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Enthesitis in IBD Patients

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28 May 2024

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29 May 2024

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Abstract
Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract and encompasses two main subtypes, Crohn’s disease (CD) and ulcerative colitis (UC). IBD is frequently accompanied by extraintestinal manifestations (EIMs), with axial and peripheral spondyloarthritis (SpA) being the most common. Enthesitis, an inflammation of the bone insertions of capsules, ligaments, and tendons, represents an initial lesion in SpA. However, enthesitis remains an underestimated and often obscured EIM. The early detection of subclinical enthesial involvement in IBD patients using ultrasound (US) could provide an opportunity for timely intervention. While previous meta-analyses have reported on the incidence and prevalence of SpA in IBD, specific attention to enthesitis has been lacking. Therefore, this narrative review aims to resume the current knowledge on existing IBD-SpA cohorts, focusing specifically on enthesitis.
Keywords: 
inflammatory bowel disease
;  
Crohn’s disease
;  
ulcerative colitis
;  
extraintestinal manifestations
;  
enthesitis
Subject: 
Medicine and Pharmacology  -   Gastroenterology and Hepatology

1. Introduction

Inflammatory bowel diseases (IBD) are a heterogeneous group of chronic and recurrent intestinal diseases made of two main clinical phenotypes: Crohn’s disease (CD) and ulcerative colitis (UC) [1]. IBD patients sometimes develop an extraintestinal manifestations (EIMs), inflammatory conditions that can involve different organs and systems with a serious impact on morbidity and quality of life [2]. EIMs occur in 25% to 40% of IBD patients and mainly affect the joints, followed by the skin, eyes, and hepatobiliary tract [3]. Musculoskeletal symptoms are the most common EIM associated with IBD [4]. The Assessment of SpondyloArthritis International Society (ASAS) has developed classification criteria for both axial and peripheral arthropathy, which includes the whole spectrum of spondyloarthritis (SpA), such as IBD related arthropathy [5]. SpA is a joint term applied to a group of rheumatic diseases with particular features in common and others distinct from other inflammatory arthritides. It includes IBD-related arthritis, ankylosing spondylitis, reactive arthritis, psoriatic arthritis and undifferentiated SpA [6].
Both axial and peripheral manifestations can be present in patients with IBD. In peripheral SpA, arthritis, dactylitis and enthesitis are the main symptoms. Enthesitis presenting with Achilles tendinitis, plantar fasciitis, and chest wall pain sometimes leads to structural changes of the underlying bones and causes disability [7]. Ultrasonography (US) or magnetic resonance imaging (MRI) examination of the affected area can help in earlier detection missed by clinical inspection [8]. However, prevalence of peripheral SpA is frequently underestimated or mistakenly related to corticosteroid overuse, due to transitory manifestation of some oligoaricular patterns or the use of chronic corticosteroid treatment [9]. Also, recognition of joint and tendon involvement could be delayed by the fact that gastroenterologists may not specifically inquire about musculoskeletal symptoms in everyday clinical inspection [10]. Enthesitis is often the principal sign of SpA in young adults [11], but only a small percentage of cases are discovered by means of a clinical examination: for example, in a population-based cohort of 499 Norwegian IBD patients, a clinical assessment identified enthesitis in only 11 patients [12]. The pathology of entheses in IBD and SpA patients is often underdiagnosed or mistaken for overuse tendon pathology [13].
Although patients with IBD and SpA appear to share many clinical, immunologic, and genetic characteristics [14], the exact relationship between these two entities has never been comprehensively defined.
The pathophysiology of enthesitis includes the innate and adaptive immunity with overlap of the interleukin (IL)-17 and IL-23 axis [14]. Accordingly abnormal gut microbiome as seen in IBD patients may be a factor in the development of entheseal pathology [15]. Patients with IBD are usually not examined for enthesitis and additionally there is no standard protocol for such examination. Clinical findings including localized pain, tenderness, and swelling are suggestive of enthesitis [16], yet it is discovered by clinical examination only in a low percentage of patients [17]. The most commonly investigated entheses are those located in the lower limbs (i.e., plantar fascia, patellar, quadriceps, and Achilles tendons) [18,19].
Enthesitis is the prime lesion in SpA, but also an isolated peripheral enthesitis has previously been reported following vedolizumab therapy in IBD patients [20,21,22]. Previous studies have shown a prevalence of SpA under vedolizumab therapy of around 5% [21,22], but in cohort of 90 cases, it was actually double [23]. This entity, so called vedolizumab-associated enthesitis, is not EIM, but it could overlap with entheseal pathology in SpA.
This review describes the current novelties on existing IBD-SpA cohorts, focusing specifically on enthesitis.

