Characteristics, risk factors and disease course of musculoskeletal manifestations in patients with inflammatory bowel disease: a prospective longitudinal cohort study

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M. Jansen, N. Broeder, T. W. Hal, E. A. M. Mahler, W. A. Dop, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4243036/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Musculoskeletal manifestations occur in half of the patients with Inflammatory bowel disease (IBD) and contribute to a reduced quality of life (QoL) and increased work disability. We aimed to evaluate the natural disease course, characteristics, and risk factors of musculoskeletal manifestations in patients with IBD. Methods We performed a prospective longitudinal cohort study in patients with IBD with and without musculoskeletal manifestations with a one year follow-up. Primary outcome was the proportion of patients with resolution of musculoskeletal manifestations. Secondary outcomes included: the proportion of patients with IBD that developed new musculoskeletal manifestations during follow-up; the correlation between IBD activity, baseline characteristics, and musculoskeletal disease course; and the difference in QoL between patients with and without musculoskeletal manifestations. Results In total, 243 patients with IBD were included (124 with and 119 without musculoskeletal manifestations). In the majority of patients (62.2%), musculoskeletal manifestations were of non-inflammatory nature. Overall, peripheral and axial manifestations were persistent in 85.7% and 44.6% at 1 year, respectively. The QoL at baseline and at 1 year was lower in the group with musculoskeletal manifestations compared to patients without these manifestations. Female gender and age above 40 were associated with the presence of musculoskeletal manifestations. Conclusion Musculoskeletal manifestations in patients with IBD are mostly non-inflammatory disorders, persist at 1 year of follow-up and occur more frequently in patients of age above 40 and female gender. Overall, patients with musculoskeletal manifestations have lower QoL compared to patients without musculoskeletal manifestations. Inflammatory Bowel Disease Musculoskeletal manifestations Extra-intestinal manifestations (spondylo)arthropathy Figures Figure 1 Brief summary This longitudinal cohort study followed 243 patients with inflammatory bowel disease with (n=124) and without (n=119) musculoskeletal manifestations during one year. Musculoskeletal manifestations were mostly non-inflammatory, persistent and associated with female gender, older age and a lower quality of life. INTRODUCTION Musculoskeletal manifestations occur in half of patients with Inflammatory Bowel Disease (IBD) and these extra-intestinal manifestations (EIMs) have a diversity of underlying diagnoses. 1–3 Musculoskeletal manifestations are often diagnosed after the IBD diagnosis, with an overall higher incidence in patients with Crohn’s Disease (CD) than ulcerative colitis (UC). 2, 4, 5 Musculoskeletal manifestations are associated with work disability and reduced quality of life (QoL), but patient characteristics and natural course of musculoskeletal manifestations remain unclear. 5–8 Musculoskeletal manifestations can be categorized by the absence or presence of inflammation, and by location i.e. peripheral joints or the vertebral column (axial joints). 9–11 Inflammatory musculoskeletal manifestations include arthritis, enthesitis and dactylitis (as part of the spondyloarthritis,SpA, disorders) or unrelated arthritis (e.g. gout). 1, 12–14 Non-inflammatory musculoskeletal manifestations are more prevalent and include for example osteoarthritis and trauma-related complaints. 5, 9, 10, 12, 15 Several factors are associated with musculoskeletal manifestations, including smoking, female gender and IBD disease activity. 3, 12, 14 However, prior studies investigating these associations are limited, poorly differentiated and often based on EIMs in general. 3, 12 In our prospective study, a dedicated rheumatologist aided with differentiation of inflammatory and non-inflammatory musculoskeletal manifestations. Secondly, the disease course of EIM has been poorly studied, although this information is important to manage expectations with patients in daily practice as musculoskeletal manifestations impair QoL. 5–8 Prospective data is needed to assess the course of musculoskeletal manifestations and the impact of underlying IBD disease activity and IBD therapies. In current literature on EIMs in IBD, non-inflammatory joint complaints has often been studied in relation to or as a consequence of inflammatory arthritis without distinguishing between these two distinctive entities and underlying etiology. 4, 16 Differentiation is important for adequate referral of patients with IBD and musculoskeletal manifestations to rheumatologists. 11, 17, 18 Moreover, smoking, female gender and IBD disease activity seems associated with EIMs in general, including musculoskeletal disorders in IBD. 3, 12 Hence, knowledge about the disease course and impact of risk factors on the different IBD-related musculoskeletal disorders is needed. In this prospective longitudinal cohort study, we aimed to describe the clinical disease course of inflammatory and non-inflammatory musculoskeletal manifestations in a multidisciplinary setting. Furthermore, we aimed to identify clinical risk factors for musculoskeletal manifestations by utilizing a control cohort of patients without musculoskeletal manifestations. METHODS Study design This single-center prospective longitudinal cohort study was conducted at the Radboud University Medical Center Nijmegen, the Netherlands, between October 2019 and February 2022. The follow-up period was 12 months. We constructed two cohorts of patients with IBD with and without musculoskeletal manifestations (control cohort). Objectives The primary objective was to determine the proportion of patients with resolution of musculoskeletal manifestations at 1 year. The secondary objectives were to identify: the clinical disease course of different musculoskeletal manifestations in IBD, the correlation between IBD activity and musculoskeletal manifestation disease course, the proportion of patients who developed new musculoskeletal manifestations within 1 year of follow-up, the difference in QoL between patients with and without musculoskeletal manifestations, and the differences in baseline characteristics (including IBD phenotype and medication use) between these two groups. Categories of musculoskeletal manifestations Articular involvement was subdivided into inflammatory disorders including SpA (peripheral or axial) and other inflammatory disorders including rheumatoid arthritis (RA) and gout. 11 We identified a second group of non-inflammatory disorders including osteoarthritis, fibromyalgia, trauma or structural, mechanical or anatomical disorders. 19 We did not use the Oxford-criteria to classify IBD-related arthropathies 1, 9, 16 since this categorization is only applied by gastroenterologists and is not based on underlying pathophysiology. 12, 13 Participants Patients with IBD were recruited from the IBD outpatient clinic at the gastroenterology department of the Radboud University Medical Center. Consecutive patients with IBD were enrolled if they provided informed consent and fulfilled the following inclusion criteria. A confirmed diagnosis of CD, UC or IBD-unclassified (IBD-U) ≥ 18 ≤ 75 years of age Enrolled in the following cohorts: Patients with musculoskeletal manifestations : reported previous (with rheumatological diagnosis or rheumatological follow-up ≤ 13 months ago) or active joint symptoms, or joint pain, at baseline during outpatient visit or consultation by phone. Joint symptoms were initially identified via the Harvey-Bradshaw Index (HBI) or Simple Clinical Colitis Activity Index (SCCAI) to patients with CD or UC/IBDU, respectively. Patients without musculoskeletal manifestations, control cohort : did not report active joint symptoms at baseline or within the previous 13 months. Work flow Patients were followed-up for 12 months. Musculoskeletal symptoms were carefully assessed and reported at baseline, 6 months and 1 year, as described below. Patients with new or pre-existent musculoskeletal manifestations without clear diagnosis or without previous analysis by a rheumatologist were first assessed in detail (see data collection for additional information) by a trained physician [F.J.] prior to consulting a rheumatologist. After assessment, all patients with musculoskeletal manifestations were discussed with a dedicated and closely involved rheumatologist [T.H.] from the Sint-Maartenskliniek (SMK) at Nijmegen, a center specialized in disorders of the musculoskeletal system. Data collection Baseline At baseline, the following data about the study population and IBD characteristics were collected. Sex, age, body mass index (BMI), smoking behavior and familial history of IBD, colorectal cancer or auto-immune diseases (including psoriasis, RA, SpA, thyroid disorders) 20 Medical history according to the Charles comorbidity index score 21 and history of EIMs or extra-intestinal complications including ocular EIMs, cutaneous EIMs Previous IBD medication, current IBD medication including type, dose and duration, Montreal-classification 22 and IBD-related surgery Short Inflammatory Bowel Disease Questionnaire (SIBDQ) and RAND Short-Form-(SF) 36 questionnaire to measure functional impairment, wellbeing and intestinal symptoms. 23, 24 The SF-36 questionnaire consists of 8 components of which 4, including physical functioning, role-physical, bodily pain and general health are combined as one physical component score (PCS). The other 4 components including vitality, social functioning, role-emotional and mental health are combined as mental component score (MCS). At baseline, 6 months and 12 months : Detailed exploration of musculoskeletal manifestations during outpatient visit or phone consultation by specifically trained physician. IBD disease activity: Clinical parameters: physician global assessment (PGA) defined as remission, mild, moderate or severe disease activity, the HBI 25 or SCCAI 26 Endoscopic outcomes, if available (including Mayo-classification, SES-CD, or post-surgery Rutgeerts-score) defined as remission, mild, moderate or severe disease activity Biochemical disease parameters including C-reactive protein (CRP) and fecal calprotectin protein (FCP) Medication-specific data were collected including: IBD-related medication at baseline including dose and duration IBD-related medication history General medication At 12 months SIBDQ and RAND SF-36 questionnaire Medical history of joint symptoms: Age at development, historical diagnoses Presence of: morning stiffness, symptoms of inflammation (redness, warmth and swelling), duration of symptoms. The latter was defined by using the pain score defined as the numeric rating scale (NRS) counting from no pain (0) to the most severe pain ( 10 ) or, once patients were not able to give a number, via a more physician global assessment of the reported symptoms. Localization of peripheral symptoms, the variability of symptoms during the day, the effect of strain and use of COX-2i Final diagnosis made after referral to a rheumatologist or made after consultation with a rheumatologist by phone if referral was not deemed necessary. Physical examination when possible: standard rheumatological physical examination focused on the presence of swollen or tender joints (yes/no). Statistical analyses For our primary outcome we expected to achieve an inclusion of at least 100 patients with IBD and musculoskeletal manifestations in our IBD population in our hospital. To be able to find correlations between risk factors (IBD disease activity, smoking behavior and sex) and musculoskeletal manifestations, we calculated that we needed at least 100 patients with IBD and 100 without musculoskeletal manifestations to perform a logistic regression analysis based on an estimated average prevalence of 15% of musculoskeletal manifestations (including in general a prevalence of the 16–33% musculoskeletal symptoms in the IBD population, 40% non-inflammatory and 5–10% inflammatory musculoskeletal symptoms in IBD). 