Similar subclinical enthesitis in celiac and inflammatory bowel diseases by ultrasound suggests a gut enthesis axis independent of spondyloarthropathy spectrum

Similar subclinical enthesitis in celiac and inflammatory bowel diseases by ultrasound suggests a... Abstract Objective Higher subclinical enthesitis on US has been reported in IBD and celiac disease, separately. The objective of this study was to compare IBD and celiac disease for enthesitis on US. Higher enthesitis scores in IBD compared with celiac disease would support a shared pathogenic mechanism between IBD and spondyloarthritis, whereas similar scores may suggest a general impact of gut inflammation on the enthesis. Methods Patients with IBD, celiac disease and healthy controls (HCs) were recruited and 12 entheses were scanned by US, blind to the diagnosis and clinical assessment. Elementary lesions for enthesitis were scored on a scale between 0 and 3, for inflammation, damage and total US scores. Results A total of 1260 entheses were scanned in 44 patients with celiac disease, 43 patients with IBD and 18 HCs. The three groups were matched for age and BMI. Patients with celiac disease and IBD had higher inflammation scores than HCs [10.4 (6.5), 9.6 (5.4) and 5.6 (5.2), respectively, P = 0.007) whereas damage scores were similar. Both age and BMI had significant effects on the entheseal scores, mostly for inflammation scores but when controlling for these the US enthesopathy scores were still higher in celiac disease and IBD. Conclusion The magnitude of subclinical enthesopathy scores is similar between celiac disease and IBD in comparison with HCs. These findings suggest that the common factor between both diseases and enthesopathy is abnormal gut permeability, which may be modified by the genetic architecture of IBD leading to clinical arthropathy. Celiac disease, inflammatory bowel disease, enthesitis, ultrasound, inflammation, damage Rheumatology key messages Celiac disease and IBD have a similar magnitude of subclinical enthesopathies on ultrasound. BMI, age and gender may affect subclinical enthesitis in celiac disease and IBD. The common factor between both celiac disease and IBD on enthesopathies is abnormal gut permeability. Introduction Enthesitis, the inflammation of the attachment sites of ligaments, tendons, joint capsule or fascia to the bones, is a characteristic sign and hallmark of spondyloarthritis (SpA) [1]. However, it is not specific to SpA and can be seen in other inflammatory and non-inflammatory conditions [2]. Celiac disease is a systemic autoimmune disorder of the bowels induced by gluten consumption, with extra-intestinal manifestations one of which is musculoskeletal features, but it is not specifically associated with clinical enthesitis or other enthesitis-associated features including axial inflammation or nail involvement [3]. Subclinical enthesopathies were previously reported in celiac disease when screened by US [4, 5]. Similarly, IBD may also present with articular features in addition to subclinical enthesitis [6–8]. To date, there are no studies comparing the entheseal changes in celiac disease and IBD. In this study we aimed to explore the entheseal changes and confounding factors in IBD and celiac disease compared with healthy controls (HCs). Higher enthesitis scores in IBD than celiac disease would support a relationship between IBD and SpA and a shared pathogenic mechanism between the two, whereas similar scores may suggest a more general impact of gut inflammation and associated barrier dysfunction are a key feature in triggering entheseal changes. We used US to demonstrate entheseal changes as physical examination has been shown to underestimate enthesitis when compared with US [9]. Additionally US gives information about the inflammatory changes as well as tissue damage, which enables a more detailed comparison at a tissue level. We also summarized the literature to describe the similarities and differences among studies. Methods Study design In this cross-sectional study, patients with IBD and celiac disease were consecutively recruited from the gastroenterology outpatient clinic of Sakarya University Education and Research Hospital between 2016 and 2017. This study was approved by the local Ethics Committee at Sakarya University Education and Research Hospital, Turkey (No. 16214662/050.01.04/112-113) and informed consent was obtained from all individuals. Celiac disease was diagnosed clinically and on duodenal biopsy, and IBD was diagnosed based on characteristic endoscopic and/or histopathological findings. The inclusion criteria were as follows: being >18 years, no enthesitis on history and on exam, no symptoms and signs of SpA, no NSAIDs within the past 3 months and no biologics in any time frame. The HCs were enrolled among asymptomatic volunteers working in the hospital and patients’ acquaintances, excluding blood relatives. Clinical assessment Demographic data were collected including age, gender, BMI, disease duration and medications. The duration of gluten-free diet for patients with celiac disease was recorded. Prior to US scan, all subjects underwent a clinical examination by the same physician (C.K.) to record tenderness in the same entheseal sites of the US scan elicited by pressure. Ultrasonography Patients had a US scan on the same day of their clinical assessment by an experienced rheumatologist (S.B.U.), blinded to physical examination findings and diagnosis. US was performed using a LOGIQ P9 (GE Healthcare, USA), with a 7–13 MHz linear transducer. Power Doppler (PD) settings were standardized with a pulse repetition frequency of 500 Hz and low wall filter. The colour gain was increased to the highest value where no PD signal was observed below the bony cortex. The insertions of the quadriceps tendon, proximal and distal patellar tendon, Achilles tendon, plantar aponeurosis and triceps tendon were examined bilaterally, in longitudinal and transverse planes. Hypoechogenicity, thickening, enthesophytes, calcifications, erosions and entheseal PD signals were evaluated as elementary lesions [10]. Findings were graded on a scale between 0 and 3 for each of the abnormalities as described before (details provided in supplementary Table S1, available at Rheumatology online) [9]. Briefly thickening and erosions were scored quantitatively whereas the rest was defined semi-quantitatively (normal: grade 0; mild: grade 1; moderate: grade 2; severe: grade 3). Findings that are associated with inflammation (hypoechogenicity, thickening and PD) were summed to calculate an inflammation score. US findings related to tissue damage (calcifications, erosions and enthesophytes) were summed to calculate a damage score. The sum of these two scores gave the total US enthesopathy score. Statistical