Introduction

Patients with Inflammatory Bowel Disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), often experience anxiety and depression. A recent meta-analysis revealed that 32.1% of IBD patients suffer from anxiety and 25.2% experience depressive symptoms. Furthermore, previous studies have suggested that biological therapy may alter the psychopathological profile of a subset of patients treated for various diseases, including IBD. However, the lack of comprehensive understanding necessitates a more systematic analysis of this association.

Aims & Methods

The aim of this study is to longitudinally monitor the psychopathological profile of a cohort of IBD patients initiating a new biological treatment at our center, and compare the results with a cohort of IBD patients receiving traditional therapy.
In this prospective longitudinal cohort study, we recruited consecutive adult patients affected by CD and UC treated at Fondazione Policlinico Universitario “A. Gemelli”, IRCCS, Rome. Enrolled patients were divided into two cohort: those starting a new biological or small molecules therapy (Cohort 1), and those receiving traditional non-biological therapy (Cohort 2). Hetero-administered scales, including Hamilton Depression Rating Scale [Ham-D], Hamilton Anxiety Rating Scale [Ham-A], Young Mania Rating Scale [YMRS], Brief Psychiatric Rating Scale [BPRS], Partial Mayo Score [PMS] and Harvey-Bradshaw Index [HBI], were utilized to assess psychosomatic symptoms and gastrointestinal at the beginning of the new treatment (or at a random time point in the non-biological group) (baseline, T0), one month (T1), three months (T2) and six months (T3) thereafter. Results obtained at each time point were compared between the two patient groups.

Results

Ninety IBD patients were enrolled, 51 in cohort 1 (26 UC and 25 CD) and 39 in cohort 2 (22 UC and 17 CD). At T0, non-significant differences were found between cohort 1 and cohort 2 in mean scores of Ham-D (5.55 SD±6.16 vs 3.18 SD±3.85, p=0.27), Ham-A (5.84 SD±5.66 vs 4.08 SD±4.77, p=0.79), YMRS (1.10 SD±1.80 vs 0.85 SD±1.42, p=0.679), BPRS (22.43 SD±6.65 vs 20.03 SD±6.52, p=0.210). Statistically significant differences were found in the mean PMS and HBI between T0 and T2 in the 32 patients of cohort 1 who completed T2, and in the 20 patients who completed T3, as well as in cohort 2 between T0, T1 and T2 in the 30 patients who completed T2 and between T0 and T2, as well as T0 and T3 in the 11 patients who completed T3. No statistically significant differences were found in any of the psychiatric scales administrated in either cohort at the different time points.

Conclusion

Although a comprehensive understanding of psychosomatic effects of IBD biologic therapy is yet to be defined, our results suggest that they can be safely administered. Close monitoring during the early weeks and months is strongly recommended to assess possible side effects, including psychiatric adverse events.

Introduction

Infections are one of the main side effects faced by patients treated with biological agents.

Aims & Methods

Objective: We aimed to determine the rates of bacterial infections among Inflammatory Bowel Disease (IBD) patients treated with biological agents in a real-life setting.
Methods: Retrospective study based on the Clalit healthcare nationwide database, which included all patients diagnosed with IBD between 1999 and 2022. Data on bacterial infections were collected for patients treated with a biologic agent (Anti_TNF, Vedolizumab and Ustekinumab) and were compared to all other IBD patients during the corresponding timeframe.
Data regarding demographics, bacterial infection events, and mortality were collected. Data were collected using the MdClone platform from the largest Health Maintenance Organization, “Clalit” in Israel.

Results

5523 IBD patients treated with Anti-TNF were compared to 29,598 patients not treated with Anti-TNF. Patients treated with Anti-TNF were younger, age 35.62±14.29 compared to 47.06±19.49 years. Anti-TNF patients had higher rates of respiratory tract infection (36.2% vs 31.2%), genitourinary system infection, 26.7% vs 23.7%, gastrointestinal tract infection (31.8% vs 21.6%), skin infection (22.5% vs 14.3%) and Ear, Nose, throat infection (31.5% vs 24.2%). 2220 patients treated with Vedolizumab compared to 35,100 not treated with Vedolizumab, patients treated with Vedolizumab had higher rates of bacterial infections, respiratory tract infection (13.5 vs 5.1%, p<0.001), genitourinary system infection, (9.7% vs 3.8%, p<0.001) gastrointestinal tract infection (12.6% vs 3.5%, p<0.001), skin infection (8.4% vs 3%, p<0.001) and Ear, Nose, throat infection (11% vs 4.4%, p<0.001). In addition, risk of bacterial infection was higher among 940 patients treated with Ustekinumab than those not treated with Ustekinumab.