1–4, 12, 27–30 Continuous data were presented as mean with standard deviation (SD) and in case of non-continuous data as medians with interquartile range (IQR). To make comparisons between patients with and without musculoskeletal manifestations, dichotomous and nominal data were compared using the chi-square test. Normally distributed data was analyzed by the unpaired t-test and not normally distributed data by the Mann Whitney-U test. When factors were significant in univariable logistic tests, these factors were tested in multivariable models with the presence or absence of musculoskeletal manifestations as dependent variable. A Spearman’s rho correlation-test was performed for testing the correlations between parameters for IBD disease activity (HBI, SCCAI, FCP) and musculoskeletal manifestations (NRS). A p-value of < 0.05 was considered statistically significant. RESULTS In total, 243 patients with IBD were enrolled; 124 patients with and 119 patients without (previous) musculoskeletal manifestations (control cohort) at baseline (Fig. 1 ). Overall, 112 patients with and 103 without musculoskeletal manifestations reached 1 year follow-up, while 28 patients were lost during follow-up (including 1 withdrawal of consent for filling out the questionnaires during follow-up). Characteristics of this group of 28 patients (of which n = 12 patients with musculoskeletal manifestations, n = 17 female gender, n = 18 with CD and n = 4 were referred to the rheumatology) were not significant different compared to patients who completed follow-up. Patients with musculoskeletal manifestations (N = 124) - At baseline Overall, 99.4% had joint symptoms at baseline. In total, 89.5% of the patients with musculoskeletal manifestations had peripheral symptoms and 50.8% had axial symptoms at baseline (Table 1 ). The median age to develop peripheral and axial symptoms was 41.0 (IQR 28.0–50.0) and 35.0 (IQR 24.0–49.0) years, respectively. In total, 37.9% had either a history of rheumatological diagnosis; either inflammatory axial SpA (7.3%), peripheral SpA (12.9%), RA (0.8%); or non-inflammatory osteoarthritis (11.3%) and fibromyalgia (5.6%). The total median duration of respectively peripheral and axial symptoms was 3.0 years (IQR 1.0–9.0) and 6.0 years (IQR 2.0–15.0). The median time from IBD diagnosis to peripheral and axial musculoskeletal symptoms was 6.0 years (IQR 1.0–17.0) and 10.5 years (2.0–17.0), respectively. In 46 patients with musculoskeletal manifestations, peripheral (n = 26) and axial (n = 20) symptoms developed prior to IBD diagnosis with a median duration of respectively 11.0 months (IQR 3.0–26.0) and 65.5 months (IQR 11.0-188.0). Table 1 Musculoskeletal manifestations at baseline Musculoskeletal manifestations at baseline (n = 124) General Active symptoms (including mild, moderate, severe): • Peripheral • Axial • Both No (remission) n (%) 172 (99.4) • 111 (89.5) • 63 (50.8) • 53 (42.7) 1 (0.6) Age development baseline joint symptoms (years) • Peripheral • Axial Median (IQR) 41.0 (28.0–50.0) 35.0 (24.0–49.0) (History of) rheumatological diagnosis (yes) Inflammatory backpain Inflammatory peripheral symptoms: • Arthritis • Enthesitis • Dactylitis Rheumatoid arthritis Osteoarthritis Fibromyalgia syndrome 9 (7.3) 16 (12.9) • 15 (93.8) • 5 (31.3) • 4 (25.0) 1 (0.8) 14 (11.3) 7 (5.6) Duration symptoms (years) • Peripheral • Axial Median (IQR) • 3.0 (1.0–9.0) • 6.0 (2.0–15.0) Time to IBD diagnosis (months) • Peripheral • Axial Median (IQR) • 11.0 (3.0–26.0) • 65.5 (11.0-188.0) Diagnoses of musculoskeletal manifestations after referral rheumatology n = 45 Inflammatory diagnoses n = 17 Peripheral (n = 7) • Arthritis only (n = 4) • Enthesitis only (n = 1) • Dactylitis and arthritis (n = 1) • Gout (n = 1) Axial (n = 7) • Inflammatory back pain (n = 7) Both peripheral and axial (n = 3) • Arthritis, enthesitis and axial spondylarthritis (n = 1) • Arthritis and inflammatory backpain (n = 1) • Enthesitis and inflammatory backpain (n = 1) Non-inflammatory diagnoses n = 28 Peripheral (n = 8) • Tendomyogenic (n = 6), osteoarthritis (n = 2) Axial only (n = 4) • Idiopathic chronic backpain (n = 2), osteoarthritis (n = 2) Both peripheral and axial (n = 16) • Idiopathic backpain combined with peripheral: enthesiopathy (n = 4), tendomyogenic symptoms (n = 3) and perniones (n = 1) (total of n = 8) • Peripheral and axial osteoarthritis (n = 5) including 1 combined with Dupuytren of fingers • Fibromyalgia syndrome with both peripheral and axial joint complaints (n = 3) Table 2 shows musculoskeletal manifestations in detail. Overall, peripheral symptoms involved most often more than five joints (67.6%), accompanied by general stiffness (63.4%), persisting morning stiffness (33.8%) and most often involved locations were hands, fingers, knees and wrist(s). Axial symptoms were often alternating in presence (75.4%), present in the morning (70.2%) and in 42.9% accompanied by persisting morning stiffness. Table 2 detailed information about axial and peripheral manifestations at baseline Musculoskeletal manifestations at baseline (n = 124) Axial Presence of symptoms • Alternating • Continuous n (%) n = 57 43 (75.4) 14 (24.6) Stiffness • In general • Morning stiffness > 30 minutes n (%) 49 (n = 57) (86.0) 27 (n = 63) (42.9) Moment worst symptoms • Morning • Afternoon • Evening • Night (wake-up) • Variable n (%) n = 57 40 (70.2) 3 (5.3) 12 (21.1) 17 (29.8) 19 (33.3) Pain score (NRS scale 0–10) if available Mean (SD) 6.4 (2.1) (n = 47) Movement effective n (%) 42 (n = 57) (73.7) Peripheral Localization (1 or more) • Shoulder • Elbow • Wrist • Hand/ fingers • Hip • Knee • Ankle • Feet/ toes • Achilles tendon • Fascia plantaris n (%) n = 102 27 (26.5) 21 (20.6) 30 (29.4) 70 (68.6) 27 (26.5) 53 (52.0) 23 (22.5) 15 (14.7) 4 (3.9) 3 (2.9) Involvement peripheral • 1 joint (mono) • 2–5 (oligo) • > 5 joints (poly) n (%) n = 102 6 (5.9) 27 (26.5) 69 (67.6) Presence of symptoms • Alternating • Continuous n (%) n = 101 72 (70.6) 29 (28.4) Stiffness • In general • Morning stiffness > 30 minutes n (%) 64 (n = 101) (63.4) 24 (n = 71) (33.8) Maximum pain score (NRS- scale 0–10) if available Median (IQR) 6.0 (4.0–8.0) (n = 94 ) Moment worst symptoms • Morning • Afternoon • Evening • Night (wake-up) • Variable n (%) n = 102 47 (46.1) 3 16 17 62 (60.8) Presence of (1 or more) redness, swelling or warmth n (%) 21 (20.6) Movement effective n (%) 58 (57.4) (n = 101) NRS = numeric rating scale (pain score) - Rheumatological referral outcomes In total, 33.8% (n = 45/133) of all patients with musculoskeletal manifestations at baseline and 1 patient who developed symptoms during follow-up were referred to rheumatology for the first time (Fig. 1 ). Of these referred patients, 37.8% (n = 17/45) were diagnosed with an inflammatory diagnosis of which 41.2% (n = 7/17) received either a peripheral or axial inflammatory diagnosis and 17.6% (n = 3/17) combined axial and peripheral inflammatory diagnoses with or without concomitant non-inflammatory diagnoses. Of the referred patients, 62.2% (n = 28/45) received a non-inflammatory diagnosis; in 35.7% (n = 10/28) peripheral, 14.3% axial (n = 4/28) and 50% (n = 14/28) both axial and peripheral localized symptoms. In 66.2% (n = 88/133), no rheumatological referral was deemed necessary and the majority of these patients (81.2%, n = 72/88) had non-inflammatory complaints. In 18.2% (n = 16/88) patients were already known with and treated for inflammatory diagnoses, either peripheral (56.3%, n = 9/16), axial (16%, n = 4/16) or both (18.8%, n = 3/16). - Clinical disease course and COX-2i At one year follow-up (n = 112), 85.7% (n = 96/112) of the patients with musculoskeletal manifestations still reported peripheral symptoms or had these symptoms in the previous 6 months. Axial symptoms were still present in 44.6% of these patients (n = 50/112). At one year follow-up, 23.2% (n = 26/112) of patients with musculoskeletal manifestations still used COX-2i (n = 16 etoricoxib, n = 10 celecoxib) to treat their joint symptoms. 27.7% (n = 29/112) had previously used COX-2i during 1 year of follow-up but discontinued mostly because of inefficacy (n = 14), other reasons included: remission of joint complaints (n = 7) and side-effects (n = 6). In two patients it was ceased prior to referral to rheumatology and start of other trial. - Incidence of musculoskeletal manifestations during follow-up During follow-up, in total 7.6% (n = 9/119) patients without musculoskeletal manifestations at baseline developed new musculoskeletal symptoms (n = 6 peripheral, n = 3 axial). One patient reported a relapse of his known ankylosing spondylitis, but last consulted rheumatology in 2001. One patient had a relapse of inflammatory back pain symptoms last active 2 years ago without an established SpA-diagnosis. Only one patient was referred to a rheumatologist and received the non-inflammatory diagnosis fibromyalgia syndrome (Fig. 1 ). Other patients received the following non-inflammatory diagnoses (diagnosed by gastroenterologists); joint complaints unspecified (n = 3/9) and/or in combination with osteoarthritis or mechanical disorders (n = 3/9) and joint symptoms based on polyneuropathy provoked by tofacitinib (n = 1/9). - Correlation between IBD disease activity at baseline and 12 months and musculoskeletal disease course There was no correlation between the pain scores (NRS) at baseline and 12 months and IBD activity at baseline including HBI, SCCAI or FCP-values (highest correlation was 0.154 between HBI/SCCAI at one year and baseline NRS) (supplementary Table 1). - Factors associated with musculoskeletal manifestations The multivariable analysis showed that older age at inclusion and female gender were significantly associated with the presence of musculoskeletal manifestations at baseline, whereas smoking and different IBD phenotypes were not (Table 3 ). Table 3 Multivariable regression analysis of baseline variables from patients with musculoskeletal manifestations n = 243 Odds ratio (95% confidence interval P-value Variables Age at inclusion 1.020 (1.003–1.039) 0.025* Females 2.122 (1.217–3.697) 0.008* Smoking 1.999 (0.967–4.131) 0.061 IBD diagnosis (CD, UC/IBD-U) 0.780 (0.449–1.358) 0.380 CD = Crohn’s disease IBD-U = inflammatory bowel disease- unclassified UC = ulcerative colitis Differences between patients with and without musculoskeletal manifestations - Baseline characteristics At baseline, patients with musculoskeletal manifestations were more often females (69.4%) compared to patients without musculoskeletal manifestations (53.8%) (Odds ratio, OR: 2.122, confidence interval, CI: 1.217–3.697) and had a higher prevalence of previous ocular (7.3%) and dermatological (18.5%) manifestations compared with patients without musculoskeletal manifestations (0.8% and 7.6%, respectively) (Tables 3 and 4 ). Moreover, all patients with musculoskeletal manifestations had more often an auto-immune disease in their history (other than IBD and SpA) (41.9%) than patients without musculoskeletal manifestations (15.1%). Table 4 Baseline characteristics Control cohort n = 119 Musculoskeletal manifestations n = 124 p-value Females n (%) 64 (53.8) 86 (69.4) 0.013* a Age at inclusion (years) Median (IQR) 38.0 (26.0–58.0) 47.0 (32.3–54.8) 0.083 b BMI (kg/m 2 ) Mean (SD) 24.9 (4.6) 26.8 (5.4) 0.076 c Smoking (yes) n (%) 15 (12.6) 26 (21.0) 0.082 a Medical history (Charlson comorbidity index): Malignancy (yes) • Colorectal cancer • Solid organ n (%) 2 (1.7) 6 (5.0) 1 (0.8) 6 (4.8) 0.537 a 0.537 a Kidney recipient (yes) n (%) 1 1 0.953 a Ocular manifestations (episcleritis, uveitis) (yes) n (%) 1 (0.8) 9 (7.3) 0.010* a Cutaneous manifestations (aphthous stomatitis, psoriasis, pyoderma gangrenosum, erythema nodosum) (yes) n (%) 9 (7.6) 23 (18.5) 0.013* a Familial diseases (first relatives if known) (yes) • Inflammatory bowel disease • Colorectal cancer • Auto-immune diseases (psoriasis, rheumatoid arthritis, spondyloarthitis, thyroid disorders) n (%) 17 (14.3) 5 (4.2) 18 (15.1) 15 (12.1) 9 (7.3) 52 (41.9) 0.614 a 0.307 a 0.000* a a Chi-square test b Mann-Whitney U-test c Unpaired t-test * statistically significant # Unclassified type seen as CD # missings: n = 3 BMI = body mass index IQR = interquartile range SD = standard deviation - QoL QoL was compared between, respectively, patients with musculoskeletal manifestations with patients in the control cohort. At baseline, patients with musculoskeletal manifestations had a lower IBD-related QoL (median 49.5 [IQR 42.8–58.3] versus 59.0 [50.0–63.0], respectively) and general QoL which was subdivided into physical component score (median 41.2 [IQR 