Phenotype and Clinical Course of Inflammatory Bowel Disease With Co-existent Celiac Disease

Phenotype and Clinical Course of Inflammatory Bowel Disease With Co-existent Celiac Disease Abstract Background and Aims Inflammatory bowel diseases, principally Crohn’s disease and ulcerative colitis, and celiac disease are among the most common immune-mediated gastrointestinal diseases. We aim to elucidate the clinical course and outcomes of patients with concomitant inflammatory bowel disease and celiac disease, a unique population that remains scarcely studied to date. Methods A retrospective matched case-control study of adults with co-existent inflammatory bowel disease [IBD] and celiac disease was performed at a tertiary referral institution in North America. Logistic regression and Kaplan-Meier curves compared disease characteristics and clinical outcomes of the two groups. Results A total of 342 inflammatory bowel disease patients were included in this study, of whom 114 had co-existent celiac disease and 228 did not. Patients with co-existent inflammatory bowel disease and celiac disease had higher rates of primary sclerosing cholangitis [19.3% vs 5.7%; odds ratio, 4.4; 95% confidence interval, 2.1–9.4; p <0.001], extensive ulcerative colitis [78.1% vs 59.0%; odds ratio, 2.8; 95% confidence interval, 1.5–5.5; p =0.002], and family history of celiac disease [10.5% vs 3.5%; odds ratio 3.2; 95% confidence interval, 1.3–8.2; p =0.01], compared with patients without concomitant celiac disease. Conclusions Patients with inflammatory bowel disease with concomitant celiac disease have unique phenotypic features compared with non-celiac inflammatory bowel disease, with higher risks for colitis-related hospitalisations, extensive colitis, and primary sclerosing cholangitis. Increased recognition of co-existent IBD and celiac disease can prompt clinicians to investigate for concomitant disease sooner, particularly in patients with seemingly refractory disease. Inflammatory bowel disease, celiac disease, primary sclerosing cholangitis, clinical course, concurrent immune-mediated gastrointestinal diseases 1. Introduction Inflammatory bowel diseases [IBD], principally Crohn’s disease [CD] and ulcerative colitis [UC], and celiac disease are immune-mediated gastrointestinal diseases with complex interactions between genetic and environmental factors.1 IBD and celiac disease have overlapping clinical features, including abdominal pain, diarrhoea, and malabsorption.2 The prevalence of celiac disease in IBD is estimated to be 0.5–0.9%,3,4 similar to the prevalence of 0.8–1% in the general population.4,5 Conversely, approximately 1–3.2% of celiac disease patients have IBD,4,6,7 a rate that is 3–10 times higher than the estimated IBD prevalence of 0.3% in the general population.8,9 IBD with concomitant celiac disease has not been extensively studied. To date, only one published retrospective case-control study has examined the phenotypic differences and outcomes of patients with IBD and concomitant celiac disease [IBD-Celiac] compared with non-celiac IBD individuals [IBD-only]. In that study,2 pancolitis was more common in UC-Celiac patients compared with UC-only controls, though no differences were reported in CD behaviour or IBD-related medications, hospitalisations, and surgeries between the IBD-Celiac and IBD-only patient groups. Whereas there is a complex interplay between genetic predisposition and environmental influence in the pathogenesis of IBD and celiac disease, the phenotypic overlap of these immune-mediated diseases has been under-explored. We herein aim to comprehensively analyse the interrelation between IBD and celiac disease with a matched case-control retrospective cohort study at a large tertiary referral centre in North America. In this study, we sought to determine the clinical course of IBD with concomitant celiac disease compared with patients with IBD alone; namely, the differences in disease phenotype, clinically relevant IBD outcomes, and extra-intestinal manifestations including primary sclerosing cholangitis [PSC]. 2. Materials and Methods With Institutional Review Board approval from the Mayo Foundation [protocol #16-007857], we conducted a retrospective case-control study conducted on patients from the Mayo Clinic’s tri-campus [Minnesota, Florida, and Arizona]. Each UC/CD-Celiac study patient was matched by gender and IBD-subtype to two randomly selected IBD-only controls out of the pool of all IBD patients seen at the Mayo Clinic. Patients with a diagnosis of IBD-unclassified were excluded from further analysis. Potential cases and controls were identified through a query of an internal centralised data repository from 1997–2016, based on International Classification of Diseases [ICD] 9th and 10th edition diagnosis codes. Matched controls were identified based on the first appearance of ICD-9/10 diagnosis codes for IBD in our institution’s electronic medical records; controls were matched +/- 3 years of the study patients’ IBD diagnosis date, based on the control pools’ second date appearance of two ICD-9/10 codes identified at least 30 days apart [to limit the false-positives]. Review of the electronic medical records was performed to confirm the diagnosis of IBD based on the standard clinical, radiographic and histological criteria.10,11 For celiac disease, the diagnosis was made based on abnormal serum tests for IgA antibodies against tissue transglutaminase, gliadin, or endomysial antigens, and/or histological evidence of villous atrophy on duodenal biopsy.12 Patients were excluded if they had microscopic colitis, negative HLA-DQ2 or HLA-DQ8 locus genetic analysis, or were <18 years old. Baseline demographics, disease characteristics, and outcome variables were collected from the electronic medical records. The Montreal classification13 was used to classify CD and UC phenotype. UC disease extent was further reclassified to limited UC [ulcerative proctitis and left sided UC] versus extensive UC [extensive UC and pancolitis] for statistical analysis. In this study, the UC extent was classified by the most extensive involvement known in the patient’s history to reflect the UC phenotype, as the clinical course of UC can range from quiescent to fulminant disease with relapses interspersed with periods of remission.14 Thus, in order to most accurately represent the phenotype of UC in the UC-Celiac and UC-only groups, we listed the most extensive UC involvement that was known in Table 1 [and in Supplementary Table 1, available as Supplementary data at ECCO-JCC online]. Disease characteristics analysed included IBD/celiac disease duration, follow-up time, and extra-intestinal manifestations of IBD. Because PSC was a primary outcome of interest that could be diagnosed independently of IBD, it was analysed separately from other extra-intestinal manifestations in this study, in order to more accurately describe its associations both before and after IBD and IBD-Celiac diagnoses. Table 1. Comparison of the characteristics of the inflammatory bowel disease- [IBD]-Celiac cases and non-celiac IBD controls. Characteristic IBD-Celiaca N = 114 IBD-only controls N = 228 Odds ratio [95% CI] p-Value Female 54 [47.4%] 108 [47.4%] 1.1 [0.7-1.8] 0.6 Ethnicity White 105 [97.2%] 219 [96.5%] Ref 0.8 Non-White 3 [2.8%] 8 [3.5%] 0.8 [0.2-3.2] Age, median [IQR] At IBD diagnosis 28.9 [18.8, 39.9] 24.4 [17.9-34.5] 1.0 [1.0-1.0] 0.05 At Celiac diagnosis 33.1 [24.1, 49.4] / / / IBD Type Crohn’s disease 35 [30.7%] 70 [30.7%] 1.0 [0.6-1.7] 10 Ulcerative colitis 79 [69.3%] 158 [69.3%] Ref Smoking Never 80 [70.2%] 157 [68.9%] Ref 0.4 Ever 34 [29.8%] 71 [31.1%] 0.8 [0.4-1.3] Family history IBD 25 [21.9%] 50 [22.0%] 1.0 [0.6-1.8] 0.9 Crohn’s disease 10 [8.9%] 19 [8.8%] 1.1 [0.5-2.6] 0.8 Ulcerative colitis 13 [11.6%] 21 [9.7%] 1.3 [0.6-2.7] 0.5 Celiac disease 12 [10.5%] 8 [3.5%] 3.2 [1.3-8.2] 0.01 Referral IBD case 89 [78.1%] 202 [88.6%] 0.5 [0.3-0.9] 0.02 Years of IBD prior to Time 0,b median [IQR] 3.4 [0.6, 12.0] 3.6 [0.5, 12.0] 1.0 [1.0-1.0] 0.3 Years of follow-up, median [IQR] 3.0 [0.7, 6.8] 6.3 [2.6, 12.2] 0.9 [0.8-0.9] <0.001 Order of diagnosis IBD before celiac 75 [65.8%] / / / IBD after celiac 32 [26.5%] Concurrent [within +/- 7 days] 9 [8.0%] Years to celiac diagnosis after IBD, median [IQR] 7.7 [1.4, 14.2] / / / Years to IBD after celiac diagnosis, median [IQR] 3.4 [0.4, 8.0] / / / Crohn’s disease location Ileal, N [%] 26 [76.5%] 46 [57.5%] 3.2 [1.0-10.3] 0.08 Ileocolonic, N [%] 4 [11.8%] 11 [13.8%] 2.0 [0.4-9.9] 0.9 Colonic, N [%] 4 [11.8%] 23 [28.8%] Ref / Upper GI Crohn’s disease 6 [17.1%] 12 [17.1%] 1.0 [0.3-2.9] 1.0 Perianal Crohn’s disease 6 [17.1%] 16 [22.9%] 0.7 [0.2-2.1] 0.5 Crohn’s disease phenotype Inflammatory 26 [76.5%] 40 [57.1%] 3.7 [1.1-11.9] 0.1 Stricturing 4 [11.8%] 7 [10.0%] 3.2 [0.6-16.6] 0.5 Fistulising 4 [11.8%] 23 [32.9%] Ref / Ulcerative colitis extent Limited colitis 16 [21.9%] 64 [41.0%] Ref / Extensive colitis 57 [78.1%] 92 [59.0%] 2.8 [1.5-5.5] 0.002 PSC at Time 0b Present 22 [19.3%] 13 [5.7%] 4.4 [2.1-9.4] <0.001 Absent 92 [80.7%] 215 [94.3%] Ref Extra-intestinal manifestations [any time, excluding PSC] Any 16 [14.0%] 35 [15.4%] 0.9 [0.5-1.8] 0.8 Sacroileitis 2 [1.8%] 2 [0.9%] 2.5 [0.3,18.0] 0.4 Ankylosing spondylitis 1 [0.9%] 4 [1.8%] 0.5 [0.06-4.8] 0.6 Pyoderma gangrenosum 1 [0.9%] 3 [1.3%] 0.6 [0.06-5.6] 0.6 Erythema nodosum 1 [0.9%] 6 [2.6%] 0.3 [0.04-3.0] Uveitis/episcleritis 2 [1.8%] 5 [2.2%] 0.8 [0.1-4.2] 0.8 Oral ulcers/aphthous stomatitis 8 [7.0%] 11 [4.8%] 1.5 [0.6-3.9] 0.4 Deep vein thrombosis 3 [2.6%] 8 [3.5%] 0.7 [0.2-2.8] 0.7 Medications ever used 5-ASA 70 [61.4%] 111 [48.7%] 1.8 [1.1-2.9] 0.02 Corticosteroids 41 [36.0%] 75 [32.9%] 1.2 [0.7-1.9] 0.5 Immunomodulator 15 [13.2%] 39 [17.1%] 0.7 [0.4-1.4] 0.4 Biologics 20 [17.5%] 37 [15.4%] 1.2 [0.7-2.2] 0.6 Celiac diagnosis method Serology and histology 70 [61.9%] / / / Histology alone 22 [19.5%] Serology alone 11 [9.7%] Clinical history 10 [8.8%] Characteristic IBD-Celiaca N = 114 IBD-only controls N = 228 Odds ratio [95% CI] p-Value Female 54 [47.4%] 108 [47.4%] 1.1 [0.7-1.8] 0.6 Ethnicity White 105 [97.2%] 219 [96.5%] Ref 0.8 Non-White 3 [2.8%] 8 [3.5%] 0.8 [0.2-3.2] Age, median [IQR] At IBD diagnosis 28.9 [18.8, 39.9] 24.4 [17.9-34.5] 1.0 [1.0-1.0] 0.05 At Celiac diagnosis 33.1 [24.1, 49.4] / / / IBD Type Crohn’s disease 35 [30.7%] 70 [30.7%] 1.0 [0.6-1.7] 10 Ulcerative colitis 79 [69.3%] 158 [69.3%] Ref Smoking Never 80 [70.2%] 157 [68.9%] Ref 0.4 Ever 34 [29.8%] 71 [31.1%] 0.8 [0.4-1.3] Family history IBD 25 [21.9%] 50 [22.0%] 1.0 [0.6-1.8] 0.9 Crohn’s disease 10 [8.9%] 19 [8.8%] 1.1 [0.5-2.6] 0.8 Ulcerative colitis 13 [11.6%] 21 [9.7%] 1.3 [0.6-2.7] 0.5 Celiac disease 12 [10.5%] 8 [3.5%] 3.2 [1.3-8.2] 0.01 Referral IBD case 89 [78.1%] 202 [88.6%] 0.5 [0.3-0.9] 0.02 Years of IBD prior to Time 0,b median [IQR] 3.4 [0.6, 12.0] 3.6 [0.5, 12.0] 1.0 [1.0-1.0] 0.3 Years of follow-up, median [IQR] 3.0 [0.7, 6.8] 6.3 [2.6, 12.2] 0.9 [0.8-0.9] <0.001 Order of diagnosis IBD before celiac 75 [65.8%] / / / IBD after celiac 32 [26.5%] Concurrent [within +/- 7 days] 9 [8.0%] Years to celiac diagnosis after IBD, median [IQR] 7.7 [1.4, 14.2] / / / Years to IBD after celiac diagnosis, median [IQR] 3.4 [0.4, 8.0] / / / Crohn’s disease location Ileal, N [%] 26 [76.5%] 46 [57.5%] 3.2 [1.0-10.3] 0.08 Ileocolonic, N [%] 4 [11.8%] 11 [13.8%] 2.0 [0.4-9.9] 0.9 Colonic, N [%] 4 [11.8%] 23 [28.8%] Ref / Upper GI Crohn’s disease 6 [17.1%] 12 [17.1%] 1.0 [0.3-2.9] 1.0 Perianal Crohn’s