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

The use of biologics has become an increasingly common treatment option for inflammatory bowel disease (IBD). However, data on maternal and fetal exposure to ustekinumab (UST) and vedolizumab (VDZ) remain scarce.

Aims & Methods

This systematic review and meta-analysis aimed to assess the safety of UST and VDZ in pregnant women with IBD. We systematically searched PubMed, Embase, and Cochrane Library databases in March 2025. The inclusion criteria were randomized and non-randomized studies comparing UST and VDZ for the treatment of IBD in pregnant patients and evaluating at least one predefined outcome of interest. Primary outcomes were spontaneous abortion and preterm delivery. Secondary outcomes included live birth, low birth weight, serious infections, neonatal intensive care unit (NICU) admission, and malignancies. Statistical analysis was performed using RStudio, applying a random-effects model to calculate the pooled risk ratios (RRs) for binary outcomes.

Results

This systematic review included six studies. Median maternal age ranged from 30 to 33 years, with similar distributions between groups. The average disease duration ranged from 8 to 14 years. Crohn’s disease was more prevalent in the ustekinumab group, while ulcerative colitis was more common in the vedolizumab group. No statistically significant differences were observed in spontaneous abortion (RR 1.66; 95% CI 0.89–3.10), preterm delivery (RR 0.60; 95% CI 0.31–1.16), live birth (RR 0.97; 95% CI 0.90–1.05), low birth weight (RR 0.65; 95% CI 0.31–1.40), serious infections (RR 1.34; 95% CI 0.39–4.66), NICU admission (RR 1.02; 95% CI 0.56–1.85), or malignancies (RR 1.25; 95% CI 0.67–2.32) between UST and VDZ treatments.

Conclusion

No significant differences were observed across the outcomes analyzed when comparing ustekinumab and vedolizumab for the treatment of pregnant patients with IBD.

Introduction

Biologic drugs are key in the current treatment of patients with inflammatory bowel disease (IBD). Identifying patients at high risk of primary non-response or loss of response is key to individualize treatment

Aims & Methods

Aim: To identify risk factors associated with primary nonresponse, loss of response and adverse effects to the first biologic drug used in patients with IBD.
Methoids: Single-centre retrospective cohort study including all consecutive patients with IBD naïve to biologic treatment who have started biologic treatment from 2000 to January 2022. A minimum follow-up of 6 months from the start of the biologic was required. Only the first biologic used in each patient was evaluated. HLA-DQA1 genotyping was done in all patients. Primary response rate was assessed at 24 weeks. Regression analyses were used to assess risk factors. The possible risk factors evaluated were sex, HLADQA1 genotype, smoking at diagnosis, body mass index, age at diagnosis, disease type, location, extent and phenotype disease according to Montreal classification, type biologic drug, disease severity at biologic initiation (Mayo index and Harvey Bradshaw index), combotherapy (≥ 6 months), and history of IBD resective surgery.

Results

A total of 421 patients were included, 290 with Crohn's disease and 131 with Ulcerative Colitis. 51.1% were male. The mean age at biologic initiation was 39 years. The most commonly used biologic was infliximab (IFX) (50.1%), followed by adalimumab (ADA) (46.8%). 46.1% carried HLADQA1*05 allele/s and 24.2% carried HLADQA1*03 allele/s. Almost half of the patients (47.7%) were treated with combotherapy ( biologic + inmmunomodulator). The primary response rate was high: 84.8% (IFX 82.5%, ADA 87.8%). The loss of response rate was 33.3% (IFX 29.9%, ADA 35.5%), with a mean time of 5 years. Adverse effects occurred in 22.1% of patients (IFX 28.9%, ADA 16.2%). In multivariate analysis, carrying HLADQA1*05 allele was the only factor of all evaluated that was associated with an increased risk of loss of response [Odds Ratio: 1.83 (1.16-2.87), p=0.009], while carrying an HLADQA1*03 allele was protective for loss of response [Odds ratio: 0.37 (0.15- 0.89), p=0.026]. Female sex [Odds ratio: 1.61 (1.04-2.49), p=0.032)], the use of infliximab [Odds ratio: 2.00 (1.28-3.14), p=0.003] and the use of higher than standard doses in the IFX induction regimen [Odds Ratio: 3.28 (1.10-9.81), p=0.034] were identified as risk factors for the development of adverse effects.