Conclusion

Significantly increased risk found among IBD patients treated with biologic agents; clinicians should consider the increased susceptibility to bacterial infections when deciding which biological agent to prescribe to their asthma patients

Introduction

The therapeutic armamentarium for inflammatory bowel disease (IBD) includes several biological agents: infliximab (IFX), adalimumab (ADA), vedolizumab (VED) and ustekinumab (UST). Persistence in therapy with these drugs is not satisfactory, not only due to the loss of clinical response over time but also due to adverse events. Acute infusion reactions (AIRs) occur during or within 24 hours of the infusion. The intensity of AIRs ranges from mild (flushing, dizziness, headache, itching, rash) to severe (anaphylactic).

Aims & Methods

The primary aim of this study was to compare the prevalence rates of AIRs due to the different biological agents in a large cohort of patients with IBD and to assess risk factors for AIRs.
All reports of AIRs occurring from January 2021 to October 2023 in IBD patients treated with different biological agents (IFX, ADA, VED and UST) in a tertiary IBD center were retrospectively reviewed. The electronic records of the identified patients were checked for the type of IBD, whether Crohn's disease (CD) or ulcerative colitis (UC), type of biological agent, route of administration (intravenous or subcutaneous), concomitant immunosuppressive therapies, atopic status. Furthermore, the type of treatment for the AIRs and the subsequent therapy undertaken for IBD were also recorded.

Results

22 AIRs were recorded out of 1911 patients (1.1%). Of these, 16/550 in patients on IFX biosimilars (2.9 %), 4/590 (0.7%) in patients on ADA biosimilars, 2/318 (0.6%) in patients on VED and 0/453 (0%) in patients on UST (Table 1). The difference in the prevalence of AIR rates observed with the different biological agents was statistically significant (p<0.01). 7 of 16 post-IFX AIRs were moderate-severe, with two episodes of anaphylaxis occurring in patients with CD. The two patients treated with VED experienced only mild symptoms, and no anti-reactive treatment has been used; two mild and two moderate AIRs, respectively, have been reported among patients on ADA. 12 of 22 AIRs occurred during the induction period (from the first to the third administration). 7 of 22 patients had previous allergic reactions.

Conclusion

Our real-world data on a large population of IBD patients treated with biologic agents confirm that AIRs are rare and occur mainly in patients treated with IFX biosimilars. Most patients who experienced AIRs were atopic. Almost all patients after AIRs changed biological agents within or out of the same biological class. Further studies are necessary to confirm our results and better characterise the profile of patients at greater risk of AIRs.

Introduction

Inflammatory bowel disease (IBD) is strongly associated with joint inflammation, as is highlighted by the high prevalence of spondyloarthritis (SpA) in patients with IBD (up to 13%) compared to the general population (0.2-1.6%) [1, 2]. IBD and SpA have many overlapping features, including genetic risk factors, changes in the gut microbiota, and therapies targeting TNF-α , IL-23, or JAK [3]. However, current therapies for both diseases are unable to break the cycle of chronic inflammation, and still a significant proportion of patients fail to respond. Disease heterogeneity likely plays a role in this [4, 5], underscoring the necessity to improve management and refine classification.

Aims & Methods

In this study, 92 inflammation-related proteins were quantified in serum of patients from one IBD and one SpA cohort using the novel Olink proteomics proximity extension assay. Fold changes (FC) in expression with |log₂FC| > 0.5 were considered meaningful, and false discovery rates (FDR) <0.05 were considered significant. The IBD cohort existed of 255 IBD patients with (n=155) and without (n=100) self-reported joint complaints [8]. From the patients with joint complaints, 58 fulfilled any of the SpA criteria. The SpA cohort, or SPACE cohort, consisted of 169 patients with chronic back pain (≥3 months, ≤2 years) of unknown origin [9]. After 2 years of follow-up, 85 patients had proven axSpA. Serum samples were taken at baseline, and 167/169 samples from the SPACE cohort and 241/255 samples from the IBD cohort passed quality control and were included in the analysis.

