Arthralgia and Extraintestinal Manifestations in Crohn's Disease: PDF

Rheumatol Ther (2025) 12:99–108 https://doi.org/10.1007/s40744-024-00728-4 ORIGINAL RESEARCH Arthralgia and Extraintestinal Manifestations in Crohn’s Disease Elevate the Risk of IBD‑Related Arthritis over Sacroiliitis Ivan Giovannini · Nicola Cabas · Marco Marino · Annarita Tullio · Ilaria Tinazz...

Rheumatol Ther (2025) 12:99–108 https://doi.org/10.1007/s40744-024-00728-4 ORIGINAL RESEARCH Arthralgia and Extraintestinal Manifestations in Crohn’s Disease Elevate the Risk of IBD‑Related Arthritis over Sacroiliitis Ivan Giovannini · Nicola Cabas · Marco Marino · Annarita Tullio · Ilaria Tinazzi · Angela Variola · Carmelo Cicciò · Fabro Cinzia · Berretti Debora · Chiara Zuiani · Rossano Girometti · Luca Quartuccio · Alen Zabotti · Lorenzo Cereser Received: September 10, 2024 / Accepted: November 11, 2024 / Published online: December 14, 2024 © The Author(s) 2024 ABSTRACT IBD-related arthritis development in a cohort of adult patients with CD. Methods: Between December 2012 and May Introduction: Inflammatory bowel disease 2020, consecutive patients with CD who per- (IBD) related arthritis is the most prevalent formed MRE were enrolled in the study. Patients extraintestinal manifestation (EIM) of IBD, rang- with a previous diagnosis of IBD-related arthri- ing between 10 and 39%. Magnetic resonance tis were excluded. A baseline demographics and enterography (MRE) is used to assess small bowel clinical characteristics of the patients were retro- disease involvement in Crohn’s disease (CD) and spectively collected. The identification of new- can detect signs of sacroiliitis in up to 23.5% onset IBD-related arthritis events during the of patients. The predicting role of sacroiliitis follow-up was based on rheumatological clinical detected on MRE is still unknown. The aim of diagnosis and fulfillment of the ASAS classifica- this study is to evaluate the predictive role of tion criteria. sacroiliitis at MRE and other clinical features for Results: Ninety-five patients, mean age 43.9 years (standard deviation [SD] ± 16.6), 52.6% female were enrolled in the study with a median Alen Zabotti and Lorenzo Cereser contributed equally and shared last name authorship. follow-up of 83 months (Q25:75 25:143). Six out I. Giovannini · N. Cabas · A. Tullio · F. Cinzia · A. Variola L. Quartuccio · A. Zabotti (*) Department of Gastroenterology, IRCCS Sacro Rheumatology Clinic, Rheumatology Institute, Cuore Don Calabria Hospital, Negrar di Valpolicella, Department of Medicine, Azienda Sanitaria Verona, Italy Universitaria Friuli Centrale c/o University C. Cicciò of Udine, Piazzale Santa Maria della Misericordia 15, Department of Diagnostic Imaging 33100 Udine, Italy and Interventional Radiology, IRCCS Sacro Cuore e-mail: [email protected] Don Calabria Hospital, Negrar di Valpolicella, M. Marino · B. Debora Verona, Italy Department of Gastroenterology, Azienda Sanitaria C. Zuiani · R. Girometti · L. Cereser Universitaria Friuli Centrale c/o University of Udine, Institute of Radiology, Department of Medicine, Udine, Italy University of Udine, Azienda Sanitaria-Universitaria I. Tinazzi Friuli Centrale (ASUFC), p.le S. Maria della Department of Rheumatology, IRCCS Sacro Cuore Misericordia, 15, 33100 Udine, Italy Don Calabria Hospital, Negrar di Valpolicella, Verona, Italy Vol.:(0123456789) 100 Rheumatol Ther (2025) 12:99–108 95 (6.3%) developed IBD-related arthritis with Sacroiliitis detected by magnetic resonance a mean time of 11 months (SD ± 16.8). Sacroili- enterography (MRE) is present in 20% of itis detected on MRE was not associated with an patients with Crohn’s disease within our increased risk of IBD-related arthritis (odds ratio cohort; however, it is not linked to the later [OR] = 2.12 [95% confidence interval (CI) 0.36, development of IBD-related arthritis. 