36.1–48.3] versus 52.3 [46.6–56.3], respectively) and mental component score (median 50.4 [IQR 36.1–56.1] versus 53.3 [46.8–57.4], respectively) (supplementary Table 2). At one year, patients with musculoskeletal manifestations still had a lower IBD-related QoL and physical component score as part of the general QoL (median 52.0 [40.0–60.0] and median 42.3 [IQR 35.6–48.3], respectively) compared to patients without musculoskeletal manifestations (median 59.0 [IQR 49.5–64.0] and 51.7 [44.9–55.6], respectively). - IBD clinical course Overall, most patients had either pancolitis (UC) or ileocolonic disease (CD) extension and developed IBD between 17–39 years (supplementary Table 3). Patients with musculoskeletal manifestations more often received the IBD diagnosis at age above 40 (classification A3 according the Montreal classification) (22.6%) than patients without musculoskeletal manifestations (14.3%). At baseline, almost half of the patients were clinically and endoscopically in remission. Patients with musculoskeletal manifestations had significantly higher HBI and SCCAI-outcomes and historically underwent more surgery (39.5%) but had less often an elevated FCP of ≥ 150mg/L (16.5%) compared to patients without musculoskeletal manifestations (27.7% and 37.8%, respectively). - IBD therapy at baseline Overall, 79% versus 86% of patients with and without musculoskeletal manifestations, respectively, used IBD medication at baseline (Supplementary Table 4). When musculoskeletal manifestations were absent at baseline, thiopurines were used more often (26.1%) than when musculoskeletal manifestations were present (15.3%) while patients with musculoskeletal manifestations used more COX-2i at baseline than patients without musculoskeletal manifestations (15.3% versus 2.5%). There were some differences in historical medication use. Patients with musculoskeletal manifestations had more often been exposed to thiopurines (75.0%) and tumor-necrosis factor inhibitors (47.6%) compared to patients without musculoskeletal manifestations (58.8% and 31.1%, respectively). Patients without musculoskeletal manifestations had more often been exposed to local (intestinal) corticosteroids (29.4%) compared to patients in the control cohort (16.9%). DISCUSSION In this prospective cohort study, we evaluated 124 patients with IBD and musculoskeletal manifestations and 119 with IBD and no musculoskeletal manifestations at baseline. The majority of patients with musculoskeletal complaints consisted of non-inflammatory joint disorders. Overall, peripheral and axial manifestations were persistent in 85.7% and 44.6% at the end of 1 year follow-up, respectively. Musculoskeletal manifestations were associated with older age above 40 and female gender and negatively influenced QoL despite therapeutic interventions. Musculoskeletal manifestations persisted at the end of follow-up for 91% of patients. These findings are comparable with a previously published longitudinal cohort that also showed persisting musculoskeletal symptoms in 91.7% of 155 patients with IBD during follow-up. 12 Other studies about the disease course of musculoskeletal manifestations in IBD are scarce. Furthermore, 33.8% of our patients were referred to a rheumatologist of which 62.2% were non-inflammatory and only 37.8% of the symptoms were of inflammatory origin. This finding underlines the importance of expert rheumatologic consultation to come to timely and appropriate therapy. We did not find a correlation between IBD activity and the presence of musculoskeletal manifestations, also when distinguishing inflammatory versus non-inflammatory causes of musculoskeletal manifestations. These results are comparable with two studies about peripheral arthritis and non-inflammatory musculoskeletal symptoms in IBD 5, 14 , but are conflicting with studies that observed an independent association between IBD activity and musculoskeletal manifestations. 7, 12, 31–33 This discrepancy could be explained by differences in definitions of clinical IBD activity. In our cohort this was defined as an HBI or SCCAI above 5, since joint disorders are part of this scoring system, while two of the previous studies were less strict and used an HBI or SCCAI of above 4. 7, 12 In addition, clinical disease activity indices do not consistently reflect endoscopic disease activity which could explain this discrepancy. We observed more patients who had a history of thiopurine and TNFi use, or IBD-related surgery in the subgroup with musculoskeletal manifestations compared to patients without musculoskeletal manifestations. A more severe IBD phenotype and/or a more complicated disease course could be an explanation for these findings, since it is known that the severity of IBD course is associated with the occurrence of EIMs in general, including musculoskeletal manifestations. 1, 3, 19, 33 Furthermore the long-term presence of musculoskeletal symptoms, 3 to 6 years in our cohort, could have previously been treated with TNFi, especially in case of inflammatory manifestations, and explain the higher historical TNFi use in patients with musculoskeletal manifestations. The latter is in line with other studies that observed favorable results of TNFi in the treatment of EIMs in general and musculoskeletal manifestations in specific. 34, 35 In line with previous studies, older age, female gender and a history of EIMs were associated with the presence of other EIMs including musculoskeletal manifestations. 3, 12, 14, 36 We did not find evidence for the other known associations for musculoskeletal manifestations in patients with IBD, such as smoking behavior or IBD phenotype and localization or extend of IBD. 1, 3, 12, 33 This can be explained by the predominant focus on inflammatory joint disorders in previous studies, which was only a small subgroup in our cohort. In addition, the subgroup of patients with an active smoking behavior in our study population was also relatively small. Even though almost all patients were in stable IBD remission at inclusion, we still found a significant proportion of patients with musculoskeletal manifestations. This finding indicates that quiescent IBD by itself does not exclude activity of musculoskeletal manifestations. We found that patients with IBD who experienced musculoskeletal manifestations had a lower QoL, confirming previous study findings. 5, 7, 8 This finding further emphasizes the importance of early recognition of musculoskeletal manifestations in IBD. Our findings will aid in informing patients about expectations of their symptoms, including the predominantly persistent character of symptoms and most frequently non-inflammatory nature without risks of irreversible articular destruction when left untreated. At time of high clinical suspicion of an inflammatory joint disorder, referral to a rheumatologist should be considered. Future research is warranted about the efficacy of therapy, preferably a prospective longitudinal cohort study with clear defined outcomes, such as a rheumatological score or NRS, in which patients with musculoskeletal manifestations receive therapy in a step-up manner. The strengths of this study include the longitudinal prospective follow-up of one year in two well-defined groups of patients with IBD and with and without musculoskeletal manifestations. We were able to follow the disease course, QoL and resolution of different types of musculoskeletal manifestations. Our collaboration with rheumatology allowed for expert assessment. We provide new insights and patient specific associations that could be relevant for daily practice to help gastroenterologists decide whether patients would benefit from referral to a rheumatologist. Moreover, by collecting data from patients without musculoskeletal manifestations, we were able to compare important baseline and IBD characteristics to extract risk factors between the two groups. We also acknowledge some limitations. Since specific validated scoring systems or guidelines are not available for IBD patients, we were not able to classify the musculoskeletal manifestations or efficacy of therapy (COX-2i) other than with NRS. Objective diagnostic tools were not always available. As our subgroup of COX2i users or other joint-specific therapies was small and clear endpoints of therapeutic outcomes were not available, we were not able to draw conclusions about efficient therapies for joint disorders. Moreover, we did not compare our results with musculoskeletal manifestations in the general population which could be interesting for future research to define which musculoskeletal manifestations are associated with IBD, or even broader, with immune mediated inflammatory diseases. The study design restricted us to draw conclusions about the prevalence. CONCLUSION In our cohort, musculoskeletal manifestations in patients with IBD were most often of non-inflammatory nature and generally persisted beyond 1 year of follow-up despite the use of COX-2i and well-controlled underlying IBD. Although female gender and age above 40 were associated with the presence of musculoskeletal manifestations, other correlations appeared not significant. Since musculoskeletal manifestations were associated with a lower QoL, larger follow-up studies are needed to evaluate therapeutic strategies for patients with both IBD and musculoskeletal manifestations. Declarations Funding No funding has been received for this study Conflicts of interests F. Hoentjen has served on advisory boards, or as speaker or consultant for Abbvie, Celgene, Janssen-Cilag, MSD, Takeda, Teva, Sandoz and Dr. Falk, and has received unrestricted grants from Dr. Falk, Janssen-Cilag, Abbvie, Takeda. E. Mahler has served on advisory boards, or as speaker or consultant for Celgene, Eli Lilly, Pfizer, Novartis, UCB. Other authors have no potential conflict of interest to disclose. Ethical consideration The study was approved by Radboud University Medical Ethics Assessment Committee (2019-5817). All participants provided written consent. This study was performed according to the Declaration of Helsinki and Good Clinical Practice. Acknowledgements Guarantors of the article : Fenna M. Jansen, MD, Nathan den Broeder, Tamara W. van Hal, MD, Elien .M. Mahler, MD, PhD, Willemijn A. van Dop, MD, PhD, Frank Hoentjen, MD, PhD. Author contributors : study concept and design: FJ, NB, TH, WD, FH. Data acquisition: FJ, TH. Data analysis and interpretation: FJ, NB. Drafting the manuscript: FJ, NB, WD, FH. Critical revision of the manuscript for important intellectual additions: FJ, NB, TH, EM, WD and FH. All authors approved the final version of the manuscript for publication. References Greenstein AJ, Janowitz HD, Sachar DB. The extra-intestinal complications of Crohn's disease and ulcerative colitis: a study of 700 patients. Medicine (Baltimore) 1976;55:401–12. Vavricka SR, Rogler G, Gantenbein C, et al. Chronological Order of Appearance of Extraintestinal Manifestations Relative to the Time of IBD Diagnosis in the Swiss Inflammatory Bowel Disease Cohort. Inflamm Bowel Dis 2015;21:1794–800. Karmiris K, Avgerinos A, Tavernaraki A, et al. Prevalence and Characteristics of Extra-intestinal Manifestations in a Large Cohort of Greek Patients with Inflammatory Bowel Disease. J Crohns Colitis 2016;10:429–36. Roberts H, Rai SN, Pan J, et al. Extraintestinal manifestations of inflammatory bowel disease and the influence of smoking. Digestion 2014;90:122–9. Palm O, Bernklev T, Moum B, et al. Non-inflammatory joint pain in patients with inflammatory bowel disease is prevalent and has a significant impact on health related quality of life. J Rheumatol 2005;32:1755–9. Spekhorst LM, Oldenburg B, van Bodegraven AA, et al. Prevalence of- and risk factors for work disability in Dutch patients with inflammatory bowel disease. World J Gastroenterol 2017;23:8182–8192. van der Have M, Brakenhoff LK, van Erp SJ, et al. Back/joint pain, illness perceptions and coping are important predictors of quality of life and work productivity in patients with inflammatory bowel disease: a 12-month longitudinal study. J Crohns Colitis 2015;9:276–83. Ossum AM, Palm O, Cvancarova M, et al. The Impact of Spondyloarthritis and Joint Symptoms on Health-Related Quality of Life and Fatigue in IBD Patients. Results From a Population-Based Inception Cohort (20-Year Follow-up in the Ibsen Study). Inflamm Bowel Dis 2020;26:114–124. Orchard TR, Wordsworth BP, Jewell DP. Peripheral arthropathies