Results

Thirty-four proteins were differentially expressed between 95 IBD patients without joint complaints and 85 proven axial SpA (axSpA) patients from the SPACE cohort, of which 14 were higher in IBD patients (including 4E‑BP1, IFN‑γ, TNF, FGF‑21, CD8A, and CCL9), and 20 were higher in axSpA patients (including CASP‑8, SIRT2, STAMBP, FGF‑19, ST1A1, and EN‑RAGE). In addition, the immune profile of IBD patients with joint complaints differed from IBD patients without joint complaints: 4E‑BP1, CASP-8, STAMBP, SIRT2, AXIN1, and TNFSF14, were significantly upregulated in patients with joint complaints. Of note, if IBD patients without joint complaints were compared to the subgroup of 58 patients with joint complaints who met criteria for SpA, the same proteins showed significant upregulation, suggesting minimal difference between IBD patients with joint complaints who meet or who do not meet SpA criteria. Direct comparison of patients who met and who did not meet SpA criteria within the group of IBD patients with joint complaints indeed showed no noteworthy difference in serum immune profile. Within the SPACE cohort, comparison of patients with chronic back pain with and without axSpA diagnosis also showed no significant difference in serum protein expression.

Conclusion

This study shows that patients with axSpA versus patients with IBD without joint complaints have differing serum immune profiles. Within IBD patients with self-reported joint complaints and within patients with self-reported chronic back pain (from the SPACE cohort), no distinct difference in immune profile is observed, regardless of SpA diagnosis. The inflammation signatures of patients with chronic inflammatory diseases should be further investigated to provide insights for enhancing disease management in the future.

References

1. Karreman, M.C., 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(5): p. 631-642.
2. Stolwijk, C., et al., Global Prevalence of Spondyloarthritis: A Systematic Review and Meta-Regression Analysis. Arthritis Care Res (Hoboken), 2016. 68(9): p. 1320-31.
3. Gracey, E., et al., Revisiting the gut-joint axis: links between gut inflammation and spondyloarthritis. Nat Rev Rheumatol, 2020. 16(8): p. 415-433.
4. van Unen, V., et al., Mass Cytometry of the Human Mucosal Immune System Identifies Tissue- and Disease-Associated Immune Subsets. Immunity, 2016. 44(5): p. 1227-39.
5. Gulino, G.R., M. Van Mechelen, and R. Lories, Cellular and molecular diversity in spondyloarthritis. Semin Immunol, 2021. 58: p. 101521.
6. van Erp, S.J., 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(2): p. 166-75.
7. Marques, M.L., et al., Can rheumatologists unequivocally diagnose axial spondyloarthritis in patients with chronic back pain of less than 2 years duration? Primary outcome of the 2-year SPondyloArthritis Caught Early (SPACE) cohort. Ann Rheum Dis, 2024. 83(5): p. 589-598.

Disclosure

FAG: grants from Stichting vrienden van Sole Mio and Stichting ASAS, grants and/or consulting fees from Abbvie, ASAS, BMS, Galapagos, Janssen, Lilly, Novartis, Pfizer, and UCB.
AEM: grants from Nestle, Norgine, Cablon, Galapagos, and ZonMW, ad boards/speaker fees from Tramedico, Janssen, Takeda, Galapagos, Vedanta, Ferring, AbbVie, and Dear Health.
PV: speaker fees from Takeda and Galapagos, advisory board: Takeda, Galapagos, Lilly, BMS, Janssen, and Abbvie

Introduction

Surgery represents an important part of the therapeutic armamentarium for the treatment of IBD, and has been associated with variable effects on the psychological profile of patients with inflammatory bowel disease. However, surgical treatment is often distressingly perceived by these patients as the failure of their therapies, and can be a trigger for anguish, anxiety or depression.

Aims & Methods

The aim of this study is to describe the psychological impact of surgery on operated IBD patients.
This is a prospective descriptive monocentric study, conducted at the Department of Hepato-Gastro-Enterology and Proctology "Medicine B" CHU Ibn Sina Rabat, which collected all patients followed for IBD (Crohn's + UC) and who were operated between August 2021 and August 2023, the psychological impact and apprehension regarding surgery will be addressed in this study. Patients of both sexes who agreed to answer the questionnaire were included, and patients who refused to answer the questionnaire and complicated patients who stayed in intensive care were excluded.

