Biomarkers in Inflammatory Bowel Disease-Associated Spondyloarthritis: State of the Art and Unmet Needs

Abstract

Inflammatory bowel disease-associated spondyloarthritis is a systemic disease characterized by the chronic inflammation of both the gastrointestinal tract and the musculoskeletal system. Since inflammatory bowel disease-associated spondyloarthritis has been associated with a significant diagnostic delay, which may lead to poor quality of life and progression of joint damage, efforts to discover new reliable and noninvasive diagnostic biomarkers have been made. We reviewed the state of the art of biomarker research in inflammatory bowel disease-associated spondyloarthritis, showing that to date it has been largely unsatisfactory. Only a few of the biomarkers that have been investigated are likely to enter the clinical practice upon further validation in independent cohorts. The research of new and innovative biomarkers for inflammatory bowel disease-associated spondyloarthritis is warranted.

1. Introduction

Inflammatory bowel disease-associated spondyloarthritis (SpA/IBD) is a systemic disease characterized by the chronic inflammation of both the gastrointestinal tract and the musculoskeletal system [1]. From the rheumatologist’s point of view, SpA/IBD is included in the group of spondyloarthritides (SpA), together with ankylosing spondylitis (AS), reactive arthritis, undifferentiated arthritis, and psoriatic arthritis [2]. In fact, inflammatory bowel diseases (IBD), namely, Crohn’s disease (CD) and ulcerative colitis (UC), are among the most frequent extra-articular complications that may occur in patients with AS. From the gastroenterologist’s perspective, arthritis is the most frequent extraintestinal manifestation in IBD and may develop before, simultaneously with, or after the diagnosis of overt intestinal disease [3].

The prevalence of IBD in patients with AS is estimated between 5 and 10%, but nearly 50% of AS patients have subclinical gut inflammation [4]. From the point of view of IBD, 3% of the patients have concomitant AS and 13% have peripheral SpA according to a recent meta-analysis [5], but radiographic sacroiliitis, either symptomatic or subclinical, may involve half of the IBD patients [6].

The fact that joint symptoms may be mild or absent and the use of concomitant immunosuppressive therapies for IBD and the use of the New York criteria for AS may hamper the early diagnosis of SpA/IBD, resulting in a significant diagnostic delay, has been associated with several adverse outcomes for the patient, including poor quality of life and progression of joint damage [7, 8].

Evidence from preclinical studies corroborated the hypothesis that IBD and SpA may share a common pathogenesis, as in both diseases there is an involvement of tumor necrosis factor (TNF-α) and interleukin (IL) 23/17 pathways [9]. If the involvement of TNF-α is well known and further attested by the long experience of treatment with TNF inhibitors for both SpA and IBD, clinical trials of anti-IL17A agents in IBD failed to reach the primary endpoint and even appear to have a worsening effect on CD [10]. Conversely, ustekinumab, the first IL-12/23 inhibitor, is now approved for the treatment of CD but failed to improve symptoms and signs of axial SpA [11].

Taken together, these differences suggest that, despite the several features that SpA and IBD have in common, the coexistence of joint and gut inflammations is unique. This is further suggested by the proportion of human leukocyte antigen- (HLA-) B27-positive patients in the axial SpA/IBD group, far lower than AS and SpA in general [3, 12, 13]. Moreover, asymptomatic sacroiliitis, which is present in a significant percentage of IBD patients, is not associated with HLA-B27 [12]. Finally, the coexistence of gut and joint involvements advocates the multidisciplinary management of SpA/IBD patients, like in another multifaceted SpA like psoriatic arthritis [14].

Overall, SpA/IBD may be not only a subset of the broad entities of IBD and SpA but also a distinct and rather peculiar disease requesting a tailored clinical evaluation and therapeutic approach. For such an accomplishment, referral strategies such as the use of screening questionnaires [15] and the identification of simple biomarkers are warranted.

2. What Are Biomarkers?

A biomarker is a “characteristic that can be objectively measured and evaluated as an indicator of a normal biologic process, a pathophysiologic process, or a pharmacologic response to a therapeutic intervention” [16].

Ideal biomarkers should be sensitive, specific, reproducible, and derived from a noninvasive procedure. Each biomarker could theoretically be useful for the processes of diagnosis, treatment response, and prognosis evaluation, but such instruments are rare in clinical practice.

A further differentiation should be made between molecular, imaging, and clinical biomarkers of disease. Molecular biomarkers are biochemical variables that can be measured in the blood, stools, and other fluids or tissues of the human body. Objective, quantitative measurements of molecular biomarkers through a variety of techniques serve as indicators of normal or pathologic processes or indicators of response to therapy. Of note, the availability of new sequencing technologies allowed the identification of newer genetic biomarkers of disease [17].

Imaging technologies, such as MRI, CT scans, and ultrasound, can be regarded as biomarkers when they are used for the evaluation of disease activity and response to treatment. Imaging methods allow structural and functional assessments of disease activity and therapy.

Clinical biomarkers are physical signs and symptoms that may contribute to the diagnosis and assessment of established disease, but they are rarely followed by a game-changing decision making.

Biomarkers can further be divided into descriptive and mechanistic. Descriptive biomarkers reflect the state of a disease but are not directly involved in disease pathogenesis, whereas mechanistic biomarkers participate in the biologic mechanisms of disease. If descriptive biomarkers provide limited diagnostic and prognostic information, mechanistic biomarkers, reflecting the dysregulation of molecular pathways directly involved in pathogenesis of the disease, are more useful for guiding clinical decision making [18].

Several biomarkers have already been studied in SpA and IBD, but specific biomarkers addressing the coexistence of gut and joint inflammations, respectively, in SpA and IBD patients are lacking.

In this review, we will summarize the state of the art of biomarker research in SpA/IBD, trying to highlight lights and shadows of every tool that has been endorsed. Unless stated otherwise, we will primarily consider biomarkers that may be helpful to diagnose or identify SpA/IBD among patients with IBD or SpA.

3. Overview of Biomarkers in SpA/IBD

3.1. Genetic Biomarkers

A genetic biomarker is a DNA sequence that causes disease or is associated with susceptibility to disease.

To date, a variety of genetic loci that increase susceptibility to AS have been identified.

HLA-B27 is the prototype of genetic biomarkers in SpA, but several other nonmajor histocompatibility complex (MHC) loci like endoplasmic reticulum aminopeptidase 1 (ERAP-1), IL-23R, lymphotoxin beta receptor (LTBR), and TNFRSF1A (tumor necrosis factor receptor 1) have been described [19, 20].

HLA-B27 is present in about 85–95% of patients with AS in the US, Europe, and China. However, within a population, only 5% of HLA-B27-positive individuals develop AS or another form of SpA [20].

In addition to being a risk factor for SpA, HLA-B27 is likely implicated in the pathogenesis of AS by several mechanisms which include arthritogenic peptide theory, noncanonical HLA dimerization, HLA-B27 misfolded response, or alteration of gut microbiome by HLA-B27 [21].