Conclusion

1) Our results support that carrying HLADQA1*05 increases the risk of secondary loss of response to anti-TNF drugs and suggest that carrying HLADQA1*03 decreases this risk.
2) Female sex is an independent risk factor for the development of adverse effects to anti-TNF drugs.
3) Infliximab is the biologic drug with the highest rate of adverse effects and the use of higher than standard doses during induction is associated with an increased risk of adverse effects.

Introduction

Ustekinumab (UST) is a monoclonal antibody that inhibits the p40 subunit of IL-12 and IL-23, approved for the treatment of Crohn's Disease (CD) and Ulcerative Colitis (UC). Its administration is intravenous during induction and subcutaneous during maintenance. Several studies have assessed the efficacy of reinduction and intensification of this treatment in patients with loss of response. However, there are few studies evaluating the effectiveness of intravenous UST for maintenance.

Aims & Methods

The aim of the study is to evaluate the efficacy and safety of maintenance with intravenous UST in patients with Inflammatory Bowel Disease (IBD).
Observational, retrospective, and single-center study. All patients receiving maintenance with intravenous UST until June 2023 were reviewed. Clinical response was evaluated with Harvey-Bradshow Index for CD and partial Mayo for UC. Biochemical response was evaluated with calprotectin and C-reactive protein.

Results

A total of 29 patients with IBD (24 CD and 5 UC) were included. The mean follow-up of patients was 449 days (74-948). The cohort's characteristics are summarized in Table 1.
In all cases, intravenous maintenance was performed with UST 130mg/4 weeks. In 4 cases (13.8%), maintenance was initiated directly with intravenous UST. In 9 (31%) patients due to primary failure to UST and in 16 (55.2%) patients due to secondary failure.
The clinical response to intravenous UST maintenance in patients with CD at week 8 and 16 and at one year of follow-up was 87.5% (n=21/24), 83.3% (n=20/24), 73.3% (n=11/15) respectively. For UC, the response was 60% (n=3/5) at week 8 and 16 and at one year. The drug survival was 723 days (± 74) (Figure 1). No predictive variable for treatment response was identified. Two patients (both with CD) experienced recurrent respiratory infections as an adverse effect, without the need to discontinue UST.

Conclusion

Maintenance treatment with intravenous UST can be useful and safe in patients with severe IBD and/or failure of subcutaneous UST maintenance.

Introduction

The use of infliximab (IFX) is limited by low treatment persistence. Proactive therapeutic drug monitoring (pTDM) has been shown to increase the treatment persistence in inflammatory bowel disease (IBD) patients but the real-life data evaluating effectiveness, safety and costs of this approach are scarce.

Aims & Methods

The aim of this study was to assess survival on treatment, safety and costs of pTDM of IFX in the treatment IBD.
IBD patients who started IFX in a referral centre using pTDM between January 2018 and March 2021 were included. The main outcomes were treatment persistence, adverse events and incremental costs of pTDM.
IFX trough levels were assessed in the week 14 and subsequently every six months by commercially available ELISA kit (Ridascreen R-Biopharm) and the intensification of treatment the cut-off of 3μg/ml was used.
Costs related to the measurements of levels and the costs of intensified treatment were calculated. The costs of pTDM were compared costs of a modelled cohort using reactive TDM (rTDM) based on the data from the same cohort. The model used arbitrarily determined intensification regimen to 5mg/kg of IFX every 4 weeks in pharmacokinetically determined clinical or endoscopic loss of response. The calculation was performed for the first year of treatment.

