses [viral, drug-induced, alcohol-induced, autoimmune hepatitis, or obstructive disease]. Pancreatitis was captured as a consequence of IBD treatment [predominantly azathioprine-induced], or gallstone disease, or when IgG4 antibodies were present and other apparent causes were excluded. Nephrolithiasis was registered based either on a history of at least one episode of renal stone impaction or, again, relevant sonographic findings. Bone disease was defined as a T-score in DEXA scan of [-1.0]-[-2.5] [osteopenia] or ≤ [-2.5] [osteoporosis] in patients older than 40 years. Anaemia was defined according to Word Health Organization criteria and was registered when: [i] IBD was in remission; [ii] heterozygous beta-thalassaemia was excluded; and [iii] no other apparent disorder or chronic disease manifesting anaemia was present. Data were also collected regarding diabetes mellitus, coronary artery disease, multiple sclerosis, and other concomitant autoimmune diseases. The rates of these accompanying entities were calculated separately, not included in the rate of EIMs. A family history of IBD and EIMs was also sought. Finally, any association between IBD therapeutic regimens and the presence of EIMs was investigated.

2.2. Statistics

All statistical analyses [frequencies, descriptive statistics, Shapiro-Wilk for normality, Fisher’s exact test for significance and chi-square, Mann-Whitney test, t-test for group comparison, and binary logistic regression for multivariate analysis] were done with SPSS 20.0 software package [IBM SPSS Statistics, Armonk, NY, USA]. Tests were two-sided and p -value < 0.05 was considered statistically significant.

3. Results

3.1. Patient characteristics

In total, 1860 IBD patients [1001 CD, 859 UC] were registered [ Table 1 ]. Of those, 615 [33.1%] exhibited at least one EIM (median [interquartile range; IQR] age at first EIM diagnosis: 32.0 [22.4–45.4] years, at second EIM diagnosis: 35.2 [26.2–47.3] years, and at third EIM diagnosis: 38.1 [28.6–53.3] years). In all, 238 patients [38.6%] developed an EIM before IBD diagnosis (median first EIM duration until IBD diagnosis: 3.0 [1.0–10.0] years). IBD was diagnosed in older age in these patients (age at IBD diagnosis: 35.0 [25.6–49.4] vs 29.3 [21.2–41.3] years, p < 0.0001). IBD was clinically judged as active in 225/346 [65%] patients at first EIM diagnosis. A relationship between active IBD and presence of any EIM was concluded in 190/311 patients [61.1%]. EIMs were more frequent in patients who had IBD diagnosis at young age (odds ratio[OR] for patients aged > 30 years 0.8, 95% confidence interval [CI] 0.66–0.98, p = 0.032]. Finally in 221/1859 patients [11.9%], a positive family history of IBD was reported. Among them, 25/176 [14.2%] had a positive family history of EIMs.

Table 1.

Demographic and clinical characteristics of the 1860 patients with inflammatory bowel disease.

Female/male [%]	807/1053 [43.4/56.6]
CD/UC [%]	1001/859 [53.8/46.2]
Median age at IBD diagnosis [years, IQR]	33.0 [23.2–48.6]
Median IBD duration until 1st EIM diagnosis [years, IQR]	2.7 [0.3–8.0]
Family history of IBD, n = 1860 [%]	221 [11.9]
Family history of IBD-related EIMs n = 176 [%]	25 [14.2]
Smokers/non-smokers/ ex-smokers, n = 1748 [%]	553/758/437 [31.6/43.4/25.0]
Disease activity: active/ quiescent, n = 346 [%]	225/121 [65/35]
CD location: L1/L2/L3/ L4/perianal, n = 976, %	33.7/17.0/49.3/11.2/17.2
CD behaviour: B1/B2/B3, n = 969, %	74.6/22.7/8.3
UC extent: E1/E2/E3, n = 839, %	14.8/39.6/45.6
History of major IBD-related surgeries at entry, n = 1848 [%]	216 [11.7]
History of appendectomy, n = 1727 [%] /	190 [11.0]
History of tonsillectomy, n = 1856 [%]	228 [12.3]

CD, Crohn’s disease; EIMs, extra-intestinal manifestations; IBD, inflammatory bowel disease; UC, ulcerative colitis; IQR, interquartile range.

Figure 1 shows the prevalence of EIMs in CD and UC patients. It is noteworthy that none of the UC patients developed more than three EIMs.