disease 6 [17.1%] 16 [22.9%] 0.7 [0.2-2.1] 0.5 Crohn’s disease phenotype Inflammatory 26 [76.5%] 40 [57.1%] 3.7 [1.1-11.9] 0.1 Stricturing 4 [11.8%] 7 [10.0%] 3.2 [0.6-16.6] 0.5 Fistulising 4 [11.8%] 23 [32.9%] Ref / Ulcerative colitis extent Limited colitis 16 [21.9%] 64 [41.0%] Ref / Extensive colitis 57 [78.1%] 92 [59.0%] 2.8 [1.5-5.5] 0.002 PSC at Time 0b Present 22 [19.3%] 13 [5.7%] 4.4 [2.1-9.4] <0.001 Absent 92 [80.7%] 215 [94.3%] Ref Extra-intestinal manifestations [any time, excluding PSC] Any 16 [14.0%] 35 [15.4%] 0.9 [0.5-1.8] 0.8 Sacroileitis 2 [1.8%] 2 [0.9%] 2.5 [0.3,18.0] 0.4 Ankylosing spondylitis 1 [0.9%] 4 [1.8%] 0.5 [0.06-4.8] 0.6 Pyoderma gangrenosum 1 [0.9%] 3 [1.3%] 0.6 [0.06-5.6] 0.6 Erythema nodosum 1 [0.9%] 6 [2.6%] 0.3 [0.04-3.0] Uveitis/episcleritis 2 [1.8%] 5 [2.2%] 0.8 [0.1-4.2] 0.8 Oral ulcers/aphthous stomatitis 8 [7.0%] 11 [4.8%] 1.5 [0.6-3.9] 0.4 Deep vein thrombosis 3 [2.6%] 8 [3.5%] 0.7 [0.2-2.8] 0.7 Medications ever used 5-ASA 70 [61.4%] 111 [48.7%] 1.8 [1.1-2.9] 0.02 Corticosteroids 41 [36.0%] 75 [32.9%] 1.2 [0.7-1.9] 0.5 Immunomodulator 15 [13.2%] 39 [17.1%] 0.7 [0.4-1.4] 0.4 Biologics 20 [17.5%] 37 [15.4%] 1.2 [0.7-2.2] 0.6 Celiac diagnosis method Serology and histology 70 [61.9%] / / / Histology alone 22 [19.5%] Serology alone 11 [9.7%] Clinical history 10 [8.8%] CI, confidence interval; IQR, interquartile range; GI, gastrointestinal; PSC, primary sclerosing cholangitis; 5-ASA, 5-aminosalicylic acid. aThree study cases had indeterminate colitis [and celiac disease]; fpor control cases had indeterminate colitis [without celiac disease]. These were not matched. b‘Time 0’ refers to the starting time point defined as the latest occurrence of IBD diagnosis, first presentation date at Mayo, or Celiac diagnosis, in the IBD-Celiac study group. In the IBD-only group, ‘time 0’ refers to the latest occurrence of IBD diagnosis or first presentation date at Mayo. View Large Table 1. Comparison of the characteristics of the inflammatory bowel disease- [IBD]-Celiac cases and non-celiac IBD controls. Characteristic IBD-Celiaca N = 114 IBD-only controls N = 228 Odds ratio [95% CI] p-Value Female 54 [47.4%] 108 [47.4%] 1.1 [0.7-1.8] 0.6 Ethnicity White 105 [97.2%] 219 [96.5%] Ref 0.8 Non-White 3 [2.8%] 8 [3.5%] 0.8 [0.2-3.2] Age, median [IQR] At IBD diagnosis 28.9 [18.8, 39.9] 24.4 [17.9-34.5] 1.0 [1.0-1.0] 0.05 At Celiac diagnosis 33.1 [24.1, 49.4] / / / IBD Type Crohn’s disease 35 [30.7%] 70 [30.7%] 1.0 [0.6-1.7] 10 Ulcerative colitis 79 [69.3%] 158 [69.3%] Ref Smoking Never 80 [70.2%] 157 [68.9%] Ref 0.4 Ever 34 [29.8%] 71 [31.1%] 0.8 [0.4-1.3] Family history IBD 25 [21.9%] 50 [22.0%] 1.0 [0.6-1.8] 0.9 Crohn’s disease 10 [8.9%] 19 [8.8%] 1.1 [0.5-2.6] 0.8 Ulcerative colitis 13 [11.6%] 21 [9.7%] 1.3 [0.6-2.7] 0.5 Celiac disease 12 [10.5%] 8 [3.5%] 3.2 [1.3-8.2] 0.01 Referral IBD case 89 [78.1%] 202 [88.6%] 0.5 [0.3-0.9] 0.02 Years of IBD prior to Time 0,b median [IQR] 3.4 [0.6, 12.0] 3.6 [0.5, 12.0] 1.0 [1.0-1.0] 0.3 Years of follow-up, median [IQR] 3.0 [0.7, 6.8] 6.3 [2.6, 12.2] 0.9 [0.8-0.9] <0.001 Order of diagnosis IBD before celiac 75 [65.8%] / / / IBD after celiac 32 [26.5%] Concurrent [within +/- 7 days] 9 [8.0%] Years to celiac diagnosis after IBD, median [IQR] 7.7 [1.4, 14.2] / / / Years to IBD after celiac diagnosis, median [IQR] 3.4 [0.4, 8.0] / / / Crohn’s disease location Ileal, N [%] 26 [76.5%] 46 [57.5%] 3.2 [1.0-10.3] 0.08 Ileocolonic, N [%] 4 [11.8%] 11 [13.8%] 2.0 [0.4-9.9] 0.9 Colonic, N [%] 4 [11.8%] 23 [28.8%] Ref / Upper GI Crohn’s disease 6 [17.1%] 12 [17.1%] 1.0 [0.3-2.9] 1.0 Perianal Crohn’s disease 6 [17.1%] 16 [22.9%] 0.7 [0.2-2.1] 0.5 Crohn’s disease phenotype Inflammatory 26 [76.5%] 40 [57.1%] 3.7 [1.1-11.9] 0.1 Stricturing 4 [11.8%] 7 [10.0%] 3.2 [0.6-16.6] 0.5 Fistulising 4 [11.8%] 23 [32.9%] Ref / Ulcerative colitis extent Limited colitis 16 [21.9%] 64 [41.0%] Ref / Extensive colitis 57 [78.1%] 92 [59.0%] 2.8 [1.5-5.5] 0.002 PSC at Time 0b Present 22 [19.3%] 13 [5.7%] 4.4 [2.1-9.4] <0.001 Absent 92 [80.7%] 215 [94.3%] Ref Extra-intestinal manifestations [any time, excluding PSC] Any 16 [14.0%] 35 [15.4%] 0.9 [0.5-1.8] 0.8 Sacroileitis 2 [1.8%] 2 [0.9%] 2.5 [0.3,18.0] 0.4 Ankylosing spondylitis 1 [0.9%] 4 [1.8%] 0.5 [0.06-4.8] 0.6 Pyoderma gangrenosum 1 [0.9%] 3 [1.3%] 0.6 [0.06-5.6] 0.6 Erythema nodosum 1 [0.9%] 6 [2.6%] 0.3 [0.04-3.0] Uveitis/episcleritis 2 [1.8%] 5 [2.2%] 0.8 [0.1-4.2] 0.8 Oral ulcers/aphthous stomatitis 8 [7.0%] 11 [4.8%] 1.5 [0.6-3.9] 0.4 Deep vein thrombosis 3 [2.6%] 8 [3.5%] 0.7 [0.2-2.8] 0.7 Medications ever used 5-ASA 70 [61.4%] 111 [48.7%] 1.8 [1.1-2.9] 0.02 Corticosteroids 41 [36.0%] 75 [32.9%] 1.2 [0.7-1.9] 0.5 Immunomodulator 15 [13.2%] 39 [17.1%] 0.7 [0.4-1.4] 0.4 Biologics 20 [17.5%] 37 [15.4%] 1.2 [0.7-2.2] 0.6 Celiac diagnosis method Serology and histology 70 [61.9%] / / / Histology alone 22 [19.5%] Serology alone 11 [9.7%] Clinical history 10 [8.8%] Characteristic IBD-Celiaca N = 114 IBD-only controls N = 228 Odds ratio [95% CI] p-Value Female 54 [47.4%] 108 [47.4%] 1.1 [0.7-1.8] 0.6 Ethnicity White 105 [97.2%] 219 [96.5%] Ref 0.8 Non-White 3 [2.8%] 8 [3.5%] 0.8 [0.2-3.2] Age, median [IQR] At IBD diagnosis 28.9 [18.8, 39.9] 24.4 [17.9-34.5] 1.0 [1.0-1.0] 0.05 At Celiac diagnosis 33.1 [24.1, 49.4] / / / IBD Type Crohn’s disease 35 [30.7%] 70 [30.7%] 1.0 [0.6-1.7] 10 Ulcerative colitis 79 [69.3%] 158 [69.3%] Ref Smoking Never 80 [70.2%] 157 [68.9%] Ref 0.4 Ever 34 [29.8%] 71 [31.1%] 0.8 [0.4-1.3] Family history IBD 25 [21.9%] 50 [22.0%] 1.0 [0.6-1.8] 0.9 Crohn’s disease 10 [8.9%] 19 [8.8%] 1.1 [0.5-2.6] 0.8 Ulcerative colitis 13 [11.6%] 21 [9.7%] 1.3 [0.6-2.7] 0.5 Celiac disease 12 [10.5%] 8 [3.5%] 3.2 [1.3-8.2] 0.01 Referral IBD case 89 [78.1%] 202 [88.6%] 0.5 [0.3-0.9] 0.02 Years of IBD prior to Time 0,b median [IQR] 3.4 [0.6, 12.0] 3.6 [0.5, 12.0] 1.0 [1.0-1.0] 0.3 Years of follow-up, median [IQR] 3.0 [0.7, 6.8] 6.3 [2.6, 12.2] 0.9 [0.8-0.9] <0.001 Order of diagnosis IBD before celiac 75 [65.8%] / / / IBD after celiac 32 [26.5%] Concurrent [within +/- 7 days] 9 [8.0%] Years to celiac diagnosis after IBD, median [IQR] 7.7 [1.4, 14.2] / / / Years to IBD after celiac diagnosis, median [IQR] 3.4 [0.4, 8.0] / / / Crohn’s disease location Ileal, N [%] 26 [76.5%] 46 [57.5%] 3.2 [1.0-10.3] 0.08 Ileocolonic, N [%] 4 [11.8%] 11 [13.8%] 2.0 [0.4-9.9] 0.9 Colonic, N [%] 4 [11.8%] 23 [28.8%] Ref / Upper GI Crohn’s disease 6 [17.1%] 12 [17.1%] 1.0 [0.3-2.9] 1.0 Perianal Crohn’s disease 6 [17.1%] 16 [22.9%] 0.7 [0.2-2.1] 0.5 Crohn’s disease phenotype Inflammatory 26 [76.5%] 40 [57.1%] 3.7 [1.1-11.9] 0.1 Stricturing 4 [11.8%] 7 [10.0%] 3.2 [0.6-16.6] 0.5 Fistulising 4 [11.8%] 23 [32.9%] Ref / Ulcerative colitis extent Limited colitis 16 [21.9%] 64 [41.0%] Ref / Extensive colitis 57 [78.1%] 92 [59.0%] 2.8 [1.5-5.5] 0.002 PSC at Time 0b Present 22 [19.3%] 13 [5.7%] 4.4 [2.1-9.4] <0.001 Absent 92 [80.7%] 215 [94.3%] Ref Extra-intestinal manifestations [any time, excluding PSC] Any 16 [14.0%] 35 [15.4%] 0.9 [0.5-1.8] 0.8 Sacroileitis 2 [1.8%] 2 [0.9%] 2.5 [0.3,18.0] 0.4 Ankylosing spondylitis 1 [0.9%] 4 [1.8%] 0.5 [0.06-4.8] 0.6 Pyoderma gangrenosum 1 [0.9%] 3 [1.3%] 0.6 [0.06-5.6] 0.6 Erythema nodosum 1 [0.9%] 6 [2.6%] 0.3 [0.04-3.0] Uveitis/episcleritis 2 [1.8%] 5 [2.2%] 0.8 [0.1-4.2] 0.8 Oral ulcers/aphthous stomatitis 8 [7.0%] 11 [4.8%] 1.5 [0.6-3.9] 0.4 Deep vein thrombosis 3 [2.6%] 8 [3.5%] 0.7 [0.2-2.8] 0.7 Medications ever used 5-ASA 70 [61.4%] 111 [48.7%] 1.8 [1.1-2.9] 0.02 Corticosteroids 41 [36.0%] 75 [32.9%] 1.2 [0.7-1.9] 0.5 Immunomodulator 15 [13.2%] 39 [17.1%] 0.7 [0.4-1.4] 0.4 Biologics 20 [17.5%] 37 [15.4%] 1.2 [0.7-2.2] 0.6 Celiac diagnosis method Serology and histology 70 [61.9%] / / / Histology alone 22 [19.5%] Serology alone 11 [9.7%] Clinical history 10 [8.8%] CI, confidence interval; IQR, interquartile range; GI, gastrointestinal; PSC, primary sclerosing cholangitis; 5-ASA, 5-aminosalicylic acid. aThree study cases had indeterminate colitis [and celiac disease]; fpor control cases had indeterminate colitis [without celiac disease]. These were not matched. b‘Time 0’ refers to the starting time point defined as the latest occurrence of IBD diagnosis, first presentation date at Mayo, or Celiac diagnosis, in the IBD-Celiac study group. In the IBD-only group, ‘time 0’ refers to the latest occurrence of IBD diagnosis or first presentation date at Mayo. View Large 2.1. Statistical analysis Continuous baseline characteristics were summarised with median and interquartile range [IQR], and categorical characteristics were presented as frequency and percentage. Logistic regression adjusted for age [at IBD diagnosis] and gender to assess for associations in baseline characteristics, and an odds ratio [OR] with a 95% confidence interval, were presented for each association. Analysis of outcomes was performed using the Kaplan-Meier method, and the relationship with celiac disease was assessed using Cox proportional hazard regression. ‘Time 0’ refers to the starting time point for being ‘at risk’ as defined by the latest occurrence of IBD diagnosis, celiac disease diagnosis, or first presentation date at the Mayo Clinic. Because clinical visits and diagnostic work-up can be spread across multiple days, a diagnosis of PSC or celiac disease within +/- 7 days on either side of the IBD diagnosis date were considered to be concurrent diagnoses and not treated as an outcome. Hazard ratios with a 95% confidence interval were used to summarise the proportional hazards models. Because event counts were small, all proportional hazard models were analysed without adjustment. An α = 0.05 was considered statistically significant. Analyses were performed with SAS [v9.4, SAS Institute, Cary, NC] and R [v3.2.3, Vienna, Austria]. 3. Results 3.1. Study population A total of 448 patients with a diagnosis of both IBD and celiac disease were identified. A detailed review of the electronic medical records verified 117 IBD-Celiac study patients [n = 79 UC, n = 35 CD, and n = 3 IBD unclassified] who were then matched with 1:2 control patients [n = 158 UC and n = 70 CD]. Three patients with IBD-unclassified,, and 331 patients initially identified by ICD 9/10 coding but with either IBD or celiac disease diagnosis disconfirmed on review of electronic records [clinical notes and/or laboratory studies], were excluded from further analysis. The estimated proportion of IBD patients with concomitant celiac disease at our institution is 0.6%. The baseline characteristics of the IBD-Celiac study group and IBD-only control group are summarised in Table 1 [and in Supplementary Table S1, available as Supplementary data at ECCO-JCC online], comparing the CD-Celiac and UC-Celiac cohorts and their respective controls. As seen in Table 1, baseline characteristics, including the median age at IBD diagnosis [28.9 vs. 24.4 years, p = 0.06] and duration of disease preceding time 0 [median 4.7 vs 4.9 years, p = 0.34], were similar between the two groups. In our study cohort, 89 [78%] of IBD-Celiac study patients and 202 [89%] of IBD-only control patients were diagnosed with IBD 8.4 years and 7.4 years [p = 0.6] before referral to our institution. IBD was diagnosed in the median year 2006 (interquartile range [IQR], 1994–2007) in the IBD-Celiac study group and 2000 [IQR, 1992–2014] in the IBD-only control group. Patients in the IBD-Celiac group had shorter follow-up time [median 3.0 vs 6.3 years, p < 0.001] and were less likely to be referred from other institutions [78.1% vs 88.6%, p = 0.02] compared with IBD-only control patients. Family history of celiac disease was more common among IBD-Celiac patients compared with IBD-only controls (10.5% vs 3.5%; odds ratio [OR], 3.2; 95% confidence interval [CI], 1.3–8.2; p = 0.01] [Table 1]). Within the IBD subtypes, family history of celiac disease was more common among CD-Celiac [20.0% vs 2.9%; OR, 8.9; 95% CI, 1.7–46.2; p = 0.01] but not in UC-Celiac patients [6.3% vs 3.8%; OR, 1.7; 95% CI, 0.5–5.8; p = 0.4] [Table S1]. Among IBD-Celiac patients, the majority were diagnosed with IBD first [65.8%] followed by diagnosis of celiac disease after a median of 7.7 years [IQR, 1.4–14.2]. Patients in the IBD-Celiac group who were diagnosed first with celiac disease [26.3%] received a diagnosis of IBD after a median of 3.4 years [IQR, 0.4–8.0]. A small percentage [7.9%] of patients was concurrently diagnosed with IBD and celiac disease. 