Introduction

Thiopurines are widely used for treating inflammatory bowel disease, either alone or in combination with anti-tumor necrosis factor alpha therapy. However, intolerance to thiopurines is common, leading to discontinuation of treatment in over 30% of individuals.

Aims & Methods

This study aims to evaluate the effectiveness of combined therapy of allopurinol with low-dose azathioprine concerning therapeutic response and improvement of therapy tolerance. We performed a systematic review in PubMed, Embase, Cochrane and Web of Science databases, searching for randomized studies that evaluated low-dose azathioprine therapy plus allopurinol versus azathioprine monotherapy. The primary outcome was clinical remission at weeks 14-16. The secondary outcomes were 6-TGN, 6-MMP and FC (fecal calprotectin) levels and FC lesser than 50ug/g rate. The odds ratio (OR) was used for binary outcomes with their respective 95% confidence interval (CI). Heterogeneity was assessed using the Cochran Q test and I² statistics.

Results

The meta-analyses included 3 studies and 237 patients. There was a significant difference favoring low-dose azathioprine plus allopurinol in clinical remission (OR 2.46; 95% CI 1.43 to 4.25; p=0.001; I2=0%) and in 6-MMP levels (MD -2,329.89; 95% CI -3,869.68 to -790.11; p<0.01; I2=94%). There is no difference in 6-TGN levels (p=0.05) and FC levels (p=0.68).

Conclusion

Patients using allopurinol plus low-dose azathioprine showed improved therapeutic adherence while maintaining superior clinical remission rates compared to azathioprine monotherapy.

References

1. Kiszka-Kanowitz M, Theede K, Thomsen SB, Bjerrum JT, Brynskov J, Gottschalck IB, et al. Low-dose azathioprine and allopurinol versus azathioprine monotherapy in patients with ulcerative colitis (AAUC): An investigator-initiated, open, multicenter, parallel-arm, randomised controlled trial. EClinicalMedicine. 2022 Mar;45:101332.
2. Kiszka-Kanowitz M, Theede K, Mertz-Nielsen A. Randomized clinical trial: a pilot study comparing efficacy of low-dose azathioprine and allopurinol to azathioprine on clinical outcomes in inflammatory bowel disease. Scand J Gastroenterol. 2016 Dec;51(12):1470–5.
3. Vasudevan A, Con D, De Cruz P, Sparrow MP, Friedman AB, Garg M, et al. Clinical trial: Combination allopurinol-thiopurine versus standard thiopurine in patients with IBD escalating to immunomodulators (the DECIDER study). Aliment Pharmacol Ther. 2024 Feb;59(4):504–14.

Introduction

Severe Crohn's disease (CD) may progress to short bowel syndrome (SBS). Teduglutide stands as a validated treatment for SBS offering promising results for these patients.

Aims & Methods

This study aims to evaluate the performance of teduglutide in the subgroup of patients with SBS secondary to CD. We performed a systematic review in PubMed, Embase and Cochrane databases, searching for studies with patients with SBS and CD treated with teduglutide. The primary outcome was the reduction of parenteral support (PS). The secondary outcome was discontinuation of PS. The odds ratio (OR) was used for binary outcomes with their respective 95% confidence interval (CI). Heterogeneity was assessed using the Cochran Q test and I² statistics.

Results

The meta-analyses included 4 studies and 77 patients. All studies evaluated PS reduction and teduglutide demonstrated a good performance (PS reduction in 79.94% of the patients; 95% CI 57.97% to 100.00%; I2=85%). Three studies (61 patients) evaluated PS discontinuation and teduglutide demonstrated a good performance too (PS discontinuation in 28.59% of the patients; 95% CI 17.43% to 39.75%; I2=0%).

Conclusion

Teduglutide is a good therapeutic option for patients with SBS in the subgroup of CD patients, improving PS reduction and discontinuation and leading to better quality of life of these patients.

References

1. Joly F, Seguy D, Nuzzo A, Chambrier C, Beau P, Poullenot F, et al. Six-month outcomes of teduglutide treatment in adult patients with short bowel syndrome with chronic intestinal failure: A real-world French observational cohort study. Clin Nutr Edinb Scotl. 2020 Sep;39(9):2856–62.
2. Kochar B, Long MD, Shelton E, Young L, Farraye FA, Yajnik V, et al. Safety and Efficacy of Teduglutide (Gattex) in Patients With Crohn’s Disease and Need for Parenteral Support Due to Short Bowel Syndrome-associated Intestinal Failure. J Clin Gastroenterol. 2017 Jul;51(6):508–11.
3. Sato T, Uchino M, Takeuchi J, Fujihira Y, Shimizu K, Yokoyama K, et al. Short-term clinical evaluation of teduglutide for patients with Crohn’s disease on home parenteral support for postoperative short bowel syndrome with intestinal failure. Clin Nutr Edinb Scotl. 2023 May;42(5):722–31.
4. Siu RK, Karime C, Hashash JG, Kinnucan J, Picco MF, Farraye FA. Improved Outcomes Associated With Teduglutide Use in Patients With Both Short Bowel Syndrome and Crohn’s Disease. Crohns Colitis 360. 2024 Jan;6(1):otae007.