in inflammatory bowel disease: their articular distribution and natural history. Gut 1998;42:387–91. Varkas G, Ribbens C, Louis E, et al. Expert consensus: practical algorithms for management of inflammatory bowel disease patients presenting with back pain or peripheral arthropathies. Aliment Pharmacol Ther 2019;50:1204–1213. Rudwaleit M, van der Heijde D, Landewé R, et al. The Assessment of SpondyloArthritis International Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general. Ann Rheum Dis 2011;70:25–31. van Erp SJ, Brakenhoff LK, van Gaalen FA, et al. Classifying Back Pain and Peripheral Joint Complaints in Inflammatory Bowel Disease Patients: A Prospective Longitudinal Follow-up Study. J Crohns Colitis 2016;10:166–75. Karreman MC, Luime JJ, Hazes JMW, et al. The Prevalence and Incidence of Axial and Peripheral Spondyloarthritis in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. J Crohns Colitis 2017;11:631–642. Ossum AM, Palm O, Cvancarova M, et al. Peripheral arthritis in patients with long-term inflammatory bowel disease. Results from 20 years of follow-up in the IBSEN study. Scand J Gastroenterol 2018;53:1250–1256. Brakenhoff LK, van der Heijde DM, Hommes DW, et al. The joint-gut axis in inflammatory bowel diseases. J Crohns Colitis 2010;4:257–68. Vavricka SR, Schoepfer A, Scharl M, et al. Extraintestinal Manifestations of Inflammatory Bowel Disease. Inflamm Bowel Dis 2015;21:1982–92. Rudwaleit M, van der Heijde D, Landewe R, et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis 2009;68:777–83. Poddubnyy D, van Tubergen A, Landewe R, et al. Development of an ASAS-endorsed recommendation for the early referral of patients with a suspicion of axial spondyloarthritis. Ann Rheum Dis 2015;74:1483–7. Brakenhoff LK, van der Heijde DM, Hommes DW. IBD and arthropathies: a practical approach to its diagnosis and management. Gut 2011;60:1426–35. Davidson A, Diamond B. Autoimmune diseases. N Engl J Med 2001;345:340–50. Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373–83. Satsangi J, Silverberg MS, Vermeire S, et al. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut 2006;55:749–53. de Jong ME, Taal E, Thomas PWA, et al. Cross-cultural translation and validation of the IBD-control questionnaire in The Netherlands: a patient-reported outcome measure in inflammatory bowel disease. Scand J Gastroenterol 2021;56:155–161. Brazier JE, Harper R, Jones NM, et al. Validating the SF-36 health survey questionnaire: new outcome measure for primary care. Bmj 1992;305:160–4. Harvey RF, Bradshaw JM. A simple index of Crohn's-disease activity. Lancet 1980;1:514. Walmsley RS, Ayres RC, Pounder RE, et al. A simple clinical colitis activity index. Gut 1998;43:29–32. Vavricka SR, Brun L, Ballabeni P, et al. Frequency and risk factors for extraintestinal manifestations in the Swiss inflammatory bowel disease cohort. Am J Gastroenterol 2011;106:110–9. Bernstein CN, Blanchard JF, Rawsthorne P, et al. The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study. Am J Gastroenterol 2001;96:1116–22. Severs M, van Erp SJ, van der Valk ME, et al. Smoking is Associated With Extra-intestinal Manifestations in Inflammatory Bowel Disease. J Crohns Colitis 2016;10:455–61. Peduzzi P, Concato J, Kemper E, et al. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol 1996;49:1373–9. Ossum AM, Palm O, Lunder AK, 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. J Crohns Colitis 2018;12:96–104. Orchard TR. Management of arthritis in patients with inflammatory bowel disease. Gastroenterol Hepatol (N Y) 2012;8:327–9. Ditisheim S, Fournier N, Juillerat P, et al. Inflammatory Articular Disease in Patients with Inflammatory Bowel Disease: Result of the Swiss IBD Cohort Study. Inflamm Bowel Dis 2015;21:2598–604. Greuter T, Rieder F, Kucharzik T, et al. Emerging treatment options for extraintestinal manifestations in IBD. Gut 2020. Vavricka SR, Gubler M, Gantenbein C, et al. Anti-TNF Treatment for Extraintestinal Manifestations of Inflammatory Bowel Disease in the Swiss IBD Cohort Study. Inflamm Bowel Dis 2017;23:1174–1181. Hiller A, Biedermann L, Fournier N, et al. The appearance of joint manifestations in the Swiss inflammatory bowel disease cohort. PLoS One 2019;14:e0211554. Additional Declarations No competing interests reported. Supplementary Files SUPPLEMENTARYFILES.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4243036","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":289843777,"identity":"ec2b4406-aa9c-474a-9071-084242df0a94","order_by":0,"name":"F. M. 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Hoentjen","email":"","orcid":"","institution":"University of Alberta","correspondingAuthor":false,"prefix":"","firstName":"F.","middleName":"","lastName":"Hoentjen","suffix":""}],"badges":[],"createdAt":"2024-04-09 15:42:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4243036/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4243036/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":54785166,"identity":"5b883da0-8c83-4e3a-88e4-3c3eb1beeffa","added_by":"auto","created_at":"2024-04-16 18:04:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":268654,"visible":true,"origin":"","legend":"\u003cp\u003eflow chart disease course joint symptoms\u003c/p\u003e","description":"","filename":"20240129Figure1flowchartMSMDDS.png","url":"https://assets-eu.researchsquare.com/files/rs-4243036/v1/5dec3c3365430a515aeadd5a.png"},{"id":54785664,"identity":"2b77ad66-6f6f-4705-bf03-a8e23787b61f","added_by":"auto","created_at":"2024-04-16 18:20:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":802482,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4243036/v1/3c12f344-4938-4236-984e-5ad2072c949e.pdf"},{"id":54785165,"identity":"61122bb0-c265-4b02-83ed-efa0ada67452","added_by":"auto","created_at":"2024-04-16 18:04:03","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":33284,"visible":true,"origin":"","legend":"","description":"","filename":"SUPPLEMENTARYFILES.docx","url":"https://assets-eu.researchsquare.com/files/rs-4243036/v1/6013f744bd1118274574080b.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Characteristics, risk factors and disease course of musculoskeletal manifestations in patients with inflammatory bowel disease: a prospective longitudinal cohort study","fulltext":[{"header":"Brief summary","content":"\u003cp\u003eThis longitudinal cohort study followed 243 patients with inflammatory bowel disease with (n=124) and without (n=119) musculoskeletal manifestations during one year. Musculoskeletal manifestations were mostly non-inflammatory, persistent and associated with female gender, older age and a lower quality of life.\u0026nbsp;\u003c/p\u003e"},{"header":"INTRODUCTION","content":"\u003cp\u003eMusculoskeletal manifestations occur in half of patients with Inflammatory Bowel Disease (IBD) and these extra-intestinal manifestations (EIMs) have a diversity of underlying diagnoses. \u003csup\u003e1\u0026ndash;3\u003c/sup\u003e Musculoskeletal manifestations are often diagnosed after the IBD diagnosis, with an overall higher incidence in patients with Crohn\u0026rsquo;s Disease (CD) than ulcerative colitis (UC).\u003csup\u003e2, 4, 5\u003c/sup\u003e Musculoskeletal manifestations are associated with work disability and reduced quality of life (QoL), but patient characteristics and natural course of musculoskeletal manifestations remain unclear. \u003csup\u003e5\u0026ndash;8\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eMusculoskeletal manifestations can be categorized by the absence or presence of inflammation, and by location i.e. peripheral joints or the vertebral column (axial joints). \u003csup\u003e9\u0026ndash;11\u003c/sup\u003e Inflammatory musculoskeletal manifestations include arthritis, enthesitis and dactylitis (as part of the spondyloarthritis,SpA, disorders) or unrelated arthritis (e.g. gout).\u003csup\u003e1, 12\u0026ndash;14\u003c/sup\u003e Non-inflammatory musculoskeletal manifestations are more prevalent and include for example osteoarthritis and trauma-related complaints. \u003csup\u003e5, 9, 10, 12, 15\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSeveral factors are associated with musculoskeletal manifestations, including smoking, female gender and IBD disease activity. \u003csup\u003e3, 12, 14\u003c/sup\u003e However, prior studies investigating these associations are limited, poorly differentiated and often based on EIMs in general. \u003csup\u003e3, 12\u003c/sup\u003e In our prospective study, a dedicated rheumatologist aided with differentiation of inflammatory and non-inflammatory musculoskeletal manifestations. Secondly, the disease course of EIM has been poorly studied, although this information is important to manage expectations with patients in daily practice as musculoskeletal manifestations impair QoL. \u003csup\u003e5\u0026ndash;8\u003c/sup\u003e Prospective data is needed to assess the course of musculoskeletal manifestations and the impact of underlying IBD disease activity and IBD therapies.\u003c/p\u003e \u003cp\u003eIn current literature on EIMs in IBD, non-inflammatory joint complaints has often been studied in relation to or as a consequence of inflammatory arthritis without distinguishing between these two distinctive entities and underlying etiology. \u003csup\u003e4, 16\u003c/sup\u003e Differentiation is important for adequate referral of patients with IBD and musculoskeletal manifestations to rheumatologists. \u003csup\u003e11, 17, 18\u003c/sup\u003e Moreover, smoking, female gender and IBD disease activity seems associated with EIMs in general, including musculoskeletal disorders in IBD. \u003csup\u003e3, 12\u003c/sup\u003e Hence, knowledge about the disease course and impact of risk factors on the different IBD-related musculoskeletal disorders is needed.\u003c/p\u003e \u003cp\u003eIn this prospective longitudinal cohort study, we aimed to describe the clinical disease course of inflammatory and non-inflammatory musculoskeletal manifestations in a multidisciplinary setting. Furthermore, we aimed to identify clinical risk factors for musculoskeletal manifestations by utilizing a control cohort of patients without musculoskeletal manifestations.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis single-center prospective longitudinal cohort study was conducted at the Radboud University Medical Center Nijmegen, the Netherlands, between October 2019 and February 2022. The follow-up period was 12 months. We constructed two cohorts of patients with IBD with and without musculoskeletal manifestations (control cohort).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eThe primary objective was to determine the proportion of patients with resolution of musculoskeletal manifestations at 1 year. The secondary objectives were to identify: the clinical disease course of different musculoskeletal manifestations in IBD, the correlation between IBD activity and musculoskeletal manifestation disease course, the proportion of patients who developed new musculoskeletal manifestations within 1 year of follow-up, the difference in QoL between patients with and without musculoskeletal manifestations, and the differences in baseline characteristics (including IBD phenotype and medication use) between these two groups.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eCategories of musculoskeletal manifestations\u003c/h2\u003e \u003cp\u003eArticular involvement was subdivided into inflammatory disorders including SpA (peripheral or axial) and other inflammatory disorders including rheumatoid arthritis (RA) and gout. \u003csup\u003e11\u003c/sup\u003e We identified a second group of non-inflammatory disorders including osteoarthritis, fibromyalgia, trauma or structural, mechanical or anatomical disorders. \u003csup\u003e19\u003c/sup\u003e We did not use the Oxford-criteria to classify IBD-related arthropathies \u003csup\u003e1, 9, 16\u003c/sup\u003e since this categorization is only applied by gastroenterologists and is not based on underlying pathophysiology. \u003csup\u003e12, 13\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003ePatients with IBD were recruited from the IBD outpatient clinic at the gastroenterology department of the Radboud University Medical Center. Consecutive patients with IBD were enrolled if they provided informed consent and fulfilled the following inclusion criteria.