analysis Continuous data were described using means (s.d.) and categorical variables were expressed as frequencies (percentages). The independent-samples Kruskal–Wallis test was used to compare US scores between groups, followed by the Mann–Whitney U test for paired comparisons, and the chi-square test was used to compare categorical variables. Correlations between clinical variables and US scores were analysed using the Spearman rank-correlation test. A regression analysis was performed to understand the impact on the US scores including age, gender, BMI and diagnosis as independent variables. P < 0.05 was considered statistically significant, but when three groups were compared, a Bonferroni correction was made and the P-value was set to 0.017. SPSS version 24 (IBM, Chicago, IL, USA) and R statistical software (R Foundation for Statistical Computing, Vienna, Austria) were used for analysis. Results Forty-four patients with celiac disease, 43 patients with IBD (12 Crohn’s disease, 31 ulcerative colitis) and 18 HCs were enrolled (Table 1). The groups were matched for BMI and age whereas there were more males in the IBD group. Table 1 Demographics and US scores of patients with celiac disease, IBD and HCs Demographics and US scores Celiac disease IBD HCs (n = 44) (n = 43) (n = 18) Age, mean (s.d.), years 38 (12.4) 42.5 (13) 39.2 (8.7) Female, n (%) 35 (79.5) 16 (37.2) 13 (72.2) BMI, mean (s.d.), kg/m2 24.4 (4.5) 26.2 (5.5) 26.7 (5.8) Disease duration, mean (s.d.), months 4.5 (5.6) 70.79 (81.5) — Total inflammation score, mean (s.d.) 10.4 (6.5) 9.6 (5.4) 5.6 (5.2) Damage score, mean (s.d.) 1.07 (1.5) 1.1 (2.3) 1.0 (1.7) Total US score, mean (s.d.) 11.5 (7.1) 10.8 (6.6) 6.6 (6.3) Disease activity for IBD     Remission, n (%) — 22 (51.2) —     Mild-moderate, n (%) — 13 (30.2) —     Moderate-severe, n (%) — 8 (18.6) — Site of intestinal involvement for IBD Ulcerative colitis         Left sided colitis, n (%) — 19 (44.2) —         Extensive colitis, n (%) — 6 (14) —         Proctitis, n (%) — 6 (14) — Crohn’s disease         Ileo-colonic, n (%) — 2 (4.7) —         Ileum, n (%) — 9 (20.9) —         Colon, n (%) — 1 (2.3) — Gluten-free diet duration, mean (s.d.), months 4.3 (5.6) — — Demographics and US scores Celiac disease IBD HCs (n = 44) (n = 43) (n = 18) Age, mean (s.d.), years 38 (12.4) 42.5 (13) 39.2 (8.7) Female, n (%) 35 (79.5) 16 (37.2) 13 (72.2) BMI, mean (s.d.), kg/m2 24.4 (4.5) 26.2 (5.5) 26.7 (5.8) Disease duration, mean (s.d.), months 4.5 (5.6) 70.79 (81.5) — Total inflammation score, mean (s.d.) 10.4 (6.5) 9.6 (5.4) 5.6 (5.2) Damage score, mean (s.d.) 1.07 (1.5) 1.1 (2.3) 1.0 (1.7) Total US score, mean (s.d.) 11.5 (7.1) 10.8 (6.6) 6.6 (6.3) Disease activity for IBD     Remission, n (%) — 22 (51.2) —     Mild-moderate, n (%) — 13 (30.2) —     Moderate-severe, n (%) — 8 (18.6) — Site of intestinal involvement for IBD Ulcerative colitis         Left sided colitis, n (%) — 19 (44.2) —         Extensive colitis, n (%) — 6 (14) —         Proctitis, n (%) — 6 (14) — Crohn’s disease         Ileo-colonic, n (%) — 2 (4.7) —         Ileum, n (%) — 9 (20.9) —         Colon, n (%) — 1 (2.3) — Gluten-free diet duration, mean (s.d.), months 4.3 (5.6) — — HC: healthy control. Table 1 Demographics and US scores of patients with celiac disease, IBD and HCs Demographics and US scores Celiac disease IBD HCs (n = 44) (n = 43) (n = 18) Age, mean (s.d.), years 38 (12.4) 42.5 (13) 39.2 (8.7) Female, n (%) 35 (79.5) 16 (37.2) 13 (72.2) BMI, mean (s.d.), kg/m2 24.4 (4.5) 26.2 (5.5) 26.7 (5.8) Disease duration, mean (s.d.), months 4.5 (5.6) 70.79 (81.5) — Total inflammation score, mean (s.d.) 10.4 (6.5) 9.6 (5.4) 5.6 (5.2) Damage score, mean (s.d.) 1.07 (1.5) 1.1 (2.3) 1.0 (1.7) Total US score, mean (s.d.) 11.5 (7.1) 10.8 (6.6) 6.6 (6.3) Disease activity for IBD     Remission, n (%) — 22 (51.2) —     Mild-moderate, n (%) — 13 (30.2) —     Moderate-severe, n (%) — 8 (18.6) — Site of intestinal involvement for IBD Ulcerative colitis         Left sided colitis, n (%) — 19 (44.2) —         Extensive colitis, n (%) — 6 (14) —         Proctitis, n (%) — 6 (14) — Crohn’s disease         Ileo-colonic, n (%) — 2 (4.7) —         Ileum, n (%) — 9 (20.9) —         Colon, n (%) — 1 (2.3) — Gluten-free diet duration, mean (s.d.), months 4.3 (5.6) — — Demographics and US scores Celiac disease IBD HCs (n = 44) (n = 43) (n = 18) Age, mean (s.d.), years 38 (12.4) 42.5 (13) 39.2 (8.7) Female, n (%) 35 (79.5) 16 (37.2) 13 (72.2) BMI, mean (s.d.), kg/m2 24.4 (4.5) 26.2 (5.5) 26.7 (5.8) Disease duration, mean (s.d.), months 4.5 (5.6) 70.79 (81.5) — Total inflammation score, mean (s.d.) 10.4 (6.5) 9.6 (5.4) 5.6 (5.2) Damage score, mean (s.d.) 1.07 (1.5) 1.1 (2.3) 1.0 (1.7) Total US score, mean (s.d.) 11.5 (7.1) 10.8 (6.6) 6.6 (6.3) Disease activity for IBD     Remission, n (%) — 22 (51.2) —     Mild-moderate, n (%) — 13 (30.2) —     Moderate-severe, n (%) — 8 (18.6) — Site of intestinal involvement for IBD Ulcerative colitis         Left sided colitis, n (%) — 19 (44.2) —         Extensive colitis, n (%) — 6 (14) —         Proctitis, n (%) — 6 (14) — Crohn’s disease         Ileo-colonic, n (%) — 2 (4.7) —         Ileum, n (%) — 9 (20.9) —         Colon, n (%) — 1 (2.3) — Gluten-free diet duration, mean (s.d.), months 4.3 (5.6) — — HC: healthy control. The comparison of US findings among the three groups There were significant differences among disease groups and HCs for inflammation and total US scores but not for damage score (P = 0.007, P = 0.012 and P = 0.53, respectively). When compared within pairs, IBD and celiac disease patients had similar inflammation (P = 0.652), damage (P = 0.278) and total US scores (P = 0.628). The inflammation score of celiac disease was higher than that in HCs (P = 0.004) as well as the total inflammation score (P = 0.005) but not the damage score (P = 0.508). The same results could be observed with IBD vs HCs (inflammation, P = 0.003; damage, P = 0.947; total US score, P = 0.009) (Table 1, supplementary Fig. S1, available at Rheumatology online). When the frequency of each elementary lesion was evaluated, there was a significant difference for the presence of thickening at quadriceps, distal patella, Achilles, triceps entheses and Doppler signals at the distal patellar enthesis. When compared as two groups, the thickening of the distal patellar enthesis, Achilles and triceps enthesis was more frequent compared with celiac (P = 0.002, P = 0.006 and P = 0.001, respectively) with more frequent Doppler signals at the distal patellar enthesis (P < 0.001). The distal patellar tendon thickening in the IBD group also was more frequent than for the HCs (P < 0.001). The rest of the comparisons were not significant, after Bonferroni correction (supplementary Table S2, available at Rheumatology online). Factors associated