12.53, p = 0.408]). In contrast, the presence of arthralgia and EIMs were found to be a predictor for IBD-related arthritis development (OR = 84.0 [95% CI 8.18, 862.39, p < 0.0001] and OR = 7.37 [95% CI 1.25, 43.32, p = 0.027], respectively). INTRODUCTION Conclusions: This study highlights that sacro- iliitis, as assessed by MRE, was not associated Background and Rationale with the development of IBD-related arthritis, whereas extraintestinal manifestations and Inflammatory bowel diseases (IBDs) are chronic arthralgia were significantly associated with later inflammatory diseases resulting from a complex IBD-related arthritis development in patients relationship between genetic, environmental, with CD. and microbiota factors. The etiology is still unknown and IBDs include ulcerative colitis (UC) and Crohn’s disease (CD). IBDs are a sys- Keywords: Arthralgia; Extraintestinal manifes- temic condition affecting the gastrointestinal tations; IBD-related arthritis; Crohn’s disease; tract. Nevertheless, about half of the patients Spondyloarthritis may also show extraintestinal manifestations (EIMs), such as arthritis, eye, and skin disease (i.e., uveitis, episcleritis, erythema nodosum, and pyoderma gangrenosum), hepatobiliary Key Summary Points system (i.e., sclerosant cholangitis) or meta- bolic disorder (i.e., malabsorption with conse- Why carry out this study? quent micronutrient deficiencies, osteoporosis) Inflammatory bowel diseases (IBDs) are. Musculoskeletal manifestations, mainly systemic conditions primarily affecting the arthralgia, are the most frequent extraintestinal gastrointestinal tract; however, around half features of IBDs and affect up to 50% of patients; of the patients may also exhibit extraintes- while the prevalence of IBD-related arthritis tinal manifestations (EIMs) such as arthritis, varies significantly depending on joint involve- uveitis, and skin disease. ment’s definition, ranging from 10 to 39%, and usually manifests after the diagnosis of IBD IBD-related arthritis is the most frequent [3–5]. IBD-related arthritis has been included in extraintestinal manifestation, affecting the group of spondylarthritis (SpA) and can be approximately 10–39% of individuals with divided into peripheral (p-SpA) and axial (ax- IBD. SpA), depending on the joint pattern involved. The identification of predictors for the onset Despite this well-known association between of arthritis in patients with IBD is essential IBD and SpA and the availability of advanced for developing preventive measures and early diagnostic techniques, the delay in diagnosis is diagnostic strategies. still a major problem. The diagnostic delay has What was learned from the study? been described up to 10 years, especially for axial disease that remains undiagnosed in around This study highlights that the presence of 5% of cases [6, 7]. Magnetic resonance imaging EIMs and arthralgia were associated with (MRI) of sacroiliac joints (SIJ) plays a central role the development of IBD-related arthritis in in the diagnosis of ax-SpA and can detect the patients with Chron’s disease. disease in the early stages. However, the pres- ence of clinical symptoms, such as inflammatory Rheumatol Ther (2025) 12:99–108 101 back pain (IBP), drives the suspect and the imag- the opportunity for proactive intervention. ing choice (Fig. 1A, B). Magnetic resonance This approach is currently being evaluated in enterography (MRE) is currently the method psoriatic arthritis. of choice to evaluate small-bowel involvement The aim of the study is to evaluate the pre- in adults with suspected CD and often during dictive role of sacroiliitis detected by MRE and the follow-up of the disease. A few papers pro- other clinical features for SpA development in a posed to use MRE images to identify sacroiliac cohort of adult patients with CD. joint involvement in adult patients with IBD, reporting a prevalence of asymptomatic sacro- iliitis ranging from 15.4 to 23.5% [8–11]. These findings suggest a subset