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The link between spondyloarthritis and inflammatory bowel disease (IBD) is well-established, with 5%–10% of patients with axial spondyloarthritis (axSpA) having concurrent IBD. Beyond that, ~50%–60% display microscopic gut inflammation,1 and faecal calprotectin (F-calprotectin) is elevated,2 although neither of these findings have been clearly linked to gut symptoms.1 2 Nevertheless, >50% of patients with ankylosing spondylitis (AS) report frequent gut pain/diarrhoea.3 This calls for investigating other potential causes, including irritable bowel syndrome (IBS), for which data in axSpA remain sparse. IBS (general population prevalence ~11%4) is thought to arise through mechanisms similar to fibromyalgia, common in axSpA (affecting up to 25% versus ~2% in the general population).
We aimed to compare the prevalence of gut symptoms meeting ROME III criteria for IBS between patients with axSpA and healthy controls.5 Hence, 182 consecutive patients with well-characterised axSpA without known IBD from the population-based SPARTAKUS study,2 and 50 controls, frequency-matched for sex/age, without rheumatic disease or IBD, were included (online supplementary table S1). For SPARTAKUS protocol/classification algorithm details, see online supplementary file 1.
Supplemental material
We found that gut symptoms meeting IBS criteria were significantly more frequent among patients with axSpA (30%) than controls (16%; OR: 2.5 (95% CI 1.1 to 5.7); p=0.036) by sex/age-adjusted logistic regression (figure 1A). Additional adjustments for F-calprotectin levels and non-steroidal anti-inflammatory drug (NSAID)-use, respectively, as well as excluding patients/controls reporting ‘alarm symptoms’ (frequent bloody/black stools; unexplained weight-loss), yielded similar OR-estimates for the patients/controls difference (online supplementary file 1).
Proportions of patients with axSpA and controls reporting gut symptoms meeting ROME III IBS criteria. (A) Frequencies of self-reported symptoms meeting IBS criteria in patients with axSpA without known comorbid IBD (n=182) versus controls without rheumatic disease or IBD (n=50), compared by logistic regression adjusted for sex and age. (B) Frequencies of patients with axSpA reporting symptoms meeting IBS criteria, stratified according to different disease/treatment characteristics and with comparisons between strata of each variable by unadjusted logistic regression. *Variables displaying p<0.10 in these univariate analyses were then introduced into a multivariate logistic regression model, in which female sex (adjusted OR: 2.4 (95% CI 1.2 to 5.0); p=0.017) and comorbid fibromyalgia (adjusted OR: 4.2 (95% CI 1.3 to 13.3); p=0.016; analysed in a separate model from sex due to multicollinearity (Spearman’s rho>0.3)) remained significantly associated with IBS symptoms. NSAID-use, any versus no use during the last 3 months; DMARD-use, any versus no ongoing conventional and/or biological DMARD-treatments at the study visit; Comorbid fibromyalgia, assessed by the 1990 fibromyalgia classification criteria. Missing data was not imputed, n (%): ASDAS-CRP 24 (13%), CRP 19 (10%), F-calprotectin 25 (14%), fibromyalgia 8 (4%). AS, ankylosing spondylitis; ASDAS-CRP, ankylosing spondylitis disease activity score based on CRP; AxSpA, axial spondyloarthritis; CRP, C reactive protein (mg/L); DMARD, disease-modifying antirheumatic drug; F-Calpr, faecal calprotectin (mg/kg); IBD, inflammatory bowel disease; IBS, irritable bowel syndrome; Nr-axSpA, non-radiographic axial spondyloarthritis; NSAID, non-steroidal anti-inflammatory drug.
Within the axSpA group (n=182), hypothesis-generating analyses of potential drivers behind the IBS symptoms were performed by examining distributions according to disease/treatment characteristics. Univariate associations were assessed, and variables displaying p<0.10 analysed multivariately (logistic regression). Results are displayed in figure 1B. By multivariate analysis, IBS symptoms were linked to female sex (OR: 2.4 (95% CI 1.2 to 5.0); p=0.017) and comorbid fibromyalgia (1990 criteria; OR: 4.2 (95% CI 1.3 to 13.3); p=0.016), whereas the univariate associations observed with NSAID-use and higher disease activity (ankylosing spondylitis disease activity score based on C reactive protein (CRP)) lost significance. No associations were observed with overall CRP or F-calprotectin levels (Calpro AS, Lysaker, Norway, F-calprotectin ELISA, using the manufacturer-recommended 50 mg/kg cut-off), age, disease subtype (AS/nr-axSpA) or conventional/biological disease-modifying antirheumatic drug use (figure 1B; online supplementary table S2). Exploration of associations between different intensities of diarrhoea/increased stool frequencies and F-calprotectin levels, and a discussion on F-calprotectin cut-offs for IBD detection are presented in online supplementary file 1.