with US score In IBD, age was significantly correlated with inflammation, damage and total US scores (supplementary Table S3, available at Rheumatology online). BMI was also correlated to inflammation and total US scores but not to damage score. Disease duration was independent of inflammation and damage scores. Men had higher inflammation [11.30 (5.398) vs 6.94 (4.434), P = 0.005] and total US [12.44 (6.241) vs 8.06 (6.567), P = 0.005] scores than women whereas damage score was similar. For celiac disease, age was correlated with damage score but not with inflammation and total US scores (supplementary Table S3, available at Rheumatology online). Interestingly there was an inverse correlation between the disease duration of celiac disease and inflammation and total US scores, which possibly reflected the fact that longer durations of gluten-free diet resulted in intestinal repair. Damage score was not linked to the duration. Men had higher inflammation score then women at a borderline significance [14.67 (7.55) vs 9.41 (5.934); P = 0.05], whereas the other scores were not significantly different (data not given). BMI was not correlated with either inflammation or damage score in celiac disease. In HCs, both age and BMI had significant correlations with the US scores (supplementary Table S3, available at Rheumatology online). Gender did not have an effect on the US scores (data not given). Regression analysis For females, keeping all other predictors constant, patients with celiac disease had 2.469 times (at significance level 0.05) and IBD patients had 1.650 times more inflammation than HCs (at significance level 0.1). Patients with celiac disease had 0.819 of the inflammation score of IBD patients (at significance level 0.1). For males, celiac patients had 2.347 times more inflammation than HCs. The mean inflammation scores were similar in IBD and HCs and the difference between celiac and IBD groups was significant at a lower significance level, 0.05. Again keeping all other predictors constant, the mean damage scores are not statistically different from each other in celiac disease, IBD and HCs, either in females or in males (details given in supplementary Tables S4–S9, available at Rheumatology online). Discussion This is the first study to compare the entheseal abnormalities in patients with IBD and celiac disease without signs of entheseal involvement of SpA as compared with HCs. Entheseal inflammation scores were higher in patients with IBD and in celiac disease patients than in HCs whereas the damage scores were similar. Celiac disease and IBD had similar inflammation, damage and total US scores, but the regression analysis surprisingly showed even higher inflammation score in celiac disease. Our results are compatible with the literature where all studies found subclinical entheseal disease in celiac disease and IBD, but this is the first direct study comparing the two [4–8] (supplementary Table S10, available at Rheumatology online). Our findings also supported the idea that restoration of intestinal barrier function with a gluten-free diet was associated with less enthesopathy since celiac cases with shorter disease duration had more sonographic changes. One of the major differences of this study vs the literature is the effect of BMI, gender and age on the US scores. We saw a clear relationship between these and US scores whereas the study by Atteno et al. [4, 5] had found no effects of BMI on celiac disease. Our observations are also supported by other publications where these factors have been linked to US findings in SpA [11, 12]. The lower limb enthesis is exposed to biomechanical stress continuously and obesity is a risk factor increasing the load over the enthesis. Age is also another factor that reflects the duration of biomechanical stress and therefore the impact of these on the US scores would be quite expected. Another difference is the effect of gluten-free diet on US scores in celiac disease. The first study by Atteno et al. [4, 5] did not show any connections between these two, whereas later on they published another study where patients on gluten-free diet had lower US scores than untreated patients. Similarly, in our study the correlations between disease duration and the US scores were found to be in opposite directions in IBD and celiac disease. Although the impact of the gluten-free diet did not reach statistical significance in our study, people may have started a gluten-free diet soon as after getting a diagnosis, making it difficult to analyse the effect of disease duration and the treatment effect due to their overlapping in celiac disease. Gluten-free diet may reverse some of the sonographic entheseal abnormalities [5]. Whether this is linked to the reduction of the intestinal inflammation needs further investigation. The importance of subclinical enthesopathy in IBD is not known, but one small study in psoriasis showed that subclinical enthesopathy may precede the arthritis [13]. We can not make any further inference due to the cross-sectional design of our study. There is emerging evidence to support the link between the gut and the joints. Subclinical gut inflammation is reported in 60% of patients with SpA, and IBD can develop in 7–12% of SpA patients [14]. Historically it has been demonstrated that HLA-B27 and human β2-microglobulin transgenic rats did not develop arthritis or colitis when raised in a germ free environment [15]. The role of intestinal microbiota is increasingly recognized in SpA and it plays a critical role in the pathogenesis of IBD [16]. Finally a large number of genes have been found to be linked to both IBD and AS [17]. The enthesis is increasingly recognized as the primary site of inflammation in IBD-related arthropathy and hence we studied the gut–enthesis axis with the present study further supporting this concept. Finally, although IBD and celiac disease are viewed as completely separate immunopathogenetic disease entities, some studies have shown that IBD is 10 times more common in celiac disease sufferers whereas celiac disease is not common in primary IBD [18, 19]. An interesting hypothesis to consider is that abnormal gut permeability associated with both celiac disease and IBD may result in subclinical entheseal inflammation (Fig. 1). Also, it is possible that these subclinical entheseal changes may relate to the patterns of clinical arthropathy reported in celiac disease, although such arthropathy is rare in our experience. Fig. 1 View largeDownload slide The gut–enthesis connection The association between enthesopathy and gut disease extends beyond IBD, as seen in celiac disease. It is proposed that abnormal gut permeability in both major classes of enteropathy leads to access of bacterial adjuvant and other intestinal products