Gout in Patients with Inflammatory Bowel Disease
Overview
Arthritis is a well-established extra-intestinal manifestation of inflammatory bowel disease (IBD). Recent studies have indicated disruptions in uric acid metabolism among individuals with IBD. This investigation aimed to explore the link between IBD and gout using a comprehensive multi-center database (Explorys Inc.) comprising data from various US healthcare systems.
The study focused on adults diagnosed with either Crohn’s disease (CD) or ulcerative colitis (UC) between 1999 and 2022. Within this cohort, individuals diagnosed with gout were identified, and demographic information was collected. The analysis also included patients with IBD-associated arthritis and those who underwent intestinal resection. Various risk factors associated with gout were considered, and multivariate analysis was employed for a comprehensive assessment.
Among the extensive database encompassing 69,260,780 patients, 209,020 individuals were identified with UC (0.30%), of whom 9,130 exhibited gout (4.3%). Additionally, 249,480 individuals had CD (0.36%), with 14,000 diagnosed with gout (5.61%). The male gender was more prevalent in the UC and gout group compared to the CD and gout group (58% vs. 51%). Following adjustment, CD demonstrated a significant association with gout (odds ratio [OR] 1.68, confidence interval [CI]: 1.60–1.75). Similarly, UC exhibited a noteworthy association with gout (OR 1.38, CI: 1.31–1.44). Subgroup analysis, particularly involving individuals with intestinal resection, revealed that CD patients undergoing such surgery displayed a higher association with gout compared to those without surgery (OR 2.34, CI: 2.25–2.43). A parallel increase in gout risk was observed in the UC group with intestinal resection (OR 1.53, CI: 1.49–1.56).
In conclusion, this study establishes a robust association between IBD and gout, with a more pronounced correlation noted in individuals with CD. Furthermore, intestinal resection was identified as a factor contributing to an elevated risk of gout. Therefore, individuals with IBD presenting with new-onset arthritis should undergo thorough investigation for the potential presence of gout.
Introduction
Inflammatory Bowel Disease and Gouty Arthritis
Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory condition, with a rising global prevalence, particularly in North America. Despite primarily affecting the bowel, IBD often manifests in extraintestinal organs, occurring in 25% of patients. Arthritis is a well-known extraintestinal manifestation (EIM) of IBD, though it lacks a definitive diagnostic factor and is considered a diagnosis of exclusion.
Gout, a clinical syndrome resulting from elevated extracellular urate concentration leading to hyperuricemia, is characterized by monosodium urate crystal deposition in bones, joints, and soft tissues, causing acute or chronic arthritis. While gout prevalence in the U.S. is approximately 3.9% in adults, it’s crucial to distinguish gout from hyperuricemia, which is a common outcome of elevated uric acid levels. Uric acid, the end product of purine nucleoside breakdown, is produced mainly in the liver and intestines and is influenced by dietary habits, cellular processes, and high cell turnover, often seen in malignancies.
Approximately one-third of uric acid is eliminated through the gut, emphasizing the intestines’ role in uric acid metabolism. Studies have consistently demonstrated hyperuricemia in IBD patients, making gout a relevant clinical expression of this phenomenon. This study, utilizing a substantial database, aims to investigate the association between IBD and gout, shedding light on the intricate interplay between IBD, uric acid metabolism, and the development of gout.
The Use of Propolis in Inflammatory Bowel Disease and Irritable Bowel Syndrome
Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder characterized by recurrent abdominal pain and altered bowel function. Diagnosis traditionally relies on clinical criteria, such as the Rome IV criteria, due to the absence of specific markers. IBS predominantly affects women, with an overall prevalence of 10%.
The multifactorial pathophysiology of IBS involves factors like gut microbiota alterations, gut-brain axis dysfunction, intestinal inflammation, psychological stress, chronic infections, dietary components, and genetic factors. Inflammatory and oxidative stress also contribute to heightened nervous system sensitivity and abdominal pain perception in IBS.
Management strategies, including the low FODMAP diet, have been recommended, but long-term adherence raises concerns about potential negative health effects. While the FODMAP diet is perceived to impact microbial diversity, controlled studies suggest it primarily influences bacterial abundance.
