Symptoms compatible with Rome IV functional bowel disorder in patients with ankylosing spondylitis - Oxford Academic

Symptoms compatible with Rome IV functional bowel
disorder in patients with ankylosing spondylitis
Lei Wanga,b,† , Chuan Songa,b,† , Yiwen Wanga , Lidong Hua , Xingkang Liua , Jiaxin Zhanga,b ,

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Xiaojian Jia , Siliang Manc , Nana Zhangb,d , Gang Lie , Yunsheng Yangd , Lihua Pengd,* , Zhimin Weie,*
and Feng Huanga,*
a
 Department of Rheumatology and Immunology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
b
 Medical School of Chinese PLA, Beijing, China
c
 Department of Rheumatology, Beijing Jishuitan Hospital, Beijing, China
d
 Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
e
 Health Service Department of the Guard Bureau of the General Office of the Central Committee of the Communist Party of China, Beijing,
China
† These authors contributed equally to this work.
*Correspondence: Feng Huang; fhuang@301hospital.com.cn; Department of Rheumatology and Immunology, The First Medical Center, Chinese PLA General
Hospital, 28 Fuxing Road, Haidian District, Beijing 100853, China.
Zhimin Wei; 51807124@qq.com; Health Service Department of the Guard Bureau of the General Office of the Central Committee of the Communist Party of
China, 81 Nanchang Road, Xicheng District, Beijing 100031, China.
Lihua Peng; penglihua301@126.com; Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, 28 Fuxing
Road, Haidian District, Beijing 100853, China.

ABSTRACT
Objectives: To determine the frequency of symptoms meeting Rome IV functional bowel disorder (FBD) in patients with ankylosing spondylitis
(AS), investigate factors associated with FBD symptoms, and assess whether having FBD symptoms might influence AS disease activity.
Methods: In this cross-sectional study, we enrolled 153 AS patients without known colonic ulcers and 56 sex- and age-matched controls to
evaluate FBD (or its subtypes) symptoms. Disease characteristics were also evaluated in the AS group.
Results: Sixty (39.2%) of 153 AS patients had FBD symptoms, which were more prevalent than controls (23.2%). Besides, symptoms compatible
with irritable bowel syndrome (IBS) and chronic diarrhoea were detected in 18 and 43 AS patients, respectively. For the AS group, multivariable
logistic regression analyses showed that symptoms of FBD, IBS, and chronic diarrhoea were negatively associated with using non-steroidal anti-
inflammatory drugs and positively associated with comorbid fibromyalgia, respectively. In exploration about the effects of FBD (or its subtypes)
symptoms on AS disease activity by multivariable linear regression analyses, FBD symptoms and chronic diarrhoea had universal positive
associations with assessments of AS disease characteristics, respectively.
Conclusions: Patients with AS had frequent symptoms compatible with FBD, IBS, and chronic diarrhoea, proportions of which were lower
in those with non-steroidal anti-inflammatory drug use. The improvement of FBD symptoms and chronic diarrhoea might be conducive to the
disease status of AS patients.
KEYWORDS: Ankylosing spondylitis; chronic diarrhoea; functional bowel disorder; irritable bowel syndrome; non-steroidal anti-inflammatory drug

Introduction Functional bowel disorder (FBD) is an umbrella term for a
Ankylosing spondylitis (AS), an immune-mediated inflamma- group of conditions characterized by predominant symptoms
tory arthritis, is the prototype of a broader class of axial of abdominal pain, constipation, diarrhoea, and bloating or
spondyloarthritis (axSpA) [1]. Beyond explorations of the distention. According to the Rome IV criteria, FBD is now
bone, the gut involvement in AS had also been discovered, classified as irritable bowel syndrome (IBS), functional consti-
which altered gut microbiota and subclinical gut inflamma- pation (FC), functional diarrhoea (FDr), functional abdom-
tion were detected in ileal/colonic biopsies of patients with AS inal bloating/distention (FAB/D), unspecified FBD (U-FBD),
[2, 3]. A systematic review and meta-analysis reported that and opioid-induced constipation. Considering predominant
the prevalence of inflammatory bowel disease (IBD) in 30,410 stool patterns, IBS patients are divided into four groups: IBS
AS patients was 6.8% [4]. However, clinical manifestations of with constipation (IBS-C), IBS with diarrhoea (IBS-D), IBS
gut problems except for IBD have not been well established in with mixed stool pattern (IBS-M), and IBS unclassified (IBS-U)
patients with AS. [5]. For patients with AS, abdominal pain and/or diarrhoea