to the circulation. Given the micro-damage and subtle vascular perturbations at the entheseal sites of high stress, these adjuvants may get deposited at the entheseal sites, leading to perturbation of normal immune homeostasis and tissue repair. The shared genetics perturbations between the gut and the enthesis in SpA with greater magnitude of systemic inflammation may lead to the eventual SpA clinical enthesitis phenotype. Fig. 1 View largeDownload slide The gut–enthesis connection The association between enthesopathy and gut disease extends beyond IBD, as seen in celiac disease. It is proposed that abnormal gut permeability in both major classes of enteropathy leads to access of bacterial adjuvant and other intestinal products to the circulation. Given the micro-damage and subtle vascular perturbations at the entheseal sites of high stress, these adjuvants may get deposited at the entheseal sites, leading to perturbation of normal immune homeostasis and tissue repair. The shared genetics perturbations between the gut and the enthesis in SpA with greater magnitude of systemic inflammation may lead to the eventual SpA clinical enthesitis phenotype. Our study has some limitations. Although we were still able to see clear differences among groups, our relatively small sample size might not give us enough power for analysis of subgroups including gender. A longitudinal study is needed to be able to capture the impact of the gluten-free diet on the entheseal features. It would also be interesting to determine whether the US enthesopathy score is linked to the titres of tissue transglutaminase since autoantibodies against this may correlate with the degree of subclinical disease activity. However, no link was seen in a previous study [5]. In conclusion, patients with celiac disease and IBD have higher subclinical enthesopathy scores in comparison with HCs. Although these diseases have different pathogenic mechanisms, the common mechanism among them might be intestinal permeability disorders due to inflammation of the gut. Based on these data, we hypothesized that this common pathway may lead to similar enthesitis US findings in these diseases. It is likely that the shared genetics of IBD and SpA around the IL-23 and several other pathways leads to the supervening inflammatory phenotype in the SpA [20]. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: S.Z.A. has received honoraria from Abbvie, Novartis, Pfizer, UCB and Sanofi. All other authors have declared no conflicts of interest. Supplementary data Supplementary data are available at Rheumatology online. References 1 McGonagle D , Khan MA , Marzo-Ortega H et al. Enthesitis in spondyloarthropathy . Curr Opin Rheumatol 1999 ; 11 : 244 – 50 . Google Scholar CrossRef Search ADS PubMed 2 Slobodin G , Rimar D , Boulman N et al. Entheseal involvement in systemic disorders . Clin Rheumatol 2015 ; 34 : 2001 – 10 . Google Scholar CrossRef Search ADS PubMed 3 Maiuri L , Ciacci C , Ricciardelli I et al. Association between innate response to gliadin and activation of pathogenetic T cells in coeliac disease . Lancet 2003 ; 362 : 30 – 7 . Google Scholar CrossRef Search ADS PubMed 4 Atteno M , Costa L , Tortora R et al. The occurrence of lower limb enthesopathy in coeliac disease patients without clinical signs of articular involvement . Rheumatology 2013 ; 52 : 893 – 7 . Google Scholar CrossRef Search ADS PubMed 5 Atteno M , Costa L , Cozzolino A et al. The enthesopathy of celiac patients: effects of gluten-free diet . Clin Rheumatol 2014 ; 33 : 537 – 41 . Google Scholar CrossRef Search ADS PubMed 6 Bandinelli F , Milla M , Genise S et al. Ultrasound discloses entheseal involvement in inactive and low active inflammatory bowel disease (IBD) without clinical signs and symptoms of spondyloarthropathy . Rheumatology 2010 ; 50 : 1275 – 9 . Google Scholar CrossRef Search ADS 7 Rovisco J , Duarte C , Batticcioto A et al. Hidden musculoskeletal involvement in inflammatory bowel disease: a multicenter ultrasound study . BMC Musculoskelet Disord 2016 ; 17 : 84 . Google Scholar CrossRef Search ADS PubMed 8 Hsiao YF , Chen Wei S , Lu CH et al. Patients with inflammatory bowel disease have higher sonographic enthesitis scores than normal individuals: pilot Study in Taiwan . J Med Ultrasound 2014 ; 22 : 194 – 9 . Google Scholar CrossRef Search ADS 9 Aydin SZ , Ash ZR , Tinazzi I et al. The link between enthesitis and arthritis in psoriatic arthritis: a switch to a vascular phenotype at insertions may play a role in arthritis development . Ann Rheum Dis 2013 ; 72 : 992 – 5 . Google Scholar CrossRef Search ADS PubMed 10 Wakefield RJ , Balint PV , Szkudlarek M et al. OMERACT 7 Special Interest Group. Musculoskeletal ultrasound including definitions for ultrasonographic pathology . J Rheumatol 2005 ; 32 : 2485 – 7 . Google Scholar PubMed 11 Polachek A , Cook R , Chandran V , Gladman DD , Eder L. The association between sonographic enthesitis and radiographic damage in psoriatic arthritis . Arthritis Res Ther 2017 ; 19 : 189 . Google Scholar CrossRef Search ADS PubMed 12 Rudwaleit M , Baeten D. Ankylosing spondylitis and bowel disease . Best Pract Res Clin Rheumatol 2006 ; 20 : 451 – 71 . Google Scholar CrossRef Search ADS PubMed 13 Tinazzi I , McGonagle D , Biasi D et al. Preliminary evidence that subclinical enthesopathy may predict psoriatic arthritis in patients with psoriasis . J Rheumatol 2011 ; 38 : 2691 – 2 . Google Scholar CrossRef Search ADS PubMed 14 Mielants H , Veys EM , Cuvelier C et al. The evolution of spondyloarthropathies in relation to gut histology: III relation between gut and joint . J Rheumatol 1995 ; 22 : 2279 – 84 . Google Scholar PubMed 15 Taurog JD , Richardson JA , Croft JT et al. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats . J Exp Med 1994 ; 180 : 2359 – 64 . Google Scholar CrossRef Search ADS PubMed 16 Rosenbaum JT , Lin P , Asquith M et al. Does the microbiome play a causal role in spondyloarthritis? Clin Rheumatol 2014 ; 33 : 763 – 7 . Google Scholar CrossRef Search ADS PubMed 17 Bowness P , Gafney K , Gaston H et al. Identification of multiple risk variants for ankylosing spondylitis through high density genotyping of immune-related loci . Nat Genet 2013 ; 45 : 730 – 8 . Google Scholar CrossRef Search ADS PubMed 18 Leeds JS , Höroldt 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 19 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 20 McGonagle D , Aydin SZ , Gül A , Mahr A , Direskeneli H. ‘MHC-I-opathy’-unified concept for spondyloarthritis and Behçet disease . Nat Rev Rheumatol 2015 ; 11 : 731 – 40 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. 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/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology Oxford University Press