Introduction

Anti-TNF agents play a significant role in the induction and maintenance therapy of moderate to severe ulcerative colitis. However, at least 30% of patients experience loss of response within the first year of treatment.

Aims & Methods

This study aims to compare Tofacitinib versus Vedolizumab in patients with ulcerative colitis in the setting of previous anti-TNF failure. We performed a systematic review in PubMed, Embase and Cochrane databases, searching for randomized and non-randomized studies comparing Tofacetinib versus Vedolizumab in this population. The primary outcome was colectomy rate. The secondary outcomes were thromboembolic event rate and infectious incidence. The odds ratio (OR) was used for binary outcomes with their respective 95% confidence interval (CI). Heterogeneity was assessed using the Cochran Q test and I² statistics.

Results

The meta-analyses included 6 studies and 2,241 patients. There was a significant difference favoring Vedolizumab in colectomy rate (OR 2.03; 95% CI 1.30 to 3.16, p=0.002; I2=0%). There were no difference in thromboembolic event rate (OR 0.90; 95% CI 0.39 to 2.06; p=0.798; I2=0%) and infection incidence (OR 0.83; 95% CI 0.56 to 1.25; p=0.378; I2=0%).

Conclusion

In patients with ulcerative colitis with prior anti-TNF failure, tofacitinib showed higher colectomy rate compared to vedolizumab, with no difference in thromboembolic and infectious events between both groups. Considering this, vedolizumab seems to be a reasonable option in this population.

References

1. Straatmijer T, Biemans V, Visschedijk MC, Hoentjen F, De Vries A, Van Bodegraven AA, et al. SUPERIOR EFFECTIVENESS OF TOFACITINIB COMPARED TO VEDOLIZUMAB IN ANTI-TNF EXPERIENCED ULCERATIVE COLITIS PATIENTS: A NATIONWIDE DUTCH REGISTRY STUDY. United Eur Gastroenterol J. 2022;10((Straatmijer T., t.straatmijer@amsterdamumc.nl; De Boer K.H.N.) Amsterdam UMC, Amsterdam, Netherlands):390–1.
2. Buisson A, Serrero M, Altwegg R, Guilmoteau T, Bouguen G, Nachury M, et al. Real-world comparison of effectiveness between tofacitinib and ustekinumab in patients with ulcerative colitis exposed to at least one anti-TNF agent: Results from the TORUS study. J Crohns Colitis. 2023;17((Buisson A.; Guilmoteau T.) CHU Clermont-Ferrand, IBD Unit, Clermont-Ferrand, France):i707.
3. Adimadhyam S, Lewis JD, Simon AL, Wolfe AE, Smith S, Hou L, et al. Real-world Evidence Comparing Tofacitinib and Vedolizumab in Anti-TNF-experienced Patients With Ulcerative Colitis. Inflamm Bowel Dis. 2024 Apr 3;30(4):554–62.
4. Hyun HK, Zhang HS, Yu J, Kang EA, Park J, Park SJ, et al. Comparative effectiveness of second-line biological therapies for ulcerative colitis and Crohn’s disease in patients with prior failure of anti-tumour necrosis factor treatment. BMC Gastroenterol. 2022 Mar 27;22(1):143.

Introduction

Anti-TNF plays a mean role in induction and maintenance therapy of moderate to severe Crohn’s disease. However, approximately 30% of patients lose response to treatment after the first year of therapy.

Aims & Methods

This study aims to compare Vedolizumab vs Ustekinumab in the setting of anti-TNF failure. We performed a systematic review in PubMed, Embase and Cochrane databases, searching for randomized and non-randomized studies comparing Vedolizumab vs. Ustekinumab in patients with Crohn’s disease with previous anti-TNF failure or intolerance. The primary outcome was steroid-free clinical remission (SFR) at the pos-induction and maintenance period. The odds ratio (OR) was used for binary outcomes with their respective 95% confidence interval (CI). Heterogeneity was assessed using the Cochran Q test and I² statistics.