3.2. Extensive colitis is more common in UC patients with concomitant celiac disease As seen in Table 1, the presence of extensive colitis [versus limited colitis] was more common in UC-Celiac patients compared with UC-only controls [78.1% vs 59.0 %; OR, 2.8; 95% CI, 1.5–5.5; p = 0.002]. In contrast, no differences in location or phenotypic behaviour were found between CD-Celiac and CD-only patients [Table 1]. Extra-intestinal manifestations, excluding PSC which was analysed separately, were less common among CD-Celiac patients compared with CD-only patients [8.6% vs 27.1%; OR, 0.3; 95% CI, 0.1–0.9; p = 0.04] but no differences were found among UC-Celiac and UC-only patients [Table S1]. 3.3. Higher PSC prevalence among IBD patients with co-existent celiac disease Before time 0, the prevalence of PSC among IBD-Celiac study patients was 19.3% [OR, 4.4; 95% CI, 2.1-9.4; p <0.001] compared with 5.7% of IBD-only control patients [Table 1]. From time 0 onward, the hazard ratio [HR] of the cumulative probability of PSC at 5 years in IBD-Celiac patients was 4.070 [95% CI, 1.3-12.4; p = 0.01] compared with IBD-only patients [Figure 1]. For CD-Celiac and UC-Celiac study patients after time 0, the hazard ratios for PSC were 9.751 [95% CI, 0.9-107.6; p = 0.06] and 3.308 [95% CI, 0.9-12.8; p = 0.08] compared with CD-only and UC-only controls, respectively. In a sensitivity analysis that excluded IBD-celiac study patients with clinically diagnosed celiac disease and their respective matched IBD-only cohorts, the risk for PSC was also higher among IBD-Celiac study patients compared with IBD-only controls [HR, 4.1; 95% CI, 1.1-15.6; p = 0.04]. All UC-Celiac patients with PSC had extensive colitis. Figure 1. View largeDownload slide Cumulative probability of primary sclerosing cholangitis [PSC] diagnosis in inflammatory bowel disease- [IBD]-celiac cases versus IBD-only controls. Figure 1. View largeDownload slide Cumulative probability of primary sclerosing cholangitis [PSC] diagnosis in inflammatory bowel disease- [IBD]-celiac cases versus IBD-only controls. Among patients with PSC [diagnosed at any time], the median alkaline phosphatase [ALP] at the time of PSC diagnosis was 173.0 [IQR, 133.0-640.0] and 415.0 [IQR, 137.0-990.0] for IBD-Celiac study patients [n = 13] and IBD-only control patients [n = 15], respectively. Magnetic resonance cholangiopancreatography [MRCP] was performed in 71.4% [10 of 14] of IBD-Celiac study patients and 58.8% [10 of 17] of IBD-only control patients within 4 weeks of PSC diagnosis. Large-duct PSC was observed in 89% [8 of 9] of IBD-Celiac patients and 80% [8 of 10] IBD-only patients. Endoscopic retrograde cholangiopancreatography [ERCP] was performed within 4 weeks of PSC diagnosis in 38.5% [5 of 13] and 47.1% [8 of 17] IBD-Celiac and IBD-only patients, respectively. During the ERCP, large-duct PSC was observed in 80% [4 of 5] and 87.5% [7 of 8] study and control patients, respectively. Biliary atresia was not identified in any index ERCP/MRCP studies. Small-duct PSC was identified in one [of 1] IBD-Celiac patient and three [of 6] IBD-only patients who underwent liver biopsy. In terms of outcomes, of the 53 patients diagnosed with PSC [28 IBD-Celiac; 25 IBD-only], 11 [20.7%] had liver transplantation [two cholangiocarcinoma, eight cirrhotic-stage PSC, and one recurrent cholangitis secondary to biliary strictures], 14 [26.4%] had bowel resections [12 for medically refractory IBD, one for neoplasia/dysplasia, and one for intestinal stricture/bowel obstruction]. 3.4. Outcomes of IBD with co-existent celiac disease: hospitalisations, rescue steroid, and surgery From time 0 to 5 years later, the rate of IBD-related hospitalisations was higher among IBD-Celiac and IBD-only patients [38.9% versus 20.9%; HR, 2.0; 95% CI, 1.1-3.9; p = 0.03] [Figure 2]. Within the IBD subtypes, CD-Celiac patients required more IBD-related hospitalisations [HR, 3.3; 95% CI, 1.1-9.6; p = 0.03] compared with CD-only controls, though no difference was observed among UC-Celiac and UC-only patients. Figure 2. View largeDownload slide Cumulative probability of hospitalisations in inflammatory bowel disease- [IBD]-Celiac cases versus IBD-only controls. Figure 2. View largeDownload slide Cumulative probability of hospitalisations in inflammatory bowel disease- [IBD]-Celiac cases versus IBD-only controls. The requirement for high-dose rescue corticosteroids for IBD flare was lower among IBD-Celiac patients compared with IBD-only patients [15.4% versus 40.5%; HR, 0.3; 95% CI, 0.1-0.9; p = 0.025] [Figure 3], a pattern that was observed among UC-Celiac patients [HR, 0.2; 95% CI, 0.05-0.8; p = 0.03] but not among CD-Celiac patients compared with UC/CD-only controls. Figure 3. View largeDownload slide Cumulative probability of rescue steroids used in inflammatory bowel disease- [IBD]-Celiac cases versus IBD-only controls. Figure 3. View largeDownload slide Cumulative probability of rescue steroids used in inflammatory bowel disease- [IBD]-Celiac cases versus IBD-only controls. No differences were found in rates of IBD-related surgery [46.9% and 50.0%; HR, 0.9; 95% CI, 0.5-1.6; p = 0.8] [Supplementary Figure 1, available as Supplementary data at ECCO-JCC online] among IBD-Celiac and IBD-only patients, respectively, or among the CD/UC subgroups. In a multivariate analysis with IBD diagnosis age, IBD duration, and UC extent, the presence of concomitant celiac disease with IBD continues to be associated with an increased risk for PSC [OR, 2.3; 95% CI, 1.02-5.3; p = 0.04] and decreased need for rescue steroids [OR, 0.3; 95% CI, 0.1-0.5; p = 0.0002], though no statistical significant differences were seen with IBD-related surgeries [p = 0.07] or IBD-related hospitalisations [p = 0.4]. In a sensitivity analysis that excluded IBD-celiac study patients with clinically diagnosed celiac disease and their respective matched IBD-only cohorts, no statistically significant differences were observed between IBD-Celiac and IBD-only patients with regards to rescue steroid use [HR, 0.4; 95% CI, 0.1-1.2; p = 0.1], IBD-related surgeries [HR, 0.9; 95% CI, 0.5-1.8; p = 0.8], and IBD-related hospitalisations [HR, 1.7; 95% CI, 0.747-4.0; p = 0.2]. We observed no differences in the use of immunomodulators or biologics between the UC-Celiac and UC-only cohorts over a 5-year follow-up period following the initial presentation at our institution. However, we observed an increased usage of systemic steroids [19.2% vs 4.7%; OR, 4.3; 95% CI, 1.0-18.0; p = 0.05] at year 5 in the UC-Celiac group compared with the UC-only controls [Supplementary Figure 2, available as Supplementary data at ECCO-JCC online]. However, this effect was no longer significant [p = 0.0752] in multivariate analysis to include UC extent and IBD duration. 4. Discussion Our study represents the largest case-control study to analyse the clinical course and phenotype of patients with IBD and concomitant celiac disease. Important findings of our study include the association of co-existent IBD-celiac with PSC, family history of celiac disease, and IBD-related hospitalisations. Patients with concurrent IBD and celiac disease were more likely to have IBD diagnosed first, and there was a delay of several years in the diagnosis of the other concomitant disease. Primary sclerosing cholangitis [PSC] is a chronic, autoimmune, cholestatic liver disease that is strongly associated with IBD. Up to 90% of patients with PSC have UC,8,15 and 5-7.5% of UC patients develop PSC during the course of their disease.8,16 The association between PSC and celiac disease is less clear. A large population-based study from Sweden found a 4- to 8-fold increase in the prevalence of PSC among individuals with celiac disease compared with non-celiac individuals in the general population,17,18 suggesting that there may be an association between these two immune-mediated gastrointestinal and hepatobiliary diseases. A limited number of studies to date have examined the clinical association between IBD, celiac disease, and PSC, which are all believed to be immune-mediated disorders involving the gastrointestinal tract and the hepatobiliary system. A large Swedish epidemiological study found that first-degree relatives of PSC patients without IBD have a 7-fold risk for developing UC.19 Our study found that patients with IBD and concurrent celiac disease were more likely to have PSC, a finding that was also noted in a few small case series.20,21 The association of PSC and UC with concomitant celiac disease, particularly those with pancolitis, could be related to common immunopathogenesis where gut-derived memory T-cells are recruited to the liver to induce biliary inflammation in PSC.22,23 Celiac disease and ulcerative colitis may share common polymorphisms in the receptor gene for IL-23, a major cytokine involved in Th17 cell differentiation.24 Shared genetic risk loci for PSC and UC are under study.24–26 Consequently, patients with UC and co-existent celiac disease may benefit from evaluation of co-existent PSC with laboratory screening tests and confirmatory evaluation with MRCP, ERCP, and/or liver biopsy. IBD, celiac disease, and PSC may also share common environmental risk factors, such as vitamin D deficiency. Vitamin D metabolism is closely related to liver function as this is the site for enzymatic conversion of the inactive vitamin D3 to 25-hydroxy vitamin D3, a precursor to the active 1, 25-hydroxyvitamin D3. Vitamin D deficiency is common in patients with IBD,27,28 with a prevalence of up to 70%29 and 45%30 in CD and UC, respectively. Several studies have shown that 22–57% of PSC patients also had vitamin D deficiency,31,32 and that PSC was an independent factor for vitamin D deficiency in UC patients with ileal pouch-anal anastomosis [IPAA].33 The immunoregulatory properties of Vitamin D may be mediated by signalling through its receptor expressed in the gut.34 Recent genome-wide association analysis has identified variation in vitamin D receptor, among several host factors influencing the gut microbiota.35 In turn, the gut microbiota are essential for the metabolism of bile acids,36 which acts as key vitamin D receptor ligands and regulate its expression.37,38 Further studies are needed to explore how vitamin D and other micronutrients may influence the clinical course of immune-mediated gastrointestinal diseases. Our study findings may be limited by referral bias, and we attempted to minimise this by using a case-control design of patients who were identified from a common referral pool. The retrospective study design of our study also limits the availability, accessibility, and