Results

Overall, 99 patients with IBD were included (58 men – 59%; mean age 39,96 years, minimum-maximum, 20-73 years; 64% patients with Crohn´disease; mean disease duration 103 months, minimum – maximum, 8-402 months).
The treatment was intensified in 57 patients (58%). Overall treatment survival with pTDM was 87% at 6 months, 77% at one year, 66% at two years and 60% at both, the third and fourth year of treatment. There were no differences between patients on conventional regimen vs. intensified regimen with regards to adverse events.
The costs related to pTDM in this cohort of 99 patients were € 90 306,56 while the costs of the modelled cohort using rTDM were € 24 846,30. The overall incremental costs were thus € 65 460,26 with mean costs per patient for the first year of treatment of € 661,21.

Conclusion

Proactive TDM of IFX results in a steady 60% treatment persistence beyond the second year of treatment with no impact on the safety.
In the context of this solid treatment persistence, the incremental costs related to proactive TDM seem negligible when considering the costs of alternative biologicals used in case of loss of response to IFX.

Disclosure

nothing to disclose

Introduction

Anti-TNF therapy has revolutionised the treatment of patients with Crohn’s disease (CD) and ulcerative colitis (UC). However, primary resistance or loss of efficacy are serious clinical challenges. Therapeutic drug monitoring (TDM) could help to manage these unfavourable therapeutic outcomes. The measurement of anti-TNF drug levels (DL) with point-of-care tests (POCT) is fast, simple tool to guide the therapy. TDM can be performed reactively in patients with active disease and proactively in asymptomatic patients. Nevertheless, the optimal utilization of TDM is still debated.

Aims & Methods

Our aim was to evaluate the impact of proactive and reactive TDM on the medium-term course of inflammatory bowel disease. We enrolled patients with UC and CD who were treated at our department with infliximab or adalimumab and underwent reactive or proactive TDM with POCT method between October 2021 and September 2023. We examined the types of therapeutical decision (dose intensification, switch within or out of class) were performed knowing DL and how the changes have affected the half-yearly outcome. Laboratory findings such as C-reactive protein (CRP), iron, albumin, haemoglobin, platelet, stool calprotectin level and calculated disease activity indices, Crohn’s disease activity index (CDAI), Harvey-Bradshaw Index (HBI), partial Mayo score (pMayo) and Simple clinical colitis activity index (SCCAI) were analysed at baseline and after 6 months. Statistical analysis was carried out with Graphpad Prism and SPSS.

Results

175 patients were enrolled, 80 men, 95 women, median age was 38 (IQR 30-50 years). 81 UC and 94 CD patients. In 79 cases proactive, in 96 cases reactive TDM was performed. In the reactive group the CRP (5.9 vs 12.2 mg/l, p=0.010), platelet count (278.3 vs 314.5 G/l, p=0.024) and the four activity indices (CDAI p=0.004, HBI p=0.0004, SCCAI p<0.0001, pMayo p<0.0001) were significantly higher, the albumin level (46.5 vs 45 g/l, p=0.019) was significantly lower compared to the proactive group at baseline. In the reactive group CRP (12.2 vs 5.7 mg/l, p=0.0083) and albumin level (46.5 vs 45 g/l p=0.0186) and all examined activity indices (CDAI p<0.0001, HBI p=0.0003, SCCAI p<0.0001, pMayo p=0.0002) changed significantly after 6 month from baseline. In the proactive group the lowering of SCCAI (p=0.0232), pMayo (p=0.0077) and CDAI (p=0.0471) were significant comparing baseline and 6-month parameters. Between the proactive and reactive groups no significant difference was found at month 6. In 41 (52%) cases in the proactive group subtherapeutical DL was found. Within these cases in CD patients CDAI (p=0.035, OR:1.02, 95%CI: 1.0-1.05) had a significant predictive value for the half-yearly outcome, in UC platelet count appeared to be nearly significant (p=0.097, OR: 1.07, 95%CI: 0.99-1.15) as a predictive factor. In 41 (52%) of the proactively measured cases no intervention was done, 27 (34%) dose-intesification, 5 (6%) de-escalation, 5 (6%) stop and 2 (3%) switch was carried out. In the reactively measured group 55 patients (57%) had subtherapeutical DL. In the reactive group no therapeutical change happened in 25 cases (26%), 42 (44%) underwent dose-intensification, 29 (30%) had switch (13 within class, 16 out of class).