Similar subclinical enthesitis in celiac and inflammatory bowel diseases by ultrasound suggests a gut enthesis axis independent of spondyloarthropathy spectrum

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Abstract

Abstract Objective Higher subclinical enthesitis on US has been reported in IBD and celiac disease, separately. The objective of this study was to compare IBD and celiac disease for enthesitis on US. Higher enthesitis scores in IBD compared with celiac disease would support a shared pathogenic mechanism between IBD and spondyloarthritis, whereas similar scores may suggest a general impact of gut inflammation on the enthesis. Methods Patients with IBD, celiac disease and healthy controls (HCs) were recruited and 12 entheses were scanned by US, blind to the diagnosis and clinical assessment. Elementary lesions for enthesitis were scored on a scale between 0 and 3, for inflammation, damage and total US scores. Results A total of 1260 entheses were scanned in 44 patients with celiac disease, 43 patients with IBD and 18 HCs. The three groups were matched for age and BMI. Patients with celiac disease and IBD had higher inflammation scores than HCs [10.4 (6.5), 9.6 (5.4) and 5.6 (5.2), respectively, P = 0.007) whereas damage scores were similar. Both age and BMI had significant effects on the entheseal scores, mostly for inflammation scores but when controlling for these the US enthesopathy scores were still higher in celiac disease and IBD. Conclusion The magnitude of subclinical enthesopathy scores is similar between celiac disease and IBD in comparison with HCs. These findings suggest that the common factor between both diseases and enthesopathy is abnormal gut permeability, which may be modified by the genetic architecture of IBD leading to clinical arthropathy. Celiac disease, inflammatory bowel disease, enthesitis, ultrasound, inflammation, damage Rheumatology key messages Celiac disease and IBD have a similar magnitude of subclinical enthesopathies on ultrasound. BMI, age and gender may affect subclinical enthesitis in celiac disease and IBD. The common factor between both celiac disease and IBD on enthesopathies is abnormal gut permeability. Introduction Enthesitis, the inflammation of the attachment sites of ligaments, tendons, joint capsule or fascia to the bones, is a characteristic sign and hallmark of spondyloarthritis (SpA) [1]. However, it is not specific to SpA and can be seen in other inflammatory and non-inflammatory conditions [2]. Celiac disease is a systemic autoimmune disorder of the bowels induced by gluten consumption, with extra-intestinal manifestations one of which is musculoskeletal features, but it is not specifically associated with clinical enthesitis or other enthesitis-associated features including axial inflammation or nail involvement [3]. Subclinical enthesopathies were previously reported in celiac disease when screened by US [4, 5]. Similarly, IBD may also present with articular features in addition to subclinical enthesitis [6–8]. To date, there are no studies comparing the entheseal changes in celiac disease and IBD. In this study we aimed to explore the entheseal changes and confounding factors in IBD and celiac disease compared with healthy controls (HCs). Higher enthesitis scores in IBD than celiac disease would support a relationship between IBD and SpA and a shared pathogenic mechanism between the two, whereas similar scores may suggest a more general impact of gut inflammation and associated barrier dysfunction are a key feature in triggering entheseal changes. We used US to demonstrate entheseal changes as physical examination has been shown to underestimate enthesitis when compared with US [9]. Additionally US gives information about the inflammatory changes as well as tissue damage, which enables a more detailed comparison at a tissue level. We also summarized the literature to describe the similarities and differences among studies. Methods Study design In this cross-sectional study, patients with IBD and celiac disease were consecutively recruited from the gastroenterology outpatient clinic of Sakarya University Education and Research Hospital between 2016 and 2017. This study was approved by the local Ethics Committee at Sakarya University Education and Research Hospital, Turkey (No. 16214662/050.01.04/112-113) and informed consent was obtained from all individuals. Celiac disease was diagnosed clinically and on duodenal biopsy, and IBD was diagnosed based on characteristic endoscopic and/or histopathological findings. The inclusion criteria were as follows: being >18 years, no enthesitis on history and on exam, no symptoms and signs of SpA, no NSAIDs within the past 3 months and no biologics in any time frame. The HCs were enrolled among asymptomatic volunteers working in the hospital and patients’ acquaintances, excluding blood relatives. Clinical assessment Demographic data were collected including age, gender, BMI, disease duration and medications. The duration of gluten-free diet for patients with celiac disease was recorded. Prior to US scan, all subjects underwent a clinical examination by the same physician (C.K.) to record tenderness in the same entheseal sites of the US scan elicited by pressure. Ultrasonography Patients had a US scan on the same day of their clinical assessment by an experienced rheumatologist (S.B.U.), blinded to physical examination findings and diagnosis. US was performed using a LOGIQ P9 (GE Healthcare, USA), with a 7–13 MHz linear transducer. Power Doppler (PD) settings were standardized with a pulse repetition frequency of 500 Hz and low wall filter. The colour gain was increased to the highest value where no PD signal was observed below the bony cortex. The insertions of the quadriceps tendon, proximal and distal patellar tendon, Achilles tendon, plantar aponeurosis and triceps tendon were examined bilaterally, in longitudinal and transverse planes. Hypoechogenicity, thickening, enthesophytes, calcifications, erosions and entheseal PD signals were evaluated as elementary lesions [10]. Findings were graded on a scale between 0 and 3 for each of the abnormalities as described before (details provided in supplementary Table S1, available at Rheumatology online) [9]. Briefly thickening and erosions were scored quantitatively whereas the rest was defined semi-quantitatively (normal: grade 0; mild: grade 1; moderate: grade 2; severe: grade 3). Findings that are associated with inflammation (hypoechogenicity, thickening and PD) were summed to calculate an inflammation score. US findings related to tissue damage (calcifications, erosions and enthesophytes) were summed to calculate a damage score. The sum of these two scores gave the total US enthesopathy score. Statistical analysis Continuous data were described using means (s.d.) and categorical