Emerging research emphasizes the role of prebiotic and probiotic supplements, along with dietary polyphenols, in modulating the GI immune system and gut microbiota to alleviate IBS symptoms. Propolis, a resinous hive product with antioxidant properties and over 300 phytochemicals, has garnered attention for its potential to modulate inflammatory pathways, immune function, gut microbiota, and GI permeability.
A study has been carried out to evaluate the efficacy of propolis supplementation in alleviating the severity of IBS symptoms, considering its diverse components and their potential to modify various aspects of the disorder.
This clinical trial demonstrates that a 6-week administration of propolis at 900 mg/day significantly improves the severity of irritable bowel syndrome (IBS) symptoms, particularly abdominal pain’s severity and frequency. Patients receiving propolis are 6.22 times more likely to experience improvements in IBS symptoms compared to those in the placebo group. This study, the first of its kind, provides evidence supporting the efficacy of propolis supplementation in alleviating IBS symptoms.
Previous research has linked IBS to microscopic gut inflammation, and propolis, a natural product rich in polyphenolic and flavonoid compounds, acts within an antioxidant network. The study aligns with findings from trials on dietary supplements, including green tea, curcumin, and selenomethionine combinations, as well as co-supplementation of curcumin and fennel essential oil, demonstrating positive effects on IBS symptoms. Quercetin glycosides in propolis, the predominant flavonoid fraction, have been associated with reduced visceral motor response and increased pain threshold pressure in postinflammatory IBS rats.
Propolis, with its diverse effects on the immune response, platelet aggregation, prostaglandin synthesis, and 5-lipoxygenase inhibition, emerges as a potential therapeutic option for IBS. Importantly, propolis administration did not affect dietary intakes or anthropometric indices, suggesting its safety and minimal impact on these parameters. The trial’s strengths include adherence to Rome IV criteria for IBS diagnosis, stratified block randomization, and a high patient compliance rate.
Despite self-reported physical activity and dietary intake as limitations, the study concludes that propolis can be considered an adjunctive therapy for reducing abdominal pain in IBS with mixed and constipation-dominant subtypes. The research recommends future investigations focusing on propolis effects on diarrhea-predominant IBS (IBS-D) and the gut microbiome of IBS patients.
Method
This retrospective analysis utilizes a large multicenter electronic health record (EHR) database provided by IBM (Explorys Inc., Cleveland, OH, USA). The database aggregates EHRs from 26 major healthcare systems nationwide in the United States, encompassing over 70 million unique health records. Patient information is systematically de-identified, standardized, and securely stored in a cloud-based database.
The Explorys platform employs the Systemized Nomenclature of Clinical Medical Terms (SNOMED-CT) for medical terminology, diagnoses, and procedures. Diagnoses are categorized using the International Classification of Disease, 10th Revision, Clinical Modification (ICD-10-CM) codes, which are then mapped into the SNOMED-CT hierarchy. The platform adheres to the Health Insurance Portability and Accountability Act (HIPAA) and the Health Information Technology for Economic and Clinical Health Act (HITECH) for compliance.
The use of Explorys in studies is considered exempt from approval by the Cleveland Clinic Institutional Review Board, as all patient information is de-identified, ensuring compliance with privacy regulations. Patient confidentiality is rigorously maintained by approximating cohort counts to 10, treating all counts between 0 and 10 equally.
Patient Selection
This study focused on adult patients (aged 18 years and above) with active Electronic Health Records (EHRs) from 1999 to 2022, identified through the Explorys search tool. The search utilized SNOMED-CT diagnosis terms “Crohn’s disease” and “Ulcerative colitis” to identify individuals with Inflammatory Bowel Disease (IBD). The control group consisted of patients without these IBD diagnoses. The term “gout” in SNOMED-CT was employed to identify patients diagnosed with gout, with a particular emphasis on assessing gout prevalence post-IBD diagnosis due to altered uric acid metabolism in IBD.
The platform, while lacking specific laboratory data such as uric acid levels, collected cross-sectional information on patient demographics, including gender, age, and race. Comorbidities associated with gout, such as chronic kidney disease (CKD), malignancy, alcohol abuse, and smoking, were identified using their respective SNOMED-CT terms. Additionally, patients with diagnosed IBD-associated arthritis and those requiring intestinal resection were identified for further analysis, utilizing the SNOMED-CT term “intestinal resection,” encompassing both small bowel resection and colectomy.