Figure 1.

Prevalence of extraintestinal manifestations according to disease type.

Arthritic EIMs were more prevalent in females and CD patients except for ankylosing spondylitis, which was more prevalent in males. Erythema nodosum and ocular EIMs were more frequent in CD with the exception of posterior uveitis [ Table 2 ].

Table 2.

Classification of extraintestinal manifestations in patients with inflammatory bowel disease according to gender and disease type.

n Total cohort [%] EIMs cohort [%]	Total [ n = 1860] [ n = 615]	Males [ n = 1053] [ n = 272]	Females [ n = 807] [ n = 343]	OR [95%CI] [ p -value]	CD [ n = 1001] [ n = 407]	UC [ n = 859] [ n = 208]	OR [95%CI] [ p -value]
Arthritic EIMs	434 [23.3] [70.6]	169 [16.0] [62.1]	265 [32.8] [77.3]	0.5 [0.3–0.7] [< 0.0001]	308 [30.8] [75.7]	126 [14.7] [60.6]	2.0 [1.4–2.9] [< 0.0001]
Arthralgia	311 [16.7] [50.6]	108 [10.3] [39.7]	203 [25.2] [59.2]	0.5 [0.3–0.8] [0.005]	218 [21.8] [53.6]	93 [10.8] [44.7]	NS
Peripheral arthritis	221 [11.9] [35.9]	74 [7.0] [27.2]	147 [18.2] [42.9]	0.6 [0.4–0.9] [0.018]	155 [15.5] [38.1]	66 [7.7] [31.7]	NS
Ankylosing spondylitis	39 [2.1] [6.3]	26 [2.5] [9.6]	13 [1.6] [3.8]	3.5 [1.7–7.1] [< 0.0001]	34 [3.4] [8.4]	5 [0.6] [2.4]	3.0 [1.1–7.8] [0.025]
Sacroiliitis	86 [4.6] [14.0]	39 [3.7] [14.3]	47 [5.8] [13.7]	NS	70 [7.0] [17.2]	16 [1.9] [7.7]	2.0 [1.1–3.6] [0.017]
Mucocutaneous EIMs	260 [14.0] [42.3]	120 [11.4] [44.1]	140 [17.3] [40.8]	NS	169 [16.9] [41.5]	91 [10.6] [43.8]	NS
Erythema nodosum	99 [5.3] [16.1]	39 [3.7] [14.3]	60 [7.4] [17.5]	NS	75 [7.5] [18.4]	24 [2.8] [11.5]	2.2 [1.3–3.9] [0.005]
Pyoderma gangrenosum	15 [0.8] [2.4]	7 [0.7] [2.6]	8 [1.0] [2.3]	NS	7 [0.7] [1.7]	8 [0.9] [3.8]	NS
Psoriasis	51 [2.7] [8.3]	23 [2.2] [8.5]	28 [3.5] [8.2]	NS	33 [3.3] [8.1]	18 [2.1] [8.7]	NS
Sweet’s syndrome	4 [0.2] [0.7]	1 [0.1] [0.4]	3 [0.4] [0.9]	NS	2 [0.2] [0.5]	2 [0.2] [1.0]	NS
Hydradenitis suppurativa	5 [0.3] [0.8]	1 [0.1] [0.4]	4 [0.5] [1.2]	NS	4 [0.4] [1.0]	1 [0.1] [0.5]	NS
Aphthous stomatitis	114 [6.1] [18.5]	59 [5.6] [21.7]	55 [6.8] [16.0]	NS	69 [6.9] [17.0]	45 [5.2] [21.6]	NS
Ophthalmological EIMs	55 [3.0] [8.9]	25 [2.4] [9.2]	30 [3.7] [8.7]	NS	45 [4.5] [11.1]	10 [1.2] [4.8]	2.4 [1.2–5.0] [0.011]
Episcleritis	16 [0.9] [2.6]	9 [0.9] [3.3]	7 [0.9] [2.0]	NS	16 [1.6] [3.9]	-	1.3 [1.1–1.6] [0.026]
Scleritis	-	-	-	NA	-	-	NA
Anterior uveitis [iridocyclitis]	31 [1.7] [5.0]	13 [1.2] [4.8]	18 [2.2] [5.2]	NS	25 [2.5] [6.1]	6 [0.7] [2.9]	NS
Posterior uveitis [vitritis, choroiditis, retinitis]	7 [0.4] [1.1]	3 [0.3] [1.1]	4 [0.5] [1.2]	NS	3 [0.3] [0.7]	4 [0.5] [1.9]	0.1 [0.0–0.6] [0.016]
Primary sclerosing cholangitis	8 [0.4] [1.3]	4 [0.4] [1.5]	4 [0.5] [1.2]	NS	5 [0.5] [1.2]	3 [0.3] [1.4]	NS
Deep vein thrombosis	16 [0.9] [2.6]	5 [0.5] [1.8]	11 [1.4] [3.2]	NS	7 [0.7] [1.7]	9 [1.0] [4.3]	NS
Portal vein thrombosis	1 [0.1] [0.2]	1 [0.1] [0.4]	-	NA	1 [0.1] [0.2]	-	NA