Results

The meta-analyses included 10 studies and 2,514 patients. There was a significant difference favoring Ustekinumab in SFR at pos-induction period (OR 1.44; 95% CI 1.11 to 1.88, p=0.006; I2=27%), in SFR at the maintenance period (OR 1.74; 95% CI 1.12 to 2.70, p=0.014; I2=80%), in clinical remission at pos-induction period (OR 2.04; 95% CI 1.58 to 2.63, p<0.001; I2=3%) and in treatment discontinuation due to adverse events (OR 0.48; 95% CI 0.26 to 0.88; p=0.018; I²=0%).

Conclusion

In patients with Crohn’s disease with prior anti-TNF failure, ustekinumab showed higher SFR during both the post induction and maintenance period and lower rate of treatment discontinuation due to adverse events.

References

1. Alrashed F, Abdullah I, Alfadhli A, Shehab M. Effectiveness of vedolizumab and ustekinumab as second biologic agent in achieving target outcomes in tumor necrosis factor antagonists experienced patients with inflammatory bowel disease (enroll-ex study). Front Pharmacol. 2023;14:1243080.
2. Alric H, Amiot A, Kirchgesner J, Tréton X, Allez M, Bouhnik Y, et al. The effectiveness of either ustekinumab or vedolizumab in 239 patients with Crohn’s disease refractory to anti-tumour necrosis factor. Aliment Pharmacol Ther. 2020 May;51(10):948–57.
3. Onali S, Pugliese D, Caprioli FA, Orlando A, Biancone L, Nardone OM, et al. An Objective Comparison of Vedolizumab and Ustekinumab Effectiveness in Crohn’s Disease Patients’ Failure to TNF-Alpha Inhibitors. Am J Gastroenterol. 2022 Aug 1;117(8):1279–87.
4. Townsend T, Razanskaite V, Michail S, Morgan J, Davies M, Storey D, et al. Comparative effectiveness of vedolizumab and ustekinumab in anti-tnf refractory Crohn’s disease: Multi-centre retrospective cohort study. Gut. 2021;70(SUPPL 1):A127.
5. Yang H, Huang Z, Li M, Zhang H, Fu L, Wang X, et al. Comparative effectiveness of ustekinumab vs. vedolizumab for anti-TNF-naïve or anti-TNF-exposed Crohn’s disease: a multicenter cohort study. eClinicalMedicine. 2023 Dec;66:102337.

Introduction

Biologic therapies are commonly used for inflammatory bowel disease (IBD) patients. Multiple biologic medicines can now be given both intravenously and subcutaneously. The different administration routes present provide different advantages regarding dose escalation, healthcare resource utilisation, pharmacokinetics, convenience, and safety.^1,2 Comparator effectiveness studies between intravenous and subcutaneous administration are lacking.

Aims & Methods

Our primary outcome was to compare the effectiveness between intravenous (IV) and subcutaneous (SC) biologics in rates of clinical remission. We performed a systematic review and meta-analysis to include all relevant articles from MEDLINE (Ovid), EMBASE, PubMed, and Cochrane central register of controlled trials from January 1^st, 1946 to January 28th, 2024. Studies that compared intravenous and subcutaneous administration of the same biologic therapy in IBD patients and reported effectiveness outcomes were included. Eligible studies had to include one of the following outcomes: [a] Clinical remission or response with a formalised clinical scoring system as defined by each study; [b] CRP remission; [c] faecal calprotectin remission. This study was registered on PROSPERO (CRD42023442675).

Results

Twenty studies met the inclusion criteria for the systematic review. There were only two randomised controlled trials and therefore were not analysed. There were eighteen cohort studies. One study was a prospective clinical trial switch from IV to SC vedolizumab. Twelve were prospective cohort studies. Five were retrospective cohort studies. Ten studies compared vedolizumab, seven studies compared infliximaband one study compared ustekinumab. We excluded the ustekinumab study given it was the only study evaluating ustekinumab. Of the 17 included studies, 15 were whole cohort switches from IV to SC formulations, with only 2 studies having both IV and SC arms. Nine vedolizumab cohort studies were meta-analysed for clinical remission and no difference was found in clinical remission rates between IV and SC administration (RR 0.99; 95% CI 0.88, 1.11). Six infliximab cohort studies were meta-analysed for clinical remission and no difference was found in rates of clinical remission between IV and SC administration (RR 0.91; 95% CI 0.77, 1.08). Four studies reported CRP remission rates (1 infliximab study and 3 vedolizumab studies), and the vedolizumab studies were meta-analysed. Seventy one percent (159/224) of the SC group and 71% (207/291) of the IV group were in CRP remission. The pooled RR was 0.88 (95% CI 0.88, 1.07; p=0.09). We observed a high degree of heterogeneity (I² = 76%). Four studies, all studying vedolizumab, reported faecal calprotectin remission, and they were meta-analysed. Seventy six percent (158/207) of the SC group and 76% (140/183) of the IV group were in faecal calprotectin remission. The pooled RR was 0.99 (95% CI 0.90, 1.09). We observed no heterogeneity (I² = 0%). The quality of the cohort studies was high, with no studies found to be at a high risk of bias.