accuracy of data from existing electronic medical records. In future studies, age at IBD diagnosis could be considered as a matching factor, though this was not feasible in our study. Surveillance bias might contribute to residual confounding for family history of IBD or celiac disease [e.g., providers may be more likely to ask about family history in setting of celiac disease]. There is a possibility that some patients in our control group may have ‘silent’ or asymptomatic celiac disease. Nonetheless, previous studies have shown the expected prevalence of co-existent celiac disease among IBD patients to be 0.5–0.9%3,4 and hence unlikely to have influenced our results. Moreover, 8.8% of the IBD-Celiac study patients had an established celiac disease diagnosis before presentation at the Mayo Clinic, without further details on the previous diagnostic testing available in our database. This may lead to over-diagnosis of celiac disease and introduce bias to the results. Nonetheless, we were able to confirm celiac diagnosis by histology in the majority [81.4%] of study patients, which is considered by the American College of Gastroenterology to have a high level of evidence for the diagnosis of celiac disease.12 Of note, our study has explored the order of diagnosis in patients with IBD and celiac disease, as well as the time-to-diagnosis of the concomitant disease. This is important, as a delay in making a diagnosis or a delay in the initiation of proper treatment in patients with co-existent IBD-Celiac disease may increase morbidity and even mortality.39 It is, therefore, important to evaluate for co-existing celiac disease [e.g., by serology or histopathology] in IBD patients, particularly those with seemingly ‘refractory’ IBD who have ongoing clinical symptoms. Funding This work was supported by the AGA Student Abstract Prize 2017 to CST. Conflict of Interest PD has received a research grant from Takeda, participated in advisory boards for Pfizer and Janssen, and served as speaker for Abbvie Speaker’s bureau. Author Contributions CST was involved in the study design, data acquisition, interpretation of data, drafting of manuscript, and obtaining funding. PD was involved in study concept and design and interpretation of data. JDF and ACB were involved in the acquisition of data. JJL was involved in the analysis of data. JAM was involved in the study concept and study design. KAP was involved in the study concept, study design, and obtaining funding. All authors were involved in critical revision of the manuscript for important intellectual content and approved the final submitted version. An earlier version of this manuscript was a poster at Digestive Diseases Week 2017 in Chicago, IL Supplementary Data Supplementary data are available at ECCO-JCC online. References 1. Silverberg MS , Satsangi J , Ahmad T , et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a working party of the 2005 Montreal World Congress of Gastroenterology . Can J Gastroenterol 2005 ; 19 [ Suppl A ]: 5A – 36A . Google Scholar CrossRef Search ADS PubMed 2. Oxford EC , Nguyen DD , Sauk J , et al. Impact of co-existent celiac disease on phenotype and natural history of inflammatory bowel diseases . Am J Gastroenterol 2013 ; 108 : 1123 – 9 . Google Scholar CrossRef Search ADS PubMed 3. Casella G , D’Inca R , Oliva L , et al. Prevalence of celiac disease in inflammatory bowel diseases: An IG-IBD multicentre study . Dig Liver Dis 2010 ; 42 : 175 – 8 . Google Scholar CrossRef Search ADS PubMed 4. Leeds JS , Horoldt BS , Sidhu R , et al. Is there an association between coeliac disease and inflammatory bowel diseases? A study of relative prevalence in comparison with population controls . Scand J Gastroenterol 2007 ; 42 : 1214 – 20 . Google Scholar CrossRef Search ADS PubMed 5. Fasano A , Berti I , Gerarduzzi T , et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study . Arch Intern Med 2003 ; 163 : 286 – 92 . Google Scholar CrossRef Search ADS PubMed 6. Kocsis D , Toth Z , Csontos AA , et al. Prevalence of inflammatory bowel disease among coeliac disease patients in a Hungarian coeliac centre . BMC Gastroenterol 2015 ; 15 : 141 . Google Scholar CrossRef Search ADS PubMed 7. Yang A , Chen Y , Scherl E , et al. Inflammatory bowel disease in patients with celiac disease . Inflamm Bowel Dis 2005 ; 11 : 528 – 32 . Google Scholar CrossRef Search ADS PubMed 8. Lee YM , Kaplan MM . Primary sclerosing cholangitis . N Engl J Med 1995 ; 332 : 924 – 33 . Google Scholar CrossRef Search ADS PubMed 9. Molodecky NA , Soon IS , Rabi DM , et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review . Gastroenterology 2012 ; 142 : 46 – 54 .e42; quiz e30. Google Scholar CrossRef Search ADS PubMed 10. Bhavik M . Bhandari RSB . Inflammatory Bowel Disease . 2017 . Accessed July 7 , 2017. https://www.ncbi.nlm.nih.gov/pubmed/17970872 11. Schafer AI , Goldman L. Goldman-Cecil Medicine . Elsevier Health Sciences , 2016 . 12. Rubio-Tapia A , Hill ID , Kelly CP , et al. ACG clinical guidelines: Diagnosis and management of celiac disease . Am J Gastroenterol 2013 ; 108 : 656 – 76 ; quiz 77. Google Scholar CrossRef Search ADS PubMed 13. Satsangi J , Silverberg MS , Vermeire S , Colombel JF . The Montreal Classification of inflammatory bowel disease: controversies, consensus, and implications . Gut 2006 ; 55 : 749 – 53 . Google Scholar CrossRef Search ADS PubMed 14. Monstad I , Hovde O , Solberg IC , A Moum B . Clinical course and prognosis in ulcerative colitis: results from population-based and observational studies . Ann Gastroenterol 2014 ; 27 : 95 – 104 . Google Scholar PubMed 15. Bambha K , Kim WR , Talwalkar J , et al. Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community . Gastroenterology 2003 ; 125 : 1364 – 9 . Google Scholar CrossRef Search ADS PubMed 16. Olsson R , Danielsson A , Jarnerot G , et al. Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis . Gastroenterology 1991 ; 100 : 1319 – 23 . Google Scholar CrossRef Search ADS PubMed 17. Rubio-Tapia A , Murray JA . The liver in celiac disease . Hepatology 2007 ; 46 : 1650 – 8 . Google Scholar CrossRef Search ADS PubMed 18. Ludvigsson JF , Elfstrom P , Broome U , Ekbom A , Montgomery SM . Celiac disease and risk of liver disease: a general population-based study . Clin Gastroenterol Hepatol 2007 ; 5 : 63 – 9 .e1. Google Scholar CrossRef Search ADS PubMed 19. Bergquist A , Montgomery SM , Bahmanyar S , et al. Increased risk of primary sclerosing cholangitis and ulcerative colitis in first-degree relatives of patients with primary sclerosing cholangitis . Clin Gastroenterol Hepatol 2008 ; 6 : 939 – 43 . Google Scholar CrossRef Search ADS PubMed 20. Hay JE , Wiesner RH , Shorter RG , LaRusso NF , Baldus WP . Primary sclerosing cholangitis and celiac disease. A novel association . Ann Intern Med 1988 ; 109 : 713 – 7 . Google Scholar CrossRef Search ADS PubMed 21. Habior A , Rawa T , Orlowska J , et al. Association of primary sclerosing cholangitis, ulcerative colitis and coeliac disease in female siblings . Eur J Gastroenterol Hepatol 2002 ; 14 : 787 – 91 . Google Scholar CrossRef Search ADS PubMed 22. Schrumpf E , Tan C , Karlsen TH , et al. The biliary epithelium presents antigens to and activates natural killer T cells . Hepatology 2015 ; 62 : 1249 – 59 . Google Scholar CrossRef Search ADS PubMed 23. Henriksen EK , Jorgensen KK , Kaveh F , et al. Gut and liver T-cells of common clonal origin in primary sclerosing cholangitis-inflammatory bowel disease . J Hepatol 2017 ; 66 : 116 – 22 . Google Scholar CrossRef Search ADS PubMed 24. Glas J , Stallhofer J , Ripke S , et al. Novel genetic risk markers for ulcerative colitis in the il2/il21 region are in epistasis with il23r and suggest a common genetic background for ulcerative colitis and celiac disease . Am J Gastroenterol 2009 ; 104 : 1737 – 44 . Google Scholar CrossRef Search ADS PubMed 25. Wapenaar MC , Monsuur AJ , van Bodegraven AA , et al. Associations with tight junction genes pard3 and magi2 in Dutch patients point to a common barrier defect for coeliac disease and ulcerative colitis . Gut 2008 ; 57 : 463 – 7 . Google Scholar CrossRef Search ADS PubMed 26. Einarsdottir E , Koskinen LL , Dukes E , et al. Il23r in the Swedish, Finnish, Hungarian and Italian populations: association with IBD and psoriasis, and linkage to celiac disease . BMC Med Genet 2009 ; 10 : 8 . Google Scholar CrossRef Search ADS PubMed 27. Ananthakrishnan AN , Khalili H , Higuchi LM , et al. Higher predicted vitamin D status is associated with reduced risk of Crohn’s disease . Gastroenterology 2012 ; 142 : 482 – 9 . Google Scholar CrossRef Search ADS PubMed 28. Pappa HM , Grand RJ , Gordon CM . Report on the vitamin D status of adult and pediatric patients with inflammatory bowel disease and its significance for bone health and disease . Inflamm Bowel Dis 2006 ; 12 : 1162 – 74 . Google Scholar CrossRef Search ADS PubMed 29. Siffledeen JS , Siminoski K , Steinhart H , Greenberg G , Fedorak RN . The frequency of vitamin D deficiency in adults with Crohn’s disease . Can J Gastroenterol 2003 ; 17 : 473 – 8 . Google Scholar CrossRef Search ADS PubMed 30. Silvennoinen J . Relationships between vitamin D, parathyroid hormone and bone mineral density in inflammatory bowel disease . J Intern Med 1996 ; 239 : 131 – 7 . Google Scholar CrossRef Search ADS PubMed 31. Jorgensen RA , Lindor KD , Sartin JS , LaRusso NF , Wiesner RH . Serum lipid and fat-soluble vitamin levels in primary sclerosing cholangitis . J Clin Gastroenterol 1995 ; 20 : 215 – 9 . Google Scholar CrossRef Search ADS PubMed 32. Khanna R , Wu X , Shen B . Low levels of vitamin D are common in patients with ileal pouches irrespective of pouch inflammation . J Crohns Colitis 2013 ; 7 : 525 – 33 . Google Scholar CrossRef Search ADS PubMed 33. Fialho A , Fialho A , Kochhar G , Shen B . The presence of primary sclerosing cholangitis in patients with ileal pouch-anal anastomosis is associated with an additional risk for vitamin D deficiency . Gastroenterol Rep [Oxf] 2016 ; 4 : 320 – 4 . Google Scholar CrossRef Search ADS PubMed 34. Lu R , Wu S , Xia Y , Sun J . The vitamin D receptor, inflammatory bowel diseases, and colon cancer . Curr Colorectal Cancer Rep 2012 ; 8 : 57 – 65 . Google Scholar CrossRef Search ADS PubMed 35. Wang J , Thingholm LB , Skieceviciene J , et al. Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota . Nat Genet 2016 ; 48 : 1396 – 406 . Google Scholar CrossRef Search ADS PubMed 36. Haussler MR , Haussler CA , Bartik L , et al. Vitamin D receptor: molecular signaling and actions of nutritional ligands in disease prevention . Nutr Rev 2008 ; 66 : S98 – 112 . Google Scholar CrossRef Search ADS PubMed 37. D’Aldebert E , Biyeyeme Bi Mve MJ , Mergey M , et al. Bile salts control the antimicrobial peptide cathelicidin through nuclear receptors in the human biliary epithelium . Gastroenterology 2009 ; 136 : 1435 – 43 . Google Scholar CrossRef Search ADS PubMed 38. Makishima M , Lu TT , Xie W , et al. Vitamin D receptor as an intestinal bile acid sensor . Science 2002 ; 296 : 1313 – 6 . Google Scholar CrossRef Search ADS PubMed 39. Rubio-Tapia A , Kyle RA , Kaplan EL , et al. Increased prevalence and mortality in undiagnosed celiac disease . Gastroenterology 2009 ; 137 : 88 – 93 . Google Scholar CrossRef Search ADS PubMed Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Crohn's and Colitis Oxford University Press

Phenotype and Clinical Course of Inflammatory Bowel Disease With Co-existent Celiac Disease

Loading next page...