2. Materials and Methods

In this narrative review, we conducted search of a PubMed, Scopus, Web of Science, and Cochrane databases. The following terms were used: IBD, CD, UC, enthesitis.
Articles published from January 2013 - March 2023 were included if they evaluated the prevalence/incidence of enthesitis in cohorts of IBD patients. Articles selected for inclusion were limited to availability of full text, English language articles, clinical studies with adult patients. Meta-analyses, case reports and reviews were excluded. Article titles were first reviewed for inclusion by one study investigator (IAO). Abstracts and the full text were further screened by IAO for final inclusion and confirmed by the co-authors (JV, MR, ZS). Studies were included if they evaluated the prevalence/incidence of enthesitis in a cohort of patients with IBD.
Data was extracted by single investigator (IAO) and reviewed by the co-authors. The following data was observed: study setting and design, number of patients with IBD, type of IBD, method of rheumatologic evaluation, imaging modalities used. The prevalence and incidence of enthesitis in the IBD group, individualized for CD and UC where available, was also collected.
There was no direct patient or public involvement in designing, interpreting, discussing or drawing of conclusions.

3. Results

Literature review
We performed a systematic literature review of studies that evaluated enthesitis in IBD cohorts. The initial database search yielded 71 articles; two were removed because they evaluated vedolizumab-associated enthesitis, and four were removed because they evaluated enthesitis in children. After removing non-English language articles, reviews, meta-analyses, and case reports, only 11 studies remained for abstract/full text assessment.
Study design characteristics
Focusing on study design, one was population-based, and ten were clinic-based. Most studies were conducted at a single center, with only two multicentre studies. Three studies reported data for IBD without distinguishing between CD and UC. Rheumatologists were involved in all of eleven studies. A physical examination was included in all studies. Other methods of evaluation included questionnaires in 2/11 studies. US was performed in 7/11 studies. Information stratified based on IBD disease duration was obtained in three studies.
Bertolini et al. [24] found clinical evidence of enthesitis (tenderness and/or swelling) in 33% of IBD patients, and it was significantly more frequent in UC patients compared to CD patients (37.7% versus 25%, p=0.012). This is the one of two studies that observed and distinguished acute and chronic entheseal lesions. Patients with longer disease duration had more frequently entheseal abnormalities at US evaluation (85/98 patients (90%) versus 38/53 (72%), p=0.003) [24]. The following entheses were examined for tenderness and swelling bilaterally: common extensor tendon (CET), insertion on the lateral epicondyle of the humerus, quadriceps tendon (QT), patellar tendon (PT), tibial tuberosity (TT), Achilles tendon (AT) and plantar fascia (PF) insertion on the calcaneus. US was performed in B-mode and power Doppler (PD) mode. Abnormal findings were entheseal thickening, entheseal hypoechogenicity, bony erosions, enthesophytes and enlargement of bursae. Entheseal thickening, entheseal hypoechogenicity, and bursal enlargement were considered acute lesions. Bony erosions, calcifications, and enthesophytes were considered chronic lesions. Vascularization was examined using PD-mode, and studied at the following areas: cortical bone insertion, body of tendon and bursa. The detection of vascularization in any of these areas was considered abnormal. Enthesis US vascularity was classified into four distinctive patterns according to the number of vessels involved: 0 = none; 1 = 1-3 vessels; 2 = 4-5 vessels; 3 = >5 vessels. The presence of PD ≥1 was considered indicative of an acute lesion [24]. Ultrasonographic findings were scored according to the Madrid sonography enthesitis index (MASEI) [25] and Glasgow ultrasound enthesitis scoring system (GUESS) [26]. No statistically significant differences were observed comparing patients with shorter or longer disease duration (≤12 months versus >12 months) regarding rheumatological evaluation (data not shown). As expected, patients with longer disease duration (≤12 months versus >12 months) had more frequently entheseal abnormalities at US evaluation, at least one enthesis with erosions and more entheses with chronic lesions/patient.