Conclusion

There was no difference in the effectiveness between subcutaneous and intravenous administration of infliximab and vedolizumab respectively. However, further high-quality studies, particularly head-to-head studies are required to confirm this finding.

References

1. Little RD, Ward MG, Wright E, Jois AJ, Boussioutas A, Hold GL, Gibson PR, Sparrow MP. Therapeutic Drug Monitoring of Subcutaneous Infliximab in Inflammatory Bowel Disease-Understanding Pharmacokinetics and Exposure Response Relationships in a New Era of Subcutaneous Biologics. J Clin Med. 2022 Oct 19;11(20):6173. doi: 10.3390/jcm11206173. PMID: 36294494; PMCID: PMC9605309.
2. Heald A, Bramham-Jones S, Davies M. Comparing cost of intravenous infusion and subcutaneous biologics in COVID-19 pandemic care pathways for rheumatoid arthritis and inflammatory bowel disease: A brief UK stakeholder survey. Int J Clin Pract. 2021 Sep;75(9):e14341. doi: 10.1111/ijcp.14341. Epub 2021 Jul 8. PMID: 33963659; PMCID: PMC8236906.

Disclosure

Dr. Alexander Elford is supported by the Australian Commonwealth government via a Research Training Program Scholarship. Dr Shahed Kamal and Miss Rishni Heldt have no conflicts of interest. A/Prof Christensen has received speaking fees from Abbvie, Janssen, Pfizer, Takeda and Ferring; research grants from Janssen and Ferring Pharmaceuticals and served on the advisory board of Gilead and Novartis. A/Prof. Jonathan P. Segal received speaker fees for Takeda and Abbvie, BMS and Falk Pharma and has a non-restricted grant from Tillots.

Introduction

Proactive therapeutic drug monitoring (TDM) has been suggested to improve outcomes in patients with inflammatory bowel disease (IBD) treated with anti-tumour necrosis factor (anti-TNFα) therapy. A systematic review and a meta-analysis of the literature was conducted to assess treatment efficacy and safety, and a systematic review to compare the cost-effectiveness of proactive TDM versus conventional management during maintenance treatment with anti-TNFα.

Aims & Methods

A search was conducted of MEDLINE, EMBASE, and the Cochrane Library up to January 2022. The primary outcome was the ability to maintain clinical remission at 12 months. The certainty of evidence was determined using the GRADE approach.

Results

Nine studies were identified: one systematic review, six randomised clinical trials, and two cohort studies (for safety evaluation). The analysis of the clinical trials showed no superior efficacy of proactive TDM [relative risk 1.16; 95% confidence interval (CI): 0.98–1.37, n=528; I²=55%]. In contrast, the analysis of the cohort studies and systematic review revealed that proactive TDM could improve the durability of anti-TNFα treatment [odds ratio (OR) 0.12; 95%CI: 0.05–0.27; n=390; I²=45%), prevent acute infusion reactions (OR 0.21; 95%CI: 0.05–0.82; n=390; I²=0%), decrease adverse events (OR 0.38; 95%CI: 0.15–0.98; n=390; I²=14%), and reduce the probability of surgery, at lower economical expenditure.

Conclusion

The analysed evidence did not confirm the superiority of proactive TDM of anti-TNFα agents over conventional management. Therefore, proactive TDM should not be recommended for the management of IBD patients receiving maintenance anti-TNFα treatment.