Received 11 January 2022; Accepted 18 June 2022
© Japan College of Rheumatology 2022. Published by Oxford University Press.
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was previously found to be prevalent [6, 7]; however, a lack American College of Rheumatology Preliminary Diagnostic
of standard scale makes it difficult to assess and conclude gut Criteria for Fibromyalgia [18].
symptoms. One study investigated that 30% of patients with
axSpA had IBS symptoms meeting Rome III criteria [8], sup- Statistics
porting that the diagnostic questionnaire of FBD might be Statistical analyses were performed using IBM SPSS statistics
appropriate for AS patients to record gut symptoms. version 24.0 (IBM). Descriptive statistics were presented as
 In this study, we aimed to determine the frequency of FBD mean and standard deviation (SD) or median and interquartile
symptoms in patients with AS, explore factors associated with range (IQR). Categorical variables were presented as n (%). In
FBD symptoms, and assess whether having FBD symptoms comparisons between groups, the t-test or the Mann–Whitney
might influence AS disease activity. U test was used for continuous variables, where appropriate,

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 and the chi-squared test or Fisher’s exact test was used for
 categorical variables, respectively. Univariate logistic regres-
Materials and methods sion analyses were performed, in which variables displaying
Ethics statement p < .20 were subsequently evaluated in multivariable analy-
The study was approved by the Ethics Committee of Chinese ses. Results of logistic regression were reported as odds ratio
PLA General Hospital (approval no. S2020-024-02). Before (OR) and 95% confidence interval (CI) for individual vari-
study inclusion, each participant signed an informed consent ables. Effects of gut symptoms on assessments of AS were
according to the Declaration of Helsinki. evaluated by linear regression analyses. Considering other
 clinical variables related to disease activity, hierarchical mul-
Participants tivariable analyses with co-linearity tools were conducted.
 Owing to skewed distributions, CRP, ESR, and F-Calpr were
This was a cross-sectional study. Patients fulfilling the 1984
 log-transformed before analysis. Block-1 adopting the for-
modified New York criteria were recruited consecutively from
 ward step-wise model included age, sex, body mass index
outpatient rheumatology clinics in the First Medical Center of
 (BMI), smoking status, HLA-B27, lnCRP, lnESR, lnF-Calpr,
Chinese PLA General Hospital [9]. In a sex- and age-matched
 NSAID, TNFi, csDMARD, and CM, and Block-2 using the
control group, subjects without inflammatory joint disease
 enter method, respectively, included gut symptoms display-
and IBD were recruited among the hospital staff and relatives
 ing p < .20 in univariate analyses. Results were reported as
of researchers. Participant characteristics including age, sex,
 unstandardized coefficients for gut symptoms. All tests were
height, weight, and smoking status were recorded.
 two-tailed, and p ≤ .05 was considered statistically significant.