In study of Bakirci Ureyen et al., entheseal inflammation scores were higher in patients with IBD than in healthy control group. Also, IBD disease duration was independent of inflammation and damage score. Interestingly, they showed BMI correlation to US scores and inflammation in IBD patients [27].
Cantini et al. [28] showed that enthesitis frequency was significantly higher in IBD-SpA patients with associated psoriasis. Enthesitis occurrence was not different in patients with UC and those with CD.
Husic et al. [29] did not find a significant correlation of disease duration and activity of IBD with MASEI score, but US verified enthesitis was more common in patients with IBD as compared to healthy subjects. No association was found between clinical IBD activity and MASEI, nor between clinical IBD activity and erosion, PD and enthesophyte subscores.
Bandinelli et al. [30] suggested that entheseal involvement may also be present in early IBD disease. The entheseal involvement is related neither to duration nor to disease activity according to their study. In disagreement with Kiris et al [31], who showed that entheseal pain tightly correlated with vascularity shown by PD, 16% of Bandinelli patients were positive at PD signal on entheses without symptoms.
Tavassoli et al [32] found enthesopathy in 6.5% IBD patients without US assessment.
Table 1. Study characteristics.
Table 1. Study characteristics.
Study Setting Design IBD RI PE US PD A/C EE MASEI GUESS ASAS Q UC CD
Variola et al. [33] clinic cross-sectional 181 yes yes no IBIS Partial Mayo score HBI
Bakici Ureyen et al. [27] clinic cross-sectional 43 yes yes yes yes no QT, AT, PT, TT no no no no no no
Ossum et al. [34] population-based cohort 441 yes yes no yes no no
Tavassoli et al. [32] clinic cross-sectional 96 yes yes no no no no
Bandinelli et al. [30] clinic cross-sectional 81 yes yes yes yes no QT, AT, PF no yes yes no Truelove CDAI
Bertolini et al. [24] clinic cross-sectional 148 yes yes yes yes yes CET, QT, PT, TT, AT, PF yes yes yes no Mayo HBI
Husic et al. [29] clinic cross-sectional 47 yes yes yes yes no QT, PT, AT, PF, TT yes no yes no Mayo CDAI
Cantini et al. [28] clinic case-control 88 yes yes no no no no
Hsiao et al [35] clinic prospective 18 yes yes yes yes no PT, AT, PF no yes yes no no no
Rovisco et al. [36] clinic case-control 76 yes yes yes yes no PT, AT, PF, QT no no yes no Mayo CDAI
Martinis et al. [37] clinic case-control 301 yes yes yes yes yes CET, PT, TT, PF, AT yes yes no no Mayo HBI
Abbrevations: IBD: number of patients with IBD; RI: rheumatologist input; PE: physical examination; US: studies with performed ultrasound examination; PD: power Doppler mode; A/C: studies with US made distinguish between acute vs chronic lesions; EE: examined entheses; MASEI: Madrid sonography enthesitis index; GUESS: Glasgow ultrasound enthesitis scoring system; ASAS: PD positive entheseal site in ASAS neg patients; Q: questionnaire; UC: ulcerative colitis; CD: Crohn’s disease; HBI: Harvey Bradshaw Index; CDAI: Crohn Disease Activity Index; CET: common extensor tendon; QT: quadriceps; PT: patellar tendon; TT: tibial tuberosity; AT: Achilles tendon; PF: plantar fascia; IBIS: IBd Identification of Spondyloarthritis Questionnaire.
Rovisco et al. conducted a multicenter study using US assessment to explore joint and entheseal involvement in IBD patients with no signs or symptoms of musculoskeletal disease, and their findings indicate that the prevalence of sub-clinical entheseal and joint involvement is high in IBD patients [36].
The study of Martinis et al. found that a positive Doppler signal at entheseal level was more frequently observed in IBD subjects with SpA than in IBD patients with fibromyalgia [37].
The most affected entheseal site in these studies was the patellar tendon, followed by the Achilles tendon, which is often described as being the most affected in patients with SpA [38,39]. The most relevant findings shown by US in the early phase of entheseal pathology were thickness and PD signal at entheses in accordance to previous studies [40,41], probably due to edema, neovascularization, and cell infiltration.