Results

43 operated patients were included in our study, including 29 (67.4%) in the emergency setting and 14 (32.6%) scheduled. Mean age was 43 ± 16.17 years. The sex ratio was 1.26 (F/H=24/19). 35 patients (81.4%) were being followed for Crohn's disease and 8 patients (18.6%) for ulcerative colitis (UC), of whom 11 patients (25.5%) had a history of previous resection, and 1 patient (2.3%) was being followed for depression.
The surgical indications were GCA in 12 cases (27.9%), stenosis in 18 cases (41.8%), perforation in 1 case (2.3%), abscess in 8 cases (18.6%), and fistula in 4 cases (9.3%).
Our patients underwent ileo-caecal resection in 22 cases (51.2%), hemicolectomy in 6 patients (14%), coloproctectomy in 3 patients (7%), sub-total colectomy in 11 patients (25.6%), of whom 18 patients (41.9%) had an ostomy.
On the announcement of a possible surgical procedure, the thymic symptoms and feelings expressed by patients can be classified as follows: preoperative anxiety in 18 patients (41.9%), fear of death in 7 patients (16.3%), while 24 patients (55.8%) were indifferent.
The main anxiety-generating concern was postoperative pain in 7 patients (14%), potential complications in 7 patients (16.3%), failure of the procedure in 6 patients (14%), fear of dying in 7 patients (16.3%), and 25 patients (58.1%) expressed no anxiety.
The postoperative psychological experience was unremarkable in 37 patients (86%), 3 patients (7%) reported transient postoperative sadness and 3 patients (7%) developed postoperative depression, prompting consultation with a psychiatrist.

Conclusion

The impact of surgery in IBD patients not only concerns the body, but also has an effect on psychological well-being.
This study found that the pre-operative period induces a significant burden of anxiety in these patients, and depression in some.

Introduction

Nephrolithiasis (NL) is a common extra-intestinal complication of inflammatory bowel diseases (IBD) with significant morbidity and mortality¹. Its pathogenesis and risk factors still need to be completely elucidated. Because of intestinal malabsorption, enteric hyperoxaluria is a critical pathogenic mechanism responsible for the development of NL in IBD patients². Growing evidence has highlighted the association between gut microbiota and NL, particularly emphasising the role of some oxalate-degrading bacteria, such as Oxalobacter formigenes, representing the mainstay of the so-called “gut-kidney axis”³. More recent studies also hypothesize the involvement of urinary microbiota⁴, but no data on IBD patients are currently available. Thus, our study aims to analyse the urinary lithogenic profile in IBD patients and its relationship with gut and urinary microbiota.

Aims & Methods

Consecutive adult patients with IBD were prospectively enrolled. The presence of ileoanal pouch, ileostomy, colostomy or short-bowel syndrome were exclusion criteria. Demographic and clinical data, including previous episodes of NL, were collected. Disease activity was evaluated using Harvey-Bradshaw index for Crohn’s disease (CD) and Mayo score for ulcerative colitis (UC). All patients underwent abdominal ultrasound for NL detection. Blood tests of kidney function (notably creatinine, blood urea nitrogen, creatinine clearance, and electrolytes) were also measured, together with a 24h-urine collection for lithogenic profile analysis, including calcium oxalate relative saturation ratio (RSRCaOx). In a subgroup of patients, urinary and faecal microbiota were also analysed through 16S rRNA sequencing.

Results

48 patients (52.1% men, mean age 42.6±17.4 years) were enrolled. Twenty-five patients were affected by CD and 23 by UC and 10 presented active disease at enrollement. NL was more frequent in CD than in UC (32% vs. 13%). In CD, 24-h urinary volume was lower and 24-h oxaluria was higher than in UC. Moreover, 24-h oxaluria was higher in patients with previous or present NL. Gut microbiota analysis was performed on 22 patients, stratified based on median RSRCaOx (higher or lower than the median). Significantly different β-diversity was observed between the two groups (p =0.025) and patients with an elevated RSRCaOx showed a higher relative abundance of Bacteroidetes and a lower abundance of Firmicutes (p value <0.05). No statistically significant difference was found in urinary microbiota composition between patients with high or low levels of RSRCaOx.

Conclusion

NL is more common in CD patients, who generally present lower urine volume and higher 24-h oxaluria than UC patients. Furthermore, NL is more frequent in IBD patients with higher oxaluria levels, confirming oxalate excretion's crucial role in NL pathogenesis. Again, our study reports an association between urinary stone development and Firmicutes/Bacteroidetes imbalance in the gut microbiota, suggesting possible further studies to identify patients at higher risk of NL.