References

1. Vande Casteele N, et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology. 2015;148(7):1320-1329.
2. D’Haens G, et al. Increasing Infliximab Dose Based on Symptoms, Biomarkers, and Serum Drug Concentrations Does Not Increase Clinical, Endoscopic, and Corticosteroid-Free Remission in Patients With Active Luminal Crohn’s Disease. Gastroenterology. 2018;154(5):1343-1351.
3. Assa A, et al. Proactive Monitoring of Adalimumab Trough Concentration Associated With Increased Clinical Remission in Children With Crohn’s Disease Compared With Reactive Monitoring. Gastroenterology. 2019;157(4):985-996.
4. Syversen SW, et al. Effect of Therapeutic Drug Monitoring vs Standard Therapy During Maintenance Infliximab Therapy on Disease Control in Patients With Immune-Mediated Inflammatory Diseases: A Randomized Clinical Trial. JAMA. 2021;326(23):2375-84.
5. Strik AS, et al. Efficacy of dashboard driven dosing of infliximab in inflammatory bowel disease patients; a randomized controlled trial. Scand J Gastroenterol. 2021;56(2):145-54.
06. D’Haens GR, et al. Higher vs Standard Adalimumab Induction Dosing Regimens and Two Maintenance Strategies: Randomized SERENE CD Trial Results. Gastroenterology. 2022;162(7):1876-90.
07. Papamichael K, et al. Improved Long-term Outcomes of Patients With Inflammatory Bowel Disease Receiving Proactive Compared With Reactive Monitoring of Serum Concentrations of Infliximab. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2017;15(10):1580-1588.e3.

Disclosure

B Novella Arribas, F Rodríguez Salvanés, and P Loeches Belinchón have no conflict of interest. N Manceñido Marcos has served as a speaker and consultant for or received financial support for educational activities from Janssen, Abbvie, Pfizer, Takeda, Ferring, Faes Farma, Dr. Falk Pharma, and Tillots Pharma. G Mora Navarro has served as a speaker and consultant for or has received research and training funding from Sanofi, Lilly, ESTEVE, and AstraZeneca. JP Gisbert has served as a speaker, consultant, and advisory member for or has received research funding from MSD, Abbvie, Hospira, Pfizer, Kern Pharma, Biogen, Takeda, Janssen, Roche, Sandoz, Celgene, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, and Vifor Pharma.

Introduction

Psychiatric manifestations in individuals with inflammatory bowel disease (IBD) have been the subject of extensive research. Still, uncertainties remain regarding its precise magnitude, its impact on intestinal disease, and the whole burden of psychiatric manifestations.

Aims & Methods

This systematic review aims to synthesize available evidence on the prevalence and impact of psychiatric symptoms, including depression, anxiety, bipolar disorders, and schizophrenia in IBD patients.
A systematic search was conducted in the PubMed/MEDLINE, EMBASE and SCOPUS databases to identify relevant studies published between January 2010 and January 2023. Cross-sectional, case-control, cohort, registry and population studies were selected that addressed the prevalence of depression, anxiety, bipolar disorder, and schizophrenia in people with IBD compared to the general population. A meta-analysis was also conducted to assess the strength of the association. Data extraction and quality assessment were performed.

Results

The search yielded a total of 3209 articles. Although 193 met the inclusion criteria, only 26 studies provided complete data. Overall, the prevalence of psychiatric comorbidities was found to be significantly higher in IBD patients compared to the general population. The analysis revealed a moderate but significant association between IBD and depression, with a calculated pooled odds ratio (OR) of 1.42 (p<.0001). Also, anxiety disorders emerged as a prevalent comorbidity in IBD with a calculated pooled OR of 1.3 (p<.0001). Evidence for the association between bipolar disorders and IBD was limited but significant, with a pooled OR of 1.64 (p<.0001), despite a substantial heterogeneity (I2=94.01%). Only 3 studies examined the association between schizophrenia and IBD, providing widely heterogeneous results, with an inconclusive OR (0.93, p= 0.73).

Conclusion

This systematic review with meta-analysis highlights that psychiatric comorbidities such as depression, anxiety, and bipolar disorders are more prevalent in IBD than in the general population. Depression and anxiety are particularly prevalent. Bipolar disorder is still an under-researched area in the context of IBD. Data on the association between schizophrenia and IBD is sparse and inconclusive and requires further research. Given the findings of this systematic review, there is a need for a deeper understanding of these associations and early detection in order to develop tailored mental health interventions for patients with IBD.

References

1. Jairath V, Feagan BG. Global burden of inflammatory bowel disease. Lancet Gastroenterol Hepatol. 2020;5(1):2-3.
2. Barberio B, Zamani M, Black CJ, Savarino EV, Ford AC. Prevalence of symptoms of anxiety and depression in patients with inflammatory bowel disease: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2021;6(5):359-70.
3. Piovani D, Armuzzi A, Bonovas S. Association of Depression With Incident Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis. Inflamm Bowel Dis. 2023.