variables were expressed as frequencies (percentages). The independent-samples Kruskal–Wallis test was used to compare US scores between groups, followed by the Mann–Whitney U test for paired comparisons, and the chi-square test was used to compare categorical variables. Correlations between clinical variables and US scores were analysed using the Spearman rank-correlation test. A regression analysis was performed to understand the impact on the US scores including age, gender, BMI and diagnosis as independent variables. P < 0.05 was considered statistically significant, but when three groups were compared, a Bonferroni correction was made and the P-value was set to 0.017. SPSS version 24 (IBM, Chicago, IL, USA) and R statistical software (R Foundation for Statistical Computing, Vienna, Austria) were used for analysis. Results Forty-four patients with celiac disease, 43 patients with IBD (12 Crohn’s disease, 31 ulcerative colitis) and 18 HCs were enrolled (Table 1). The groups were matched for BMI and age whereas there were more males in the IBD group. Table 1 Demographics and US scores of patients with celiac disease, IBD and HCs Demographics and US scores Celiac disease IBD HCs (n = 44) (n = 43) (n = 18) Age, mean (s.d.), years 38 (12.4) 42.5 (13) 39.2 (8.7) Female, n (%) 35 (79.5) 16 (37.2) 13 (72.2) BMI, mean (s.d.), kg/m2 24.4 (4.5) 26.2 (5.5) 26.7 (5.8) Disease duration, mean (s.d.), months 4.5 (5.6) 70.79 (81.5) — Total inflammation score, mean (s.d.) 10.4 (6.5) 9.6 (5.4) 5.6 (5.2) Damage score, mean (s.d.) 1.07 (1.5) 1.1 (2.3) 1.0 (1.7) Total US score, mean (s.d.) 11.5 (7.1) 10.8 (6.6) 6.6 (6.3) Disease activity for IBD     Remission, n (%) — 22 (51.2) —     Mild-moderate, n (%) — 13 (30.2) —     Moderate-severe, n (%) — 8 (18.6) — Site of intestinal involvement for IBD Ulcerative colitis         Left sided colitis, n (%) — 19 (44.2) —         Extensive colitis, n (%) — 6 (14) —         Proctitis, n (%) — 6 (14) — Crohn’s disease         Ileo-colonic, n (%) — 2 (4.7) —         Ileum, n (%) — 9 (20.9) —         Colon, n (%) — 1 (2.3) — Gluten-free diet duration, mean (s.d.), months 4.3 (5.6) — — Demographics and US scores Celiac disease IBD HCs (n = 44) (n = 43) (n = 18) Age, mean (s.d.), years 38 (12.4) 42.5 (13) 39.2 (8.7) Female, n (%) 35 (79.5) 16 (37.2) 13 (72.2) BMI, mean (s.d.), kg/m2 24.4 (4.5) 26.2 (5.5) 26.7 (5.8) Disease duration, mean (s.d.), months 4.5 (5.6) 70.79 (81.5) — Total inflammation score, mean (s.d.) 10.4 (6.5) 9.6 (5.4) 5.6 (5.2) Damage score, mean (s.d.) 1.07 (1.5) 1.1 (2.3) 1.0 (1.7) Total US score, mean (s.d.) 11.5 (7.1) 10.8 (6.6) 6.6 (6.3) Disease activity for IBD     Remission, n (%) — 22 (51.2) —     Mild-moderate, n (%) — 13 (30.2) —     Moderate-severe, n (%) — 8 (18.6) — Site of intestinal involvement for IBD Ulcerative colitis         Left sided colitis, n (%) — 19 (44.2) —         Extensive colitis, n (%) — 6 (14) —         Proctitis, n (%) — 6 (14) — Crohn’s disease         Ileo-colonic, n (%) — 2 (4.7) —         Ileum, n (%) — 9 (20.9) —         Colon, n (%) — 1 (2.3) — Gluten-free diet duration, mean (s.d.), months 4.3 (5.6) — — HC: healthy control. Table 1 Demographics and US scores of patients with celiac disease, IBD and HCs Demographics and US scores Celiac disease IBD HCs (n = 44) (n = 43) (n = 18) Age, mean (s.d.), years 38 (12.4) 42.5 (13) 39.2 (8.7) Female, n (%) 35 (79.5) 16 (37.2) 13 (72.2) BMI, mean (s.d.), kg/m2 24.4 (4.5) 26.2 (5.5) 26.7 (5.8) Disease duration, mean (s.d.), months 4.5 (5.6) 70.79 (81.5) — Total inflammation score, mean (s.d.) 10.4 (6.5) 9.6 (5.4) 5.6 (5.2) Damage score, mean (s.d.) 1.07 (1.5) 1.1 (2.3) 1.0 (1.7) Total US score, mean (s.d.) 11.5 (7.1) 10.8 (6.6) 6.6 (6.3) Disease activity for IBD     Remission, n (%) — 22 (51.2) —     Mild-moderate, n (%) — 13 (30.2) —     Moderate-severe, n (%) — 8 (18.6) — Site of intestinal involvement for IBD Ulcerative colitis         Left sided colitis, n (%) — 19 (44.2) —         Extensive colitis, n (%) — 6 (14) —         Proctitis, n (%) — 6 (14) — Crohn’s disease         Ileo-colonic, n (%) — 2 (4.7) —         Ileum, n (%) — 9 (20.9) —         Colon, n (%) — 1 (2.3) — Gluten-free diet duration, mean (s.d.), months 4.3 (5.6) — — Demographics and US scores Celiac disease IBD HCs (n = 44) (n = 43) (n = 18) Age, mean (s.d.), years 38 (12.4) 42.5 (13) 39.2 (8.7) Female, n (%) 35 (79.5) 16 (37.2) 13 (72.2) BMI, mean (s.d.), kg/m2 24.4 (4.5) 26.2 (5.5) 26.7 (5.8) Disease duration, mean (s.d.), months 4.5 (5.6) 70.79 (81.5) — Total inflammation score, mean (s.d.) 10.4 (6.5) 9.6 (5.4) 5.6 (5.2) Damage score, mean (s.d.) 1.07 (1.5) 1.1 (2.3) 1.0 (1.7) Total US score, mean (s.d.) 11.5 (7.1) 10.8 (6.6) 6.6 (6.3) Disease activity for IBD     Remission, n (%) — 22 (51.2) —     Mild-moderate, n (%) — 13 (30.2) —     Moderate-severe, n (%) — 8 (18.6) — Site of intestinal involvement for IBD Ulcerative colitis         Left sided colitis, n (%) — 19 (44.2) —         Extensive colitis, n (%) — 6 (14) —         Proctitis, n (%) — 6 (14) — Crohn’s disease         Ileo-colonic, n (%) — 2 (4.7) —         Ileum, n (%) — 9 (20.9) —         Colon, n (%) — 1 (2.3) — Gluten-free diet duration, mean (s.d.), months 4.3 (5.6) — — HC: healthy control. The comparison of US findings among the three groups There were significant differences among disease groups and HCs for inflammation and total US scores but not for damage score (P = 0.007, P = 0.012 and P = 0.53, respectively). When compared within pairs, IBD and celiac disease patients had similar inflammation (P = 0.652), damage (P = 0.278) and total US scores (P = 0.628). The inflammation score of celiac disease was higher than that in HCs (P = 0.004) as well as the total inflammation score (P = 0.005) but not the damage score (P = 0.508). The same results could be observed with IBD vs HCs (inflammation, P = 0.003; damage, P = 0.947; total US score, P = 0.009) (Table 1, supplementary Fig. S1, available at Rheumatology online). When the frequency of each elementary lesion was evaluated, there was a significant difference for the presence of thickening at quadriceps, distal patella, Achilles, triceps entheses and Doppler signals at the distal patellar enthesis. When compared as two groups, the thickening of the distal patellar enthesis, Achilles and triceps enthesis was more frequent compared with celiac (P = 0.002, P = 0.006 and P = 0.001, respectively) with more frequent Doppler signals at the distal patellar enthesis (P < 0.001). The distal patellar tendon thickening in the IBD group also was more frequent than for the HCs (P < 0.001). The rest of the comparisons were not significant, after Bonferroni correction (supplementary Table S2, available at Rheumatology online). Factors associated with US score In IBD, age was significantly correlated with inflammation, damage