References

1. Varda BK, McNabb-Baltar J, Sood A, et al. Urolithiasis and urinary tract infection among patients with inflammatory bowel disease: a review of US emergency department visits between 2006 and 2009. Urology. 2015;85(4):764-770. doi:10.1016/j.urology.2014.12.011
2. Witting C, Langman CB, Assimos D, et al. Pathophysiology and Treatment of Enteric Hyperoxaluria. Clin J Am Soc Nephrol. 2021;16(3):487-495. doi:10.2215/CJN.08000520
3. Ticinesi A, Milani C, Guerra A, et al. Understanding the gut-kidney axis in nephrolithiasis: an analysis of the gut microbiota composition and functionality of stone formers. Gut. 2018;67(12):2097-2106. doi:10.1136/gutjnl-2017-315734
4. Xie J, Huang JS, Huang XJ, et al. Profiling the urinary microbiome in men with calcium-based kidney stones. BMC Microbiol. 2020;20(1):41. doi:10.1186/s12866-020-01734-6

Introduction

A key feature of IBD pathogenesis is response dysregulation of both the innate and adaptive immune system^1,2. Hence specific inflammatory protein profiles may be a promising biomarker approach for diagnosis and personalized therapy in IBD. Serum proteome of IBD, particularly in multi-ethnic Asian patients, remains less defined.

Aims & Methods

We aim to investigate the systemic inflammatory protein profiles in multi-ethnic Asian patients with IBD and compare them to healthy controls.
The study cohort was made up of 92 patients with IBD (50.0% Ulcerative colitis (UC), 43.5% Crohn's disease (CD), 6.5% Unclassified IBD)), and 42 control subjects, who are asymptomatic patients undergoing screening colonoscopy with no endoscopic pathology. Serum protein profiling was performed using the Olink Target 96 Inflammation assay. A partial-least square discriminant analysis was undertaken to identify additional discriminative inflammatory proteins. Univariate t-test analyses, with false discovery rate correction, were also performed to identify proteins unique to either UC or CD.

Results

Participants with IBD were younger (42.0 (±14.7) in UC, 43.2 (±15.1) in CD, p<0.01), with greater representation of South Asian ethnicity (32.5% amongst UC, 19.6% amongst CD, p<0.01) and males (75.0% amongst UC, 69.6% amongst CD, p=0.03), as compared to controls.
We found 18 proteins were differentially abundant amongst IBD patients (p<0.05). Half (n=9) of these inflammatory proteins (AXIN-1, CD8A, CXCL1, EN-RAGE, FGF-23, HGF, IL17A, OSM, TGF-alpha) were elevated in both UC and CD. The other six proteins were elevated only in patients with UC (4E-BP1, CCL11, IL-18R1, IL-20, MMP-10, TRANCE). Of the remaining three, two were less abundant in patients with CD (DNER, SCF) and TNF was elevated only in patients with CD. Of interest, three immunoproteins were differentially abundant in participants with either UC or CD (i.e. CCL11, MMP10, TRANCE).

Table1: List of immunoproteins differentially abundant (p<0.05) in varying IBD subtypes, grouped by their key common molecular functions. *indicates that the immunoprotein of interest to be less abundant compared to controls. ^AXIN1 functions - Activation of protein kinase (GO:0032147), WNT signaling process (GO:0016055). ^#MMP-10 function - extracellular matrix organization (GO:0030198). ^$4E-BP1 function - TOR signaling (GO:0031929). ^@DNER function - Notch receptor processing (GO:0007220).

Conclusion

Our pilot study in a multi-ethnic Asian population found distinctive serum protein profile in IBD patients. While some protein changes were shared in both UC and CD, other changes were specific for either UC or CD, suggesting different disease pathways in these two IBD subtypes. We reaffirmed that inflammatory proteins, such as EN-RAGE³, MMP-10⁴ and OSM⁵, were differentially abundant in IBD, consistent with previous reports in predominantly Caucasian cohorts. Further studies with large sample sizes would be required to validate these biomarkers for IBD activity, and prognosis for biologic therapy response.

References

1. Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol. 2014 May;14(5):329-42.
2. Mahida YR. The key role of macrophages in the immunopathogenesis of inflammatory bowel disease. Inflamm Bowel Dis. 2000;6:21–33.
3. Foell D, Kucharzik T, Kraft M, et al. Neutrophil derived human S100A12 (EN-RAGE) is strongly expressed during chronic active inflammatory bowel disease. Gut 2003;52:847-853.
4. Fonseca-Camarillo G, Furuzawa-Carballeda J, Martínez-Benitez B, et al. Increased expression of extracellular matrix metalloproteinase inducer (EMMPRIN) and MMP10, MMP23 in inflammatory bowel disease: Cross-sectional study. Scand J Immunol. 2021 Jan;93(1):e12962.
5. Sare Verstockt, Bram Verstockt, Kathleen Machiels, et al. Oncostatin M Is a Biomarker of Diagnosis, Worse Disease Prognosis, and Therapeutic Nonresponse in Inflammatory Bowel Disease. Inflamm Bowel Dis. 2021 Oct 18;27(10):1564-1575.