 
/lp/ou_press/phenotype-and-clinical-course-of-inflammatory-bowel-disease-with-co-J9rTP8CvV2
Publisher
Elsevier Science
Copyright
Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
ISSN
1873-9946
eISSN
1876-4479
D.O.I.
10.1093/ecco-jcc/jjy061
Publisher site
See Article on Publisher Site

Abstract

Abstract Background and Aims Inflammatory bowel diseases, principally Crohn’s disease and ulcerative colitis, and celiac disease are among the most common immune-mediated gastrointestinal diseases. We aim to elucidate the clinical course and outcomes of patients with concomitant inflammatory bowel disease and celiac disease, a unique population that remains scarcely studied to date. Methods A retrospective matched case-control study of adults with co-existent inflammatory bowel disease [IBD] and celiac disease was performed at a tertiary referral institution in North America. Logistic regression and Kaplan-Meier curves compared disease characteristics and clinical outcomes of the two groups. Results A total of 342 inflammatory bowel disease patients were included in this study, of whom 114 had co-existent celiac disease and 228 did not. Patients with co-existent inflammatory bowel disease and celiac disease had higher rates of primary sclerosing cholangitis [19.3% vs 5.7%; odds ratio, 4.4; 95% confidence interval, 2.1–9.4; p <0.001], extensive ulcerative colitis [78.1% vs 59.0%; odds ratio, 2.8; 95% confidence interval, 1.5–5.5; p =0.002], and family history of celiac disease [10.5% vs 3.5%; odds ratio 3.2; 95% confidence interval, 1.3–8.2; p =0.01], compared with patients without concomitant celiac disease. Conclusions Patients with inflammatory bowel disease with concomitant celiac disease have unique phenotypic features compared with non-celiac inflammatory bowel disease, with higher risks for colitis-related hospitalisations, extensive colitis, and primary sclerosing cholangitis. Increased recognition of co-existent IBD and celiac disease can prompt clinicians to investigate for concomitant disease sooner, particularly in patients with seemingly refractory disease. Inflammatory bowel disease, celiac disease, primary sclerosing cholangitis, clinical course, concurrent immune-mediated gastrointestinal diseases 1. Introduction Inflammatory bowel diseases [IBD], principally Crohn’s disease [CD] and ulcerative colitis [UC], and celiac disease are immune-mediated gastrointestinal diseases with complex interactions between genetic and environmental factors.1 IBD and celiac disease have overlapping clinical features, including abdominal pain, diarrhoea, and malabsorption.2 The prevalence of celiac disease in IBD is estimated to be 0.5–0.9%,3,4 similar to the prevalence of 0.8–1% in the general population.4,5 Conversely, approximately 1–3.2% of celiac disease patients have IBD,4,6,7 a rate that is 3–10 times higher than the estimated IBD prevalence of 0.3% in the general population.8,9 IBD with concomitant celiac disease has not been extensively studied. To date, only one published retrospective case-control study has examined the phenotypic differences and outcomes of patients with IBD and concomitant celiac disease [IBD-Celiac] compared with non-celiac IBD individuals [IBD-only]. In that study,2 pancolitis was more common in UC-Celiac patients compared with UC-only controls, though no differences were reported in CD behaviour or IBD-related medications, hospitalisations, and surgeries between the IBD-Celiac and IBD-only patient groups. Whereas there is a complex interplay between genetic predisposition and environmental influence in the pathogenesis of IBD and celiac disease, the phenotypic overlap of these immune-mediated diseases has been under-explored. We herein aim to comprehensively analyse the interrelation between IBD and celiac disease with a matched case-control retrospective cohort study at a large tertiary referral centre in North America. In this study, we sought to determine the clinical course of IBD with concomitant celiac disease compared with patients with IBD alone; namely, the differences in disease phenotype, clinically relevant IBD outcomes, and extra-intestinal manifestations including primary sclerosing cholangitis [PSC]. 2. Materials and Methods With Institutional Review Board approval from the Mayo Foundation [protocol #16-007857], we conducted a retrospective case-control study conducted on patients from the Mayo Clinic’s tri-campus [Minnesota, Florida, and Arizona]. Each UC/CD-Celiac study patient was matched by gender and IBD-subtype to two randomly selected IBD-only controls out of the pool of all IBD patients seen at the Mayo Clinic. Patients with a diagnosis of IBD-unclassified were excluded from further analysis. Potential cases and controls were identified through a query of an internal centralised data repository from 1997–2016, based on International Classification of Diseases [ICD] 9th and 10th edition diagnosis codes. Matched controls were identified based on the first appearance of ICD-9/10 diagnosis codes for IBD in our institution’s electronic medical records; controls were matched +/- 3 years of the study patients’ IBD diagnosis date, based on the control pools’ second date appearance of two ICD-9/10 codes identified at least 30 days apart [to limit the false-positives]. Review of the electronic medical records was performed to confirm the diagnosis of IBD based on the standard clinical, radiographic and histological criteria.10,11 For celiac disease, the diagnosis was made based on abnormal serum tests for IgA antibodies against tissue transglutaminase, gliadin, or endomysial antigens, and/or histological evidence of villous atrophy on duodenal biopsy.12 Patients were excluded if they had microscopic colitis, negative HLA-DQ2 or HLA-DQ8 locus genetic analysis, or were <18 years old. Baseline demographics, disease characteristics, and outcome variables were collected from the electronic medical records. The Montreal classification13 was used to classify CD and UC phenotype. UC disease extent was further reclassified to limited UC [ulcerative proctitis and left sided UC] versus extensive UC [extensive UC and pancolitis] for statistical analysis. In this study, the UC extent was classified by the most extensive involvement known in the patient’s history to reflect the UC phenotype, as the clinical course of UC can range from quiescent to fulminant disease with relapses interspersed with periods of remission.14 Thus, in order to most accurately represent the phenotype of UC in the UC-Celiac and UC-only groups, we listed the most extensive UC involvement that was known in Table 1 [and in Supplementary Table 1, available as Supplementary data at ECCO-JCC online]. Disease characteristics analysed included IBD/celiac disease duration, follow-up time, and extra-intestinal manifestations of IBD. Because PSC was a primary outcome of interest that could be diagnosed independently of IBD, it was analysed separately from other extra-intestinal manifestations in this study, in order to more accurately describe its associations both before and after IBD and IBD-Celiac diagnoses. Table 1. Comparison of the characteristics of the inflammatory bowel disease- [IBD]-Celiac cases and non-celiac IBD controls. Characteristic IBD-Celiaca N = 114 IBD-only controls N = 228 Odds ratio [95% CI] p-Value Female 54 [47.4%] 108 [47.4%] 1.1 [0.7-1.8] 0.6 Ethnicity White 105 [97.2%] 219 [96.5%] Ref 0.8 Non-White 3 [2.8%] 8 [3.5%] 0.8 [0.2-3.2] Age, median [IQR] At IBD diagnosis 28.9 [18.8, 39.9] 24.4 [17.9-34.5] 1.0 [1.0-1.0] 0.05 At Celiac diagnosis 33.1 [24.1, 49.4] / / / IBD Type Crohn’s disease 35 [30.7%] 70 [30.7%] 1.0 [0.6-1.7] 10 Ulcerative colitis 79 [69.3%] 158 [69.3%] Ref Smoking Never 80 [70.2%] 157 [68.9%] Ref 0.4 Ever 34 [29.8%] 71 [31.1%] 0.8 [0.4-1.3] Family history IBD 25 [21.9%] 50 [22.0%] 1.0 [0.6-1.8] 0.9 Crohn’s disease 10 [8.9%] 19 [8.8%] 1.1 [0.5-2.6] 0.8 Ulcerative colitis 13 [11.6%] 21 [9.7%] 1.3 [0.6-2.7] 0.5 Celiac disease 12 [10.5%] 8 [3.5%] 3.2 [1.3-8.2] 0.01 Referral IBD case 89 [78.1%] 202 [88.6%] 0.5 [0.3-0.9] 0.02 Years of IBD prior to Time 0,b median [IQR] 3.4 [0.6, 12.0] 3.6 [0.5, 12.0] 1.0 [1.0-1.0] 0.3 Years of follow-up, median [IQR] 3.0 [0.7, 6.8] 6.3 [2.6, 12.2] 0.9 [0.8-0.9] <0.001 Order of diagnosis IBD before celiac 75 [65.8%] / / / IBD after celiac 32 [26.5%] Concurrent [within +/- 7 days] 9 [8.0%] Years to celiac diagnosis after IBD, median [IQR] 7.7 [1.4, 14.2] / / / Years to IBD after celiac diagnosis, median [IQR] 3.4 [0.4, 8.0] / / / Crohn’s disease location Ileal, N [%] 26 [76.5%] 46 [57.5%] 3.2 [1.0-10.3] 0.08 Ileocolonic, N [%] 4 [11.8%] 11 [13.8%] 2.0 [0.4-9.9] 0.9 Colonic, N [%] 4 [11.8%] 23 [28.8%] Ref / Upper GI Crohn’s disease 6 [17.1%] 12 [17.1%] 1.0 [0.3-2.9] 1.0 Perianal Crohn’s disease 6 [17.1%] 16 [22.9%] 0.7 [0.2-2.1] 0.5 Crohn’s disease phenotype Inflammatory 26 [76.5%] 40 [57.1%] 3.7 [1.1-11.9] 0.1 Stricturing 4 [11.8%] 7 [10.0%] 3.2 [0.6-16.6] 0.5 Fistulising 4 [11.8%] 23 [32.9%] Ref / Ulcerative colitis extent Limited colitis 16 [21.9%] 64 [41.0%] Ref / Extensive colitis 57 [78.1%] 92 [59.0%] 2.8 [1.5-5.5] 0.002 PSC at Time 0b Present 22 [19.3%] 13 [5.7%] 4.4 [2.1-9.4] <0.001 Absent 92 [80.7%] 215 [94.3%] Ref Extra-intestinal manifestations [any time, excluding PSC] Any 16 [14.0%] 35 [15.4%] 0.9 [0.5-1.8] 0.8 Sacroileitis 2 [1.8%] 2 [0.9%] 2.5 [0.3,18.0] 0.4 Ankylosing spondylitis 1 [0.9%] 4 [1.8%] 0.5 [0.06-4.8] 0.6 Pyoderma gangrenosum 1 [0.9%] 3 [1.3%] 0.6 [0.06-5.6] 0.6 Erythema nodosum 1 [0.9%] 6 [2.6%] 0.3 [0.04-3.0] Uveitis/episcleritis 2 [1.8%] 5 [2.2%] 0.8 [0.1-4.2] 0.8 Oral ulcers/aphthous stomatitis 8 [7.0%] 11 [4.8%] 1.5 [0.6-3.9] 0.4 Deep vein thrombosis 3 [2.6%] 8 [3.5%] 0.7 [0.2-2.8] 0.7 Medications ever used 5-ASA 70 [61.4%] 111 [48.7%] 1.8 [1.1-2.9] 0.02 Corticosteroids 41 [36.0%] 75 [32.9%] 1.2 [0.7-1.9] 0.5 Immunomodulator 15 [13.2%] 39 [17.1%] 0.7 [0.4-1.4] 0.4 Biologics 20 [17.5%] 37 [15.4%] 1.2 [0.7-2.2] 0.6 Celiac diagnosis method Serology and histology 70 [61.9%] / / / Histology alone 22 [19.5%] Serology alone 11 [9.7%] Clinical history 10 [8.8%] Characteristic IBD-Celiaca N = 114 IBD-only controls N = 228 Odds ratio [95% CI] p-Value Female 54 [47.4%] 108 [47.4%] 1.1 [0.7-1.8] 0.6 Ethnicity White 105 [97.2%] 219 [96.5%] Ref 0.8 Non-White 3 [2.8%] 8 [3.5%] 0.8 [0.2-3.2] Age, median [IQR] At IBD diagnosis 28.9 [18.8, 39.9] 24.4 [17.9-34.5] 1.0 [1.0-1.0] 0.05 At Celiac diagnosis 33.1 [24.1, 49.4] / / / IBD Type Crohn’s disease 35 [30.7%] 70 [30.7%] 1.0 [0.6-1.7] 10 Ulcerative colitis 79 [69.3%] 158 [69.3%] Ref Smoking Never 80 [70.2%] 157 [68.9%] Ref 0.4 Ever 34 [29.8%] 71 [31.1%] 0.8 [0.4-1.3] Family history IBD 25 [21.9%] 50 [22.0%] 1.0 [0.6-1.8] 0.9 Crohn’s disease 10 [8.9%] 19 [8.8%] 1.1 [0.5-2.6] 0.8 Ulcerative colitis 13 [11.6%] 21 [9.7%] 1.3 [0.6-2.7] 0.5 Celiac disease 12 [10.5%] 8 [3.5%] 3.2 [1.3-8.2] 0.01 Referral IBD case 89 [78.1%] 202 [88.6%] 0.5 [0.3-0.9] 0.02 Years of IBD prior to Time 0,b median [IQR] 3.4 [0.6, 12.0] 3.6 [0.5, 12.0] 1.0 [1.0-1.0] 0.3 Years of follow-up, median [IQR] 3.0 [0.7, 6.8] 6.3 [2.6, 12.2] 0.9 [0.8-0.9] <0.001 Order of diagnosis IBD before celiac 75 [65.8%] / / / IBD after celiac 32 [26.5%] Concurrent [within +/- 7 days] 9 [8.0%] Years to celiac diagnosis after IBD, median [IQR] 7.7 [1.4, 14.2] / / / Years to IBD after celiac diagnosis, median [IQR] 3.4 [0.4, 8.0] / / / Crohn’s disease location Ileal, N [%] 26 [76.5%] 46 [57.5%] 3.2 [1.0-10.3] 0.08 Ileocolonic, N [%] 4 [11.8%] 11 [13.8%] 2.0 [0.4-9.9] 0.9 Colonic, N [%] 4 [11.8%] 