of patients with sacro- METHODS iliitis and few/absent inflammatory symptoms who could benefit from early rheumatological Study Design and Participants assessment. Indeed, the presence of sacroiliitis on MRI + IBP falls in the definition of non-radi- This study used a multicenter retrospective ographic (nr)-axSpA and the progression from cohort study design. The study included con- nr-axSpA form to a radiographic-axSpA may take secutive adult patients with a diagnosis of CD up to 8–10 years. who underwent MRE between December 2012 However, it is not clear whether the sacroiliitis and May 2020 in the IBD center of Santa Maria identified by MRE can predict the future devel- della Misericordia Hospital (Udine) and IRCCS opment of SpA in patients with IBD. The iden- Sacro Cuore Don Calabria Hospital (Negrar di tification of predictors for the onset of arthritis Valpolicella). Patients with a previous diagnosis in patients with IBD assumes significance in the of IBD-related arthritis were excluded from the pursuit of preventative measures and early diag- study. nostic strategies. The examination of preclinical Baseline demographic information (i.e., age, phases preceding the onset of arthritis enhances sex, body mass index (BMI), smoking habits, Fig. 1  Sacroiliitis at magnetic resonance enterography indicating bone marrow edema (arrows). B Coronal con- in a 56-year-old female patient with Crohn’s disease. A trast-enhanced fat-saturated T1-weighted image show- Coronal fat-saturated T2-weighted image showing bilat- ing corresponding bilateral, subchondral sacroiliac joint eral, subchondral sacroiliac joint hyperintense areas, enhancement, indicating active osteitis (arrows) 102 Rheumatol Ther (2025) 12:99–108 alcohol intake); family history of other rheu- statistical computing. R Foundation for Statis- matic diseases (i.e., psoriasis, SpA); presence of tical Computing, Vienna, Austria). EIMs (i.e., eye involvement, primary sclerosing cholangitis, erythema nodosum, stomatitis/ aphthosis, pyoderma gangrenosum); presence RESULTS of arthralgia (defined as the presence of non- inflammatory musculoskeletal pain ); CD Study Population activity index (CDAI), Harvey–Bradshaw Index (HBI) and simple endoscopy score-CD (SES- Ninety-five patients were included in the study. CD); laboratory test (i.e., C-reactive protein The mean age was 43.9 years (SD ± 16.6), and (CRP), serum calprotectin) and SIJ evaluation 50/95 (52.6%) were female. The mean BMI was on MRE were recorded for all patients. 23.6 (SD ± 4.35) and 26/95 (27.4%) were current The presence of sacroiliitis on MRE was smokers. The family history of psoriasis or SpA defined as the presence of inflammatory and/ in a first-degree relative was present in 2.1% and or chronic structural changes involving SIJ 5.3%, respectively. according to EULAR criteria [10, 16]. Twenty-three out of 95 patients (24.2%) The identification of new-onset IBD-related exhibited at least one EIM: specifically, nine arthritis during the follow-up was based on patients had psoriasis, five had stomatitis/aph- rheumatological clinical diagnosis and fulfill- thosis, four had sclerosing cholangitis, two had ment of the ASAS classification criteria [17, erythema nodosum, and six had other EIMs 18]. Informed consent was obtained from (e.g., pyoderma gangrenosum, uveitis). Arthral- each patient in accordance with the Declara- gia was present in ten out of 95 (10.5%) patients tion of Helsinki and with local guidelines for at the time of enrollment. A total of 19 out of good clinical practice. Ethical approvals for the 95 patients (20.0%) showed signs of sacroiliitis study were obtained from Santa Maria della on MRE. Misericordia Hospital (Udine) (CEUR FVG: At baseline, 57 out 95 (60.0%) had at least MRE_SIJ2021, n° 807) and IRCCS Sacro Cuore mild activity of IBD calculated by CDAI while Don Calabria Hospital (Negrar, Verona) (CEUR the mean HBI was 5.2 (SD ± 3.9). Complete