CI, confidence interval; EIMs, extra-intestinal manifestations; IBD, inflammatory bowel disease; NA, non-applicable; NS, non-significant; OR, odds ratio. Bold: broad categories of extraintestinal manifestations/significant associations.

Rare extra-intestinal manifestations are shown in Table 3 . No difference could be detected regarding gender or IBD type.

Table 3.

Rare extraintestinal manifestations in patients with inflammatory bowel disease.

	n	Male/ female [ n ]	CD/ UC [ n ]
Atopic dermatitis	3	2/1	1/2
Barrett’s oesophagus	1	1/0	0/1
Budd-Chiari syndrome	2	1/1	0/2
Central serous retinopathy	1	0/1	1/0
Dry eye	1	0/1	0/1
Eosinophilic oesophagitis	1	1/0	0/1
Glomerulonephritis	2	1/1	2/0
Leukocytoclastic vasculitis	1	0/1	0/1
Lichen planus	1	0/1	1/0
Mastitis	1	0/1	1/0
Mesenteric vessels stenosis	1	1/0	0/1
Metrorhagy	1	0/1	0/1
Pemphigoid	1	0/1	1/0
Penile lichen	1	1/0	1/0
Pericarditis	1	1/0	0/1
Pleural effusion	1	0/1	0/1
Pyelonephritis	1	0/1	1/0
Raynaud syndrome	1	1/0	1/0
Palmar and plantar seborrheic dermatitis	1	1/0	1/0
Small airways obstructive syndrome	1	0/1	0/1
Tracheal-broncheal stenosis	1	0/1	1/0
Vitiligo	1	0/1	0/1
Total	26	11/15	12/14

CD, Crohn’s disease; UC, ulcerative colitis.

3.2. Correlation between EIMs and IBD characteristics

In general, EIMs were more prevalent in females [OR for males 0.47, 95% CI 0.39–0.57], patients with CD [OR 2.14, 95% CI 1.75–2.62], smokers [OR 1.47, 95% CI 1.19–1.81, p < 0.0001 for all], patients born or living in urban areas [OR 1.26, 95% CI 1.03–1.56, p = 0.025 and OR 1.56, 95% CI 1.24–1.97, p < 0.0001, respectively], patients with extensive UC [OR 1.55, 95% CI 1.12–2.15, p = 0.007] and those with a history of a major IBD surgery [OR 1.45, 95% CI 1.08–1.94, p = 0.012], appendectomy [OR 1.76, 95% CI 1.29–2.39, p < 0.0001], or tonsillectomy [OR 1.47, 95% CI 1.11–1.96, p = 0.007]. However, only female gender ( p < 0.0001, standard error [SE] 0.18) and the presence of extensive UC [ p = 0.036, SE 0.18] remained significant in multivariate analysis. The presence of an EIM was also positively associated with a worsening [from B1 to B2 or B3] in CD behaviour [OR 1.81, 95% CI 1.20–2.74, p = 0.004] but not with an increase in UC extent. Finally, EIMs were more frequent in patients reporting a history of EIM in their IBD relatives [OR 3.10, 95% CI 1.28–7.49, p = 0.009].