23 [28.8%] Ref / Upper GI Crohn’s disease 6 [17.1%] 12 [17.1%] 1.0 [0.3-2.9] 1.0 Perianal Crohn’s disease 6 [17.1%] 16 [22.9%] 0.7 [0.2-2.1] 0.5 Crohn’s disease phenotype Inflammatory 26 [76.5%] 40 [57.1%] 3.7 [1.1-11.9] 0.1 Stricturing 4 [11.8%] 7 [10.0%] 3.2 [0.6-16.6] 0.5 Fistulising 4 [11.8%] 23 [32.9%] Ref / Ulcerative colitis extent Limited colitis 16 [21.9%] 64 [41.0%] Ref / Extensive colitis 57 [78.1%] 92 [59.0%] 2.8 [1.5-5.5] 0.002 PSC at Time 0b Present 22 [19.3%] 13 [5.7%] 4.4 [2.1-9.4] <0.001 Absent 92 [80.7%] 215 [94.3%] Ref Extra-intestinal manifestations [any time, excluding PSC] Any 16 [14.0%] 35 [15.4%] 0.9 [0.5-1.8] 0.8 Sacroileitis 2 [1.8%] 2 [0.9%] 2.5 [0.3,18.0] 0.4 Ankylosing spondylitis 1 [0.9%] 4 [1.8%] 0.5 [0.06-4.8] 0.6 Pyoderma gangrenosum 1 [0.9%] 3 [1.3%] 0.6 [0.06-5.6] 0.6 Erythema nodosum 1 [0.9%] 6 [2.6%] 0.3 [0.04-3.0] Uveitis/episcleritis 2 [1.8%] 5 [2.2%] 0.8 [0.1-4.2] 0.8 Oral ulcers/aphthous stomatitis 8 [7.0%] 11 [4.8%] 1.5 [0.6-3.9] 0.4 Deep vein thrombosis 3 [2.6%] 8 [3.5%] 0.7 [0.2-2.8] 0.7 Medications ever used 5-ASA 70 [61.4%] 111 [48.7%] 1.8 [1.1-2.9] 0.02 Corticosteroids 41 [36.0%] 75 [32.9%] 1.2 [0.7-1.9] 0.5 Immunomodulator 15 [13.2%] 39 [17.1%] 0.7 [0.4-1.4] 0.4 Biologics 20 [17.5%] 37 [15.4%] 1.2 [0.7-2.2] 0.6 Celiac diagnosis method Serology and histology 70 [61.9%] / / / Histology alone 22 [19.5%] Serology alone 11 [9.7%] Clinical history 10 [8.8%] CI, confidence interval; IQR, interquartile range; GI, gastrointestinal; PSC, primary sclerosing cholangitis; 5-ASA, 5-aminosalicylic acid. aThree study cases had indeterminate colitis [and celiac disease]; fpor control cases had indeterminate colitis [without celiac disease]. These were not matched. b‘Time 0’ refers to the starting time point defined as the latest occurrence of IBD diagnosis, first presentation date at Mayo, or Celiac diagnosis, in the IBD-Celiac study group. In the IBD-only group, ‘time 0’ refers to the latest occurrence of IBD diagnosis or first presentation date at Mayo. View Large Table 1. Comparison of the characteristics of the inflammatory bowel disease- [IBD]-Celiac cases and non-celiac IBD controls. Characteristic IBD-Celiaca N = 114 IBD-only controls N = 228 Odds ratio [95% CI] p-Value Female 54 [47.4%] 108 [47.4%] 1.1 [0.7-1.8] 0.6 Ethnicity White 105 [97.2%] 219 [96.5%] Ref 0.8 Non-White 3 [2.8%] 8 [3.5%] 0.8 [0.2-3.2] Age, median [IQR] At IBD diagnosis 28.9 [18.8, 39.9] 24.4 [17.9-34.5] 1.0 [1.0-1.0] 0.05 At Celiac diagnosis 33.1 [24.1, 49.4] / / / IBD Type Crohn’s disease 35 [30.7%] 70 [30.7%] 1.0 [0.6-1.7] 10 Ulcerative colitis 79 [69.3%] 158 [69.3%] Ref Smoking Never 80 [70.2%] 157 [68.9%] Ref 0.4 Ever 34 [29.8%] 71 [31.1%] 0.8 [0.4-1.3] Family history IBD 25 [21.9%] 50 [22.0%] 1.0 [0.6-1.8] 0.9 Crohn’s disease 10 [8.9%] 19 [8.8%] 1.1 [0.5-2.6] 0.8 Ulcerative colitis 13 [11.6%] 21 [9.7%] 1.3 [0.6-2.7] 0.5 Celiac disease 12 [10.5%] 8 [3.5%] 3.2 [1.3-8.2] 0.01 Referral IBD case 89 [78.1%] 202 [88.6%] 0.5 [0.3-0.9] 0.02 Years of IBD prior to Time 0,b median [IQR] 3.4 [0.6, 12.0] 3.6 [0.5, 12.0] 1.0 [1.0-1.0] 0.3 Years of follow-up, median [IQR] 3.0 [0.7, 6.8] 6.3 [2.6, 12.2] 0.9 [0.8-0.9] <0.001 Order of diagnosis IBD before celiac 75 [65.8%] / / / IBD after celiac 32 [26.5%] Concurrent [within +/- 7 days] 9 [8.0%] Years to celiac diagnosis after IBD, median [IQR] 7.7 [1.4, 14.2] / / / Years to IBD after celiac diagnosis, median [IQR] 3.4 [0.4, 8.0] / / / Crohn’s disease location Ileal, N [%] 26 [76.5%] 46 [57.5%] 3.2 [1.0-10.3] 0.08 Ileocolonic, N [%] 4 [11.8%] 11 [13.8%] 2.0 [0.4-9.9] 0.9 Colonic, N [%] 4 [11.8%] 23 [28.8%] Ref / Upper GI Crohn’s disease 6 [17.1%] 12 [17.1%] 1.0 [0.3-2.9] 1.0 Perianal Crohn’s disease 6 [17.1%] 16 [22.9%] 0.7 [0.2-2.1] 0.5 Crohn’s disease phenotype Inflammatory 26 [76.5%] 40 [57.1%] 3.7 [1.1-11.9] 0.1 Stricturing 4 [11.8%] 7 [10.0%] 3.2 [0.6-16.6] 0.5 Fistulising 4 [11.8%] 23 [32.9%] Ref / Ulcerative colitis extent Limited colitis 16 [21.9%] 64 [41.0%] Ref / Extensive colitis 57 [78.1%] 92 [59.0%] 2.8 [1.5-5.5] 0.002 PSC at Time 0b Present 22 [19.3%] 13 [5.7%] 4.4 [2.1-9.4] <0.001 Absent 92 [80.7%] 215 [94.3%] Ref Extra-intestinal manifestations [any time, excluding PSC] Any 16 [14.0%] 35 [15.4%] 0.9 [0.5-1.8] 0.8 Sacroileitis 2 [1.8%] 2 [0.9%] 2.5 [0.3,18.0] 0.4 Ankylosing spondylitis 1 [0.9%] 4 [1.8%] 0.5 [0.06-4.8] 0.6 Pyoderma gangrenosum 1 [0.9%] 3 [1.3%] 0.6 [0.06-5.6] 0.6 Erythema nodosum 1 [0.9%] 6 [2.6%] 0.3 [0.04-3.0] Uveitis/episcleritis 2 [1.8%] 5 [2.2%] 0.8 [0.1-4.2] 0.8 Oral ulcers/aphthous stomatitis 8 [7.0%] 11 [4.8%] 1.5 [0.6-3.9] 0.4 Deep vein thrombosis 3 [2.6%] 8 [3.5%] 0.7 [0.2-2.8] 0.7 Medications ever used 5-ASA 70 [61.4%] 111 [48.7%] 1.8 [1.1-2.9] 0.02 Corticosteroids 41 [36.0%] 75 [32.9%] 1.2 [0.7-1.9] 0.5 Immunomodulator 15 [13.2%] 39 [17.1%] 0.7 [0.4-1.4] 0.4 Biologics 20 [17.5%] 37 [15.4%] 1.2 [0.7-2.2] 0.6 Celiac diagnosis method Serology and histology 70 [61.9%] / / / Histology alone 22 [19.5%] Serology alone 11 [9.7%] Clinical history 10 [8.8%] Characteristic IBD-Celiaca N = 114 IBD-only controls N = 228 Odds ratio [95% CI] p-Value Female 54 [47.4%] 108 [47.4%] 1.1 [0.7-1.8] 0.6 Ethnicity White 105 [97.2%] 219 [96.5%] Ref 0.8 Non-White 3 [2.8%] 8 [3.5%] 0.8 [0.2-3.2] Age, median [IQR] At IBD diagnosis 28.9 [18.8, 39.9] 24.4 [17.9-34.5] 1.0 [1.0-1.0] 0.05 At Celiac diagnosis 33.1 [24.1, 49.4] / / / IBD Type Crohn’s disease 35 [30.7%] 70 [30.7%] 1.0 [0.6-1.7] 10 Ulcerative colitis 79 [69.3%] 158 [69.3%] Ref Smoking Never 80 [70.2%] 157 [68.9%] Ref 0.4 Ever 34 [29.8%] 71 [31.1%] 0.8 [0.4-1.3] Family history IBD 25 [21.9%] 50 [22.0%] 1.0 [0.6-1.8] 0.9 Crohn’s disease 10 [8.9%] 19 [8.8%] 1.1 [0.5-2.6] 0.8 Ulcerative colitis 13 [11.6%] 21 [9.7%] 1.3 [0.6-2.7] 0.5 Celiac disease 12 [10.5%] 8 [3.5%] 3.2 [1.3-8.2] 0.01 Referral IBD case 89 [78.1%] 202 [88.6%] 0.5 [0.3-0.9] 0.02 Years of IBD prior to Time 0,b median [IQR] 3.4 [0.6, 12.0] 3.6 [0.5, 12.0] 1.0 [1.0-1.0] 0.3 Years of follow-up, median [IQR] 3.0 [0.7, 6.8] 6.3 [2.6, 12.2] 0.9 [0.8-0.9] <0.001 Order of diagnosis IBD before celiac 75 [65.8%] / / / IBD after celiac 32 [26.5%] Concurrent [within +/- 7 days] 9 [8.0%] Years to celiac diagnosis after IBD, median [IQR] 7.7 [1.4, 14.2] / / / Years to IBD after celiac diagnosis, median [IQR] 3.4 [0.4, 8.0] / / / Crohn’s disease location Ileal, N [%] 26 [76.5%] 46 [57.5%] 3.2 [1.0-10.3] 0.08 Ileocolonic, N [%] 4 [11.8%] 11 [13.8%] 2.0 [0.4-9.9] 0.9 Colonic, N [%] 4 [11.8%] 23 [28.8%] Ref / Upper GI Crohn’s disease 6 [17.1%] 12 [17.1%] 1.0 [0.3-2.9] 1.0 Perianal Crohn’s disease 6 [17.1%] 16 [22.9%] 0.7 [0.2-2.1] 0.5 Crohn’s disease phenotype Inflammatory 26 [76.5%] 40 [57.1%] 3.7 [1.1-11.9] 0.1 Stricturing 4 [11.8%] 7 [10.0%] 3.2 [0.6-16.6] 0.5 Fistulising 4 [11.8%] 23 [32.9%] Ref / Ulcerative colitis extent Limited colitis 16 [21.9%] 64 [41.0%] Ref / Extensive colitis 57 [78.1%] 92 [59.0%] 2.8 [1.5-5.5] 0.002 PSC at Time 0b Present 22 [19.3%] 13 [5.7%] 4.4 [2.1-9.4] <0.001 Absent 92 [80.7%] 215 [94.3%] Ref Extra-intestinal manifestations [any time, excluding PSC] Any 16 [14.0%] 35 [15.4%] 0.9 [0.5-1.8] 0.8 Sacroileitis 2 [1.8%] 2 [0.9%] 2.5 [0.3,18.0] 0.4 Ankylosing spondylitis 1 [0.9%] 4 [1.8%] 0.5 [0.06-4.8] 0.6 Pyoderma gangrenosum 1 [0.9%] 3 [1.3%] 0.6 [0.06-5.6] 0.6 Erythema nodosum 1 [0.9%] 6 [2.6%] 0.3 [0.04-3.0] Uveitis/episcleritis 2 [1.8%] 5 [2.2%] 0.8 [0.1-4.2] 0.8 Oral ulcers/aphthous stomatitis 8 [7.0%] 11 [4.8%] 1.5 [0.6-3.9] 0.4 Deep vein thrombosis 3 [2.6%] 8 [3.5%] 0.7 [0.2-2.8] 0.7 Medications ever used 5-ASA 70 [61.4%] 111 [48.7%] 1.8 [1.1-2.9] 0.02 Corticosteroids 41 [36.0%] 75 [32.9%] 1.2 [0.7-1.9] 0.5 Immunomodulator 15 [13.2%] 39 [17.1%] 0.7 [0.4-1.4] 0.4 Biologics 20 [17.5%] 37 [15.4%] 1.2 [0.7-2.2] 0.6 Celiac diagnosis method Serology and histology 70 [61.9%] / / / Histology alone 22 [19.5%] Serology alone 11 [9.7%] Clinical history 10 [8.8%] CI, confidence interval; IQR, interquartile range; GI, gastrointestinal; PSC, primary sclerosing cholangitis; 5-ASA, 5-aminosalicylic acid. aThree study cases had indeterminate colitis [and celiac disease]; fpor control cases had indeterminate colitis [without celiac disease]. These were not matched. b‘Time 0’ refers to the starting time point defined as the latest occurrence of IBD diagnosis, first presentation date at Mayo, or Celiac diagnosis, in the IBD-Celiac study group. In the IBD-only group, ‘time 0’ refers to the latest occurrence of IBD diagnosis or first presentation date at Mayo. View Large 2.1. Statistical analysis Continuous baseline characteristics were summarised with median and interquartile range [IQR], and categorical characteristics were presented as frequency and percentage. Logistic regression adjusted for age [at IBD diagnosis] and gender to assess for associations in baseline characteristics, and an odds ratio [OR] with a 95% confidence interval, were presented for each association. Analysis of outcomes was performed using the Kaplan-Meier method, and the relationship with celiac disease was assessed using Cox proportional hazard regression. ‘Time 0’ refers to the starting time point for being ‘at risk’ as defined by the latest occurrence of IBD diagnosis, celiac disease diagnosis, or first presentation date at the Mayo Clinic. Because clinical visits and diagnostic work-up can be spread across multiple days, a diagnosis of PSC or celiac disease within +/- 7 days on either side of the IBD diagnosis date were considered to be concurrent diagnoses and not treated as an outcome. Hazard ratios with a 95% confidence interval were used to summarise the proportional hazards models. Because event counts were small, all proportional hazard models were analysed without adjustment. An α = 0.05 was considered statistically significant. Analyses were performed with SAS [v9.4, SAS Institute, Cary, NC] and R [v3.2.3, Vienna, Austria]. 3. Results 3.1. Study population A total of 448 patients with a diagnosis of both IBD and celiac disease were identified. A detailed review of the electronic medical records verified 117 IBD-Celiac study patients [n = 79 UC, n = 35 CD, and n = 3 IBD unclassified] who were then matched with 1:2 control patients [n = 158 UC and n = 70 CD]. Three patients with IBD-unclassified,, and 331 patients initially identified by ICD 9/10 coding but with either IBD or celiac disease diagnosis disconfirmed on review of electronic records [clinical notes and/or laboratory studies], were excluded from further analysis. The estimated proportion of IBD patients with concomitant celiac disease at our institution is 0.6%. The baseline characteristics of the IBD-Celiac study group and IBD-only control group are summarised in Table 1 [and in Supplementary Table S1, available as Supplementary data at ECCO-JCC online], comparing the CD-Celiac and UC-Celiac cohorts and their respective controls. As seen in Table 1, baseline characteristics, including the median age at IBD diagnosis [28.9 vs. 24.4 years, p = 0.06] and duration of disease preceding time 0 [median 4.7 vs 4.9 years, p = 0.34], were similar between the two groups. In our study cohort, 89 [78%] of IBD-Celiac study patients and 202 [89%] of IBD-only control patients were diagnosed with IBD 8.4 years and 7.4 years [p = 0.6] before referral to our institution. IBD was diagnosed in the median year 2006 (interquartile range [IQR], 1994–2007) in the IBD-Celiac study group and 2000 [IQR, 1992–2014] in the IBD-only control group. Patients in the IBD-Celiac group had shorter follow-up time [median 3.0 vs 6.3 years, p < 0.001] and were less likely to be referred from other institutions [78.1% vs 88.6%, p = 0.02] compared with IBD-only control patients. Family history of celiac disease was more common among IBD-Celiac patients compared with IBD-only controls (10.5% vs 3.5%; odds ratio [OR], 3.2; 95% confidence interval [CI], 1.3–8.2; p = 0.01] [Table 1]). Within the IBD subtypes, family history of celiac disease was more common among CD-Celiac [20.0% vs 2.9%; OR, 8.9; 95% CI, 1.7–46.2; p = 0.01] but not in UC-Celiac patients [6.3% vs 3.8%; OR, 1.7; 95% CI, 0.5–5.8; p = 0.4] [Table S1]. Among IBD-Celiac patients, the majority were diagnosed with IBD first [65.8%] followed by diagnosis of celiac disease after a median of 7.7 years [IQR, 1.4–14.2]. Patients in the IBD-Celiac group who were diagnosed first with celiac disease [26.3%] received a diagnosis of IBD after a median of 3.4 years [IQR, 0.4–8.0]. A small percentage [7.9%] of patients was concurrently diagnosed with IBD and celiac disease. 