base- AOUI VR: 3175CESC 2021, n 14899). line data are available in Table 1. Statistical Analysis IBD‑Related Arthritis Development The baseline demographic and clinical traits During the study period (median follow-up of of all patients were recorded and inputted into 83 months, Q25:75 25:143), six patients (6.3%) an anonymous database. Continuous variables developed IBD-related arthritis. The mean time were described by means ± standards deviation between CD diagnosis and IBD-related arthritis (SD) a median with interquartile range (IQR); diagnosis was 11.0 months (SD ± 16.8), result- dichotomous variables were described by fre- ing in an incidence rate of 6.9 cases/year per quencies and percentages. Considering the 1000 patients. Overall, patients with a new non-parametric nature of continuous data, IBD-related arthritis diagnosis exhibited a pure we used Mann–Whitney U tests. The univari- peripheral phenotype. Notably, none of patients ate logistic regression model was used to esti- in our cohort developed axial involvement. mate the odds ratio (OR) values and 95% con- fidence interval (CI) for factor who potentially MRE‑detected sacroiliitis predict SpA. p values < 0.05 were considered statistically significant. All the analyses were Sacroiliitis on MRE was detected in 19 out 95 conducted with R version 4.3.0 (R Core Team (20%) patients. These patients had a median (2021). R: A language and environment for follow-up of 86.5 months (Q1:Q3 3.5:127.0) and Rheumatol Ther (2025) 12:99–108 103 Table 1  Baseline assessment (N = 95) two out 19 (10.5%) developed IBD-related arthri- tis. The incidence rate of IBD-related arthritis in Age, mean (SD) years 43.9 (16.6) patients with sacroiliitis detected on MRE was Female, n (%) 50 (52.6) 11.8 cases/years per 1000 patients, not reaching a significant (p = 0.500) difference compared to BMI, mean (SD) 23.6 those without signs of SIJ inflammation on MRE (4.3) (5.8 cases/years per 1000 patients). The presence Smoking habits, n (%) 26 (27.4) of sacroiliitis on MRE at the time of CD diagno- sis was not associated with an increased risk of Alcohol intake, n (%) 28 (29.5) IBD-related arthritis development (OR = 2.12 [95% Psoriasis history in a first-degree relative, n 2 (2.1) CI 0.36, 12.53; p = 0.408]) (Table 2). None of the (%) patients with sacroiliitis on MRE developed axial IBD-related arthritis over time. Of the 95 patients, SpA history in a first-degree relative, n (%) 5 (5.3) 26 (27.4%) had undergone abdominal surgery due Extra-gastrointestinal manifestations, n (%) 23 (24.2) to CD activity prior to MRE. A significant propor- tion of these patients (8/26, 30.8%) exhibited sac- Arthralgia, n (%) 10 (10.5) roiliitis on MRE compared to those who had not Localization CD, n (%) undergone surgery (p < 0.039). Nevertheless, this finding was not associated with a higher burden L1 (ileal) 29 (30.5) of CD disease activity at MRE time (HBI p = 0.603; L2 (colonic) 18 (18.9) CDAI p = 0.638; SES-CD p = 0.502) (Table 1). L3 (ileocolonic) 38 (40.0) Risk Factors for IBD‑Related Arthritis L4 (isolated upper disease) 1 (1.1) L1 + L4 5 (5.3) The presence of arthralgia prior to arthritis onset was associated with significantly increased risk, L3 + L4 4 (4.2) exhibiting an odds ratio of 84.0 [95% CI 8.18, HBI, mean (SD) 5.2 (3.9) 862.39, p < 0.0001]. Symptoms appeared a median of 23 months (Q25:75 12:28) before SpA diag- CDAI, n (%) nosis. Additionally, the presence of at least one 0 (remission) 38 (40.0) EIM was identified as a potential predictor of SpA development with OR = 7.37 [95% CI 1.25, 43.32, 1 (mild) 30 (31.6) p = 0.027]). 