and total US scores (supplementary Table S3, available at Rheumatology online). BMI was also correlated to inflammation and total US scores but not to damage score. Disease duration was independent of inflammation and damage scores. Men had higher inflammation [11.30 (5.398) vs 6.94 (4.434), P = 0.005] and total US [12.44 (6.241) vs 8.06 (6.567), P = 0.005] scores than women whereas damage score was similar. For celiac disease, age was correlated with damage score but not with inflammation and total US scores (supplementary Table S3, available at Rheumatology online). Interestingly there was an inverse correlation between the disease duration of celiac disease and inflammation and total US scores, which possibly reflected the fact that longer durations of gluten-free diet resulted in intestinal repair. Damage score was not linked to the duration. Men had higher inflammation score then women at a borderline significance [14.67 (7.55) vs 9.41 (5.934); P = 0.05], whereas the other scores were not significantly different (data not given). BMI was not correlated with either inflammation or damage score in celiac disease. In HCs, both age and BMI had significant correlations with the US scores (supplementary Table S3, available at Rheumatology online). Gender did not have an effect on the US scores (data not given). Regression analysis For females, keeping all other predictors constant, patients with celiac disease had 2.469 times (at significance level 0.05) and IBD patients had 1.650 times more inflammation than HCs (at significance level 0.1). Patients with celiac disease had 0.819 of the inflammation score of IBD patients (at significance level 0.1). For males, celiac patients had 2.347 times more inflammation than HCs. The mean inflammation scores were similar in IBD and HCs and the difference between celiac and IBD groups was significant at a lower significance level, 0.05. Again keeping all other predictors constant, the mean damage scores are not statistically different from each other in celiac disease, IBD and HCs, either in females or in males (details given in supplementary Tables S4–S9, available at Rheumatology online). Discussion This is the first study to compare the entheseal abnormalities in patients with IBD and celiac disease without signs of entheseal involvement of SpA as compared with HCs. Entheseal inflammation scores were higher in patients with IBD and in celiac disease patients than in HCs whereas the damage scores were similar. Celiac disease and IBD had similar inflammation, damage and total US scores, but the regression analysis surprisingly showed even higher inflammation score in celiac disease. Our results are compatible with the literature where all studies found subclinical entheseal disease in celiac disease and IBD, but this is the first direct study comparing the two [4–8] (supplementary Table S10, available at Rheumatology online). Our findings also supported the idea that restoration of intestinal barrier function with a gluten-free diet was associated with less enthesopathy since celiac cases with shorter disease duration had more sonographic changes. One of the major differences of this study vs the literature is the effect of BMI, gender and age on the US scores. We saw a clear relationship between these and US scores whereas the study by Atteno et al. [4, 5] had found no effects of BMI on celiac disease. Our observations are also supported by other publications where these factors have been linked to US findings in SpA [11, 12]. The lower limb enthesis is exposed to biomechanical stress continuously and obesity is a risk factor increasing the load over the enthesis. Age is also another factor that reflects the duration of biomechanical stress and therefore the impact of these on the US scores would be quite expected. Another difference is the effect of gluten-free diet on US scores in celiac disease. The first study by Atteno et al. [4, 5] did not show any connections between these two, whereas later on they published another study where patients on gluten-free diet had lower US scores than untreated patients. Similarly, in our study the correlations between disease duration and the US scores were found to be in opposite directions in IBD and celiac disease. Although the impact of the gluten-free diet did not reach statistical significance in our study, people may have started a gluten-free diet soon as after getting a diagnosis, making it difficult to analyse the effect of disease duration and the treatment effect due to their overlapping in celiac disease. Gluten-free diet may reverse some of the sonographic entheseal abnormalities [5]. Whether this is linked to the reduction of the intestinal inflammation needs further investigation. The importance of subclinical enthesopathy in IBD is not known, but one small study in psoriasis showed that subclinical enthesopathy may precede the arthritis [13]. We can not make any further inference due to the cross-sectional design of our study. There is emerging evidence to support the link between the gut and the joints. Subclinical gut inflammation is reported in 60% of patients with SpA, and IBD can develop in 7–12% of SpA patients [14]. Historically it has been demonstrated that HLA-B27 and human β2-microglobulin transgenic rats did not develop arthritis or colitis when raised in a germ free environment [15]. The role of intestinal microbiota is increasingly recognized in SpA and it plays a critical role in the pathogenesis of IBD [16]. Finally a large number of genes have been found to be linked to both IBD and AS [17]. The enthesis is increasingly recognized as the primary site of inflammation in IBD-related arthropathy and hence we studied the gut–enthesis axis with the present study further supporting this concept. Finally, although IBD and celiac disease are viewed as completely separate immunopathogenetic disease entities, some studies have shown that IBD is 10 times more common in celiac disease sufferers whereas celiac disease is not common in primary IBD [18, 19]. An interesting hypothesis to consider is that abnormal gut permeability associated with both celiac disease and IBD may result in subclinical entheseal inflammation (Fig. 1). Also, it is possible that these subclinical entheseal changes may relate to the patterns of clinical arthropathy reported in celiac disease, although such arthropathy is rare in our experience. Fig. 1 View largeDownload slide The gut–enthesis connection The association between enthesopathy and gut disease extends beyond IBD, as seen in celiac disease. It is proposed that abnormal gut permeability in both major classes of enteropathy leads to access of bacterial adjuvant and other intestinal products to the circulation. Given the micro-damage and subtle vascular perturbations