As already pointed out, the role of HLA-B27 positivity in predicting SpA development in IBD patients is questionable, given the lower prevalence in SpA/IBD populations [3, 12, 13]. More recently, in a Norwegian cohort of IBD patients followed up to 20 years, the prevalence of HLA-B27 among IBD patients with AS was 57.1%, confirming the lower prevalence than in AS without IBD [22]. However, the presence of HLA-B27 was associated with an increased occurrence of inflammatory back pain, axial SpA, and AS. In this study, the quite high frequency of HLA-B27 in the Norwegian population probably contributed to the higher prevalence of AS and axial SpA in IBD patients (4.5% and 7.7%, respectively) [22].

Coming to IBD, the first CD susceptibility gene that has been identified is CARD15, also known as NOD2. Variants within this gene increase the risk for CD by threefold for heterozygous individuals and 33-44-fold for homozygous and compound heterozygous individuals [23]. Disappointingly, several studies excluded an association between CARD15 variants and AS or SpA in IBD populations [22, 24–26]. However, in SpA patients, an association was found between the carriage of CARD15 variants and the development of chronic subclinical gut inflammation, with an OR of 2.9 as compared to control population and of 5.8 as compared to SpA patients without gut inflammation [27].

In a Turkish study, the ERAP1 (rs26653) polymorphism was found to increase the disease risk in patients with AS and IBD compared with the control group (OR 2.6 for both groups). The results of the study also suggest that ERAP1 (rs26653) polymorphism may be an important genetic factor influencing the pathogenesis of UC with axial SpA (OR 2.9).

By contrast, IL-23R gene polymorphisms seem to have a protecting role in both IBD (OR 0.38 and 0.73 for CD and UC, respectively) and AS () [28–30].

Several other common risk variants for CD and AS have been described, but their significance should be evaluated in independent studies [31].

3.2. Biochemical Biomarkers

Biochemical markers are soluble molecules that may serve as an aid in diagnosing or in predicting susceptibility to the disease, monitoring disease activity, and predicting response to treatment and relapse. They can be measured in blood, urine, stools, or other body fluids or tissues.

Traditional serum markers of inflammation such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are not useful for the diagnosis of SpA in IBD patients and vice versa, since they lack both sensitivity and specificity [21]. This is not surprising, since inflammation may originate from both gut and joints. Moreover, the proportion of SpA and IBD patients that display abnormal CRP levels is variable, and it is not unusual to find patients with active disease and normal values of ESR and CRP. As a result, the serum concentrations of CRP are not significantly different between SpA/IBD and IBD patients [32].

Of note, in the proportion of SpA patients in which they are elevated (30-50%), CRP serum levels may be useful to assess disease activity [33] and to predict response to treatment [34] and radiographic progression [35]. CRP has therefore been included in the Ankylosing Spondylitis Disease Activity Score (ASDAS-CRP), which is currently used to assess disease activity in SpA. Also, in IBD, CRP levels have been correlated with higher disease activity and response to treatment [36, 37]. Therefore, even if the measurement of CRP is not useful for the diagnostic evaluation of SpA/IBD, it could be used to monitor disease activity and response to treatment.

Several cytokines have been measured in the serum of patients with either SpA or IBD, and their potential use as biomarkers has been evaluated.

Since IL-6 is the main driver of CRP production, it is not surprising that higher serum levels of IL-6 have been described in both SpA and IBD patients, though the clinical utility of serum IL-6 measurement is uncertain. In fact, IL-6 serum levels could not discriminate between SpA/IBD and IBD patients, as did not several other cytokines, like IL-10, IL-21, IL-22, IL-23, and interferon gamma (IFN-γ) [32]. Nevertheless, in SpA/IBD patients, a moderate positive correlation was found between serum concentrations of IL-23 and clinical disease activity of SpA [32]. In another small study, the authors evaluated the serum levels of IL-23 in 26 IBD vs. 11 SpA/IBD patients and found that IL-23 was significantly higher in SpA/IBD () compared to IBD patients () [38]. Another study, found a weak association between elevated IL-1 alpha and its receptor antagonist and SpA/IBD [39]. To date, there is no convincing evidence that inflammatory markers and cytokines could be used as disease biomarkers in SpA/IBD.

Several serological antibodies have been studied in IBD, including anti-Saccharomyces cerevisiae (ASCA), perinuclear anti-neutrophil cytoplasmic antibodies (pANCA), anti-I2, anti-Escherichia coli outer membrane porin (anti-OmpC), and anti-flagellin (anti-CBir1), but only ASCA and pANCA showed meaningful accuracy for the diagnosis of CD and UC, respectively [40].

In an early study conducted in patients with SpA, ASCA IgA levels, but not ASCA IgG, were higher than in control groups, but they were not related to the presence of gut inflammation. Conversely, ASCA IgG were found to be strongly associated with CD. The authors conclude that ASCA IgG may serve as a biomarker of CD in AS patients, though they did not include SpA/IBD patients in their evaluations [41].

Two later studies confirmed that ASCA IgA are higher in SpA patients than healthy controls [42, 43], whereas a third study failed to observe such an association [44]. In a recent study, ASCA levels seem to be associated with higher disease activity in a cohort of SpA patients [45].

Mundwiler et al. studied serum from 80 AS patients and 80 controls assessing for ASCA, anti-I2, anti-OmpC, anti-CBir1, and ANCA. They found no difference in positivity rates between AS and control groups with the established IBD values. Significantly more AS patients had ASCA IgG (26% vs. 13%), ASCA IgG and IgA (27% vs. 12%), and anti-I2 (25% vs. 14%) [46]. Another study failed to replicate these findings and reported higher levels of ANCA, but not ASCA, anti-I2, anti-OmpC, and anti-CBir1, in AS patients [47].

To assess the utility of these IBD-related biomarkers in SpA/IBD patients, De Vries et al. enrolled 179 patients (52 with AS, 50 with UC, 51 with CD, and 26 with IBD and AS). pANCA, ASCA (IgA and/or IgG), and OmpC antibodies were found in 21%, 30%, and 19% of the AS patients, respectively, but only pANCA could be considered a predictor of UC in AS patients (OR 8.2) [48].

Conversely, Wallis et al. could not replicate these results and found that among 76 patients with AS, 77 patients with AS/IBD, and 48 patients with mechanical back pain, SpA/IBD patients demonstrated a higher prevalence of ASCA, anti-OmpC, and anti-CBir1, but not ANCA, when compared to AS alone [49]. Overall, these studies provided conflicting results, and to date, these antibodies have no role in the assessment of SpA/IBD.

Fecal calprotectin is one of the most extensively studied stool markers in IBD. In a meta-analysis, the accuracy of fecal calprotectin to differentiate IBD and non-IBD patients was exceptionally high (AUC 0.95-0.98 using a cut-off level of 50 μg/g and 100 μg/g, respectively) [50].

Moreover, in IBD patients, fecal calprotectin decreased upon treatment and may predict disease relapse [51–53].

Several studies reported elevated levels of fecal calprotectin in patients with SpA. Abnormal fecal calprotectin is found in around 40-70% of the SpA patients and seems to correlate with articular disease activity [47, 54, 55]. However, only a minority of the SpA patients with elevated fecal calprotectin actually exhibited either clinical or subclinical gut disease [55].

In addition, the measurement of serum calprotectin, another marker of inflammation, provided conflicting results. Whereas some studies found significantly higher serum calprotectin in AS patients compared to healthy controls [56–58], other did not [55]. Even if serum calprotectin could be a predictor of radiographic progression [59], its specificity and sensitivity are too poor to be transferred in the clinical practice [58].