Arthritic EIMs were additionally more prevalent in married patients [OR 1.51, 95% CI 1.06–2.15, p = 0.022]. However, only female gender [ p < 0.0001, SE 0.2] and the presence of CD [ p < 0.0001, SE 0.2] remained significant in multivariate analysis. IBD was diagnosed in an older age in patients exhibiting an arthritic EIM (33.0 [23.8–46.0] vs 28.0 [20.3–39.7] years, p < 0.0001). Peripheral arthritis was additionally associated with upper gastrointestinal [GI] involvement in CD patients [OR 2.12, 95% CI 1.05–4.30, p = 0.033] and inversely correlated with axial manifestation [OR 0.36, 95% CI 0.22–0.60, p < 0.0001] and ileal pouch anal anastomosis [OR 0.11, 95% CI 0.01–0.95, p = 0.029]. Ankylosing spondylitis and sacroiliitis were diagnosed more frequently before IBD diagnosis [OR 8.98, 95% CI 4.01–20.13, p < 0.0001 and OR 2.12, 95% CI 1.31–3.42, p = 0.002 respectively] and were associated with a worsening in IBD behaviour [OR 3.15, 95% CI 1.40–708, p = 0.004 and OR 2.12, 95% CI 1.09–4.15, p = 0.025, respectively]. Ankylosing spondylitis was positively associated with CD ileocolitis [OR 2.39, 95% CI 1.09–5.24, p = 0.026] and sacroiliitis was reversely associated with CD colitis [OR 0.31, 95% CI 0.12–0.84, p = 0.016] as opposed to the other two Montreal classification major location categories in both associations. Moreover, ankylosing spondylitis was strongly associated with a history of right hemicolectomy [OR: 13.5, 95% CI: 1.6–114.9, p = 0.005]. IBD duration until first EIM diagnosis was longer in patients with ankylosing spondylitis in whom IBD diagnosis preceded, compared with patients who never developed this particular EIM (11.3 [6.8–17.1] vs 2.2 [0.3–7.7] years, p = 0.006).

Mucocutaneous EIMs [except for erythema nodosum] were diagnosed more frequently before IBD compared with the other EIMs [OR 2.12, 95% CI 1.52–2.96, p < 0.0001] and were additionally associated with ileal pouch anal anastomosis [OR 4.09, 95% CI 1.22–13.61, p = 0.03] and a familial EIMs history [OR 3.42, 95% CI 1.07–10.91, p = 0.043] in univariate analysis, but only the association with ileal pouch anal anastomosis remained significant in multivariate analysis [ p = 0.047]. The presence of erythema nodosum was associated with IBD activity [OR 4.6, 95% CI 1.79–11.81, p = 0.001]. Patients exhibiting a mucocutaneous EIM had their IBD diagnosed at a younger age (29.4 [21.6–41.8] vs 33.0 [23.4–46.0] years, p = 0.004) and IBD duration until first EIM diagnosis was shorter (2.1 [0.0–5.9] vs 3.0 [0.6–8.6] years, p = 0.034). Moreover, first EIM duration until IBD diagnosis was longer (6.5 [2.0–20.6] vs 1.4 [0.5–6.5] years, p < 0.0001] since first EIM was more frequently diagnosed before IBD [OR 2.65, 95% CI 1.60–4.39, p < 0.0001] in patients with aphthous stomatitis.

Episcleritis was exclusively diagnosed in CD patients. PSC was associated with single marital status [OR 9.07, 95% CI 1.08–75.90, p = 0.019]. IBD was diagnosed at a younger age in PSC patients (14.3 [10.8–24.1] vs 31.8 [22.5–44.6], p < 0.0001). DVT was associated with a stricturing CD phenotype [OR 7.16, 95% CI 1.28–39.87, p = 0.025]. IBD was diagnosed at an older age (45.0 [40.3–56.7] vs 31.0 [22.2–43.8], p = 0.001], and IBD duration until first EIM diagnosis was longer in patients with DVT (12.1 [2.6–15.2] vs 2.6 [0.2–8.0] years, p = 0.02).

3.3. Co-existence of EIMs

Patients with an arthritic EIM were less likely to carry a mucocutaneous EIM [except for erythema nodosum] or to suffer from DVT. However, ankylosing spondylitis was strongly associated with the presence of an ocular EIM [ Table 4 ]. None of the patients with PSC reported an arthritic EIM.

Table 4.

Correlation between different extraintestinal manifestations in inflammatory bowel disease patients.