4. Discussion

In this narrative review of eleven studies analyzing enthesitis in patients with IBD, several limitations were identified. The majority of the included studies were clinic-based, single-center, and cross-sectional in design. This limited number of studies is unlikely to provide sufficient evidence to fully describe the involvement of enthesitis and its correlation with IBD activity. Additionally, there were variations in the scoring systems used to assess IBD activity among these studies, further complicating the interpretation of results.
Also, there were variations in US assessment. While the MASEI included retrocalcaneal and infrapatellar bursitis in the score, bursitis is not considered an elementary lesion of enthesitis according to OMERACT. The OMERACT experts were of the opinion, that bursae are not part of the enthesitis complex, and that inflammation affects them only at a later stage of enthesitis when it extends toward the tendon and peri-tendinous structures [42].
Previous reviews attempted to identify relevant studies about EIMs from database inception to August 2016., and found only few estimates available for enthesitis (prevalence range from 1% to 54%) [43].
Systematic review by Sakellariou et al. provided an overview on the clinical applicability of musculoskeletal ultrasonography in patients with IBD without an overt joint involvement, and they included only studies with US assessment. They did not find any correlation between the type of IBD and the disease activity. They have found that only IBD disease duration correlated with a higher frequency of US abnormalities; but this result emerged from a single study which enrolled patients with a very short disease duration (<12 months of disease duration) [44].
This review represents an attempt to systematically investigate the study design and characteristics of entheseal involvement in IBD patients. Still, it was limited by incomplete or absent reporting of important variables such as body mass index (BMI), medication usage, and heterogeneity in disease activity classification.
Also, small number of studies performed US assessment, and those who did performed it, did not use the same scoring system.
Based on the available data, it is recommended to assess the frequency of enthesitis using both physical examination and ultrasound as the reference standard. However, it is important to acknowledge that data on such assessments are limited. Future studies with larger and more extensive cohorts are necessary to better evaluate enthesitis in IBD patients.
The relationship between enthesitis and IBD activity index remains unclear, and further research is required to explore this association. It is worth noting that enthesitis may be asymptomatic in majority of patients, and there is currently a lack of standardized protocols for examining enthesitis in IBD patients. Consequently, many IBD patients are not routinely examined for enthesitis.
The researchers express a particular interest in studies investigating the impact of increased BMI on entheseal involvement in IBD patients, as this information could help prevent further complications. Effective treatment is available for both axial and peripheral SpA and early diagnosis and treatment are important to modify disease progression and decrease the disease burden [45]. Every patient with possible SpA should be seen by a rheumatologist for final diagnosis and the coordination of multidisciplinary nonpharmacological and pharmacological treatment [46]. For example, in patients with predominant enthesitis, a biologic may provide efficacy that supersedes conventional disease modifying anti-rheumatic medications [47,48,49]. US is increasingly being used in the identification of inflammatory arthritis [50], and it has the potential to provide a unique opportunity to assess SpA, particularly in early disease stage, in IBD.
To the best of our knowledge, this is the first study that systematically highlights the limitations of the available studies on enthesitis in IBD patients, emphasizing the need for more extensive research with standardized protocols. The presence of enthesitis should be assessed using both physical examination and ultrasound, and future studies should aim to clarify the relationship between enthesitis and IBD activity. Additionally, efforts should be made to establish a standard protocol for examining enthesitis in IBD patients, and further investigations into the impact of increased BMI on entheseal involvement are warranted to improve patient outcomes and prevent complications.
Authors should discuss the results and how they can be interpreted from the perspective of previous studies and of the working hypotheses. The findings and their implications should be discussed in the broadest context possible. Future research directions may also be highlighted.

5. Conclusions

The frequency of the enthesitis should be assessed using both physical examination and ultrasound as the reference standard. Data of such assessments are limited. Future studies with more extensive cohorts are needed to evaluate enthesitis. Is enthesitis generally independent of IBD activity index? Enthesitis may be asymptomatic in majority of patients. IBD patients are often not examined for enthesitis and there is a lack of standard protocol. We are looking forward to seeing some studies about impact of increased BMI on entheseal involvement in IBD patients in order to prevent further complications. The use of inexpensive and rapid imaging techniques, such as US, could be routinely represented in daily clinical examination and trials to correctly evaluate occult SpA, thus preventing disability and worsening of quality of life in IBD patients.
This section is not mandatory but can be added to the manuscript if the discussion is unusually long or complex.

Author Contributions

Conceptualization, M.R. and I.A.O.; methodology, J.V.; software, J.V.; validation, M.R., I.A.O. and J.V.; formal analysis, M.R.; investigation, I.A.O.; resources, I.A.O.; data curation, I.A.O.; writing—original draft preparation, J.V., M.R.; writing—review and editing, M.R.; visualization, M.R.; supervision, M.R., Z.S.; project administration, M.R., Z.S; funding acquisition, Z.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

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