With regard to the possible use of calprotectin as a biomarker in SpA/IBD, Klingberg et al. designed a longitudinal study studying 164 AS patients after a 5-year follow-up and found that baseline fecal calprotectin was directly correlated with SpA disease activity at the 5-year follow-up. Moreover, fecal calprotectin could predict the development of CD (cumulative incidence 1.5% at 5 years) [55]. The latter study is encouraging, but further longitudinal studies are certainly needed to prove the role of serum and fecal calprotectin as gut disease biomarkers in SpA patients.

The identification of biomarkers of articular involvement in IBD patients is more intriguing and difficult at the same time. SpA and AS are traditionally considered seronegative diseases, and in recent years, considerable efforts have been made to discover reliable biomarkers of disease, with little or no success [60]. Even if a variety of biomarkers have been investigated, only a few showed potential diagnostic accuracy in order to be transferred in the clinical practice after being validated in independent cohorts.

Promising candidate biomarkers of SpA, other than CRP and cytokines, include the following: vascular endothelial growth factor (VEGF), matrix metalloproteinase-3 (MMP-3), Dickkopf-1 (DKK-1), sclerostin (SOST), and anti-CD74 antibodies.

VEGF levels are elevated in patients with AS and axial SpA and seem to correlate with radiographic progression [61, 62].

Higher MMP3 levels have been shown to reflect disease activity and treatment response in SpA, though the results among the studies are inconsistent [63, 64].

The Wnt family consists of a number of small secreted glycoproteins involved in regulation of a variety of cellular activities with critical roles during development [65]. The Dickkopf family, which includes DKK-1, inhibits the Wnt pathway. DKK-1 serum levels have been described as being lower in most [66–68] but not all studies [69] conducted in AS patients. However, DKK-1 levels appear to be inversely correlated with radiographic progression.

Sclerostin (SOST) is another inhibitor of the Wnt pathway that has been extensively studied in SpA.

The majority of the studies report lower serum levels of SOST in AS patients compared to controls [70–74], with a significant inverse correlation between SOST levels and radiographic progression, but other studies failed to confirm these findings [69, 75]. Furthermore, Tsui et al. previously reported the detection of higher levels of anti-SOST IgG in patients with AS [76].

Recently, Baerlecken et al. reported the detection of high serum levels of CD74 IgG in SpA patients [77]. The authors analyzed 145 sera from 94 axial SpA and 51 non-SpA patients, reporting that anti-CD74 antibodies were detected in 85.1% in axial SpA but in only 7.8% in non-SpA patients and their sensitivity and specificity for diagnosing axial SpA were, respectively, 85.1% and 92.2% [78]. Unfortunately, the diagnostic value of anti-CD74 antibodies has been recently questioned by an independent study that observed a low specificity of anti-CD74 when used for diagnostic purposes in early axial SpA, even if they confirmed the presence of higher serum levels in SpA patients compared to controls [79].

Only a few of these biomarkers, borrowed from AS, have been also evaluated in SpA/IBD.

YKL-40 (also known as Chitinase 3-like 1) is a glycoprotein produced by inflammatory, cancer, and stem cells. An old report identified YKL-40 as a possible biomarker for SpA/IBD [80]. In this study, serum YKL-40 was measured in 171 patients, 29 PsA, 66 IBD, and 76 SpA/IBD. The authors observed significant differences in YKL-40 values in SpA/IBD patients compared to IBD patients without joint involvement. In particular, YKL-40 was higher in SpA/IBD than IBD patients and healthy controls. The AUC for YKL-40 was 0.82, superior to that of CRP.

In another study, serum antibodies against anti-mutated citrullinated vimentin (anti-MCV) and second-generation anti-cyclic citrullinated peptide (anti-CCP2) antibodies were measured in 125 IBD patients, 35% of which had SpA/IBD [81]. Disappointingly, the proportion of anti-MCV and anti-CCP2 positivity was similar between IBD patients with or without articular involvement.

A more recent study reported that serum SOST and anti-SOST IgG levels may be useful to detect axial SpA in IBD patients [74]. Luchetti et al. measured serum SOST and anti-SOST levels in 85 SpA/IBD patients, 40 IBD patients, and healthy controls. Patients affected by SpA/IBD with axial involvement displayed significantly lower levels of SOST and higher levels of anti-SOST-IgG compared to patients with only peripheral arthritis, IBD, and controls. Moreover, SOST and anti-SOST-IgG serum levels were inversely correlated and associated with the duration of articular symptoms. Both biomarkers showed good accuracy in predicting the presence of axial SpA in patients with IBD (AUC 0.88 and 0.84 for SOST and anti-SOST, respectively).

In recent years, significant alterations in the intestinal microbiome of both IBD and SpA patients have been extensively reported [82, 83]. Early studies in AS observed an increased frequency of anti-Klebsiella pneumoniae antibodies in the serum of both SpA and IBD patients [84–87], but the clinical significance of these findings is uncertain.

Recently, the SpA/IBD microbiome has been studied using a novel technique, which couples the sorting of IgA-coated microbiota with 16S ribosomal RNA (rRNA) sequencing (called IgA-seq), focusing the analysis only on microbiota identified by the immune system [88]. Viladomiu et al. observed a selective enrichment in IgA-coated Escherichia coli in patients with SpA/CD compared to CD alone. These bacteria were similar to adherent-invasive E. coli (AIEC) pathotype. The authors could also demonstrate that colonization of germ-free mice with SpA/CD-derived E. coli isolates induced T helper 17 (Th17) cell mucosal immunity, providing evidence of a mechanistic link between intestinal microbiota and systemic inflammation.

Table 1 summarizes the properties of the candidate biochemical markers that have been evaluated in SpA/IBD to date. Overall, none of them possess the characteristics of the perfect biomarker, i.e., accuracy, reproducibility, and noninvasivity, though SOST and anti-SOST serum levels are promising tools for the assessment of axial disease in IBD patients. Other antibodies (such as ASCA and pANCA) and fecal calprotectin may be useful to suspect IBD in SpA patients, but all of them need further validation in well-designed studies.

3.3. Clinical Biomarkers

Clinical associations may contribute to the suspicion of extraintestinal and/or extra-articular manifestations, but they are not reliable as disease biomarkers.

Documented clinical associations between AS (or SpA) and IBD include the link between higher intestinal disease activity and the development of peripheral arthritis [89, 90], though a recent study with a longer follow-up failed to confirm this finding [91]. Conversely, patients reporting persistent or relapsing intestinal disease activity over a 20-year IBD course seemed to be more prone to developing axial SpA [22], even though this finding was quite unexpected, since axial SpA was thought to progress independently of the intestinal disease activity [92, 93].

Articular disease has been further independently associated more with CD than UC [5], with female gender [94, 95], with older age [89], and with smoking [90].

In patients with AS, development of IBD has been significantly associated with markers of increased articular disease activity but to some extent also with worse physical function and worse patient global well-being at the time of diagnosis of IBD [96].

In another larger study conducted in 1250 axial SpA patients, the development of IBD was associated with disease duration, with an increase of the risk by 30% per 10 years of disease duration [97].

In the Esperanza cohort, IBD was associated with peripheral SpA more than axial SpA [98].