OR [95% CI] [ p -value]	Ankylosing spondylitis	Sacroiliiitis	Mucocutaneous EIMs	Erythema nodosum	Ocular EIMs	DVT
Arthritic EIMs			0.1 [0.1–0.2] [< 0.0001]	2.6 [1.6–4.4] [< 0.0001]		0.2 [0.1–0.7] [0.009]
Peripheral arthritis	0.3 [0.1–0.6] [0.001]	0.4 [0.2–0.6] [< 0.0001]		0.4 [0.2–0.7] [0.007]
Ankylosing spondylitis			0.2 [0.1–0.7] [0.005]		3.8 [1.6–8.7] [0.004]
Mucocutaneous EIMs

CI, confidence interval; DVT, deep vein thrombosis; EIMs, extra-intestinal manifestations; OR, odds ratio. Bold: significant positive associations.

3.4. Concomitant diseases

Table 5 shows the presence of other concomitant diseases in the study population. NAFLD, diabetes mellitus and coronary artery disease were more prevalent in UC patients, whereas osteoporosis and anaemia were more prevalent in CD patients. Patients with nephrolithiasis, osteoporosis, anaemia, or one other autoimmune disease exhibited an EIM more often.

Table 5.

Concomitant frequent diseases classification according to inflammatory bowel disease type and the presence of extraintestinal manifestations.

	CD [%]	UC [%]	OR [95% CI] [ p -value]	EIMs [+] [%]	EIMs [-] [%]	OR [95% CI] [ p -value]
Pulmonary embolism	4/1001 [0.4]	2/859 [0.2]	NS	NA	NA	NS
Asthma a	6/1001 [0.6]	9/859 [1.0]	NS	NA	NA	NS
Bronchiectasis/chronic bronchitis a	2/1001 [0.2]	3/859 [0.3]	NS	NA	NA	NS
Cholelithiasis	80/877 [9.1]	46/706 [6.5]	NS	51/527 [9.7]	75/1056 [7.1]	NS
Non-alcoholic fatty liver disease	86/878 [9.8]	94/706 [13.3]	0.7 [0.5–0.9] [0.031]	66/527 [12.5]	114/1057 [10.8]	NS
Pancreatitis	27/947 [2.9]	22/820 [2.7]	NS	21/569 [3.7]	28/1198 [2.3]	NS
IBD-related autoimmune pancreatitis	5/947 [0.5]	1/820 [0.1]	NS	3/569 [0.5]	3/1198 [0.3]	NS
Drug-induced pancreatitis	20/947 [2.1]	15/820 [1.8]	NS	13/569 [2.3]	22/1198 [1.8]	NS
Gallstones-related pancreatitis	2/947 [0.2]	6/820 [0.7]	NS	5/569 [0.9]	3/1198 [0.3]	NS
Nephrolithiasis	87/938 [9.3]	61/757 [8.1]	NS	62/584 [10.6]	86/1111 [7.7]	1.4 [1.0–2.0] [0.046]
Bone disease	168/457 [36.7]	102/363 [28.1]		136/339 [40.1]	134/481 [27.8]
Osteopenia	88/457 [19.3]	57/363 [15.7]	NS	67/339 [19.8]	78/481 [16.2]	NS
Osteoporosis	80/457 [17.5]	45/363 [12.4]	1.5 [1.0–2.2] [0.043]	69/339 [20.4]	56/481 [11.6]	1.9 [1.3–2.8] [0.001]
Anaemia b	201/998 [20.1]	116/858 [13.5]	1.6 [1.2–2.1] [< 0.0001]	178/614 [29.0]	139/1242 [11.2]	3.2 [2.5–4.1] [< 0.0001]
Iron deficiency anaemia	144/998 [14.4]	108/858 [12.6]	NS	147/614 [23.9]	105/1242 [8.5]	3.4 [2.6–4.8] [< 0.0001]
Anaemia of chronic disease	73/998 [7.3]	14/858 [1.6]	4.7 [2.7–8.5] [< .0001]	42/614 [6.8]	45/1242 [3.6]	1.9 [1.3–3.0] [0.003]
Anaemia due to folate or vitamin B 12 deficiency	21/998 [2.1]	2/858 [0.2]	9.2 [2.1–39.3] [< 0.0001]	12/614 [2.0]	11/1242 [0.9]	NS
Diabetes mellitus	34/1001 [3.4]	49/859 [5.7]	0.6 [0.4–0.9] [0.018]	27/615 [4.4]	56/1245 [4.5]	NS
Coronary heart disease	19/1001 [1.9]	59/858 [6.9]	0.3 [0.1–0.4] [< 0.0001]	21/615 [3.4]	57/1244 [4.6]	NS
Multiple sclerosis	3/1001 [0.3]	2/859 [0.2]	NS	1/615 [0.2]	4/1245 [0.3]	NS
Other autoimmune diseases c	86/1001 [8.6]	60/859 [7.0]	NS	89/615 [14.5]	57/1245 [4.6]	3.5 [2.5–5.0] [< 0.0001]

CD, Crohn’s disease; CI, confidence interval;;NS, non-significant; OR, odds ratio; UC, ulcerative colitis. Bold: significant associations.