Finally, relations between IBS symptoms and axSpA outcomes were assessed by sex/age-adjusted analysis of covariance. All patient-reported outcomes, including visual analogue scales of global disease activity/pain/fatigue, Bath ankylosing spondylitis disease activity index, Bath ankylosing spondylitis functional index and health-related quality-of-life (by EuroQol 5-Dimensions) were significantly worse among patients reporting IBS symptoms (table 1).
AxSpA outcome measures in relation to IBS status
We demonstrate a prevalence of 30% for gut symptoms meeting IBS criteria among patients with axSpA without known IBD, a proportion twice that of matched controls and four times higher than comorbid IBD estimates. Since IBS is a rule-out diagnosis, the lack of endoscopic examinations represents a limitation. Notably, however, no differences in IBS symptoms were detected between patients with axSpA with elevated versus normal F-calprotectin or CRP levels, making gut inflammation unlikely as a main cause. This conclusion is further strengthened by the association of IBS symptoms to female sex (as in IBS generally),6 as opposed to the male predominance for microscopic inflammation at endoscopy.1 Rather—although NSAID side-effects and low-grade gut inflammation cannot be ruled out as being important in certain cases—the lack of overall associations with gut/systemic inflammation, the female overrepresentation, and clear links to fibromyalgia and worse patient-reported outcomes, suggest the observed IBS symptoms to stem from similar mechanisms as axSpA unrelated IBS.6 Moreover, similar to fibromyalgia, IBS symptoms may contribute to worse self-perceived axSpA disease activity, a link entailing important treatment implications.
In conclusion, IBS may be an overlooked, frequent axSpA comorbidity, warranting further research and increased awareness to enable adequate symptom-relieving IBS therapy.
Acknowledgments
We are indebted to all patients, controls and staff involved in the SPARTAKUS study and to the Department of Clinical Immunology and Transfusion Medicine, Skåne University Hospital, Lund, Sweden, for performing the F-calprotectin analyses. A particular thanks to our research nurse Miriam Walsh Ingelström for study coordination.
Footnotes
Handling editor Josef S Smolen
Contributors TO and JKW participated in study design, acquisition of data, analysis and interpretation of data and draft and revision of the manuscript. EM and EL participated in study design, acquisition and interpretation of data and revision of the manuscript. JM, KA, AJ, MG and LEK participated in study design, interpretation of data and revision of the manuscript. All authors read and approved the final manuscript.
Funding This study was supported by unrestricted grants from Skåne University Hospital, the Swedish Rheumatism Association, the Anna-Greta Crafoord Foundation, the Kock Foundation and the Lundgren Foundation. Funding from the Faculty of Medicine, Lund University, contributed to financing EM’s research time. Funding from the Hedlund Foundation and the Österlund Foundation contributed to financing JM’s research time. Grants to researchers in public healthcare from the Swedish government (ALF) contributed to financing JKW’s, JM’s, KA’s and TO’s research time.
Disclaimer The sponsors had no role in study design, data collection, data analysis, data interpretation or writing of the report.
Competing interests JKW has received consultancy fees from AbbVie, Celgene, Eli Lilly, Novartis and UCB Pharma (unrelated to the present work). JM has received investigator-initiated study funding from AbbVie, Ferring, Pfizer and Takeda and has served as a speaker, a consultant and/or an advisory board member for AbbVie, Ferring, Janssen-Cilag, Svar/EuroDiagnostica, Takeda and Tillotts (unrelated to the present work). MG has received consultancy fees from AbbVie, Novartis and Pfizer (unrelated to the present work). LEK has received consultancy and speaker’s bureau fees from AbbVie, Amgen, Biogen, Bristol-Myers Squibb (BMS), Celgene, Eli Lilly, Janssen Pharmaceuticals, Merck, Sharp & Dohme (MSD), Novartis, Pfizer, Roche, Sanofi and UCB Pharma (unrelated to the present work). Remaining authors report no competing interests.
Patient consent for publication Not required.
Ethics approval Ethical approval for the SPARTAKUS study has been granted by the Regional Ethics Committee in Lund, Sweden (Dnr. 2015/436 with amendment Dnr. 2018/238). Oral and written informed consent was granted by all patients and controls before entry in the study.
Provenance and peer review Not commissioned; externally peer reviewed.