at the entheseal sites of high stress, these adjuvants may get deposited at the entheseal sites, leading to perturbation of normal immune homeostasis and tissue repair. The shared genetics perturbations between the gut and the enthesis in SpA with greater magnitude of systemic inflammation may lead to the eventual SpA clinical enthesitis phenotype. Fig. 1 View largeDownload slide The gut–enthesis connection The association between enthesopathy and gut disease extends beyond IBD, as seen in celiac disease. It is proposed that abnormal gut permeability in both major classes of enteropathy leads to access of bacterial adjuvant and other intestinal products to the circulation. Given the micro-damage and subtle vascular perturbations at the entheseal sites of high stress, these adjuvants may get deposited at the entheseal sites, leading to perturbation of normal immune homeostasis and tissue repair. The shared genetics perturbations between the gut and the enthesis in SpA with greater magnitude of systemic inflammation may lead to the eventual SpA clinical enthesitis phenotype. Our study has some limitations. Although we were still able to see clear differences among groups, our relatively small sample size might not give us enough power for analysis of subgroups including gender. A longitudinal study is needed to be able to capture the impact of the gluten-free diet on the entheseal features. It would also be interesting to determine whether the US enthesopathy score is linked to the titres of tissue transglutaminase since autoantibodies against this may correlate with the degree of subclinical disease activity. However, no link was seen in a previous study [5]. In conclusion, patients with celiac disease and IBD have higher subclinical enthesopathy scores in comparison with HCs. Although these diseases have different pathogenic mechanisms, the common mechanism among them might be intestinal permeability disorders due to inflammation of the gut. Based on these data, we hypothesized that this common pathway may lead to similar enthesitis US findings in these diseases. It is likely that the shared genetics of IBD and SpA around the IL-23 and several other pathways leads to the supervening inflammatory phenotype in the SpA [20]. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: S.Z.A. has received honoraria from Abbvie, Novartis, Pfizer, UCB and Sanofi. All other authors have declared no conflicts of interest. Supplementary data Supplementary data are available at Rheumatology online. References 1 McGonagle D , Khan MA , Marzo-Ortega H et al. Enthesitis in spondyloarthropathy . Curr Opin Rheumatol 1999 ; 11 : 244 – 50 . Google Scholar CrossRef Search ADS PubMed 2 Slobodin G , Rimar D , Boulman N et al. Entheseal involvement in systemic disorders . Clin Rheumatol 2015 ; 34 : 2001 – 10 . Google Scholar CrossRef Search ADS PubMed 3 Maiuri L , Ciacci C , Ricciardelli I et al. Association between innate response to gliadin and activation of pathogenetic T cells in coeliac disease . Lancet 2003 ; 362 : 30 – 7 . Google Scholar CrossRef Search ADS PubMed 4 Atteno M , Costa L , Tortora R et al. The occurrence of lower limb enthesopathy in coeliac disease patients without clinical signs of articular involvement . Rheumatology 2013 ; 52 : 893 – 7 . Google Scholar CrossRef Search ADS PubMed 5 Atteno M , Costa L , Cozzolino A et al. The enthesopathy of celiac patients: effects of gluten-free diet . Clin Rheumatol 2014 ; 33 : 537 – 41 . Google Scholar CrossRef Search ADS PubMed 6 Bandinelli F , Milla M , Genise S et al. Ultrasound discloses entheseal involvement in inactive and low active inflammatory bowel disease (IBD) without clinical signs and symptoms of spondyloarthropathy . Rheumatology 2010 ; 50 : 1275 – 9 . Google Scholar CrossRef Search ADS 7 Rovisco J , Duarte C , Batticcioto A et al. Hidden musculoskeletal involvement in inflammatory bowel disease: a multicenter ultrasound study . BMC Musculoskelet Disord 2016 ; 17 : 84 . Google Scholar CrossRef Search ADS PubMed 8 Hsiao YF , Chen Wei S , Lu CH et al. Patients with inflammatory bowel disease have higher sonographic enthesitis scores than normal individuals: pilot Study in Taiwan . J Med Ultrasound 2014 ; 22 : 194 – 9 . Google Scholar CrossRef Search ADS 9 Aydin SZ , Ash ZR , Tinazzi I et al. The link between enthesitis and arthritis in psoriatic arthritis: a switch to a vascular phenotype at insertions may play a role in arthritis development . Ann Rheum Dis 2013 ; 72 : 992 – 5 . Google Scholar CrossRef Search ADS PubMed 10 Wakefield RJ , Balint PV , Szkudlarek M et al. OMERACT 7 Special Interest Group. Musculoskeletal ultrasound including definitions for ultrasonographic pathology . J Rheumatol 2005 ; 32 : 2485 – 7 . Google Scholar PubMed 11 Polachek A , Cook R , Chandran V , Gladman DD , Eder L. The association between sonographic enthesitis and radiographic damage in psoriatic arthritis . Arthritis Res Ther 2017 ; 19 : 189 . Google Scholar CrossRef Search ADS PubMed 12 Rudwaleit M , Baeten D. Ankylosing spondylitis and bowel disease . Best Pract Res Clin Rheumatol 2006 ; 20 : 451 – 71 . Google Scholar CrossRef Search ADS PubMed 13 Tinazzi I , McGonagle D , Biasi D et al. Preliminary evidence that subclinical enthesopathy may predict psoriatic arthritis in patients with psoriasis . J Rheumatol 2011 ; 38 : 2691 – 2 . Google Scholar CrossRef Search ADS PubMed 14 Mielants H , Veys EM , Cuvelier C et al. The evolution of spondyloarthropathies in relation to gut histology: III relation between gut and joint . J Rheumatol 1995 ; 22 : 2279 – 84 . Google Scholar PubMed 15 Taurog JD , Richardson JA , Croft JT et al. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats . J Exp Med 1994 ; 180 : 2359 – 64 . Google Scholar CrossRef Search ADS PubMed 16 Rosenbaum JT , Lin P , Asquith M et al. Does the microbiome play a causal role in spondyloarthritis? Clin Rheumatol 2014 ; 33 : 763 – 7 . Google Scholar CrossRef Search ADS PubMed 17 Bowness P , Gafney K , Gaston H et al. Identification of multiple risk variants for ankylosing spondylitis through high density genotyping of immune-related loci . Nat Genet 2013 ; 45 : 730 – 8 . Google Scholar CrossRef Search ADS PubMed 18 Leeds JS , Höroldt 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 19 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 20 McGonagle D , Aydin SZ , Gül A , Mahr A , Direskeneli H. ‘MHC-I-opathy’-unified concept for spondyloarthritis and Behçet disease . Nat Rev Rheumatol 2015 ; 11 : 731 – 40 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. 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/about_us/legal/notices)

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RheumatologyOxford University Press

Published: May 8, 2018

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