^a In non-smokers.

^b Patients with absence of beta-thalassemia and in remission of inflammatory bowel disease.

^c Autoimmune thyroiditis, psoriasis, autoimmune haemolytic anemia, autoimmune hepatitis, antiphospholipidic syndrome, Biermer disease, coeliac disease, glomerulonephritis, idiopathic thrombopenic purpura, primary biliary cirrhosis, rheumatoid arthritis, sarcoidosis, Sjögren syndrome, and systemic lupus erythematosus.

4. Discussion

This is a multicentre retrospective study investigating the prevalence and risk factors of EIMs and other accompanying abnormalities in a large national cohort of IBD patients. EIMs were present in one-third of our patients, and in one-third of those at least one EIM appeared before IBD diagnosis. Development of EIMs was associated with demographic parameters such as young age, female gender, smoking, urban environment, and a positive family history for EIMs, as well as with clinical parameters such as diagnosis of CD, extensive UC and a history of an IBD-related surgery, appendectomy, and tonsillectomy in univariate analysis, but only female gender and the presence of extensive UC remained significant in multivariate analysis. Multiple EIMs were less frequently seen in UC and EIMs presence was associated with a worsening of disease phenotype in CD.

EIMs frequency in our population [33.1%] is within the range of rates reported in several retrospective national studies; 40.6% in an Italian, ⁸ 38.1% in a Swiss, ⁹ 21.3% in a Hungarian, ¹⁰ and 36% in a Canadian ¹¹ cohort. Moreover, the cumulative prevalence of first EIM was 16.9% in a European inception cohort prospectively followed for a median of 10.1 years. ⁷ First EIM diagnosis was established before IBD in 38.6% of our patients. This rate was 11.2% in the Italian cohort ⁸ and 25.8% in the Swiss cohort. ²⁰ IBD was active in two-thirds of our patients at first EIM diagnosis. CD was active in 58.5% and UC in 35.5% of patients at EIMs capture in the Swiss cohort. ⁹ These variations could be attributed to differences in definitions, specific characteristics of the populations studied, spectrum of EIMs included in each study, accuracy of diagnosis, recall bias, and previous medical treatment.

Although EIMs were more prevalent in younger patients, IBD was diagnosed at an older age in those with an EIM diagnosis prior to IBD, and this is probably due to delayed referral of patients with prominent EIMs and subtle gastrointestinal symptoms to an IBD specialist. This study confirms the higher prevalence of clusters of EIMs in CD rather in UC and their association with an aggressive course of CD. Isene et al . claimed that the risk of developing an additional immune-mediated manifestation after the first is low. ⁷ However, we observed that 8.1% of patients with two and 3.2% of patients with three EIMs developed these manifestations within a short time interval and the median age at disease diagnosis was still low, even after the development of three or four EIMs.

A unique observation of this study is that patients with an EIM having also relative[s] with IBD reported more frequently presence of EIMs in these affected family members, further supporting the genetic predisposition and similar disease phenotype in families with more than one IBD member, but also shared genetic pathways between certain EIMs and IBD. Isene et al . ⁷ reported the absence and Vavricka et al . ⁹ the presence of a correlation of EIMs with a positive IBD family history, both without investigating any possible association with the presence of an EIM in these relatives.

Most studies report an increased prevalence of EIM in females, patients with CD, and smokers. ^{9 , 10 , 11 , 21} However, Isene et al.⁷ and Zippi et al.⁸ found no difference between genders, and Isene et al.⁷ and Vavricka et al.⁹ did not observe any correlation with smoking. We, for the first time, describe an association between EIMs and an urban environment, albeit only in univariate analysis, either as a place of birth or residence, reinforcing the hypothesis of increased prevalence and more complicated forms of immune-mediated diseases in this setting. Appendectomy but not tonsillectomy has been described as a risk factor for the presence of EIMs. ²¹ Both were associated with the development of EIMs again only in univariate analysis.