3.2. Extensive colitis is more common in UC patients with concomitant celiac disease As seen in Table 1, the presence of extensive colitis [versus limited colitis] was more common in UC-Celiac patients compared with UC-only controls [78.1% vs 59.0 %; OR, 2.8; 95% CI, 1.5–5.5; p = 0.002]. In contrast, no differences in location or phenotypic behaviour were found between CD-Celiac and CD-only patients [Table 1]. Extra-intestinal manifestations, excluding PSC which was analysed separately, were less common among CD-Celiac patients compared with CD-only patients [8.6% vs 27.1%; OR, 0.3; 95% CI, 0.1–0.9; p = 0.04] but no differences were found among UC-Celiac and UC-only patients [Table S1]. 3.3. Higher PSC prevalence among IBD patients with co-existent celiac disease Before time 0, the prevalence of PSC among IBD-Celiac study patients was 19.3% [OR, 4.4; 95% CI, 2.1-9.4; p <0.001] compared with 5.7% of IBD-only control patients [Table 1]. From time 0 onward, the hazard ratio [HR] of the cumulative probability of PSC at 5 years in IBD-Celiac patients was 4.070 [95% CI, 1.3-12.4; p = 0.01] compared with IBD-only patients [Figure 1]. For CD-Celiac and UC-Celiac study patients after time 0, the hazard ratios for PSC were 9.751 [95% CI, 0.9-107.6; p = 0.06] and 3.308 [95% CI, 0.9-12.8; p = 0.08] compared with CD-only and UC-only controls, respectively. In a sensitivity analysis that excluded IBD-celiac study patients with clinically diagnosed celiac disease and their respective matched IBD-only cohorts, the risk for PSC was also higher among IBD-Celiac study patients compared with IBD-only controls [HR, 4.1; 95% CI, 1.1-15.6; p = 0.04]. All UC-Celiac patients with PSC had extensive colitis. Figure 1. View largeDownload slide Cumulative probability of primary sclerosing cholangitis [PSC] diagnosis in inflammatory bowel disease- [IBD]-celiac cases versus IBD-only controls. Figure 1. View largeDownload slide Cumulative probability of primary sclerosing cholangitis [PSC] diagnosis in inflammatory bowel disease- [IBD]-celiac cases versus IBD-only controls. Among patients with PSC [diagnosed at any time], the median alkaline phosphatase [ALP] at the time of PSC diagnosis was 173.0 [IQR, 133.0-640.0] and 415.0 [IQR, 137.0-990.0] for IBD-Celiac study patients [n = 13] and IBD-only control patients [n = 15], respectively. Magnetic resonance cholangiopancreatography [MRCP] was performed in 71.4% [10 of 14] of IBD-Celiac study patients and 58.8% [10 of 17] of IBD-only control patients within 4 weeks of PSC diagnosis. Large-duct PSC was observed in 89% [8 of 9] of IBD-Celiac patients and 80% [8 of 10] IBD-only patients. Endoscopic retrograde cholangiopancreatography [ERCP] was performed within 4 weeks of PSC diagnosis in 38.5% [5 of 13] and 47.1% [8 of 17] IBD-Celiac and IBD-only patients, respectively. During the ERCP, large-duct PSC was observed in 80% [4 of 5] and 87.5% [7 of 8] study and control patients, respectively. Biliary atresia was not identified in any index ERCP/MRCP studies. Small-duct PSC was identified in one [of 1] IBD-Celiac patient and three [of 6] IBD-only patients who underwent liver biopsy. In terms of outcomes, of the 53 patients diagnosed with PSC [28 IBD-Celiac; 25 IBD-only], 11 [20.7%] had liver transplantation [two cholangiocarcinoma, eight cirrhotic-stage PSC, and one recurrent cholangitis secondary to biliary strictures], 14 [26.4%] had bowel resections [12 for medically refractory IBD, one for neoplasia/dysplasia, and one for intestinal stricture/bowel obstruction]. 3.4. Outcomes of IBD with co-existent celiac disease: hospitalisations, rescue steroid, and surgery From time 0 to 5 years later, the rate of IBD-related hospitalisations was higher among IBD-Celiac and IBD-only patients [38.9% versus 20.9%; HR, 2.0; 95% CI, 1.1-3.9; p = 0.03] [Figure 2]. Within the IBD subtypes, CD-Celiac patients required more IBD-related hospitalisations [HR, 3.3; 95% CI, 1.1-9.6; p = 0.03] compared with CD-only controls, though no difference was observed among UC-Celiac and UC-only patients. Figure 2. View largeDownload slide Cumulative probability of hospitalisations in inflammatory bowel disease- [IBD]-Celiac cases versus IBD-only controls. Figure 2. View largeDownload slide Cumulative probability of hospitalisations in inflammatory bowel disease- [IBD]-Celiac cases versus IBD-only controls. The requirement for high-dose rescue corticosteroids for IBD flare was lower among IBD-Celiac patients compared with IBD-only patients [15.4% versus 40.5%; HR, 0.3; 95% CI, 0.1-0.9; p = 0.025] [Figure 3], a pattern that was observed among UC-Celiac patients [HR, 0.2; 95% CI, 0.05-0.8; p = 0.03] but not among CD-Celiac patients compared with UC/CD-only controls. Figure 3. View largeDownload slide Cumulative probability of rescue steroids used in inflammatory bowel disease- [IBD]-Celiac cases versus IBD-only controls. Figure 3. View largeDownload slide Cumulative probability of rescue steroids used in inflammatory bowel disease- [IBD]-Celiac cases versus IBD-only controls. No differences were found in rates of IBD-related surgery [46.9% and 50.0%; HR, 0.9; 95% CI, 0.5-1.6; p = 0.8] [Supplementary Figure 1, available as Supplementary data at ECCO-JCC online] among IBD-Celiac and IBD-only patients, respectively, or among the CD/UC subgroups. In a multivariate analysis with IBD diagnosis age, IBD duration, and UC extent, the presence of concomitant celiac disease with IBD continues to be associated with an increased risk for PSC [OR, 2.3; 95% CI, 1.02-5.3; p = 0.04] and decreased need for rescue steroids [OR, 0.3; 95% CI, 0.1-0.5; p = 0.0002], though no statistical significant differences were seen with IBD-related surgeries [p = 0.07] or IBD-related hospitalisations [p = 0.4]. In a sensitivity analysis that excluded IBD-celiac study patients with clinically diagnosed celiac disease and their respective matched IBD-only cohorts, no statistically significant differences were observed between IBD-Celiac and IBD-only patients with regards to rescue steroid use [HR, 0.4; 95% CI, 0.1-1.2; p = 0.1], IBD-related surgeries [HR, 0.9; 95% CI, 0.5-1.8; p = 0.8], and IBD-related hospitalisations [HR, 1.7; 95% CI, 0.747-4.0; p = 0.2]. We observed no differences in the use of immunomodulators or biologics between the UC-Celiac and UC-only cohorts over a 5-year follow-up period following the initial presentation at our institution. However, we observed an increased usage of systemic steroids [19.2% vs 4.7%; OR, 4.3; 95% CI, 1.0-18.0; p = 0.05] at year 5 in the UC-Celiac group compared with the UC-only controls [Supplementary Figure 2, available as Supplementary data at ECCO-JCC online]. However, this effect was no longer significant [p = 0.0752] in multivariate analysis to include UC extent and IBD duration. 4. Discussion Our study represents the largest case-control study to analyse the clinical course and phenotype of patients with IBD and concomitant celiac disease. Important findings of our study include the association of co-existent IBD-celiac with PSC, family history of celiac disease, and IBD-related hospitalisations. Patients with concurrent IBD and celiac disease were more likely to have IBD diagnosed first, and there was a delay of several years in the diagnosis of the other concomitant disease. Primary sclerosing cholangitis [PSC] is a chronic, autoimmune, cholestatic liver disease that is strongly associated with IBD. Up to 90% of patients with PSC have UC,8,15 and 5-7.5% of UC patients develop PSC during the course of their disease.8,16 The association between PSC and celiac disease is less clear. A large population-based study from Sweden found a 4- to 8-fold increase in the prevalence of PSC among individuals with celiac disease compared with non-celiac individuals in the general population,17,18 suggesting that there may be an association between these two immune-mediated gastrointestinal and hepatobiliary diseases. A limited number of studies to date have examined the clinical association between IBD, celiac disease, and PSC, which are all believed to be immune-mediated disorders involving the gastrointestinal tract and the hepatobiliary system. A large Swedish epidemiological study found that first-degree relatives of PSC patients without IBD have a 7-fold risk for developing UC.19 Our study found that patients with IBD and concurrent celiac disease were more likely to have PSC, a finding that was also noted in a few small case series.20,21 The association of PSC and UC with concomitant celiac disease, particularly those with pancolitis, could be related to common immunopathogenesis where gut-derived memory T-cells are recruited to the liver to induce biliary inflammation in PSC.22,23 Celiac disease and ulcerative colitis may share common polymorphisms in the receptor gene for IL-23, a major cytokine involved in Th17 cell differentiation.24 Shared genetic risk loci for PSC and UC are under study.24–26 Consequently, patients with UC and co-existent celiac disease may benefit from evaluation of co-existent PSC with laboratory screening tests and confirmatory evaluation with MRCP, ERCP, and/or liver biopsy. IBD, celiac disease, and PSC may also share common environmental risk factors, such as vitamin D deficiency. Vitamin D metabolism is closely related to liver function as this is the site for enzymatic conversion of the inactive vitamin D3 to 25-hydroxy vitamin D3, a precursor to the active 1, 25-hydroxyvitamin D3. Vitamin D deficiency is common in patients with IBD,27,28 with a prevalence of up to 70%29 and 45%30 in CD and UC, respectively. Several studies have shown that 22–57% of PSC patients also had vitamin D deficiency,31,32 and that PSC was an independent factor for vitamin D deficiency in UC patients with ileal pouch-anal anastomosis [IPAA].33 The immunoregulatory properties of Vitamin D may be mediated by signalling through its receptor expressed in the gut.34 Recent genome-wide association analysis has identified variation in vitamin D receptor, among several host factors influencing the gut microbiota.35 In turn, the gut microbiota are essential for the metabolism of bile acids,36 which acts as key vitamin D receptor ligands and regulate its expression.37,38 Further studies are needed to explore how vitamin D and other micronutrients may influence the clinical course of immune-mediated gastrointestinal diseases. Our study findings may be limited by referral bias, and we attempted to minimise this by using a case-control design of patients who were identified from a common referral pool. The retrospective study design of our