AS characteristics
Laboratory parameters including erythrocyte sedimentation Results
rate (ESR) and C-reactive protein (CRP) in 1 week, as well Clinical characteristics
as human leucocyte antigen B-27 (HLA-B27) status, were Of 165 consecutive AS patients assessed, 11 patients with
recorded. Medical history of non-steroidal anti-inflammatory colonic ulcers (5 ulcerative colitis, 3 Crohn’s disease, 2
drug (NSAID), tumour necrosis factor inhibitor (TNFi), autoimmunity-associated colitis, and 1 NSAID-related gas-
conventional synthetic disease-modifying antirheumatic drug trointestinal ulcer) and 1 patient, which was at risk
(csDMARD), and Chinese medicine (CM) during the last for IBD but declined further examination, were excluded
3 months was reported. (Supplementary file 1). The final analysis included 153
 Smart-phone SpondyloArthritis Management System was patients with AS and 56 control subjects, characteristics of
used to record assessments of AS [10] including the Anky- which were presented in Table 1. Approximately two-fifths
losing Spondylitis Disease Activity Score based on CRP (60/153) of AS patients reported symptoms compatible with
(ASDAS-CRP), Bath Ankylosing Spondylitis Disease Activ- the Rome IV criteria for FBD, which was more frequently
ity Index (BASDAI), Bath Ankylosing Spondylitis Patient encountered than that (13/56) in the control group (p = .032,
Global Score (BAS-G), Assessment of Spondyloarthritis Inter- Figure 1). For the AS group, each of the symptoms meeting
national Society Health Index (ASAS HI), and Bath Ankylos- IBS, FC, FDr, FAB/D, and U-FBD was reported, respectively,
ing Spondylitis Functional Index (BASFI) [11–15]. Besides, in 18, 4, 15, 5, and 18 patients. Furthermore, loose or watery
Bath Ankylosing Spondylitis Metrology Index (BASMI) was stools in >25% of stools, which fulfilled for the last 3 months
calculated through the measurement of back mobility [16]. with symptom onset at least 6 months before coming to out-
 patient rheumatology clinics, were found in more than 70%
FBD symptoms and faecal examination (43/60) of AS patients with FBD symptoms.
The Rome IV diagnostic questionnaire was used to assess
the FBD symptoms of all participants [5]. Patients with gut Influence of clinical characteristics on FBD
symptoms were required to exclude IBD by colonoscopy if symptoms in the AS group
they had at least one IBD alarm feature, including uninten- Relations between clinical characteristics and FBD symptoms
tional weight loss, anaemia, positive result of faecal occult were explored by the logistic regression model. Multivariable
blood (FOB) test by guaiac FOB test kit (BaSO, Zhuhai, analysis showed that FBD symptoms were negatively associ-
China), and elevated faecal calprotectin (F-Calpr) by enzyme- ated with NSAID use (adjusted OR 0.40; 95% CI 0.16–0.97;
linked immunosorbent assay kit (Bühlmann Laboratories AG, p = .044) and positively associated with comorbid FM
 ̈
Schonenbuch Basel, Switzerland). In addition, fibromyalgia (adjusted OR 7.51; 95% CI 1.94–28.98; p = .003), whereas
(FM), being the comorbidity of AS and sharing many features ASDAS-CRP, another relevant factor in univariate analysis,
with IBS [17], was evaluated by a modification of the 2010 lost significance (Figure 2A; Supplementary Table S1).

Table 1. Characteristics of AS patients and controls. Links of NSAID use (adjusted OR 0.25; 95% CI 0.07–0.88;
 p = .030), TNFi use (adjusted OR 3.23; 95% CI 1.03–10.11;
 AS patients Controls p = .044), and comorbid FM (adjusted OR 16.88; 95% CI
 (n = 153) (n = 56) p
 4.64–61.46; p < .001) were also discovered in the analysis
Age (years) 34.0 ± 8.7 31.9 ± 8.1 .11 of IBS symptoms (Supplementary Figure S1; Supplementary
Male, n (%) 128 (83.7) 43 (76.8) .25 Table S2).
BMI (kg/m2 ) 24.5 ± 3.7 22.9 ± 3.2 .003 The high frequency of chronic diarrhoea in FBD symptoms
Smoke, n (%) 34 (22.2) 8 (14.3) .21
 prompted that it deserved to be further analysed. The nega-
HLA-B27 +, n (%) 135 (89.4) NA
CRP (mg/l) 3.0 (1.0, 10.7) NA tive association of NSAID use (adjusted OR 0.34; 95% CI
ESR (mm/h) 8.0 (4.0, 18.0) NA 0.14–0.87; p = .024) and the positive association of comor-