\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eA confirmed diagnosis of CD, UC or IBD-unclassified (IBD-U)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e\u0026ge;\u0026thinsp;18\u0026thinsp;\u0026le;\u0026thinsp;75 years of age\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eEnrolled in the following cohorts:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003ePatients with musculoskeletal manifestations\u003c/span\u003e: reported previous (with rheumatological diagnosis or rheumatological follow-up \u0026le;\u0026thinsp;13 months ago) or active joint symptoms, or joint pain, at baseline during outpatient visit or consultation by phone. Joint symptoms were initially identified via the Harvey-Bradshaw Index (HBI) or Simple Clinical Colitis Activity Index (SCCAI) to patients with CD or UC/IBDU, respectively.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003ePatients without musculoskeletal manifestations, control cohort\u003c/span\u003e: did not report active joint symptoms at baseline or within the previous 13 months.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eWork flow\u003c/h2\u003e \u003cp\u003ePatients were followed-up for 12 months. Musculoskeletal symptoms were carefully assessed and reported at baseline, 6 months and 1 year, as described below. Patients with new or pre-existent musculoskeletal manifestations without clear diagnosis or without previous analysis by a rheumatologist were first assessed in detail (see data collection for additional information) by a trained physician [F.J.] prior to consulting a rheumatologist. After assessment, all patients with musculoskeletal manifestations were discussed with a dedicated and closely involved rheumatologist [T.H.] from the Sint-Maartenskliniek (SMK) at Nijmegen, a center specialized in disorders of the musculoskeletal system.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003eBaseline\u003c/h2\u003e \u003cp\u003eAt baseline, the following data about the study population and IBD characteristics were collected.\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eSex, age, body mass index (BMI), smoking behavior and familial history of IBD, colorectal cancer or auto-immune diseases (including psoriasis, RA, SpA, thyroid disorders)\u003csup\u003e20\u003c/sup\u003e\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eMedical history according to the Charles comorbidity index score \u003csup\u003e21\u003c/sup\u003e and history of EIMs or extra-intestinal complications including ocular EIMs, cutaneous EIMs\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePrevious IBD medication, current IBD medication including type, dose and duration, Montreal-classification \u003csup\u003e22\u003c/sup\u003e and IBD-related surgery\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eShort Inflammatory Bowel Disease Questionnaire (SIBDQ) and RAND Short-Form-(SF) 36 questionnaire to measure functional impairment, wellbeing and intestinal symptoms. \u003csup\u003e23, 24\u003c/sup\u003e The SF-36 questionnaire consists of 8 components of which 4, including physical functioning, role-physical, bodily pain and general health are combined as one physical component score (PCS). The other 4 components including vitality, social functioning, role-emotional and mental health are combined as mental component score (MCS).\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eAt baseline, 6 months and 12 months\u003c/em\u003e:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eDetailed exploration of musculoskeletal manifestations during outpatient visit or phone consultation by specifically trained physician.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIBD disease activity:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eClinical parameters: physician global assessment (PGA) defined as remission, mild, moderate or severe disease activity, the HBI \u003csup\u003e25\u003c/sup\u003e or SCCAI \u003csup\u003e26\u003c/sup\u003e\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eEndoscopic outcomes, if available (including Mayo-classification, SES-CD, or post-surgery Rutgeerts-score) defined as remission, mild, moderate or severe disease activity\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eBiochemical disease parameters including C-reactive protein (CRP) and fecal calprotectin protein (FCP)\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eMedication-specific data were collected including:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eIBD-related medication at baseline including dose and duration\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIBD-related medication history\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eGeneral medication\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAt 12 months SIBDQ and RAND SF-36 questionnaire\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eMedical history of joint symptoms:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eAge at development, historical diagnoses\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePresence of: morning stiffness, symptoms of inflammation (redness, warmth and swelling), duration of symptoms. The latter was defined by using the pain score defined as the numeric rating scale (NRS) counting from no pain (0) to the most severe pain (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) or, once patients were not able to give a number, via a more physician global assessment of the reported symptoms.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eLocalization of peripheral symptoms, the variability of symptoms during the day, the effect of strain and use of COX-2i\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eFinal diagnosis made after referral to a rheumatologist or made after consultation with a rheumatologist by phone if referral was not deemed necessary.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePhysical examination when possible: standard rheumatological physical examination focused on the presence of swollen or tender joints (yes/no).\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eFor our primary outcome we expected to achieve an inclusion of at least 100 patients with IBD and musculoskeletal manifestations in our IBD population in our hospital. To be able to find correlations between risk factors (IBD disease activity, smoking behavior and sex) and musculoskeletal manifestations, we calculated that we needed at least 100 patients with IBD and 100 without musculoskeletal manifestations to perform a logistic regression analysis based on an estimated average prevalence of 15% of musculoskeletal manifestations (including in general a prevalence of the 16\u0026ndash;33% musculoskeletal symptoms in the IBD population, 40% non-inflammatory and 5\u0026ndash;10% inflammatory musculoskeletal symptoms in IBD). \u003csup\u003e1\u0026ndash;4, 12, 27\u0026ndash;30\u003c/sup\u003e Continuous data were presented as mean with standard deviation (SD) and in case of non-continuous data as medians with interquartile range (IQR). To make comparisons between patients with and without musculoskeletal manifestations, dichotomous and nominal data were compared using the chi-square test. Normally distributed data was analyzed by the unpaired t-test and not normally distributed data by the Mann Whitney-U test. When factors were significant in univariable logistic tests, these factors were tested in multivariable models with the presence or absence of musculoskeletal manifestations as dependent variable. A Spearman\u0026rsquo;s rho correlation-test was performed for testing the correlations between parameters for IBD disease activity (HBI, SCCAI, FCP) and musculoskeletal manifestations (NRS). A p-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eIn total, 243 patients with IBD were enrolled; 124 patients with and 119 patients without (previous) musculoskeletal manifestations (control cohort) at baseline (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Overall, 112 patients with and 103 without musculoskeletal manifestations reached 1 year follow-up, while 28 patients were lost during follow-up (including 1 withdrawal of consent for filling out the questionnaires during follow-up). Characteristics of this group of 28 patients (of which n\u0026thinsp;=\u0026thinsp;12 patients with musculoskeletal manifestations, n\u0026thinsp;=\u0026thinsp;17 female gender, n\u0026thinsp;=\u0026thinsp;18 with CD and n\u0026thinsp;=\u0026thinsp;4 were referred to the rheumatology) were not significant different compared to patients who completed follow-up.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003ePatients with musculoskeletal manifestations (N\u0026thinsp;=\u0026thinsp;124)\u003c/b\u003e \u003c/p\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e- At baseline\u003c/h2\u003e \u003cp\u003eOverall, 99.4% had joint symptoms at baseline. In total, 89.5% of the patients with musculoskeletal manifestations had peripheral symptoms and 50.8% had axial symptoms at baseline (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The median age to develop peripheral and axial symptoms was 41.0 (IQR 28.0\u0026ndash;50.0) and 35.0 (IQR 24.0\u0026ndash;49.0) years, respectively. In total, 37.9% had either a history of rheumatological diagnosis; either inflammatory axial SpA (7.3%), peripheral SpA (12.9%), RA (0.8%); or non-inflammatory osteoarthritis (11.3%) and fibromyalgia (5.6%). The total median duration of respectively peripheral and axial symptoms was 3.0 years (IQR 1.0\u0026ndash;9.0) and 6.0 years (IQR 2.0\u0026ndash;15.0). The median time from IBD diagnosis to peripheral and axial musculoskeletal symptoms was 6.0 years (IQR 1.0\u0026ndash;17.0) and 10.5 years (2.0\u0026ndash;17.0), respectively. In 46 patients with musculoskeletal manifestations, peripheral (n\u0026thinsp;=\u0026thinsp;26) and axial (n\u0026thinsp;=\u0026thinsp;20) symptoms developed prior to IBD diagnosis with a median duration of respectively 11.0 months (IQR 3.0\u0026ndash;26.0) and 65.5 months (IQR 11.0-188.0).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMusculoskeletal manifestations at baseline\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMusculoskeletal manifestations at baseline (n\u0026thinsp;=\u0026thinsp;124)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGeneral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eActive symptoms (including mild, moderate, severe):\u003c/p\u003e \u003cp\u003e\u0026bull; Peripheral\u003c/p\u003e \u003cp\u003e\u0026bull; Axial\u003c/p\u003e \u003cp\u003e\u0026bull; Both\u003c/p\u003e \u003cp\u003eNo (remission)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e172 (99.4)\u003c/p\u003e \u003cp\u003e\u0026bull; 111 (89.5)\u003c/p\u003e \u003cp\u003e\u0026bull; 63 (50.8)\u003c/p\u003e \u003cp\u003e\u0026bull; 53 (42.7)\u003c/p\u003e \u003cp\u003e1 (0.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge development baseline joint symptoms (years)\u003c/p\u003e \u003cp\u003e\u0026bull; Peripheral\u003c/p\u003e \u003cp\u003e\u0026bull; Axial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedian (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41.0 (28.0\u0026ndash;50.0)\u003c/p\u003e \u003cp\u003e35.0 (24.0\u0026ndash;49.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e(History of) rheumatological diagnosis (yes)\u003c/p\u003e \u003cp\u003eInflammatory backpain\u003c/p\u003e \u003cp\u003eInflammatory peripheral symptoms:\u003c/p\u003e \u003cp\u003e\u0026bull; Arthritis\u003c/p\u003e \u003cp\u003e\u0026bull; Enthesitis\u003c/p\u003e \u003cp\u003e\u0026bull; Dactylitis\u003c/p\u003e \u003cp\u003eRheumatoid arthritis\u003c/p\u003e \u003cp\u003eOsteoarthritis\u003c/p\u003e \u003cp\u003eFibromyalgia syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (7.3)\u003c/p\u003e \u003cp\u003e16 (12.9)\u003c/p\u003e \u003cp\u003e\u0026bull; 15 (93.8)\u003c/p\u003e \u003cp\u003e\u0026bull; 5 (31.3)\u003c/p\u003e \u003cp\u003e\u0026bull; 4 (25.0)\u003c/p\u003e \u003cp\u003e1 (0.8)\u003c/p\u003e \u003cp\u003e14 (11.3)\u003c/p\u003e \u003cp\u003e7 (5.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration symptoms (years)\u003c/p\u003e \u003cp\u003e\u0026bull; Peripheral\u003c/p\u003e \u003cp\u003e\u0026bull; Axial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedian (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026bull; 3.0 (1.0\u0026ndash;9.0)\u003c/p\u003e \u003cp\u003e\u0026bull; 6.0 (2.0\u0026ndash;15.