The prevalence of arthritic EIMs in our study falls in the range of previous studies. ²² The most common objectively captured EIM seen in 16.7% of patients was peripheral arthritis; its prevalence was similar in CD and UC patients and comparable to other studies. ²³ Ankylosing spondylitis was observed in 2.1% of the patients, being more prevalent in males and CD, as in other reports [2–6%]. ^{7 , 8 , 9 , 11 , 24} An inverse association was observed between peripheral arthritis and axial involvement as well as ileal pouch anal anastomosis. The latter could be attributed to altered gut flora and resolution of bacterial translocation due to restoration of bowel wall integrity after the operation. Ankylosing spondylitis and sacroiliitis were more frequently diagnosed before IBD, supporting their independent evolution.

The prevalence of mucocutaneous EIMs in our cohort was 14% [16.9% in CD and 10.6% in UC]. Different inclusion and diagnostic criteria could explain variations in rates between studies. ^{8 , 10} Mucocutaneous EIMs were more frequently diagnosed before IBD diagnosis and consequently it was unusual for them to be associated with IBD activity. However, erythema nodosum [5.3% in total, 7.5% in CD and 2.8% in UC] represented an exception, being more prevalent at IBD diagnosis or at disease flares. The earlier diagnosis of IBD in patients with a mucocutaneous EIM is probably explained by the increased awareness of dermatologists fof the association of specific skin lesions with underlying IBD. Aphthous stomatitis was the second most common EIM [6.1%].

Ocular EIMs represented the third most frequent group of EIMs. It is noteworthy that all patients with episcleritis suffered from CD and no cases of scleritis were observed. We also captured for the first time cases with anterior and posterior uveitis. It is interesting that no such cases are generally described, even in cohorts with ocular EIMs as primary outcome. ²⁵

We also detected several rare EIMs, which are infrequently reported. ²⁶ In addition, we investigated the association of certain conditions and diseases that are not strictly classified as EIMs but are more frequently described in IBD patients with the ‘classic’ EIMs. These entities are usually reported separately. ^{27 , 28 , 29 , 30 , 31} This is, to our knowledge, the first study that collectively assessed these disorders in such a cohort.

The present study has limitations. This is not a population-based study and data collection was done retrospectively from tertiary referral centres, being prone to recall bias. We cannot rule out a potential misinterpretation by participants of the definitions applied to characterise EIMs, since there was no central reading. However, we believe that the population included in our study is representative of the overall Greek IBD population,since these patients are principally followed up in tertiary referral centres and only a minority visit individual physicians or low-volume private or public regional institutions. We also feel confident that we have captured the vast majority of EIMs preceding IBD, due to the fact that all participating centres are very specialised in following up IBD patients and thus medical records included such information in most cases. The treating physician was asked to interview the patient either during an outpatient clinic visit or through a call in the few cases that this information was missing. On the other hand, there are certain strengths. This is among the largest series ever published and the largest spectrum of EIMs simultaneously studied. Definitions for inclusion were straightforward, since consulting procedures were easy due to the availability of respective specialists in all centres. Association between different EIMs and several frequent clinical entities was conducted for the first time in IBD patients.

In conclusion, the present study shows that EIMs are present in a third of Greek IBD patients, and in another third of those the appearance of an EIM precedes IBD diagnosis. Specific correlations were also detected between the EIMs studied and certain abnormal conditions or diseases frequently observed in IBD. Clinicians have to raise increased awareness for the identification of an IBD-related EIM and for the early diagnosis of IBD, in order to offer the appropriate treatment and to avoid long-term complications.

Funding

None.

Conflict of Interest

None.

Author Contributions

KK participated in study design, registered affiliation data, gathered, analysed and interpreted final data, and drafted the manuscript; AA participated in study design and manuscript drafting, registered affiliation data, and critically revised the manuscript; AT, CZ, PK, TK, KO, AK, EZ, and VP registered affiliation data and critically revised the manuscript; AT, NV, DP, SM, GB, AK, DGK, GM, and CT contributed cases and critically revised the manuscript; IEK participated in study design, interpretation of the data, and drafting and critical revision of the manuscript; All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.