Exclusion Criteria
Patients receiving thiazides or loop diuretics were carefully excluded from the study.
Statistical Analysis
The study compared gout patients diagnosed with inflammatory bowel disease (IBD), including Crohn’s disease (CD) or ulcerative colitis (UC), with a control group of patients without IBD. The overall period prevalence was calculated by dividing the total number of patients with IBD by the total number of individuals in Explorys. Prevalence rates of gout in patients with IBD and control patients were determined by dividing the total number of gout patients by the respective total number of individuals with and without IBD. A multivariate regression model, utilizing binary logistic regression, was employed to adjust for potential confounding factors. The variance inflating factor was used to assess independence within covariate risk factors. The goodness of fit was evaluated using the Hosmer–Lemeshow test. The study used IBM SPSS Statistics version 28.0.1 for multivariate regression analysis, considering a two-sided P-value of <0.05 as statistically significant. The Cleveland Clinic Institutional Review Board deemed the study exempt from approval, as the dataset from the Explorys platform is de-identified.
Result
Out of the 69,260,780 adult patients in the database from 1999 to 2022, 458,500 were diagnosed with inflammatory bowel disease (IBD), constituting 0.66% of the population. Within the IBD cohort, 209,020 individuals had ulcerative colitis (UC) at 0.30%, with 4.3% of them having gout, significantly higher than the 3.51% in the general population without UC (P < 0.001). Additionally, 249,480 patients had Crohn’s disease (CD) at 0.36%, with 5.61% having gout, compared to 3.53% in the general population without CD (P < 0.001).
In both UC and CD groups with gout, the majority were aged over 65 (70% vs. 61%, respectively). Males were more prevalent in the UC and gout group than in the CD and gout group (58% vs. 51%). Caucasians dominated both groups, with nearly 83% representation, followed by African Americans (9–11%). Adjusting for demographics, age, race, and gender, as well as known gout risk factors such as chronic kidney disease (CKD), malignancy, IBD-associated arthritis, intestinal resection, alcohol intake, and smoking, CD was significantly associated with gout (odds ratio [OR] 1.68, confidence interval [CI]: 1.60–1.75, P < 0.001). UC was also significantly associated with gout (OR 1.38, CI: 1.31–1.44, P < 0.001). Subgroup analysis showed a higher association with gout in the UC group that had intestinal resection compared to those without surgery (OR 2.34, CI: 2.25–2.43, P < 0.001). A similar relationship was observed in the CD group with intestinal resection versus those without surgery (OR 1.53, CI: 1.49–1.56, P < 0.001).
Conclusion
The study reveals a heightened prevalence of gout in the inflammatory bowel disease (IBD) population, notably 4.3% in ulcerative colitis (UC) and 5.6% in Crohn’s disease (CD), compared to the general population at 3.5%. The research, a large-scale database study, is the first to establish this association. The unknown pathophysiology of IBD involves immune, microbial, and genetic factors, particularly dysregulated immune responses and altered intestinal mucus and permeability. Hyperuricemia in IBD is linked to commensal microbiota, inflammation-related microbiota, and reduced expression of the ABCG2 transporter.
Gout, characterized by hyperuricemia, presents as recurrent inflammatory arthritis, and its prevalence is notably higher in IBD patients. The study explores a potential link between low tryptophan levels, immune-mediated diseases, and elevated uric acid, proposing a clinical trial’s findings on glycine and tryptophan’s impact on hyperuricemia. Patients with IBD who undergo intestinal resection face an increased risk of gout, with UC patients exhibiting a higher susceptibility than CD patients, possibly tied to post-resection nephrolithiasis and stone formation processes.
Limitations include potential bias, coding issues, and the inability to confirm disease severity, medication impact, or confirm gout diagnoses. Nevertheless, the study, driven by a large population size across multiple healthcare institutions, concludes that IBD patients with new-onset arthritis should be thoroughly assessed for gout, emphasizing the significant risk associated with IBD-related intestinal resection.
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