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime to IBD diagnosis (months)\u003c/p\u003e \u003cp\u003e\u0026bull; Peripheral\u003c/p\u003e \u003cp\u003e\u0026bull; Axial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedian (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026bull; 11.0 (3.0\u0026ndash;26.0)\u003c/p\u003e \u003cp\u003e\u0026bull; 65.5 (11.0-188.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eDiagnoses of musculoskeletal manifestations after referral rheumatology n\u0026thinsp;=\u0026thinsp;45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eInflammatory diagnoses n\u0026thinsp;=\u0026thinsp;17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003ePeripheral (n\u0026thinsp;=\u0026thinsp;7)\u003c/span\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; Arthritis only (n\u0026thinsp;=\u0026thinsp;4)\u003c/p\u003e \u003cp\u003e\u0026bull; Enthesitis only (n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003cp\u003e\u0026bull; Dactylitis and arthritis (n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003cp\u003e\u0026bull; Gout (n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eAxial (n\u0026thinsp;=\u0026thinsp;7)\u003c/span\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; Inflammatory back pain (n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eBoth peripheral and axial (n\u0026thinsp;=\u0026thinsp;3)\u003c/span\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; Arthritis, enthesitis and axial spondylarthritis (n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003cp\u003e\u0026bull; Arthritis and inflammatory backpain (n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003cp\u003e\u0026bull; Enthesitis and inflammatory backpain (n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eNon-inflammatory diagnoses n\u0026thinsp;=\u0026thinsp;28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003ePeripheral (n\u0026thinsp;=\u0026thinsp;8)\u003c/span\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; Tendomyogenic (n\u0026thinsp;=\u0026thinsp;6), osteoarthritis (n\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eAxial only (n\u0026thinsp;=\u0026thinsp;4)\u003c/span\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; Idiopathic chronic backpain (n\u0026thinsp;=\u0026thinsp;2), osteoarthritis (n\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eBoth peripheral and axial (n\u0026thinsp;=\u0026thinsp;16)\u003c/span\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; Idiopathic backpain combined with peripheral: enthesiopathy (n\u0026thinsp;=\u0026thinsp;4), tendomyogenic symptoms (n\u0026thinsp;=\u0026thinsp;3) and perniones (n\u0026thinsp;=\u0026thinsp;1) (total of n\u0026thinsp;=\u0026thinsp;8)\u003c/p\u003e \u003cp\u003e\u0026bull; Peripheral and axial osteoarthritis (n\u0026thinsp;=\u0026thinsp;5) including 1 combined with Dupuytren of fingers\u003c/p\u003e \u003cp\u003e\u0026bull; Fibromyalgia syndrome with both peripheral and axial joint complaints (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows musculoskeletal manifestations in detail. Overall, peripheral symptoms involved most often more than five joints (67.6%), accompanied by general stiffness (63.4%), persisting morning stiffness (33.8%) and most often involved locations were hands, fingers, knees and wrist(s). Axial symptoms were often alternating in presence (75.4%), present in the morning (70.2%) and in 42.9% accompanied by persisting morning stiffness.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003edetailed information about axial and peripheral manifestations at baseline\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMusculoskeletal manifestations at baseline (n\u0026thinsp;=\u0026thinsp;124)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAxial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresence of symptoms\u003c/p\u003e \u003cp\u003e\u0026bull; Alternating\u003c/p\u003e \u003cp\u003e\u0026bull; Continuous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;57\u003c/p\u003e \u003cp\u003e43 (75.4)\u003c/p\u003e \u003cp\u003e14 (24.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStiffness\u003c/p\u003e \u003cp\u003e\u0026bull; In general\u003c/p\u003e \u003cp\u003e\u0026bull; Morning stiffness\u0026thinsp;\u0026gt;\u0026thinsp;30 minutes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49 (n\u0026thinsp;=\u0026thinsp;57) (86.0)\u003c/p\u003e \u003cp\u003e27 (n\u0026thinsp;=\u0026thinsp;63) (42.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMoment worst symptoms\u003c/p\u003e \u003cp\u003e\u0026bull; Morning\u003c/p\u003e \u003cp\u003e\u0026bull; Afternoon\u003c/p\u003e \u003cp\u003e\u0026bull; Evening\u003c/p\u003e \u003cp\u003e\u0026bull; Night (wake-up)\u003c/p\u003e \u003cp\u003e\u0026bull; Variable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;57\u003c/p\u003e \u003cp\u003e40 (70.2)\u003c/p\u003e \u003cp\u003e3 (5.3)\u003c/p\u003e \u003cp\u003e12 (21.1)\u003c/p\u003e \u003cp\u003e17 (29.8)\u003c/p\u003e \u003cp\u003e19 (33.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePain score (NRS scale 0\u0026ndash;10) if available\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.4 (2.1) (n\u0026thinsp;=\u0026thinsp;47)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMovement effective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42 (n\u0026thinsp;=\u0026thinsp;57) (73.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeripheral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocalization (1 or more)\u003c/p\u003e \u003cp\u003e\u0026bull; Shoulder\u003c/p\u003e \u003cp\u003e\u0026bull; Elbow\u003c/p\u003e \u003cp\u003e\u0026bull; Wrist\u003c/p\u003e \u003cp\u003e\u0026bull; Hand/ fingers\u003c/p\u003e \u003cp\u003e\u0026bull; Hip\u003c/p\u003e \u003cp\u003e\u0026bull; Knee\u003c/p\u003e \u003cp\u003e\u0026bull; Ankle\u003c/p\u003e \u003cp\u003e\u0026bull; Feet/ toes\u003c/p\u003e \u003cp\u003e\u0026bull; Achilles tendon\u003c/p\u003e \u003cp\u003e\u0026bull; Fascia plantaris\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;102\u003c/p\u003e \u003cp\u003e27 (26.5)\u003c/p\u003e \u003cp\u003e21 (20.6)\u003c/p\u003e \u003cp\u003e30 (29.4)\u003c/p\u003e \u003cp\u003e70 (68.6)\u003c/p\u003e \u003cp\u003e27 (26.5)\u003c/p\u003e \u003cp\u003e53 (52.0)\u003c/p\u003e \u003cp\u003e23 (22.5)\u003c/p\u003e \u003cp\u003e15 (14.7)\u003c/p\u003e \u003cp\u003e4 (3.9)\u003c/p\u003e \u003cp\u003e3 (2.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInvolvement peripheral\u003c/p\u003e \u003cp\u003e\u0026bull; 1 joint (mono)\u003c/p\u003e \u003cp\u003e\u0026bull; 2\u0026ndash;5 (oligo)\u003c/p\u003e \u003cp\u003e\u0026bull; \u0026gt;\u0026thinsp;5 joints (poly)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;102\u003c/p\u003e \u003cp\u003e6 (5.9)\u003c/p\u003e \u003cp\u003e27 (26.5)\u003c/p\u003e \u003cp\u003e69 (67.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresence of symptoms\u003c/p\u003e \u003cp\u003e\u0026bull; Alternating\u003c/p\u003e \u003cp\u003e\u0026bull; Continuous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;101\u003c/p\u003e \u003cp\u003e72 (70.6)\u003c/p\u003e \u003cp\u003e29 (28.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStiffness\u003c/p\u003e \u003cp\u003e\u0026bull; In general\u003c/p\u003e \u003cp\u003e\u0026bull; Morning stiffness\u0026thinsp;\u0026gt;\u0026thinsp;30 minutes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64 (n\u0026thinsp;=\u0026thinsp;101) (63.4)\u003c/p\u003e \u003cp\u003e24 (n\u0026thinsp;=\u0026thinsp;71) (33.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaximum pain score (NRS- scale 0\u0026ndash;10) if available\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedian (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.0 (4.0\u0026ndash;8.0) (n\u0026thinsp;=\u0026thinsp;94 )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMoment worst symptoms\u003c/p\u003e \u003cp\u003e\u0026bull; Morning\u003c/p\u003e \u003cp\u003e\u0026bull; Afternoon\u003c/p\u003e \u003cp\u003e\u0026bull; Evening\u003c/p\u003e \u003cp\u003e\u0026bull; Night (wake-up)\u003c/p\u003e \u003cp\u003e\u0026bull; Variable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;102\u003c/p\u003e \u003cp\u003e47 (46.1)\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003cp\u003e16\u003c/p\u003e \u003cp\u003e17\u003c/p\u003e \u003cp\u003e62 (60.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresence of (1 or more) redness, swelling or warmth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (20.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMovement effective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58 (57.4) (n\u0026thinsp;=\u0026thinsp;101)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eNRS\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003enumeric rating scale (pain score)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e- Rheumatological referral outcomes\u003c/h2\u003e \u003cp\u003eIn total, 33.8% (n\u0026thinsp;=\u0026thinsp;45/133) of all patients with musculoskeletal manifestations at baseline and 1 patient who developed symptoms during follow-up were referred to rheumatology for the first time (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Of these referred patients, 37.8% (n\u0026thinsp;=\u0026thinsp;17/45) were diagnosed with an inflammatory diagnosis of which 41.2% (n\u0026thinsp;=\u0026thinsp;7/17) received either a peripheral or axial inflammatory diagnosis and 17.6% (n\u0026thinsp;=\u0026thinsp;3/17) combined axial and peripheral inflammatory diagnoses with or without concomitant non-inflammatory diagnoses. Of the referred patients, 62.2% (n\u0026thinsp;=\u0026thinsp;28/45) received a non-inflammatory diagnosis; in 35.7% (n\u0026thinsp;=\u0026thinsp;10/28) peripheral, 14.3% axial (n\u0026thinsp;=\u0026thinsp;4/28) and 50% (n\u0026thinsp;=\u0026thinsp;14/28) both axial and peripheral localized symptoms. In 66.2% (n\u0026thinsp;=\u0026thinsp;88/133), no rheumatological referral was deemed necessary and the majority of these patients (81.2%, n\u0026thinsp;=\u0026thinsp;72/88) had non-inflammatory complaints. In 18.2% (n\u0026thinsp;=\u0026thinsp;16/88) patients were already known with and treated for inflammatory diagnoses, either peripheral (56.3%, n\u0026thinsp;=\u0026thinsp;9/16), axial (16%, n\u0026thinsp;=\u0026thinsp;4/16) or both (18.8%, n\u0026thinsp;=\u0026thinsp;3/16).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e- Clinical disease course and COX-2i\u003c/h2\u003e \u003cp\u003eAt one year follow-up (n\u0026thinsp;=\u0026thinsp;112), 85.7% (n\u0026thinsp;=\u0026thinsp;96/112) of the patients with musculoskeletal manifestations still reported peripheral symptoms or had these symptoms in the previous 6 months. Axial symptoms were still present in 44.6% of these patients (n\u0026thinsp;=\u0026thinsp;50/112). At one year follow-up, 23.2% (n\u0026thinsp;=\u0026thinsp;26/112) of patients with musculoskeletal manifestations still used COX-2i (n\u0026thinsp;=\u0026thinsp;16 etoricoxib, n\u0026thinsp;=\u0026thinsp;10 celecoxib) to treat their joint symptoms. 27.7% (n\u0026thinsp;=\u0026thinsp;29/112) had previously used COX-2i during 1 year of follow-up but discontinued mostly because of inefficacy (n\u0026thinsp;=\u0026thinsp;14), other reasons included: remission of joint complaints (n\u0026thinsp;=\u0026thinsp;7) and side-effects (n\u0026thinsp;=\u0026thinsp;6). In two patients it was ceased prior to referral to rheumatology and start of other trial.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e- Incidence of musculoskeletal manifestations during follow-up\u003c/h2\u003e \u003cp\u003eDuring follow-up, in total 7.6% (n\u0026thinsp;=\u0026thinsp;9/119) patients without musculoskeletal manifestations at baseline developed new musculoskeletal symptoms (n\u0026thinsp;=\u0026thinsp;6 peripheral, n\u0026thinsp;=\u0026thinsp;3 axial). One patient reported a relapse of his known ankylosing spondylitis, but last consulted rheumatology in 2001. One patient had a relapse of inflammatory back pain symptoms last active 2 years ago without an established SpA-diagnosis. Only one patient was referred to a rheumatologist and received the non-inflammatory diagnosis fibromyalgia syndrome (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Other patients received the following non-inflammatory diagnoses (diagnosed by gastroenterologists); joint complaints unspecified (n\u0026thinsp;=\u0026thinsp;3/9) and/or in combination with osteoarthritis or mechanical disorders (n\u0026thinsp;=\u0026thinsp;3/9) and joint symptoms based on polyneuropathy provoked by tofacitinib (n\u0026thinsp;=\u0026thinsp;1/9).