study also limits the availability, accessibility, and accuracy of data from existing electronic medical records. In future studies, age at IBD diagnosis could be considered as a matching factor, though this was not feasible in our study. Surveillance bias might contribute to residual confounding for family history of IBD or celiac disease [e.g., providers may be more likely to ask about family history in setting of celiac disease]. There is a possibility that some patients in our control group may have ‘silent’ or asymptomatic celiac disease. Nonetheless, previous studies have shown the expected prevalence of co-existent celiac disease among IBD patients to be 0.5–0.9%3,4 and hence unlikely to have influenced our results. Moreover, 8.8% of the IBD-Celiac study patients had an established celiac disease diagnosis before presentation at the Mayo Clinic, without further details on the previous diagnostic testing available in our database. This may lead to over-diagnosis of celiac disease and introduce bias to the results. Nonetheless, we were able to confirm celiac diagnosis by histology in the majority [81.4%] of study patients, which is considered by the American College of Gastroenterology to have a high level of evidence for the diagnosis of celiac disease.12 Of note, our study has explored the order of diagnosis in patients with IBD and celiac disease, as well as the time-to-diagnosis of the concomitant disease. This is important, as a delay in making a diagnosis or a delay in the initiation of proper treatment in patients with co-existent IBD-Celiac disease may increase morbidity and even mortality.39 It is, therefore, important to evaluate for co-existing celiac disease [e.g., by serology or histopathology] in IBD patients, particularly those with seemingly ‘refractory’ IBD who have ongoing clinical symptoms. Funding This work was supported by the AGA Student Abstract Prize 2017 to CST. Conflict of Interest PD has received a research grant from Takeda, participated in advisory boards for Pfizer and Janssen, and served as speaker for Abbvie Speaker’s bureau. Author Contributions CST was involved in the study design, data acquisition, interpretation of data, drafting of manuscript, and obtaining funding. PD was involved in study concept and design and interpretation of data. JDF and ACB were involved in the acquisition of data. JJL was involved in the analysis of data. JAM was involved in the study concept and study design. KAP was involved in the study concept, study design, and obtaining funding. All authors were involved in critical revision of the manuscript for important intellectual content and approved the final submitted version. An earlier version of this manuscript was a poster at Digestive Diseases Week 2017 in Chicago, IL Supplementary Data Supplementary data are available at ECCO-JCC online. References 1. Silverberg MS , Satsangi J , Ahmad T , et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a working party of the 2005 Montreal World Congress of Gastroenterology . Can J Gastroenterol 2005 ; 19 [ Suppl A ]: 5A – 36A . Google Scholar CrossRef Search ADS PubMed 2. Oxford EC , Nguyen DD , Sauk J , et al. Impact of co-existent celiac disease on phenotype and natural history of inflammatory bowel diseases . Am J Gastroenterol 2013 ; 108 : 1123 – 9 . Google Scholar CrossRef Search ADS PubMed 3. Casella G , D’Inca R , Oliva L , et al. Prevalence of celiac disease in inflammatory bowel diseases: An IG-IBD multicentre study . Dig Liver Dis 2010 ; 42 : 175 – 8 . Google Scholar CrossRef Search ADS PubMed 4. Leeds JS , Horoldt BS , Sidhu R , et al. Is there an association between coeliac disease and inflammatory bowel diseases? A study of relative prevalence in comparison with population controls . Scand J Gastroenterol 2007 ; 42 : 1214 – 20 . Google Scholar CrossRef Search ADS PubMed 5. Fasano A , Berti I , Gerarduzzi T , et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study . Arch Intern Med 2003 ; 163 : 286 – 92 . Google Scholar CrossRef Search ADS PubMed 6. Kocsis D , Toth Z , Csontos AA , et al. Prevalence of inflammatory bowel disease among coeliac disease patients in a Hungarian coeliac centre . BMC Gastroenterol 2015 ; 15 : 141 . Google Scholar CrossRef Search ADS PubMed 7. Yang A , Chen Y , Scherl E , et al. Inflammatory bowel disease in patients with celiac disease . Inflamm Bowel Dis 2005 ; 11 : 528 – 32 . Google Scholar CrossRef Search ADS PubMed 8. Lee YM , Kaplan MM . Primary sclerosing cholangitis . N Engl J Med 1995 ; 332 : 924 – 33 . Google Scholar CrossRef Search ADS PubMed 9. Molodecky NA , Soon IS , Rabi DM , et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review . Gastroenterology 2012 ; 142 : 46 – 54 .e42; quiz e30. Google Scholar CrossRef Search ADS PubMed 10. Bhavik M . Bhandari RSB . Inflammatory Bowel Disease . 2017 . Accessed July 7 , 2017. https://www.ncbi.nlm.nih.gov/pubmed/17970872 11. Schafer AI , Goldman L. Goldman-Cecil Medicine . Elsevier Health Sciences , 2016 . 12. Rubio-Tapia A , Hill ID , Kelly CP , et al. ACG clinical guidelines: Diagnosis and management of celiac disease . Am J Gastroenterol 2013 ; 108 : 656 – 76 ; quiz 77. Google Scholar CrossRef Search ADS PubMed 13. Satsangi J , Silverberg MS , Vermeire S , Colombel JF . The Montreal Classification of inflammatory bowel disease: controversies, consensus, and implications . Gut 2006 ; 55 : 749 – 53 . Google Scholar CrossRef Search ADS PubMed 14. Monstad I , Hovde O , Solberg IC , A Moum B . Clinical course and prognosis in ulcerative colitis: results from population-based and observational studies . Ann Gastroenterol 2014 ; 27 : 95 – 104 . Google Scholar PubMed 15. Bambha K , Kim WR , Talwalkar J , et al. Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community . Gastroenterology 2003 ; 125 : 1364 – 9 . Google Scholar CrossRef Search ADS PubMed 16. Olsson R , Danielsson A , Jarnerot G , et al. Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis . Gastroenterology 1991 ; 100 : 1319 – 23 . Google Scholar CrossRef Search ADS PubMed 17. Rubio-Tapia A , Murray JA . The liver in celiac disease . Hepatology 2007 ; 46 : 1650 – 8 . Google Scholar CrossRef Search ADS PubMed 18. Ludvigsson JF , Elfstrom P , Broome U , Ekbom A , Montgomery SM . Celiac disease and risk of liver disease: a general population-based study . Clin Gastroenterol Hepatol 2007 ; 5 : 63 – 9 .e1. Google Scholar CrossRef Search ADS PubMed 19. Bergquist A , Montgomery SM , Bahmanyar S , et al. Increased risk of primary sclerosing cholangitis and ulcerative colitis in first-degree relatives of patients with primary sclerosing cholangitis . Clin Gastroenterol Hepatol 2008 ; 6 : 939 – 43 . Google Scholar CrossRef Search ADS PubMed 20. Hay JE , Wiesner RH , Shorter RG , LaRusso NF , Baldus WP . Primary sclerosing cholangitis and celiac disease. A novel association . Ann Intern Med 1988 ; 109 : 713 – 7 . Google Scholar CrossRef Search ADS PubMed 21. Habior A , Rawa T , Orlowska J , et al. Association of primary sclerosing cholangitis, ulcerative colitis and coeliac disease in female siblings . Eur J Gastroenterol Hepatol 2002 ; 14 : 787 – 91 . Google Scholar CrossRef Search ADS PubMed 22. Schrumpf E , Tan C , Karlsen TH , et al. The biliary epithelium presents antigens to and activates natural killer T cells . Hepatology 2015 ; 62 : 1249 – 59 . Google Scholar CrossRef Search ADS PubMed 23. Henriksen EK , Jorgensen KK , Kaveh F , et al. Gut and liver T-cells of common clonal origin in primary sclerosing cholangitis-inflammatory bowel disease . J Hepatol 2017 ; 66 : 116 – 22 . Google Scholar CrossRef Search ADS PubMed 24. Glas J , Stallhofer J , Ripke S , et al. Novel genetic risk markers for ulcerative colitis in the il2/il21 region are in epistasis with il23r and suggest a common genetic background for ulcerative colitis and celiac disease . Am J Gastroenterol 2009 ; 104 : 1737 – 44 . Google Scholar CrossRef Search ADS PubMed 25. Wapenaar MC , Monsuur AJ , van Bodegraven AA , et al. Associations with tight junction genes pard3 and magi2 in Dutch patients point to a common barrier defect for coeliac disease and ulcerative colitis . Gut 2008 ; 57 : 463 – 7 . Google Scholar CrossRef Search ADS PubMed 26. Einarsdottir E , Koskinen LL , Dukes E , et al. Il23r in the Swedish, Finnish, Hungarian and Italian populations: association with IBD and psoriasis, and linkage to celiac disease . BMC Med Genet 2009 ; 10 : 8 . Google Scholar CrossRef Search ADS PubMed 27. Ananthakrishnan AN , Khalili H , Higuchi LM , et al. Higher predicted vitamin D status is associated with reduced risk of Crohn’s disease . Gastroenterology 2012 ; 142 : 482 – 9 . Google Scholar CrossRef Search ADS PubMed 28. Pappa HM , Grand RJ , Gordon CM . Report on the vitamin D status of adult and pediatric patients with inflammatory bowel disease and its significance for bone health and disease . Inflamm Bowel Dis 2006 ; 12 : 1162 – 74 . Google Scholar CrossRef Search ADS PubMed 29. Siffledeen JS , Siminoski K , Steinhart H , Greenberg G , Fedorak RN . The frequency of vitamin D deficiency in adults with Crohn’s disease . Can J Gastroenterol 2003 ; 17 : 473 – 8 . Google Scholar CrossRef Search ADS PubMed 30. Silvennoinen J . Relationships between vitamin D, parathyroid hormone and bone mineral density in inflammatory bowel disease . J Intern Med 1996 ; 239 : 131 – 7 . Google Scholar CrossRef Search ADS PubMed 31. Jorgensen RA , Lindor KD , Sartin JS , LaRusso NF , Wiesner RH . Serum lipid and fat-soluble vitamin levels in primary sclerosing cholangitis . J Clin Gastroenterol 1995 ; 20 : 215 – 9 . Google Scholar CrossRef Search ADS PubMed 32. Khanna R , Wu X , Shen B . Low levels of vitamin D are common in patients with ileal pouches irrespective of pouch inflammation . J Crohns Colitis 2013 ; 7 : 525 – 33 . Google Scholar CrossRef Search ADS PubMed 33. Fialho A , Fialho A , Kochhar G , Shen B . The presence of primary sclerosing cholangitis in patients with ileal pouch-anal anastomosis is associated with an additional risk for vitamin D deficiency . Gastroenterol Rep [Oxf] 2016 ; 4 : 320 – 4 . Google Scholar CrossRef Search ADS PubMed 34. Lu R , Wu S , Xia Y , Sun J . The vitamin D receptor, inflammatory bowel diseases, and colon cancer . Curr Colorectal Cancer Rep 2012 ; 8 : 57 – 65 . Google Scholar CrossRef Search ADS PubMed 35. Wang J , Thingholm LB , Skieceviciene J , et al. Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota . Nat Genet 2016 ; 48 : 1396 – 406 . Google Scholar CrossRef Search ADS PubMed 36. Haussler MR , Haussler CA , Bartik L , et al. Vitamin D receptor: molecular signaling and actions of nutritional ligands in disease prevention . Nutr Rev 2008 ; 66 : S98 – 112 . Google Scholar CrossRef Search ADS PubMed 37. D’Aldebert E , Biyeyeme Bi Mve MJ , Mergey M , et al. Bile salts control the antimicrobial peptide cathelicidin through nuclear receptors in the human biliary epithelium . Gastroenterology 2009 ; 136 : 1435 – 43 . Google Scholar CrossRef Search ADS PubMed 38. Makishima M , Lu TT , Xie W , et al. Vitamin D receptor as an intestinal bile acid sensor . Science 2002 ; 296 : 1313 – 6 . Google Scholar CrossRef Search ADS PubMed 39. Rubio-Tapia A , Kyle RA , Kaplan EL , et al. Increased prevalence and mortality in undiagnosed celiac disease . Gastroenterology 2009 ; 137 : 88 – 93 . Google Scholar CrossRef Search ADS PubMed Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

Journal of Crohn's and ColitisOxford University Press

Published: Aug 1, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off