3.4. Imaging Biomarkers

Imaging biomarkers are image features that should be obtained by noninvasive techniques and should be relevant for the diagnosis, the assessment of disease activity, or the prediction of outcomes.

Ultrasound is a noninvasive imaging technique that is increasingly being used to assess SpA patients, especially for the diagnosis of enthesitis, which is common in IBD patients.

An Italian study group found that ultrasound abnormalities of the entheses are present in a high proportion of IBD patients without clinical signs and symptoms of SpA. Of the 81 patients, 71 (92.6%) presented almost one tendon alteration, including higher thickness, enthesophytosis, bursitis, and erosions. However, power Doppler was positive only in 13/81 (16%) patients. Furthermore, ultrasound enthesopathy was not associated with activity, duration, and type of gut disease [99].

The early diagnosis of axial involvement is essential in SpA/IBD, since the diagnostic delay is associated with poor outcomes. The prevalence of radiographic sacroiliitis is elevated in IBD [6, 100], but radiographic alterations are known to occur late in the natural history of SpA. Magnetic resonance imaging (MRI) is now the reference standard for the assessment of nonradiographic sacroiliitis. MRI colonography or enterography is also increasingly used to assess disease activity and complications in IBD. This imaging technique may have a role in the assessment of sacroiliitis in the same MRI session. A retrospective study performed on 186 IBD patients found that the prevalence of inflammatory sacroiliitis on MRI, performed for the evaluation of the intestinal disease, was 16.7%. Sacroiliitis was bilateral in 14 cases and unilateral in 17 cases. Older age and female gender were significantly associated with the presence of sacroiliitis. Other factors such as type of IBD, disease duration and localization of IBD, history of surgery, CRP, intestinal disease activity, and treatment were not associated with sacroiliitis [101].

Since systematic colonoscopy assessment demonstrated a mucosal inflammation characteristic of CD in up to one-third of patients with SpA, Kopylov et al. examined the hypothesis if video capsule endoscopy (VCE) could be superior to detect inflammatory bowel lesions in patients with SpA.

In the SpACE Capsule Study, 64 adult SpA patients underwent VCE and standard colonoscopy with biopsies. Small bowel inflammation was present in 42.2% vs. 10.9% of patients according to VCE and standard colonoscopy, respectively. Interestingly, no correlation was observed with the presence of intestinal symptoms and CRP [102].

4. Conclusions

The prominent features of SpA/IBD, such as the lower prevalence of HLA-B27, the higher proportion of female patients, and the differential response to treatment of joint and gut diseases, suggest that this is a rather peculiar entity, distinct from AS, which deserves to be properly investigated, particularly with the goal to reduce unnecessary diagnostic delay and achieve an earlier diagnosis. This target may be accomplished using accurate biomarkers of disease, but, to date, the quest for biomarkers in SpA/IBD has been quite neglected and largely unsatisfactory. In this review, we showed that only a few of the biomarkers that have been investigated are likely to enter the clinical practice upon further validation in independent cohorts. The research of new and innovative biomarkers of SpA/IBD is therefore warranted.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