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e- Correlation between IBD disease activity at baseline and 12 months and musculoskeletal disease course\u003c/h2\u003e \u003cp\u003eThere was no correlation between the pain scores (NRS) at baseline and 12 months and IBD activity at baseline including HBI, SCCAI or FCP-values (highest correlation was 0.154 between HBI/SCCAI at one year and baseline NRS) (supplementary Table\u0026nbsp;1).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e- Factors associated with musculoskeletal manifestations\u003c/h2\u003e \u003cp\u003eThe multivariable analysis showed that older age at inclusion and female gender were significantly associated with the presence of musculoskeletal manifestations at baseline, whereas smoking and different IBD phenotypes were not (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariable regression analysis of baseline variables from patients with musculoskeletal manifestations\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;243\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOdds ratio (95% confidence interval\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at inclusion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.020 (1.003\u0026ndash;1.039)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.025*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemales\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.122 (1.217\u0026ndash;3.697)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.008*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.999 (0.967\u0026ndash;4.131)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.061\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIBD diagnosis (CD, UC/IBD-U)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.780 (0.449\u0026ndash;1.358)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.380\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eCD\u0026thinsp;=\u0026thinsp;Crohn\u0026rsquo;s disease\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eIBD-U\u0026thinsp;=\u0026thinsp;inflammatory bowel disease- unclassified\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eUC\u0026thinsp;=\u0026thinsp;ulcerative colitis\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eDifferences between patients with and without musculoskeletal manifestations\u003c/b\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e- Baseline characteristics\u003c/h2\u003e \u003cp\u003eAt baseline, patients with musculoskeletal manifestations were more often females (69.4%) compared to patients without musculoskeletal manifestations (53.8%) (Odds ratio, OR: 2.122, confidence interval, CI: 1.217\u0026ndash;3.697) and had a higher prevalence of previous ocular (7.3%) and dermatological (18.5%) manifestations compared with patients without musculoskeletal manifestations (0.8% and 7.6%, respectively) (Tables\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Moreover, all patients with musculoskeletal manifestations had more often an auto-immune disease in their history (other than IBD and SpA) (41.9%) than patients without musculoskeletal manifestations (15.1%).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl cohort\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;119\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMusculoskeletal manifestations\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;124\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemales\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64 (53.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e86 (69.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.013*\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at inclusion (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedian (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38.0 (26.0\u0026ndash;58.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47.0 (32.3\u0026ndash;54.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.083\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.9 (4.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26.8 (5.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.076\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking (yes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (12.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26 (21.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.082\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003eMedical history (Charlson comorbidity index):\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMalignancy (yes)\u003c/p\u003e \u003cp\u003e\u0026bull; Colorectal cancer\u003c/p\u003e \u003cp\u003e\u0026bull; Solid organ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (1.7)\u003c/p\u003e \u003cp\u003e6 (5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0.8)\u003c/p\u003e \u003cp\u003e6 (4.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.537\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e0.537\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKidney recipient (yes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.953\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOcular manifestations (episcleritis, uveitis) (yes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (7.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.010*\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCutaneous manifestations (aphthous stomatitis, psoriasis, pyoderma gangrenosum, erythema nodosum) (yes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (7.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23 (18.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.013*\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamilial diseases (first relatives if known) (yes)\u003c/p\u003e \u003cp\u003e\u0026bull; Inflammatory bowel disease\u003c/p\u003e \u003cp\u003e\u0026bull; Colorectal cancer\u003c/p\u003e \u003cp\u003e\u0026bull; Auto-immune diseases (psoriasis, rheumatoid arthritis, spondyloarthitis, thyroid disorders)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (14.3)\u003c/p\u003e \u003cp\u003e5 (4.2)\u003c/p\u003e \u003cp\u003e18 (15.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (12.1)\u003c/p\u003e \u003cp\u003e9 (7.3)\u003c/p\u003e \u003cp\u003e52 (41.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.614\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e0.307\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e0.000*\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Chi-square test\u003c/p\u003e \u003cp\u003e\u003csup\u003eb\u003c/sup\u003e Mann-Whitney U-test\u003c/p\u003e \u003cp\u003e\u003csup\u003ec\u003c/sup\u003e Unpaired t-test\u003c/p\u003e \u003cp\u003e\u003csup\u003e*\u003c/sup\u003e statistically significant\u003c/p\u003e \u003cp\u003e\u003csup\u003e#\u003c/sup\u003e Unclassified type seen as CD\u003c/p\u003e \u003cp\u003e# missings: n\u0026thinsp;=\u0026thinsp;3\u003c/p\u003e \u003cp\u003e\u003cem\u003eBMI\u0026thinsp;=\u0026thinsp;body mass index\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eIQR\u0026thinsp;=\u0026thinsp;interquartile range\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eSD\u0026thinsp;=\u0026thinsp;standard deviation\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e- QoL\u003c/h2\u003e \u003cp\u003eQoL was compared between, respectively, patients with musculoskeletal manifestations with patients in the control cohort. At baseline, patients with musculoskeletal manifestations had a lower IBD-related QoL (median 49.5 [IQR 42.8\u0026ndash;58.3] versus 59.0 [50.0\u0026ndash;63.0], respectively) and general QoL which was subdivided into physical component score (median 41.2 [IQR 36.1\u0026ndash;48.3] versus 52.3 [46.6\u0026ndash;56.3], respectively) and mental component score (median 50.4 [IQR 36.1\u0026ndash;56.1] versus 53.3 [46.8\u0026ndash;57.4], respectively) (supplementary Table\u0026nbsp;2). At one year, patients with musculoskeletal manifestations still had a lower IBD-related QoL and physical component score as part of the general QoL (median 52.0 [40.0\u0026ndash;60.0] and median 42.3 [IQR 35.6\u0026ndash;48.3], respectively) compared to patients without musculoskeletal manifestations (median 59.0 [IQR 49.5\u0026ndash;64.0] and 51.7 [44.9\u0026ndash;55.6], respectively).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003e- IBD clinical course\u003c/h2\u003e \u003cp\u003eOverall, most patients had either pancolitis (UC) or ileocolonic disease (CD) extension and developed IBD between 17\u0026ndash;39 years (supplementary Table\u0026nbsp;3). Patients with musculoskeletal manifestations more often received the IBD diagnosis at age above 40 (classification A3 according the Montreal classification) (22.6%) than patients without musculoskeletal manifestations (14.3%). At baseline, almost half of the patients were clinically and endoscopically in remission. Patients with musculoskeletal manifestations had significantly higher HBI and SCCAI-outcomes and historically underwent more surgery (39.5%) but had less often an elevated FCP of \u0026ge;\u0026thinsp;150mg/L (16.5%) compared to patients without musculoskeletal manifestations (27.7% and 37.8%, respectively).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003e- IBD therapy at baseline\u003c/h2\u003e \u003cp\u003eOverall, 79% versus 86% of patients with and without musculoskeletal manifestations, respectively, used IBD medication at baseline (Supplementary Table\u0026nbsp;4). When musculoskeletal manifestations were absent at baseline, thiopurines were used more often (26.1%) than when musculoskeletal manifestations were present (15.3%) while patients with musculoskeletal manifestations used more COX-2i at baseline than patients without musculoskeletal manifestations (15.3% versus 2.5%). There were some differences in historical medication use. Patients with musculoskeletal manifestations had more often been exposed to thiopurines (75.0%) and tumor-necrosis factor inhibitors (47.6%) compared to patients without musculoskeletal manifestations (58.8% and 31.1%, respectively). Patients without musculoskeletal manifestations had more often been exposed to local (intestinal) corticosteroids (29.4%) compared to patients in the control cohort (16.9%).\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this prospective cohort study, we evaluated 124 patients with IBD and musculoskeletal manifestations and 119 with IBD and no musculoskeletal manifestations at baseline. The majority of patients with musculoskeletal complaints consisted of non-inflammatory joint disorders. Overall, peripheral and axial manifestations were persistent in 85.7% and 44.6% at the end of 1 year follow-up, respectively. Musculoskeletal manifestations were associated with older age above 40 and female gender and negatively influenced QoL despite therapeutic interventions.\u003c/p\u003e \u003cp\u003eMusculoskeletal manifestations persisted at the end of follow-up for 91% of patients. These findings are comparable with a previously published longitudinal cohort that also showed persisting musculoskeletal symptoms in 91.7% of 155 patients with IBD during follow-up. \u003csup\u003e12\u003c/sup\u003e Other studies about the disease course of musculoskeletal manifestations in IBD are scarce. Furthermore, 33.8% of our patients were referred to a rheumatologist of which 62.2% were non-inflammatory and only 37.8% of the symptoms were of inflammatory origin. This finding underlines the importance of expert rheumatologic consultation to come to timely and appropriate therapy.\u003c/p\u003e \u003cp\u003eWe did not find a correlation between IBD activity and the presence of musculoskeletal manifestations, also when distinguishing inflammatory versus non-inflammatory causes of musculoskeletal manifestations. These results are comparable with two studies about peripheral arthritis and non-inflammatory musculoskeletal symptoms in IBD \u003csup\u003e5, 14\u003c/sup\u003e, but are conflicting with studies that observed an independent association between IBD activity and musculoskeletal manifestations. \u003csup\u003e7, 12, 31\u0026ndash;33\u003c/sup\u003e This discrepancy could be explained by differences in definitions of clinical IBD activity. In our cohort this was defined as an HBI or SCCAI above 5, since joint disorders are part of this scoring system, while two of the previous studies were less strict and used an HBI or SCCAI of above 4. \u003csup\u003e7, 12\u003c/sup\u003e In addition, clinical disease activity indices do not consistently reflect endoscopic disease activity which could explain this discrepancy.