2 (moderate) 24 (25.3) Patients with IBD-related arthritis did not dis- 3 (severe) 3 (3.1) play a higher CD disease activity at MRE time than other patients considering HBI (mean SES-CD, mean (SD) 5.9 (5.0) 5.9 ± 4.1 vs. 5.2 ± 3.9, p = 0.912), CDAI (mean Sacroiliitis at MRE, n (%) 19 (20) 0.8 ± 0.9 vs. 0.9 ± 0.9, p = 0.756) and SES-CD (mean 5.8 ± 6.5 vs. 5.9 ± 5.0, p = 0.7489). In parallel, these Serum calprotectin (mg/kg), mean (SD) 653 parameters did not emerge as risk factors for (1120) IBD-related arthritis. In detail, OR = 1.2 [95% CI C-reactive protein (mg/l), mean (SD) 10.6 (21.1) 0.22, 7.50; p = 0.800] for HBI ≥ 8; OR = 1.2 [05% CI 0.22, 7.43; p = 0.783] for CDAI ≥ 2; OR 0.95 [95% Baseline characteristics of patients CI 0.16, 5.50; p = 0.950] for SES-CD ≥ 7. Localiza- BMI body mass index, SpA spondyloarthritis, CD Crohn’s tion of the CD did not predict the development disease, HBI Harvey–Bradshaw index, CDAI Crohn’s Dis- of IBD-related arthritis (L3: OR 2.60 [95% CI 0.40, ease Activity Index, SES-CD Simple Endoscopic Score for 15.42], p = 0.260) (Table 2). Crohn’s Disease, MRE magnetic resonance enterography 104 Rheumatol Ther (2025) 12:99–108 Table 2  Logistic regression predicting SpA Variable OR (95% CI) p value Gender, male 0.53 (0.09, 3.07) 0.483 BMI (continuous distributed variable) 0.99 (0.82, 1.21) 0.958 Smoking habit 1.33 (0.23, 7.76) 0.749 Alcohol habit 0 (0, 0) 0.993 Psoriasis history in first-degree relative 0 (0, 0) 0.993 SpA history in first-degree relative 0 (0, 0) 0.993 Presence of at least one extraintestinal manifestation psoriasis, eye involve- 7.37 (1.25, 43.32) 0.027 ment, primary sclerosing cholangitis, erythema nodosum, stomatitis/aph- thosis, pyoderma gangrenosum) Arthralgia 84.00 (8.18, 86.39) < 0.001 Localization CD L1 (ileal) 0.89 (0.15, 5.23) 0.896 L2 (colonic) 0.19 (0.02, 1.55) 0.121 L3 (ileocolonic) 2.60 (0.40, 15.42) 0.260 L4 (isolated upped disease) 1.33 (0.05, 33.36) 0.087 L1 + L4 2.86 (0.44, 18.49) 0.269 L3 + L4 0.41 (0.02, 8.00) 0.558 HBI ≥ 8 1.20 (0.22, 7.50) 0.800 CDAI ≥ 2 1.20 (0.22, 7.43) 0.783 SES-CD ≥ 7 0.95 (0.16, 5.50) 0.950 Sacroiliitis at MRE 2.12 (0.36, 12.53) 0.408 Serum calprotectin 1.00 (0.98, 1.001) 0.182 C-reactive protein (mg/dl) 0.999 (0.95, 1.04) 0.960 Logistic regression of potentially predictive factors for spondyloarthritis in patients with inflammatory bowel disease BMI body mass index, SpA spondyloarthritis, HBI Harvey–Bradshaw Index, CDAI Crohn’s Disease Activity Index, SES-CD Simple Endoscopic Score for Crohn’s Disease, MRE magnetic resonance enterography DISCUSSION IBD-related arthritis falls under the family of SpA due to its clinical involvement and pathoge- This study highlights that the presence of EIMs netic characteristics; SpA are often characterized and arthralgia were associated with the devel- by extra-articular involvement, with the charac- opment of IBD-related arthritis in patients with teristic triad including skin (psoriasis), gut (IBD), CD. However, sacroiliitis, as assessed by MRE, and eyes (uveitis). These domains can also be was not found to be associated with the develop- affected simultaneously, posing significant ther- ment of IBD-related arthritis. apeutic challenges for clinicians, therefore early recognition of IBD-related arthritis is crucial Rheumatol Ther (2025) 12:99–108 105 for implementing a target therapeutic strategy the generalizability of our results. Moreover, we and using treatments that could work for both cannot draw conclusions regarding HLA B27 gut and joint. Few studies in the literature have status, as it was not routinely assessed in our specifically focused on the predictive factors for cohort, and therefore, data are not available for arthritis in patients with IBD. In line with our all patients. However, scientific literature on this findings, some authors identified the presence of topic is limited, and the key take-home message other EIMs as risk factors for inflammatory joint that this study offers to the gastroenterological involvement in patients with IBD, emphasizing and rheumatological communities is the impor- the systemic nature of the disease [5, 19–22]. tance of recognizing EIMs in patients with CD. Furthermore, several studies have identified a These manifestations