References

1. C. Salvarani and W. Fries, “Clinical features and epidemiology of spondyloarthritides associated with inflammatory bowel disease,” World Journal of Gastroenterology, vol. 15, no. 20, pp. 2449–2455, 2009. View at: Publisher Site | Google Scholar
2. M. Rudwaleit, D. van der Heijde, R. Landewe et al., “The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection,” Annals of the Rheumatic Diseases, vol. 68, no. 6, pp. 777–783, 2009. View at: Publisher Site | Google Scholar
3. R. D’Incà, M. Podswiadek, A. Ferronato, L. Punzi, M. Salvagnini, and G. C. Sturniolo, “Articular manifestations in inflammatory bowel disease patients: a prospective study,” Digestive and Liver Disease, vol. 41, no. 8, pp. 565–569, 2009. View at: Publisher Site | Google Scholar
4. E. Gracey, E. Dumas, M. Yerushalmi, Z. Qaiyum, R. D. Inman, and D. Elewaut, “The ties that bind: skin, gut and spondyloarthritis,” Current Opinion in Rheumatology, vol. 31, no. 1, pp. 62–69, 2019. View at: Publisher Site | Google Scholar
5. M. C. Karreman, J. J. Luime, J. M. W. Hazes, and A. E. A. M. Weel, “The prevalence and incidence of axial and peripheral spondyloarthritis in inflammatory bowel disease: a systematic review and meta-analysis,” Journal of Crohn's and Colitis, vol. 11, no. 5, pp. 631–642, 2017. View at: Publisher Site | Google Scholar
6. I. De Kock, P. Hindryckx, M. De Vos, L. Delrue, K. Verstraete, and L. Jans, “Prevalence of CT features of axial spondyloarthritis in patients with Crohn’s disease,” Acta Radiologica, vol. 58, no. 5, pp. 593–599, 2017. View at: Publisher Site | Google Scholar
7. P. Conigliaro, M. S. Chimenti, M. Ascolani et al., “Impact of a multidisciplinary approach in enteropathic spondyloarthritis patients,” Autoimmunity Reviews, vol. 15, no. 2, pp. 184–190, 2016. View at: Publisher Site | Google Scholar
8. M. M. Luchetti, D. Benfaremo, F. Ciccia et al., “Adalimumab efficacy in enteropathic spondyloarthritis: a 12-mo observational multidisciplinary study,” World Journal of Gastroenterology, vol. 23, no. 39, pp. 7139–7149, 2017. View at: Publisher Site | Google Scholar
9. K. De Wilde, K. Debusschere, S. Beeckman, P. Jacques, and D. Elewaut, “Integrating the pathogenesis of spondyloarthritis: gut and joint united?” Current Opinion in Rheumatology, vol. 27, no. 2, pp. 189–196, 2015. View at: Publisher Site | Google Scholar
10. M. M. Luchetti, D. Benfaremo, and A. Gabrielli, “Biologics in inflammatory and immunomediated arthritis,” Current Pharmaceutical Biotechnology, vol. 18, no. 12, pp. 989–1007, 2018. View at: Publisher Site | Google Scholar
11. A. Deodhar, L. S. Gensler, J. Sieper et al., “Three multicenter, randomized, double-blind, placebo-controlled studies evaluating the efficacy and safety of ustekinumab in axial spondyloarthritis,” Arthritis & Rheumatology, vol. 71, no. 2, pp. 258–270, 2019. View at: Publisher Site | Google Scholar
12. H. Peeters, B. Vander Cruyssen, H. Mielants et al., “Clinical and genetic factors associated with sacroiliitis in Crohn’s disease,” Journal of Gastroenterology and Hepatology, vol. 23, no. 1, pp. 132–137, 2007. View at: Publisher Site | Google Scholar
13. T. R. Orchard, H. Holt, L. Bradbury, J. Hammersma, E. McNally, and D. P. Jewell, “The prevalence, clinical features and association of HLA-B27 in sacroiliitis associated with established Crohn’s disease,” Alimentary Pharmacology and Therapeutics, vol. 29, no. 2, pp. 193–197, 2009. View at: Publisher Site | Google Scholar
14. M. M. Luchetti, D. Benfaremo, A. Campanati et al., “Clinical outcomes and feasibility of the multidisciplinary management of patients with psoriatic arthritis: two-year clinical experience of a dermo-rheumatologic clinic,” Clinical Rheumatology, vol. 37, no. 10, pp. 2741–2749, 2018. View at: Publisher Site | Google Scholar
15. M. Di Carlo, M. M. Luchetti, D. Benfaremo et al., “The DETection of Arthritis in Inflammatory boweL diseases (DETAIL) questionnaire: development and preliminary testing of a new tool to screen patients with inflammatory bowel disease for the presence of spondyloarthritis,” Clinical Rheumatology, vol. 37, no. 4, pp. 1037–1044, 2018. View at: Publisher Site | Google Scholar
16. Biomarkers Definitions Working Group, “Biomarkers and surrogate endpoints: preferred definitions and conceptual framework,” Clinical Pharmacology and Therapeutics, vol. 69, no. 3, pp. 89–95, 2001. View at: Publisher Site | Google Scholar
17. W. H. Robinson and R. Mao, “Biomarkers to guide clinical therapeutics in rheumatology?” Current Opinion in Rheumatology, vol. 28, no. 2, pp. 168–175, 2016. View at: Publisher Site | Google Scholar
18. W. H. Robinson, T. M. Lindstrom, R. K. Cheung, and J. Sokolove, “Mechanistic biomarkers for clinical decision making in rheumatic diseases,” Nature Reviews Rheumatology, vol. 9, no. 5, pp. 267–276, 2013. View at: Publisher Site | Google Scholar
19. International Genetics of Ankylosing Spondylitis Consortium (IGAS), “Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci,” Nature Genetics, vol. 45, no. 7, pp. 730–738, 2013. View at: Publisher Site | Google Scholar
20. J. D. Reveille, “Genetics of spondyloarthritis—beyond the MHC,” Nature Reviews Rheumatology, vol. 8, no. 5, pp. 296–304, 2012. View at: Publisher Site | Google Scholar
21. A. Danve and J. O'Dell, “The ongoing quest for biomarkers in ankylosing spondylitis,” International Journal of Rheumatic Diseases, vol. 18, no. 8, pp. 826–834, 2015. View at: Publisher Site | Google Scholar
22. A. M. Ossum, Ø. Palm, A. K. Lunder et al., “Ankylosing spondylitis and axial spondyloarthritis in patients with long-term inflammatory bowel disease: results from 20 years of follow-up in the IBSEN study,” Journal of Crohn's and Colitis, vol. 12, no. 1, pp. 96–104, 2018. View at: Publisher Site | Google Scholar
23. M. De Vos, P. Hindryckx, and D. Laukens, “Novel development in extraintestinal manifestations and spondylarthropathy,” Best Practice & Research. Clinical Gastroenterology, vol. 25, Supplement 1, pp. S19–S26, 2011. View at: Publisher Site | Google Scholar
24. M. van der Paardt, J. B. A. Crusius, M. H. M. T. de Koning et al., “CARD15 gene mutations are not associated with ankylosing spondylitis,” Genes and Immunity, vol. 4, no. 1, pp. 77-78, 2003. View at: Publisher Site | Google Scholar
25. M. D'Amato, R. Sorrentino, and S. Pettersson, “The Crohn’s associated NOD2 3020InsC frameshift mutation does not confer susceptibility to ankylosing spondylitis,” The Journal of Rheumatology, vol. 41, no. 1, p. 187, 2014. View at: Publisher Site | Google Scholar
26. I. Ferreirós-Vidal, J. Amarelo, F. Barros, A. Carracedo, J. J. Gómez-Reino, and A. Gonzalez, “Lack of association of ankylosing spondylitis with the most common NOD2 susceptibility alleles to Crohn’s disease,” The Journal of Rheumatology, vol. 30, no. 1, pp. 102–104, 2003. View at: Google Scholar
27. D. Laukens, H. Peeters, D. Marichal et al., “CARD15 gene polymorphisms in patients with spondyloarthropathies identify a specific phenotype previously related to Crohn’s disease,” Annals of the Rheumatic Diseases, vol. 64, no. 6, pp. 930–935, 2005. View at: Publisher Site | Google Scholar