\u003c/p\u003e \u003cp\u003eWe observed more patients who had a history of thiopurine and TNFi use, or IBD-related surgery in the subgroup with musculoskeletal manifestations compared to patients without musculoskeletal manifestations. A more severe IBD phenotype and/or a more complicated disease course could be an explanation for these findings, since it is known that the severity of IBD course is associated with the occurrence of EIMs in general, including musculoskeletal manifestations. \u003csup\u003e1, 3, 19, 33\u003c/sup\u003e Furthermore the long-term presence of musculoskeletal symptoms, 3 to 6 years in our cohort, could have previously been treated with TNFi, especially in case of inflammatory manifestations, and explain the higher historical TNFi use in patients with musculoskeletal manifestations. The latter is in line with other studies that observed favorable results of TNFi in the treatment of EIMs in general and musculoskeletal manifestations in specific. \u003csup\u003e34, 35\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn line with previous studies, older age, female gender and a history of EIMs were associated with the presence of other EIMs including musculoskeletal manifestations. \u003csup\u003e3, 12, 14, 36\u003c/sup\u003e We did not find evidence for the other known associations for musculoskeletal manifestations in patients with IBD, such as smoking behavior or IBD phenotype and localization or extend of IBD. \u003csup\u003e1, 3, 12, 33\u003c/sup\u003e This can be explained by the predominant focus on inflammatory joint disorders in previous studies, which was only a small subgroup in our cohort. In addition, the subgroup of patients with an active smoking behavior in our study population was also relatively small. Even though almost all patients were in stable IBD remission at inclusion, we still found a significant proportion of patients with musculoskeletal manifestations. This finding indicates that quiescent IBD by itself does not exclude activity of musculoskeletal manifestations.\u003c/p\u003e \u003cp\u003eWe found that patients with IBD who experienced musculoskeletal manifestations had a lower QoL, confirming previous study findings. \u003csup\u003e5, 7, 8\u003c/sup\u003e This finding further emphasizes the importance of early recognition of musculoskeletal manifestations in IBD. Our findings will aid in informing patients about expectations of their symptoms, including the predominantly persistent character of symptoms and most frequently non-inflammatory nature without risks of irreversible articular destruction when left untreated. At time of high clinical suspicion of an inflammatory joint disorder, referral to a rheumatologist should be considered. Future research is warranted about the efficacy of therapy, preferably a prospective longitudinal cohort study with clear defined outcomes, such as a rheumatological score or NRS, in which patients with musculoskeletal manifestations receive therapy in a step-up manner.\u003c/p\u003e \u003cp\u003eThe strengths of this study include the longitudinal prospective follow-up of one year in two well-defined groups of patients with IBD and with and without musculoskeletal manifestations. We were able to follow the disease course, QoL and resolution of different types of musculoskeletal manifestations. Our collaboration with rheumatology allowed for expert assessment. We provide new insights and patient specific associations that could be relevant for daily practice to help gastroenterologists decide whether patients would benefit from referral to a rheumatologist. Moreover, by collecting data from patients without musculoskeletal manifestations, we were able to compare important baseline and IBD characteristics to extract risk factors between the two groups.\u003c/p\u003e \u003cp\u003eWe also acknowledge some limitations. Since specific validated scoring systems or guidelines are not available for IBD patients, we were not able to classify the musculoskeletal manifestations or efficacy of therapy (COX-2i) other than with NRS. Objective diagnostic tools were not always available. As our subgroup of COX2i users or other joint-specific therapies was small and clear endpoints of therapeutic outcomes were not available, we were not able to draw conclusions about efficient therapies for joint disorders. Moreover, we did not compare our results with musculoskeletal manifestations in the general population which could be interesting for future research to define which musculoskeletal manifestations are associated with IBD, or even broader, with immune mediated inflammatory diseases. The study design restricted us to draw conclusions about the prevalence.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eIn our cohort, musculoskeletal manifestations in patients with IBD were most often of non-inflammatory nature and generally persisted beyond 1 year of follow-up despite the use of COX-2i and well-controlled underlying IBD. Although female gender and age above 40 were associated with the presence of musculoskeletal manifestations, other correlations appeared not significant. Since musculoskeletal manifestations were associated with a lower QoL, larger follow-up studies are needed to evaluate therapeutic strategies for patients with both IBD and musculoskeletal manifestations.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding has been received for this study\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eF. Hoentjen has served on advisory boards, or as speaker or consultant for Abbvie, Celgene, Janssen-Cilag, MSD, Takeda, Teva, Sandoz and Dr. Falk, and has received unrestricted grants from Dr. Falk, Janssen-Cilag, Abbvie, Takeda. E. Mahler has served on advisory boards, or as speaker or consultant for Celgene, Eli Lilly, Pfizer, Novartis, UCB. Other authors have no potential conflict of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical consideration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by Radboud University Medical Ethics Assessment Committee (2019-5817). \u0026nbsp;All participants provided written consent. This study was performed according to the Declaration of Helsinki and Good Clinical Practice.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eGuarantors of the article\u003c/em\u003e: Fenna M. Jansen, MD, Nathan den Broeder, Tamara W. van Hal, MD, Elien .M. Mahler, MD, PhD, Willemijn A. van Dop, MD, PhD, Frank Hoentjen, MD, PhD.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthor contributors\u003c/em\u003e: study concept and design: FJ, NB, TH, WD, FH. Data acquisition: FJ, TH. Data analysis and interpretation: FJ, NB. Drafting the manuscript: FJ, NB, WD, FH. Critical revision of the manuscript for important intellectual additions: FJ, NB, TH, EM, WD and FH. All authors approved the final version of the manuscript for publication.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGreenstein AJ, Janowitz HD, Sachar DB. The extra-intestinal complications of Crohn's disease and ulcerative colitis: a study of 700 patients. Medicine (Baltimore) 1976;55:401\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVavricka SR, Rogler G, Gantenbein C, et al. Chronological Order of Appearance of Extraintestinal Manifestations Relative to the Time of IBD Diagnosis in the Swiss Inflammatory Bowel Disease Cohort. Inflamm Bowel Dis 2015;21:1794\u0026ndash;800.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKarmiris K, Avgerinos A, Tavernaraki A, et al. 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Validating the SF-36 health survey questionnaire: new outcome measure for primary care. Bmj 1992;305:160\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarvey RF, Bradshaw JM. A simple index of Crohn's-disease activity. Lancet 1980;1:514.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWalmsley RS, Ayres RC, Pounder RE, et al. A simple clinical colitis activity index. Gut 1998;43:29\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVavricka SR, Brun L, Ballabeni P, et al. Frequency and risk factors for extraintestinal manifestations in the Swiss inflammatory bowel disease cohort. Am J Gastroenterol 2011;106:110\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBernstein CN, Blanchard JF, Rawsthorne P, et al. The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study. 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Gastroenterol Hepatol (N Y) 2012;8:327\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDitisheim S, Fournier N, Juillerat P, et al. Inflammatory Articular Disease in Patients with Inflammatory Bowel Disease: Result of the Swiss IBD Cohort Study. Inflamm Bowel Dis 2015;21:2598\u0026ndash;604.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGreuter T, Rieder F, Kucharzik T, et al. Emerging treatment options for extraintestinal manifestations in IBD. Gut 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVavricka SR, Gubler M, Gantenbein C, et al. Anti-TNF Treatment for Extraintestinal Manifestations of Inflammatory Bowel Disease in the Swiss IBD Cohort Study. Inflamm Bowel Dis 2017;23:1174\u0026ndash;1181.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHiller A, Biedermann L, Fournier N, et al. The appearance of joint manifestations in the Swiss inflammatory bowel disease cohort. PLoS One 2019;14:e0211554.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Inflammatory Bowel Disease, Musculoskeletal manifestations, Extra-intestinal manifestations, (spondylo)arthropathy","lastPublishedDoi":"10.21203/rs.3.rs-4243036/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4243036/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMusculoskeletal manifestations occur in half of the patients with Inflammatory bowel disease (IBD) and contribute to a reduced quality of life (QoL) and increased work disability. We aimed to evaluate the natural disease course, characteristics, and risk factors of musculoskeletal manifestations in patients with IBD.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe performed a prospective longitudinal cohort study in patients with IBD with and without musculoskeletal manifestations with a one year follow-up. Primary outcome was the proportion of patients with resolution of musculoskeletal manifestations. Secondary outcomes included: the proportion of patients with IBD that developed new musculoskeletal manifestations during follow-up; the correlation between IBD activity, baseline characteristics, and musculoskeletal disease course; and the difference in QoL between patients with and without musculoskeletal manifestations.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn total, 243 patients with IBD were included (124 with and 119 without musculoskeletal manifestations). In the majority of patients (62.2%), musculoskeletal manifestations were of non-inflammatory nature. Overall, peripheral and axial manifestations were persistent in 85.7% and 44.6% at 1 year, respectively. The QoL at baseline and at 1 year was lower in the group with musculoskeletal manifestations compared to patients without these manifestations. Female gender and age above 40 were associated with the presence of musculoskeletal manifestations.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eMusculoskeletal manifestations in patients with IBD are mostly non-inflammatory disorders, persist at 1 year of follow-up and occur more frequently in patients of age above 40 and female gender. Overall, patients with musculoskeletal manifestations have lower QoL compared to patients without musculoskeletal manifestations.\u003c/p\u003e","manuscriptTitle":"Characteristics, risk factors and disease course of musculoskeletal manifestations in patients with inflammatory bowel disease: a prospective longitudinal cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-16 18:03:58","doi":"10.21203/rs.3.rs-4243036/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7fb00ba1-bde6-4269-a047-23f1ea37095a","owner":[],"postedDate":"April 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-04-16T18:04:00+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-16 18:03:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4243036","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4243036","identity":"rs-4243036","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}