are significant from a ther- significant overlap in genetic risk loci between apeutic perspective and help identify a group of EIMs and IBD [23–25]. patients at higher risk of developing arthritis. This is the first study reporting arthralgia as a predictor for the onset of SpA in individuals with CD, highlighting parallels with the pro- gression observed in another form of SpA, spe- CONCLUSIONS cifically the transition from psoriasis to psoriatic This study highlights that sacroiliitis, as assessed arthritis [26–28]. by MRE, was not associated with the develop- Undoubtedly, as with other chronic arthritis, ment of IBD-related arthritis, whereas EIMs and it is not surprising that the subclinical phase is arthralgia were significantly associated with later characterized by arthralgia. The definition IBD-related arthritis development in patients used in the study is quite general, but it high- with CD. lights the need to better characterize this phase and the clinical features of arthralgia in order to more accurately target patients at risk of devel- Author Contributions. Ivan Giovannini: oping arthritis in the future, who could there- Investigation, conceptualization, writing-origi- fore benefit from interception therapies [30, 31]. nal draft, Review and Editing, writing, supervi- Among the factors that may be associated sion, Review and Editing, Visualization; Nicola with a subclinical phase of the articular disease Cabas: Review and Editing, Visualization. Marco in IBD, imaging could certainly be a helpful tool Marino: Investigation, Visualization, supervi- for stratifying patients at risk of development of sion; Annarita Tullio: Formal analysis, supervi- arthritis. In the previous study, we observed that sion; Ilaria Tinazzi: Investigation, supervision, MRE, performed for IBD assessment, can be a visualization; Angela Variola: Investigation, reliable tool for identifying inflammation at the supervision, visualization; Carmelo Cicciò: SIJ. Therefore, we evaluated whether sacro- Investigation, supervision, visualization; Fabro iliitis detected through imaging could be a risk Cinzia: Visualization, supervision; Berretti Deb- factor for disease development. The results of ora: Investigation, supervision; Chiara Zuiani: this study do not indicate a clear predictive role Visualization, supervision; Rossano Girometti: for sacroiliitis in the development of IBD-related Conceptualization, Visualization; Luca Quar- arthritis. However, given the small sample size tuccio: Visualization, supervision; Alen Zabotti: and the absence of IBD-related arthritis with Investigation, conceptualization, writing, super- axial involvement, we believe it is important to vision, Review and Editing, Visualization; Lor- proceed with caution and emphasize the need enzo Cereser: Investigation, Visualization, Con- for evaluation in a larger cohort. ceptualization, Review and Editing. Furthermore, the implications of our findings should be viewed within the context of other Funding. No funding or sponsorship was limitations, primarily the retrospective design received for this study or publication of this and the relatively small sample size. These article. constraints, along with the lack of systematic MRE repetition during follow-up, may affect 106 Rheumatol Ther (2025) 12:99–108 Data Availability. Data generated and REFERENCES analyzed during the current study are available upon reasonable request to the corresponding 1. Zhang YZ, Li YY. Inflammatory bowel disease: author. pathogenesis. World J Gastroenterol WJG. 2014;20(1):91–9. Declarations 2. Harbord M, Carbonnel F, European Crohn’s and Colitis Organisation. The first European evidence- based consensus on extra-intestinal manifestations Conflict of Interest. Alen Zabotti is an in inflammatory bowel disease. J Crohns Colitis. Editorial Board member of Rheumatology and 2016;10(3):239–54. Therapy. 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