28. O. Kucuksahin, A. Ates, N. Turkcapar et al., “Association between single nucleotide polymorphisms in prospective genes and susceptibility to ankylosing spondylitis and inflammatory bowel disease in a single centre in Turkey,” The Turkish Journal of Gastroenterology, vol. 27, no. 4, pp. 317–324, 2016. View at: Publisher Site | Google Scholar
29. The Australo-Anglo-American Spondyloarthritis Consortium (TASC), “Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci,” Nature Genetics, vol. 42, no. 2, pp. 123–127, 2010. View at: Publisher Site | Google Scholar
30. M. Tremelling, F. Cummings, S. A. Fisher et al., “IL23R variation determines susceptibility but not disease phenotype in inflammatory bowel disease,” Gastroenterology, vol. 132, no. 5, pp. 1657–1664, 2007. View at: Publisher Site | Google Scholar
31. D. Laukens, M. Georges, C. Libioulle et al., “Evidence for significant overlap between common risk variants for Crohn’s disease and ankylosing spondylitis,” PLoS One, vol. 5, no. 11, article e13795, 2010. View at: Publisher Site | Google Scholar
32. J. Dmowska-Chalaba and E. Kontny, “Inflammatory bowel disease-related arthritis - clinical evaluation and possible role of cytokines,” Reumatologia, vol. 53, no. 5, pp. 236–242, 2015. View at: Publisher Site | Google Scholar
33. D. A. Poddubnyy, M. Rudwaleit, J. Listing, J. Braun, and J. Sieper, “Comparison of a high sensitivity and standard C reactive protein measurement in patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis,” Annals of the Rheumatic Diseases, vol. 69, no. 7, pp. 1338–1341, 2010. View at: Publisher Site | Google Scholar
34. M. K. de Vries, I. C. van Eijk, I. E. van der Horst-bruinsma et al., “Erythrocyte sedimentation rate, C-reactive protein level, and serum amyloid A protein for patient selection and monitoring of anti–tumor necrosis factor treatment in ankylosing spondylitis,” Arthritis Care & Research, vol. 61, no. 11, pp. 1484–1490, 2009. View at: Publisher Site | Google Scholar
35. D. Poddubnyy, H. Haibel, J. Listing et al., “Baseline radiographic damage, elevated acute-phase reactant levels, and cigarette smoking status predict spinal radiographic progression in early axial spondylarthritis,” Arthritis & Rheumatism, vol. 64, no. 5, pp. 1388–1398, 2012. View at: Publisher Site | Google Scholar
36. P. Chamouard, Z. Richert, N. Meyer, G. Rahmi, and R. Baumann, “Diagnostic value of C-reactive protein for predicting activity level of Crohn’s disease,” Clinical Gastroenterology and Hepatology, vol. 4, no. 7, pp. 882–887, 2006. View at: Publisher Site | Google Scholar
37. M. Jürgens, J. M. Mahachie John, I. Cleynen et al., “Levels of C-reactive protein are associated with response to infliximab therapy in patients with Crohn’s disease,” Clinical Gastroenterology and Hepatology, vol. 9, no. 5, pp. 421–427.e1, 2011. View at: Publisher Site | Google Scholar
38. T. A. Gheita, I. I. El Gazzar, H. S. El-Fishawy, M. A. Aboul-Ezz, and S. A. Kenawy, “Involvement of IL-23 in enteropathic arthritis patients with inflammatory bowel disease: preliminary results,” Clinical Rheumatology, vol. 33, no. 5, pp. 713–717, 2014. View at: Publisher Site | Google Scholar
39. P. Vounotrypidis, G. Kouklakis, K. Anagnostopoulos et al., “Interleukin-1 associations in inflammatory bowel disease and the enteropathic seronegative spondylarthritis,” Autoimmun Highlights, vol. 4, no. 3, pp. 87–94, 2013. View at: Publisher Site | Google Scholar
40. L. Prideaux, P. De Cruz, S. C. Ng, and M. A. Kamm, “Serological antibodies in inflammatory bowel disease: a systematic review,” Inflammatory Bowel Diseases, vol. 18, no. 7, pp. 1340–1355, 2012. View at: Publisher Site | Google Scholar
41. I. E. A. Hoffman, P. Demetter, M. Peeters et al., “Anti-Saccharomyces cerevisiae IgA antibodies are raised in ankylosing spondylitis and undifferentiated spondyloarthropathy,” Annals of the Rheumatic Diseases, vol. 62, no. 5, pp. 455–459, 2003. View at: Publisher Site | Google Scholar
42. H.-P. Török, J. Glas, R. Gruber et al., “Inflammatory bowel disease-specific autoantibodies in HLA-B27-associated spondyloarthropathies: increased prevalence of ASCA and pANCA,” Digestion, vol. 70, no. 1, pp. 49–54, 2004. View at: Publisher Site | Google Scholar
43. S. Z. Aydin, P. Atagunduz, M. Temel, M. Bicakcigil, D. Tasan, and H. Direskeneli, “Anti-Saccharomyces cerevisiae antibodies (ASCA) in spondyloarthropathies: a reassessment,” Rheumatology, vol. 47, no. 2, pp. 142–144, 2008. View at: Publisher Site | Google Scholar
44. L. Riente, D. Chimenti, F. Pratesi et al., “Antibodies to tissue transglutaminase and Saccharomyces cerevisiae in ankylosing spondylitis and psoriatic arthritis,” The Journal of Rheumatology, vol. 31, no. 5, pp. 920–924, 2004. View at: Google Scholar
45. C. Romero-Sánchez, W. Bautista-Molano, V. Parra et al., “Gastrointestinal symptoms and elevated levels of anti- Saccharomyces cerevisiae antibodies are associated with higher disease activity in Colombian patients with spondyloarthritis,” International Journal of Rheumatology, vol. 2017, Article ID 4029584, 8 pages, 2017. View at: Publisher Site | Google Scholar
46. M. L. Mundwiler, L. Mei, C. J. Landers, J. D. Reveille, S. Targan, and M. H. Weisman, “Inflammatory bowel disease serologies in ankylosing spondylitis patients: a pilot study,” Arthritis Research & Therapy, vol. 11, no. 6, article R177, 2009. View at: Publisher Site | Google Scholar
47. F. G. Matzkies, S. R. Targan, D. Berel et al., “Markers of intestinal inflammation in patients with ankylosing spondylitis: a pilot study,” Arthritis Research & Therapy, vol. 14, no. 6, p. R261, 2012. View at: Publisher Site | Google Scholar
48. M. De Vries, I. Van Der Horst-Bruinsma, I. Van Hoogstraten et al., “pANCA, ASCA, and OmpC antibodies in patients with ankylosing spondylitis without inflammatory bowel disease,” The Journal of Rheumatology, vol. 37, no. 11, pp. 2340–2344, 2010. View at: Publisher Site | Google Scholar
49. D. Wallis, M. Weisman, N. Haroon et al., “OP0241 Anti-flagellin antibodies in ankylosing spondylitis (AS) implicate subclinical bowel inflammation and differentiate as from mechanical back pain patients,” Annals of the Rheumatic Diseases, vol. 72, Supplement 3, 2013. View at: Publisher Site | Google Scholar
50. A. C. von Roon, L. Karamountzos, S. Purkayastha et al., “Diagnostic precision of fecal calprotectin for inflammatory bowel disease and colorectal malignancy,” The American Journal of Gastroenterology, vol. 102, no. 4, pp. 803–813, 2007. View at: Publisher Site | Google Scholar
51. M. Wagner, C. G. B. Peterson, P. Ridefelt, P. Sangfelt, and M. Carlson, “Fecal markers of inflammation used as surrogate markers for treatment outcome in relapsing inflammatory bowel disease,” World Journal of Gastroenterology, vol. 14, no. 36, pp. 5584–5588, 2008. View at: Publisher Site | Google Scholar
52. T. Sipponen, C.-G. A. F. Björkesten, M. Färkkilä, H. Nuutinen, E. Savilahti, and K.-L. Kolho, “Faecal calprotectin and lactoferrin are reliable surrogate markers of endoscopic response during Crohn’s disease treatment,” Scandinavian Journal of Gastroenterology, vol. 45, no. 3, pp. 325–331, 2010. View at: Publisher Site | Google Scholar