Conclusion

We found no difference between the proactive and reactive drug level monitoring methods with POCT. Both affected the decision-making process and presented beneficial effect for medium-term and helped to achieve stride therapy goals.

Introduction

Patients with inflammatory bowel disease (IBD) have a 2-3 fold increased risk of venous thromboembolic events (VTE) compared to the general population. The relevance of this complication is underlined by increased morbidity, longer hospitalization, additional healthcare cost, the tendency of recurrence, and the potentially fatal outcome.
The etiology of VTE in IBD is complex, modulated by the interplay of disease- and treatment-specific factors. The additive effect of these may be supposed; the role of medication is not precisely defined.

Aims & Methods

The aim of our study was to assess the proportion of VTE in IBD patients treated with anti-tumor necrosis factor-alfa (anti-TNF-α) drugs and conventional anti-inflammatory therapy, namely corticosteroids (CS), immunomodulators (IM) and 5-aminosalicylates (5-ASA).
A systematic search was performed in 5 databases (Pubmed, Embase, Cochrane Library, Scopus, Web of Science) on the 22nd of November, 2022. Population-based data, retrospective cohort, and case-control studies were found eligible for inclusion. Our protocol was prospectively registered on PROSPERO (CRD42022376118).
Based on the number of VTE we determined the proportion of this complication in the mentioned treatment groups. We calculated the odds ratio (OR) with 95% confidence intervals (CI) in the distinct categories of medications. The Joanna Briggs Institute Critical Appraisal Checklist for Prevalence Studies and the Risk of Bias in Non-randomized Studies of Interventions tool were used for quality evaluation.

Results

Out of 10.209 articles, 16 were included in the meta-analysis. A preliminary summary of analyzed data showed, that patients on anti-TNFs had less VTE compared with those treated with CS (proportion: 5%, 95%CI: 3-10 and 15%, 95%CI: 7-29, respectivelly). Comparing these treatments, the OR of VTE was 0.37 (95% CI: 0.21-0.66).
Among patients treated with anti-TNFs or IM we found similar proportions (5%, 95%CI: 3-10 vs. 7%, 95% CI: 4-11) and odds (OR: 0.88, 95% CI: 0.70-1.11) of VTE.
9% (95% CI: 5-17) of patients on 5-ASA medication had VTE; compared with TNF-inhibitors, OR was found to be 1.04 (95% CI: 0.75-0.44).

Conclusion

TNF-α is a driver of inflammation in IBD and may trigger coagulation as well. Inhibition of this key cytokine with biologicals is effective in induction and maintenance of remission in moderate and severe IBD. It may be presumed to have an effect on the risk of VTE as well.
Available literature and our summary of clinical data indicate, that CS therapy may increase the risk of VTE, while anti-TNF agents seem to be linked with decreased odds of these events. As a possible association between TNF-inhibitors and decreased risk of VTE compared with CS, we would like to underline the importance of „steroid-sparing” therapy in patients with high risk of VTE.
The rate of VTE was similar in patients on IM and 5-ASA, relative to TNF-inhibitors. This may be explained by the long-term disease remission maintained with conventional IBD therapy.
Prevention and treatment of VTE should always follow the recommandations of current guidelines.
Our work is limited by the retrospective desing of the studies, the relatively low number of VTE events, the heterogeneity of the IBD population, and the effect of concurrent anti-inflammatory medication used in IBD. To precisely assess the correlation between medication and VTE risk prospective, large, well-conducted studies are needed.

References

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