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Disease characteristics bid FM (adjusted OR 4.15; 95% CI 1.30–13.21; p = .016)
 ASDAS-CRP 1.7 ± 0.9 NA with chronic diarrhoea were showed in multivariable logistic
 BASDAI 1.7 ± 1.4 regression analysis, while BMI and ESR being observed to be
 BAS-G 2.3 ± 1.7 associated with chronic diarrhoea in univariate analysis lost
 ASAS HI 3.5 ± 3.4
 BASFI 1.2 ± 1.3
 significance (Figure 2B; Supplementary Table S3).
 BASMI 1.2 ± 1.7
FBD, n (%) 60 (39.2) 13 (23.2) .032 Influence of gut symptoms on assessments of AS
 IBS 18 (11.8) 3 (5.4) Linear regression analyses were used to assess the impacts of
 IBS-C 1 (0.7) 1 (1.8) gut symptoms on AS outcomes, and unstandardized coef-
 IBS-D 11 (7.2) 2 (3.6)
 IBS-M 6 (3.9) 0 (0.0) ficients and p-values for three gut symptoms were shown
 IBS-U 0 (0.0) 0 (0.0) in Table 2. Each of FBD symptoms and chronic diarrhoea
 FC 4 (2.6) 2 (3.6) was significantly associated with ASDAS-CRP ( 0.294 and
 FDr 15 (9.8) 3 (5.4) 0.301; p < .001 and p = .002), BASDAI ( 0.764 and 0.845;
 FAB/D 5 (3.3) 0 (0.0) p < .001 and p < .001), BAS-G ( 0.979 and 0.949; p < .001
 U-FBD 18 (11.7) 5 (8.9) and p = .001), and ASAS HI ( 1.673 and 1.343; p = .003
Stool
 FOB +, n (%) 7 (4.6) 3 (5.4) .73
 and .030) after adjusting clinical variables in multivariable
 F-Calpr (mg/kg) 126 (81, 236) 81 (56, 118)

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Figure 2. Frequencies of gut symptoms in the binary classification of each variable. (a) FBD symptoms. (b) chronic diarrhoea. CRP (+) and ESR (+) mean
results higher than reference values. The p-values in these univariate logistic regression analyses are shown. Significant differences in multivariable
analyses are marked. *p < .05, ** p < .01, *** p < .001. Missing data, n (%): HLA-B27 2 (1.3%), ASDAS-CRP 8 (5.2%), CRP 8 (5.2%), and ESR 10 (6.5%).

Table 2. Univariable and multivariable associations between gut symp- the elevated level of PGE2 was found in the colonic mucosa
toms and assessments of AS. of patients with IBS-D [22]. Visceral hypersensitivity (VH),
 Univariable Multivariable
 being involved in the pathogenesis of FBD [23, 24], could be
 promoted by PGE2 by mediating the pronociceptive effects
 p p of histamine, proteases [22], and serotonin [25]. Weakened
ASDAS-CRPa VH was observed after administration of the cyclooxygenase-
 FBD symptoms 0.234 .112 0.294

and affect the rate of IBS symptoms in AS patients using TNFi Funding
[22]. Limited by the cross-sectional design and the sample size, This work was supported by the Applied Basic Research
the relation between TNFi and IBS symptoms remains unclear Project of the Logistics Support Department of Central Mili-
and needs to be explored. tary Commission (CMC) under Grant 19BJZ41.
 F-Calpr was usually applied to exclude IBD in an epi-
demiologic investigation [47]. In accordance with previous
studies [48, 49], similar rates of gut symptoms (FBD symp- Author contributions
toms, IBS symptoms, and chronic diarrhoea) between groups F.H., Z.W., Y.Y., and L.P. contributed to the conception and
with higher/lower levels of F-Calpr were found in the present design of the study. L.W., L.H., X.J., and G.L. contributed
study, which supported the symptom-base diagnoses. Other to the data collection of the questionnaire. X.L. and J.Z.

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clinical characteristics and FBD symptoms had insignificant contributed to the calculation of BASMI. C.S. and L.W. con-
relations. tributed to stool collection. L.P. and N.Z. contributed to the
 Universal positive associations in multivariable linear exclusion of colonic ulcers. C.S., Y.W., and L.W. contributed
regression models indicated that disease activity of AS patients to the interpretation of the data. L.W., L.H., and S.M. con-
might be influenced by FBD symptoms, which was prominent tributed to the data analysis. L.W. drafted the article. F.H.
by chronic diarrhoea. Besides therapeutic options regulating critically revised the manuscript. All authors contributed to
motility, sensation, and immune dysfunction [50], treatments the article and approved the submitted version.
targeting the gut microbiota, such as faecal microbiota trans-
plantation, probiotics, prebiotics, and specific dietary pat-
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