53. R. Ferreiro-Iglesias, M. Barreiro-de Acosta, M. Otero Santiago et al., “Fecal calprotectin as predictor of relapse in patients with inflammatory bowel disease under maintenance infliximab therapy,” Journal of Clinical Gastroenterology, vol. 50, no. 2, pp. 147–151, 2016. View at: Publisher Site | Google Scholar
54. A. Duran, S. Kobak, N. Sen, S. Aktakka, T. Atabay, and M. Orman, “Fecal calprotectin is associated with disease activity in patients with ankylosing spondylitis,” Bosnian Journal of Basic Medical Sciences, vol. 16, no. 1, pp. 71–74, 2016. View at: Publisher Site | Google Scholar
55. E. Klingberg, H. Strid, A. Ståhl et al., “A longitudinal study of fecal calprotectin and the development of inflammatory bowel disease in ankylosing spondylitis,” Arthritis Research & Therapy, vol. 19, no. 1, pp. 21–29, 2017. View at: Publisher Site | Google Scholar
56. P. Oktayoglu, M. Bozkurt, N. Mete, M. Caglayan, S. Em, and K. Nas, “Elevated serum levels of calprotectin (myeloid-related protein 8/14) in patients with ankylosing spondylitis and its association with disease activity and quality of life,” Journal of Investigative Medicine, vol. 62, no. 6, pp. 880–884, 2014. View at: Publisher Site | Google Scholar
57. M. C. Turina, N. Yeremenko, J. E. Paramarta, L. De Rycke, and D. Baeten, “Calprotectin (S100A8/9) as serum biomarker for clinical response in proof-of-concept trials in axial and peripheral spondyloarthritis,” Arthritis Research & Therapy, vol. 16, no. 4, p. 413, 2014. View at: Publisher Site | Google Scholar
58. M. C. Turina, N. Yeremenko, F. van Gaalen et al., “Serum inflammatory biomarkers fail to identify early axial spondyloarthritis: results from the SpondyloArthritis Caught Early (SPACE) cohort,” RMD Open, vol. 3, no. 1, 2017. View at: Publisher Site | Google Scholar
59. M. C. Turina, J. Sieper, N. Yeremenko et al., “Calprotectin serum level is an independent marker for radiographic spinal progression in axial spondyloarthritis,” Annals of the Rheumatic Diseases, vol. 73, no. 9, pp. 1746–1748, 2014. View at: Publisher Site | Google Scholar
60. M. C. Turina, R. Landewé, and D. Baeten, “Lessons to be learned from serum biomarkers in psoriasis and IBD–the potential role in SpA,” Expert Review of Clinical Immunology, vol. 13, no. 4, pp. 333–344, 2017. View at: Publisher Site | Google Scholar
61. M. Drouart, P. Saas, M. Billot et al., “High serum vascular endothelial growth factor correlates with disease activity of spondylarthropathies,” Clinical and Experimental Immunology, vol. 132, no. 1, pp. 158–162, 2003. View at: Publisher Site | Google Scholar
62. D. Poddubnyy, K. Conrad, H. Haibel et al., “Elevated serum level of the vascular endothelial growth factor predicts radiographic spinal progression in patients with axial spondyloarthritis,” Annals of the Rheumatic Diseases, vol. 73, no. 12, pp. 2137–2143, 2014. View at: Publisher Site | Google Scholar
63. S. Arends, E. van der Veer, H. Groen et al., “Serum MMP-3 level as a biomarker for monitoring and predicting response to etanercept treatment in ankylosing spondylitis,” The Journal of Rheumatology, vol. 38, no. 8, pp. 1644–1650, 2011. View at: Publisher Site | Google Scholar
64. D. L. Mattey, J. C. Packham, N. B. Nixon et al., “Association of cytokine and matrix metalloproteinase profiles with disease activity and function in ankylosing spondylitis,” Arthritis Research & Therapy, vol. 14, no. 3, p. R127, 2012. View at: Publisher Site | Google Scholar
65. W. Xie, L. Zhou, S. Li, T. Hui, and D. Chen, “Wnt/β-catenin signaling plays a key role in the development of spondyloarthritis,” Annals of the New York Academy of Sciences, vol. 1364, no. 1, pp. 25–31, 2016. View at: Publisher Site | Google Scholar
66. G. R. Heiland, H. Appel, D. Poddubnyy et al., “High level of functional dickkopf-1 predicts protection from syndesmophyte formation in patients with ankylosing spondylitis,” Annals of the Rheumatic Diseases, vol. 71, no. 4, pp. 572–574, 2012. View at: Publisher Site | Google Scholar
67. S.-R. Kwon, M.-J. Lim, C.-H. Suh et al., “Dickkopf-1 level is lower in patients with ankylosing spondylitis than in healthy people and is not influenced by anti-tumor necrosis factor therapy,” Rheumatology International, vol. 32, no. 8, pp. 2523–2527, 2012. View at: Publisher Site | Google Scholar
68. Z. Yucong, L. Lu, L. Shengfa, Y. Yongliang, S. Ruguo, and L. Yikai, “Serum functional dickkopf-1 levels are inversely correlated with radiographic severity of ankylosing spondylitis,” Clinical Laboratory, vol. 60, no. 9, pp. 1527–1531, 2014. View at: Google Scholar
69. A. Taylan, I. Sari, B. Akinci et al., “Biomarkers and cytokines of bone turnover: extensive evaluation in a cohort of patients with ankylosing spondylitis,” BMC Musculoskeletal Disorders, vol. 13, no. 1, p. 191, 2012. View at: Publisher Site | Google Scholar
70. E. Klingberg, M. Nurkkala, H. Carlsten, and H. Forsblad-d’Elia, “Biomarkers of bone metabolism in ankylosing spondylitis in relation to osteoproliferation and osteoporosis,” The Journal of Rheumatology, vol. 41, no. 7, pp. 1349–1356, 2014. View at: Publisher Site | Google Scholar
71. C. G. S. Saad, A. C. M. Ribeiro, J. C. B. Moraes et al., “Low sclerostin levels: a predictive marker of persistent inflammation in ankylosing spondylitis during anti-tumor necrosis factor therapy?” Arthritis Research & Therapy, vol. 14, no. 5, p. R216, 2012. View at: Publisher Site | Google Scholar
72. H. Appel, G. Ruiz-Heiland, J. Listing et al., “Altered skeletal expression of sclerostin and its link to radiographic progression in ankylosing spondylitis,” Arthritis and Rheumatism, vol. 60, no. 11, pp. 3257–3262, 2009. View at: Publisher Site | Google Scholar
73. F. M. Perrotta, F. Ceccarelli, C. Barbati et al., “Serum sclerostin as a possible biomarker in ankylosing spondylitis: a case-control study,” Journal of Immunology Research, vol. 2018, Article ID 9101964, 5 pages, 2018. View at: Publisher Site | Google Scholar
74. M. M. Luchetti, F. Ciccia, C. Avellini et al., “Sclerostin and antisclerostin antibody serum levels predict the presence of axial spondyloarthritis in patients with inflammatory bowel disease,” The Journal of Rheumatology, vol. 45, no. 5, pp. 630–637, 2018. View at: Publisher Site | Google Scholar
75. M. Korkosz, J. Gąsowski, P. Leszczyński et al., “High disease activity in ankylosing spondylitis is associated with increased serum sclerostin level and decreased wingless protein-3a signaling but is not linked with greater structural damage,” BMC Musculoskeletal Disorders, vol. 14, no. 1, p. 99, 2013. View at: Publisher Site | Google Scholar
76. F. W. L. Tsui, H. W. Tsui, F. Las Heras, K. P. H. Pritzker, and R. D. Inman, “Serum levels of novel noggin and sclerostin-immune complexes are elevated in ankylosing spondylitis,” Annals of the Rheumatic Diseases, vol. 73, no. 10, pp. 1873–1879, 2014. View at: Publisher Site | Google Scholar
77. N. T. Baerlecken, S. Nothdorft, G. H. Stummvoll et al., “Autoantibodies against CD74 in spondyloarthritis,” Annals of the Rheumatic Diseases, vol. 73, no. 6, pp. 1211–1214, 2014. View at: Publisher Site | Google Scholar
78. X. Baraliakos, N. Baerlecken, T. Witte, F. Heldmann, and J. Braun, “High prevalence of anti-CD74 antibodies specific for the HLA class II-associated invariant chain peptide (CLIP) in patients with axial spondyloarthritis,” Annals of the Rheumatic Diseases, vol. 73, no. 6, pp. 1079–1082, 2014. View at: Publisher Site | Google Scholar
79. J. J. de Winter, M. G. van de Sande, N. Baerlecken et al., “Anti-CD74 antibodies have no diagnostic value in early axial spondyloarthritis: data from the SPondyloArthritis Caught Early (SPACE) cohort,” Arthritis Research & Therapy, vol. 20, no. 1, p. 38, 2018. View at: Publisher Site | Google Scholar
80. D. Bernardi, M. Podswiadek, M. Zaninotto, L. Punzi, and M. Plebani, “YKL-40 as a marker of joint involvement in inflammatory bowel disease,” Clinical Chemistry, vol. 49, no. 10, pp. 1685–1688, 2003. View at: Publisher Site | Google Scholar
81. K. Al-Jarallah, D. Shehab, R. Al-Attiyah et al., “Antibodies to mutated citrullinated vimentin and anti-cyclic citrullinated peptide antibodies in inflammatory bowel disease and related arthritis,” Inflammatory Bowel Diseases, vol. 18, no. 9, pp. 1655–1662, 2012. View at: Publisher Site | Google Scholar
82. F. Ciccia, G. Guggino, A. Rizzo et al., “Dysbiosis and zonulin upregulation alter gut epithelial and vascular barriers in patients with ankylosing spondylitis,” Annals of the Rheumatic Diseases, vol. 76, no. 6, pp. 1123–1132, 2017. View at: Publisher Site | Google Scholar
83. M.-E. Costello, F. Ciccia, D. Willner et al., “Brief report: intestinal dysbiosis in ankylosing spondylitis,” Arthritis & Rhematology, vol. 67, no. 3, pp. 686–691, 2015. View at: Publisher Site | Google Scholar
84. S. O’Mahony, N. Anderson, G. Nuki, and A. Ferguson, “Systemic and mucosal antibodies to Klebsiella in patients with ankylosing spondylitis and Crohn’s disease,” Annals of the Rheumatic Diseases, vol. 51, no. 12, pp. 1296–1300, 1992. View at: Publisher Site | Google Scholar
85. H. Tiwana, R. S. Walmsley, C. Wilson et al., “Characterization of the humoral immune response to Klebsiella species in inflammatory bowel disease and ankylosing spondylitis,” Rheumatology, vol. 37, no. 5, pp. 525–531, 1998. View at: Publisher Site | Google Scholar
86. H. Tiwana, R. S. Natt, R. Benitez-Brito et al., “Correlation between the immune responses to collagens type I, III, IV and V and Klebsiella pneumoniae in patients with Crohn’s disease and ankylosing spondylitis,” Rheumatology, vol. 40, no. 1, pp. 15–23, 2001. View at: Publisher Site | Google Scholar
87. R. Cooper, S. M. Fraser, R. D. Sturrock, and C. G. Gemmell, “Raised titres of anti-klebsiella IgA in ankylosing spondylitis, rheumatoid arthritis, and inflammatory bowel disease,” British Medical Journal, vol. 296, no. 6634, pp. 1432–1434, 1988. View at: Publisher Site | Google Scholar
88. M. Viladomiu, C. Kivolowitz, A. Abdulhamid et al., “IgA-coated E.coli enriched in Crohn’s disease spondyloarthritis promote T_H17-dependent inflammation,” Science Translational Medicine, vol. 9, no. 376, article eaaf9655, 2017. View at: Publisher Site | Google Scholar
89. S. Ditisheim, N. Fournier, P. Juillerat et al., “Inflammatory articular disease in patients with inflammatory bowel disease: result of the Swiss IBD Cohort Study,” Inflammatory Bowel Diseases, vol. 21, no. 11, pp. 2598–2604, 2015. View at: Publisher Site | Google Scholar
90. S. J. van Erp, L. K. Brakenhoff, F. A. van Gaalen et al., “Classifying back pain and peripheral joint complaints in inflammatory bowel disease patients: a prospective longitudinal follow-up study,” Journal of Crohn's & Colitis, vol. 10, no. 2, pp. 166–175, 2016. View at: Publisher Site | Google Scholar
91. A. M. Ossum, Ø. Palm, M. Cvancarova et al., “Peripheral arthritis in patients with long-term inflammatory bowel disease. Results from 20 years of follow-up in the IBSEN study,” Scandinavian Journal of Gastroenterology, vol. 53, no. 10-11, pp. 1250–1256, 2018. View at: Publisher Site | Google Scholar
92. S. R. Vavricka, L. Brun, P. Ballabeni et al., “Frequency and risk factors for extraintestinal manifestations in the Swiss inflammatory bowel disease cohort,” American Journal of Gastroenterology, vol. 106, no. 1, pp. 110–119, 2011. View at: Publisher Site | Google Scholar
93. D. Baeten, F. De Keyser, H. Mielants, and E. M. Veys, “Ankylosing spondylitis and bowel disease,” Best Practice & Research Clinical Rheumatology, vol. 16, no. 4, pp. 537–549, 2002. View at: Publisher Site | Google Scholar
94. J. K. Yamamoto-Furusho and A. Sarmiento-Aguilar, “Joint involvement in Mexican patients with ulcerative colitis: a hospital-based retrospective study,” Clinical Rheumatology, vol. 37, no. 3, pp. 677–682, 2018. View at: Publisher Site | Google Scholar
95. R. Pérez Alamino, J. A. Maldonado Cocco, G. Citera et al., “Differential features between primary ankylosing spondylitis and spondylitis associated with psoriasis and inflammatory bowel disease,” The Journal of Rheumatology, vol. 38, no. 8, pp. 1656–1660, 2011. View at: Publisher Site | Google Scholar
96. I. Essers, S. Ramiro, C. Stolwijk et al., “Characteristics associated with the presence and development of extra-articular manifestations in ankylosing spondylitis: 12-year results from OASIS,” Rheumatology, vol. 54, no. 4, pp. 633–640, 2015. View at: Publisher Site | Google Scholar
97. G. Varkas, N. Vastesaeger, H. Cypers et al., “Association of inflammatory bowel disease and acute anterior uveitis, but not psoriasis, with disease duration in patients with axial spondyloarthritis: results from two Belgian nationwide axial spondyloarthritis cohorts,” Arthritis & Rhematology, vol. 70, no. 10, pp. 1588–1596, 2018. View at: Publisher Site | Google Scholar
98. P. del Río-Martínez, V. Navarro-Compán, C. Díaz-Miguel et al., “Similarities and differences between patients fulfilling axial and peripheral ASAS criteria for spondyloarthritis: results from the Esperanza Cohort,” Seminars in Arthritis and Rheumatism, vol. 45, no. 4, pp. 400–403, 2016. View at: Publisher Site | Google Scholar
99. F. Bandinelli, M. Milla, S. Genise et al., “Ultrasound discloses entheseal involvement in inactive and low active inflammatory bowel disease without clinical signs and symptoms of spondyloarthropathy,” Rheumatology, vol. 50, no. 7, pp. 1275–1279, 2011. View at: Publisher Site | Google Scholar
100. F. Bandinelli, R. Terenzi, L. Giovannini et al., “Occult radiological sacroiliac abnormalities in patients with inflammatory bowel disease who do not present signs or symptoms of axial spondylitis,” Clinical and Experimental Rheumatology, vol. 32, no. 6, pp. 949–952, 2014. View at: Google Scholar
101. S. Leclerc-Jacob, G. Lux, A. C. Rat et al., “The prevalence of inflammatory sacroiliitis assessed on magnetic resonance imaging of inflammatory bowel disease: a retrospective study performed on 186 patients,” Alimentary Pharmacology and Therapeutics, vol. 39, no. 9, pp. 957–962, 2014. View at: Publisher Site | Google Scholar
102. U. Kopylov, M. Starr, C. Watts, S. Dionne, M. Girardin, and E. G. Seidman, “Detection of Crohn disease in patients with spondyloarthropathy: the SpACE capsule study,” The Journal of Rheumatology, vol. 45, no. 4, pp. 498–505, 2018. View at: Publisher Site | Google Scholar

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